**Microstomia: A Rare but Serious Oral Manifestation of Inherited Disorders**

### Aydin Gulses

*Gulhane Military Medical Academy, Department of Oral and Maxillofacial Surgery Turkey* 

### **1. Introduction**

448 Advances in the Study of Genetic Disorders

Salo, P; Kaariainen, H; Petrovic, V; Peltomaki, P; Page, DC. & de la Chapelle, A. (1995).

Seabright, M. (1971). A rapid banding technique for human chromosomes. *Lancet.,* Vol.2,

Sinclair, A. (2001). Eleven years of sexual discovery. *Genome Biol,* Vol.2, No.7, pp.

Spranger, S; Kirsch, S; Mertz, A; Schiebel, K; Tariverdian, G. & Rappold, GA. (1997).

Su, H & Lau, YF. (1993). Identification of the transcriptional unit, structural organization,

Tsuchiya, K; Reijo, R; Page, DC. & Disteche, CM. (1995). Gonadoblastoma: molecular

Urbach, A & Benvenisty, N. (2009). Studying Early Lethality of 45,XO (Turner's Syndrome)

Van den Berghe, H; Petit, P. & Fryns, JP. (1977). Y to X translocation in man. *Hum Genet.,* 

Werner, MH; Bianchi, ME; Gronenborn, AM. & Clore, GM. (1995). NMR spectroscopic

Witt, M & Erickson, RP. (1989). A rapid method for detection of Y-chromosomal DNA from

Witt, M & Erickson, RP. (1991). A rapid method for detection of Y-chromosomal DNA from

Yen, PH; Tsai, SP; Wenger, SL; Steele, MW; Mohandas, TK. & Shapiro, LJ. (1991). X/Y

Zinn, AR; Roeltgen, D; Stefanatos, G; Ramos, P; Elder, FF; Kushner, H; Kowal, K. & Ross, JL.

Zinn, AR & Ross, JL. (1998). Turner syndrome and haploinsufficiency. *Curr Opin Genet Dev,* 

SRY. *Biochemistry.,* Vol.34, No.37, pp. 11998-2004., ISSN 0006-2960

child. *Am J Med Genet,* Vol.72, No.2, pp. 125-8, ISSN 0148-7299

*Genes Chromosomes Cancer.,* Vol.14, No.3, pp. 210-214, ISSN 1045-2257 Schwinger, E; Kirschstein, M; Greiwe, M; Konermann, T; Orth, U. & Gal, A. (1996). Short

*Genet.,* Vol.63, No.1, pp. 239-42., ISSN 0148-7299

No.7731, pp. 971-972., ISSN 0140-6736

Vol.57, No.6, pp. 1400-1407, ISSN 0002-9297

Vol.36, No.2, pp. 129-131., ISSN 0340-6717

*Funct,* Vol.3, pp. 24-38, ISSN 1744-9081

Vol.8, No.3, pp. 322-7, ISSN 0959-437X

REPORTS4017, ISSN 1465-6914

50., ISSN 0009-9163

ISSN 1932-6203

pp. 271-4., ISSN 0340-6717

pp. 540., ISSN 0340-6717

Molecular mapping of the putative gonadoblastoma locus on the Y chromosome.

stature in a mother and daughter with terminal deletion of Xp22.3. *Am J Med* 

Molecular studies of an X;Y translocation chromosome in a woman with deletion of the pseudoautosomal region but normal height. *Clin Genet.,* Vol.51, No.5, pp. 346-

and promoter sequence of the human sex-determining region Y (SRY) gene, using a reverse genetic approach. *Am J Hum Genet.,* Vol.52, No.1, pp. 24-38., ISSN 0002-9297

definition of the susceptibility region on the Y chromosome. *Am J Hum Genet.,* 

Embryos Using Human Embryonic Stem Cells. *PLoS ONE.,* Vol.4, No.1, pp. e4175,

analysis of the DNA conformation induced by the human testis determining factor

dried blood specimens by the polymerase chain reaction. *Hum Genet.,* Vol.82, No.3,

dried blood specimens by the polymerase chain reaction. *Hum Genet.,* Vol.86, No.5,

translocations resulting from recombination between homologous sequences on Xp and Yq. *Proc Natl Acad Sci U S A.,* Vol.88, No.20, pp. 8944-8948., ISSN 0027-8424 Yenamandra, A; Deangelo, P; Aviv, H; Suslak, L. & Desposito, F. (1997). Interstitial insertion

of Y-specific DNA sequences including SRY into chromosome 4 in a 45,X male

(2007). A Turner syndrome neurocognitive phenotype maps to Xp22.3. *Behav Brain* 

Microstomia is a term used to describe a small oral aperture (Stedman, 1976). Trauma, ingestion of caustic substances, electrical and thermal burns of perioral tissues and reconstructive lip surgeries can result in undesired cicatricial scar formation and inhibit adequate mouth opening (Smith et al., 1982). Less commonly, microstomia can also occur as a result of systemic and/or inherited disorders.

The orbicularis oris muscle, the primary muscle of the lips, forms the sphincter around the mouth and the philtral columns (Wust, 2006) The muscular layer is separated from the skin by a thin subcutaneous layer and from the mucosa below by a thin submucosal layer that contains the adnexa, sensory end organs, and lymph nodes (Wust, 2006). In acquired cases, perioral facial traumas may result in scarring and contraction caused by the involvement and infiltration of the complex perioral musculature during the healing process depending on the depth of injury (Wust, 2006). However, in genetic disorder related cases, the etiology of the condition is variable and mostly remains uncertain.

Individuals with microstomia may experience several problems related to speech, nutritional needs, dental hygiene, facial expression and social interaction (Mordjikian, 2002). Additionally, airway and ventilation problems and aspiration can induce fatal consequences during general anaesthesia procedures (Jaminet et al., 2009).

Management of microstomia is a complex treatment modality and demands complex functional and aesthetic requirements of soft tissues of circumoral region. Providing well functioning lips should be the main objective of the treatment and relapses should be prevented to obtain stable and long lasting results (Koymen et al., 2009). Treatment of the latter was based on mainly on surgical techniques, non-surgical approaches or combination of both methods.

It is important to highlight the reconstruction of the orbicular sphincter for adequate lip function beside lip symmetry, which is the main objective of microstomia reconstruction.

The aim of this chapter is to review the genetic diseases associated with microstomia and briefly discusses the surgical and non surgical management options of the condition.

#### **2. Inherited disorders associated with microstomia**

#### **2.1 Scleroderma**

Scleroderma originates from the Greek words *skleros,* meaning "hard", and *derma,* meaning "skin" (Albilia et al., 2007) This pathologic condition is the initial manifestation of a disease

Microstomia: A Rare but Serious Oral Manifestation of Inherited Disorders 451

**Calcinosis cutis** Calcific deposits, usually within the dermis in the

**Esophageal dysmotility** Earliest change in the distal esophagus (primarily

**Sclerodactyly** Fibrosis of the skin of the fingers or toes, associated

**Telangiectasias** Nonpulsatile macular areas of hemorrhage

The first symptom with scleroderma is deformity in the fingers and the toes, caused by a circulation disorder, called the Raynaud phenomenon. The early skin effects begin with the oedema of the face and extremities. The physical findings in progressive systemic sclerosis

Esophageal dysmotility is the most prominent visceral manifestation of PSS, predisposing these persons to gastroesophageal reflux disease, which may be diagnosed first by a dental practitioner. The dental practitioner may then refer the patient to a gastroenterologist for a ph-Probe Test ( Barron et al., 2003; Albilia et al., 2007). A barium swallow test is then used to identify hypomotility of the esophagus. Chronic gastroesophageal reflux disease is an important risk factor for aspiration pneumonitis, and potentially pneumonia, and increases the risk of Barrett metaplasia, which in turn increases the risk of esophageal cancer ( Barron

Pulmonary disease, the second-most common systemic manifestation of PSS, is documented in over 70% of these patients (Albilia et al., 2007). Eventually pulmonary vascular disease develops and results in pulmonary arterial hypertension and subsequent right-sided myocardial hypertrophy (cor pulmonale). For reasons that are unclear, the incidence of lung cancer is higher in patients with progressive sysytemic sclerosis (Winkelmann et al., 1988).

Table 2. Features of CREST syndrome (adopted from Albilia et al., 2007)

extremities and bony prominences, also in deeper periarticular tissues around or within the joints

Triphasic colour changes in the following order: pallor, cyanosis and erythema, representing vasoconstriction, reduced blood flow and reperfusion, respectively

smooth muscle); an uncoordinated disorganized pattern of contractions resulting in low amplitude or no peristalsis

with atrophy and ulcerations of the fingertips

Characteristic Description

**Raynaud's phenomenon** 

**2.1.1 Physical findings** 

**2.1.1.1 Esophageal dysmotility** 

et al., 2003; Albilia et al., 2007). **2.1.1.2 Pulmonary disease** 

are:

process better described as progressive systemic sclerosis (PSS), which was named by (Goetz, 1945). It is a multi-system disorder of the connective tissue characterized by vascular disease and the deposition of collagen and other matrix constituents in the skin and other target organs, *i.e.*, the gut, lung, heart, kidney, joints and muscles (Seibold, 2005). Systemic sclerosis process involves damage to the vascular epithelium, immune activation, and increased matrix production. The clinical manifestations of Systemic sclerosis include Raynaud's phenomenon, as well as fibrotic complications of the skin, skeletal muscles, gastrointestinal tract, pulmonary, renal, and cardiac systems. The disease occurs more commonly in women (estimated female to male ratio, 4:1), and the age of peak onset is 30 to 50 years (Steen&Metsger, 1990). The minimum estimated values of incidence and prevalence are 20/million per year and 1,500/million, respectively (Ferri et al., 2002; Hawk&English, 2001).

Although systemic sclerosis is an uncommon autoimmune rheumatic condition affecting connective tissues, it presents great challenges to both medical and dental professionals and has a profound impact on oral health (Albilia et al., 2007). The current classification of systemic sclerosis is based on the extent and pattern of skin sclerosis and reflects the extent of the involvement of organ systems; however this is not highly specific (Albilia et al., 2007). Systemic Sclerosis is subdivided into limited and diffuse cutaneous subtypes. (Table 1) Survival of people with systemic sclerosis mainly depends on the subtype of the disease. Limited cutaneous systemic sclerosis has a 10-year survival rate of 71%; diffuse cutaneous SS, 21%.18 Pulmonary hypertension and scleroderma renal crisis are important prognostic predictors (Trad et al., 2006).

> Localized scleroderma Linear scleroderma Localized morphea Generalized morphea

Systemic sclerosis Limited cutaneous systemic sclerosis Diffuse cutaneous systemic sclerosis Systemic sclerosis sine scleroderma Environmentally induced scleroderma Overlap syndromes

Table 1. Classification system for progressive systemic sclerosis (adopted from Albilia et al., 2007)

Patients with limited cutaneous systemic sclerosis typically have skin sclerosis that is restricted to the hands, and sometimes the face and neck. They also have prominent vascular manifestations and frequently exhibit features of CREST syndrome. (Table 2) (adopted from Albilia et al., 2007)


Table 2. Features of CREST syndrome (adopted from Albilia et al., 2007)

### **2.1.1 Physical findings**

450 Advances in the Study of Genetic Disorders

process better described as progressive systemic sclerosis (PSS), which was named by (Goetz, 1945). It is a multi-system disorder of the connective tissue characterized by vascular disease and the deposition of collagen and other matrix constituents in the skin and other target organs, *i.e.*, the gut, lung, heart, kidney, joints and muscles (Seibold, 2005). Systemic sclerosis process involves damage to the vascular epithelium, immune activation, and increased matrix production. The clinical manifestations of Systemic sclerosis include Raynaud's phenomenon, as well as fibrotic complications of the skin, skeletal muscles, gastrointestinal tract, pulmonary, renal, and cardiac systems. The disease occurs more commonly in women (estimated female to male ratio, 4:1), and the age of peak onset is 30 to 50 years (Steen&Metsger, 1990). The minimum estimated values of incidence and prevalence are 20/million per year and 1,500/million, respectively (Ferri et al., 2002; Hawk&English,

Although systemic sclerosis is an uncommon autoimmune rheumatic condition affecting connective tissues, it presents great challenges to both medical and dental professionals and has a profound impact on oral health (Albilia et al., 2007). The current classification of systemic sclerosis is based on the extent and pattern of skin sclerosis and reflects the extent of the involvement of organ systems; however this is not highly specific (Albilia et al., 2007). Systemic Sclerosis is subdivided into limited and diffuse cutaneous subtypes. (Table 1) Survival of people with systemic sclerosis mainly depends on the subtype of the disease. Limited cutaneous systemic sclerosis has a 10-year survival rate of 71%; diffuse cutaneous SS, 21%.18 Pulmonary hypertension and scleroderma renal crisis are important prognostic

> Localized scleroderma Linear scleroderma Localized morphea Generalized morphea

Systemic sclerosis Limited cutaneous systemic sclerosis Diffuse cutaneous systemic sclerosis Systemic sclerosis sine scleroderma Environmentally induced scleroderma Overlap syndromes Table 1. Classification system for progressive systemic sclerosis (adopted from Albilia et al.,

Patients with limited cutaneous systemic sclerosis typically have skin sclerosis that is restricted to the hands, and sometimes the face and neck. They also have prominent vascular manifestations and frequently exhibit features of CREST syndrome. (Table 2)

2001).

2007)

predictors (Trad et al., 2006).

(adopted from Albilia et al., 2007)

The first symptom with scleroderma is deformity in the fingers and the toes, caused by a circulation disorder, called the Raynaud phenomenon. The early skin effects begin with the oedema of the face and extremities. The physical findings in progressive systemic sclerosis are:

#### **2.1.1.1 Esophageal dysmotility**

Esophageal dysmotility is the most prominent visceral manifestation of PSS, predisposing these persons to gastroesophageal reflux disease, which may be diagnosed first by a dental practitioner. The dental practitioner may then refer the patient to a gastroenterologist for a ph-Probe Test ( Barron et al., 2003; Albilia et al., 2007). A barium swallow test is then used to identify hypomotility of the esophagus. Chronic gastroesophageal reflux disease is an important risk factor for aspiration pneumonitis, and potentially pneumonia, and increases the risk of Barrett metaplasia, which in turn increases the risk of esophageal cancer ( Barron et al., 2003; Albilia et al., 2007).

#### **2.1.1.2 Pulmonary disease**

Pulmonary disease, the second-most common systemic manifestation of PSS, is documented in over 70% of these patients (Albilia et al., 2007). Eventually pulmonary vascular disease develops and results in pulmonary arterial hypertension and subsequent right-sided myocardial hypertrophy (cor pulmonale). For reasons that are unclear, the incidence of lung cancer is higher in patients with progressive sysytemic sclerosis (Winkelmann et al., 1988).

Microstomia: A Rare but Serious Oral Manifestation of Inherited Disorders 453

Management of the systemic effects of this disease is not well established, although some large uncontrolled series suggest that D-penicillamine has beneficial effects (Stone &Wigley, 1998). Interferon-gamma is effective, but its use is limited because of inflammatory sequelae.

Holoprosencephaly is considered as the most frequent anatomical central nervous system defect in humans (Orioli & Castilla, 2010). However, relatively few epidemiological studies have been performed on holoprosencephaly at older gestational ages, and no definitive risk factor has been clearly proved to be associated with holoprosencephaly. (Orioli & Castilla, 2010). Holoprosencephaly occurs when the prosencephalon fails to cleave sagittally into cerebral hemispheres, transversely into telecephalon and diencephalon, and/or horizontally into olfactory and optic bulbs. Nevertheless, substantial variations of the cerebral defect, as ell as of the accompanying facial anomalies, exist, generating differences in the ascertainment of the involved cases. Severe ear defects, as well as microstomia, were part of the spectrum of the condition. Several studies have excluded, or analyzed separately, the holoprosencephaly cases with chromosome abnormalities, and/or with recognized monogenic syndromes. The chromosome status of a holoprosencephaly patient is not easy to determine, due to their high perinatal mortality rate, and at least 10% of those with normal karyotypes have microdeletions/duplications and remain undetected by usual

(Orioli & Castilla, 2010) determined whether craniofacial and noncraniofacial defects in holoprosencephaly cases. They confirmed the observation of Mastroiacovo et al., that among craniofacial defects, severe ear anomalies with atresia of the auditory canal, as well as microstomia, were part of the spectrum of holoprosencephaly (Mastroiacovo et al., 1995). Of the noncraniofacial defects, 24% of the holoprosencephaly cases had genital anomalies, 8% postaxial polydactyly, 5% vertebral defects, 4% limb reduction defects, and 4% had transposition of great arteries; all these defects were significantly associated with holoprosencephaly, while no significant association was found between holoprosencephaly

In 1992 Richieri-Costa and Pereira (Richieri-Costa &Pereira, 1992) described a new syndrome of acrofacial dysostosis, in five unrelated Brazilian females, characterized mainly by Robin sequence, cleft mandible, and limb defects (Favaro et al., 2010). The family history showed parental consanguinity, recurrence in sibs, and increased death rate in males, which led the authors to suggest that this new condition was caused by an autosomal recessive gene(Favaro et al., 2010). Subsequently, the same authors described the first males with this condition (Favaro et al., 2010). The causative gene of this syndrome remains unknown and molecular investigations are in progress. Favaro et al stated the main features and prevalence of this syndrome as follows: microstomia (100%), micrognathia (100%), clinical or radiological abnormal fusion of the mandible (100%), cleft palate/Robin sequence (78.5%), absent central lower incisors (80%), minor ears anomalies (92.8%), hypoplastic thumbs (96.2%), hypoplastic thenar/hypothenar region (83.3%), mesomelic shortening of upper (51.8%) and lower limbs (88.8%), hypoplastic halluces (92.5%), and clubfeet (100%) (Favaro et al., 2010).. Language assessment showed learning disability in 14 cases (84%), and language disorder in 15 (77%). Favaro et al suggested that, due to the high frequency of

karyotyping (Orioli & Castilla, 2010; Mastroiacovo et al., 1995).

and anencephaly, spina bifida, or encephalocele (Orioli & Castilla, 2010)..

**2.3 Richieri-Costa–Pereira syndrome** 

**2.2 Holoprosencephaly** 

#### **2.1.1.3 Renal disease**

Severe and life-threatening renal disease develops in 10% to 15% of patients with PSS. This form of renal involvement is called "scleroderma renal crisis" and is characterized by significant arteriole thickening and constriction, and interstitial collagen deposition,resulting in acute renal failure, marked hypertension and mild proteinuria (Albilia et al., 2007). Patients who have scleroderma without acute renal failure also have physiologic evidence of compromised renal function, which can be estimated readily from the measurement of serum creatinine levels (Livi et al., 2002).

#### **2.1.1.4 Musculoskeletal findings**

Patients may have generalized arthralgias and morning stiffness that may mimic other systemic autoimmune diseases. Hand and joint function may decline over time because of skin tightening, rather than arthropathy, and may have a negative impact on daily activities, including maintenance of oral hygiene (Albilia et al., 2007).

#### **2.1.1.5 Orofacial findings and microstomia**

In progressive systemic sclerosis patients, subcutaneous collagen deposition in facial skin results in a characteristic smooth, taut, mask-like facies. Nasal alae may become atrophied and result in "mouse-like" facies (Albilia et al., 2007). Other important orofacial manifestations include fibrosis of the salivary and lacrimal glands, and symptoms consistent with dry mouth or xerostomia. Patients may develop dry eyes with keratoconjunctivitis sicca or xerophthalmia(Albilia et al., 2007). This is particularly problematic because scarring of the eyelids results in a chronic widening of the palpebral fissures and inadequate closure of the eyelid, which causes further drying of already dry eyes (Albilia et al., 2007). Inadequate salivary flow compromises buffering within the oral cavity and allows the acidity produced by bacterial metabolism and GERD to erode the dentition. Classic dental radiographic findings of PSS show a thickening of the periodontal ligament or periodontal ligament space (Albilia et al., 2007). Accentuation of periodontal disease also occurs, believed to be due not only to poor oral hygiene but also to the vascular changes associated with the disease itself. With disease progression may come a uniform widening of the periodontal ligaments of all teeth (Albilia et al., 2007).This change seen in a minority of patients occurs at the expense of alveolar bone (lamina dura) rather than root surface. In addition, in a minority of patients there is mandibular bone resorption in non-tooth bearing areas. The inferior border, the posterior border of the ramus, the mandibular angle, and the coronoid and condylar processes may exhibit radiographic evidence of resorption. A blunting of the angles of the mandible, resembling a "tail of the whale," may be seen on an orthopantograph This is believed to be related to an associated muscle atrophy, pressure of tightening of skin overlying the bone and vascular changes (Yenisey et al., 2005). Infrequently, pathologic fractures of the mandible may develop from the mandibular resorption.

Further, facial and mucosal fibrosis compromises oral access because of microstomia, which limits mouth opening in 70% of these patients (Neville et al., 2002). As a consequence, oral hygiene and fabrication of removable dentures are difficult because of limited access and the obliteration or shallowing of the mucobuccal folds.

Skin sclerosis is often treated with D-penicillamine, a chelating agent that affects unknown mechanisms of collagen formation. Experimental drugs, such as interferon-gamma and cyclophosphamide, and photophoresis have been used with varying degrees of success. Management of the systemic effects of this disease is not well established, although some large uncontrolled series suggest that D-penicillamine has beneficial effects (Stone &Wigley, 1998). Interferon-gamma is effective, but its use is limited because of inflammatory sequelae.

#### **2.2 Holoprosencephaly**

452 Advances in the Study of Genetic Disorders

Severe and life-threatening renal disease develops in 10% to 15% of patients with PSS. This form of renal involvement is called "scleroderma renal crisis" and is characterized by significant arteriole thickening and constriction, and interstitial collagen deposition,resulting in acute renal failure, marked hypertension and mild proteinuria (Albilia et al., 2007). Patients who have scleroderma without acute renal failure also have physiologic evidence of compromised renal function, which can be estimated readily from the measurement of

Patients may have generalized arthralgias and morning stiffness that may mimic other systemic autoimmune diseases. Hand and joint function may decline over time because of skin tightening, rather than arthropathy, and may have a negative impact on daily activities,

In progressive systemic sclerosis patients, subcutaneous collagen deposition in facial skin results in a characteristic smooth, taut, mask-like facies. Nasal alae may become atrophied and result in "mouse-like" facies (Albilia et al., 2007). Other important orofacial manifestations include fibrosis of the salivary and lacrimal glands, and symptoms consistent with dry mouth or xerostomia. Patients may develop dry eyes with keratoconjunctivitis sicca or xerophthalmia(Albilia et al., 2007). This is particularly problematic because scarring of the eyelids results in a chronic widening of the palpebral fissures and inadequate closure of the eyelid, which causes further drying of already dry eyes (Albilia et al., 2007). Inadequate salivary flow compromises buffering within the oral cavity and allows the acidity produced by bacterial metabolism and GERD to erode the dentition. Classic dental radiographic findings of PSS show a thickening of the periodontal ligament or periodontal ligament space (Albilia et al., 2007). Accentuation of periodontal disease also occurs, believed to be due not only to poor oral hygiene but also to the vascular changes associated with the disease itself. With disease progression may come a uniform widening of the periodontal ligaments of all teeth (Albilia et al., 2007).This change seen in a minority of patients occurs at the expense of alveolar bone (lamina dura) rather than root surface. In addition, in a minority of patients there is mandibular bone resorption in non-tooth bearing areas. The inferior border, the posterior border of the ramus, the mandibular angle, and the coronoid and condylar processes may exhibit radiographic evidence of resorption. A blunting of the angles of the mandible, resembling a "tail of the whale," may be seen on an orthopantograph This is believed to be related to an associated muscle atrophy, pressure of tightening of skin overlying the bone and vascular changes (Yenisey et al., 2005). Infrequently, pathologic fractures of the mandible may develop from the

Further, facial and mucosal fibrosis compromises oral access because of microstomia, which limits mouth opening in 70% of these patients (Neville et al., 2002). As a consequence, oral hygiene and fabrication of removable dentures are difficult because of limited access and the

Skin sclerosis is often treated with D-penicillamine, a chelating agent that affects unknown mechanisms of collagen formation. Experimental drugs, such as interferon-gamma and cyclophosphamide, and photophoresis have been used with varying degrees of success.

**2.1.1.3 Renal disease** 

serum creatinine levels (Livi et al., 2002).

**2.1.1.5 Orofacial findings and microstomia** 

including maintenance of oral hygiene (Albilia et al., 2007).

**2.1.1.4 Musculoskeletal findings** 

mandibular resorption.

obliteration or shallowing of the mucobuccal folds.

Holoprosencephaly is considered as the most frequent anatomical central nervous system defect in humans (Orioli & Castilla, 2010). However, relatively few epidemiological studies have been performed on holoprosencephaly at older gestational ages, and no definitive risk factor has been clearly proved to be associated with holoprosencephaly. (Orioli & Castilla, 2010). Holoprosencephaly occurs when the prosencephalon fails to cleave sagittally into cerebral hemispheres, transversely into telecephalon and diencephalon, and/or horizontally into olfactory and optic bulbs. Nevertheless, substantial variations of the cerebral defect, as ell as of the accompanying facial anomalies, exist, generating differences in the ascertainment of the involved cases. Severe ear defects, as well as microstomia, were part of the spectrum of the condition. Several studies have excluded, or analyzed separately, the holoprosencephaly cases with chromosome abnormalities, and/or with recognized monogenic syndromes. The chromosome status of a holoprosencephaly patient is not easy to determine, due to their high perinatal mortality rate, and at least 10% of those with normal karyotypes have microdeletions/duplications and remain undetected by usual karyotyping (Orioli & Castilla, 2010; Mastroiacovo et al., 1995).

(Orioli & Castilla, 2010) determined whether craniofacial and noncraniofacial defects in holoprosencephaly cases. They confirmed the observation of Mastroiacovo et al., that among craniofacial defects, severe ear anomalies with atresia of the auditory canal, as well as microstomia, were part of the spectrum of holoprosencephaly (Mastroiacovo et al., 1995). Of the noncraniofacial defects, 24% of the holoprosencephaly cases had genital anomalies, 8% postaxial polydactyly, 5% vertebral defects, 4% limb reduction defects, and 4% had transposition of great arteries; all these defects were significantly associated with holoprosencephaly, while no significant association was found between holoprosencephaly and anencephaly, spina bifida, or encephalocele (Orioli & Castilla, 2010)..

#### **2.3 Richieri-Costa–Pereira syndrome**

In 1992 Richieri-Costa and Pereira (Richieri-Costa &Pereira, 1992) described a new syndrome of acrofacial dysostosis, in five unrelated Brazilian females, characterized mainly by Robin sequence, cleft mandible, and limb defects (Favaro et al., 2010). The family history showed parental consanguinity, recurrence in sibs, and increased death rate in males, which led the authors to suggest that this new condition was caused by an autosomal recessive gene(Favaro et al., 2010). Subsequently, the same authors described the first males with this condition (Favaro et al., 2010). The causative gene of this syndrome remains unknown and molecular investigations are in progress. Favaro et al stated the main features and prevalence of this syndrome as follows: microstomia (100%), micrognathia (100%), clinical or radiological abnormal fusion of the mandible (100%), cleft palate/Robin sequence (78.5%), absent central lower incisors (80%), minor ears anomalies (92.8%), hypoplastic thumbs (96.2%), hypoplastic thenar/hypothenar region (83.3%), mesomelic shortening of upper (51.8%) and lower limbs (88.8%), hypoplastic halluces (92.5%), and clubfeet (100%) (Favaro et al., 2010).. Language assessment showed learning disability in 14 cases (84%), and language disorder in 15 (77%). Favaro et al suggested that, due to the high frequency of

Microstomia: A Rare but Serious Oral Manifestation of Inherited Disorders 455

psychomotor retardation, and multiple episodes of drug-resistant epileptic seizures, partial corpus callosum dysplasia documented via magnetic resonance imaging. The duplicated region was quite large extending beyond the Prader–Willi–Angelman critical region, containing a number of genes that have been shown to be involved in autism spectrum disorders, exhibiting a severe phenotype, beyond the typical PWS/AS clinical manifestations. Reporting of similar well-characterized clinical cases with clearly delineated breakpoints of the duplicated region will clarify the contribution of specific genes to the

Hallerman - Streiff syndrome or Francois Syndrome also known as oculomandibulodyscephaly with hypotrichosis was first described by Aubry in 1893. The syndrome was later defined as Hallermann-Streiff Syndrome, underlining the differences

All individuals with Hallermann- Streiff syndrome have been sporadic, without a sex predilection, but inheritance pattern is still debated (Pizzuti et al., 2004). Concordant monozygotic twins have been described (Van Balen, 1961) and the few cases of Hallermann-Streiff syndrome with children always had unaffected offspring (Hendrix& Sauer, 1991).Oculodentodigital dysplasia is a genetic disorder related to dominant mutations in the connexin 43 gene at chromosome 6q22-23 (Paznekas et al., 2003). Spaepen et al suggested that several clinical features of this autosomal dominant highly penetrant disorder overlap those of the Hallermann- Streiff syndrome (Spaepen et al., 1991). Due to the clinical overlap between Oculodentodigital dysplasia and Hallermann- Streiff syndrome Pizzuti et al tested the work hypothesis they could be allelic disorders, both caused by GJA1 gene mutations and stated that the Homozygous GJA1 Gene Mutation Causes a Hallermann-Streiff/ Oculodentodigital dysplasia Spectrum Phenotype.Hallermann in 1948 and Streiff in 1950 described the cardinal features of the condition as: dyscephaly with bird facies, frontal or parietal bossing, dehiscence of sutures with open fontanelles, hypotrichosis of scalp, eyebrows and eyelashes, cutaneous atrophy of scalp and nose, mandibular hypoplasia, forward displacement of temporomandibular joints, high arched palate, small mouth, multiple dental anomalies and proportionate small stature (Hoefnagel & Benirschke, 1965). Defraia et al assessed the following features from a dentoskeletal point of view: aplasia of the anterior teeth, skeletal Class II malocclusion, narrow upper arch, bilateral posterior crossbite, and anterior open bite (Defraia et al., 2003). Ophthalmic features of the condition are microphthalmia, congenital cataracts, blue sclerae and nystagmus. Individuals with Hallermann-Streiff Syndrome, presence of mandibular hypoplasia and microstomia can result in difficult intubation. Recognition of this syndrome should alert the physician to the

with regard to Franceschetti's mandibulofacial dysostosis (Cannistrà et al., 1999).

possibility of difficulty in airway maintenance (Malde et al., 1994).

Hutchinson-Gilford progeria syndrome (OMIM 176670) first described by the general practitioner Jonathan Hutchinson in 1886, is a very rare autosomal dominant disorder characterised by growth retardation and progressive, premature senescent changes of the skin, bones and cardiovascular system (Sevenants et al., 2005). According to Polex and Hegele, since 1886 fewer than 100 cases of Hutchinson-Gilford progeria syndrome have been reported, with approximately 40 cases currently diagnosed (Polex & Hegele, 2004).

**2.7 Hutchinson–Gilford progeria** 

phenotype (Kitsiou-Tzeli et al., 2010).

**2.6 Hallerman – Streiff syndrome** 

airway obstruction and feeding difficulties which are common findings in infancy, corroborate that individuals with Richieri-Costa–Pereira syndrome need special support, mainly in first years of life when most of the deaths occur (Favaro et al., 2010).

### **2.4 Freeman–Sheldon syndrome**

Freeman–Sheldon syndrome, also known as distal arthrogryposis, type 2a; OMIM #193700, was first described by Freeman and J.H. Sheldon in 1938 (Corrigan et al., 2006). In 1975, Antley et al introduced the term 'whistling face syndrome' for the condition (Antley et al., 1975). Freeman–Sheldon syndrome is a heterogeneous condition both in its presentation and in its mode of transmission and both sexes are equally affected Freeman–Sheldon is an uncommon, morphologically well-defined syndrome. Orofacial findings of the condition are: A distinctive facial appearance of microstomia, microglossia, a short nose, long philtrum, H-shaped chin dimple, and sunken eyes is described. Extracranially, anomalies of the long bones, scoliosis, hand abnormalities, and joint contractures are found in most of the cases. The syndrome has also been termed 'Windmill–Vane hand' and although rare, is one of the commonest causes of multiple inherited congenital joint contractures(Corrigan et al., 2006). Intelligence is usually normal, although mental disability have been also reported in some cases [4–6]. Congenital respiratory system abnormalities and microstomia related feeding problems have been documented in a number of cases (Song et al., 1996; Corrigan et al., 2006; Antley et al., 1975). Presentation of complications in adolescence has also been reported. Song *et al*. described a 13-year-old with Freeman–Sheldon syndrome who developed late-onset dysphagia and subsequent weight loss. Corrigan et al reported the dental management experience in a patient with Freeman–Sheldon syndrome (Corrigan et al., 2006).

Ohyama *et al*. presented a case in which a mouth expander was used as a nonsurgical method of correcting microstomia (Ohyama et al., 1997). The authors claimed that this therapy produced an increase in mouth width. Corrigan et al suggested that it is debatable whether this change was actually induced by mouth expander use or whether it was simply a result of normal facial growth (Corrigan et al., 2006). No other interventions to improve microstomia have been reported in relation to Freeman– Sheldon syndrome yet.

#### **2.5 De novo duplication of maternal origin of the 15q11.2-q14 pws/ as region [46, xx, dup (15) (q11.2-q14)]**

The 15q11-q13 PWS/AS critical region involves genes that are characterized by genomic rearrangements, including interstitial deletions, duplications, and triplications (Browne et al., 1995). Multiple repeat elements within the region mediate rearrangements, including interstitial duplications, interstitial triplications, and supernumerary isodicentric marker chromosomes, as well as the deletions that cause Prader–Willi syndrome and Angelman syndrome. Recently, duplications of maternal origin concerning the same critical region have been implicated in autism spectrum disorders (Kitsiou-Tzeli et al., 2010) presented a 6 month-old girl with a de novo duplication of maternal origin of the 15q11.2-q14 PWS/AS region (17.73Mb in size) [46,XX,dup(15)(q11.2-q14)] detected with a high-resolution microarray-based comparative genomic hybridization (array-CGH) Kitsiou-Tzeli et al., 2010 The features of the condition were described by the same authors as: severe hypotonia, obesity, microstomia, long eyelashes, hirsutism, microretrognathia, short nose, severe psychomotor retardation, and multiple episodes of drug-resistant epileptic seizures, partial corpus callosum dysplasia documented via magnetic resonance imaging. The duplicated region was quite large extending beyond the Prader–Willi–Angelman critical region, containing a number of genes that have been shown to be involved in autism spectrum disorders, exhibiting a severe phenotype, beyond the typical PWS/AS clinical manifestations. Reporting of similar well-characterized clinical cases with clearly delineated breakpoints of the duplicated region will clarify the contribution of specific genes to the phenotype (Kitsiou-Tzeli et al., 2010).

#### **2.6 Hallerman – Streiff syndrome**

454 Advances in the Study of Genetic Disorders

airway obstruction and feeding difficulties which are common findings in infancy, corroborate that individuals with Richieri-Costa–Pereira syndrome need special support,

Freeman–Sheldon syndrome, also known as distal arthrogryposis, type 2a; OMIM #193700, was first described by Freeman and J.H. Sheldon in 1938 (Corrigan et al., 2006). In 1975, Antley et al introduced the term 'whistling face syndrome' for the condition (Antley et al., 1975). Freeman–Sheldon syndrome is a heterogeneous condition both in its presentation and in its mode of transmission and both sexes are equally affected Freeman–Sheldon is an uncommon, morphologically well-defined syndrome. Orofacial findings of the condition are: A distinctive facial appearance of microstomia, microglossia, a short nose, long philtrum, H-shaped chin dimple, and sunken eyes is described. Extracranially, anomalies of the long bones, scoliosis, hand abnormalities, and joint contractures are found in most of the cases. The syndrome has also been termed 'Windmill–Vane hand' and although rare, is one of the commonest causes of multiple inherited congenital joint contractures(Corrigan et al., 2006). Intelligence is usually normal, although mental disability have been also reported in some cases [4–6]. Congenital respiratory system abnormalities and microstomia related feeding problems have been documented in a number of cases (Song et al., 1996; Corrigan et al., 2006; Antley et al., 1975). Presentation of complications in adolescence has also been reported. Song *et al*. described a 13-year-old with Freeman–Sheldon syndrome who developed late-onset dysphagia and subsequent weight loss. Corrigan et al reported the dental management experience in a patient with Freeman–Sheldon syndrome (Corrigan et

Ohyama *et al*. presented a case in which a mouth expander was used as a nonsurgical method of correcting microstomia (Ohyama et al., 1997). The authors claimed that this therapy produced an increase in mouth width. Corrigan et al suggested that it is debatable whether this change was actually induced by mouth expander use or whether it was simply a result of normal facial growth (Corrigan et al., 2006). No other interventions to improve microstomia have been reported in relation to Freeman– Sheldon syndrome

**2.5 De novo duplication of maternal origin of the 15q11.2-q14 pws/ as region [46, xx,** 

The 15q11-q13 PWS/AS critical region involves genes that are characterized by genomic rearrangements, including interstitial deletions, duplications, and triplications (Browne et al., 1995). Multiple repeat elements within the region mediate rearrangements, including interstitial duplications, interstitial triplications, and supernumerary isodicentric marker chromosomes, as well as the deletions that cause Prader–Willi syndrome and Angelman syndrome. Recently, duplications of maternal origin concerning the same critical region have been implicated in autism spectrum disorders (Kitsiou-Tzeli et al., 2010) presented a 6 month-old girl with a de novo duplication of maternal origin of the 15q11.2-q14 PWS/AS region (17.73Mb in size) [46,XX,dup(15)(q11.2-q14)] detected with a high-resolution microarray-based comparative genomic hybridization (array-CGH) Kitsiou-Tzeli et al., 2010 The features of the condition were described by the same authors as: severe hypotonia, obesity, microstomia, long eyelashes, hirsutism, microretrognathia, short nose, severe

mainly in first years of life when most of the deaths occur (Favaro et al., 2010).

**2.4 Freeman–Sheldon syndrome** 

al., 2006).

yet.

**dup (15) (q11.2-q14)]** 

Hallerman - Streiff syndrome or Francois Syndrome also known as oculomandibulodyscephaly with hypotrichosis was first described by Aubry in 1893. The syndrome was later defined as Hallermann-Streiff Syndrome, underlining the differences with regard to Franceschetti's mandibulofacial dysostosis (Cannistrà et al., 1999).

All individuals with Hallermann- Streiff syndrome have been sporadic, without a sex predilection, but inheritance pattern is still debated (Pizzuti et al., 2004). Concordant monozygotic twins have been described (Van Balen, 1961) and the few cases of Hallermann-Streiff syndrome with children always had unaffected offspring (Hendrix& Sauer, 1991).Oculodentodigital dysplasia is a genetic disorder related to dominant mutations in the connexin 43 gene at chromosome 6q22-23 (Paznekas et al., 2003). Spaepen et al suggested that several clinical features of this autosomal dominant highly penetrant disorder overlap those of the Hallermann- Streiff syndrome (Spaepen et al., 1991). Due to the clinical overlap between Oculodentodigital dysplasia and Hallermann- Streiff syndrome Pizzuti et al tested the work hypothesis they could be allelic disorders, both caused by GJA1 gene mutations and stated that the Homozygous GJA1 Gene Mutation Causes a Hallermann-Streiff/ Oculodentodigital dysplasia Spectrum Phenotype.Hallermann in 1948 and Streiff in 1950 described the cardinal features of the condition as: dyscephaly with bird facies, frontal or parietal bossing, dehiscence of sutures with open fontanelles, hypotrichosis of scalp, eyebrows and eyelashes, cutaneous atrophy of scalp and nose, mandibular hypoplasia, forward displacement of temporomandibular joints, high arched palate, small mouth, multiple dental anomalies and proportionate small stature (Hoefnagel & Benirschke, 1965). Defraia et al assessed the following features from a dentoskeletal point of view: aplasia of the anterior teeth, skeletal Class II malocclusion, narrow upper arch, bilateral posterior crossbite, and anterior open bite (Defraia et al., 2003). Ophthalmic features of the condition are microphthalmia, congenital cataracts, blue sclerae and nystagmus. Individuals with Hallermann-Streiff Syndrome, presence of mandibular hypoplasia and microstomia can result in difficult intubation. Recognition of this syndrome should alert the physician to the possibility of difficulty in airway maintenance (Malde et al., 1994).

#### **2.7 Hutchinson–Gilford progeria**

Hutchinson-Gilford progeria syndrome (OMIM 176670) first described by the general practitioner Jonathan Hutchinson in 1886, is a very rare autosomal dominant disorder characterised by growth retardation and progressive, premature senescent changes of the skin, bones and cardiovascular system (Sevenants et al., 2005). According to Polex and Hegele, since 1886 fewer than 100 cases of Hutchinson-Gilford progeria syndrome have been reported, with approximately 40 cases currently diagnosed (Polex & Hegele, 2004).

Microstomia: A Rare but Serious Oral Manifestation of Inherited Disorders 457

structural integrity and chromatin regulatory mechanisms (Martin, 2005). Progerin is the mutant form of lamin A and while progerin is expressed at very low levels normally, it is expressed at much greater levels in Hutchinson-Gilford progeria syndrome (Domingo et al, 2009). According to Domingo et al, Progerin accumulation in cells has been associated with instability of the nuclear membrane, progressive nuclear damage, and premature cell death. Polex and Hegele have shown structural nuclear abnormalities in 48% of Hutchinson-Gilford progeria syndrome fibroblast nuclei compared with less than 6% of normal control cells (Domingo et al, 2009). Furthermore, they stated that, Hutchinson-Gilford progeria syndrome fibroblasts undergo hyperproliferation followed by rapid

From the Greek geras, meaning \_old age,' progeria is a human disease model of accelerated senescence (Domingo et al, 2009). Affected individuals typically appear normal at birth but

Clinically, the main features of Hutchinson-Gilford progeria syndrome include alterations in skin, bone, and cardiovascular tissues, marked retardation of growth, loss of subcutaneous fat, and distinctive bone changes. These main features and their prevalances were shown in

Although, microstomia was not reported in majority of the cases, however, sclerodermatous changes which could be the first manifestation of Hutchinson-Gilford

Among individuals with Hutchinson-Gilford progeria syndrome, death occurs at 13 years of age, most commonly from progressive coronary and cardiovascular atherosclerosis

Burton skeletal dysplasia was first described by Burton et al in 1986 (Burton et al., 1986). They reported a pair of sibs suffering from a new skeletal dysplasia with clinical and radiological findings similar to those of Kniest dysplasia but with important differences. They reported the main clinical findings as: sibs with short stature, bowing and shortness of limbs, enlargement of wrists and knee joints, stiffness of knee joints, and a bell-shaped thorax with flare of lower ribs. In addition, they had a small mouth with pursed lips, downward dislocation of the lenses, and myopia. In agreement with Burton et al, Lo et al added the third case to he literature and reported also a small mouth with pursed lips that remained more or less the same size whether she laughed or cried, and a deep philtrum (Lo

In 1983, Drs. Fine and Lubinsky described a single patient with craniofacial anomalies, hearing loss, cataracts, microstomia, and developmental delay (Fine & Lubinsky, 1983). In following reports, the main clinical features of the condition was described as: craniosynostosis, prominent frontal bones, flat facial profiles, small noses, microstomia, hearing loss, developmental delay, and abnormal digits (Preus et al., 1984; Suthers et al., 1993; Ayme´ & Philip, 1996; Holder et al., 2007; Schoner et al., 2008; Cole et al., 2010). Schoner et al reported a female fetus of 24 weeks gestational age with Fine-Lubinsky syndrome and based the diagnosis of Fine-Lubinsky syndrome on growth deficiency,

begin to demonstrate features of accelerated aging within the first year of life.

progeria syndrome, can result in restriction of the oral aperture.

apoptosis.

Table 3.

et al., 1998).

(Pollex&Hegele, 2004).

**2.8 Burton skeletal dysplasia** 

**2.9 Fine–Lubinsky syndrome** 


Table 3. Major Findings in 142 Patients With Hutchinson–Gilford Progeria Syndrome (adopted from Domingo et al, 2009)

Fong stated that, most cases are caused by a de novo single-nucleotide substitution in codon 608 of prelamin A (p.G608G (GGC>GGT), p.G608S (GGC>AGC)), leading to the mutated Hutchinson-Gilford progeria syndrome gene product lamin A (LMNA), a structural component of the nuclear membrane (Fong & Meta, 2004). Lamin A contributes to nuclear structural integrity and chromatin regulatory mechanisms (Martin, 2005). Progerin is the mutant form of lamin A and while progerin is expressed at very low levels normally, it is expressed at much greater levels in Hutchinson-Gilford progeria syndrome (Domingo et al, 2009). According to Domingo et al, Progerin accumulation in cells has been associated with instability of the nuclear membrane, progressive nuclear damage, and premature cell death. Polex and Hegele have shown structural nuclear abnormalities in 48% of Hutchinson-Gilford progeria syndrome fibroblast nuclei compared with less than 6% of normal control cells (Domingo et al, 2009). Furthermore, they stated that, Hutchinson-Gilford progeria syndrome fibroblasts undergo hyperproliferation followed by rapid apoptosis.

From the Greek geras, meaning \_old age,' progeria is a human disease model of accelerated senescence (Domingo et al, 2009). Affected individuals typically appear normal at birth but begin to demonstrate features of accelerated aging within the first year of life.

Clinically, the main features of Hutchinson-Gilford progeria syndrome include alterations in skin, bone, and cardiovascular tissues, marked retardation of growth, loss of subcutaneous fat, and distinctive bone changes. These main features and their prevalances were shown in Table 3.

Although, microstomia was not reported in majority of the cases, however, sclerodermatous changes which could be the first manifestation of Hutchinson-Gilford progeria syndrome, can result in restriction of the oral aperture.

Among individuals with Hutchinson-Gilford progeria syndrome, death occurs at 13 years of age, most commonly from progressive coronary and cardiovascular atherosclerosis (Pollex&Hegele, 2004).

### **2.8 Burton skeletal dysplasia**

456 Advances in the Study of Genetic Disorders

Feature Frequency

Cranium 75-100 % Nasal bridge 75-100 % Prominent forehead 25-50 % Absent eyebrows/eyelashes 50-75 %

Small face 75-100 % Thin nasal skin 75-100 % Convex nasal profile 25-50 % Crowded teeth 50-75 % Increased dental decay 50-75 % Absent ear lobule 25-50 % High voice 75-100 % Lipodystrophy 75-100 % Narrow upper thorax 75-100 % Prominent abdomen 75-100 % Broadened finger tips 50-75 % Nail dystrophy 50-75 % Horse riding stance 50-75 %

Elbows 75-100 % Wrists 25-50 % Fingers 75-100 % Hips 75-100 % Knees 75-100 % Ankles 25-50 % Table 3. Major Findings in 142 Patients With Hutchinson–Gilford Progeria Syndrome

Fong stated that, most cases are caused by a de novo single-nucleotide substitution in codon 608 of prelamin A (p.G608G (GGC>GGT), p.G608S (GGC>AGC)), leading to the mutated Hutchinson-Gilford progeria syndrome gene product lamin A (LMNA), a structural component of the nuclear membrane (Fong & Meta, 2004). Lamin A contributes to nuclear

Prenatal growth delay 0-25 % Postnatal growth delay 75-100 % Normal skull growth 50-75 % Cognitive development 75-100 % Hair sparse/alopecia 75-100 %

**Increased visibility vessels** 

**Decreased mobility** 

(adopted from Domingo et al, 2009)

Burton skeletal dysplasia was first described by Burton et al in 1986 (Burton et al., 1986). They reported a pair of sibs suffering from a new skeletal dysplasia with clinical and radiological findings similar to those of Kniest dysplasia but with important differences. They reported the main clinical findings as: sibs with short stature, bowing and shortness of limbs, enlargement of wrists and knee joints, stiffness of knee joints, and a bell-shaped thorax with flare of lower ribs. In addition, they had a small mouth with pursed lips, downward dislocation of the lenses, and myopia. In agreement with Burton et al, Lo et al added the third case to he literature and reported also a small mouth with pursed lips that remained more or less the same size whether she laughed or cried, and a deep philtrum (Lo et al., 1998).

#### **2.9 Fine–Lubinsky syndrome**

In 1983, Drs. Fine and Lubinsky described a single patient with craniofacial anomalies, hearing loss, cataracts, microstomia, and developmental delay (Fine & Lubinsky, 1983). In following reports, the main clinical features of the condition was described as: craniosynostosis, prominent frontal bones, flat facial profiles, small noses, microstomia, hearing loss, developmental delay, and abnormal digits (Preus et al., 1984; Suthers et al., 1993; Ayme´ & Philip, 1996; Holder et al., 2007; Schoner et al., 2008; Cole et al., 2010).

Schoner et al reported a female fetus of 24 weeks gestational age with Fine-Lubinsky syndrome and based the diagnosis of Fine-Lubinsky syndrome on growth deficiency,

Microstomia: A Rare but Serious Oral Manifestation of Inherited Disorders 459

Clinical signs Cases Frequency(%)

26/26 33/46

12/27 46/47

Table 4. Clinical signs and the prevalances of Auriculo- condylar syndrome from previous

**2.12 Chromosome 22q11.2 Deletion syndrome (Velocardiofacial/DiGeorge syndrome)**  Dr. Angelo DiGeorge described a group of infants with congenital absence of the thymus and parathyroid glands In 1965 (DiGeorge et al., 1965). Facial dysmorphia, conotruncal cardiac malformations, and speech delay were included in the spectrum and various other names came to be applied to this constellation of phenotypic features, including velocardiofacial syndrome, cardiofacial syndrome, and conotruncal anomaly face syndrome( McDonald-McGinn & Sullivan, 2011). Major phenotypic features of the condition were listed in Table 5. According to the review of McDonald-McGinn and Sullivan, the estimated prevalence has

Major Phenotypic Features Cardiac anomaly Tetralogy of Fallot Ventriculoseptal defect Interrupted aortic arch Truncus arteriosus Vascular ring Immune deficiency T-cell lymphopenia Thymic aplasia with absent T cells Delayed IgG production Palatal defects Velopharyngeal insufficiency Submucous cleft palate Overt cleft palate Cleft lip and palate Table 5. Major phenotypic features of Chromosome 22q11.2 Deletion Syndrome (adopted

been cited as being 1:3000-1:6000 births ( McDonald-McGinn & Sullivan, 2011).

Microstomia 26/42 61.9 Stenotic ear canals 6/17 35.3 Mild developmental delay 3/13 23.1 Abnormal palate 14/29 48.2 Glossoptosis 11/22 50.0 Ptosis 3/11 27.3 Feeding difficulties 8/30 26.7 Prominent cheeks 29/43 67.4 Respiratory distress 14/34 41.2 Macrocephaly 3/12 25.0

100 71.7

44.4 97.9

TMJ abnormality Micrognathia

Hearing loss Ear constriction

reports (adopted from Masotti et al., 2008)

from McDonald-McGinn & Sullivan, 2011)

brachycephaly, flat face with associated dysmorphic signs, microstomia and cataract (Schoner et al., 2008).

Cole performed a G-banded chromosome analysis, telomere FISH study, and an array based comparative genome hybridization analysis in a patient with Fine-Lubinsky syndrome (Cole et al., 2010). The genetic evaluation of the individual revealed no abnormalities. However, Holder et al described the first brother and sister sibling pair with features suggestive of Fine– Lubinsky syndrome and the identification of a brother–sister sibling pair with unaffected parents suggested a possible autosomal recessive inheritance pattern with a 25% recurrence risk to future siblings (Holder et al., 2007).

#### **2.10 Leopard syndrome**

LEOPARD syndrome, also known as Multiple Lentigines syndrome, Cardio-cutaneous syndrome, Moynahan syndrome, Lentiginosis profusa and Progressive Cardiomyopathic Lentiginosis is a polymalformative disease affecting many organs and systems and was first described by Zeisler and Becker in 1936 (Zeisler& Becker, 1936).

The abnormalities related to Leopard syndrome are: Electrocardiographic anomalies, ocular hypertelorism, pulmonary stenosis. anomalies of genitalia, retardation of growth and deafness(Yam et al., 2001).

The Leopard syndrome follows an autosomal dominant mode of transmission with a wide variability in expression (Ho et al., 1989). However, according to some authors, the syndrome may arise as a result of a spontaneous mutation. Microstomia associated with Leopard syndrome was reported by Yam et al. According to Sarkozy et al, Leopard syndrome may be sporadic or inherited as an autosomal dominant fully penetrant trait (Sarkozy, et., 2008). In approximately 85% of the patients with a definite diagnosis of Leopard syndrome, a missense mutation is found in the *PTPN11* gene, located on chromosome 12q24.1 (Diglio et al., 2002; Sarkozy et al., 2004).

#### **2.11 Auriculo-condylar syndrome**

Auriculo-condylar syndrome (OMIM 602483) was first described by Jampol et al in 1998 (Jampol et al., 1998). It is an autosomal dominant disorder of first and second pharyngeal arches, is characterized by malformed ears, prominent cheeks, microstomia, abnormal temporomandibular joint, and mandibular condyle hypoplasia. Comparison of clinical signs of patients with auriculo-condylar syndrome from previous reports were shown in Table IV. Treacher Collins syndrome ( OMIM 154500), oculoauriculo- vertebral spectrum (OMIM 164210), and Townes–Brocks syndrome (07480) have several overlapping clinical signs with auriculo-conylar syndrome and should be considered for differential diagnosis of the condition. Masotti et al. (Masotti et al., 2008) stated that, the mapping and identification will certainly bring important contributions to the understanding of the development of embryonic structures derived from these pharyngeal arches, as well as to perform differential diagnosis.

The auriculo-condylar syndrome gene is still unknown. The intra- and inter-familial phenotypic variation in auriculo-condylar syndrome has been noted by several authors. (Guion-Almeida et al., 1999; Storm et al., 2005; Masotti et al., 2008; Jampol et al.,1998) Masotti et al have performed a wide genome search and observed evidence of linkage to 1p21.1–q23.3. They have also stated that an evidence for genetic heterogeneity. (Masotti et al., 2008)

brachycephaly, flat face with associated dysmorphic signs, microstomia and cataract

Cole performed a G-banded chromosome analysis, telomere FISH study, and an array based comparative genome hybridization analysis in a patient with Fine-Lubinsky syndrome (Cole et al., 2010). The genetic evaluation of the individual revealed no abnormalities. However, Holder et al described the first brother and sister sibling pair with features suggestive of Fine– Lubinsky syndrome and the identification of a brother–sister sibling pair with unaffected parents suggested a possible autosomal recessive inheritance pattern with a 25%

LEOPARD syndrome, also known as Multiple Lentigines syndrome, Cardio-cutaneous syndrome, Moynahan syndrome, Lentiginosis profusa and Progressive Cardiomyopathic Lentiginosis is a polymalformative disease affecting many organs and systems and was first

The abnormalities related to Leopard syndrome are: Electrocardiographic anomalies, ocular hypertelorism, pulmonary stenosis. anomalies of genitalia, retardation of growth and

The Leopard syndrome follows an autosomal dominant mode of transmission with a wide variability in expression (Ho et al., 1989). However, according to some authors, the syndrome may arise as a result of a spontaneous mutation. Microstomia associated with Leopard syndrome was reported by Yam et al. According to Sarkozy et al, Leopard syndrome may be sporadic or inherited as an autosomal dominant fully penetrant trait (Sarkozy, et., 2008). In approximately 85% of the patients with a definite diagnosis of Leopard syndrome, a missense mutation is found in the *PTPN11* gene, located on

Auriculo-condylar syndrome (OMIM 602483) was first described by Jampol et al in 1998 (Jampol et al., 1998). It is an autosomal dominant disorder of first and second pharyngeal arches, is characterized by malformed ears, prominent cheeks, microstomia, abnormal temporomandibular joint, and mandibular condyle hypoplasia. Comparison of clinical signs of patients with auriculo-condylar syndrome from previous reports were shown in Table IV. Treacher Collins syndrome ( OMIM 154500), oculoauriculo- vertebral spectrum (OMIM 164210), and Townes–Brocks syndrome (07480) have several overlapping clinical signs with auriculo-conylar syndrome and should be considered for differential diagnosis of the condition. Masotti et al. (Masotti et al., 2008) stated that, the mapping and identification will certainly bring important contributions to the understanding of the development of embryonic structures derived from these pharyngeal arches, as well as to perform

The auriculo-condylar syndrome gene is still unknown. The intra- and inter-familial phenotypic variation in auriculo-condylar syndrome has been noted by several authors. (Guion-Almeida et al., 1999; Storm et al., 2005; Masotti et al., 2008; Jampol et al.,1998) Masotti et al have performed a wide genome search and observed evidence of linkage to 1p21.1–q23.3. They have also stated that an evidence for genetic heterogeneity. (Masotti et

(Schoner et al., 2008).

**2.10 Leopard syndrome** 

deafness(Yam et al., 2001).

**2.11 Auriculo-condylar syndrome** 

differential diagnosis.

al., 2008)

recurrence risk to future siblings (Holder et al., 2007).

described by Zeisler and Becker in 1936 (Zeisler& Becker, 1936).

chromosome 12q24.1 (Diglio et al., 2002; Sarkozy et al., 2004).


Table 4. Clinical signs and the prevalances of Auriculo- condylar syndrome from previous reports (adopted from Masotti et al., 2008)

**2.12 Chromosome 22q11.2 Deletion syndrome (Velocardiofacial/DiGeorge syndrome)**  Dr. Angelo DiGeorge described a group of infants with congenital absence of the thymus and parathyroid glands In 1965 (DiGeorge et al., 1965). Facial dysmorphia, conotruncal cardiac malformations, and speech delay were included in the spectrum and various other names came to be applied to this constellation of phenotypic features, including velocardiofacial syndrome, cardiofacial syndrome, and conotruncal anomaly face syndrome( McDonald-McGinn & Sullivan, 2011). Major phenotypic features of the condition were listed in Table 5. According to the review of McDonald-McGinn and Sullivan, the estimated prevalence has been cited as being 1:3000-1:6000 births ( McDonald-McGinn & Sullivan, 2011).

> Major Phenotypic Features Cardiac anomaly Tetralogy of Fallot Ventriculoseptal defect Interrupted aortic arch Truncus arteriosus Vascular ring Immune deficiency T-cell lymphopenia Thymic aplasia with absent T cells Delayed IgG production Palatal defects Velopharyngeal insufficiency Submucous cleft palate Overt cleft palate Cleft lip and palate

Table 5. Major phenotypic features of Chromosome 22q11.2 Deletion Syndrome (adopted from McDonald-McGinn & Sullivan, 2011)

Microstomia: A Rare but Serious Oral Manifestation of Inherited Disorders 461

feature is the formation of blisters and erosions at the site of minor mechanical trauma in the skin, mucocutaneous layers of the oral mucosa, and respiratory and digestive tracts (Ergun

Results of the first gene therapy was reported in 2006 by De Luca and colleagues on a patient with generalized junctional epidermolysis bullosa who had compound heterozygous

Most of the more severe subtypes are associated with clinically significant extracutaneous complications. Some subtypes may lead to death, even in early infancy. Dystrophic epidemolysis bullosa has either an autosomal- dominant or recessive pattern of inheritance and is associated with loss of fibrils of anchorage and increased collagen disintegration on the superficial dermis due to excessive synthesis of collagenase (Silva et al., 2004; de Freitas, 1986). This characteristic may results in limited mouth opening. The recessive subtype of the condition is the more severe form, in which the continuous formation of cicatricial tissue, especially in the hands and feet, leads to the joining of the fingers and toes. The dominant form of epidermolysis bullose presents with bullous eruptions that develop after trauma and heal leaving atrophic scars and milium, which are small white nodules that appear

According to Stavropoulos and Abramovicz (Stavropoulos& Abramovicz, 2008). oral involvement of epidermolysis bullosa may includes occasional intraoral blistering that heals rapidly and patients may present with severe intraoral blistering and subsequent scar formation which results in restriction of the mouth opening. Spinocellular carcinoma is the most frequent complication of epidermolysis bullosa and morbidity and mortality were

The main goal and objective of microstomia treatment are: the reconstruction of the orbicularis sphincter for adequate lip functioning, obtaining lip symmetry and formation of well positioned and undistorted scars. The cause and severity of the perioral restriction and esthetic and functional requirements influence the treatment selection and procedures. Several techniques have been described for the reconstruction of the labial commissures. Surgical possibilities include z-plasties, skin grafts, commissurotomies and local flaps. In addition, a number of nonsurgical methods and designs have been used for maintaining adequate mouth opening. Individuals with restricted mouth opening were considered to be good candidates for intra- and extraoral stretching devices, static and dynamic oral

Basically, an effective surgical treatment for individuals with microstomia must solve two problems: first, to restore the oral opening size by releasing the commissural contracture; and second, to minimize the cosmetic defect caused by oral angle deformation (Griskevich, 2010). Restoration of the oral commissure is always a difficult procedure related to the complex functional and esthetic entity of the circumoral region. idely used methods usually consist of scar 'excision' in the oral angle zone and wound closure with mobilised mucosal flaps (Griskevich, 2010). Dieffenbach.(Dieffenbach, 1829; Jaminet et al., 2009) presented the first technique to correct microstomia by performing advancement of superior, inferior, and

et al., 1992; Marx&Stern, 2003).

beneath the scars.

mutations in the β3 chain of laminin 332 (Fine, 2010) .

frequently reported. (Liversidge et al., 2005).

appliances and sectional and collapsible dentures (Wust, 2006).

**3. Treatment of Microstomia** 

**3.1 Surgical therapy** 

Cytogenetic and molecular studies have showed that most patients with DiGeorge/ Velocardiofacial syndrome have interstitial or submicroscopic deletions within 22q11 (Driscoll et al., 1992) Clinical findings in Chromosome 22q11.2 Deletion syndrome were shown in Table 6.

> Clinical findings Feeding difficulties Respiratory infections Developmental delay Short stature Long face, vertical maxillary excess Abundant hair Mild, upslanting palpebal fissures High, wide nasal bridge Prominent middle nose with hypoplastic nasal alae Philtrum anomalies Microstomia Long recessed chin Abnormal ears Short, broad neck Scoliosis Heart defect Umbilical hernia

Table 6. Clinical findings in Velocardiofacial syndrome (adopted from Jaquez et al., 1997)

Microstomia was reported to be one of the clinical findings in Chromosome 22q11.2 Deletion Syndrome. (Jaquez et al., 1997, Martin Mateos et al., 2000) However, the pathogenesis and the frequency of microstomia among individuals with Chromosome 22q11.2 Deletion Syndrome are not known.

#### **2.13 Epidermolysis bullosa**

Epidermolysis bullosa is a group of rare, genetically determined disease, which is characterized by cutaneous and mucosal blistering associated with occasional subsequent scarring secondary to minor trauma. It is divided into 3 major types by histological findings, and includes approximately 23 variants, manifested by a spectrum of clinical presentations (Stavropoulos% Abramovicz, 2008; Ozgur et al., 2005).The diagnosis is confirmed by examining the basal membrane with transmission electron microscopy, immunohistochemical analysis, and complementary examinations, such as optical microscopy, immunofluorescence, and enzymatic analysis (Siqueira et al., 2008).

The condition affects approximately 1 in 50,000 to 1 in 500,000 births and encompasses a group of congenital chronic noninflammatory skin disorders. Their common primary feature is the formation of blisters and erosions at the site of minor mechanical trauma in the skin, mucocutaneous layers of the oral mucosa, and respiratory and digestive tracts (Ergun et al., 1992; Marx&Stern, 2003).

Results of the first gene therapy was reported in 2006 by De Luca and colleagues on a patient with generalized junctional epidermolysis bullosa who had compound heterozygous mutations in the β3 chain of laminin 332 (Fine, 2010) .

Most of the more severe subtypes are associated with clinically significant extracutaneous complications. Some subtypes may lead to death, even in early infancy. Dystrophic epidemolysis bullosa has either an autosomal- dominant or recessive pattern of inheritance and is associated with loss of fibrils of anchorage and increased collagen disintegration on the superficial dermis due to excessive synthesis of collagenase (Silva et al., 2004; de Freitas, 1986). This characteristic may results in limited mouth opening. The recessive subtype of the condition is the more severe form, in which the continuous formation of cicatricial tissue, especially in the hands and feet, leads to the joining of the fingers and toes. The dominant form of epidermolysis bullose presents with bullous eruptions that develop after trauma and heal leaving atrophic scars and milium, which are small white nodules that appear beneath the scars.

According to Stavropoulos and Abramovicz (Stavropoulos& Abramovicz, 2008). oral involvement of epidermolysis bullosa may includes occasional intraoral blistering that heals rapidly and patients may present with severe intraoral blistering and subsequent scar formation which results in restriction of the mouth opening. Spinocellular carcinoma is the most frequent complication of epidermolysis bullosa and morbidity and mortality were frequently reported. (Liversidge et al., 2005).

### **3. Treatment of Microstomia**

460 Advances in the Study of Genetic Disorders

Cytogenetic and molecular studies have showed that most patients with DiGeorge/ Velocardiofacial syndrome have interstitial or submicroscopic deletions within 22q11 (Driscoll et al., 1992) Clinical findings in Chromosome 22q11.2 Deletion syndrome were

Clinical findings Feeding difficulties Respiratory infections Developmental delay Short stature Long face, vertical maxillary excess Abundant hair Mild, upslanting palpebal fissures High, wide nasal bridge Prominent middle nose with hypoplastic nasal alae Philtrum anomalies Microstomia Long recessed chin Abnormal ears Short, broad neck Scoliosis Heart defect Umbilical hernia Table 6. Clinical findings in Velocardiofacial syndrome (adopted from Jaquez et al., 1997)

Microstomia was reported to be one of the clinical findings in Chromosome 22q11.2 Deletion Syndrome. (Jaquez et al., 1997, Martin Mateos et al., 2000) However, the pathogenesis and the frequency of microstomia among individuals with Chromosome

Epidermolysis bullosa is a group of rare, genetically determined disease, which is characterized by cutaneous and mucosal blistering associated with occasional subsequent scarring secondary to minor trauma. It is divided into 3 major types by histological findings, and includes approximately 23 variants, manifested by a spectrum of clinical presentations (Stavropoulos% Abramovicz, 2008; Ozgur et al., 2005).The diagnosis is confirmed by examining the basal membrane with transmission electron microscopy, immunohistochemical analysis, and complementary examinations, such as optical

The condition affects approximately 1 in 50,000 to 1 in 500,000 births and encompasses a group of congenital chronic noninflammatory skin disorders. Their common primary

microscopy, immunofluorescence, and enzymatic analysis (Siqueira et al., 2008).

22q11.2 Deletion Syndrome are not known.

**2.13 Epidermolysis bullosa** 

shown in Table 6.

The main goal and objective of microstomia treatment are: the reconstruction of the orbicularis sphincter for adequate lip functioning, obtaining lip symmetry and formation of well positioned and undistorted scars. The cause and severity of the perioral restriction and esthetic and functional requirements influence the treatment selection and procedures. Several techniques have been described for the reconstruction of the labial commissures. Surgical possibilities include z-plasties, skin grafts, commissurotomies and local flaps. In addition, a number of nonsurgical methods and designs have been used for maintaining adequate mouth opening. Individuals with restricted mouth opening were considered to be good candidates for intra- and extraoral stretching devices, static and dynamic oral appliances and sectional and collapsible dentures (Wust, 2006).

#### **3.1 Surgical therapy**

Basically, an effective surgical treatment for individuals with microstomia must solve two problems: first, to restore the oral opening size by releasing the commissural contracture; and second, to minimize the cosmetic defect caused by oral angle deformation (Griskevich, 2010). Restoration of the oral commissure is always a difficult procedure related to the complex functional and esthetic entity of the circumoral region. idely used methods usually consist of scar 'excision' in the oral angle zone and wound closure with mobilised mucosal flaps (Griskevich, 2010). Dieffenbach.(Dieffenbach, 1829; Jaminet et al., 2009) presented the first technique to correct microstomia by performing advancement of superior, inferior, and

Microstomia: A Rare but Serious Oral Manifestation of Inherited Disorders 463

Compression therapy, mouth splinting, scar massage, contact media, exercise, patient education and neck splinting are standard treatments for the prevention and management of microstomia (Wust, 2006). It has been demonstrated that, effective contracture

Basically, two forms of functional splinting devices exist: passive splints which prevent contraction, and dynamic widening devices which regain lost oral opening. These may be retained by intraoral (fixed or removable) or extraoral devices. The removable splint usually resembles a mouthguard made of acrylic resin and is retained with clasps. The fixed appliance is retained on orthodontic bands placed on the primary maxillary second molars and central incisors. Both devices support acrylic resin posts that maintain the commissural regions equidistant to the midline. Reisberg et al. recommended using an extraoral commissure conformer attached to an orthodontic headgear strap (Reisberg et al., 1983). The amount of tension needed is based on the distance from the midline to the unaffected side when the patient smiles broadly. Many investigators have documented the use of lip and cheek retractors as a splinting device. Silverglade and Ruberg stated that an expansile removable appliance to regain lost lateral dimension due to scar contracture is usefull (Silverglade.& Ruberg, 1986) Two acrylic phalanges are connected to an orthodontic palatal expanding device that expands 0.25 mm with each adjustment. Madjar et al. described a commissure widening device in which a stainless steel wire is bent into the shape of an **fl**  and fitted with acrylic resin lip holders such that force is directed laterally and distally (Madjar et al., 1987). Conine et al. evaluated the structural and clinical characteristics of major microstomia orthoses and proposed the Vancouver microstomia orthosis (Conine et al., 1989). They stated an average of 7 mm in the horizontal and 13 mm in the vertical active

Dynamic Mouth Splint designed by Van Straten, was considered for trial to improve vertical mouth opening (van Straten, 1991). However, some difficulties were identified. These

Subsequently, a Modified Dynamic Mouth Splint was developed that combines design features of the original Dynamic Mouth Splint with materials designed for intra oral use (Wust, 2006). Wust stated that, good results in functional mouth opening can be obtained

Microstomia devices have been developed to decrease the scarring and contractures imposed by the healing process. Many of these devices are useful for the control of horizontal mouth opening restriction. Recently, another Davis proposed an effective, simple, economical, orthotic device for the enlargement of the vertical mouth diameter and suggested that, patients gave positive feedback for comfort and ease of use, with increased mouth mobility and range of motion (Davis et al., 2006). Additionally, it has been suggested

management needs to provide horizontal, vertical, and circumferential lip stretch.

**3.2 Non surgical therapy** 

**3.2.1 Static and dynamic mouth splints** 

range of motion within 9 weeks of use.

*1. the thermoplastic material was not designed for intra-oral use,* 

by using the Modified Dynamic Mouth Splints (Wust, 2006).

*2. the risk of damage to dental structures caused by lack of conformity to the teeth, 3. the risk of oral infection caused by possible microbial contamination of the splint lining, 4. the fact that the application requires a vertical mouth opening of more than 25 mm.* 

included:

**3.2.2 Vertical orthosis** 

lateral mucosal flaps to reconstruct the corner of the mouth after removal of a triangular wedge of scar tissue. The procedure was modified later by Converse (Converse, 1959; Jaminet et al., 2009) and later by Mehra et al (Mehra et al., 1998; Jaminet et al., 2009) by performing either a vermilion advancement or the transposition of the buccal mucosa following the commissurotomy procedure.

 Gillies and Millard (Gillies & Millard, 1957, Jaminet et al., 2009) used a vermilion flap to reconstruct the upper lip and an oral mucosal advancement flap for the lower lip. Villoria (Villoria, 1972) transposed inner and outer orbicularis oris muscle flaps and performed an advancement of the oral mucosa to reshape the vermilion. Johns et al (Johns et al., 1998;Jaminet et al., 2009) suggested the success of the triangular pedicled flap for oral commissuroplasty, with good result. Muhlbauer (Muhlbauer, 1970; Jaminet et al., 2009) proposed 2 Z-plasties, using the rotation of 2 small skin flaps into the mucosa of the lip. However, this technique is rarely used as it does not allow restoration of the oral angle if the scars are rough. Sorensen pointed out, ''Traditionally, defects are usually closed with a Y-V plasty, but in my opinion the classical Z-plasty is better (Sorensen, 1979).'' (Griskevich, 2010). Fairbanks and Dingman reconstructed the oral aperture by obliquely dividing the existing vermilion into 2 diminishing flaps approximated to the new mouth angle (Fairbanks&Dingman, 1972). After contracture release, a trilobed flap is created from the mucosa that is advanced over the defect and sutured into place; the middle part of the flap is used to create the vertical part of the commissure; an overcorrection (2–4 mm) is advisable and a splint is recommended to prevent recurrence of the contracture. After triangular scar excision, mucosal advance- ment Y–V flap, or mucosal rhomboid flaps per side or skin grafts are used (Griskevich, 2010). Takato et al used a free forearm flap for reconstruction of the oral cavity and vermilion flaps at the oral commissure on a patient with severely constricted oral cavity because of mucosal adhesions (Takato et al., 1989). Martins et al reconstructed corners of the mouth via 4 rhomboid flaps rotated from the buccal mucosa (Martins et al., 2003). Ayhan et al described a new technique of reconstructing with a composite graft of the ear-lobule to surgically correct microstomia (Ayhan et al., 2006). Composite auricular lobule grafts, triangular pedicle flaps and bipedicled deep inferior epigastric perforator flaps are seldom used for the reconstruction of the oral commissure.

With the knowledge of the literature review, it can be stated that, no commissure reconstruction without scars of operation has been achieved so far by using the available techniques. Griskevich suggested that most of the commissuroplasties cannot bring good cosmetic results as flaps possess different qualities and the transposition of the flap inwards and placing it within the mucosa deforms the oral angle. For commisurotomy, the red mucosal flap is turned out for wound closure, creating a new angle deformation similar to mucosal ectropion. The oral angle zone becomes deeper, more rounded and wider; the red mucosa remains visible when the mouth is closed, which creates a cosmetic defect. Moreover, the end of the advanced mucosal flap was tightened with sutures, which could impair blood circulation, and it could result in microstomia recurrence. Therefore, an overcorrection and a splint are often recommended after all of microstomia operations (Griskevich, 2010). According to the same author, all techniques mentioned above can provide satisfactory functional outcomes, but the 'aesthetic' results were found only ''acceptable (Griskevich, 2010).

The need for a detailed description of anatomical features in their relation to red mucosa after surgery in the newly commissural region still remains. (Griskevich, 2010).

### **3.2 Non surgical therapy**

462 Advances in the Study of Genetic Disorders

lateral mucosal flaps to reconstruct the corner of the mouth after removal of a triangular wedge of scar tissue. The procedure was modified later by Converse (Converse, 1959; Jaminet et al., 2009) and later by Mehra et al (Mehra et al., 1998; Jaminet et al., 2009) by performing either a vermilion advancement or the transposition of the buccal mucosa

 Gillies and Millard (Gillies & Millard, 1957, Jaminet et al., 2009) used a vermilion flap to reconstruct the upper lip and an oral mucosal advancement flap for the lower lip. Villoria (Villoria, 1972) transposed inner and outer orbicularis oris muscle flaps and performed an advancement of the oral mucosa to reshape the vermilion. Johns et al (Johns et al., 1998;Jaminet et al., 2009) suggested the success of the triangular pedicled flap for oral commissuroplasty, with good result. Muhlbauer (Muhlbauer, 1970; Jaminet et al., 2009) proposed 2 Z-plasties, using the rotation of 2 small skin flaps into the mucosa of the lip. However, this technique is rarely used as it does not allow restoration of the oral angle if the scars are rough. Sorensen pointed out, ''Traditionally, defects are usually closed with a Y-V plasty, but in my opinion the classical Z-plasty is better (Sorensen, 1979).'' (Griskevich, 2010). Fairbanks and Dingman reconstructed the oral aperture by obliquely dividing the existing vermilion into 2 diminishing flaps approximated to the new mouth angle (Fairbanks&Dingman, 1972). After contracture release, a trilobed flap is created from the mucosa that is advanced over the defect and sutured into place; the middle part of the flap is used to create the vertical part of the commissure; an overcorrection (2–4 mm) is advisable and a splint is recommended to prevent recurrence of the contracture. After triangular scar excision, mucosal advance- ment Y–V flap, or mucosal rhomboid flaps per side or skin grafts are used (Griskevich, 2010). Takato et al used a free forearm flap for reconstruction of the oral cavity and vermilion flaps at the oral commissure on a patient with severely constricted oral cavity because of mucosal adhesions (Takato et al., 1989). Martins et al reconstructed corners of the mouth via 4 rhomboid flaps rotated from the buccal mucosa (Martins et al., 2003). Ayhan et al described a new technique of reconstructing with a composite graft of the ear-lobule to surgically correct microstomia (Ayhan et al., 2006). Composite auricular lobule grafts, triangular pedicle flaps and bipedicled deep inferior epigastric perforator flaps are seldom used for the reconstruction of the oral commissure. With the knowledge of the literature review, it can be stated that, no commissure reconstruction without scars of operation has been achieved so far by using the available techniques. Griskevich suggested that most of the commissuroplasties cannot bring good cosmetic results as flaps possess different qualities and the transposition of the flap inwards and placing it within the mucosa deforms the oral angle. For commisurotomy, the red mucosal flap is turned out for wound closure, creating a new angle deformation similar to mucosal ectropion. The oral angle zone becomes deeper, more rounded and wider; the red mucosa remains visible when the mouth is closed, which creates a cosmetic defect. Moreover, the end of the advanced mucosal flap was tightened with sutures, which could impair blood circulation, and it could result in microstomia recurrence. Therefore, an overcorrection and a splint are often recommended after all of microstomia operations (Griskevich, 2010). According to the same author, all techniques mentioned above can provide satisfactory functional outcomes, but the 'aesthetic' results were found only

The need for a detailed description of anatomical features in their relation to red mucosa

after surgery in the newly commissural region still remains. (Griskevich, 2010).

following the commissurotomy procedure.

''acceptable (Griskevich, 2010).

Compression therapy, mouth splinting, scar massage, contact media, exercise, patient education and neck splinting are standard treatments for the prevention and management of microstomia (Wust, 2006). It has been demonstrated that, effective contracture management needs to provide horizontal, vertical, and circumferential lip stretch.

### **3.2.1 Static and dynamic mouth splints**

Basically, two forms of functional splinting devices exist: passive splints which prevent contraction, and dynamic widening devices which regain lost oral opening. These may be retained by intraoral (fixed or removable) or extraoral devices. The removable splint usually resembles a mouthguard made of acrylic resin and is retained with clasps. The fixed appliance is retained on orthodontic bands placed on the primary maxillary second molars and central incisors. Both devices support acrylic resin posts that maintain the commissural regions equidistant to the midline. Reisberg et al. recommended using an extraoral commissure conformer attached to an orthodontic headgear strap (Reisberg et al., 1983). The amount of tension needed is based on the distance from the midline to the unaffected side when the patient smiles broadly. Many investigators have documented the use of lip and cheek retractors as a splinting device. Silverglade and Ruberg stated that an expansile removable appliance to regain lost lateral dimension due to scar contracture is usefull (Silverglade.& Ruberg, 1986) Two acrylic phalanges are connected to an orthodontic palatal expanding device that expands 0.25 mm with each adjustment. Madjar et al. described a commissure widening device in which a stainless steel wire is bent into the shape of an **fl**  and fitted with acrylic resin lip holders such that force is directed laterally and distally (Madjar et al., 1987). Conine et al. evaluated the structural and clinical characteristics of major microstomia orthoses and proposed the Vancouver microstomia orthosis (Conine et al., 1989). They stated an average of 7 mm in the horizontal and 13 mm in the vertical active range of motion within 9 weeks of use.

Dynamic Mouth Splint designed by Van Straten, was considered for trial to improve vertical mouth opening (van Straten, 1991). However, some difficulties were identified. These included:


Subsequently, a Modified Dynamic Mouth Splint was developed that combines design features of the original Dynamic Mouth Splint with materials designed for intra oral use (Wust, 2006). Wust stated that, good results in functional mouth opening can be obtained by using the Modified Dynamic Mouth Splints (Wust, 2006).

#### **3.2.2 Vertical orthosis**

Microstomia devices have been developed to decrease the scarring and contractures imposed by the healing process. Many of these devices are useful for the control of horizontal mouth opening restriction. Recently, another Davis proposed an effective, simple, economical, orthotic device for the enlargement of the vertical mouth diameter and suggested that, patients gave positive feedback for comfort and ease of use, with increased mouth mobility and range of motion (Davis et al., 2006). Additionally, it has been suggested

Microstomia: A Rare but Serious Oral Manifestation of Inherited Disorders 465

disruption of facial growth, genetic disorder pattern and the anatomical limitations faced in providing oral care and restorative treatment in patients with microstomia. The improvement of mouth opening impacts on the patients' quality of life by enabling them to perform activities such as speech, eating, dental hygiene, expression, social interaction, and receiving general anaesthesia via intubation rather than requiring a prolonged tracheostomy. This improved functional performance also impacts positively on psychosocial well being. Management of microstomia is a critical area when treating a patient with burn injuries and should be a priority due to its impact on quality of life (Wust, 2006). Additionally, long-term documentation of such cases and multicentre audit will enhance our understanding and improve our future management of similar rare and

Albilia, J.B.; Lam, D.K.; Blanas, N.; Clokie, C.M.& Sándor, G.K. (2007) Small mouths ... Big

Antley, R.M.; Uga, N.; Burzynski, N.J.; Baum, R.S.& Bixler, D. (1975) Diagnostic criteria for

Ayhan, M.; Aytug, Z.; Deren, O.; Karantinaci, B.& Gorgu, M.(2006) An alternative treatment

Aymé, S.& Philip, N. (1996) Fine-Lubinsky syndrome: a fourth patient with brachycephaly,

Barron, R.P.; Carmichael, R.P.; Marcon, M.A. & Sandor, G.K. (2003) Dental erosion in

Browne, C.E. ; Dennis, N.R. ; Maher, E. ; Long, F.L. ; Nicholson, J.C. ; Sillibourne, J.;

Burton, B.K.; Sumner, T.; Langer, L.O. Jr.; Rimoin, D.L.; Adomian, G.E.; Lachman, R.S.;

Campos de Freitas, A.C., Mussolino Ribeiro, Z.M.; Tambasco de Oliveira, M.C..& Assed, S.

*Ribeiro Preto*, Vol. 23, No. 2, (Jul-Dec 1986), pp. 71-78, ISSN 0102-129X Cannistrà, C.; Barbet, J.P.; Houette, A.& Iannetti; G. (1999) Temporomandibular region in the

*Odontol*. Vol. 41, No. 1, (Jan-Mar 1999), pp. 33-38, ISSN 0250-4693

*Assoc.* Vol. 73, No. 9, (Nov 2007), pp.831-836, ISSN 1488-2159

problems? A review of scleroderma and its oral health implications. *J Can Dent* 

the whistling face syndrome. *Birth Defects Orig Artic Ser.* Vol. 11, No. 5, (1975)pp.

for postburn microstomia treatment: composite auricular lobule graft for oral comissure reconstruction. *Burns.* Vol. 32, No. 3, (May 2006), pp. 380-384, ISSN 1879-

deafness, cataract, microstomia and mental retardation. *Clin Dysmorphol.* , Vol. 5,

gastroesophageal reflux disease. *J Can Dent Assoc* Vol 69, No. 2, (Feb 2003), pp. 84–

Christian, S.L.; Robinson, W.P.; Huang, B.; Mutirangura, A.; Line, M.R.; Nakao, M.; Surti, U.; Chakravarti, A.& Ledbetter, D.H. (1995). Molecular characterization of two proximal deletion breakpoint regions in both Prader-Willi and Angelman syndrome patients. *Am J Hum Genet,* Vol. 57, No. 1, (Jul 1995), pp.40–48, ISSN 1537-

Nicastro, J.F.; Kelly, D.L.&Weaver,R.G. (1986) A new skeletal dysplasia: clinical, radiologic, and pathologic findings. *J Pediatr.*Vol. 109, No. 4, (Oct 1986), pp. 642-

(1986) [Clinical management of a case of epidermolysis bullosa]. *Rev Fac Odontol* 

Franceschetti's Syndrome. Anatomical study. *Bull Group Int Rech Sci Stomatol* 

interesting genetic disorders.

161-168, ISSN 0547-6844

89, ISSN 1488-2159

648. ISSN 1097-6833

No. 1, (Jan 1996), pp. 55-60. ISSN 1473-5717

**5. References** 

1409

6605

that, from a visual assessment, the vertical orthoses are more comfortable to wear for an extended period because the patient can swallow and, with the lip-based device, talk while it is in place.

### **3.2.3 Sectional dentures**

Without surgical operation it is very difficult to perform prosthetic treatment for patients with microstomia, especially when the severe restriction of the mouth circumference length . Because the smallest diameter of a fully retentive denture and a impression tray may be larger than the greatest diameter of the mouth opening, a sectional impression tray and a sectional denture may be indicated (Suzuki et al., 2000).

Yenisey et al described a technique for the fabrication of mandibular and maxillary sectional trays and a sectional mandibular complete denture fabrication for a patient with microstomia induced by scleroderma a sectional mandibular denture was a suitable treatment to resolve the problem of microstomia caused by scleroderma. They stated that, the cast hinge design reduced the overall costs and simplified the laboratory technique. This technique has proven to be simple, inexpensive and applicable to selected microstomic patients (Yenisey et al., 2005). Watanabe et al reported the use of cast Fe-Pt magnetic attachments to treat an edentulous patient with microstomia induced by scleroderma (Watanabe et al., 2002) and described a cast iron-platinum magnetic attachment system applied to sectional collapsed complete denture. With the use of lingual and palatal midline hinges and an Fe-Pt magnetic attachment, the sectional collapsed complete dentures were successfully and easily inserted and continue to provide adequate function in the patient's mouth. Cura et al described an other technique used to fabricate mandibular and maxillary sectional trays and a folding maxillary complete denture for a patient with limited oral opening caused by systemic sclerosis. For the foldable denture, the anterior teeth had to be arranged on a second base and the hinge fitted at a location higher than the denture base (Cura et al., 2003).

#### **3.3 Exercise programs**

Pizzo et al assess the effects of a nonsurgical exercise program on the decreased mouth opening in a group of 10 systemic scleroderma patients with severe microstomia (maximal mouth opening ≤30 mm) (Pizzo et al., 2003). The subjects were instructed to perform an exercise program including both mouth-stretching and oral augmentation exercises. The effects of such exercises were assessed after an 18-week period by measuring the maximal mouth opening of each subject. The exercise program improved the mouth opening of all subjects without significant differences between dentate and edentulous ones. At the end of the 18-week period, all patients commented that eating, speaking and oral hygiene measures were easier. The edentulous subjects also experienced less difficulty inserting their own dentures. These findings suggest that regular application of the proposed exercise program may be useful in the management of microstomia in systemic scleroderma patients (Pizzo et al., 2003)

### **4. Conclusion**

Individuals with microstomia would benefit from early referral to several medical services. Regular follow-up with targeted preventive advice is essential, in view of the potential for disruption of facial growth, genetic disorder pattern and the anatomical limitations faced in providing oral care and restorative treatment in patients with microstomia. The improvement of mouth opening impacts on the patients' quality of life by enabling them to perform activities such as speech, eating, dental hygiene, expression, social interaction, and receiving general anaesthesia via intubation rather than requiring a prolonged tracheostomy. This improved functional performance also impacts positively on psychosocial well being. Management of microstomia is a critical area when treating a patient with burn injuries and should be a priority due to its impact on quality of life (Wust, 2006). Additionally, long-term documentation of such cases and multicentre audit will enhance our understanding and improve our future management of similar rare and interesting genetic disorders.

### **5. References**

464 Advances in the Study of Genetic Disorders

that, from a visual assessment, the vertical orthoses are more comfortable to wear for an extended period because the patient can swallow and, with the lip-based device, talk while

Without surgical operation it is very difficult to perform prosthetic treatment for patients with microstomia, especially when the severe restriction of the mouth circumference length . Because the smallest diameter of a fully retentive denture and a impression tray may be larger than the greatest diameter of the mouth opening, a sectional impression tray and a

Yenisey et al described a technique for the fabrication of mandibular and maxillary sectional trays and a sectional mandibular complete denture fabrication for a patient with microstomia induced by scleroderma a sectional mandibular denture was a suitable treatment to resolve the problem of microstomia caused by scleroderma. They stated that, the cast hinge design reduced the overall costs and simplified the laboratory technique. This technique has proven to be simple, inexpensive and applicable to selected microstomic patients (Yenisey et al., 2005). Watanabe et al reported the use of cast Fe-Pt magnetic attachments to treat an edentulous patient with microstomia induced by scleroderma (Watanabe et al., 2002) and described a cast iron-platinum magnetic attachment system applied to sectional collapsed complete denture. With the use of lingual and palatal midline hinges and an Fe-Pt magnetic attachment, the sectional collapsed complete dentures were successfully and easily inserted and continue to provide adequate function in the patient's mouth. Cura et al described an other technique used to fabricate mandibular and maxillary sectional trays and a folding maxillary complete denture for a patient with limited oral opening caused by systemic sclerosis. For the foldable denture, the anterior teeth had to be arranged on a second base and the hinge fitted at a location higher than the denture base

Pizzo et al assess the effects of a nonsurgical exercise program on the decreased mouth opening in a group of 10 systemic scleroderma patients with severe microstomia (maximal mouth opening ≤30 mm) (Pizzo et al., 2003). The subjects were instructed to perform an exercise program including both mouth-stretching and oral augmentation exercises. The effects of such exercises were assessed after an 18-week period by measuring the maximal mouth opening of each subject. The exercise program improved the mouth opening of all subjects without significant differences between dentate and edentulous ones. At the end of the 18-week period, all patients commented that eating, speaking and oral hygiene measures were easier. The edentulous subjects also experienced less difficulty inserting their own dentures. These findings suggest that regular application of the proposed exercise program may be useful in the management of microstomia in systemic scleroderma patients (Pizzo et

Individuals with microstomia would benefit from early referral to several medical services. Regular follow-up with targeted preventive advice is essential, in view of the potential for

it is in place.

**3.2.3 Sectional dentures** 

(Cura et al., 2003).

al., 2003)

**4. Conclusion** 

**3.3 Exercise programs** 

sectional denture may be indicated (Suzuki et al., 2000).


Microstomia: A Rare but Serious Oral Manifestation of Inherited Disorders 467

Ferri, C.; Valentini, G.; Cozzi, F.; Sebastiani, M.; Nichelassi, C.;La Montagna, G.; Bullo, A.;

Fine, B.A. & Lubinsky, M. (1983) Craniofacial and CNS anomalies with body asymmetry,

Fine, J.D. (2010) Inherited epidermolysis bullosa: past, present, and future. *Ann N.Y. Acad* 

Fong, LG.; Ng, J.K.; Meta, M.; Coté, N.; Yang, S.H.; Stewart, C.L.; Sullivan, T.; Burghardt, A.;

Gillies, H.M.& Millard, D.R.(eds) (1957) *Principles of Plastic Surgery*. Little Brown, Boston,

Goetz, R.H. (1945) Pathology of progressive systemic sclerosis with special reference to changes in the viscera. *Clin Proc (S. Africa)* Vol. 4, No. 6, pp. 337–342. Grishkevich, V.M. (2010) Post-burn microstomia: Anatomy and elimination with trapezeflap plasty. *Burns.* 2010 Dec 10. [Epub ahead of print]

Guion-Almeida, M.L. Kokitsu-Nakata, N.M.; Zechi-Ceide, R.M. & Vendramini, S.(1999)

Hawk, A.& English, J.C. (2001) Localized and systemic scleroderma. *Semin Cutan Med Surg*

Hendrix, S.L.& Sauer, H.J. (1991) Successful pregnancy in a patient with Hallermann-Streiff

Ho, I.C.; O'Donnell, D.& Rodrigo, C.(1989) The occurrence of supernumerary teeth with

Jaminet, P.; Werdin, F.; Kraus, A.; Pfau, M.; Schaller, H.E.; Becker, S.& Sinis, N.(2009)

Jaminet, P.; Werdin, F.; Kraus, A.; Pfau, M.; Schaller, HE.; Becker, S.& Sinis. N. (2009)

*Care Dentist*., Vol. 9, No. 6, (Nov-Dec 1989), pp. 200-202, ISSN 1754-4505 Hoefnagel, D.& Benirschke. K. (1965) Dyscephalia Mandibulo-Oculo-Facialis. (Hallermann-Streiff Syndrome). *Arch Dis Child.* Vol 40, (Feb 1965), pp.57-61, ISSN 1468-2044 Holder, A.M.; Graham, B.H.; Lee, B.& Scott, D.A.(2007) Fine-Lubinsky syndrome: sibling

Auriculo-condilar syndrome: further evidence for a new disorder. *Am J Med Genet* ,

syndrome. *Am J Obstet Gynecol*, Vol. 164, No. 4, (Apr 1991), pp. 1102-1104, ISSN

isolated, nonfamilial leopard (multiple lentigines) syndrome: report of case. *Spec* 

pair suggests possible autosomal recessive inheritance. *Am J Med Genet A.,* Vol.

Extreme microstomia in an 8-month-old infant: bilateral commissuroplasty using rhomboid buccal mucosa flaps. *Eplasty*. , Vol. 26, No. 10, (Dec 2009),pp(e) 5, ISSN

Extreme microstomia in an 8-month-old infant: bilateral commissuroplasty using rhomboid buccal mucosa flaps. *Eplasty,* Vol. 26, No. 10, (Dec 2009), pp(e).5, ISSN

*(Baltimore),* Vol. 81, No. 2, (Mar 2002), pp.139–153, ISSN 1536-5964

(Winter 1983), pp. 6-9, ISSN: 0736-4407

6490

USA

1097-6868

1937-5719

1937-5719

*Sci*, Vol. 1194, (Apr 2010), pp. 213-222, ISSN 1749-6632

doi:10.1016/j.burns.2010.09.003 ISSN 1879-1409

Vol. 86, No. 2, (Sep 1999), pp. 130– 133, ISSN 1096-8628

143A, No. 21, (Nov 2007), pp. 2576-2580, ISSN 1552-4833

Vol 20, No. 1, (Mar 2001), pp. 27–31, ISSN 1558-0768

Cazzato, M.; Tirri E.; Storino, F.; Giuggioli, D.; Cuomo, G.; Rasada, M.; Bombardieri, S.; Todesco, S. & Tirri, G. (2002) Systemic sclerosis: demographic, clinical, and serologic features and survival in 1012 Italian patients. *Medicine* 

severe retardation, and other malformations. *J Clin Dysmorphol.*, Vol. 1, No. 4,

Majumdar, S.; Reue, K.; Bergo, M.O.& Young, S.G. (2004) Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste 24-deficient mice. *Proc Natl Acad Sci U S A.*, Vol. 101, No. 52, (Dec 2004), pp. 18111-18116, ISSN 1091-


Cole, P.; Hatef, D.A.; Kaufman, Y.& Hollier, L.H. Jr. (2010) Fine-Lubinsky syndrome:

Conine, T.A.; Carlow, D.L.& Stevenson-Moore, P. (1989) The Vancouver microstomia orthosis. *J Prosthet Dent.* , Vol. 61, No. 4, (Apr 1989), pp. 476-483, ISSN 1097-6841 Converse, J.M.& Wood-Smith, D.(1977) Techniques for repair of defects of the lips and

Corrigan, L.A.; Duncan, C.A.& Gregg, T.A.(2006) Freeman-Sheldon syndrome: a case report. *Int J Paediatr Dent.* Vol. 16, No. 6, (Nov 2006), pp. 440-443, ISSN 1365-263X Cura, C.; Cotert, H.S.& User, A.(2003) Fabrication of a sectional impression tray and

Defraia, E.; Marinelli, A.& Alarashi, M. (2003) Case report: orofacial characteristics of

Dieffenbach, F.(Ed)(1829) *Chirurgische Erfahrungen besonders über die Wiederherstellung* 

DiGeorge, A.M. (1965) Discussions on a new concept of the cellular basis of immunology. J

Digilio, M.C.; Conti, E.; Sarkozy, A.; Mingarelli, R.; Dottorini, T.; Marino, B.; Pizzuti, A.&

Domingo, D.L.; Trujillo, M.I.; Council, S.E.; Merideth, M.A.; Gordon, L.B.; Wu, T.; Introne,

Driscoll, D.A.; Budarf, M.L.& Emanuel, B.S. (1992) A genetic etiology for Di- George

Ergun, G.A.; Lin, A.N.; Dannenberg, A.J.& Carter, D.M.(1992) Gastrointestinal

Fairbanks, G.R.& Dingman, R.O. (1972) Restoration of the oral commissure. *Plast Reconstr* 

Favaro, F.P.; Zechi-Ceide, R.M.; Alvarez, C.W.; Maximino, L.P.; Antunes, L.F.B.B.; Richieri-

*Surg.*, Vol. 49, No. 4, (Apr 1972), pp. 411-413, ISSN 1529-4242

*Genet Part* Vol. 155, No. 2, ( Feb 2010), pp.1–10, ISSN 1552-4833

pp.1575, WB Saunders, ISBN 0721626815,Philadelphia, USA

No. 1, (Jan 2010), pp(e). 70-72, ISSN 1878-0539

Jun 2006), pp. 352-356, ISSN 1559-0488

Pediatr, Vol. 67 (1998), pp. 907, ISSN 1097-6833

50, No. 5, (May 1992), pp. 924–933, ISSN 1537-6605

1992), pp. 121-127, ISSN 1536-5964

155-158, ISSN 1591-996X

389-394, ISSN 1537-6605

Germany

1601-0825

managing the rare syndromic synostosis. J Plast Reconstr Aesthet Surg., Vol. 63,

cheeks. In J,M, Converse.(ed.) *Reconstructive Plastic Surgery Principles and Procedures in Correction, Reconstruction and Transplantation*, 2nd edition, Volume 3, 1977,

sectional complete denture for a patient with microstomia and trismus: a clinical report. *J Prosthet Dent.* Vol. 89, No. 6, (Jun 2003), pp. 540-543, ISSN 1097-6841 Davis, S.; Thompson, J.G.; Clark, J.; Kowal-Vern, A.& Latenser, B.A.(2006) A prototype for

an economical vertical microstomia orthosis. *J Burn Care Res.,* Vol. 27, No. 3, (May-

Hallermann-Streiff Syndrome. *Eur J Paediatr Dent.* Vol. 4, No. 3, ( Sep 2003), pp.

*zerstörter Teile des menschlichen Körpers nach neuen Methoden*. Enslin, 1829, Berlin,

Dallapiccola, B.(2002) Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene*. Am J Hum Genet.,* Vol. 71, No. 2, (Aug 2002), pp.

W.J.; Gahl, W.A.& Hart, T.C. (2009) Hutchinson-Gilford progeria syndrome: oral and craniofacial phenotypes. *Oral Dis.,* Vol. 15, No. 3, (Apr 2009), pp. 187-195, ISSN

syndrome: Consistent deletions and microdeletion of 22q11. *Am J Hum Genet* Vol.

manifestations of epidermolysis bullosa. *Medicine(Baltimore)* Vol. 71, No. 3, (May

Costa, A.& Guion-Almeida, M.L. (2010). Richieri- Costa–Pereira syndrome: A unique acrofacial dysostosis type. An overview of the Brazilian cases. *Am J Med* 


Microstomia: A Rare but Serious Oral Manifestation of Inherited Disorders 469

Mastroiacovo, P.; Corchia, C.; Botto, L.D.; Lanni, R.; Zampino, G.& Fusco, D. (1995)

Mavilio, F.; Pellegrini, G,; Ferrari, S.; Di Nunzio, F.; Di Iorio,E.; Recchia, A.; Maruggi, G.;

McDonald Mc Ginn, D.M.;& Sullivan, K. E. (2011) Chromosome 22q11.2 Deletion Syndrome

Mehra, P.; Caiazzo, A.& Bestgen, S.(1998) Bilateral oral commissurotomy using buccal

Mordjikian, E. (2002) Severe microstomia due to burn by caustic soda. *Burns.,* Vol. 28, No. 8

Mühlbauer, W.D.(1970) Elongation of mouth in post-burn microstomia by a double Z-plasty. *Plast Reconstr Surg.* , Vol. 45, No. 4. (Apr 1970), pp. 400-402, ISSN 1529-4242 Neville, B.W. Damm, D.D.; Allen, C.M.,& Bouquot, J.E. (Eds) (2002) *Oral and maxillofacial* 

Ohyama, K.; Susami, T.; Kato, Y.; Amano, H.& Kuroda, T. (1997) Freeman-Sheldon

Orioli, I.M. & Castilla, E.E. (2010) Epidemiology of holoprosencephaly: Prevalence and risk

Ozgur, F.;, Sonmez, E,.& Tuncbilek, G. (2005) Cleft lip and cleft palate closure in 13 month-

Paznekas, W.A.; Boyadjiev, S.A.; Shapiro, R.E.; Daniels, O.; Wollnik, B.; Keegan, C.E.; Innis,

*Am. J. Hum. Genet*. Vol. 72, No. 2, (Feb 2003), pp. 408-418, ISSN 1537-6605 Pizzo, G.; Scardina, G.A.& Messina, P.(2003) Effects of a nonsurgical exercise program on

Pizzuti, A.; Flex, E.; Mingarelli, R.; Salpietro, C.; Zelante, L.& Dallapiccola, B.(2004) A

phenotype. *Hum Mutat.* Vol. 23, No. 3, (Mar 2004), pp. 286, ISSN 1098-1004 Pollex, R.L.& Hegele, R.A. (2004) Hutchinson-Gilford progeria syndrome. *Clin Genet.* Vol.

*Investig.*, Vol. 7, No. 3, (Sep 2003), pp. 175-178, ISSN 1436-3771

66, No. 5, (Nov 2004), pp,. 375-381, ISSN 1399-0004

*Surg.*, Vol. 56, No. 10, (Oct 1998), pp. 1200-1203, ISSN 1531-5053

*Hum Genet*, Vol. 16, No.2, (Feb 2008), pp. 145-152, ISSN 1476-5438

12, (Dec 2006), pp. 1397–1402, ISSN 1546-170X

1, (Jan 2011), pp. 1-18, ISSN 1536-5964

(Dec 2002), pp. 802-805, ISSN 1879-1409

No. 2, (Mar 1997), pp. 151-153, ISSN 1545-1569

6244

USA

ISSN 1552-4876

pp. 843-847, ISSN 1536-3732

syndrome: mapping of a first locus and evidence for genetic heterogeneity, *Eur J* 

Epidemiology and genetics of microtia-anotia: a registry based study on over one million births. *J Med Genet.* , Vol. 32, No. 6, (Jun 1995), pp. 453-457, ISSN 1468-

Ferrari, G.; Provasi, E.; Bonini, C.; Capurro, S.; Conti, A.; Magnoni, C.; Gianetti, A.& De Luca, M. (2006) Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells. *Nat. Med. Vol.* 12, No.

(DiGeorge Syndrome/Velocardiofacial Syndrome), *Medicine(Baltimore)* ,Vol. 90, No.

mucosa flaps for management of microstomia: report of a case. *J Oral Maxillofac* 

*pathology.* 2nd ed., p. 137, W.B. Saunders Co, ISBN 13: 9781416034353, Philadelphia,

syndrome: case management from age 6 to 16 years. *Cleft Palate Craniofac J.,* Vol. 34,

factors. *Am J Med Genet C Semin Med Genet.* Vol. 154C, No. 1, (Feb 2010), pp. 13-21,

old female with epidermolysis bullosa. *J Craniofac Surg*, Vol. 16, No. 5, (Sep 2005),

J.W.; Dinulos, M.B,; Christian, C.; Hannibal, M.C.& Jabs, E.W. (2003) Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia.

the decreased mouth opening in patients with systemic scleroderma. *Clin Oral* 

homozygous GJA1 gene mutation causes a Hallermann-Streiff/ODDD spectrum


Jampol, M.; Repetto, G.; Keith, D.A.; Curtin, H.; Remensynder, J.& Holmes, L.B. (1998) New

Johns, F.R.; Sandler, N.A.& Ochs, M.W.(1998) The use of a triangular pedicle flap for oral

Kitsiou-Tzeli, S.; Tzetis, M.; Sofocleous, C.; Vrettou, C.; Xaidara, A.; Giannikou, K.;

Koymen, R.; Gulses, A.; Karacayli, U, Aydintug, YS. (2009). Treatment of microstomia

Liversidge, H.M.; Kosmidou, A.; Hector, M.P.& Roberts, G.J. (2005) Epidermolysis bullosa

Livi, R.; Teghini, L.; Pignone, A.; Generini, S.; Matucci-Cerinic, M.& Cagnoni, M. (2002)

Lo, I.F.; Roebuck, D.J.; Lam, S.T.& Kozlowski, K. (1998) Burton skeletal dysplasia: the

Madjar, D.; Shifman, A.& Kusner, W. (1987) Dynamic labial commissure widening device

Malde, A.D.; Jagtap, S.R.& Pantvaidya, S.H. (1994) Hallermann-Streiff syndrome: airway

Martin, G.M. (2005) Genetic modulation of senescent phenotypes in Homo sapiens. *Cell*.,

Martin Mateos, M.A.; Pérez Dueñas, B.P.; Iriondo, M.; Krauel, J.& Gean Molins, E. (2000)

Martins, W.D.; Westphalen, F.H.& Westphalen, V.P.(2003) Microstomia caused by

Masotti, C.; Oliveira, K.G.; Poemer, F.; Splendore, A.; Souza, J.; Freitas Rda, S.; Zechi-Ceide,

Vol. 120, No. 4, (Feb 2005), pp. 523-532. ISSN 1097-4172

*Am J Med Genet,* Vol 75, No. 5, (Feb 1998),pp. 449–452, ISSN 1096-8628 Jaquez, M.; Driscoll, D.A.; Li, M.; Emanule, B.S.; Hernandez, I.; Jaqquez, F.; Lembert, N.;

70, No. 1, (May 1997), pp. 6-10, ISSN 1096-8628

8, (Aug 2010), pp.1925–1932, ISSN1552-4833

pp.228-231, ISSN 1531-5053

335-341, ISSN 1365-263X

682–686, ISSN 1468-2060

216-218, ISSN 0022-3859

(Nov 2003), pp. 91-99, ISSN 1526-3711

395X

1096-8628

9068

ISSN 1936-7163

Syndrome? Prominent constricted ears with malformed condyle of the mandible.

Ramirez, J.&Matalon, R. (1997) Unbalanced 15;22 translocation in a patient with manifestations of DiGeorge and velocardiofacial syndrome, Am J Med Genet., Vol.

commisuroplasty: report of a case. *J Oral Maxillofac Surg.,* Vol. 56, No. 2, ( Feb 1998),

Pampanos, A. Mavrou, A.& Kanavakis, E. (2010) De novo interstitial duplication of the 15q11.2-q14 PWS/AS region of maternal origin: Clinical description, array CGH analysis, and review of the literature. *Am J Med Genet Part A* , Vol. 152A, No.

with commissuroplasties and semidynamic acrylic splints. *Oral Surg Oral Med Oral Pathol Oral Radiol Endod.*, Vol. 107, No. 4, (Apr 2009), pp. 503-507, ISSN 1528-

and dental developmental age. *Int J Paediatr Dent.,* Vol. 15, No. 5, (Sep 2005), pp.

Renal functional reserve is impaired in patients with systemic sclerosis without clinical signs of kidney involvement. *Ann Rheum Dis* Vol. 61, No. 8, (Aug 2002), pp.

second case report. *Am J Med Genet*. , Vol. 79, No. 3, (Sep 1998), pp. 168-171, ISSN

for the facial burn patient. *Quintessence Int.* , Vol. 18, No. 5, (May 1987), pp.361-363,

problems during anaesthesia. *J Postgrad Med*, Vol. 40, No. 4, ( Oct- Dec 1994), pp.

Clinical and immunological spectrum of partial DiGeorge syndrome. *J Investig Allergol Clin Immunol*., Vol. 10, No. 6, ( Nov-Dec2000), pp. 352-360, ISSN 1018-

swallowing of caustic soda: report of a case. *J Contemp Dent Pract.* Vol. 4, No. 4,

R.; Guion- Almeida, M.L.& Passos-Bueno, M.R. (2008) Auriculo-condylar

syndrome: mapping of a first locus and evidence for genetic heterogeneity, *Eur J Hum Genet*, Vol. 16, No.2, (Feb 2008), pp. 145-152, ISSN 1476-5438


Microstomia: A Rare but Serious Oral Manifestation of Inherited Disorders 471

Stavropoulos, F.& Abramovicz, S. (2008) Management of the oral surgery patient diagnosed

Steen, V.D.& Medsger, T.A. Jr. (1990) Epidemiology and natural history of systemic

Stone, J.H.& Wigley, F.M.(1998) Management of systemic sclerosis: the art and science. *Semin Cutan Med Surg,* Vol. 17, No. 1, (Mar 1998), pp. 55–64, ISSN 1558-0768 Storm, A.L.; Johnson, J.M.; Lammer, E.; Green, G.E.& Cunniff, C. (2005) Auriculo-condylar

Suthers, G.K.; Earley, A.E. & Huson, S.M. (1993) A distinctive syndrome of brachycephaly,

Suzuki, Y.; Abe, M.; Hosoi, T.& Kurtz, K.S.(2000) Sectional collapsed denture for a partially

Takato, T.; Ohsone. H.& Tsukakoshi, H. (1989) Treatment of severe microstomia caused by

Trad, S.; Amoura, Z.; Beigelman, C.; Haroche, J.; Costedoat, N.; Boutin, le T.H.; Cacoub, P.;

Van Balen, A.T.M. (1961) Dyscephaly with microphtalmos, cataract and hypoplasia of the mandible. *Ophtalmologica*, Vol. 141, No. 1 (Jan 1961), pp. 53-56, ISSN 1423-0267 Van Straten, O. (1991) A dynamic mouth splint for the patient with facial burns*. J Burn Care Rehabil.* , Vol. 12, No. 2, (Mar-Apr 1991), pp. 174-176, ISSN 0273-8481 Villoria, J.M. (1972) A new method of elongation of the corner of the mouth. *Plast Reconstr* 

Watanabe, I.; Tanaka, Y.; Ohkubo, C.& Miller, A.W.(2002) Application of cast magnetic

Winkelmann, R.K.; Flach, D.B.& Unni, K.K. (1988) Lung cancer and scleroderma. *Arch Dermatol Res*, Vol. 28, No. Suppl., (Feb 1988), pp.(S) 15–18. ISSN 1432-069X Wust, K.J. (2006). A modified dynamic mouth splint for burn patients. *J Burn Care Res.* Vol

attachments to sectional complete dentures for a patient with microstomia: a clinical report. *J Prosthet Dent.*, Vol. 88, No. 6, (Dec 2002), pp. 573-577, ISSN 1097-

*Surg.* Vol. 49, No. 1, (Jan 1972), pp. 52-5, ISSN 1529-4242

27, No. 1, (Jan-Feb 2006), pp 86-92, ISSN 1559-0488

Maxillofac Surg, Vol. 66, No. 3, (Mar 2008), pp. 554-559, ISSN 1399-0020 Stedman, T.L. (ed) (1976), *Stedman's Medical Dictionary,* 23rd edition, p. 875, The Williams &

*Med Genet.* Vol. 41, No. 4, (Dec 1991), pp. 517-520, ISSN 1096-8628

Wilkins Company, ISBN 0683079247, Baltimore, USA

3163

ISSN 1552-4833

ISSN 1529-0131.

6841

1993), pp. 342-345, ISSN 1473-5717

1989), pp. 20-24, ISSN 0030-4220

3, (Sep 2000), pp. 256-259, ISSN 1097-6841

findings in children. Nosologic overlap with oculodentodigital dysplasia? *Am J* 

with epidermolysis bullosa: Report of 3 cases and review of the literature, J Oral

sclerosis. *Rheum Dis Clin North Am*. Vol. 16, No. 1, (Feb 1990), pp.1-10. ISSN 1558-

syndrome is associated with highly variable ear and mandibular defects in multiple kindreds. *Am J Med Genet A* Vol. 138A, No. 2, ( Oct 2008), pp. 141–145,

deafness, cataracts and mental retardation. *Clin Dysmorphol.* Vol. 2, No. 4, (Oct

edentulous patient with microstomia: a clinical report. *J Prosthet Dent.,* Vol. 84, No.

swallowing of caustic soda.*Oral Surg Oral Med Oral Pathol.,*Vol. 67, No. 1, ( Jan

Frances, C.; Wechsler, B.; Grenier, P.& Piette, J.C. (2006) Pulmonary arterial hypertension is a major mortality factor in diffuse systemic sclerosis, independent of interstitial lung disease. *Arthritis Rheum.* Vol. 54, No. 1, (Jan 2006), pp.184-191,


Preus, M.; Cooper, A.R. & O'Leary, E. (1984) Sensorineural hearing loss, small facial

Reisberg, D.J.; Fine, L.; Fattore, L.& Edmonds, D.C.(1983) Electrical burns of the oral

Richieri-Costa, A. & Pereira, S.C.S.(1992) Short stature, Robin sequence, cleft mandible,

Sarkozy, A.; Digilio, M.C.& Dallapiccola, B.(2008) Leopard syndrome. *Orphanet J Rare Dis.* 

Schoner, K.; Bald, R:; Fritz, B.& Rehder, H. (2008) Fetal manifestation of the Fine-Lubinsky

Seibold, J.R. (2005). Scleroderma. *In* E.D. JR. Harris, R.C. Budd& G.S. Firestein (Eds.): *Kelley's* 

Sevenants, L.; Wouters, C.; De Sandre-Giovannoli, A.; Devlieger, H.; Devriendt, K.; van den

*Care Dentist* Vol. 24, No. 1, (Jan-Feb 2004), pp. 22-27, ISSN 1754-4505 Silverglade, D.& Ruberg, R.L. (1986) Nonsurgical management of burns to the lips and commissures. *Clin Plast Surg.* , Vol. 13, No. 1, (Jan 1986), pp. 87-94, ISSN 1558-0504 Siqueira, M.A.; de Souza Silva, J.; Silva, F.W.; Diaz-Serrano, K.V.; Freitas, A.C.& Queiroz,

Dentist, Vol.28, No. 3, (May-Jun 2008), pp. 92-95,ISSN 1754-4505

*Am J Med Genet*, Vol. 42, No. 5, (Mar 1992), pp. 681–687, ISSN 1096-8628 Sarkozy, A.; Conti, E.; Digilio, M.C.; Marino, B.; Morini, E.; Pacileo, G.; Wilson, M.; Calabrò,

No. 1, (Spring 1984), pp. 30-31, ISSN: 0736-4407

Vol. 27, No. 3, (May 2008), pp. 13, ISSN 1750-1172

*Ther.*, Vol. 23, No. 3, (Feb 2008), pp. 228-232, ISSN 1421-9964

2004), pp(e). 68, ISSN 1468-6244

9781416032854, Philadelphia, USA

4470

ISSN 1423-0305

Arbor, Michigan, USA

features, submucous cleft palate, and myoclonic seizures. *J Clin Dysmorphol.* Vol. 2,

commissure.*J Prosthet Dent*. , Vol. 49, No. 1, (Jan 1983), pp. 71-76. ISSN 1097-6841

pre/postaxial hand anomalies, and clubfoot: A new autosomal recessive syndrome.

R.; Pizzuti, A.& Dallapiccola, B.(2004) Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. *J Med Genet.* , Vol. 41, No. 5, (May

syndrome. Brachycephaly, deafness, cataract, microstomia and mental retardation syndrome complicated by Pierre-Robin anomaly and polyhydramnios. *Fetal Diagn* 

*Textbook 's of Rheumatology*, 7th ed.,1279-1308. Elsevier Saunders, ISBN 13:

Oord, J.J.; Marien, K.; Lévy, N.& Morren, M.A.(2005) Tight skin and limited joint movements as early presentation of Hutchinson-Gilford progeria in a 7-week-old infant. *Eur J Pediatr.* Vol. 164, No. 5, (May 2005), pp. 283-286, ISSN 1432-1076 Silva, L.C.; Cruz, R.A.; Abou-Id, L.R.; Brini, L.N.& Moreira, L.S.(2004) Clinical evaluation of

patientswith epidermolysis bullosa: review of the literature and case reports. *Spec* 

A.M. (2008) Dental treatment in a patient with epidermolysis bullosa Spec Care

Alternatives to cross-lip and distant flaps in the reconstruction of ablative lip defects. *Arch Otolaryngol*. Vol.108, No.11, (Nov 1982), pp. 714-718, ISSN 0886-

(whistling face syndrome) and cranio-vertebral junction malformation producing dysphagia and weight loss. *Pediatr Neurosurg.* , Vol. 24, No. 5, (1996), pp. 272-274,

(eds) Reconstruction and rehabilitation of the burned patient. 1979, p. 224. Ann

den Berghe H. (1991) Hallermann-Streiff syndrome: clinical and psychological

Smith, P.G.; Muntz, H.R.& Thawley S.E. (1982). Local myocutaneous advancement flaps.

Song, H.R.; Sarwark, J.F.; Sauntry, S.& Grant, J. (1996) Freeman-Sheldon syndrome

Sorensen, B. (1979) Contraction of the oral stoma: microstomia. In: I. Feller, W.C. Grabb,

Spaepen, A.; Schrander-Stumpel, C.; Fryns, J.P.; de Die-Smulders, C.; Borghgraef, M.& Van

findings in children. Nosologic overlap with oculodentodigital dysplasia? *Am J Med Genet.* Vol. 41, No. 4, (Dec 1991), pp. 517-520, ISSN 1096-8628


Yam, A.A.; Faye, M.; Kane, A.; Diop, F.; Coulybaly-Ba, D.; Tamba-Ba, A.; Mbaye, NG.& Ba, I.

Yenisey, M.; Külünk, T.; Kurt, S.& Ural, C. (2005) A prosthodontic management alternative

Zeisler, E.P.& Becker, S.W.(1936) Generalized Lentigo: its relation to systemic nonelevated nevi. *Arch Dermat Syph,* Vol.33, No.2 (1936), pp. 109-125, ISSN 0365-6020

Vol. 7, No. 1, (May 2001), pp.200-202. ISSN 1601-0825

1365-2842

(2001) Oro-dental and craniofacial anomalies in LEOPARD syndrome. *Oral Dis.*,

for scleroderma patients. *J Oral Rehabil.* Vol. 32, No. 9, (Sep 2005), pp.696-700, ISSN

## *Edited by Kenji Ikehara*

The studies on genetic disorders have been rapidly advancing in recent years as to be able to understand the reasons why genetic disorders are caused. The first Section of this volume provides readers with background and several methodologies for understanding genetic disorders. Genetic defects, diagnoses and treatments of the respective unifactorial and multifactorial genetic disorders are reviewed in the second and third Sections. Certainly, it is quite difficult or almost impossible to cure a genetic disorder fundamentally at the present time. However, our knowledge of genetic functions has rapidly accumulated since the double-stranded structure of DNA was discovered by Watson and Crick in 1956. Therefore, nowadays it is possible to understand the reasons why genetic disorders are caused. It is probable that the knowledge of genetic disorders described in this book will lead to the discovery of an epoch of new medical treatment and relieve human beings from the genetic disorders of the future.

Photo by sumkinn / iStock

Advances in the Study of Genetic Disorders

Advances in the Study of

Genetic Disorders

*Edited by Kenji Ikehara*