Oral Signs of Genetic Disease
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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.
KeywordsGenodermatoses Oral disease Incontinentia pigmenti Pachyonychia congenita Dyskeratosis congenita Rothmund-Thomson syndrome Hereditary hemorrhagic telangiectasia Hermansky-Pudlak syndrome
Incontinentia Pigmenti (Bloch-Sulzberger Syndrome)
Incontinentia pigmenti (IP) is an ectodermal dysplasia with an estimated prevalence of 0.7 cases per 100,000 births, almost exclusively affecting females .
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.
Oral Signs and Symptoms
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.
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.
PC is an autosomal dominant disorder. Keratins are structural proteins usually expressed in pairs . 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 . 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.
Oral Signs and Symptoms
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 . Natal teeth are either soft or crumbly and rapidly lost or normal appearing and persistent until permanent tooth eruption . Angular cheilitis and median rhomboid glossitis have been described in patients with PC [18, 21].
Oral leukokeratosis in PC can be mistaken for white sponge nevus, oral leukoplakia, hairy tongue, and oral candidiasis . 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 , lesions did not respond to anti-candidal treatment despite a positive culture.
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 . Systemic retinoids may lead to improvement of oral leukoplakia . However, the development of side effects limits its use in patients with PC .
Dyskeratosis congenita (DC) is a very rare genetic disease with a prevalence of 0.1/100,000 births .
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].
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 . Patients with DC are also predisposed to pulmonary complications and malignancy.
Oral Signs and Symptoms
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.
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 (RTS) is a rare autosomal recessive disorder with only 300 cases reported in the literature.
RTS is due to a compound heterozygous mutation in the DNA helicase gene RECQL4 on chromosome 8q24.3 . 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 .
Oral Signs and Symptoms
Numerous dental malformations of deciduous teeth, ectopic eruptions, and failed tooth eruption have been recognized in RTS . In 1985, Starr and colleagues described hypodontia as one of the non-dermatologic complications of RTS . Early periodontal disease has also been noted in this patient population  as well as microdontia, dystrophic teeth, and short root anomaly .
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 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
Hereditary hemorrhagic telangiectasia (HHT), aka Osler-Weber-Rendu syndrome, has an estimated prevalence of at least 1 in 5000 .
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 . 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 . In addition, mutations in SMAD4 on chromosome 18q21 cause a form of HHT called juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome .
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 . 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  but in the oral mucosa is usually cherry red . 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 .
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 .
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 . Nd:YAG laser has also been successfully used in the management of oral hemorrhage secondary to telangiectasias . Some authors advocate the use of prophylactic antibiotics before oral procedures using the same guidelines as for patients at high risk of bacterial endocarditis .
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 . In Puerto Rico, the carrier frequency is estimated to be 1 in 21 .
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 . 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 .
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 .
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 . 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 .
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 .
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 .
The estimated prevalence of Lesch-Nyhan syndrome (LNS) at birth is about 0.34/100,000 .
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 .
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 .
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].
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 . 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 .
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 . Psychologic therapy and uric acid reduction have not been shown to be of value in the treatment of self-mutilating behavior . Extraction of primary and permanent teeth may be necessary .
The reported prevalence of Peutz-Jeghers syndrome (PJS) is 2.2 cases per 100,000 births .
The disorder is due to mutations in the serine/threonine kinase, STK11, gene located at chromosomal locus 19p13 . 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 . A clinical genetic test is currently available for PJS.
Oral Signs and Symptoms
The pigmented macules are usually present at birth or are first noted in early childhood . 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 .
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.
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 . Other treatment modalities such as dermabrasion, cryotherapy and CO2, or Argon laser may be associated with incomplete removal, scarring, or pigmentary changes .
Pseudoxanthoma elasticum (PXE) occurs in 2.5 per 100,000 births .
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 .
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 . Carriers of heterozygous mutations in ABCC6 gene may present with partial manifestations of the disease.
Oral Signs and Symptoms
Because of their location and color, the lesions may be misdiagnosed as Fordyce spots .
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
The exact prevalence of white sponge nevus of Canon is unknown, but it is estimated to affect less than 1 in 200,000 individuals .
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
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.
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 . 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 .
Familial Adenomatous Polyposis (Gardner Syndrome)
Familial adenomatous polyposis (FAP) occurs in 1 in 7500 births.
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 . It is inherited in an autosomal dominant fashion.
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 . 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 , cutaneous lesions (epidermoid cysts, lipomas, fibromas, pilomatricomas, leiomyomas), desmoid tumors, as well as malignancies of the thyroid, pancreas, stomach, adrenals, and gallbladder .
Oral Signs and Symptoms
Supernumerary, impacted, and missing teeth have been reported in GS . Supernumerary teeth are small and peg shaped . The impacted teeth are usually canines . 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 . Osteomas of the mandibular condyle may be diagnostic; they are usually asymptomatic but can cause limited mandibular movement  or cause facial asymmetry . 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 .
Odontomas are also more frequent in FAP than in the general population . They are well-defined, encapsulated, hard tissue growths with an odontogenic origin.
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.
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 . Mutations in COL1A1 and COL1A2 are responsible for about 90% of cases of OI .
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% . 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 . Radiographically, the teeth have short roots and dentin hypertrophy leading to pulpal obliteration either before or just after eruption . 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 .
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 .
Early institution of treatment will ensure good occlusion, adequate mandibular and maxillary growth, and preservation of the temporomandibular joints . 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 . When eruption of the permanent dentition is complete, prosthetic restoration of the permanent teeth can be considered . 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 .
Basal Cell Nevus Syndrome
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 . PTCH1 encodes the receptor for Sonic hedgehog protein and accounts for most cases of BCNS . The mechanism of inheritance is autosomal dominant.
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 . Other commonly observed features are frontal and biparietal bossing, broad nasal root, strabismus, iris coloboma, glaucoma , bifid ribs , calcification of the falx cerebri , medulloblastomas, ovarian fibromas/carcinomas, and palmoplantar pits .
Oral Signs and Symptoms
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 of KCOTs is a matter of debate . 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 . 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 .
Tuberous Sclerosis Complex
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% .
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 . 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 .
Oral Signs and Symptoms
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 . 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.  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.
Oral fibromas can be misdiagnosed as fibrous hyperplasias, focal papillomas, hemangiomas, lymphangiomas, or lipomas .
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 . Surgical resection of the most prominent ones could be considered on an individual basis.
Darier disease (DD) has an estimated prevalence of 1 in 55,000. Disease onset is usually before the third decade of life .
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 .
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 . 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 . 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)  and 50% (12/24) . Lesions are painless, whitish, coalescing papules, primarily present on the palate (most common location), followed by the gingiva, oral mucosa, and tongue . 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 . Most recently, esophageal affliction, including carcinoma, has been noted [161, 162].
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.
Oral findings in DD are of no clinical significance, and treatment is not needed.
The prevalence of Ehlers-Danlos syndrome (EDS) is approximately 1 in 5000–10,000. There is no racial predilection .
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 . EDS can be inherited in an autosomal or recessive fashion.
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 .
The most comprehensive review on the oral manifestations of EDS is by Abel and Carrasco . 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 . Hemorrhagic bulla of the oral mucosa as an early manifestation of EDS type 4 (vascular type) has been reported . KCOTs can be found in association with supernumerary teeth . Patients with EDS type 4 may also experience tooth loss following orthodontic treatment due to severe destruction of the periodontal support .
Hypermobility of the temporomandibular joint (TMJ) is a frequent sign  as is pain in the masticatory muscles upon mouth opening. Increased mobility of the joints can also cause permanent locking of the TMJ .
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.
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 . 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 .
Down syndrome (DS) is estimated to occur in approximately 1 in 732 infants in the United States, but there is racial and ethnic variability .
DS is the most common numeric chromosome abnormality due to trisomy 21. Dosage imbalance of many genes is responsible for the phenotype.
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 . In another series, although the crown-to-root ratio was maintained, microdontia and progressive reduction in tooth size with senesce were documented . Microdontia affects both primary and permanent dentitions . In addition, there is a higher prevalence of malocclusion (anterior cross bite, anterior open bite) probably due to skeletal and soft tissue abnormalities . 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 . Due to small craniofacial parameters, patients with DS have relative rather than true macroglossia . Cleft lip and/or palate and broad, dry, and fissured lips are observed .
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.
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 . Retrognathia, hypotonia, and macroglossia can lead to obstructive sleep apnea; therefore, overnight polysomnograph should be obtained and early referral to otolaryngology made, if indicated . As with EDS patients, an interdisciplinary approach is necessary to achieve functional, phonetic, and esthetic outcomes .
Xeroderma Pigmentosum (XP)
Xeroderma pigmentosum (XP) has an estimated incidence of 1 in 20,000 in Japan to 1 in 250,000 in the United States .
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.
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 .
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 .
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.
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 . Mouthwashes with a high alcohol concentration should also be avoided.
PLS is a rare autosomal recessive disorder with an increased rate of consanguinity in parents of affected patients . Most cases are due to mutations of the cathepsin C gene on chromosome 11q14 .
Papillon-Lefevre syndrome (PLS) is a very rare genetic condition characterized by well-demarcated palmoplantar hyperkeratosis. Periodontitis separates PLS from other inherited palmoplantar keratodermas . The features of the condition usually first become apparent between the age of 2 and 4 . The palmoplantar hyperkeratosis has been reported to improve with time .
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 . The wisdom teeth, however, are spared . 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 .
Mutations in cathepsin C also cause Haim-Munk syndrome with palmoplantar keratoderma, aggressive periodontitis, acroosteolysis, arachnodactyly, atrophic nail changes, and deformity of the fingers .
For years, prosthodontic rehabilitation has been the cornerstone of therapy in PLS . Unfortunately, despite aggressive post-implant care, patients are at high risk of peri-implantitis and implant loss . Recent advances in treatment suggest that low-dose acitretin improves periodontitis and results in increased alveolar bone height and periodontal attachment .
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