Advertisement

Oral Signs of Genetic Disease

  • Julio C. Sartori-Valinotti
  • Jennifer L. HandEmail author
Chapter
  • 649 Downloads

Abstract

Many genetic disorders affect the oral mucous membranes. Several of these conditions are associated with late-onset complications with great impact in the individual’s overall life expectancy and quality of life. For example, patients with dyskeratosis congenita develop premalignant oral leukoplakia, and patients with osteogenesis imperfecta have severe dental anomalies necessitating early and specialized dental care. Most importantly, individuals with undiagnosed disease may undergo banal procedures with lethal consequences such as exsanguination following tooth extraction in patients with Hermansky-Pudlak syndrome. With recent advances in technology and improved screening tests, the opportunity to prevent such complications and improve life expectancy is greater than ever before.

This chapter focuses on the etiopathogenesis and clinical findings of specific genetic disorders with special emphasis on the oral manifestations. A brief discussion on current treatment approaches is also presented.

Keywords

Genodermatoses Oral disease Incontinentia pigmenti Pachyonychia congenita Dyskeratosis congenita Rothmund-Thomson syndrome Hereditary hemorrhagic telangiectasia Hermansky-Pudlak syndrome 

Incontinentia Pigmenti (Bloch-Sulzberger Syndrome)

Epidemiology

Incontinentia pigmenti (IP) is an ectodermal dysplasia with an estimated prevalence of 0.7 cases per 100,000 births, almost exclusively affecting females [1].

Etiopathogenesis

IP is an X-linked disease caused by mutation in the IKK-gamma gene (inhibitor of nuclear factor kappa-B kinase subunit gamma), previously known as NEMO, located on chromosome Xq28. Disruption, usually by deletion, of the IKK-gamma gene is responsible for downstream activation of cellular apoptosis. Programmed cell death in different tissues such as the skin, teeth, nails, eyes, skeleton, and central nervous system (CNS) accounts for the clinical manifestations of the disease. The disease is lethal in males, usually prenatally.

Clinical Manifestations

In affected females, the striking cutaneous findings evolve sequentially in four distinct, overlapping stages that follow developmental skin lines (Fig. 11.1): inflammatory vesicles, verrucous phase, hyperpigmentation, and finally hypopigmented linear or reticular lesions. The latter is due to epidermal atrophy and dermal scarring [2]. Mild, patchy alopecia is a common feature. Anomalies of the eyebrows and eyelashes have also been reported [3]. Dystrophic nail changes may vary from mild to severe [2]. Retinal abnormalities (telangiectasias, hemorrhages, neovascularization, disorders of the retinal pigment epithelium, etc.) may unexpectedly cause blindness in early childhood, and non-retinal abnormalities (microphthalmia, vitreous and lens anomalies) may present in the neonatal period [3, 4]. CNS complications of IP, present in up to 30–46% of patients, include microcephaly, mental retardation, motor incoordination, and seizures [5, 6]. Unilateral breast and nipple hypoplasia as well as supernumerary nipples may be seen [2].
Fig. 11.1

Female infant with cutaneous hyperpigmentation along developmental skin (Blaschko’s) lines, typical of incontinentia pigmenti

Oral Signs and Symptoms

The most comprehensive review of the oral and dental manifestations of IP included 1286 IP patients from 1993 to 2010. In this study, Minić and coworkers found that 54% of patients had dental and/or oral anomalies. Most recently, dental and/or oral changes have been regarded as the most important minor diagnostic criteria for IP. While dental changes are not appreciable until after tooth eruption, they are often the feature most concerning to parents, which brings the disorder to medical attention. Cleft and high-arched (gothic) palate present at birth and may aid in early diagnosis. Dental anomalies are, however, more common than oral anomalies in IP. In descending order of frequency, dental shape anomalies (coni- or peg-like teeth) (Fig. 11.2), hypodontia, and delayed dentition are the most common. Enamel and tooth strength are normal [7]. Other manifestations include extensive dental decay and early loss of dentition [8]. The mean number of missing permanent teeth is 5.9 [9]. In a small case series, salivary secretion was lower than normal in 43% of patients [10].
Fig. 11.2

Misshapen deciduous tooth in female infant with incontinentia pigmenti

Differential Diagnosis

Several skin disorders may present with cutaneous findings similar to IP. The differential diagnosis relies on the age/stage of the lesions. From an orodental perspective, abnormally-shaped teeth are seen in other forms of ectodermal dysplasias; extensive tooth loss and dental decay are seen in dyskeratosis congenita. Inflammatory periodontitis and premature loss of deciduous teeth are features of Papillon-Lefevre syndrome (PLS). The associated skin and oral (cleft and gothic palate) findings help distinguish IP from other genodermatoses.

Treatment Recommendations

Orthopedic and/or orthodontic repositioning of malpositioned teeth and bone expansion are recommended for subsequent prosthesis procedures [11, 12]. Early treatment is thought to improve self-esteem and nutrition. The National Foundation for Ectodermal Dysplasias (http://www.nfed.org) discusses strategies for affected families to obtain insurance coverage for necessary dental treatment.

Pachyonychia Congenita

Epidemiology

Pachyonychia congenital (PC) is a group of disorders unified by painful, plantar keratoderma [13] and characteristic, distinct nail changes with distal onycholysis, subungual hyperkeratosis that causes transverse arching of the distal nail plate, and yellow-brown discoloration [14] (Fig. 11.3). There is a paucity of data regarding the incidence and prevalence of the disease, but approximately 1000 cases have been published in the literature [1].
Fig. 11.3

Thickened nails with yellowish discoloration and transverse arching in a 6-year-old girl with pachyonychia congenita

Etiopathogenesis

PC is an autosomal dominant disorder. Keratins are structural proteins usually expressed in pairs [15]. The keratin pair K6b/K17 is expressed in nails and the palmoplantar surface. Mutations in either of these keratins cause PC type 2. Mutations in either K16 or K6a cause PC type 1 [15]. The genes for keratin 6a and 6b are on chromosome 12, and the genes for keratin 16 and 17 are on chromosome 17. A clinical genetic test is available.

Clinical Manifestations

In PC type 1 (aka Jadassohn-Lewandowsky syndrome), hyperkeratosis of the palms, soles, knees, and elbows, follicular hyperkeratosis (Fig. 11.4), and hyperhidrosis of the hands and feet are associated features. Oral leukokeratosis may be mild or absent in PC type 2 (aka Jackson-Lawler syndrome), which is associated with natal teeth, milder keratoderma, epidermal cysts, and steatocysts. Oral leukokeratosis may be found but is less marked than in PC type 1 [15].
Fig. 11.4

Follicular hyperkeratosis over the extensor elbow in a young man with pachyonychia congenita

Oral Signs and Symptoms

Oral lesions of PC are white, opaque thickenings in small areas of the tongue or buccal mucosa (Fig. 11.5) or confluently covering the entire surface of the tongue, lips, and cheeks [14], with the tongue being the most common location [16]. Oral leukokeratosis is seen in 70% of patients with genetically confirmed PC [17]. Onset at birth has been reported in 54% of patients [17] and may represent the earliest manifestation of the disease. It can also be exacerbated by or interfere with breastfeeding [18]. The oral plaques can be painful as a result of trauma due to food intake or entirely painless [18, 19, 20]. Involvement of the oropharynx may create a hoarse voice. Histologic examination demonstrates acanthosis, marked hyperkeratosis, and absence of the granular layer. Malignant transformation of the leukokeratosis has not been reported [14].
Fig. 11.5

Leukokeratosis over the lateral tongue in a young girl with pachyonychia congenita

Fifteen percent of patients with keratin 17 mutations have “natal teeth” compared to only 3% of patients with keratin 6a mutation and none with keratin 6b or 16 [17]. Natal teeth are either soft or crumbly and rapidly lost or normal appearing and persistent until permanent tooth eruption [16]. Angular cheilitis and median rhomboid glossitis have been described in patients with PC [18, 21].

Differential Diagnosis

Oral leukokeratosis in PC can be mistaken for white sponge nevus, oral leukoplakia, hairy tongue, and oral candidiasis [20]. Oral leukokeratosis is often misdiagnosed as thrush but does not improve with antifungal therapy. Interestingly, superinfection with C. albicans has been described [14, 22]. In a patient reported by Hannaford and Stapleton [22], lesions did not respond to anti-candidal treatment despite a positive culture.

Treatment Recommendations

Oral rehabilitation to eliminate the possibility of chronic trauma to the oral mucosa may be accomplished with the use of a well-designed prosthesis or intraoral devices [20]. Systemic retinoids may lead to improvement of oral leukoplakia [23]. However, the development of side effects limits its use in patients with PC [24].

Dyskeratosis Congenita

Epidemiology

Dyskeratosis congenita (DC) is a very rare genetic disease with a prevalence of 0.1/100,000 births [1].

Etiopathogenesis

All forms of the disease are caused by a disorder in telomere maintenance and feature short telomeres. Multiple genes with different mechanisms of inheritance have been described. The most common type, X-linked DC, is caused by a mutation in DKC1, which encodes dyskerin, on chromosome Xq28. Autosomal dominant DC is due to heterozygous mutations in either TERT or TERC. Autosomal recessive DC is caused by homozygous or compound heterozygous mutation in NOLA2, TCAB1, RTEL1, and TERT genes [25, 26, 27].

Clinical Manifestations

Typically, DC presents with a triad of reticulated hyperpigmentation of the skin (usually neck and chest), dystrophy of the nails, and oral leukoplakia. In addition, patients have a predisposition to hematologic abnormalities and bone marrow failure [28, 29]. Bone marrow failure is the chief cause of early death. New treatments are under development, but currently no treatments are found to be uniformly effective in all patients [28]. Patients with DC are also predisposed to pulmonary complications and malignancy.

Oral Signs and Symptoms

Oral leukoplakia is a diagnostic feature of this disorder and usually appears early in life in association with skin hyperpigmentation [29]. In a cohort of 17 patients with DC, oral leukoplakia was noted in 65% of patients. Other findings included decreased root/crown ratio and mild taurodontism [30]. Leukoplakia is generally only seen in the mucous membranes of the mouth (Figs. 11.6 and 11.7) but may also be found in the esophagus and anogenital mucosa. The leukoplakia tends to progress with time and may undergo malignant transformation [29]. Extensive dental caries and loss of teeth are reported in 18% of patients with DC [28]. Anomalies in ectodermal structures coupled with neutropenia lead to a suboptimal host response and periodontal disease. Gingival inflammation, bleeding, recession, and alveolar bone loss trigger periodontitis [31, 32].
Fig. 11.6

Leukoplakia of the tongue in a man with dyskeratosis congenita

Fig. 11.7

Leukoplakia and telangiectasias on the buccal mucosa with evidence of prior dental caries in a man with dyskeratosis congenita

Differential Diagnosis

Oral leukoplakia in DC should be distinguished from that of PC. Periodontal disease may mimic changes of Papillon-Lefevre syndrome. As with many of the genodermatoses, the presence of accompanying cutaneous findings is a useful aid in establishing the correct diagnosis.

Treatment Recommendations

Appropriate dental and periodontal care are imperative in DC. In addition, due to the risk of malignant transformation, these patients should be followed closely. Most recently, the use of photodynamic therapy and CO2 laser therapy has emerged as effective and safe options for the treatment of oral premalignant lesions [33, 34].

Rothmund-Thomson Syndrome

Epidemiology

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder with only 300 cases reported in the literature.

Etiopathogenesis

RTS is due to a compound heterozygous mutation in the DNA helicase gene RECQL4 on chromosome 8q24.3 [35]. The gene product plays a role in sister-chromatid cohesion that, when defective, leads to chromosomal instability with subsequent increased cancer susceptibility and cutaneous and skeletal abnormalities [36].

Clinical Manifestations

The most salient cutaneous finding in RTS is the presence of poikiloderma (skin atrophy, telangiectasias, hyper-, and hypopigmentation) on the face (Fig. 11.8) and extensor extremities, hence the synonym poikiloderma congenitale. Afflicted patients have skeletal abnormalities (short stature, absent or hypoplastic thumbs, severe kyphoscoliosis, and hip dislocation), soft tissue contractures, juvenile cataracts, anemia, hypogonadism, and increased risk of malignancy (especially osteogenic sarcoma and lymphomas) [37, 38, 39, 40].
Fig. 11.8

Poikiloderma and atrophy of the skin and lips in an individual with Rothmund-Thomson syndrome V

Oral Signs and Symptoms

Numerous dental malformations of deciduous teeth, ectopic eruptions, and failed tooth eruption have been recognized in RTS [41]. In 1985, Starr and colleagues described hypodontia as one of the non-dermatologic complications of RTS [42]. Early periodontal disease has also been noted in this patient population [43] as well as microdontia, dystrophic teeth, and short root anomaly [44].

Differential Diagnosis

RAPADILINO syndrome is a rare disorder caused by RECQL4 mutation. Therefore, overlap with RTS exists. Hypoplastic radius and thumb are common features (RA in RAPADILINO stands for radial ray malformations). From a dental/oral perspective, patients with RAPADILINO syndrome may have a high-arched palate and micrognathia, but other dental or periodontal changes are usually not seen [45, 46]. In contrast, Papillon-Lefevre, Haim-Munk, and Ehlers-Danlos syndromes feature early periodontal disease and should be considered in the differential diagnosis of RTS.

Treatment Recommendations

Treatment should be individualized on a case-by-case basis. Periodontal care is of utmost importance to prevent or minimize tooth decay. For patients with tooth abnormalities (anodontia, microdontia, etc.), prosthetic devices are necessary to ensure proper masticatory function.

Hereditary Hemorrhagic Telangiectasia

Epidemiology

Hereditary hemorrhagic telangiectasia (HHT), aka Osler-Weber-Rendu syndrome, has an estimated prevalence of at least 1 in 5000 [47].

Etiopathogenesis

HHT is an autosomal dominant disorder. Four main genetic subtypes have been described. The disease-causing mutation in HHT1 is in the endoglin (ENG) gene on chromosome 9q34.1 (8162076). For HHT2, the mutation is in the activin receptor gene on chromosome 12q1 [48]. HHT3 and HHT4 are mapped to chromosome 5 and 7, respectively. The candidate genes have not been elucidated. HHT5 is caused by heterozygous mutation in the GDF2 gene (also known as BMP9) on chromosome 10q11 [49]. In addition, mutations in SMAD4 on chromosome 18q21 cause a form of HHT called juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome [50].

Clinical Manifestations

HHT is characterized by multiple small and large arteriovenous malformations that become more prominent with age. The most common areas of involvement include the mucous membranes, skin (Fig. 11.9), gastrointestinal tract, liver, brain, and lung. Bleeding may cause sudden and devastating consequences. The earliest manifestation of the disease is epistaxis during childhood [47].
Fig. 11.9

Telangiectasias of the lip in a man with hereditary hemorrhagic telangiectasia

Oral Signs and Symptoms

Oral lesions may be punctate, spider-like, or nodular and can be found on the buccal mucosa, tongue, lips, palate, and gingivae [51]. Punctate telangiectasias on the tip of the tongue may be the first sign to present in childhood. More lesions usually develop after puberty. Color may vary from bright red to purple [4] but in the oral mucosa is usually cherry red [51]. Presentation of HHT as oral vascular malformations, hemorrhagic vesicles, and ulcers of the gingivae and oral mucosa has also been reported [52, 53]. Brain abscess formation following dental extractions and other dental procedures is a feared complication [54, 55]. Use of a very soft toothbrush may help prevent trauma from routine oral hygiene [53].

Differential Diagnosis

In the setting of mucosal telangiectasias in a patient with a history of epistaxis, multiple cutaneous telangiectasias, and a positive family history, the diagnosis should be straightforward. However, for atypical presentations, a high index of suspicion is needed. Patients with hereditary benign telangiectasia develop cutaneous plaque-like, arborizing, radiating, or punctate telangiectasias beginning in childhood. However, there are no mucosal or systemic vascular lesions [56].

Treatment Recommendations

Patients should be educated on the importance of avoiding oral trauma to prevent hemorrhage. Vascular malformations are amenable to treatment with sclerotherapy which obviates the need for more invasive surgical procedures and reduces the risk for postsurgical complications [52]. Nd:YAG laser has also been successfully used in the management of oral hemorrhage secondary to telangiectasias [57]. Some authors advocate the use of prophylactic antibiotics before oral procedures using the same guidelines as for patients at high risk of bacterial endocarditis [55].

Hermansky-Pudlak Syndrome

Epidemiology

Overall, the prevalence of Hermansky-Pudlak syndrome (HPS) is very low with approximately 0.15 cases per 100,000 births. However, in Puerto Rico HPS likely represents the most frequent single-gene disorder. It is also prevalent in a village of canton Valais, Switzerland [58]. In Puerto Rico, the carrier frequency is estimated to be 1 in 21 [59].

Etiopathogenesis

HPS is an autosomal recessive condition. Nine subtypes have been identified, each of which is caused by homozygous or compound heterozygous mutations in several different genes. HPS1 is due to mutations in the HPS1 gene on chromosome 10q23 [60]. These genes encode components of the biogenesis of the lysosome-related organelles complexes (BLOC 1-3) or play a role in protein sorting to lysosomes (AP3B1). Dysfunction of cytoplasmic organelles related to lysosomes (melanosomes, platelet-dense granules, and lysosomes) accounts for the variety of symptoms seen in this disease [61].

Clinical Manifestations

As previously mentioned, clinical findings are a reflection of defective intracellular organelle trafficking/sorting and include pigmentary dilution of the skin, hair, and eyes, freckles in sun-exposed areas, pigmented nevi, nystagmus, reduced vision, epistaxis, bloody diarrhea, bleeding diathesis leading to prolonged bleeding time, and easy bruisability. Lysosomal ceroid storage results in interstitial pulmonary fibrosis, granulomatous colitis, renal failure, and cardiomyopathy [62].

Oral Signs and Symptoms

From an orodental viewpoint, the most important consideration in HPS patients is their bleeding tendency, which makes them prone to gingival hemorrhage. Indeed, fatal bleeding following tooth extraction has been documented [63]. Pediatric dentists should be aware of this possibility, especially when practicing in areas of high prevalence. Dental care practice recommendations including the use of protective UV glasses, as to avoid excessive glare from dental light, to administration of blood derivatives to assist with hemostasis are available [64].

Differential Diagnosis

Other disorders of hemostasis that may cause excessive gingival bleeding either with minor trauma or following dental procedures are Bernard-Soulier syndrome, Glanzmann thrombasthenia, gray platelet syndrome, and Chediak-Higashi syndrome [65].

Treatment Recommendations

For information regarding use of eyeglasses with UV filters, brushing techniques, antifibrinolytic agents, and local hemostatic measures during dental procedures, please refer to the article by Feliciano NZ and colleagues [64].

Lesch-Nyhan Syndrome

Epidemiology

The estimated prevalence of Lesch-Nyhan syndrome (LNS) at birth is about 0.34/100,000 [1].

Etiopathogenesis

LNS is an X-linked recessive disease caused by mutation in the HPRT gene, which encodes hypoxanthine guanine phosphoribosyltransferase. This enzyme catalyzes conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate via transfer of the 5-phosphoribosyl group from 5-phosphoribosyl 1-pyrophosphate. Therefore, it has a pivotal role in the purine salvage pathway [66].

Clinical Manifestations

Clinical features are secondary to abnormal purine metabolism. Affected patients have short stature, growth and mental retardation (IQ 45–75), gout, nephrolithiasis, motor delay, hypotonia, extrapyramidal signs, choreoathetosis, spasticity, hyperreflexia, dysarthria, hyperuricemia, and hyperuricosuria [67].

Oral Signs and Symptoms

One of the most striking findings of the disease is the self-mutilating behavior with biting of the fingers and lips. The median age of onset is 2 years when eruption of the primary dentition is almost complete. The sites more frequently affected are the lower lip, inner cheeks, and tongue [67, 68].

Differential Diagnosis

Self-injury with involvement of the oral and perioral regions and the hands may be seen in a variety of neurological disorders (congenital, posttraumatic, and degenerative), congenital insensitivity pain with anhidrosis, and mental retardation [69, 70]. Limeres et al. proposed that the pattern of oral self-injury is not disease specific [68]. As such, the diagnosis relies on other condition-specific findings, which are usually apparent before self-mutilation ensues. Classic LNS features near complete absence of residual HPRT activity (less than 1.5%), whereas patients with Kelley-Seegmiller syndrome have a residual enzyme activity of at least 8%. The latter group of patients develops gout after puberty. Up to 25% of patients may have mild neurologic abnormalities but no self-injurious behavior [71].

Treatment Recommendations

According to Limeres and colleagues, intraoral devices alone (i.e., soft mouthguard or nonsurgical splint) or in combination with pharmacologic therapy offer the best management strategy for patients with oral self-injury of organic origin including LNS [68]. Psychologic therapy and uric acid reduction have not been shown to be of value in the treatment of self-mutilating behavior [68]. Extraction of primary and permanent teeth may be necessary [72].

Peutz-Jeghers Syndrome

Epidemiology

The reported prevalence of Peutz-Jeghers syndrome (PJS) is 2.2 cases per 100,000 births [1].

Etiopathogenesis

The disorder is due to mutations in the serine/threonine kinase, STK11, gene located at chromosomal locus 19p13 [73]. It is estimated that in 50% of cases, the condition is inherited from a parent, and in 50% of cases, the condition is the result of a new or de novo mutation [73]. A clinical genetic test is currently available for PJS.

Clinical Manifestations

PJS is a genetic condition characterized by gastrointestinal polyposis and tan to dark brown or blue macules on the skin and oral mucosa (Figs. 11.10 and 11.11) [74]. Diagnosis is based on these clinical findings. Polyps may cause intussusception or bowel obstruction. A study by Boardman et al. [75] determined that patients with Peutz-Jeghers syndrome had a 9.9 times relative risk for cancer. The incidence of gastrointestinal cancers and breast cancer is particularly increased [73, 75]. Therefore, cancer surveillance comprises an important part of management for these patients.
Fig. 11.10

Hyperpigmented macules affecting the lips in Peutz-Jeghers syndrome

Fig. 11.11

Hyperpigmented macules over the buccal mucosa in a patient with Peutz-Jeghers syndrome

Oral Signs and Symptoms

The pigmented macules are usually present at birth or are first noted in early childhood [74]. The macules are usually found on the lips, buccal mucosa, and perioral skin. In the mouth, they may also be found on the palate and tongue. On the skin, distribution may include the face, dorsum of the hands, feet, fingers, eyes, umbilicus, and anus. Macules may be found in a periorificial distribution around the eyes in some patients. Skin macules are reported to fade with age, but the macules involving the oral mucosa tend to be persistent [74].

Differential Diagnosis

Lentigines with a distribution similar to that of PJS are found in Bandler syndrome and Laugier-Hunziker syndrome. Periorificial pigmented macules are seen in Carney Complex. Centrofacial lentiginosis and inherited patterned lentiginosis feature lentigines on the lips. Patients with Cronkhite-Canada syndrome develop lentigines on the buccal mucosa.

Treatment Recommendations

While lentigines in PJS are asymptomatic, they can be cosmetically distressful. Q-switched alexandrite laser is considered the treatment of choice for mucocutaneous melanosis associated with PJS [76, 77]. Q-switched ruby has also been used with satisfactory results [78]. Other treatment modalities such as dermabrasion, cryotherapy and CO2, or Argon laser may be associated with incomplete removal, scarring, or pigmentary changes [78].

Pseudoxanthoma Elasticum

Epidemiology

Pseudoxanthoma elasticum (PXE) occurs in 2.5 per 100,000 births [79].

Etiopathogenesis

PXE is an autosomal recessive condition due to mutations in the ATP-binding cassette, subfamily C, member 6 (ABCC6) gene. ABCC6 belongs to the multidrug resistance-associated protein (MRP) subfamily of ATP-binding cassette (ABC) transmembrane transporters [80].

Clinical Manifestations

The hallmark of the disease is the accumulation of fragmented and calcified elastic fibers in the skin, blood vessel walls, and Bruch’s membrane in the eye resulting in soft, ivory-colored papules in a reticular pattern on the neck and intertriginous areas, as well as coronary artery occlusive disease, gastrointestinal hemorrhage, and retinal angioid streaks and choroidal neovascularizations [80]. Carriers of heterozygous mutations in ABCC6 gene may present with partial manifestations of the disease.

Oral Signs and Symptoms

Mucosal lesions of PXE are yellowish-to-white, macules and papules coalescing into reticulated patches or plaques. They appear on the inner aspect of the lower lip, cheeks, and palate [81] (Fig. 11.12). In patients without classic cutaneous findings, mucosal involvement of the lower lip may be the only clue to the diagnosis [82]. Oligodontia with agenesis of most of the permanent teeth has been reported [83]. More importantly, the presence of mucosal lesions may be a surrogate marker for potentially life-threatening cardiovascular disease [84].
Fig. 11.12

Whitish papules on the inner lower lip caused by abnormal elastin in a patient with pseudoxanthoma elasticum

Differential Diagnosis

Because of their location and color, the lesions may be misdiagnosed as Fordyce spots [85].

Treatment Recommendations

Oral lesions in PXE are asymptomatic, and no treatment is necessary. For rare cases with tooth abnormalities, treatment of the specific dental problem should be undertaken. Patients are vulnerable to early death from cardiovascular disease. Increasing evidence links poor oral health and vascular endothelial cell dysfunction. Therefore, meticulous oral hygiene may be especially important for affected individuals.

White Sponge Nevus

Epidemiology

The exact prevalence of white sponge nevus of Canon is unknown, but it is estimated to affect less than 1 in 200,000 individuals [86].

Etiopathogenesis

White sponge nevus (WSN) is a rare autosomal dominant condition due to heterozygous mutations in the keratin-4 gene on chromosome 12q13 or the keratin-13 gene on chromosome 17q21 [87, 88].

Clinical Manifestations

WSN is a disorder of non-keratinizing squamous epithelial differentiation that presents with leukokeratosis of the oral mucosa. However, the nose, esophagus, genitalia, and rectum may also be involved.

Oral Signs and Symptoms

The buccal mucosa is most commonly affected with white, bilateral, velvety, or “spongy” plaques (Fig. 11.13). The lesions are asymptomatic and first noted at birth or in early childhood. The labial and gingival mucosa, the floor of the mouth, or the entire oral cavity may be involved. While the lesions are painless, patients complain of an altered texture of the mucosa or that the lesions are cosmetically unappealing [89].
Fig. 11.13

Hyperkeratosis on the buccal mucosa in white sponge nevus

Differential Diagnosis

WSN should be differentiated from morsicatio buccarum (chronic cheek chewing), oral lichen planus, candidiasis, leukoedema, leukokeratosis nicotina palati (from smoking), dyskeratosis congenita, Darier’s disease, benign intraepithelial dyskeratosis, and pachyonychia congenita. Early onset, bilateral involvement of the buccal mucosa, the lack of other systemic symptoms or signs, and a positive family history help distinguish WSN from the abovementioned conditions.

Treatment Recommendations

Most treatment recommendations are based on a handful of case reports/case series. Oral amoxicillin and tetracycline may afford some improvement, but prolonged treatment with a low maintenance dose is required [89]. Tetracycline mouth rinse and chlorhexidine have been used successfully [90, 91, 92]. Recurrence after CO2 laser therapy has been noted. Surgical excision may be curative [93].

Familial Adenomatous Polyposis (Gardner Syndrome)

Epidemiology

Familial adenomatous polyposis (FAP) occurs in 1 in 7500 births.

Etiopathogenesis

FAP is caused by heterozygous mutation in the adenomatous polyposis coli (APC) gene on chromosome 5q22.2. APC encodes a tumor suppression protein that antagonizes the WNT signaling pathway [94]. It is inherited in an autosomal dominant fashion.

Clinical Manifestations

The hallmark of FAP is the development of hundreds of adenomatous colorectal polyps, which have a 100% risk of malignant transformation, if prophylactic colectomy is not performed [95]. The polyps typically develop in the second or third decade of life. Extraintestinal manifestations include congenital hypertrophy of the retinal pigment epithelium which is found in up to 80% of patients and is usually present at birth allowing for early diagnosis [96], cutaneous lesions (epidermoid cysts, lipomas, fibromas, pilomatricomas, leiomyomas), desmoid tumors, as well as malignancies of the thyroid, pancreas, stomach, adrenals, and gallbladder [97].

Oral Signs and Symptoms

Supernumerary, impacted, and missing teeth have been reported in GS [98]. Supernumerary teeth are small and peg shaped [99]. The impacted teeth are usually canines [100]. Osteomas are the most common skeletal manifestation of the disease. They are present in 46–93% of patients and can arise in the skull, mandible, maxilla, and long bones. The largest are located at the angle of the mandible [101]. Osteomas of the mandibular condyle may be diagnostic; they are usually asymptomatic but can cause limited mandibular movement [102] or cause facial asymmetry [103]. In general, osteomas of the mandible and maxilla are common incidental findings on routine dental panoramic radiography. However, the presence of three or more should raise suspicion for the possibility of FAP [104].

Odontomas are also more frequent in FAP than in the general population [105]. They are well-defined, encapsulated, hard tissue growths with an odontogenic origin.

Differential Diagnosis

Full-blown FAP offers no diagnostic challenge. For early disease, the differential diagnosis is that of the individual lesions or findings. However, if two or more of the above listed cutaneous or maxillofacial findings coincide in the same patient, evaluation for colonic polyposis should be undertaken.

Treatment Recommendations

Osteomas are asymptomatic and usually removed for cosmetic reasons or when they restrict the oral aperture and/or mandibular movement [106]. Recurrence after surgical resection is rare [102].

Osteogenesis Imperfecta

Epidemiology

Osteogenesis imperfecta (OI) has an estimated prevalence of 1 in 12,000–15,000 children [107, 108].

Etiopathogenesis

OI is a genetically and phenotypically heterogeneous disorder with autosomal dominant and recessive inheritance. Autosomal dominant OI is due to mutations in COL1A1 gene on chromosome 17, COL1A2 on chromosome 7, or IFITM5 gene, encoding interferon-induced transmembrane protein-5, on chromosome 11p15. Genes responsible for autosomal recessive OI include SERPINF1, CRTAP, LEPRE1, PPIB, SERPINH1, FKBP10, BMP1 SP7, and WNT1 [109]. Mutations in COL1A1 and COL1A2 are responsible for about 90% of cases of OI [110].

Clinical Manifestations

OI is characterized by varying degrees of bone fragility and low bone mass leading to multiple bone fractures from minimal trauma. Wormian (intra sutural) bones of the skull, osteopenia, biconcave flattened vertebrae, femoral bowing, and joint hypermobility are among the most common skeletal abnormalities. Patients may present with blue sclera, thin skin, and easy bruisability. In addition, there are numerous extraskeletal manifestations such as progressive sensorineural and/or conductive hearing loss, otosclerosis, mitral valve prolapse, aortic root dilatation, basilar impression, macrocephaly, and hydrocephalus. The presence and severity of the aforementioned findings are highly variable owing to multiple genetic defects implicated in this condition [109, 111, 112, 113].

Oral Signs and Symptoms

Dentinogenesis imperfecta (DI) may be a feature of some forms of OI with an estimated prevalence of about 28% [114]. The teeth are typically yellow/brown or opalescent gray with significant attrition. Discoloration is due to dentin dysplasia. There is no correlation between the type of OI and the type/shade of discoloration [115]. Radiographically, the teeth have short roots and dentin hypertrophy leading to pulpal obliteration either before or just after eruption [116]. Individuals with OI types III and IV have more severe oral problems such as malocclusion (anterior and posterior cross bites and open bites), micrognathia, and delayed, accelerated, or ectopic tooth eruption [114].

Differential Diagnosis

DI types II and III are not associated with other inherited disorders. The main differential diagnosis is dentin dysplasia. The latter has an incidence of 1 in 100,000 [116].

Treatment Recommendations

Early institution of treatment will ensure good occlusion, adequate mandibular and maxillary growth, and preservation of the temporomandibular joints [117]. Initial management of the primary dentition includes placement of stainless steel crowns for the posterior teeth and acrylic crowns for the anterior teeth in conjunction with meticulous oral hygiene for prevention of dental caries and periodontal disease [118]. When eruption of the permanent dentition is complete, prosthetic restoration of the permanent teeth can be considered [119]. Nowadays, dental implants and ceramometal restoration (for posterior teeth) and glass-ceramic pressed veneers and crowns (for anterior teeth and premolars) offer a more functional and cosmetically appealing solution [120].

Basal Cell Nevus Syndrome

Epidemiology

The prevalence of basal cell nevus syndrome or Gorlin syndrome is between 1 in 31,000 [121] and 1 in 164,000 [122].

Etiopathogenesis

Basal cell nevus syndrome (BCNS) is caused by mutations in the PTCH1 gene on chromosome 9q22, the PTCH2 gene on 1p32, or the SUFU gene on 10q24-q25 [123]. PTCH1 encodes the receptor for Sonic hedgehog protein and accounts for most cases of BCNS [124]. The mechanism of inheritance is autosomal dominant.

Clinical Manifestations

Individuals with BCNS develop multiple basal cell carcinomas early in life, and the rate increases with age up to a frequency of about 97% in patients older than 40 years old, with the first tumor occurring at a mean age of 23 [125]. Other commonly observed features are frontal and biparietal bossing, broad nasal root, strabismus, iris coloboma, glaucoma [126], bifid ribs [127], calcification of the falx cerebri [128], medulloblastomas, ovarian fibromas/carcinomas, and palmoplantar pits [129].

Oral Signs and Symptoms

Keratocyst odontogenic tumors (KCOT), formerly odontogenic keratocysts, are benign cystic lesions reclassified as neoplasms due to their potential for slow growth and locally destructive behavior [130] (Fig. 11.14). KCOTs may be the presenting sign of NBCS [131]. Indeed, they are considered a major diagnostic criterion for this syndrome. The mandible: maxilla ratio is 2:1. The most common locations are the posterior mandible, near the third molars, and the ramus areas [132]. The most common complaint is jaw swelling (45%). Other symptoms include pain and altered taste. About 25% are asymptomatic and incidentally discovered on radiographs [133]. Seventy five percent of patients with BCNS develop KCOTs, 80% of them before the age of 20. They are usually multiple (median, 3; range, 1–28) [125]. Recurrence after surgical removal is common. Cleft lip and palate have also been documented in BCNS [134, 135]. An uncommon finding is bilateral hyperplasia of the mandibular coronoid processes [136].
Fig. 11.14

Odontogenic keratocyst in the right upper jaw in a patient with basal cell nevus syndrome

Differential Diagnosis

BCNS has a limited number of oral manifestations. Nonetheless, because KCOTs are very common and arise early in this condition, the finding of a histologically proven KCOT should prompt further investigation to exclude BCNS.

Treatment Recommendations

Treatment of KCOTs is a matter of debate [137]. Conservative management (enucleation or marsupialization) may be attempted for small lesions [138, 139]. For more complex and large lesions, surgical removal via intraoral or endoscopic approaches is recommended [140]. BCNS patients are especially vulnerable to ionizing radiation which increases their risk of cutaneous basal cell skin cancers. Minimization of diagnostic X-rays is recommended. Because of the risk of odontogenic keratocysts, panoramic radiography is indicated every 12–18 months in those older than age 8 [141].

Tuberous Sclerosis Complex

Epidemiology

Tuberous sclerosis complex (TSC) affects about 2,000,000 people worldwide with an incidence of about 1 in 5000–10,000 live births [142, 143, 144].

Etiopathogenesis

TSC complex is inherited in an autosomal dominant manner and considered to be a heterogeneous disorder. About two-thirds of cases represent new mutations in patients with no family history of the disorder. The majority of cases are caused by a mutation of the TSC1 gene on chromosome 9q34 or the TSC2 gene on chromosome 16p13. In addition, TSC has a high rate of somatic mosaicism among affected individuals estimated to be 10–25% [144].

Clinical Manifestations

Tuberous sclerosis complex (TSC) has been described and studied for more than 160 years [145, 146]. As a result, diagnostic criteria have been well defined [147]. Abnormalities of the skin, central nervous system, kidney, and heart are prominent features of this disorder. TSC shows a great deal of variability in the degree of severity even among affected family members. Central nervous system abnormalities such as cognitive deficits and seizures affect long-term prognosis the most. Up to 14% of patients with TSC develop subependymal giant cell astrocytomas. Associated skin findings such as hypomelanotic macules, facial angiofibromas, and ungual fibromas have been reviewed in detail [147].

Oral Signs and Symptoms

Current diagnostic criteria include the oral finding of gingival fibromas (Fig. 11.15). These are described as small, fibrous nodules on the gingiva. Oral fibromas in TSC have also been described on the buccal mucosa and dorsum of the tongue [148]. Gingival fibromas are found in some patients with TSC and, therefore, are not essential to establishing a diagnosis. Also, gingival hyperplasia caused by antiseizure medication such as phenytoin may obscure gingival fibromas in these patients. A lack of oral hygiene has been associated with TSC, but this is thought to be due to mental deficiency rather than a growth or neoplastic change [145].
Fig. 11.15

Gingival hyperplasia in a patient with tuberous sclerosis

Multiple randomly distributed enamel pits provide another diagnostic feature of TSC. Enamel pitting may be seen by direct inspection and usually affects the labial surfaces of the central and lateral incisors and canine teeth [145]. The prevalence of enamel pits in patients with TS is thought to range from 48% to 100% [145, 149]. Smaller pits can be better appreciated using dental plaque-disclosing stain on the surfaces of the teeth. Electron microscopy can also be used, once a tooth has been extracted. Enamel pits may be found on the teeth of otherwise healthy patients but are usually fewer and less obvious. A study by Flanagan et al. [149] found that the majority of patients with TSC had greater than 14 pits per person, whereas the majority of normal controls had less than 6 pits per person.

Differential Diagnosis

Oral fibromas can be misdiagnosed as fibrous hyperplasias, focal papillomas, hemangiomas, lymphangiomas, or lipomas [150].

Treatment Recommendations

Oral fibromas may interfere with oral hygiene. As such, education on oral hygiene and dietary habits, fluoride therapy, and frequent in-office cleanings are advisable [151]. Surgical resection of the most prominent ones could be considered on an individual basis.

Darier Disease

Epidemiology

Darier disease (DD) has an estimated prevalence of 1 in 55,000. Disease onset is usually before the third decade of life [152].

Etiopathogenesis

DD, an autosomal dominant disorder, results from a heterozygous mutation in the ATP2A2 gene, which encodes the sarcoplasmic reticulum Ca(2+)-ATPase-2 (SERCA2), on chromosome 12q23-q24.1. The SERCA2b pump specifically maintains low cytosolic Ca(2+) concentrations by actively transporting Ca(2+) from the cytosol into the sarco/endoplasmic reticulum lumen of keratinocytes [153, 154]. Gene penetrance may be complete by age 10, but expressivity is variable [155].

Clinical Manifestations

Disease onset is usually between the ages of 6 and 20 years. The characteristic skin findings are brown, warty, hyperkeratotic, 2–4 mm papules with predilection for the seborrheic areas (scalp, forehead, trunk, and intertriginous regions). Acral involvement is almost universal (96% of patients) with palmar keratotic plaques, palmoplantar pits, and acrokeratosis verruciformis-like lesions on the dorsal hands [156]. The hyperkeratotic plaques are often malodorous and moderately pruritic. Nail changes include longitudinal erythro- and leukonychia, distal V-shaped notching, longitudinal fissuring and ridging, and subungual hyperkeratotic fragments [157]. Interestingly, several neuropsychiatric conditions have been documented in a subset of patients with DD. Mild mental retardation, seizures, schizophrenia, bipolar disorder, major depression, and suicidal attempts have been reported [156, 158, 159].

Oral Signs and Symptoms

The incidence of oral lesions in DD varies between 15% (24/163) [156] and 50% (12/24) [160]. Lesions are painless, whitish, coalescing papules, primarily present on the palate (most common location), followed by the gingiva, oral mucosa, and tongue [160]. The severity of oral involvement seems to mirror that of cutaneous disease. Parotid gland swelling has also been described but only in patients with concomitant oral involvement [160]. Most recently, esophageal affliction, including carcinoma, has been noted [161, 162].

Differential Diagnosis

The differential diagnosis of oral lesions in DD are that in leukokeratosis/leukoplakia and includes morsicatio buccarum, candidiasis, leukoedema, leukokeratosis nicotina palate, dyskeratosis congenita, white sponge nevus, benign intraepithelial dyskeratosis and pachyonychia congenita.

Treatment Recommendations

Oral findings in DD are of no clinical significance, and treatment is not needed.

Ehlers-Danlos Syndrome

Epidemiology

The prevalence of Ehlers-Danlos syndrome (EDS) is approximately 1 in 5000–10,000. There is no racial predilection [163].

Etiopathogenesis

Mutations in collagen and collagen-processing enzymes are responsible for the various phenotypes of the disease. EDS types 1 and 2 are caused by mutations in either the collagen alpha-1(V) gene (COL5A1) on chromosome 9q34 or the collagen alpha-2(V) gene (COL5A2) on chromosome 2q31. EDS type 3 is caused by mutation in the tenascin-XB or COL3A1 genes. Mutations in COL3A1 genes are also responsible for EDS type 4. EDS type 6 is due to mutations in lysyl hydroxylase (PLOD1) on chromosome 1. Lastly, mutations in COL1A1, COL1A2, and procollagen protease ADAMTS2 cause EDS type 7A, 7B, and 7C, respectively [163]. EDS can be inherited in an autosomal or recessive fashion.

Clinical Manifestations

EDS is a group of connective tissue disorders with shared features including skin hyperextensibility, joint hypermobility, and tissue fragility. Each EDS type has one or more defining findings. A detailed description is beyond the scope of this chapter and can be found in the Online Mendelian Inheritance in Men website (www.omim.org). Briefly, patients have a variety of skeletal (osteoarthritis, joint hypermobility, joint dislocation, pes planus), cutaneous (fragile and velvety skin, easy bruisability, poor wound healing, molluscoid pseudotumors, spheroids, wide and cigarette-paper scars), cardiovascular (mitral valve prolapse, aortic root dilatation), ocular (blue sclerae, epicanthal folds, ectopia lentis, myopia, and eyelid extensibility), and oral manifestations.

Oral Signs and Symptoms

About 50% of EDS patients are able to touch their nasal tip with their tongue compared to 10% of the general population, the so-called Gorlin’s sign. Absence of the inferior labial frenulum has a 100% sensitivity, whereas absence of the lingual frenulum has a 100% specificity for the EDS types I, II, and III [164].

The most comprehensive review on the oral manifestations of EDS is by Abel and Carrasco [163]. Patients may present with periodontal disease with early-onset periodontitis, gingival fibrinoid deposits, and bleeding as well as increased tooth mobility, congenital absence of teeth, and supernumerary teeth. Teeth can be small, irregularly placed with short, malformed, or dilacerated roots. Enamel hypoplasia and dentin structural irregularities are also observed and may render teeth prone to dental caries [165]. Hemorrhagic bulla of the oral mucosa as an early manifestation of EDS type 4 (vascular type) has been reported [166]. KCOTs can be found in association with supernumerary teeth [167]. Patients with EDS type 4 may also experience tooth loss following orthodontic treatment due to severe destruction of the periodontal support [168].

Hypermobility of the temporomandibular joint (TMJ) is a frequent sign [169] as is pain in the masticatory muscles upon mouth opening. Increased mobility of the joints can also cause permanent locking of the TMJ [170].

Differential Diagnosis

Due to the heterogeneous presentation with several oral and mucosal findings, the differential diagnosis matches that of each individual condition or symptom. For example, KCOTs are major diagnostic criteria for basal cell nevus syndrome but can also be found in EDS. Periodontal disease is a feature of Papillon-Lefevre, supernumerary teeth are seen in Job syndrome, and Gorlin’s sign may be a physiologic variant. Therefore, when considered in isolation, these individual findings may lead to an erroneous diagnosis. Nonetheless, their occurrence in association with skin and other organ system abnormalities along with a compatible pedigree or family history should help distinguish EDS cases.

Treatment Recommendations

Oral care in EDS is complex and requires a multidisciplinary approach with input from dental hygienists, general dentists, endodontists, orthodontists, orthopedic surgeons, and physical therapists [163]. These patients may develop complications during standard orthopedic treatment such as rapid migration and increased tooth mobility. Similarly, the gingiva is more prone to inflammation and the TMJ to subluxation [171].

Down Syndrome

Epidemiology

Down syndrome (DS) is estimated to occur in approximately 1 in 732 infants in the United States, but there is racial and ethnic variability [172].

Etiopathogenesis

DS is the most common numeric chromosome abnormality due to trisomy 21. Dosage imbalance of many genes is responsible for the phenotype.

Clinical Manifestations

Almost every organ system is affected in DS. Characteristically, patients have brachycephaly, short stature, flat facies, small ears, folded helices, conductive hearing loss, epicanthal folds, iris Brushfield spots, and upslanting palpebral fissures. Congenital heart disease, duodenal atresia, imperforate anus, and Hirschsprung disease are additional features. Patients are prone to Alzheimer, leukemia, and hypothyroidism (www.omim.org).

Oral Signs and Symptoms

DS patients present with a variety of dental anomalies. In one series the most common abnormality was taurodontism (vertical enlargement of the tooth and pulp, usually most striking in the molars), followed by rotation, hypodontia, tooth impaction, ectopic eruption, microdontia, and hyperdontia, in that order [173]. In another series, although the crown-to-root ratio was maintained, microdontia and progressive reduction in tooth size with senesce were documented [174]. Microdontia affects both primary and permanent dentitions [175]. In addition, there is a higher prevalence of malocclusion (anterior cross bite, anterior open bite) probably due to skeletal and soft tissue abnormalities [176]. Interestingly, DS patients are more resistant to dental caries but have a higher prevalence of gingival and periodontal disease.

Tonsillar hyperplasia has been implicated in the pathogenesis of sleep-disordered breathing in children with DS [177]. Due to small craniofacial parameters, patients with DS have relative rather than true macroglossia [178]. Cleft lip and/or palate and broad, dry, and fissured lips are observed [179].

Differential Diagnosis

Healthcare professionals are very well aware of the classic clinical findings associated with DS. Moreover, prenatal diagnosis is available. Therefore, in developed countries, the diagnosis has already been established by the time oral manifestations arise (i.e., primary dentition). In areas where neonatal screening is not universal, congenital hypothyroidism may be considered in the differential diagnosis.

Treatment Recommendations

Due to poor oral hygiene and high levels of periodontal disease in patients with DS, adequate oral health education for patients, their families, and other caregivers is an important priority [180]. Retrognathia, hypotonia, and macroglossia can lead to obstructive sleep apnea; therefore, overnight polysomnograph should be obtained and early referral to otolaryngology made, if indicated [181]. As with EDS patients, an interdisciplinary approach is necessary to achieve functional, phonetic, and esthetic outcomes [182].

Xeroderma Pigmentosum (XP)

Epidemiology

Xeroderma pigmentosum (XP) has an estimated incidence of 1 in 20,000 in Japan to 1 in 250,000 in the United States [183].

Etiopathogenesis

XP is a rare autosomal recessive genetic condition characterized by hypersensitivity to ultraviolet radiation and carcinogenic agents due to defective DNA repair after ultraviolet radiation damage. Nine different gene mutations are accountable for the XP phenotype. Eight of them belong to the nucleotide excision repair pathway (NER), a group of enzymes involved in DNA repair and one is involved in error-free replication of UV damaged DNA. Characterization of each individual XP group and variant is beyond the scope of this chapter.

Clinical Manifestations

The vast majority of XP clinical manifestations occur in sun-exposed areas of the skin including increased photosensitivity, development of ephelides, poikiloderma, skin atrophy, telangiectasias, angiomas, actinic keratoses, and, importantly, cutaneous malignancies (keratoacanthoma, squamous cell carcinoma, basal cell carcinoma, and melanoma). Up to 70% of patients with XP are diagnosed with a malignant skin neoplasm at a median age of 8 years [184, 185]. Additionally, patients present with photophobia, conjunctivitis, keratitis, ectropion, entropion, early cataracts, decreased visual acuity, corneal neovascularization, and tumors of the eyelid and cornea. Microcephaly, sensorineural hearing loss, and central nervous system abnormalities are also a features in some types of the disease [186].

Oral Signs and Symptoms

The oral manifestations are mainly due to sun-induced damage of the lips, exposed oral mucosa, and tip of the tongue and include actinic cheilitis and basal cell and squamous cell carcinomas. Perioral scarring from repeated episodes of actinic cheilitis and reconstruction of skin defects around the mouth (after excision of cutaneous malignancy) may result in microstomia. In such cases, limitation of the oral aperture may lead to poor oral hygiene and sequelae of periodontal disease and tooth decay. Enamel hypoplasia has also been reported [187].

Differential Diagnosis

Suspicious lesions may be white or red and should be biopsied for definitive diagnosis. The differential diagnosis is usually restricted to malignant neoplasms given that the diagnosis of XP has typically already been established by the time oral and dental complications arise.

Treatment Recommendations

Periodic dental exams are mandatory for early detection and treatment of precancerous and malignant lesions. Caution should be taken when treating dental caries in XP patients. It is recommended that glass-ionomer or auto-cure filling material be substituted for light-cure fillings as there is potential for light-induced malignant transformation of the epithelium and connective tissue [188]. Mouthwashes with a high alcohol concentration should also be avoided.

Papillon-Lefevre Syndrome

Epidemiology

The prevalence of Papillon-Lefevre syndrome (PLS) is approximately 1–4 cases per 1,000,000 [189, 190].

Etiopathogenesis

PLS is a rare autosomal recessive disorder with an increased rate of consanguinity in parents of affected patients [191]. Most cases are due to mutations of the cathepsin C gene on chromosome 11q14 [191].

Clinical Manifestations

Papillon-Lefevre syndrome (PLS) is a very rare genetic condition characterized by well-demarcated palmoplantar hyperkeratosis. Periodontitis separates PLS from other inherited palmoplantar keratodermas [191]. The features of the condition usually first become apparent between the age of 2 and 4 [192]. The palmoplantar hyperkeratosis has been reported to improve with time [192].

Oral Signs and Symptoms

Severe, inflammatory periodontitis results in complete loss of deciduous teeth by age 4. The same process results in complete loss of the permanent teeth. Late-onset periodontitis (age 12) has been documented as a rare phenotypic variation [193]. The wisdom teeth, however, are spared [192]. It has recently been proposed that deficits of antimicrobial and immunomodulatory functions of gingival LL-37 allow infection with Aggregatibacter actinomycetemcomitans leading to severe periodontal disease [194].

Differential Diagnosis

Mutations in cathepsin C also cause Haim-Munk syndrome with palmoplantar keratoderma, aggressive periodontitis, acroosteolysis, arachnodactyly, atrophic nail changes, and deformity of the fingers [195].

Treatment Recommendations

For years, prosthodontic rehabilitation has been the cornerstone of therapy in PLS [196]. Unfortunately, despite aggressive post-implant care, patients are at high risk of peri-implantitis and implant loss [197]. Recent advances in treatment suggest that low-dose acitretin improves periodontitis and results in increased alveolar bone height and periodontal attachment [198].

References

  1. 1.
    Orphanet Report Series, Prevalence of rare diseases: Bibliographic Data. 2014.Google Scholar
  2. 2.
    Landy SJ, Donnai D. Incontinentia pigmenti (Bloch-Sulzberger syndrome). J Med Genet. 1993;30(1):53–9.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Minic S, Trpinac D, Obradovic M. Incontinentia pigmenti diagnostic criteria update. Clin Genet. 2014;85(6):536–42.PubMedGoogle Scholar
  4. 4.
    Equi RA, Bains HS, Jampol L, Goldberg MF. Retinal tears occurring at the border of vascular and avascular retina in adult patients with incontinentia pigmenti. Retina. 2003;23(4):574–6.PubMedGoogle Scholar
  5. 5.
    Kim BJ, Shin HS, Won CH, Lee JH, Kim KH, Kim MN, et al. Incontinentia pigmenti: clinical observation of 40 Korean cases. J Korean Med Sci. 2006;21(3):474–7.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Minic S, Trpinac D, Obradovic M. Systematic review of central nervous system anomalies in incontinentia pigmenti. Orphanet J Rare Dis. 2013;8:25.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Wu HP, Wang YL, Chang HH, Huang GF, Guo MK. Dental anomalies in two patients with incontinentia pigmenti. J Formos Med Assoc. 2005;104(6):427–30.PubMedGoogle Scholar
  8. 8.
    Minic S, Trpinac D, Gabriel H, Gencik M, Obradović M. Dental and oral anomalies in incontinentia pigmenti: a systematic review. Clin Oral Investig. 2013;17(1):1–8.PubMedGoogle Scholar
  9. 9.
    Bergendal B. Orodental manifestations in ectodermal dysplasia-a review. Am J Med Genet A. 2014;164A(10):2465–71.PubMedGoogle Scholar
  10. 10.
    Holmstrom G, Bergendal B, Hallberg G, Marcus S, Hallén A, Dahl N. Incontinentia pigmenti. A rare disease with many symptoms. Lakartidningen. 2002;99(12):1345–50.PubMedGoogle Scholar
  11. 11.
    Doruk C, Bicakci AA, Babacan H. Orthodontic and orthopedic treatment of a patient with incontinentia pigmenti. Angle Orthod. 2003;73(6):763–8.PubMedGoogle Scholar
  12. 12.
    Yamashiro T, Nakagawa K, Takada K. Case report: orthodontic treatment of dental problems in incontinentia pigmenti. Angle Orthod. 1998;68(3):281–4.PubMedGoogle Scholar
  13. 13.
    McLean WH, Hansen CD, Eliason MJ, Smith FJ. The phenotypic and molecular genetic features of pachyonychia congenita. J Invest Dermatol. 2011;131(5):1015–7.PubMedGoogle Scholar
  14. 14.
    Dahl PR, Daoud MS, Su WP. Jadassohn-Lewandowski syndrome (pachyonychia congenita). Semin Dermatol. 1995;14(2):129–34.PubMedGoogle Scholar
  15. 15.
    Smith FJ, Coleman CM, Bayoumy NM, Tenconi R, Nelson J, David A, et al. Novel keratin 17 mutations in pachyonychia congenita type 2. J Invest Dermatol. 2001;116(5):806–8.PubMedGoogle Scholar
  16. 16.
    Shah S, Boen M, Kenner-Bell B, Schwartz M, Rademaker A, Paller AS. Pachyonychia congenita in pediatric patients: natural history, features, and impact. JAMA Dermatol. 2014;150(2):146–53.PubMedGoogle Scholar
  17. 17.
    Eliason MJ, Leachman SA, Feng BJ, Schwartz ME, Hansen CD. A review of the clinical phenotype of 254 patients with genetically confirmed pachyonychia congenita. J Am Acad Dermatol. 2012;67(4):680–6.PubMedGoogle Scholar
  18. 18.
    Leachman SA, Kaspar RL, Fleckman P, Florell SR, Smith FJ, McLean WH, et al. Clinical and pathological features of pachyonychia congenita. J Investig Dermatol Symp Proc. 2005;10(1):3–17.PubMedGoogle Scholar
  19. 19.
    Su WP, Chun SI, Hammond DE, Gordon H. Pachyonychia congenita: a clinical study of 12 cases and review of the literature. Pediatr Dermatol. 1990;7(1):33–8.PubMedGoogle Scholar
  20. 20.
    da Silva Santos PS, Mannarino F, Lellis RF, Osório LH. Oral manifestations of pachyonychia congenita. Dermatol Online J. 2010;16(10):3.PubMedGoogle Scholar
  21. 21.
    Karen JK, Schaffer JV. Pachyonychia congenita associated with median rhomboid glossitis. Dermatol Online J. 2007;13(1):21.PubMedGoogle Scholar
  22. 22.
    Hannaford RS, Stapleton K. Pachyonychia congenita tarda. Australas J Dermatol. 2000;41(3):175–7.PubMedGoogle Scholar
  23. 23.
    Rondon Lugo AJ. Congenital pachyonychia treated by oral retinoid. Med Cutanea Ibero-Lat-Am. 1982;10(6):395–8.Google Scholar
  24. 24.
    Gruber R, Edlinger M, Kaspar RL, Hansen CD, Leachman S, Milstone LM, et al. An appraisal of oral retinoids in the treatment of pachyonychia congenita. J Am Acad Dermatol. 2012;66(6):e193–9.PubMedGoogle Scholar
  25. 25.
    Kirwan M, Dokal I. Dyskeratosis congenita: a genetic disorder of many faces. Clin Genet. 2008;73(2):103–12.PubMedGoogle Scholar
  26. 26.
    Lamm N, Ordan E, Shponkin R, Richler C, Aker M, Tzfati Y. Diminished telomeric 3′ overhangs are associated with telomere dysfunction in Hoyeraal-Hreidarsson syndrome. PLoS One. 2009;4(5):e5666.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Vulliamy T, Beswick R, Kirwan M, Marrone A, Digweed M, Walne A, et al. Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc Natl Acad Sci U S A. 2008;105(23):8073–8.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Dokal I. Dyskeratosis congenita: recent advances and future directions. J Pediatr Hematol Oncol. 1999;21(5):344–50.PubMedGoogle Scholar
  29. 29.
    Solder B, Weiss M, Jäger A, Belohradsky BH. Dyskeratosis congenita: multisystemic disorder with special consideration of immunologic aspects. A review of the literature. Clin Pediatr. 1998;37(9):521–30.Google Scholar
  30. 30.
    Atkinson JC, Harvey KE, Domingo DL, Trujillo MI, Guadagnini JP, Gollins S, et al. Oral and dental phenotype of dyskeratosis congenita. Oral Dis. 2008;14(5):419–27.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Fernandez Garcia MS, Teruya-Feldstein J. The diagnosis and treatment of dyskeratosis congenita: a review. J Blood Med. 2014;5:157–67.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Yavuzyilmaz E, Yamalik N, Yetgin S, Kansu O. Oral-dental findings in dyskeratosis congenita. J Oral Pathol Med. 1992;21(6):280–4.PubMedGoogle Scholar
  33. 33.
    Vohra F, Al-Kheraif AA, Qadri T, Hassan MI, Ahmed A, Warnakulasuriya S, et al. Efficacy of photodynamic therapy in the management of oral premalignant lesions. A systematic review. Photodiagn Photodyn Ther. 2015;12(1):150–9.Google Scholar
  34. 34.
    Tambuwala A, Sangle A, Khan A, Sayed A. Excision of oral leukoplakia by CO2 lasers versus traditional scalpel: a comparative study. J Maxillofac Oral Surg. 2014;13(3):320–7.PubMedGoogle Scholar
  35. 35.
    Kitao S, Shimamoto A, Goto M, Miller RW, Smithson WA, Lindor NM, et al. Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome. Nat Genet. 1999;22(1):82–4.PubMedGoogle Scholar
  36. 36.
    Mann MB, Hodges CA, Barnes E, Vogel H, Hassold TJ, Luo G. Defective sister-chromatid cohesion, aneuploidy and cancer predisposition in a mouse model of type II Rothmund-Thomson syndrome. Hum Mol Genet. 2005;14(6):813–25.PubMedGoogle Scholar
  37. 37.
    Simon T, Kohlhase J, Wilhelm C, Kochanek M, De Carolis B, Berthold F. Multiple malignant diseases in a patient with Rothmund-Thomson syndrome with RECQL4 mutations: case report and literature review. Am J Med Genet A. 2010;152A(6):1575–9.PubMedGoogle Scholar
  38. 38.
    Pujol LA, Erickson RP, Heidenreich RA, Cunniff C. Variable presentation of Rothmund-Thomson syndrome. Am J Med Genet. 2000;95(3):204–7.PubMedGoogle Scholar
  39. 39.
    Wang LL, Levy ML, Lewis RA, Chintagumpala MM, Lev D, Rogers M, et al. Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients. Am J Med Genet. 2001;102(1):11–7.PubMedGoogle Scholar
  40. 40.
    Thomson MS. Poikiloderma congenitale: two cases for diagnosis. Proc R Soc Med. 1936;29(5):453–5.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Kraus BS, Gottlieb MA, Meliton HR. The dentition in Rothmund’s syndrome. J Am Dent Assoc. 1970;81(4):895–915.PubMedGoogle Scholar
  42. 42.
    Starr DG, McClure JP, Connor JM. Non-dermatological complications and genetic aspects of the Rothmund-Thomson syndrome. Clin Genet. 1985;27(1):102–4.PubMedGoogle Scholar
  43. 43.
    Haytac MC, Oztunç H, Mete UO, Kaya M. Rothmund-Thomson syndrome: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002;94(4):479–84.PubMedGoogle Scholar
  44. 44.
    Roinioti TD, Stefanopoulos PK. Short root anomaly associated with Rothmund-Thomson syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;103(1):e19–22.PubMedGoogle Scholar
  45. 45.
    Kant SG, Baraitser M, Milla PJ, Winter RM. Rapadilino syndrome – a non-Finnish case. Clin Dysmorphol. 1998;7(2):135–8.PubMedGoogle Scholar
  46. 46.
    Vargas FR, de Almeida JC, Llerena Júnior JC, Reis DF. Rapadilino syndrome. Am J Med Genet. 1992;44(6):716–9.PubMedGoogle Scholar
  47. 47.
    Faughnan ME, Palda VA, Garcia-Tsao G, Geisthoff UW, McDonald J, Proctor DD, et al. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet. 2011;48(2):73–87.PubMedGoogle Scholar
  48. 48.
    McDonald JE, Miller FJ, Hallam SE, Nelson L, Marchuk DA, Ward KJ. Clinical manifestations in a large hereditary hemorrhagic telangiectasia (HHT) type 2 kindred. Am J Med Genet. 2000;93(4):320–7.PubMedGoogle Scholar
  49. 49.
    Wooderchak-Donahue WL, McDonald J, O’Fallon B, Upton PD, Li W, Roman BL, et al. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am J Hum Genet. 2013;93(3):530–7.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Schwenter F, Faughnan ME, Gradinger AB, Berk T, Gryfe R, Pollett A, et al. Juvenile polyposis, hereditary hemorrhagic telangiectasia, and early onset colorectal cancer in patients with SMAD4 mutation. J Gastroenterol. 2012;47(7):795–804.PubMedGoogle Scholar
  51. 51.
    Austin GB, Quart AM, Novak B. Hereditary hemorrhagic telangiectasia with oral manifestations. Report of periodontal treatment in two cases. Oral Surg Oral Med Oral Pathol. 1981;51(3):245–51.PubMedGoogle Scholar
  52. 52.
    Hopp RN, de Siqueira DC, Sena-Filho M, Jorge J. Oral vascular malformation in a patient with hereditary hemorrhagic telangiectasia: a case report. Spec Care Dent. 2013;33(3):150–3.Google Scholar
  53. 53.
    Haitjema TJ, van Snippenburg R, Disch FJ, Overtoom TT, Westermann CJ. Recurrent epistaxis: sometimes Rendu-Osler-Weber disease. Ned Tijdschr Geneeskd. 1996;140(44):2157–60.PubMedGoogle Scholar
  54. 54.
    Mylona E, Vadala C, Papastamopoulos V, Skoutelis A. Brain abscess caused by Enterococcus faecalis following a dental procedure in a patient with hereditary hemorrhagic telangiectasia. J Clin Microbiol. 2012;50(5):1807–9.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Corre P, Perret C, Isidor B, Khonsari RH. A brain abscess following dental extractions in a patient with hereditary hemorrhagic telangiectasia. Br J Oral Maxillofac Surg. 2011;49(5):e9–11.PubMedGoogle Scholar
  56. 56.
    Brancati F, Valente EM, Tadini G, Caputo V, Di Benedetto A, Gelmetti C, et al. Autosomal dominant hereditary benign telangiectasia maps to the CMC1 locus for capillary malformation on chromosome 5q14. J Med Genet. 2003;40(11):849–53.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Galletta A, Amato G. Hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease) management of epistaxis and oral hemorrhage by Nd-Yag laser. Minerva Stomatol. 1998;47(6):283–6.PubMedGoogle Scholar
  58. 58.
    Schallreuter KU, Frenk E, Wolfe LS, Witkop CJ, Wood JM. Hermansky-Pudlak syndrome in a Swiss population. Dermatology. 1993;187(4):248–56.PubMedGoogle Scholar
  59. 59.
    Wildenberg SC, Oetting WS, Almodóvar C, Krumwiede M, White JG, King RA. A gene causing Hermansky-Pudlak syndrome in a Puerto Rican population maps to chromosome 10q2. Am J Hum Genet. 1995;57(4):755–65.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Oh J, Bailin T, Fukai K, Feng GH, Ho L, Mao JI, et al. Positional cloning of a gene for Hermansky-Pudlak syndrome, a disorder of cytoplasmic organelles. Nat Genet. 1996;14(3):300–6.PubMedGoogle Scholar
  61. 61.
    Oh J, Ho L, Ala-Mello S, Amato D, Armstrong L, Bellucci S, et al. Mutation analysis of patients with Hermansky-Pudlak syndrome: a frameshift hot spot in the HPS gene and apparent locus heterogeneity. Am J Hum Genet. 1998;62(3):593–8.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Kinnear PE, Tuddenham EG. Albinism with haemorrhagic diathesis: Hermansky-Pudlak syndrome. Br J Ophthalmol. 1985;69(12):904–8.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Theuring F, Fiedler J. Fatal bleeding following tooth extraction. Hermansky-Pudlak-syndrome. Dtsch Stomatol. 1973;23(1):52–5.PubMedGoogle Scholar
  64. 64.
    Feliciano NZ, Rivera E, Agrait E, Rodriguez K. Hermansky-Pudlak syndrome: dental management considerations. J Dent Child. 2006;73(1):51–6.Google Scholar
  65. 65.
    Valera MC, Kemoun P, Cousty S, Sie P, Payrastre B. Inherited platelet disorders and oral health. J Oral Pathol Med. 2013;42(2):115–24.PubMedGoogle Scholar
  66. 66.
    Keebaugh AC, Sullivan RT, Thomas JW. Gene duplication and inactivation in the HPRT gene family. Genomics. 2007;89(1):134–42.PubMedGoogle Scholar
  67. 67.
    Torres RJ, Puig JG. Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome. Orphanet J Rare Dis. 2007;2:48.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Limeres J, Feijoo JF, Baluja F, Seoane JM, Diniz M, Diz P. Oral self-injury: an update. Dent Traumatol. 2013;29(1):8–14.PubMedGoogle Scholar
  69. 69.
    Bodner L, Woldenberg Y, Pinsk V, Levy J. Orofacial manifestations of congenital insensitivity to pain with anhidrosis: a report of 24 cases. ASDC J Dent Child. 2002;69(3):293–6.. 235PubMedGoogle Scholar
  70. 70.
    Rojahn J. Self-injurious and stereotypic behavior of noninstitutionalized mentally retarded people: prevalence and classification. Am J Ment Defic. 1986;91(3):268–76.PubMedGoogle Scholar
  71. 71.
    Brunner J, Lotschutz D. Kelley-Seegmiller syndrome. Klin Padiatr. 2008;220(1):21–3.PubMedGoogle Scholar
  72. 72.
    Cusumano FJ, Penna KJ, Panossian G. Prevention of self-mutilation in patients with Lesch-Nyhan syndrome: review of literature. ASDC J Dent Child. 2001;68(3):175–8.PubMedGoogle Scholar
  73. 73.
    Amos CI, Bali D, Thiel TJ, Anderson JP, Gourley I, Frazier ML, et al. Fine mapping of a genetic locus for Peutz-Jeghers syndrome on chromosome 19p. Cancer Res. 1997;57(17):3653–6.PubMedGoogle Scholar
  74. 74.
    Kitagawa S, Townsend BL, Hebert AA. Peutz-Jeghers syndrome. Dermatol Clin. 1995;13(1):127–33.PubMedGoogle Scholar
  75. 75.
    Boardman LA, Thibodeau SN, Schaid DJ, Lindor NM, McDonnell SK, Burgart LJ, et al. Increased risk for cancer in patients with the Peutz-Jeghers syndrome. Ann Intern Med. 1998;128(11):896–9.PubMedGoogle Scholar
  76. 76.
    Li Y, Tong X, Yang J, Yang L, Tao J, Tu Y. Q-switched alexandrite laser treatment of facial and labial lentigines associated with Peutz-Jeghers syndrome. Photodermatol Photoimmunol Photomed. 2012;28(4):196–9.PubMedGoogle Scholar
  77. 77.
    Xi Z, Hui Q, Zhong L. Q-switched alexandrite laser treatment of oral labial lentigines in Chinese subjects with Peutz-Jeghers syndrome. Dermatol Surg. 2009;35(7):1084–8.PubMedGoogle Scholar
  78. 78.
    Chang CJ, Nelson JS. Q-switched ruby laser treatment of mucocutaneous melanosis associated with Peutz-Jeghers syndrome. Ann Plast Surg. 1996;36(4):394–7.PubMedGoogle Scholar
  79. 79.
    Finger RP, Charbel Issa P, Ladewig MS, Götting C, Szliska C, Scholl HP, et al. Pseudoxanthoma elasticum: genetics, clinical manifestations and therapeutic approaches. Surv Ophthalmol. 2009;54(2):272–85.PubMedGoogle Scholar
  80. 80.
    Bergen AA, Plomp AS, Schuurman EJ, Terry S, Breuning M, Dauwerse H, et al. Mutations in ABCC6 cause pseudoxanthoma elasticum. Nat Genet. 2000;25(2):228–31.PubMedGoogle Scholar
  81. 81.
    Spinzi G, Strocchi E, Imperiali G, Sangiovanni A, Terruzzi V, Minoli G. Pseudoxanthoma elasticum: a rare cause of gastrointestinal bleeding. Am J Gastroenterol. 1996;91(8):1631–4.PubMedGoogle Scholar
  82. 82.
    Goette DK, Carpenter WM. The mucocutaneous marker of pseudoxanthoma elasticum. Oral Surg Oral Med Oral Pathol. 1981;51(1):68–72.PubMedGoogle Scholar
  83. 83.
    Sayin MO, Atilla AO, Esenlik E, Ozen T, Karahan N. Oligodontia in pseudoxanthoma elasticum. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;103(5):e60–4.PubMedGoogle Scholar
  84. 84.
    Utani A, Tanioka M, Yamamoto Y, Taki R, Araki E, Tamura H, et al. Relationship between the distribution of pseudoxanthoma elasticum skin and mucous membrane lesions and cardiovascular involvement. J Dermatol. 2010;37(2):130–6.PubMedGoogle Scholar
  85. 85.
    Sherer DW, Sapadin AN, Lebwohl MG. Pseudoxanthoma elasticum: an update. Dermatology. 1999;199(1):3–7.PubMedGoogle Scholar
  86. 86.
    Shibuya Y, Zhang J, Yokoo S, Umeda M, Komori T. Constitutional mutation of keratin 13 gene in familial white sponge nevus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;96(5):561–5.PubMedGoogle Scholar
  87. 87.
    Rugg EL, McLean WH, Allison WE, Lunny DP, Macleod RI, Felix DH, et al. A mutation in the mucosal keratin K4 is associated with oral white sponge nevus. Nat Genet. 1995;11(4):450–2.PubMedGoogle Scholar
  88. 88.
    Richard G, De Laurenzi V, Didona B, Bale SJ, Compton JG. Keratin 13 point mutation underlies the hereditary mucosal epithelial disorder white sponge nevus. Nat Genet. 1995;11(4):453–5.PubMedGoogle Scholar
  89. 89.
    Lamey PJ, Bolas A, Napier SS, Darwazeh AM, Macdonald DG. Oral white sponge naevus: response to antibiotic therapy. Clin Exp Dermatol. 1998;23(2):59–63.PubMedGoogle Scholar
  90. 90.
    Otobe IF, de Sousa SO, Matthews RW, Migliari DA. White sponge naevus: improvement with tetracycline mouth rinse: report of four cases. Clin Exp Dermatol. 2007;32(6):749–51.PubMedGoogle Scholar
  91. 91.
    Otobe IF, de Sousa SO, Migliari DA, Matthews RW. Successful treatment with topical tetracycline of oral white sponge nevus occurring in a patient with systemic lupus erythematosus. Int J Dermatol. 2006;45(9):1130–1.PubMedGoogle Scholar
  92. 92.
    Satriano RA, Errichetti E, Baroni A. White sponge nevus treated with chlorhexidine. J Dermatol. 2012;39(8):742–3.PubMedGoogle Scholar
  93. 93.
    Dufrasne L, Magremanne M, Parent D, Evrard L. Current therapeutic approach of the white sponge naevus of the oral cavity. Bull Group Int Rech Sci Stomatol Odontol. 2011;50(1):1–5.PubMedGoogle Scholar
  94. 94.
    Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB, et al. Identification of FAP locus genes from chromosome 5q21. Science. 1991;253(5020):661–5.PubMedGoogle Scholar
  95. 95.
    Petersen GM, Slack J, Nakamura Y. Screening guidelines and premorbid diagnosis of familial adenomatous polyposis using linkage. Gastroenterology. 1991;100(6):1658–64.PubMedGoogle Scholar
  96. 96.
    Traboulsi EI, Maumenee IH, Krush AJ, Giardiello FM, Levin LS, Hamilton SR. Pigmented ocular fundus lesions in the inherited gastrointestinal polyposis syndromes and in hereditary nonpolyposis colorectal cancer. Ophthalmology. 1988;95(7):964–9.PubMedGoogle Scholar
  97. 97.
    Jagelman DG. Extracolonic manifestations of familial polyposis coli. Semin Surg Oncol. 1987;3(2):88–91.PubMedGoogle Scholar
  98. 98.
    Fader M, Kline SN, Spatz SS, Zubrow HJ. Gardner’s syndrome (intestinal polyposis, osteomas, sebaceous cysts) and a new dental discovery. Oral Surg Oral Med Pathol. 1962;15:153–72.Google Scholar
  99. 99.
    Ida M, Nakamura T, Utsunomiya J. Osteomatous changes and tooth abnormalities found in the jaw of patients with adenomatosis coli. Oral Surg Oral Med Pathol. 1962;15:153–72.. 1981. 52(1): 2–11Google Scholar
  100. 100.
    Kubo K, Miyatani H, Takenoshita Y, Abe K, Oka M, Iida M, et al. Widespread radiopacity of jaw bones in familial adenomatosis coli. J Craniomaxillofac Surg. 1989;17(8):350–3.PubMedGoogle Scholar
  101. 101.
    Wijn MA, Keller JJ, Giardiello FM, Brand HS. Oral and maxillofacial manifestations of familial adenomatous polyposis. Oral Dis. 2007;13(4):360–5.PubMedGoogle Scholar
  102. 102.
    Lew D, DeWitt A, Hicks RJ, Cavalcanti MG. Osteomas of the condyle associated with Gardner’s syndrome causing limited mandibular movement. J Oral Maxillofac Surg. 1999;57(8):1004–9.PubMedGoogle Scholar
  103. 103.
    Jones EL, Cornell WP. Gardner’s syndrome; review of the literature and report on a family. Arch Surg. 1966;92(2):287–300.PubMedGoogle Scholar
  104. 104.
    Payne M, Anderson JA, Cook J. Gardner’s syndrome – a case report. Br Dent J. 2002;193(7):383–4.PubMedGoogle Scholar
  105. 105.
    Wijn MA, Keller JJ, Brand HS. Oral and maxillofacial manifestations of familial adenomatosis polyposis. Gardner’s syndrome. Ned Tijdschr Tandheelkd. 2005;112(9):340–4.PubMedGoogle Scholar
  106. 106.
    Boffano P, Bosco GF, Gerbino G. The surgical management of oral and maxillofacial manifestations of Gardner syndrome. J Oral Maxillofac Surg. 2010;68(10):2549–54.PubMedGoogle Scholar
  107. 107.
    Stevenson DA, Carey JC, Byrne JL, Srisukhumbowornchai S, Feldkamp ML. Analysis of skeletal dysplasias in the Utah population. Am J Med Genet A. 2012;158A(5):1046–54.PubMedGoogle Scholar
  108. 108.
    Stoll C, Dott B, Roth MP, Alembik Y. Birth prevalence rates of skeletal dysplasias. Clin Genet. 1989;35(2):88–92.PubMedGoogle Scholar
  109. 109.
    Harrington J, Sochett E, Howard A. Update on the evaluation and treatment of osteogenesis imperfecta. Pediatr Clin N Am. 2014;61(6):1243–57.Google Scholar
  110. 110.
    Bodian DL, Chan TF, Poon A, Schwarze U, Yang K, Byers PH, et al. Mutation and polymorphism spectrum in osteogenesis imperfecta type II: implications for genotype-phenotype relationships. Hum Mol Genet. 2009;18(3):463–71.PubMedGoogle Scholar
  111. 111.
    Paterson CR, Monk EA, McAllion SJ. How common is hearing impairment in osteogenesis imperfecta? J Laryngol Otol. 2001;115(4):280–2.PubMedGoogle Scholar
  112. 112.
    Bonita RE, Cohen IS, Berko BA. Valvular heart disease in osteogenesis imperfecta: presentation of a case and review of the literature. Echocardiography. 2010;27(1):69–73.PubMedGoogle Scholar
  113. 113.
    Charnas LR, Marini JC. Communicating hydrocephalus, basilar invagination, and other neurologic features in osteogenesis imperfecta. Neurology. 1993;43(12):2603–8.PubMedGoogle Scholar
  114. 114.
    O’Connell AC, Marini JC. Evaluation of oral problems in an osteogenesis imperfecta population. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;87(2):189–96.PubMedGoogle Scholar
  115. 115.
    Majorana A, Bardellini E, Brunelli PC, Lacaita M, Cazzolla AP, Favia G. Dentinogenesis imperfecta in children with osteogenesis imperfecta: a clinical and ultrastructural study. Int J Paediatr Dent. 2010;20(2):112–8.PubMedGoogle Scholar
  116. 116.
    Barron MJ, McDonnell ST, Mackie I, Dixon MJ. Hereditary dentine disorders: dentinogenesis imperfecta and dentine dysplasia. Orphanet J Rare Dis. 2008;3:31.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Abukabbos H, Al-Sineedi F. Clinical manifestations and dental management of dentinogenesis imperfecta associated with osteogenesis imperfecta: case report. Saudi Dent J. 2013;25(4):159–65.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Sapir S, Shapira J. Dentinogenesis imperfecta: an early treatment strategy. Pediatr Dent. 2001;23(3):232–7.PubMedGoogle Scholar
  119. 119.
    Mars M, Smith BG. Dentinogenesis imperfecta. An integrated conservative approach to treatment. Br Dent J. 1982;152(1):15–8.PubMedGoogle Scholar
  120. 120.
    Bencharit S, Border MB, Mack CR, Byrd WC, Wright JT. Full-mouth rehabilitation for a patient with dentinogenesis imperfecta: a clinical report. J Oral Implantol. 2014;40(5):593–600.PubMedGoogle Scholar
  121. 121.
    Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson SM, et al. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A. 2010;152A(2):327–32.PubMedGoogle Scholar
  122. 122.
    Shanley S, Ratcliffe J, Hockey A, Haan E, Oley C, Ravine D, et al. Nevoid basal cell carcinoma syndrome: review of 118 affected individuals. Am J Med Genet. 1994;50(3):282–90.PubMedGoogle Scholar
  123. 123.
    Smith MJ, Beetz C, Williams SG, Bhaskar SS, O’Sullivan J, Anderson B, et al. Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations. J Clin Oncol. 2014;32(36):4155–61.PubMedGoogle Scholar
  124. 124.
    Fujii K, Miyashita T. Gorlin syndrome (nevoid basal cell carcinoma syndrome): update and literature review. Pediatr Int. 2014;56(5):667–74.PubMedGoogle Scholar
  125. 125.
    Kimonis VE, Goldstein AM, Pastakia B, Yang ML, Kase R, DiGiovanna JJ, et al. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet. 1997;69(3):299–308.PubMedGoogle Scholar
  126. 126.
    Levine DJ, Robertson DB, Varma VA. Familial subconjunctival epithelial cysts associated with the nevoid basal cell carcinoma syndrome. Arch Dermatol. 1987;123(1):23–4.PubMedGoogle Scholar
  127. 127.
    Gorlin RJ, Goltz RW. Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib. A syndrome. N Engl J Med. 1960;262:908–12.PubMedGoogle Scholar
  128. 128.
    Evans DG, Sims DG, Donnai D. Family implications of neonatal Gorlin’s syndrome. Arch Dis Child. 1991;66(10. Spec No):1162–3.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Lile HA, Rogers JF, Gerald B. The basal cell nevus syndrome. Am J Roentgenol Radium Ther Nucl Med. 1968;103(1):214–7.PubMedGoogle Scholar
  130. 130.
    Wright JM, Odell EW, Speight PM, Takata T. Odontogenic tumors, WHO 2005: where do we go from here? Head Neck Pathol. 2014;8(4):373–82.PubMedPubMedCentralGoogle Scholar
  131. 131.
    Lo Muzio L, Nocini P, Bucci P, Pannone G, Consolo U, Procaccini M. Early diagnosis of nevoid basal cell carcinoma syndrome. J Am Dent Assoc. 1999;130(5):669–74.PubMedGoogle Scholar
  132. 132.
    Brannon RB. The odontogenic keratocyst. A clinicopathologic study of 312 cases. Part I. Clinical features. Oral Surg Oral Med Oral Pathol. 1976;42(1):54–72.PubMedGoogle Scholar
  133. 133.
    Habibi A, Saghravanian N, Habibi M, Mellati E, Habibi M. Keratocystic odontogenic tumor: a 10-year retrospective study of 83 cases in an Iranian population. J Oral Sci. 2007;49(3):229–35.PubMedGoogle Scholar
  134. 134.
    Evans DG, Ladusans EJ, Rimmer S, Burnell LD, Thakker N, Farndon PA. Complications of the naevoid basal cell carcinoma syndrome: results of a population based study. J Med Genet. 1993;30(6):460–4.PubMedPubMedCentralGoogle Scholar
  135. 135.
    Kimonis VE, Singh KE, Zhong R, Pastakia B, Digiovanna JJ, Bale SJ. Clinical and radiological features in young individuals with nevoid basal cell carcinoma syndrome. Genet Med. 2013;15(1):79–83.PubMedGoogle Scholar
  136. 136.
    Leonardi R, Sorge G, Caltabino M. Bilateral hyperplasia of the mandibular coronoid processes associated with the nevoid basal cell carcinoma syndrome in an Italian boy. Br Dent J. 2001;190(7):349–50.PubMedGoogle Scholar
  137. 137.
    Roopak B, Singh M, Shah A, Patel G. Keratocystic odontogenic tumor: treatment modalities: study of 3 cases. Niger J Clin Pract. 2014;17(3):378–83.PubMedGoogle Scholar
  138. 138.
    Sembronio S, Albiero AM, Zerman N, Costa F, Politi M. Endoscopically assisted enucleation and curettage of large mandibular odontogenic keratocyst. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;107(2):193–6.PubMedGoogle Scholar
  139. 139.
    Terranova F, Trevisiol L, Nocini PF, Bissolotti G, Bondì V, De Santis D, Bertossi D, D’agostino A. Keratocyst, conservative treatment: case report. Minerva Stomatol. 2013;62(8 Suppl 1):71–8. Epub 2013 Aug 1.Google Scholar
  140. 140.
    Nakayama T, Otori N, Asaka D, Okushi T, Haruna S. Endoscopic modified medial maxillectomy for odontogenic cysts and tumours. Rhinology. 2014;52(4):376–80.PubMedGoogle Scholar
  141. 141.
    Gene Reviews. Nevoid basal cell carcinoma syndrome. 2013. 12/08/2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1151/.
  142. 142.
    Hallett L, Foster T, Liu Z, Blieden M, Valentim J. Burden of disease and unmet needs in tuberous sclerosis complex with neurological manifestations: systematic review. Curr Med Res Opin. 2011;27(8):1571–83.PubMedGoogle Scholar
  143. 143.
    Osborne JP, Fryer A, Webb D. Epidemiology of tuberous sclerosis. Ann N Y Acad Sci. 1991;615:125–7.PubMedGoogle Scholar
  144. 144.
    Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet. 2008;372(9639):657–68.PubMedGoogle Scholar
  145. 145.
    Cutando A, Gil JA, Lopez J. Oral health management implications in patients with tuberous sclerosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90(4):430–5.PubMedGoogle Scholar
  146. 146.
    Gomez MR. History of the tuberous sclerosis complex. Brain Dev. 1995;17(Suppl):55–7.PubMedGoogle Scholar
  147. 147.
    Teng JM, Cowen EW, Wataya-Kaneda M, Gosnell ES, Witman PM, Hebert AA, et al. Dermatologic and dental aspects of the 2012 International Tuberous Sclerosis Complex Consensus Statements. JAMA Dermatol. 2014;150(10):1095–101.PubMedGoogle Scholar
  148. 148.
    Tillman HH, De Caro F. Tuberous sclerosis. Oral Surg Oral Med Oral Pathol. 1991;71(3):301–2.PubMedGoogle Scholar
  149. 149.
    Flanagan N, O’Connor WJ, McCartan B, Miller S, McMenamin J, Watson R. Developmental enamel defects in tuberous sclerosis: a clinical genetic marker? J Med Genet. 1997;34(8):637–9.PubMedPubMedCentralGoogle Scholar
  150. 150.
    Valerio RA, de Queiroz AM, Romualdo PC, Brentegani LG, de Paula-Silva FW. Mucocele and fibroma: treatment and clinical features for differential diagnosis. Braz Dent J. 2013;24(5):537–41.PubMedGoogle Scholar
  151. 151.
    Ammari MM, Ribeiro de Souza IP, Maia LC, Primo LG. Oral findings in a family with tuberous sclerosis complex. Spec Care Dent. 2014. [Epub ahead of print].Google Scholar
  152. 152.
    Sakuntabhai A, Ruiz-Perez V, Carter S, Jacobsen N, Burge S, Monk S, et al. Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease. Nat Genet. 1999;21(3):271–7.PubMedGoogle Scholar
  153. 153.
    MacLennan DH, Brandl CJ, Korczak B, Green NM. Amino-acid sequence of a Ca2+ + Mg2+-dependent ATPase from rabbit muscle sarcoplasmic reticulum, deduced from its complementary DNA sequence. Nature. 1985;316(6030):696–700.PubMedGoogle Scholar
  154. 154.
    Ruiz-Perez VL, Carter SA, Healy E, Todd C, Rees JL, Steijlen PM, et al. ATP2A2 mutations in Darier’s disease: variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of mutation class. Hum Mol Genet. 1999;8(9):1621–30.PubMedGoogle Scholar
  155. 155.
    Munro CS. The phenotype of Darier’s disease: penetrance and expressivity in adults and children. Br J Dermatol. 1992;127(2):126–30.PubMedGoogle Scholar
  156. 156.
    Burge SM, Wilkinson JD. Darier-White disease: a review of the clinical features in 163 patients. J Am Acad Dermatol. 1992;27(1):40–50.PubMedGoogle Scholar
  157. 157.
    Burge S. Darier’s disease – the clinical features and pathogenesis. Clin Exp Dermatol. 1994;19(3):193–205.PubMedGoogle Scholar
  158. 158.
    Craddock N, Dawson E, Burge S, Parfitt L, Mant B, Roberts Q, et al. The gene for Darier’s disease maps to chromosome 12q23-q24.1. Hum Mol Genet. 1993;2(11):1941–3.PubMedGoogle Scholar
  159. 159.
    Gordon-Smith K, Jones LA, Burge SM, Munro CS, Tavadia S, Craddock N. The neuropsychiatric phenotype in Darier disease. Br J Dermatol. 2010;163(3):515–22.PubMedGoogle Scholar
  160. 160.
    Macleod RI, Munro CS. The incidence and distribution of oral lesions in patients with Darier’s disease. Br Dent J. 1991;171(5):133–6.PubMedGoogle Scholar
  161. 161.
    Thiagarajan MK, Narasimhan M, Sankarasubramanian A. Darier disease with oral and esophageal involvement: a case report. Indian J Dent Res. 2011;22(6):843–6.PubMedGoogle Scholar
  162. 162.
    Shimizu H, Tan Kinoshita MT, Suzuki H. Darier’s disease with esophageal carcinoma. Eur J Dermatol. 2000;10(6):470–2.PubMedGoogle Scholar
  163. 163.
    Abel MD, Carrasco LR. Ehlers-Danlos syndrome: classifications, oral manifestations, and dental considerations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;102(5):582–90.PubMedGoogle Scholar
  164. 164.
    De Felice C, Toti P, Di Maggio G, Parrini S, Bagnoli F. Absence of the inferior labial and lingual frenula in Ehlers-Danlos syndrome. Lancet. 2001;357(9267):1500–2.PubMedGoogle Scholar
  165. 165.
    Majorana A, Facchetti F. The orodental findings in the Ehlers-Danlos syndrome. A report of 2 clinical cases. Minerva Stomatol. 1992;41(3):127–33.PubMedGoogle Scholar
  166. 166.
    Colebatch AN, Shaw EC, Foulds NC, Davidson BK. Hemorrhagic bullae of the oral mucosa as an early manifestation of vascular-type ehlers-danlos syndrome. J Clin Rheumatol. 2011;17(7):383–4.PubMedGoogle Scholar
  167. 167.
    Ferreira O Jr, Cardoso CL, Capelozza AL, Yaedú RY, da Costa AR. Odontogenic keratocyst and multiple supernumerary teeth in a patient with Ehlers-Danlos syndrome – a case report and review of the literature. Quintessence Int. 2008;39(3):251–6.PubMedGoogle Scholar
  168. 168.
    Badauy CM, Gomes SS, Sant’Ana Filho M, Chies JA. Ehlers-Danlos syndrome (EDS) type IV: review of the literature. Clin Oral Investig. 2007;11(3):183–7.PubMedGoogle Scholar
  169. 169.
    Letourneau Y, Perusse R, Buithieu H. Oral manifestations of Ehlers-Danlos syndrome. J Can Dent Assoc. 2001;67(6):330–4.PubMedGoogle Scholar
  170. 170.
    Hagberg C, Korpe L, Berglund B. Temporomandibular joint problems and self-registration of mandibular opening capacity among adults with Ehlers-Danlos syndrome. A questionnaire study. Orthod Craniofac Res. 2004;7(1):40–6.PubMedGoogle Scholar
  171. 171.
    Norton LA, Assael LA. Orthodontic and temporomandibular joint considerations in treatment of patients with Ehlers-Danlos syndrome. Am J Orthod Dentofac Orthop. 1997;111(1):75–84.Google Scholar
  172. 172.
    Sherman SL, Allen EG, Bean LH, Freeman SB. Epidemiology of Down syndrome. Ment Retard Dev Disabil Res Rev. 2007;13(3):221–7.PubMedGoogle Scholar
  173. 173.
    Sekerci AE, Cantekin K, Aydinbelge M, Ucar Fİ. Prevalence of dental anomalies in the permanent dentition of children with Down syndrome. J Dent Child. 2014;81(2):78–83.Google Scholar
  174. 174.
    Abeleira MT, Outumuro M, Ramos I, Limeres J, Diniz M, Diz P. Dimensions of central incisors, canines, and first molars in subjects with Down syndrome measured on cone-beam computed tomographs. Am J Orthod Dentofac Orthop. 2014;146(6):765–75.Google Scholar
  175. 175.
    Oredugba FA, Eigbobo JO, Temisanren OT. Tooth crown dimensions in a selected population of Nigerians with Down syndrome. West Afr J Med. 2014;33(2):146–50.PubMedGoogle Scholar
  176. 176.
    Rao D, Hegde S, Naik S, Shetty P. Malocclusion in individuals with mental subnormality – a review. Oral Health Dent Manag. 2014;13(3):786–91.PubMedGoogle Scholar
  177. 177.
    de Miguel-Diez J, Villa-Asensi JR, Alvarez-Sala JL. Prevalence of sleep-disordered breathing in children with Down syndrome: polygraphic findings in 108 children. Sleep. 2003;26(8):1006–9.PubMedGoogle Scholar
  178. 178.
    Guimaraes CV, Donnelly LF, Shott SR, Amin RS, Kalra M. Relative rather than absolute macroglossia in patients with Down syndrome: implications for treatment of obstructive sleep apnea. Pediatr Radiol. 2008;38(10):1062–7.PubMedGoogle Scholar
  179. 179.
    Anuthama K, Prasad H, Ramani P, Premkumar P, Natesan A, Sherlin HJ. Genetic alterations in syndromes with oral manifestations. Dent Res J. 2013;10(6):713–22.Google Scholar
  180. 180.
    Al-Sufyani GA, Al-Maweri SA, Al-Ghashm AA, Al-Soneidar WA. Oral hygiene and gingival health status of children with Down syndrome in Yemen: a cross-sectional study. J Int Soc Prevent Commun Dent. 2014;4(2):82–6.Google Scholar
  181. 181.
    Chin CJ, Khami MM, Husein M. A general review of the otolaryngologic manifestations of Down syndrome. Int J Pediatr Otorhinolaryngol. 2014;78(6):899–904.PubMedGoogle Scholar
  182. 182.
    Ribeiro CG, Siqueira AF, Bez L, Cardoso AC, Ferreira CF. Dental implant rehabilitation of a patient with Down syndrome: a case report. J Oral Implantol. 2011;37(4):481–7.PubMedGoogle Scholar
  183. 183.
    Lehmann AR, McGibbon D, Stefanini M. Xeroderma pigmentosum. Orphanet J Rare Dis. 2011;6:70.PubMedPubMedCentralGoogle Scholar
  184. 184.
    Kraemer KH, Lee MM, Andrews AD, Lambert WC. The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer. The xeroderma pigmentosum paradigm. Arch Dermatol. 1994;130(8):1018–21.PubMedGoogle Scholar
  185. 185.
    Li C, Hu Z, Liu Z, Wang LE, Strom SS, Gershenwald JE, et al. Polymorphisms in the DNA repair genes XPC, XPD, and XPG and risk of cutaneous melanoma: a case-control analysis. Cancer Epidemiol Biomark Prev. 2006;15(12):2526–32.Google Scholar
  186. 186.
    Anttinen A, Koulu L, Nikoskelainen E, Portin R, Kurki T, Erkinjuntti M, et al. Neurological symptoms and natural course of xeroderma pigmentosum. Brain. 2008;131(Pt 8):1979–89.PubMedGoogle Scholar
  187. 187.
    Wayli HA. Xeroderma pigmentosum and its dental implications. Eur J Dent. 2015;9(1):145–8.PubMedPubMedCentralGoogle Scholar
  188. 188.
    Lopes-Cardoso C, Paes da Silva Ramos Fernandes LM, Ferreira-Rocha J, Teixeira-Soares C, Antônio-Barreto J, Humberto-Damante J. Xeroderma Pigmentosum – a case report with oral implications. J Clin Exp Dent. 2012;4(4):e248–51.PubMedPubMedCentralGoogle Scholar
  189. 189.
    Gorlin RJ, Sedano H, Anderson VE. The syndrome of palmar-plantar hyperkeratosis and premature periodontal destruction of the teeth. A clinical and genetic analysis of the Papillon-Lefevre syndrome. J Pediatr. 1964;65:895–908.PubMedGoogle Scholar
  190. 190.
    Cury VF, Costa JE, Gomez RS, Boson WL, Loures CG, De ML. A novel mutation of the cathepsin C gene in Papillon-Lefevre syndrome. J Periodontol. 2002;73(3):307–12.PubMedGoogle Scholar
  191. 191.
    Zhang Y, Lundgren T, Renvert S, Tatakis DN, Firatli E, Uygur C, et al. Evidence of a founder effect for four cathepsin C gene mutations in Papillon-Lefevre syndrome patients. J Med Genet. 2001;38(2):96–101.PubMedPubMedCentralGoogle Scholar
  192. 192.
    Wiebe CB, Häkkinen L, Putnins EE, Walsh P, Larjava HS. Successful periodontal maintenance of a case with Papillon-Lefevre syndrome: 12-year follow-up and review of the literature. J Periodontol. 2001;72(6):824–30.PubMedGoogle Scholar
  193. 193.
    Ragunatha S, Ramesh M, Anupama P, Kapoor M, Bhat M. Papillon-Lefevre syndrome with homozygous nonsense mutation of cathepsin C gene presenting with late-onset periodontitis. Pediatr Dermatol. 2015;32(2):292–4.PubMedGoogle Scholar
  194. 194.
    Eick S, Puklo M, Adamowicz K, Kantyka T, Hiemstra P, Stennicke H, et al. Lack of cathelicidin processing in Papillon-Lefevre syndrome patients reveals essential role of LL-37 in periodontal homeostasis. Orphanet J Rare Dis. 2014;9:148.PubMedPubMedCentralGoogle Scholar
  195. 195.
    Hart TC, Hart PS, Michalec MD, Zhang Y, Firatli E, Van Dyke TE, et al. Haim-Munk syndrome and Papillon-Lefevre syndrome are allelic mutations in cathepsin C. J Med Genet. 2000;37(2):88–94.PubMedPubMedCentralGoogle Scholar
  196. 196.
    Ahmed B. Prosthodontic rehabilitation of Papillon-Lefevre syndrome. J Coll Phys Surg Pak JCPSP. 2014;24(Suppl 2):S132–4.Google Scholar
  197. 197.
    Nickles K, Schacher B, Ratka-Krüger P, Krebs M, Eickholz P. Long-term results after treatment of periodontitis in patients with Papillon-Lefevre syndrome: success and failure. J Clin Periodontol. 2013;40(8):789–98.PubMedGoogle Scholar
  198. 198.
    Sarma N, Ghosh C, Kar S, Bazmi BA. Low-dose acitretin in Papillon-Lefevre syndrome: treatment and 1-year follow-up. Dermatol Ther. 2015;28(1):28–31.PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Julio C. Sartori-Valinotti
    • 1
  • Jennifer L. Hand
    • 1
    Email author
  1. 1.Department of DermatologyMayo Clinic and FoundationRochesterUSA

Personalised recommendations