**Prenatal Sonographic Diagnosis and Evaluation of Isolated Macrodactyly**

Hande Yağmur1, Atl Yüksel2 and Hülya Kayserili3 *1Fulya Acbadem Hastanesi, İstanbul <sup>2</sup>İstanbul Faculty of Medicine, Department of Obstetrics and Gynecology, Division of Perinatology, İstanbul Üniversitesi <sup>3</sup>İstanbul Faculty of Medicine, Department of Medical Genetics, İstanbul Üniversitesi Turkey* 

### **1. Introduction**

58 Prenatal Diagnosis – Morphology Scan and Invasive Methods

INCO (1988). International nomenclature and classification of the osteochondrodysplasias (1977) *American Journal of Medical Genetics part A,* Vol. 79, pp. 376-382 Kniffin, C. (June 2010). #268300 Roberts Syndrome; RBS In: *Online Mendelian Inheritance in Man* [*OMIM*], 20.07.2011, Available from http://omim.org/entry/268300 Konstantinidou, AE, Agrogiannis, G, Sifakis, S, et al. (2009). Genetic skeletal disorders of the

Konstantinidou, AE, Fryssira, H, Sifakis, S, Karadimas, C, Kaminopetros, P, Agrogiannis, G,

Kornak, U, Mundlos, S. (2003). Genetic disorders of the skeleton: a developmental approach.

Krakow, D, Alanay, Y, Rimoin, LP, Lin V, Wilcox, WR, Lachman, RS, & Rimoin, DL. (2008).

O' Neill, M. (January 2011). #277300 Spondylocostal Dysostosis 1, autosomal recessive

O' Neill, M. (November 2011). #119100 Split-hand/foot malformation with long bone

Nikkels, P.G.J. (2009). Diagnostic approach to congenital osteochondrodysplasias at autopsy. *Diagnostic Histopathology*, Vol.15, No.9 (September 2009), p.p. 413-424 Offiah, AC, Hall, CM. (2003). Radiological diagnosis of the constitutional disorders of bone.

Parilla, BV, Leeth, EA, Kambich, MP, Chilis, P, & MacGregor, SN. (2003). Antenatal detection of skeletal dysplasias*. Journal of Ultrasound Medicine*, Vol. 2, p.p. 255-258 Rasmussen, SA, Bieber, FR, Benacerraf, BR, Lachman, RS, Rimoin, DL, & Holmes, LB. (1996).

prenatal diagnosis. *American Journal of Medical Genetics,* Vol. 61, p.p. 49-58 Solomon, L., Jimenez, R. B., Reiner, L. (1978). Spondylothoracic dysostosis: report of 2 cases

Superti-Furga, A, Unger, S, and the Nosology Group of the International Skeletal Dysplasia

Warman, ML, Cormier-Daire, V, Hall, C, Krakow, D, Lachman, R, LeMerrer, M, Mortier, G,

Witters, I, Moerman, P, Fryns, JP. (2008). Skeletal dysplasias: 38 prenatal cases. *Genetic* 

Revision. *American Journal of Medical Genetics part A,* Vol. 143A, p.p. 1–18 Pavlopoulos, PM, Konstantinidou, AE, Agapitos, E, & Davaris, P. (1998). Cell proliferation

*Defects Research (Part A),* Vol. 85, pp. 811–821

http://omim.org/entry/277300#reference20

Available from http://omim.org/entry/119100

As easy as A, B, C? *Pediatric Radiology,* Vol. 33, p.p.153-161

*American Journal of Human Genetics,* Vol. 73, p.p. 447-474

2206-2211

Vol. 146A, p.p. 1917–1924

No.4, (April 1978), p.p. 201-205

*Genetics part A,* Vol. 155A, p.p. 943–68

*Counseling,* Vol. 19, p.p. 267-275

512-516

fetus and infant: Pathological and molecular findings in a series of 41 cases. *Birth* 

Velonis, S, Nikkels, PGH, & Patsouris, E. (2009). Cranioectodermal Dysplasia: a Probable Ciliopathy. *American Journal of Medical Genetics part A,* Vol. 149A, p.p.

Evaluation of Prenatal-Onset Osteochondrodysplasias by Ultrasonography: A Retrospective and Prospective Analysis. *American Journal of Medical Genetics part A,* 

SCDO1, In: *Online Mendelian Inheritance in Man [OMIM]*, 23.07.2011, Available from

deficiency 1; SHFLD1, In: *Online Mendelian Inheritance in Man [OMIM],* 23.07.2011,

Epidemiology of osteochondrodysplasias: changing trends due to advances in

and review of the literature. *Archives of Pathology and Laboratory Medicine*, Vol.102,

Society. (2007). Nosology and Classification of Genetic Skeletal disorders: 2006

rate and nuclear morphology in Roberts syndrome. *Clinical Genetics*, Vol. 54, p.p.

Mundlos, S, Nishimura, G, Rimoin, DL, Robertson, S, Savarirayan, R, Sillence, D, Spranger, J, Unger, S, Zabel, B, & Superti-Furga, A. (2011). Nosology and classification of genetic skeletal disorders: 2010 revision. *American Journal of Medical*  Macrodactyly, defined as enlargement of one or several digits of the hands or feet, is a rare malformation. It may be due tumorous enlargement of a single tissue element, as in hemangioma, lymphangioma or enchondroma or it may be caused by overgrowth of all structures of the digit, including phalanges, subcutaneous tissue, nerves, vessels and skin as in 'true macrodactyly'(Barsky, 1967). Furthermore, it may either be isolated or associated with other anomalies such as hemihypertrophy, vascular malformations, lipomas, cutaneous lesions or visceral anomalies as a feature of a syndrome.

There is only one case report of prenatally diagnosed isolated macrodactyly till then by Yüksel et al. Macrodactyly of the second toe of the left foot was noted on a routine fetal anomaly scan at 24 weeks (Figure 1). The other toes were of normal size and there were no other associated anomalies on serial scans. The fetal karyotype was also normal. The baby was born at term and evaluations carried out at birth, 6 months and 2 years of age revealed no other additional abnormalities; neither hemihypertrophy, macrocephaly, lipomas nor vascular abnormalities were detected. Diagnosis of congenital isolated true macrodactyly was confirmed. Distal phalangectomy was performed at 6 months of age and due to progressive enlargement after the first operation, the digit had to be amputated at 9 months of age. Histopathological evaluation of the specimen was consistent with true macrodactyly, with enlargement of all mesenchymal tissues, mainly of fibroadipose tissue origin (Yüksel et al., 2009).

Macrodactyly is an isolated finding without evidence of other systemic involvement in the majority of cases. However, there is a well-established association of macrodactyly with overgrowth syndromes such as Proteus syndrome, Bannayan-Riley-Ruvalcaba syndrome, CLOVES (Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, and Skeletal/Spinal abnormalities) syndrome, Maffucci syndrome, Ollier's disease, Klippel-Trenaunay-Weber syndrome, neurofibromatosis, tuberous sclerosis and Milroy disease (Alomari, 2009; Norman-Taylor & Mayou, 1994; Yüksel et al., 2009). Therefore, prenatal diagnosis of macrodactyly necessitates thorough evaluation of all systems to differentiate between isolated and syndromic macrodactyly, which have different prognostic implications.

Prenatal Sonographic Diagnosis and Evaluation of Isolated Macrodactyly 61

as the normal digits whereas in the progressive type, growth is accelerated compared to the rest. The progressive type is less common and involvement of the metacarpal and metatarsal bones is more likely in the progressive type (Turkington & Grey, 2005). Abnormal accelerated growth usually ceases at puberty (Singla et al., 2008; Turkington & Grey, 2005). Marked increase in adipose tissue within a mesh of fibrous tissue that involves the bone marrow, periosteum, muscles, nerve sheaths and subcutaneous tissues is the characteristic pathological finding in true macrodactyly (Kelikian, 1974 and Thorne et al., 1968 as cited in Goldman & Kaye, 1977). The most striking difference between macrodactyly of the hand and foot is neural involvement. Hypertrophy and tortuosity of the digital nerve is a notable finding in macrodactyly of the hand whereas it is rarely seen in the foot (Syed et al., 2005; Dennyson et al., 1977 as cited in Syed et al., 2005). The etiology is unclear and proposed mechanisms include lipomatous degeneration, neurofibromatosis, disturbed fetal circulation and local deficiency of growth inhibiting or overexpression of growth promoting factors

Macrodactyly causes cosmetic disfigurement and may also impair function due to secondary degenerative joint disease and nerve entrapment (Turkington & Grey, 2005). Treatment is usually not entirely satisfactory and may require several bulk reducing operations, carpal

In contrast to true macrodactyly whereby all the structures of the digit are overgrown as a whole, there is tumourous enlargement of a single tissue element. Most of the tumors (95%) are benign and they may be classified according to the tissue of origin. Abnormal growth of vascular (hemangiomas, glomus tumors), osseous (enchondromas –multiple enchondromas as in Ollier disease-, osteoid osteomas, osteoblastomas, giant cell tumors, aneurysmal and unicameral bone cysts), neural (schwannomas, fibrolipomatous hamartomas, neurofibromas), cutaneous (mucous cysts, nodular fasciitis, pyogenic granulomas) and soft tissue (ganglions, lipomas, nodular tenosynovitis) elements cause localized masses of the

Fibrolipomatous hamartoma is a rare, intraneural tumor characterized by fibrofatty infiltration around the nerve fascicles (Razzaghi & Anastakis, 2005). It is associated with macrodactyly due to overgrowth of bone and subcutaneous fat in more than one-third of the patients and it presents early in childhood with macrodactyly or later with a volar forearm mass and compressive neuropathy (Silverman & Enzinger, 1985, as cited in Razzaghi &

Malignant tumors are rare. Primary malignant tumors may be of skin (most common site for malignant tumors), bone or soft tissue origin whereas metastatic tumors are mainly due to

Proteus syndrome (MIM 176920) is a sporadic disorder that may be caused by a somatic alteration in a gene, that probably controls local production or regulation of tissue growth

(Syed et al., 2005; Gupta et al., 1992, as cited in Singla et al. 2008).

**2.2 Macrodactyly due to tumorous enlargement** 

hand and digits (Lin SJ et al., 2011).

**3.1 Proteus syndrome** 

Anastakis, 2005; Razzaghi & Anastakis, 2005).

lung, kidney or head and neck cancers (Marrero IC et al., 2011).

**3. Syndromes associated with macrodactyly** 

tunnel release, phalangectomy, and amputation (Kotwal & Farooque, 1998).

Fig. 1. Ultrasonographic scan of the fetus at 24 gestational weeks demonstrating the difference in size between two second toes. Macrodactyly of the left second toe is confirmed by comparable measurements. This is another image of the same case presented in 'Prenatal diagnosis of isolated macrodactyly' in Ultrasound in Obstetrics and Gynecology 2009; 33: 360-362.

### **2. Macrodactyly**

### **2.1 True macrodactyly**

Congenital true macrodactyly is a rare, nonhereditary malformation and appears to be more common in the hands than in the feet (Barsky, 1967). Overall, it constitutes around 1% of all congenital anomalies of the upper limb (Flatt, 1977, as cited in Kotwal & Farooque, 1998).

The disease is almost always unilateral and a single digit or several, usually adjacent digits may be involved (D'Costa et al., 1996, as cited in Singla et al., 2008; Syed et al., 2005). The second or third digit of the hand or foot are frequently involved in the majority of cases, corresponding to the median nerve and medial plantar nerve distribution (Krengel et al., 2000; Sone et al., 2000). The enlargement is most pronounced at the distal end of the digits on the volar side and therefore causes dorsal angulation (Singla et al., 2008). It may also be associated with syndactyly, polydactyly, or clinodactyly (Goldman & Kaye, 1977).

Two subtypes of true macrodactyly, namely, static and progressive types, have been described (Barsky, 1967). In the static type, the growth rate of the involved digit is the same

Fig. 1. Ultrasonographic scan of the fetus at 24 gestational weeks demonstrating the

360-362.

**2. Macrodactyly** 

**2.1 True macrodactyly** 

difference in size between two second toes. Macrodactyly of the left second toe is confirmed by comparable measurements. This is another image of the same case presented in 'Prenatal diagnosis of isolated macrodactyly' in Ultrasound in Obstetrics and Gynecology 2009; 33:

Congenital true macrodactyly is a rare, nonhereditary malformation and appears to be more common in the hands than in the feet (Barsky, 1967). Overall, it constitutes around 1% of all congenital anomalies of the upper limb (Flatt, 1977, as cited in Kotwal & Farooque, 1998). The disease is almost always unilateral and a single digit or several, usually adjacent digits may be involved (D'Costa et al., 1996, as cited in Singla et al., 2008; Syed et al., 2005). The second or third digit of the hand or foot are frequently involved in the majority of cases, corresponding to the median nerve and medial plantar nerve distribution (Krengel et al., 2000; Sone et al., 2000). The enlargement is most pronounced at the distal end of the digits on the volar side and therefore causes dorsal angulation (Singla et al., 2008). It may also be

associated with syndactyly, polydactyly, or clinodactyly (Goldman & Kaye, 1977).

Two subtypes of true macrodactyly, namely, static and progressive types, have been described (Barsky, 1967). In the static type, the growth rate of the involved digit is the same as the normal digits whereas in the progressive type, growth is accelerated compared to the rest. The progressive type is less common and involvement of the metacarpal and metatarsal bones is more likely in the progressive type (Turkington & Grey, 2005). Abnormal accelerated growth usually ceases at puberty (Singla et al., 2008; Turkington & Grey, 2005).

Marked increase in adipose tissue within a mesh of fibrous tissue that involves the bone marrow, periosteum, muscles, nerve sheaths and subcutaneous tissues is the characteristic pathological finding in true macrodactyly (Kelikian, 1974 and Thorne et al., 1968 as cited in Goldman & Kaye, 1977). The most striking difference between macrodactyly of the hand and foot is neural involvement. Hypertrophy and tortuosity of the digital nerve is a notable finding in macrodactyly of the hand whereas it is rarely seen in the foot (Syed et al., 2005; Dennyson et al., 1977 as cited in Syed et al., 2005). The etiology is unclear and proposed mechanisms include lipomatous degeneration, neurofibromatosis, disturbed fetal circulation and local deficiency of growth inhibiting or overexpression of growth promoting factors (Syed et al., 2005; Gupta et al., 1992, as cited in Singla et al. 2008).

Macrodactyly causes cosmetic disfigurement and may also impair function due to secondary degenerative joint disease and nerve entrapment (Turkington & Grey, 2005). Treatment is usually not entirely satisfactory and may require several bulk reducing operations, carpal tunnel release, phalangectomy, and amputation (Kotwal & Farooque, 1998).

### **2.2 Macrodactyly due to tumorous enlargement**

In contrast to true macrodactyly whereby all the structures of the digit are overgrown as a whole, there is tumourous enlargement of a single tissue element. Most of the tumors (95%) are benign and they may be classified according to the tissue of origin. Abnormal growth of vascular (hemangiomas, glomus tumors), osseous (enchondromas –multiple enchondromas as in Ollier disease-, osteoid osteomas, osteoblastomas, giant cell tumors, aneurysmal and unicameral bone cysts), neural (schwannomas, fibrolipomatous hamartomas, neurofibromas), cutaneous (mucous cysts, nodular fasciitis, pyogenic granulomas) and soft tissue (ganglions, lipomas, nodular tenosynovitis) elements cause localized masses of the hand and digits (Lin SJ et al., 2011).

Fibrolipomatous hamartoma is a rare, intraneural tumor characterized by fibrofatty infiltration around the nerve fascicles (Razzaghi & Anastakis, 2005). It is associated with macrodactyly due to overgrowth of bone and subcutaneous fat in more than one-third of the patients and it presents early in childhood with macrodactyly or later with a volar forearm mass and compressive neuropathy (Silverman & Enzinger, 1985, as cited in Razzaghi & Anastakis, 2005; Razzaghi & Anastakis, 2005).

Malignant tumors are rare. Primary malignant tumors may be of skin (most common site for malignant tumors), bone or soft tissue origin whereas metastatic tumors are mainly due to lung, kidney or head and neck cancers (Marrero IC et al., 2011).

### **3. Syndromes associated with macrodactyly**

#### **3.1 Proteus syndrome**

Proteus syndrome (MIM 176920) is a sporadic disorder that may be caused by a somatic alteration in a gene, that probably controls local production or regulation of tissue growth

Prenatal Sonographic Diagnosis and Evaluation of Isolated Macrodactyly 63

CLOVES syndrome (MIM 612918) is a disorder with complex truncal lipomatous mass, vascular malformations, epidermal nevi, acral deformities including large, wide feet and hands, macrodactyly and wide sandal gap and scoliosis and other musculoskeletal, neurologic, renal and cutaneous malformations (Alomari, 2009). Sapp et al. described 7 patients with progressive, primarily truncal vascular malformations, dysregulated adipose tissue, scoliosis and enlarged, but not severely distorted, bony structures without progressive overgrowth and designated the condition as a distinct entity, namely, CLOVE (Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi) syndrome (Sapp et al., 2007). They stated that bony distortion in these patients was limited to areas of the body that had undergone major surgery in contrast to patients with Proteus syndrome. Later in 2009, the acronym CLOVES syndrome was proposed to emphasize the association of Skeletal/Scoliosis and Spinal abnormalities with this syndrome (Alomari, 2009). Spinal-paraspinal fast-flow lesions within or adjacent to the truncal overgrowth or a cutaneous birthmark in 6 patients with CLOVES syndrome were also reported (Alomari

There is one case report regarding antenatal findings of a multicystic abdominal wall mass, asymmetry of the cerebral hemispheres and face in a fetus, where postnatal clinical and imaging findings led to the diagnosis of CLOVES syndrome (Fernandez-Pineda et al., 2010).

Klippel-Trenaunay-Weber (KTW) (MIM 149000) syndrome is a rare disorder associated with large cutaneous capillary and venous malformations with hypertrophy of the related bones and soft tissues. The cutaneous lesions include one or several port-wine stains over the affected limb and large venous ectatic vessels and vesicular lymphatic lesions. The lower extremity is more commonly involved. The enlargement of the limb is due to muscle hypertrophy, thickened skin, excessive subcutaneous fat, abnormal vascular tissue and occasionally lymphedema (Requena & Sangueza, 1997, as cited in Gonçalves et al., 2000). Hypoplasia or aplasia of the venous system is also a feature of the syndrome although it is

The mosaic pattern and occasional familial cases of KTW syndrome have been explained by paradominant inheritance, whereby heterozygous individuals for the single gene defect are phenotypically normal and the trait is expressed when a somatic mutation occurs in the normal allele at an early stage of embryogenesis (Happle, 1993, as cited in

Peng et al. have reviewed the prenatal findings of 21 cases with Klippel-Trenaunay-Weber syndrome involving the thigh until 2006. Asymmetric limb hypertrophy was the prominent prenatal finding and extensive involvement of other parts of the body such as the pelvis, abdomen, retroperitoneum or thorax was noted in around 70% of cases (Peng et al., 2006). Signs of high cardiac output probably due to the rapid development of numerous arteriovenous fistulas, such as cardiomegaly, polyhydramnios, non-immune hydrops fetalis

and thick placenta have also been reported (Paladini et al., 1998; Peng et al., 2006).

less commonly encountered (Jacob et al., 1998, as cited in Coombs at al., 2009).

**3.3 CLOVES syndrome** 

et al., 2011).

Gonçalves et al., 2000).

**3.4 Klippel-Trenaunay-Weber syndrome** 

factor receptors (Cohen MM Jr., 1993 and Samlaska et al., 1989, as cited in Jamis-Dow et al., 2004). The infants affected by the disorder usually appear normal or show only mildly asymmetric development at birth, but progressively develop the characteristic features of the syndrome during childhood. As the manifestations are highly variable, standard diagnostic criteria have been developed to minimise misdiagnosis (Biesecker et al., 1999, as cited in Jamis-Dow et al., 2004 ). Skeletal abnormalities such as macrodactyly, scoliosis, asymmetric overgrowth and limb length discrepancy, soft tissue abnormalities such as lipomas or regional absence of fat, asymmetric muscle development, connective tissue nevi and vascular malformations are common manifestations of the disease wheareas visceral anomalies such as splenomegaly, asymmetric megalencephaly, white matter abnormalities, nephromegaly, and masses other than fatty, muscular or vascular masses are uncommon (Jamis-Dow et al., 2004). Macrodactyly was encountered in 16 of 21 (76%) patients with Proteus syndrome in whom the diagnosis was based on standardized criteria (Jamis-Dow et al., 2004). Isolated macrodactyly has also been proposed as an extremely localized form of Proteus syndrome (van Bever & Hennekam, 1994).

Sigaudy et al. reported a prenatally diagnosed case of Proteus syndrome presenting with a large cystic mass on the right side of the abdomen and thorax and possible syndactyly of the fourth and fifth fingers at 26 weeks. The pregnancy was terminated at 28 weeks due to massive enlargement of the mass and autopsy revealed cystic lymphangioma on the right side, enlargement of the left arm, lateral deviation of the third to fifth fingers of the left hand with a large fixed gap between the second and the third finger, bilateral enlargement of the third toes, a small thymic cyst and left hemimegalencephaly confirming the diagnosis of Proteus syndrome (Sigaudy et al., 1998). Brasseur et al. reported a very similar case with antenatally diagnosed large, cervico-thoraco-brachial cystic lymphangioma at 22 weeks. After birth, macrodactyly of the first and second toes were noted and Proteus syndrome was diagnosed (Brasseur et al., 2009). Another prenatally diagnosed case with Proteus syndrome had a cystic enlargement of one limb and abnormal positioning of the toes (Richards et al., 1991, as cited in Sigaudy et al., 1998). These case reports show that severe cases of Proteus syndrome with early manifestations can be detected in utero. Most of the cases show at least one manifestation at birth and this finding can be either strongly suggestive of Proteus syndrome or more subtle (Sigaudy et al., 1998). Furthermore, as the phenotype develops over time, cases with apparently isolated findings such as macrodactyly may ultimately be diagnosed with Proteus syndrome (Lacombe & Battin, 1996, as cited in Sigaudy et al., 1998).

#### **3.2 Bannayan-Riley-Ruvalcaba syndrome**

Bannayan-Riley-Ruvalcaba (MIM 153480) syndrome is an autosomal dominant disorder, associated with mutations of the PTEN gene. Macrocephaly, lipomas, vascular malformations, intestinal polyps, and pigmented macules of the penis are the characteristic features of this syndrome. Macrodactyly of the right index finger along with a hamartoma of the small bowel mesentery with angiomatous, lipomatous and lymphangiomatous components has been reported by Zonana et al (Zonana et al., 1976).

There have been no reports regarding the prenatal diagnosis of Bannayan-Riley-Ruvalcaba syndrome; however, as it is characterized by hamartomatous changes leading to localized overgrowth, it may be included in the differential diagnosis of overgrowth syndromes like Proteus syndrome and macrodactyly (Jamis-Dow et al., 2004).

#### **3.3 CLOVES syndrome**

62 Prenatal Diagnosis – Morphology Scan and Invasive Methods

factor receptors (Cohen MM Jr., 1993 and Samlaska et al., 1989, as cited in Jamis-Dow et al., 2004). The infants affected by the disorder usually appear normal or show only mildly asymmetric development at birth, but progressively develop the characteristic features of the syndrome during childhood. As the manifestations are highly variable, standard diagnostic criteria have been developed to minimise misdiagnosis (Biesecker et al., 1999, as cited in Jamis-Dow et al., 2004 ). Skeletal abnormalities such as macrodactyly, scoliosis, asymmetric overgrowth and limb length discrepancy, soft tissue abnormalities such as lipomas or regional absence of fat, asymmetric muscle development, connective tissue nevi and vascular malformations are common manifestations of the disease wheareas visceral anomalies such as splenomegaly, asymmetric megalencephaly, white matter abnormalities, nephromegaly, and masses other than fatty, muscular or vascular masses are uncommon (Jamis-Dow et al., 2004). Macrodactyly was encountered in 16 of 21 (76%) patients with Proteus syndrome in whom the diagnosis was based on standardized criteria (Jamis-Dow et al., 2004). Isolated macrodactyly has also been proposed as an extremely localized form of

Sigaudy et al. reported a prenatally diagnosed case of Proteus syndrome presenting with a large cystic mass on the right side of the abdomen and thorax and possible syndactyly of the fourth and fifth fingers at 26 weeks. The pregnancy was terminated at 28 weeks due to massive enlargement of the mass and autopsy revealed cystic lymphangioma on the right side, enlargement of the left arm, lateral deviation of the third to fifth fingers of the left hand with a large fixed gap between the second and the third finger, bilateral enlargement of the third toes, a small thymic cyst and left hemimegalencephaly confirming the diagnosis of Proteus syndrome (Sigaudy et al., 1998). Brasseur et al. reported a very similar case with antenatally diagnosed large, cervico-thoraco-brachial cystic lymphangioma at 22 weeks. After birth, macrodactyly of the first and second toes were noted and Proteus syndrome was diagnosed (Brasseur et al., 2009). Another prenatally diagnosed case with Proteus syndrome had a cystic enlargement of one limb and abnormal positioning of the toes (Richards et al., 1991, as cited in Sigaudy et al., 1998). These case reports show that severe cases of Proteus syndrome with early manifestations can be detected in utero. Most of the cases show at least one manifestation at birth and this finding can be either strongly suggestive of Proteus syndrome or more subtle (Sigaudy et al., 1998). Furthermore, as the phenotype develops over time, cases with apparently isolated findings such as macrodactyly may ultimately be diagnosed with Proteus syndrome (Lacombe & Battin, 1996, as cited in Sigaudy et al., 1998).

Bannayan-Riley-Ruvalcaba (MIM 153480) syndrome is an autosomal dominant disorder, associated with mutations of the PTEN gene. Macrocephaly, lipomas, vascular malformations, intestinal polyps, and pigmented macules of the penis are the characteristic features of this syndrome. Macrodactyly of the right index finger along with a hamartoma of the small bowel mesentery with angiomatous, lipomatous and lymphangiomatous

There have been no reports regarding the prenatal diagnosis of Bannayan-Riley-Ruvalcaba syndrome; however, as it is characterized by hamartomatous changes leading to localized overgrowth, it may be included in the differential diagnosis of overgrowth syndromes like

components has been reported by Zonana et al (Zonana et al., 1976).

Proteus syndrome and macrodactyly (Jamis-Dow et al., 2004).

Proteus syndrome (van Bever & Hennekam, 1994).

**3.2 Bannayan-Riley-Ruvalcaba syndrome** 

CLOVES syndrome (MIM 612918) is a disorder with complex truncal lipomatous mass, vascular malformations, epidermal nevi, acral deformities including large, wide feet and hands, macrodactyly and wide sandal gap and scoliosis and other musculoskeletal, neurologic, renal and cutaneous malformations (Alomari, 2009). Sapp et al. described 7 patients with progressive, primarily truncal vascular malformations, dysregulated adipose tissue, scoliosis and enlarged, but not severely distorted, bony structures without progressive overgrowth and designated the condition as a distinct entity, namely, CLOVE (Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi) syndrome (Sapp et al., 2007). They stated that bony distortion in these patients was limited to areas of the body that had undergone major surgery in contrast to patients with Proteus syndrome. Later in 2009, the acronym CLOVES syndrome was proposed to emphasize the association of Skeletal/Scoliosis and Spinal abnormalities with this syndrome (Alomari, 2009). Spinal-paraspinal fast-flow lesions within or adjacent to the truncal overgrowth or a cutaneous birthmark in 6 patients with CLOVES syndrome were also reported (Alomari et al., 2011).

There is one case report regarding antenatal findings of a multicystic abdominal wall mass, asymmetry of the cerebral hemispheres and face in a fetus, where postnatal clinical and imaging findings led to the diagnosis of CLOVES syndrome (Fernandez-Pineda et al., 2010).

#### **3.4 Klippel-Trenaunay-Weber syndrome**

Klippel-Trenaunay-Weber (KTW) (MIM 149000) syndrome is a rare disorder associated with large cutaneous capillary and venous malformations with hypertrophy of the related bones and soft tissues. The cutaneous lesions include one or several port-wine stains over the affected limb and large venous ectatic vessels and vesicular lymphatic lesions. The lower extremity is more commonly involved. The enlargement of the limb is due to muscle hypertrophy, thickened skin, excessive subcutaneous fat, abnormal vascular tissue and occasionally lymphedema (Requena & Sangueza, 1997, as cited in Gonçalves et al., 2000). Hypoplasia or aplasia of the venous system is also a feature of the syndrome although it is less commonly encountered (Jacob et al., 1998, as cited in Coombs at al., 2009).

The mosaic pattern and occasional familial cases of KTW syndrome have been explained by paradominant inheritance, whereby heterozygous individuals for the single gene defect are phenotypically normal and the trait is expressed when a somatic mutation occurs in the normal allele at an early stage of embryogenesis (Happle, 1993, as cited in Gonçalves et al., 2000).

Peng et al. have reviewed the prenatal findings of 21 cases with Klippel-Trenaunay-Weber syndrome involving the thigh until 2006. Asymmetric limb hypertrophy was the prominent prenatal finding and extensive involvement of other parts of the body such as the pelvis, abdomen, retroperitoneum or thorax was noted in around 70% of cases (Peng et al., 2006). Signs of high cardiac output probably due to the rapid development of numerous arteriovenous fistulas, such as cardiomegaly, polyhydramnios, non-immune hydrops fetalis and thick placenta have also been reported (Paladini et al., 1998; Peng et al., 2006).

Prenatal Sonographic Diagnosis and Evaluation of Isolated Macrodactyly 65

fibrous facial plaques, and ungual fibromas, brain abnormalities like cortical tubers, subependymal nodules, astrocytomas causing seizures, intellectual disability, and mental retardation, renal anomalies such as angiomyolipomas and cysts, and cardiac rhabdomyomas (Northrup & Au, 1999). Bone changes also occur and macrodactyly has been reported in 11 patients with tuberous sclerosis complex (Aldrich et al., 2010; Ghalli, 2001; Norman-Taylor & Mayou, 1994; Sahoo et al., 2000; Sharma et al., 2011; Shin & Garay,1997; Tung & Shih, 2009; Kousseff, 1989, and Ortonne et al., 1982 and Wallis & Beighton, 1989, and Zaremba, 1968, as cited in Norman-Taylor & Mayou, 1994). Mesodermal dysplasia as a component of tuberous sclerosis complex is postulated to be responsible for the macrodactyly (Sahoo et al., 2000) and overgrowth of the tissues and bones of the forearm

and wrist has also been reported (Webb et al., 1996, as cited in Sahoo et al., 2000 ).

second left toe was present at birth.

diagnosis has not been reported.

**3.8 Milroy disease** 

2010).

**3.7 Ollier disease and Maffucci syndrome** 

bony structures are of normal size in Milroy disease .

the disease, it may be considered in the differential diagnosis.

The cases of tuberous sclerosis complex with macrodactyly were mainly in the infancy and childhood age group and in most of them the diagnosis of tuberous sclerosis was clinically obvious (Norman-Taylor & Mayou, 1994). The case reported by Sharma et al. developed macrodactyly of the index and middle finger of the right hand at 9 nine months of age along with a fibrous hamartoma at his right wrist whereas in Ghalli's case macrodactyly of the

Cardiac rhabdomyomas, arrhythmias, cerebral lesions such as cortical tubers and subependymal nodules, hydrops, and stillbirth are the most prevalent findings in the fetus (Isaacs, 2009). Although there are no reports of prenatal diagnosis of macrodactyly associated with tuberous sclerosis, regarding the highly variable phenotypic expression of

Ollier disease and Maffucci syndrome (MIM 166000) are rare, sporadic disorders characterized by multiple enchondromas of primarily small bones of the hands and feet, the long tubular bones, and also the flat bones like the pelvis. Maffucci syndrome is also associated with hemangiomas of the skin, mucosa and internal organs (Casal et al.,

These two entities usually become manifest during childhood and adolescence and prenatal

Milroy disease (MIM 153100) is a rare, autosomal dominant disorder characterized by lymphedema of the lower extremities, either of the whole leg or limited to the feet or toes (Lev-Sagie et al., 2003). Although the associated localized overgrowth may mimic the clinical picture of macrodactyly, it is differentiated easily from true macrodactyly since the

Prenatal diagnosis of Milroy disease has previously been reported; with edema of the dorsum of both feet in two cases, bilateral leg edema and hydrothorax in one case and bilateral edema of the lower extremities most marked in the calves and feet in another case (Lev-Sagie et al., 2003; Makhoul et al., 2002; Franceschini et al., 2001). Lymphedema has been

There are two case reports demonstrating the association of Klippel-Trenaunay syndrome with macrodactyly. The first one presented antenatally with multiple distorted cystic areas involving the right leg and abdomen and cardiomegaly with early fetal heart failure who was found to have bilateral macrodactyly of the second toe as well after birth (Zoppi et al., 2001). The second one is a fetus with marked lower limb edema, cystic areas in the abdomen/pelvis/lower limbs and abnormal development of the feet demonstrating bilateral hypoplasia of the femoral and popliteal veins in whom postnatal clinical evaluation also revealed right foot hemihypertrophy/syndactyly and left hallux hypertrophy (Coombs at al., 2009).

### **3.5 Neurofibromatosis type 1**

Neurofibromatosis type 1 (NF1) (MIM 162200) is a relatively common, autosomal dominant multisystem disorder that affects around one in 3500 individuals. Nearly half of the cases occur as a result of a new mutation (Freidman, 1998, as cited in McEwing et al., 2006) and expressivity is highly variable even among family members who carry the same mutation (Korf & Rubenstein, 2005, and Riccardi & Lewis, 1998, as cited in Boyd et al., 2009). It is characterized by cafe-au-lait macules, neurofibromas (plexiform neurofibroma being pathognomonic), axillary or inguinal freckling, optic glioma, iris hamartomas (Lisch nodules), and osseus lesions such as sphenoid dysplasia or thinning of long bone cortex. Macrodactyly in patients with neurofibromatosis is due to plexiform neurofibroma; it may be bilateral and involvement of the distal phalanx may not be as prominent as in true macrodactyly (Goldman & Kaye, 1977).

The prenatal diagnosis is very unlikely as the neonatal clinical features are usually solitary and cutaneous such as cafe-au-lait macules (McEwing et al., 2006) and spesific clinical findings increase in frequency with age (Freidman, 1998, as cited in McEwing et al., 2006). Nevertheless, there are a few cases with early and severe prenatal manifestations proven to be associated with neurofibromatosis postnatally. McEwing et al. reported a case presenting with a large oropharyngeal tumor, macrocephaly, ventriculomegaly, cardiomegaly, pleural and pericardial effusion, ascites and polyhydramnios. There was a positive paternal history of NF1 and after termination of pregnancy at 32 weeks, postmortem histologic evaluation was consistent with plexiform neurofibroma, confirming the diagnosis (McEwing et al., 2006). Another similar fetus with an oral tumor was also found to have NF1 postnatally (Hoyme et al., 1987, as cited in McEwing et al., 2006). Lastly, Drouin et al. reported a fetus with ambiguous genitalia, macrocephaly, shortened long bones and polyhydramnios in whom postnatal evaluation demonstrated a large abdominopelvic tumor and skeletal abnormalities consistent with NF1 (Drouin et al, 1997, as cited in McEwing et al., 2006).

#### **3.6 Tuberous sclerosis**

Tuberous sclerosis (MIM 191100/191092) is an autosomal dominant, hamartomatous disorder with variable expressivity. It affects about 1/6000 to 1/10000 live births and two thirds of the cases are considered to result from *de novo* mutations. It is associated with skin abnormalities such as hypomelanotic macules, facial angiofibromas, shagreen patches, fibrous facial plaques, and ungual fibromas, brain abnormalities like cortical tubers, subependymal nodules, astrocytomas causing seizures, intellectual disability, and mental retardation, renal anomalies such as angiomyolipomas and cysts, and cardiac rhabdomyomas (Northrup & Au, 1999). Bone changes also occur and macrodactyly has been reported in 11 patients with tuberous sclerosis complex (Aldrich et al., 2010; Ghalli, 2001; Norman-Taylor & Mayou, 1994; Sahoo et al., 2000; Sharma et al., 2011; Shin & Garay,1997; Tung & Shih, 2009; Kousseff, 1989, and Ortonne et al., 1982 and Wallis & Beighton, 1989, and Zaremba, 1968, as cited in Norman-Taylor & Mayou, 1994). Mesodermal dysplasia as a component of tuberous sclerosis complex is postulated to be responsible for the macrodactyly (Sahoo et al., 2000) and overgrowth of the tissues and bones of the forearm and wrist has also been reported (Webb et al., 1996, as cited in Sahoo et al., 2000 ).

The cases of tuberous sclerosis complex with macrodactyly were mainly in the infancy and childhood age group and in most of them the diagnosis of tuberous sclerosis was clinically obvious (Norman-Taylor & Mayou, 1994). The case reported by Sharma et al. developed macrodactyly of the index and middle finger of the right hand at 9 nine months of age along with a fibrous hamartoma at his right wrist whereas in Ghalli's case macrodactyly of the second left toe was present at birth.

Cardiac rhabdomyomas, arrhythmias, cerebral lesions such as cortical tubers and subependymal nodules, hydrops, and stillbirth are the most prevalent findings in the fetus (Isaacs, 2009). Although there are no reports of prenatal diagnosis of macrodactyly associated with tuberous sclerosis, regarding the highly variable phenotypic expression of the disease, it may be considered in the differential diagnosis.

### **3.7 Ollier disease and Maffucci syndrome**

Ollier disease and Maffucci syndrome (MIM 166000) are rare, sporadic disorders characterized by multiple enchondromas of primarily small bones of the hands and feet, the long tubular bones, and also the flat bones like the pelvis. Maffucci syndrome is also associated with hemangiomas of the skin, mucosa and internal organs (Casal et al., 2010).

These two entities usually become manifest during childhood and adolescence and prenatal diagnosis has not been reported.

#### **3.8 Milroy disease**

64 Prenatal Diagnosis – Morphology Scan and Invasive Methods

There are two case reports demonstrating the association of Klippel-Trenaunay syndrome with macrodactyly. The first one presented antenatally with multiple distorted cystic areas involving the right leg and abdomen and cardiomegaly with early fetal heart failure who was found to have bilateral macrodactyly of the second toe as well after birth (Zoppi et al., 2001). The second one is a fetus with marked lower limb edema, cystic areas in the abdomen/pelvis/lower limbs and abnormal development of the feet demonstrating bilateral hypoplasia of the femoral and popliteal veins in whom postnatal clinical evaluation also revealed right foot hemihypertrophy/syndactyly and left hallux hypertrophy (Coombs

Neurofibromatosis type 1 (NF1) (MIM 162200) is a relatively common, autosomal dominant multisystem disorder that affects around one in 3500 individuals. Nearly half of the cases occur as a result of a new mutation (Freidman, 1998, as cited in McEwing et al., 2006) and expressivity is highly variable even among family members who carry the same mutation (Korf & Rubenstein, 2005, and Riccardi & Lewis, 1998, as cited in Boyd et al., 2009). It is characterized by cafe-au-lait macules, neurofibromas (plexiform neurofibroma being pathognomonic), axillary or inguinal freckling, optic glioma, iris hamartomas (Lisch nodules), and osseus lesions such as sphenoid dysplasia or thinning of long bone cortex. Macrodactyly in patients with neurofibromatosis is due to plexiform neurofibroma; it may be bilateral and involvement of the distal phalanx may not be as prominent as in true

The prenatal diagnosis is very unlikely as the neonatal clinical features are usually solitary and cutaneous such as cafe-au-lait macules (McEwing et al., 2006) and spesific clinical findings increase in frequency with age (Freidman, 1998, as cited in McEwing et al., 2006). Nevertheless, there are a few cases with early and severe prenatal manifestations proven to be associated with neurofibromatosis postnatally. McEwing et al. reported a case presenting with a large oropharyngeal tumor, macrocephaly, ventriculomegaly, cardiomegaly, pleural and pericardial effusion, ascites and polyhydramnios. There was a positive paternal history of NF1 and after termination of pregnancy at 32 weeks, postmortem histologic evaluation was consistent with plexiform neurofibroma, confirming the diagnosis (McEwing et al., 2006). Another similar fetus with an oral tumor was also found to have NF1 postnatally (Hoyme et al., 1987, as cited in McEwing et al., 2006). Lastly, Drouin et al. reported a fetus with ambiguous genitalia, macrocephaly, shortened long bones and polyhydramnios in whom postnatal evaluation demonstrated a large abdominopelvic tumor and skeletal abnormalities consistent with

Tuberous sclerosis (MIM 191100/191092) is an autosomal dominant, hamartomatous disorder with variable expressivity. It affects about 1/6000 to 1/10000 live births and two thirds of the cases are considered to result from *de novo* mutations. It is associated with skin abnormalities such as hypomelanotic macules, facial angiofibromas, shagreen patches,

at al., 2009).

**3.5 Neurofibromatosis type 1** 

macrodactyly (Goldman & Kaye, 1977).

**3.6 Tuberous sclerosis** 

NF1 (Drouin et al, 1997, as cited in McEwing et al., 2006).

Milroy disease (MIM 153100) is a rare, autosomal dominant disorder characterized by lymphedema of the lower extremities, either of the whole leg or limited to the feet or toes (Lev-Sagie et al., 2003). Although the associated localized overgrowth may mimic the clinical picture of macrodactyly, it is differentiated easily from true macrodactyly since the bony structures are of normal size in Milroy disease .

Prenatal diagnosis of Milroy disease has previously been reported; with edema of the dorsum of both feet in two cases, bilateral leg edema and hydrothorax in one case and bilateral edema of the lower extremities most marked in the calves and feet in another case (Lev-Sagie et al., 2003; Makhoul et al., 2002; Franceschini et al., 2001). Lymphedema has been

Prenatal Sonographic Diagnosis and Evaluation of Isolated Macrodactyly 67

associated with several other syndromes in early childhood such as lymphedema-distichiasis, Cholestasis-Lymphedema Syndrome (Aagenaes Syndromes) and Hennekam syndrome.

The main features of above named syndromes associated with macrodactyly are

In addition to these syndromes which are well-known and more frequent, macrodactyly as a feature of several other rare conditions has also been observed. In this context, macrodactyly has been reported in association with minor tibial duplication (Adamsbaum et al., 1991), benign lipoblastomatosis with the relationship of this condition to Proteus syndrome being unclear (Colot et al., 1984), terminal osseous dysplasia with pigmentary defects (Brunetti-Pieri et al., 2010), macrocephaly-capillary malformation syndrome (reported as enlarged hands in one case) (Barnicoat et al., 1996), segmentary fibrous dysplasia (Keymolen et al., 1999) and a lethal skeletal dysplasia associated with ectopic digits (Morton et al., 1998). These conditions have overlapping features such as overgrowth and vascular malformations with well defined syndromes like Proteus syndrome and therefore, they should be kept in

Although the majority of cases with macrodactyly are isolated, prenatal recognition of an enlarged digit mandates thorough evaluation of all systems in search for associated anomalies which may indicate syndromic involvement. Moreover, serial scans are recommended as some of the features such as hemihypertrophy may develop over time and indirect signs such as cardiac overload or hydrops fetalis may lead to recognition of an additional finding. In addition, fetal magnetic resonance imaging may be considered in cases with associated anomalies, although its contribution is controversial. As macrodactyly can be a clinical finding in several autosomal dominantly inherited disorders such as neurofibromatosis, tuberous sclerosis, Bannayan-Riley-Ruvalcaba syndrome and Milroy disease, family history and examination of further family members, prospect mother and father being the first ones to be evaluated, are mandatory to reveal the familial occurrence of a further case (Yüksel et al., 2009). Amniotic band syndrome, which causes swelling and edema distal to the point of constriction, should also be included in the differential

A practical algorythym for the prenatal evaluation of macrodactyly is depicted in Fig. 2. Further case reports/series and information on the outcome of isolated and syndromic macrodactyly cases will help to improve the evaluation and management of this entity.

It could be speculated that the most critical aspect in the management of isolated macrodactyly is its possible association with a syndrome which could become evident later in childhood, and emphasizing this possibility is mandatory when counselling the parents. Knowing that there is a significant clinical overlap between the overgrowth syndromes and that the phenotype may well develop in time, postnatal follow-up of the newborn during the first decade on a yearly basis by a multidisciplinary team consisting of a geneticist, dermatologist and orthopedic surgeon should be considered and the parents should be

mind for the differential diagnosis of syndromic macrodactyly.

diagnosis of prenatally diagnosed macrodactyly (Yüksel et al., 2009).

summarized in Table 1.

**4. Conclusion** 

counselled accordingly.


Table 1. Characteristics of syndromes associated with macrodactyly.

associated with several other syndromes in early childhood such as lymphedema-distichiasis, Cholestasis-Lymphedema Syndrome (Aagenaes Syndromes) and Hennekam syndrome.

The main features of above named syndromes associated with macrodactyly are summarized in Table 1.

In addition to these syndromes which are well-known and more frequent, macrodactyly as a feature of several other rare conditions has also been observed. In this context, macrodactyly has been reported in association with minor tibial duplication (Adamsbaum et al., 1991), benign lipoblastomatosis with the relationship of this condition to Proteus syndrome being unclear (Colot et al., 1984), terminal osseous dysplasia with pigmentary defects (Brunetti-Pieri et al., 2010), macrocephaly-capillary malformation syndrome (reported as enlarged hands in one case) (Barnicoat et al., 1996), segmentary fibrous dysplasia (Keymolen et al., 1999) and a lethal skeletal dysplasia associated with ectopic digits (Morton et al., 1998). These conditions have overlapping features such as overgrowth and vascular malformations with well defined syndromes like Proteus syndrome and therefore, they should be kept in mind for the differential diagnosis of syndromic macrodactyly.

### **4. Conclusion**

66 Prenatal Diagnosis – Morphology Scan and Invasive Methods

Proteus syndrome Sporadic Macrodactyly, asymmetric overgrowth

CLOVES syndrome Sporadic Complex truncal lipomatous mass,

**Common manifestations**

and limb length discrepancy, vertebral abnormalities, soft tissue abnormalities,

malformations, visceral anomalies such

vascular malformations, epidermal nevi, acral deformities including large, wide feet and hands, macrodactyly, and wide

musculoskeletal, neurologic, renal and

Cafe-au-lait macules, neurofibromas, axillary or inguinal freckling, optic glioma, iris hamartomas (Lisch nodules),

dysplasia or thinning of long bone cortex

angiofibromas, shagreen patches, fibrous facial plaques, ungual fibromas, brain abnormalities like cortical tubers, subependymal nodules, and

astrocytomas, renal anomalies such as angiomyolipomas and cysts, cardiac

Lymphedema of the lower extremities

osseus lesions such as sphenoid

Hypomelanotic macules, facial

rhabdomyomas

connective tissue nevi, vascular

as splenomegaly, asymmetric megalencephaly, white matter abnormalities and nephromegaly

Macrocephaly, lipomas, vascular malformations, intestinal polyps, pigmented macules of the penis

sandal gap, scoliosis and other

Cutaneous capillary and venous malformations with hypertrophy of the

related bones and soft tissues, hypoplasia or aplasia of the venous

cutaneous malformations

system

**Inheritance**

Autosomal dominant/*de novo*

Paradominant inheritance

Autosomal dominant/*de novo*

mutation

mutation

dominant/*de novo*

dominant/*de novo*

mutation

Table 1. Characteristics of syndromes associated with macrodactyly.

Ollier disease Sporadic Enchondromas, cerebral tumors

Maffucci syndrome Sporadic Enchondromas, vascular malformations

mutation

**Syndrome Mode of** 

Bannayan-Riley-Ruvalcaba syndrome

Klippel-Trenaunay-Weber syndrome

Neurofibromatosis

Tuberous sclerosis Autosomal

Milroy disease Autosomal

type 1

Although the majority of cases with macrodactyly are isolated, prenatal recognition of an enlarged digit mandates thorough evaluation of all systems in search for associated anomalies which may indicate syndromic involvement. Moreover, serial scans are recommended as some of the features such as hemihypertrophy may develop over time and indirect signs such as cardiac overload or hydrops fetalis may lead to recognition of an additional finding. In addition, fetal magnetic resonance imaging may be considered in cases with associated anomalies, although its contribution is controversial. As macrodactyly can be a clinical finding in several autosomal dominantly inherited disorders such as neurofibromatosis, tuberous sclerosis, Bannayan-Riley-Ruvalcaba syndrome and Milroy disease, family history and examination of further family members, prospect mother and father being the first ones to be evaluated, are mandatory to reveal the familial occurrence of a further case (Yüksel et al., 2009). Amniotic band syndrome, which causes swelling and edema distal to the point of constriction, should also be included in the differential diagnosis of prenatally diagnosed macrodactyly (Yüksel et al., 2009).

A practical algorythym for the prenatal evaluation of macrodactyly is depicted in Fig. 2. Further case reports/series and information on the outcome of isolated and syndromic macrodactyly cases will help to improve the evaluation and management of this entity.

It could be speculated that the most critical aspect in the management of isolated macrodactyly is its possible association with a syndrome which could become evident later in childhood, and emphasizing this possibility is mandatory when counselling the parents. Knowing that there is a significant clinical overlap between the overgrowth syndromes and that the phenotype may well develop in time, postnatal follow-up of the newborn during the first decade on a yearly basis by a multidisciplinary team consisting of a geneticist, dermatologist and orthopedic surgeon should be considered and the parents should be counselled accordingly.

Prenatal Sonographic Diagnosis and Evaluation of Isolated Macrodactyly 69

Boyd KP, Korf BR & Theos A. Neurofibromatosis type 1. *J Am Acad Dermatol*. 2009 Jul;61(1):1-14. Brasseur A, Seryer D, Plancq MC, Krim G, Lanta S & Le Blanche A. [Thoraco-brachial cystic

Brunetti-Pierri N, Lachman R, Lee K, Leal SM, Piccolo P, Van Den Veyver IB &Bacino CA.

Coombs PR, James PA & Edwards AG. Sonographic identification of lower limb venous

Fernandez-Pineda I, Fajardo M, Chaudry G & Alomari AI. Perinatal clinical and imaging features of CLOVES syndrome. *Pediatr Radiol*. 2010 Aug;40(8):1436-9. Franceschini P, Licata D, Rapello G, Guala A, Di Cara G & Franceschini D. Prenatal diagnosis of Nonne-Milroy lymphedema. *Ultrasound Obstet Gynecol*. 2001 Aug;18(2):182-3. Ghalli FE. Macrodactyly in tuberous sclerosis. *Pediatr Dermatol.* 2001 Jul-Aug;18(4):364-5. Goldman AB & Kaye JJ. Macrodystrophia lipomatosa: radiographic diagnosis. *AJR Am J* 

Gonçalves LF, Rojas MV, Vitorello D, Pereira ET, Pereima M & Saab Neto JA. Klippel-

Jamis-Dow CA, Turner J, Biesecker LG & Choyke PL. Radiologic manifestations of Proteus

Keymolen K, De Smet L, Kenis H &Fryns JP. Segmentary fibrous dysplasia manifesting as

Krengel S, Fustes-Morales A, Carrasco D, Vázquez M, Durán-McKinster C & Ruiz-

Lev-Sagie A, Hamani Y, Raas-Rothschild A, Yagel S & Anteby EY. Prenatal ultrasonographic

Lin SJ et al., (updated May 18, 2011). Benign Hand Tumors, In: *Medscape,* January 10, 2012,Available from: http://emedicine.medscape.com/article/1286448-overview Makhoul IR, Sujov P, Ghanem N & Bronshtein M. Prenatal diagnosis of Milroy's primary

Marrero IC et al., (updated Nov 17, 2011). Malignant Hand Tumors, In: *Medscape,* January 10, 2012, Available from: http://emedicine.medscape.com/article/1286560-overview McEwing RL, Joelle R, Mohlo M, Bernard JP, Hillion Y & Ville Y. Prenatal diagnosis of

Maldonado R. Macrodactyly: report of eight cases and review of the literature.

diagnosis of atypical Nonne-Milroy lymphedema. *Ultrasound Obstet Gynecol*. 2003

neurofibromatosis type 1: sonographic and MRI findings. *Prenat Diagn*. 2006

syndrome. *Radiographics*. 2004 Jul-Aug;24(4):1051-68. Review.

Kotwal PP & Farooque M. Macrodactyly. *J Bone Joint Surg Br.* 1998 Jul;80(4):651-3.

congenital lymphedema. *Prenat Diagn*. 2002 Sep;22(9):823-6.

macrodactyly. *Genet Couns.* 1999;10(4):373-6.

*Pediatr Dermatol*. 2000 Jul-Aug;17(4):270-6.

Trenaunay-Weber syndrome presenting as massive lymphangiohemangioma of the thigh: prenatal diagnosis. *Ultrasound Obstet Gynecol.* 2000 Jun;15(6):537-41. Review. Isaacs H. Perinatal (fetal and neonatal) tuberous sclerosis: a review. *Am J Perinatol*. 2009

lymphangioma and Proteus syndrome: prenatal diagnosis and MR follow-up]. *J* 

Terminal osseous dysplasia with pigmentary defects (TODPD): Follow-up of the first reported family, characterization of the radiological phenotype, and refinement of the linkage region. *Am J Med Genet A*. 2010 Jul;152A(7):1825-31. Casal D, Mavioso C, Mendes MM & Mouzinho MM. Hand involvement in Ollier Disease and Maffucci Syndrome: a case series. *Acta Reumatol Port*. 2010 Jul-Sep;35(3):375-8. Colot G, Castermans-Elias S &Philippet G. Macrodactyly associated with benign

hypoplasia in the prenatal diagnosis of Klippel-Trénaunay syndrome. *Ultrasound* 

Barsky AJ. Macrodactyly. *J Bone Joint Surg Am.* 1967 Oct;49(7):1255-66.

lipoblastomatosis. *Ann Chir Main.* 1984;3(3):262-5.

*Radiol.* 2009 May;90(5 Pt 1):608-11.

*Obstet Gynecol*. 2009 Dec;34(6):727-9.

*Roentgenol.* 1977 Jan;128(1):101-5.

Nov;26(10):755-60.

Jan;21(1):72-4.

Dec;26(12):1110-4.

\* Associated anomalies may become overt postnatally and may ultimately lead to the diagnosis of a specific syndrome associated with macrodactyly

\*\* Prenatal diagnosis has not been reported previously.

Fig. 2. Algorythym for the management and work-up for differential diagnosis of prenatal finding of macrodactyly.

#### **5. References**


\* Associated anomalies may become overt postnatally and may ultimately lead to the diagnosis of a

Fig. 2. Algorythym for the management and work-up for differential diagnosis of prenatal

Adamsbaum C, Kalifa G, Seringe R & Bonnet JC. Minor tibial duplication: a new cause of

Aldrich CS, Hong CH, Groves L, Olsen C, Moss J & Darling TN. Acral lesions in tuberous

Alomari AI. Characterization of a distinct syndrome that associates complex truncal

Alomari AI, Chaudry G, Rodesch G, Burrows PE, Mulliken JB, Smith ER, Fishman SJ &

Barnicoat A, Salman M, Chitty L &Baraitser M. A distinctive overgrowth syndrome with

sclerosis complex: insights into pathogenesis. *J Am Acad Dermatol*. 2010 Aug;63(2):244-51.

overgrowth, vascular, and acral anomalies: a descriptive study of 18 cases of

Orbach DB. Complex Spinal-Paraspinal Fast-Flow Lesions in CLOVES Syndrome: Analysis of Clinical and Imaging Findings in 6 Patients. *AJNR Am J Neuroradiol*.

congenital bowing of the tibia. *Pediatr Radiol*. 1991;21(3):185-8.

CLOVES syndrome. *Clin Dysmorphol.* 2009 Jan;18(1):1-7.

polysyndactyly. Clin Dysmorphol. 1996 Oct;5(4):339-46.

specific syndrome associated with macrodactyly \*\* Prenatal diagnosis has not been reported previously.

finding of macrodactyly.

2011 Feb 10.

**5. References** 

Barsky AJ. Macrodactyly. *J Bone Joint Surg Am.* 1967 Oct;49(7):1255-66.

Boyd KP, Korf BR & Theos A. Neurofibromatosis type 1. *J Am Acad Dermatol*. 2009 Jul;61(1):1-14.


**5** 

*Turkey* 

**Prenatal Evaluation of Fetuses** 

**Presenting with Short Femurs** 

Funda Gungor Ugurlucan1, Hülya Kayserili2 and Atil Yuksel1

*2Department of Medical Genetics, Istanbul Medical Faculty Istanbul University* 

*1Department of Obstetrics and Gynecology, Istanbul Medical Faculty Istanbul University* 

Femur length (FL) is the measurement between the distal and proximal ossification centers of the femoral diaphysis. FL is one of the fetal biometry measurements which is measured ordinarily during the routine second trimester scanning and onwards in determining the

gestational age and growth between ultrasound examinations.

Fig. 1. The scan showing the correct FL measurement

**1. Introduction** 

