*3.2.2 Clinical manifestations*

Patients with PLS present first clinical signs in the oral cavity as soon as the deciduous teeth erupt [34, 36]. Oral manifestations become apparent by the age of 2 to 3 years with rapid periodontal destruction: plaque accumulation, obvious gingival inflammation and bleeding, periodontal abscess, deep periodontal pocket formation, alveolar bone resorption, loose teeth, halitosis, following by premature exfoliation of all deciduous teeth by the age of 4 to 5 years (**Figure 7**) [38]. Radiographic investigations show generalized alveolar bone loss and migration of teeth whit no evidence of root resorption (**Figure 8**). Inflammation disappears during the edentulous period, but the disease process reappears when permanent dentition erupts, with the affected losing most of the teeth at teenage (**Figure 9**).

PLS is characterized by development of hyperkeratosis or dry scaly skin patches at early age of one to five years old. These patches usually confined to palms and

#### **Figure 7.**

*Oral manifestations of a Papillon-Lefèvre syndrome (PLS) patient (3 years) with serious periodontitis (A) and her fraternal twin sister with healthy periodontal tissue (B).*

#### **Figure 8.**

*Panoramic radiographs of the PLS patient in Figure 7 when she was 3–5, or 8 years old.*

#### **Figure 9.**

*Flow chart of oral manifestations of PLS.*

soles, but may spread to knees and elbows. In rare occasions, upper portions of hands and feet, eyelids, lips, cheeks, and/or other bodily surfaces may also be affected. Affected skin may appear unusually thick and red, but variation in texture and color is possible. Skin lesions may worsen upon exposure to cold which lead to pain upon movement like walking. Other symptoms that may accompany the condition are hyperhidrosis, nail dystrophy, cranial calcification, and increased susceptibility to infections. Most patients show susceptibility to mild skin infections like pyodermas or furunculosis. Severe infections like pyogenic liver abscess or pneumonia, and malignancies like melanoma have been reported in PLS patients [34, 42, 43].

#### *3.2.3 Diagnosis*

Early diagnosis and prompt treatment can potentially prevent aggressive periodontitis, tooth loss, and improve overall quality of life of patients with PLS [34, 36, 44]. PLS becomes clinically apparent at 1–5 years old; palmar-plantar hyperkeratosis or dry scaly patches of palms and soles, together with severe, aggressive, or rapidly progressing periodontitis are considered its main clinical features, with or without additional symptoms like pyogenic skin infections, nail dystrophies, and hyperhidrosis. Radiographic examination of advanced PLS cases reveal severe loss of the alveolar bone, and teeth appear to be "floating in air" (**Figure 8**).

#### *Periodontal Disease Associated with Genetic Disorders DOI: http://dx.doi.org/10.5772/intechopen.97497*

Differential diagnoses should include Haim-Munk syndrome, Chediak-Higashi syndrome, juvenile periodontitis, and so on (**Table 1**). Haim-Munk syndrome (HMS) is a skin condition caused by *CTSC* mutation. It is an extremely rare disorder of keratinization of recessive inheritance that manifests with scaly, red, and thickened patches of the skin of soles of the feet and palms of the hands, pes planus, arachnodactyly, acroosteolysis, atrophic changes of nails, a radiographic deformity of fingers, recurrent abscess formations, and a severe 'early-onset' periodontitis [45].

Neutrophil function tests reveal anomalies of chemotaxis and phagocytosis by polymorphonuclear leukocytes. Skin biopsy shows hyperkeratosis with focal parakeratosis, moderate perivascular infiltration, hypergranulosis, and acanthosis. Biochemical analysis reveals a loss of *CTSC* activity. Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect alterations in the *CTSC* gene known to cause PLS, but is available only as a diagnostic service at specialized laboratories [36, 44].

#### *3.2.4 Treatment*

A multidisciplinary approach involving the dermatologist, pediatrician, pediatric dentist, periodontist, and prosthodontist is important for the overall care of patient with PLS [34, 46]. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support is recommended for the entire family as well. Oral retinoids with aims to attenuate palmoplantar keratoderma and to diminish alveolar bone lysis remained the main line of the therapy. Oral hygiene, chemical plaque control with or without antibiotics are the recommended therapeutic protocol for reducing periodontitis progression. Eventually, primary or terminally periodontal involved teeth are extracted. Antibiotic therapy is also used in the treatment of recurrent infections. Etretinate (a synthetic retinoid) shows promising results in the treatment of PLS.

Successful periodontal management of PLS patients is the key to improve the prognosis of the dentition, preventing or delaying primary and permanent tooth loss. During the past decades, dental treatment efforts other than extraction have been attempted in PLS patients. Several articles have been published on the treatment of PLS. Ullbro et al. proposed a mode of periodontal therapy of patients with PLS [47] (**Table 2**).


#### **Table 2.**

*Suggested mode of periodontal therapy for patients with Papillon-Lefèvre syndrome (PLS). Adopted from Ullbro et al. [47].*

Most PLS patients ended up edentulous at an early age and were presented with rehabilitation problems due to severely atrophic thin alveolar ridges. Various preprosthetic surgical management approaches are introduced to maximize retention and stability of dentures. Along such line, dental implants are also advocated for enhancing stability and retention of prosthesis, improving comfort, masticatory efficiency and perhaps esthetics. Reports concerning installation of titanium implants in PLS patients with treated severe periodontitis to support and retain oral reconstructions indicated under good care and dedications in prevention or oral health maintenance, indicated the approach could be successful [48, 49].

#### *3.2.5 Genetic counseling*

Transmission is autosomal recessive. Genetic counseling should be offered to the parents of an affected individual informing them that 25% of their future offspring could inherit the disease-causing mutation.

#### *3.2.6 Prognosis*

Despite meticulous dental care, PLS patients eventually become edentulous at the beginning of adulthood while their life expectancy is normal [32, 42, 46].

#### **3.3 Cyclic neutropenia**

Neutropenia (absolute neutrophil count or ANC <sup>&</sup>lt;1.5 <sup>10</sup><sup>9</sup> /L), includes diagnoses ranging from normal variants like benign ethnic neutropenia to lifethreatening acquired or congenital disorders like agranulocytosis. The biological consequences depend mainly on neutropenia severity and corresponding responses from the affected individual: e.g. an ANC of 1.0–1.5 <sup>10</sup><sup>9</sup> /L does not normally impair host defense so far enough normally functioning neutrophils could be produced by bone marrow when needed, however the underlying cause of the low ANC need to be investigated; an ANC of 0.5–1.0 109 /L may increase infections risk but only if other immune defense element of the affected individual are also impaired; while an ANC of 0.2–0.5 <sup>10</sup><sup>9</sup> /L normally associates with increased infections risk in most patients, an ANC <sup>≤</sup>0.2 <sup>10</sup><sup>9</sup> /L, i.e. agranulocytosis, often implies susceptibility to opportunistic infection with high risk of severe, life threatening consequences [50].

Cyclic neutropenia (CN), first described in 1910 based on the recurrence of neutropenia, fever, and mouth ulcers in a 19-month-old boy, is a rare hematologic disease characterized by regular oscillations in blood neutrophil counts from normal levels (ANC <sup>&</sup>gt; 1.5 <sup>10</sup><sup>9</sup> /L) to severe neutropenia (ANC <sup>&</sup>lt; 0.2 <sup>10</sup><sup>9</sup> /L), usually with a cycle length of about 21 days, and lasts for 3–6 days at a time [51]. It has been designated by such terms as "cyclic hematopoiesis", "human cyclic neutropenia", and "periodic neutropenia". During intervals of neutropenia, affected patients exhibit fever, mouth ulcers and are at risk for opportunistic infection. CN affects males and females in equal numbers, and the prevalence is unknown. Most cases of CN are thought to be present at birth (congenital); however, in some cases, the diagnosis may not become obvious until childhood, adolescence, or early adulthood [52, 53].

#### *3.3.1 Etiology and pathogenesis*

As mentioned above, CN may be congenital or acquired. Congenital cases include sporadic CN without apparent causes [54, 55], inherited cases transmitted *Periodontal Disease Associated with Genetic Disorders DOI: http://dx.doi.org/10.5772/intechopen.97497*

in an autosomal dominant trait related to mutations in the elastase, neutrophil expressed or gene encoding neutrophil elastase. Heterozygous mutations in *ELANE* gene have been reported in a high frequency of single base pair/amino acid mutations and identified in 80–100% of patients with CN. Neutrophil elastase is synthesized and packaged in promyelocytes at an early stage in neutrophil development. Mutations in the *ELANE* gene induce unfolded protein response-associated apoptosis at the promyelocyte stage and result in ineffective myelopoiesis, and bone marrow fail to maintain consistent production of mature neutrophils. Severe neutropenia recurs when the bone marrow supply is exhausted [56, 57].
