- Email: [email protected]
Oral manifestations of genodermatoses
Dermatol Clin 21 (2003) 183 – 194
Oral manifestations of genodermatoses Jennifer L. Hand, MDa,b,*, Roy S. Rogers III, MDa b
a Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Department of Medical Genetics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
Hundreds of known genetic disorders affect the mouth and oral mucous membranes. Many of these conditions are associated with late-onset complications that affect a patient’s overall life expectancy. For example, almost all patients with multiple endocrine neoplasia (MEN) type IIB develop an aggressive form of medullary thyroid cancer [1]. With recent advances in technology and improved screening techniques, the opportunity to prevent life-threatening complications in patients with genetic disorders is greater than ever before. Optimal prevention of secondary complications, however, is dependent on an early, correct initial diagnosis. This article provides a focused review of specific genetic disorders that affect the mouth and also have prominent associated dermatologic features. In several conditions presented here, the oral findings are distinct and may provide the first clue of an underlying genetic diagnosis. In each discussion, clinical features that help confirm a genetic diagnosis are discussed. For these genetic disorders, family members may be at risk. Molecular genetic testing, when available as an aid for diagnosis and genetic counseling, is included in the discussion.
Multiple endocrine neoplasia type IIB Multiple endocrine neoplasia refers to a group of genetic disorders named for their association with
* Corresponding author. Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail address: [email protected] (J.L. Hand).
neoplasm and malignancy of endocrine glands. In MEN type I, the parathyroid gland is most frequently affected by malignancy [2]. In MEN type II, the thyroid gland is most frequently affected [3]. One subtype, MEN IIB, is of particular interest because of its association with oral mucosal neuromas. MEN IIB represents about 5% of cases of MEN II and is also known as mucosal neuroma syndrome or Wagenmann-Froboese syndrome [1,3]. Oral mucosal neuromas may be the first feature to present in infancy or early childhood [3,4]. Mucosal neuromas may be found on the dorsal surface of the tongue, the palate, or pharynx. When found on the tongue, they are considered to be almost pathognomonic of medullary thyroid carcinoma (Fig. 1) [1]. The tongue may appear crenated or notched [4]. Pedunculated symmetric nodules on the buccal mucosa behind each lip commissure have been described [4]. When mucosal neuromas appear as submucosal nodules on the vermilion border of the lips, the resultant thickening of the lips (Fig. 2) is described as ‘‘pebbly’’ or ‘‘blubbery’’ [3]. The palate may be high and arched. The jaw may be prominent [1]. All of the oral findings in MEN IIB are generally thought of as asymptomatic and benign [4]. Multiple endocrine neoplasia IIB is distinguished from other MEN syndromes because it alone has associated physical characteristics other than the endocrine findings [4]. Distinct features of MEN IIB include thickened corneal nerves visible by slit lamp examination, a ‘‘wide-eyed’’ facies (Figs. 3 and 4), a Marfanoid body habitus with joint laxity, and medullary thyroid carcinoma [1,3]. Virtually all patients with MEN IIB develop aggressive medullary thyroid cancer. Early thyroidectomy (eg, at less than 1 year of age) is imperative to prevent metastasis [3].
0733-8635/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. PII: S 0 7 3 3 - 8 6 3 5 ( 0 2 ) 0 0 0 8 2 - 7
184
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
Fig. 1. Multiple endocrine neoplasia (MEN) IIB. Mucosal neuromas of the tongue.
Continued monitoring is recommended after thyroidectomy for residual or recurrent cancer. About 50% of patients develop pheochromocytoma [3]. Gastrointestinal problems may be associated because of hamartomatous ganglioneuromatosis of the gastrointestinal tract [1].
Fig. 3. MEN IIB. Characteristic facies. Neuromas cause thickening and eversion of the upper eyelids and a wide-eyed appearance. Eyebrows appear prominent.
Molecular genetics Multiple endocrine neoplasia IIB is inherited in an autosomal-dominant manner. The disease-causing mutation is found in the RET gene at the chromosomal locus 10q11. The American Society of Clinical Oncologists denotes MEN II as a welldefined hereditary cancer syndrome for which genetic testing is considered standard of care for affected probands and at-risk family members [3]. A clinical genetic test is available that detects a disease-causing mutation in 95% of patients with MEN IIB. Interestingly, more than 95% of patients with MEN IIB have
Fig. 2. MEN IIB. Note thick lips with pebbly nodules at the vermilion border.
the same mutation caused by substitution of a single methionine to threonine in the affected protein [1]. Linkage testing is available when no mutation is found and multiple family members are affected. RET mutation analysis should be performed soon after birth in all children known to be at risk [3]. About half of affected individuals with MEN IIB have a de novo or new mutation [3], usually paternally inherited [1]. In patients without a family history,
Fig. 4. MEN IIB. Mucosal neuroma of the eyelid.
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
185
RET mutation analysis should be performed as soon as the diagnosis is being considered [3].
Carney syndrome (NAME or LAMB syndrome) Carney syndrome is also called NAME syndrome (Nevi, Atrial myxomas, Myxoid neurofibromas, Ephelides) and LAMB syndrome (Lentigines, Atrial myxomas, Mucocutaneous myxomas, Blue nevi). Carney syndrome is considered to be an MEN syndrome. Cardiac myxomas are an associated complication that may, unfortunately, present as an embolic stroke if not detected or removed. Myxomas may also appear in the skin or breasts [5]. Endocrine abnormalities include Cushing’s syndrome caused by primary pigmented nodular adrenocortical disease, elevated growth hormone and acromegaly caused by pituitary adenomas, and prolactinemia thought to be caused by hyperplasia of cells within the pituitary gland [6]. In affected men, tumors of the testicular Sertoli’s and Leydig’s cells are associated [6]. Oral features of Carney syndrome include pigmented maculae over the lips and oral mucosa (Fig. 5). Mucosal pigmented maculae may also be found on the conjunctiva (Fig. 6). Associated skin pigmented maculae may appear on all body surfaces and include ephelides or freckles, darkly pigmented nevi, cafe´ au lait maculae, and as blue nevi. Molecular genetics Carney syndrome is inherited in an autosomaldominant manner. A causative mutation in the gene called PRKAR1A on chromosome 17 has been identified and clinical genetic testing is available for this alteration. Many affected patients, however, may have an alteration at a separate site. A second
Fig. 5. Carney’s syndrome. Pigmented maculae, also called lentigines, affect the lips and facial skin.
Fig. 6. Carney’s syndrome. Pigmented maculae affect the conjunctiva and periorbital skin.
gene is suspected on chromosome 2p, but has not yet been identified.
Cowden disease (multiple hamartoma syndrome) Cowden disease, also known as multiple hamartoma syndrome, is characterized by facial and oral papules and hamartomas. The hamartomas may appear in any body organ [7]. Lifetime risk of malignancy is increased. Affected women have a 20% to 50% risk of breast cancer and increased risk of endometrial cancer. All patients have a 10% risk of nonmedullary cancers of the thyroid [8]. The incidence of malignant melanoma and renal cell cancer is also suspected to be increased [8]. Diagnostic criteria have been developed and published [7] by the International Cowden Consortium (Box 1). These are expected to be updated as further information about the disorder becomes known. Oral findings are present in 80% of patients [9,10] and may aid early identification of the diagnosis. In most cases, the oral findings are found in multiple locations, such as the gingival mucosa (Figs. 7 and 8) and buccal mucosa [10]. The oropharynx, larynx, tongue (Fig. 9), nasal mucosa, and anogenital region may be involved [10]. The typical appearance of multiple, coalescent mucosal papillomas has been described as cobblestone-like and is seen in 40% of patients [10]. Skin findings are included among the current major and minor criteria for diagnosis [8,10]. The finding of multiple facial trichilemmomas is considered pathognomonic for the disorder. Other characteristic skin findings include lichenoid papules, acral keratoses, palmoplantar keratoses, and lipomas. Acral keratoses are skin colored to slightly pigmented flat, warty papules on the backs of the hands and feet and
186
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
Box 1. Diagnostic criteria for Cowden disease* Pathognomonic criteria Facial trichilemmomas Acral keratoses Papillomatous lesions Mucosal lesions Major criteria Thyroid carcinoma Macrocephaly Lhermitte-Duclos diseasey Minor criteria Other thyroid lesions Mental retardation Gastrointestinal hamartomas Fibrocystic breast disease Lipomas Fibromas Genitourinary tumors Operational Diagnosis if: Pathognomonic lesions alone including at least six facial papules with at least three trichilemmomas or facial papules and oral papillomatosis or oral papillomatosis and acral keratoses or at lease six palmoplantar keratoses Two major criteria including macrocephaly or LhermitteDuclos disease One major and three minor criteria Four minor criteria * Criteria are considered operational and expected to evolve as further information becomes available. y Hamartomatous change of cerebellar cells with characteristic appearance on MRI or CT.
Fig. 7. Cowden disease. Oral mucosal papillomatosis may affect the gingival mucosa.
been found in the PTEN gene in 80% of patients who meet established diagnostic criteria [7]. The chromosomal locus of the PTEN gene is 10q23.3 [8]. Clinical genetic testing is currently available.
Tuberous sclerosis complex Tuberous sclerosis complex (TSC) has been described and studied for more than 160 years [12,13]. As a result, diagnostic criteria have been well defined [12,14] and are available in updated format at www.geneclinics.org (Box 2). 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 mental retardation and seizures, affect long-term prognosis most. Up to 14% of patients with TSC develop subependymal giant cell astrocytoma. Associated skin findings, such as hypomelanotic maculae, facial
palmoplantar keratoses are translucent and punctate keratoses on the palms and soles. Vitiligo, neuromas, xanthomas, and cafe´ au lait spots are additional skin findings that have a reported infrequent association with Cowden disease [11]. Facial papules usually show a periorificial distribution (Fig. 10) [10]. Molecular genetics Cowden disease is inherited in an autosomaldominant manner. A disease-causing mutation has
Fig. 8. Cowden disease. Verrucous or papular fibrous overgrowths are typical on the gingiva.
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
187
Box 2. Diagnostic criteria for TSC*
Fig. 9. Cowden disease. Oral papillomatosis affects the tongue causing a ‘‘cobblestone’’ appearance.
angiofibromas, and ungual fibromas, have been reviewed in detail [15]. Current diagnostic criteria include the oral finding of gingival fibromas (Fig. 11). 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 [16]. Gingival fibromas are found in some patients with TSC, but
Fig. 10. Cowden disease. A periorificial distribution of facial trichilemmomas is characteristic.
Major features Facial angiofibromas or forehead plaque Periungual fibromas Hypomelanotic macules (greater than three) Shagreen patch or connective tissue nevus Nodular retinal hamartomas Cortical tubery Subependymal nodule Subependymal giant cell astrocytoma Cardaic rhabdomyomas Lymphangiomatosisz Renal agiomyolipomaz Minor features Multiple dental enamel pits Hamartomatous rectal polyps Bone cysts Cerebral white matter radial migration linesy Gingival fibromas Nonrenal hamartoma Retinal achromic patch ‘‘Confetti’’ skin macules Multiple renal cysts Definite TSC if two major or one major and two minor features Probable TSC if one major and one minor feature Possible TSC if one major or two or more minor features * Criteria are available in updated form at www.geneclinics.org. y Cortical tuber and white matter migration lines count as only one feature when diagnosed together. z Lymphangiomatosis and renal aniomyolipoma, when found together, are insufficient to make the diagnosis of TSC.
not others and are not essential to make the diagnosis. Also, gingival hyperplasia caused by antiseizure medication, such as phenytoin, may obscure gingival fibromas in these patients [17]. Lack of oral hygiene has been associated with TSC, but this is thought to be caused by mental subnormality rather than a growth or neoplastic change [12].
188
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
Molecular genetics
Fig. 11. Tuberous sclerosis. Gingival fibromas.
Multiple randomly distributed pits in dental enamel (Fig. 12) provide another diagnostic feature of TSC. Enamel pitting may be seen by direct inspection and usually affects the labial surfaces of the front and lateral incisor and canine teeth [12]. The prevalence of dental pits in patients with TSC is thought to range from 48% to 100% [12,18]. Smaller pits can be appreciated better using dental plaquedisclosing stain on the surfaces of the teeth. Electron microscopy can also be used once a tooth has been removed. Dental enamel pits may be found on the teeth of normal patients, but are usually fewer and less obvious. A study by Flanagan et al [18] found that most patients with TSC had great than 14 pits per person, whereas most normal controls had less than 6 pits per person.
Fig. 12. Tuberous sclerosis. Example of enamel pitting made more prominent by use of dental plaque-disclosing stain. (From Gomez MR, Sampson JR, Whittemore VH. Tuberous sclerosis complex: developmental perspectives in psychiatry. 3rd Ed. Oxford University Press; 1999. p. 178; with permission.)
The TSC complex is inherited in an autosomaldominant 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. Most cases are caused by a mutation of the TSC1 gene on chromosome 9q34 or the TSC2 gene on chromosome 16p13. An identifiable mutation has not yet been found to explain the remainder of cases. In addition, TSC has a high rate of somatic mosaicism among affected individuals estimated to be 10% to 25% [14]. Because of these and other complexities, the diagnosis of TSC is currently based on clinical findings. Genetic testing is available on a research basis only.
Peutz-Jeghers syndrome Peutz-Jeghers syndrome is a genetic condition characterized by gastrointestinal polyposis and tan to dark brown or blue maculae on the skin and oral mucosa (Fig. 13) [19]. Diagnosis is based on these clinical findings. Polyps may cause intussusception or bowel obstruction. A study by Boardman et al [20] determined that patients with Peutz-Jeghers syndrome had a relative risk for cancer increased to 9.9 times normal. The incidence of gastrointestinal cancers and breast cancer is particularly increased [20,21]. Cancer
Fig. 13. Peutz-Jeghers syndrome. Characteristic pigmented maculae of the lips and buccal mucosa.
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
189
predisposition to hematologic abnormalities and bone marrow failure [23,24]. Failure of the bone marrow is the chief cause of early death. New treatments are under development, but no treatment has been found to be effective uniformly in all patients [23]. Patients with dyskeratosis congenita are also predisposed to pulmonary complications and malignancy. Oral leukoplakia is a diagnostic feature of this disorder and usually appears early in life in association with skin hyperpigmentation [24]. Leukoplakia is generally only seen in the mucous membranes of the mouth, but may also be found in the esophagus and anal and genital mucosa. The leukoplakia tends to progress with time and may undergo malignant transformation [24]. Extensive dental caries and loss of teeth is reported in 18% of patients with dyskeratosis congenita [23]. Molecular genetics Fig. 14. Peutz-Jeghers syndrome. Characteristic perianal pigmented maculae.
surveillance comprises an important part of management for these patients. The pigmented maculae usually are present at birth or are first noted in early childhood [19]. The maculae are usually found on the lips, on the buccal mucosa and on the skin around the mouth. 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 (Fig. 14). Maculae may be found in a periorificial distribution around the eyes in some patients [22]. Skin maculae are reported to fade with age, but the maculae on the oral mucosa remain [19].
Most affected family members are males with pedigrees that show no male-to-male transmission. Most cases are thought to be X-linked. Female cases
Molecular genetics Peutz-Jeghers syndrome is inherited in an autosomal-dominant manner. 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 [21]. The causative gene in 30% to 70% of cases is the STK11 gene located at chromosomal locus 19p13 [21]. A clinical genetic test is currently available for Peutz-Jeghers syndrome.
Dyskeratosis congenita Dyskeratosis congenita is a genetic disease characterized by reticulated hyperpigmentation of the skin, dystrophy of the nails, oral leukoplakia, and a
Fig. 15. Pachyonychia congenita. Leukokeratosis affects the tongue.
190
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
Fig. 16. Pachyonychia congenita. Leukokeratosis affects the buccal mucosa.
have been reported. These are thought to be caused by an autosomal-recessive form of the disorder [23]. A causative gene, DKC1, has been localized to Xq28. A clinical genetic test for a mutation in this gene is available.
Pachyonychia congenita Pachyonychia congenital (PC) is a group of disorders unified by characteristic, distinct nail changes with distal onycholysis, subungual hyperkeratosis that causes transverse arching of the distal nail plate, and yellow-brown discoloration [25,26]. In PC type I (also called Jadassohn-Lewandowsky syndrome), hyperkeratosis of the palms, soles, knees, and elbows and follicular hyperkeratosis are associated features. Oral leukokeratosis separates PC type I from PC type II (or Jackson-Lawler syndrome). In PC type II, natal teeth, epidermal cysts, and steatocysts are associated. Oral leukokeratosis may be found, but is less marked than in PC type I [26]. Oral lesions are white, opaque thickenings in areas of the tongue or buccal mucosa (Figs. 15 and 16), or may present as white plaques that cover the entire surface of the tongue, lips, and cheeks [25]. Superinfection with Candida albicans has been reported [25,26]. In a patient reported by Hannaford and Stapleton [26], lesions did not respond to anticandidal treatment despite a positive culture. Malignant transformation of the leukokeratosis has not been reported [25].
Fig. 17. Hypohidrotic ectodermal dysplasia. Female carrier. Note sparse, fine, blond hair and mild flattening of the nasal bridge.
Molecular genetics Pachyonychia congenital is an autosomal-dominant disorder. Keratins are structural proteins usually expressed in pairs [27]. The keratin pair K6b-K17 is expressed in nails and the palmoplantar surface.
Fig. 18. Hypohidrotic ectodermal dysplasia. Hypodontia and conical teeth in a female carrier.
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
191
dentition usually requires extensive dental treatment at an early age with prosthetic teeth. This intervention is considered critical for development of positive selfimage and overall oral health [28,29]. Molecular genetics Hypohidrotic ectodermal dysplasia is X-linked and affects mostly males. Female carriers may also express the disorder, however, usually in a less severe form. Clinical genetic testing is available for the disease causing EDA mutation on the X chromosome [30]. Fig. 19. Papillon-Lefe`vre syndrome. Well-circumscribed hyperkeratosis of the elbows and knees in an affected patient.
Mutations in either of these keratins cause PC type II. Mutations in either K16 or K6a cause PC type I [27]. 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.
Papillon-Lefe`vre syndrome Papillon-Lefe`vre syndrome is a very rare genetic condition characterized by well-demarcated palmoplantar hyperkeratosis (Fig. 19). Periodontitis separates Papillon-Lefe`vre syndrome from other inherited palmoplantar keratodermas [31]. The features of the condition usually first become apparent about ages 2
Hypohidrotic ectodermal dysplasia Hypohidrotic ectodermal dysplasia is an inherited condition that affects ectodermal structures, specifically hair, teeth, and sweat glands. Hair is often fine, sparse, and blond (Fig. 17). Lack of sweating may result in heat intolerance and frequent fevers of seemingly unknown cause [28]. Variable associated facial features include a prominent forehead, thick lips, and a depressed nasal bridge (see Fig. 17) [28]. Because features of this disorder may be subtle and unrecognized, the oral findings may first reveal the diagnosis [28]. These include hypodontia and conical teeth (Fig. 18). Feeding may be difficult because of lack of teeth and saliva [28]. Lack of
Fig. 20. Papillon-Lefe`vre syndrome. Inflammatory periodontitis and tooth loss.
Fig. 21. Hereditary hemorrhagic telangiectasia. Characteristic papular telangiectasia affecting the skin.
192
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
Molecular genetics Box 3. Diagnostic criteria for HHT* Diagnostic criteria Spontaneous and recurrent nosebleeds Telangiectasias Internal arteriovenous malformations (pulmonary, cerebral, hepatic, spinal, or gastrointestinal) Positive family history of HHT in firstdegree relative Definite HHT if three or more criteria Possible or suspected HHT if two criteria Unlikely HHT if less than two criteria * Criteria are available in updated form at www.geneclinics.org.
to 4 [32]. Palmoplantar hyperkeratosis has been reported to improve with time [32]. Severe, inflammatory periodontitis results in complete loss of deciduous teeth by 4 years (Fig. 20). The same process results in complete loss of the adult teeth when they appear. The wisdom teeth, however, are spared [32]. The specific mechanism that causes the periodontitis is not yet known.
Papillon-Lefe`vre syndrome is a rare autosomalrecessive disorder with an increased rate of consanguinity in parents of affected patients [31]. Most cases are caused by mutations of the cathespin C gene on chromosome 11q14 [31]. A clinical genetic test is not yet currently available.
Hereditary hemorrhagic telangiectasia Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, 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. 21), gastrointestinal tract, brain, and lung. Bleeding may cause sudden and devastating consequences. Diagnostic criteria are available for this disorder in updated form at www.geneclinics.org (Box 3). Oral lesions may be punctate, spider-like, or nodular and be found on the buccal mucosa, tongue, lips, palate, and gingiva [33]. Color may vary from bright red to purple [34], but in the oral mucosa is usually cherry-red [33]. Presentation of HHT as hemorrhagic vesicles and ulcers of the gingival and oral mucosa has also been reported [34]. Use of a
Table 1 Summary findings Genetic condition
Oral findings
Gene and locus
Genetic test
Multiple endocrine neoplasia IIB
Tuberous sclerosis complex
Gingival fibromas; oral fibromas
Peutz-Jeghers syndrome
Pachyonychia congenita type 1
Pigmented macules on lips, buccal mucosa Oral leukoplakia; dental caries and tooth loss Oral leukokeratosis
Hypohidrotic ectodermal dysplasia
Hypodontia; conical teeth
Papillon-Lefe´vre syndrome
Inflammatory periodontitis; tooth loss
Hereditary hemorrhagic telangiectasia
Oral telangiectasias
RET gene 10q11 PRKAR1A 17 PTEN 10q23.3 TSC1, TSC2 9q34, 16p13 STK11 19p13 DKC1 Xq28 K6a/K16 17q12,12q13 EDA Xq12 Cathespin C 11q14 ENG, ACVRL1 9q34.1,12q1
Yes
Cowden disease
Mucosal neuromas; high, arched palate; prominent jaw Pigmented macules on lips and oral mucosa; dental enamel pits Mucosal papillomatosis
Carney syndrome
Dyskeratosis congenita
Yes Yes Research only Yes Yes Yes Yes No Research only
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
very soft toothbrush may help prevent trauma from routine oral hygiene [34]. Molecular genetics Hereditary hemorrhagic telangiectasia is an autosomal-dominant disorder. Two main genetic subtypes of HHT have been described: HHT1 and HHT2 [35]. The disease causing mutation in HHT1 is in the endoglin (ENG) gene on chromosome 9q34.1. For HHT2, the mutation is in the activin receptor gene on chromosome 12q1 [35]. Currently, only researchbased genetic testing is available.
[7]
[8]
[9]
[10]
[11]
Summary Many genodermatoses have distinct oral features that may help identify or confirm a genetic diagnosis. Oral features of the disorders described here are summarized in Table 1. These conditions provide clear examples of rapid progress in the field of genetic technology relevant to patient care. Less than a decade ago, the exact genetic locus of most of these disorders was unknown. Today, for many of these disorders, the exact location of the disease-causing mutation is known and clinical genetic testing is available for patients. This information has impact not only for genetic counseling and anticipatory medical care, but also provides insight into the mechanisms of disease. How this rapid progress will impact care, and ultimately treatment of patients, remains to be seen.
[12]
[13] [14]
[15]
[16]
[17]
References [18] [1] Morrison PJ, Nevin NC. Multiple endocrine neoplasia type IIB (mucosal neuroma syndrome, WagenmannFroboese syndrome). J Med Genet 1996;33:779 – 82. [2] Rimoin DL, Connor JM, Pyeritz RE. Emery and Rimoin’s principles and practices of medical genetics. 3rd edition. New York: Churchill Livingstone; 1996. p. 1383 – 5. [3] Wiesner GL, Snow K. Multiple endocrine neoplasia type 2. Available at: www.geneclinics.org. Accessed September 20, 1999. [4] Schenberg ME, Zajac JD, Lim-Tio S, et al. Multiple endocrine neoplasia syndrome-type 2b. Int J Oral Maxillofac Surg 1992;21:110 – 4. [5] Quintal MC, Tabet JC, Oligny L, et al. Oral soft tissue myxoma: report of a case and review of the literature. J Otolaryngol 1994;23:42 – 5. [6] Raff SB, Carney JA, Krugman D, et al. Prolactin secretion abnormalities in patients with the ‘‘syndrome of
[19] [20]
[21]
[22] [23]
[24]
193
spotty skin pigmentation, myxomas, endocrine overactivity and Schwannomas’’ (Carney complex). J Pediatr Endocrinol Metab 2000;13:373 – 9. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet 2000;37: 828 – 30. Eng C, Hampel H, de la Chapelle A. Genetic testing for cancer predisposition. Annu Rev Med 2001;52: 371 – 400. Chaudhry SI, Shirlaw PJ, Morgan PR, Challacombe SJ. Cowden’s syndrome (multiple hamartoma and neoplasia syndrome): diagnostic dilemmas in three cases. Oral Dis 2000;6:248 – 52. Hildebrand C, Burgdorf WHC, Lautenschlager S. Cowden syndrome: diagnostic skin signs. Dermatology 2001;202:362 – 6. Thyresson HN, Doyle JA. Cowden’s disease (multiple hamartoma syndrome). Mayo Clin Proc 1981;56: 179 – 84. 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; 90:430 – 5. Gomez MR. History of the tuberous sclerosis complex. Brain Dev 1995;17:55 – 7. Northrup H, Kit-Sing A. Tuberous sclerosis complex. Available at: www.geneclinics.org. Accessed April 13, 2002. Rogers RS, O’Connor WJ. Dermatologic manifestations. In: Gomez MR, Sampson JR, Whittemore VH, editors. Tuberous sclerosis complex. 3rd edition. Oxford: Oxford University Press; 1999. p. 160 – 80. Tillman HH, DeCaro F. Tuberous sclerosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1991;71: 301 – 2. Gomez MR. Liver, digestive tract, spleen, arteries, thymus, and lymphatics. In: Gomez MR, Sampson JR, Whittemore VH, editors. Tuberous sclerosis complex. 3rd edition. Oxford: Oxford University Press; 1999. p. 228 – 39. Flanagan N, O’Connor WJ, McCartan B, et al. Developmental enamel defects in tuberous sclerosis: a clinical genetic marker? J Med Genet 1997;34:637 – 9. Kitagawa S, Townsend BL, Hebert AA. Peutz-Jeghers syndrome. Dermatol Clin 1995;13:127 – 31. Boardman LA, Thibodeau SN, Schaid DJ, et al. Increased risk for cancer in patients with Peutz-Jeghers syndrome. Ann Intern Med 1998;128:896 – 9. Amos CI, Frazier ML, McGarrity TJ. Peutz-Jeghers syndrome. Available at: www.geneclinics.org. Accessed February 23, 2001. Mallory SB, Stough DB. Genodermatoses with malignant potential. Dermatol Clin 1987;5:221 – 30. Andrews NC, Fleming MD. Dyskeratosis congenita: recent advances and future directions. J Pediatr Hematol Oncol 1999;21:344 – 55. Solder B, Weiss M, Jager A, et al. Dyskeratosis congenita: multisystemic disorder with special consideration of immunologic aspects. Clin Pediatr 1998;37:521 – 30.
194
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
[25] Dahl PR, Daoud MS, Su WPD. Jadassohn-Lewandowsky syndrome (pachyonychia congenita). Semin Dermatol 1995;14:129 – 34. [26] Hannaford RS, Stapleton K. Pachyonychia congenital tarda. Australas J Dermatol 2000;41:175 – 7. [27] Smith FJD, Coleman CM, Bayoumy NM, et al. Novel keratin 17 mutations in pachyonychia congenita type 2. J Invest Derm 2001;116:806 – 8. [28] Kupietzky A, Houpt M. Hypohidrotic ectodermal dysplasia: characteristics and treatment. Oral Pathol 1995; 26:285 – 91. [29] Ohno K, Ohmori I. Anondontia with hypohidrotic ectodermal dysplasia in a young female: a case report. Pediatr Dent 2000;22:49 – 52. [30] Kobielak K, Kobeilak A, Roszkiewicz J, et al. Mutations in the EDA gene in three unrelated families reveal no correlation between phenotype and genotype in the patients with an X-linked anhydrotic ectodermal dysplasia. Am J Med Genet 2001;100:191 – 7.
[31] Zhang Y, Lundgren T, Renvert S, et al. Evidence of a founder effect for four cathepsin C gene mutations in Papillon-Lefe`vre syndrome patients. J Med Genet 2001;38:96 – 101. [32] Wiebe CB, Hakkinen L, Putnins EE, et al. Successful periodontal maintenance of a case with PapillonLefe`vre syndrome:12-year follow-up and review of the literature. J Periodontol 2001;72:824 – 30. [33] Austin GB, Quart AM, Nvak B. HHT with oral manifestations. Oral Med 1981;51:245 – 51. [34] Bartolucci EG, Swan RH, Hurt WC. Oral manifestations of hereditary hemorrhagic telangiectasia (Osler-WeberRendu disease). Review and case reports. J Periodontol 1982;53:163 – 7. [35] McDonald J, Guttmacher AE. Hereditary hemorrhagic telangiectasia. Available at: www.geneclinics.org. Accessed June 26, 2000.
Oral manifestations of genodermatoses Jennifer L. Hand, MDa,b,*, Roy S. Rogers III, MDa b
a Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Department of Medical Genetics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
Hundreds of known genetic disorders affect the mouth and oral mucous membranes. Many of these conditions are associated with late-onset complications that affect a patient’s overall life expectancy. For example, almost all patients with multiple endocrine neoplasia (MEN) type IIB develop an aggressive form of medullary thyroid cancer [1]. With recent advances in technology and improved screening techniques, the opportunity to prevent life-threatening complications in patients with genetic disorders is greater than ever before. Optimal prevention of secondary complications, however, is dependent on an early, correct initial diagnosis. This article provides a focused review of specific genetic disorders that affect the mouth and also have prominent associated dermatologic features. In several conditions presented here, the oral findings are distinct and may provide the first clue of an underlying genetic diagnosis. In each discussion, clinical features that help confirm a genetic diagnosis are discussed. For these genetic disorders, family members may be at risk. Molecular genetic testing, when available as an aid for diagnosis and genetic counseling, is included in the discussion.
Multiple endocrine neoplasia type IIB Multiple endocrine neoplasia refers to a group of genetic disorders named for their association with
* Corresponding author. Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail address: [email protected] (J.L. Hand).
neoplasm and malignancy of endocrine glands. In MEN type I, the parathyroid gland is most frequently affected by malignancy [2]. In MEN type II, the thyroid gland is most frequently affected [3]. One subtype, MEN IIB, is of particular interest because of its association with oral mucosal neuromas. MEN IIB represents about 5% of cases of MEN II and is also known as mucosal neuroma syndrome or Wagenmann-Froboese syndrome [1,3]. Oral mucosal neuromas may be the first feature to present in infancy or early childhood [3,4]. Mucosal neuromas may be found on the dorsal surface of the tongue, the palate, or pharynx. When found on the tongue, they are considered to be almost pathognomonic of medullary thyroid carcinoma (Fig. 1) [1]. The tongue may appear crenated or notched [4]. Pedunculated symmetric nodules on the buccal mucosa behind each lip commissure have been described [4]. When mucosal neuromas appear as submucosal nodules on the vermilion border of the lips, the resultant thickening of the lips (Fig. 2) is described as ‘‘pebbly’’ or ‘‘blubbery’’ [3]. The palate may be high and arched. The jaw may be prominent [1]. All of the oral findings in MEN IIB are generally thought of as asymptomatic and benign [4]. Multiple endocrine neoplasia IIB is distinguished from other MEN syndromes because it alone has associated physical characteristics other than the endocrine findings [4]. Distinct features of MEN IIB include thickened corneal nerves visible by slit lamp examination, a ‘‘wide-eyed’’ facies (Figs. 3 and 4), a Marfanoid body habitus with joint laxity, and medullary thyroid carcinoma [1,3]. Virtually all patients with MEN IIB develop aggressive medullary thyroid cancer. Early thyroidectomy (eg, at less than 1 year of age) is imperative to prevent metastasis [3].
0733-8635/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. PII: S 0 7 3 3 - 8 6 3 5 ( 0 2 ) 0 0 0 8 2 - 7
184
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
Fig. 1. Multiple endocrine neoplasia (MEN) IIB. Mucosal neuromas of the tongue.
Continued monitoring is recommended after thyroidectomy for residual or recurrent cancer. About 50% of patients develop pheochromocytoma [3]. Gastrointestinal problems may be associated because of hamartomatous ganglioneuromatosis of the gastrointestinal tract [1].
Fig. 3. MEN IIB. Characteristic facies. Neuromas cause thickening and eversion of the upper eyelids and a wide-eyed appearance. Eyebrows appear prominent.
Molecular genetics Multiple endocrine neoplasia IIB is inherited in an autosomal-dominant manner. The disease-causing mutation is found in the RET gene at the chromosomal locus 10q11. The American Society of Clinical Oncologists denotes MEN II as a welldefined hereditary cancer syndrome for which genetic testing is considered standard of care for affected probands and at-risk family members [3]. A clinical genetic test is available that detects a disease-causing mutation in 95% of patients with MEN IIB. Interestingly, more than 95% of patients with MEN IIB have
Fig. 2. MEN IIB. Note thick lips with pebbly nodules at the vermilion border.
the same mutation caused by substitution of a single methionine to threonine in the affected protein [1]. Linkage testing is available when no mutation is found and multiple family members are affected. RET mutation analysis should be performed soon after birth in all children known to be at risk [3]. About half of affected individuals with MEN IIB have a de novo or new mutation [3], usually paternally inherited [1]. In patients without a family history,
Fig. 4. MEN IIB. Mucosal neuroma of the eyelid.
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
185
RET mutation analysis should be performed as soon as the diagnosis is being considered [3].
Carney syndrome (NAME or LAMB syndrome) Carney syndrome is also called NAME syndrome (Nevi, Atrial myxomas, Myxoid neurofibromas, Ephelides) and LAMB syndrome (Lentigines, Atrial myxomas, Mucocutaneous myxomas, Blue nevi). Carney syndrome is considered to be an MEN syndrome. Cardiac myxomas are an associated complication that may, unfortunately, present as an embolic stroke if not detected or removed. Myxomas may also appear in the skin or breasts [5]. Endocrine abnormalities include Cushing’s syndrome caused by primary pigmented nodular adrenocortical disease, elevated growth hormone and acromegaly caused by pituitary adenomas, and prolactinemia thought to be caused by hyperplasia of cells within the pituitary gland [6]. In affected men, tumors of the testicular Sertoli’s and Leydig’s cells are associated [6]. Oral features of Carney syndrome include pigmented maculae over the lips and oral mucosa (Fig. 5). Mucosal pigmented maculae may also be found on the conjunctiva (Fig. 6). Associated skin pigmented maculae may appear on all body surfaces and include ephelides or freckles, darkly pigmented nevi, cafe´ au lait maculae, and as blue nevi. Molecular genetics Carney syndrome is inherited in an autosomaldominant manner. A causative mutation in the gene called PRKAR1A on chromosome 17 has been identified and clinical genetic testing is available for this alteration. Many affected patients, however, may have an alteration at a separate site. A second
Fig. 5. Carney’s syndrome. Pigmented maculae, also called lentigines, affect the lips and facial skin.
Fig. 6. Carney’s syndrome. Pigmented maculae affect the conjunctiva and periorbital skin.
gene is suspected on chromosome 2p, but has not yet been identified.
Cowden disease (multiple hamartoma syndrome) Cowden disease, also known as multiple hamartoma syndrome, is characterized by facial and oral papules and hamartomas. The hamartomas may appear in any body organ [7]. Lifetime risk of malignancy is increased. Affected women have a 20% to 50% risk of breast cancer and increased risk of endometrial cancer. All patients have a 10% risk of nonmedullary cancers of the thyroid [8]. The incidence of malignant melanoma and renal cell cancer is also suspected to be increased [8]. Diagnostic criteria have been developed and published [7] by the International Cowden Consortium (Box 1). These are expected to be updated as further information about the disorder becomes known. Oral findings are present in 80% of patients [9,10] and may aid early identification of the diagnosis. In most cases, the oral findings are found in multiple locations, such as the gingival mucosa (Figs. 7 and 8) and buccal mucosa [10]. The oropharynx, larynx, tongue (Fig. 9), nasal mucosa, and anogenital region may be involved [10]. The typical appearance of multiple, coalescent mucosal papillomas has been described as cobblestone-like and is seen in 40% of patients [10]. Skin findings are included among the current major and minor criteria for diagnosis [8,10]. The finding of multiple facial trichilemmomas is considered pathognomonic for the disorder. Other characteristic skin findings include lichenoid papules, acral keratoses, palmoplantar keratoses, and lipomas. Acral keratoses are skin colored to slightly pigmented flat, warty papules on the backs of the hands and feet and
186
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
Box 1. Diagnostic criteria for Cowden disease* Pathognomonic criteria Facial trichilemmomas Acral keratoses Papillomatous lesions Mucosal lesions Major criteria Thyroid carcinoma Macrocephaly Lhermitte-Duclos diseasey Minor criteria Other thyroid lesions Mental retardation Gastrointestinal hamartomas Fibrocystic breast disease Lipomas Fibromas Genitourinary tumors Operational Diagnosis if: Pathognomonic lesions alone including at least six facial papules with at least three trichilemmomas or facial papules and oral papillomatosis or oral papillomatosis and acral keratoses or at lease six palmoplantar keratoses Two major criteria including macrocephaly or LhermitteDuclos disease One major and three minor criteria Four minor criteria * Criteria are considered operational and expected to evolve as further information becomes available. y Hamartomatous change of cerebellar cells with characteristic appearance on MRI or CT.
Fig. 7. Cowden disease. Oral mucosal papillomatosis may affect the gingival mucosa.
been found in the PTEN gene in 80% of patients who meet established diagnostic criteria [7]. The chromosomal locus of the PTEN gene is 10q23.3 [8]. Clinical genetic testing is currently available.
Tuberous sclerosis complex Tuberous sclerosis complex (TSC) has been described and studied for more than 160 years [12,13]. As a result, diagnostic criteria have been well defined [12,14] and are available in updated format at www.geneclinics.org (Box 2). 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 mental retardation and seizures, affect long-term prognosis most. Up to 14% of patients with TSC develop subependymal giant cell astrocytoma. Associated skin findings, such as hypomelanotic maculae, facial
palmoplantar keratoses are translucent and punctate keratoses on the palms and soles. Vitiligo, neuromas, xanthomas, and cafe´ au lait spots are additional skin findings that have a reported infrequent association with Cowden disease [11]. Facial papules usually show a periorificial distribution (Fig. 10) [10]. Molecular genetics Cowden disease is inherited in an autosomaldominant manner. A disease-causing mutation has
Fig. 8. Cowden disease. Verrucous or papular fibrous overgrowths are typical on the gingiva.
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
187
Box 2. Diagnostic criteria for TSC*
Fig. 9. Cowden disease. Oral papillomatosis affects the tongue causing a ‘‘cobblestone’’ appearance.
angiofibromas, and ungual fibromas, have been reviewed in detail [15]. Current diagnostic criteria include the oral finding of gingival fibromas (Fig. 11). 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 [16]. Gingival fibromas are found in some patients with TSC, but
Fig. 10. Cowden disease. A periorificial distribution of facial trichilemmomas is characteristic.
Major features Facial angiofibromas or forehead plaque Periungual fibromas Hypomelanotic macules (greater than three) Shagreen patch or connective tissue nevus Nodular retinal hamartomas Cortical tubery Subependymal nodule Subependymal giant cell astrocytoma Cardaic rhabdomyomas Lymphangiomatosisz Renal agiomyolipomaz Minor features Multiple dental enamel pits Hamartomatous rectal polyps Bone cysts Cerebral white matter radial migration linesy Gingival fibromas Nonrenal hamartoma Retinal achromic patch ‘‘Confetti’’ skin macules Multiple renal cysts Definite TSC if two major or one major and two minor features Probable TSC if one major and one minor feature Possible TSC if one major or two or more minor features * Criteria are available in updated form at www.geneclinics.org. y Cortical tuber and white matter migration lines count as only one feature when diagnosed together. z Lymphangiomatosis and renal aniomyolipoma, when found together, are insufficient to make the diagnosis of TSC.
not others and are not essential to make the diagnosis. Also, gingival hyperplasia caused by antiseizure medication, such as phenytoin, may obscure gingival fibromas in these patients [17]. Lack of oral hygiene has been associated with TSC, but this is thought to be caused by mental subnormality rather than a growth or neoplastic change [12].
188
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
Molecular genetics
Fig. 11. Tuberous sclerosis. Gingival fibromas.
Multiple randomly distributed pits in dental enamel (Fig. 12) provide another diagnostic feature of TSC. Enamel pitting may be seen by direct inspection and usually affects the labial surfaces of the front and lateral incisor and canine teeth [12]. The prevalence of dental pits in patients with TSC is thought to range from 48% to 100% [12,18]. Smaller pits can be appreciated better using dental plaquedisclosing stain on the surfaces of the teeth. Electron microscopy can also be used once a tooth has been removed. Dental enamel pits may be found on the teeth of normal patients, but are usually fewer and less obvious. A study by Flanagan et al [18] found that most patients with TSC had great than 14 pits per person, whereas most normal controls had less than 6 pits per person.
Fig. 12. Tuberous sclerosis. Example of enamel pitting made more prominent by use of dental plaque-disclosing stain. (From Gomez MR, Sampson JR, Whittemore VH. Tuberous sclerosis complex: developmental perspectives in psychiatry. 3rd Ed. Oxford University Press; 1999. p. 178; with permission.)
The TSC complex is inherited in an autosomaldominant 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. Most cases are caused by a mutation of the TSC1 gene on chromosome 9q34 or the TSC2 gene on chromosome 16p13. An identifiable mutation has not yet been found to explain the remainder of cases. In addition, TSC has a high rate of somatic mosaicism among affected individuals estimated to be 10% to 25% [14]. Because of these and other complexities, the diagnosis of TSC is currently based on clinical findings. Genetic testing is available on a research basis only.
Peutz-Jeghers syndrome Peutz-Jeghers syndrome is a genetic condition characterized by gastrointestinal polyposis and tan to dark brown or blue maculae on the skin and oral mucosa (Fig. 13) [19]. Diagnosis is based on these clinical findings. Polyps may cause intussusception or bowel obstruction. A study by Boardman et al [20] determined that patients with Peutz-Jeghers syndrome had a relative risk for cancer increased to 9.9 times normal. The incidence of gastrointestinal cancers and breast cancer is particularly increased [20,21]. Cancer
Fig. 13. Peutz-Jeghers syndrome. Characteristic pigmented maculae of the lips and buccal mucosa.
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
189
predisposition to hematologic abnormalities and bone marrow failure [23,24]. Failure of the bone marrow is the chief cause of early death. New treatments are under development, but no treatment has been found to be effective uniformly in all patients [23]. Patients with dyskeratosis congenita are also predisposed to pulmonary complications and malignancy. Oral leukoplakia is a diagnostic feature of this disorder and usually appears early in life in association with skin hyperpigmentation [24]. Leukoplakia is generally only seen in the mucous membranes of the mouth, but may also be found in the esophagus and anal and genital mucosa. The leukoplakia tends to progress with time and may undergo malignant transformation [24]. Extensive dental caries and loss of teeth is reported in 18% of patients with dyskeratosis congenita [23]. Molecular genetics Fig. 14. Peutz-Jeghers syndrome. Characteristic perianal pigmented maculae.
surveillance comprises an important part of management for these patients. The pigmented maculae usually are present at birth or are first noted in early childhood [19]. The maculae are usually found on the lips, on the buccal mucosa and on the skin around the mouth. 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 (Fig. 14). Maculae may be found in a periorificial distribution around the eyes in some patients [22]. Skin maculae are reported to fade with age, but the maculae on the oral mucosa remain [19].
Most affected family members are males with pedigrees that show no male-to-male transmission. Most cases are thought to be X-linked. Female cases
Molecular genetics Peutz-Jeghers syndrome is inherited in an autosomal-dominant manner. 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 [21]. The causative gene in 30% to 70% of cases is the STK11 gene located at chromosomal locus 19p13 [21]. A clinical genetic test is currently available for Peutz-Jeghers syndrome.
Dyskeratosis congenita Dyskeratosis congenita is a genetic disease characterized by reticulated hyperpigmentation of the skin, dystrophy of the nails, oral leukoplakia, and a
Fig. 15. Pachyonychia congenita. Leukokeratosis affects the tongue.
190
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
Fig. 16. Pachyonychia congenita. Leukokeratosis affects the buccal mucosa.
have been reported. These are thought to be caused by an autosomal-recessive form of the disorder [23]. A causative gene, DKC1, has been localized to Xq28. A clinical genetic test for a mutation in this gene is available.
Pachyonychia congenita Pachyonychia congenital (PC) is a group of disorders unified by characteristic, distinct nail changes with distal onycholysis, subungual hyperkeratosis that causes transverse arching of the distal nail plate, and yellow-brown discoloration [25,26]. In PC type I (also called Jadassohn-Lewandowsky syndrome), hyperkeratosis of the palms, soles, knees, and elbows and follicular hyperkeratosis are associated features. Oral leukokeratosis separates PC type I from PC type II (or Jackson-Lawler syndrome). In PC type II, natal teeth, epidermal cysts, and steatocysts are associated. Oral leukokeratosis may be found, but is less marked than in PC type I [26]. Oral lesions are white, opaque thickenings in areas of the tongue or buccal mucosa (Figs. 15 and 16), or may present as white plaques that cover the entire surface of the tongue, lips, and cheeks [25]. Superinfection with Candida albicans has been reported [25,26]. In a patient reported by Hannaford and Stapleton [26], lesions did not respond to anticandidal treatment despite a positive culture. Malignant transformation of the leukokeratosis has not been reported [25].
Fig. 17. Hypohidrotic ectodermal dysplasia. Female carrier. Note sparse, fine, blond hair and mild flattening of the nasal bridge.
Molecular genetics Pachyonychia congenital is an autosomal-dominant disorder. Keratins are structural proteins usually expressed in pairs [27]. The keratin pair K6b-K17 is expressed in nails and the palmoplantar surface.
Fig. 18. Hypohidrotic ectodermal dysplasia. Hypodontia and conical teeth in a female carrier.
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
191
dentition usually requires extensive dental treatment at an early age with prosthetic teeth. This intervention is considered critical for development of positive selfimage and overall oral health [28,29]. Molecular genetics Hypohidrotic ectodermal dysplasia is X-linked and affects mostly males. Female carriers may also express the disorder, however, usually in a less severe form. Clinical genetic testing is available for the disease causing EDA mutation on the X chromosome [30]. Fig. 19. Papillon-Lefe`vre syndrome. Well-circumscribed hyperkeratosis of the elbows and knees in an affected patient.
Mutations in either of these keratins cause PC type II. Mutations in either K16 or K6a cause PC type I [27]. 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.
Papillon-Lefe`vre syndrome Papillon-Lefe`vre syndrome is a very rare genetic condition characterized by well-demarcated palmoplantar hyperkeratosis (Fig. 19). Periodontitis separates Papillon-Lefe`vre syndrome from other inherited palmoplantar keratodermas [31]. The features of the condition usually first become apparent about ages 2
Hypohidrotic ectodermal dysplasia Hypohidrotic ectodermal dysplasia is an inherited condition that affects ectodermal structures, specifically hair, teeth, and sweat glands. Hair is often fine, sparse, and blond (Fig. 17). Lack of sweating may result in heat intolerance and frequent fevers of seemingly unknown cause [28]. Variable associated facial features include a prominent forehead, thick lips, and a depressed nasal bridge (see Fig. 17) [28]. Because features of this disorder may be subtle and unrecognized, the oral findings may first reveal the diagnosis [28]. These include hypodontia and conical teeth (Fig. 18). Feeding may be difficult because of lack of teeth and saliva [28]. Lack of
Fig. 20. Papillon-Lefe`vre syndrome. Inflammatory periodontitis and tooth loss.
Fig. 21. Hereditary hemorrhagic telangiectasia. Characteristic papular telangiectasia affecting the skin.
192
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
Molecular genetics Box 3. Diagnostic criteria for HHT* Diagnostic criteria Spontaneous and recurrent nosebleeds Telangiectasias Internal arteriovenous malformations (pulmonary, cerebral, hepatic, spinal, or gastrointestinal) Positive family history of HHT in firstdegree relative Definite HHT if three or more criteria Possible or suspected HHT if two criteria Unlikely HHT if less than two criteria * Criteria are available in updated form at www.geneclinics.org.
to 4 [32]. Palmoplantar hyperkeratosis has been reported to improve with time [32]. Severe, inflammatory periodontitis results in complete loss of deciduous teeth by 4 years (Fig. 20). The same process results in complete loss of the adult teeth when they appear. The wisdom teeth, however, are spared [32]. The specific mechanism that causes the periodontitis is not yet known.
Papillon-Lefe`vre syndrome is a rare autosomalrecessive disorder with an increased rate of consanguinity in parents of affected patients [31]. Most cases are caused by mutations of the cathespin C gene on chromosome 11q14 [31]. A clinical genetic test is not yet currently available.
Hereditary hemorrhagic telangiectasia Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, 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. 21), gastrointestinal tract, brain, and lung. Bleeding may cause sudden and devastating consequences. Diagnostic criteria are available for this disorder in updated form at www.geneclinics.org (Box 3). Oral lesions may be punctate, spider-like, or nodular and be found on the buccal mucosa, tongue, lips, palate, and gingiva [33]. Color may vary from bright red to purple [34], but in the oral mucosa is usually cherry-red [33]. Presentation of HHT as hemorrhagic vesicles and ulcers of the gingival and oral mucosa has also been reported [34]. Use of a
Table 1 Summary findings Genetic condition
Oral findings
Gene and locus
Genetic test
Multiple endocrine neoplasia IIB
Tuberous sclerosis complex
Gingival fibromas; oral fibromas
Peutz-Jeghers syndrome
Pachyonychia congenita type 1
Pigmented macules on lips, buccal mucosa Oral leukoplakia; dental caries and tooth loss Oral leukokeratosis
Hypohidrotic ectodermal dysplasia
Hypodontia; conical teeth
Papillon-Lefe´vre syndrome
Inflammatory periodontitis; tooth loss
Hereditary hemorrhagic telangiectasia
Oral telangiectasias
RET gene 10q11 PRKAR1A 17 PTEN 10q23.3 TSC1, TSC2 9q34, 16p13 STK11 19p13 DKC1 Xq28 K6a/K16 17q12,12q13 EDA Xq12 Cathespin C 11q14 ENG, ACVRL1 9q34.1,12q1
Yes
Cowden disease
Mucosal neuromas; high, arched palate; prominent jaw Pigmented macules on lips and oral mucosa; dental enamel pits Mucosal papillomatosis
Carney syndrome
Dyskeratosis congenita
Yes Yes Research only Yes Yes Yes Yes No Research only
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
very soft toothbrush may help prevent trauma from routine oral hygiene [34]. Molecular genetics Hereditary hemorrhagic telangiectasia is an autosomal-dominant disorder. Two main genetic subtypes of HHT have been described: HHT1 and HHT2 [35]. The disease causing mutation in HHT1 is in the endoglin (ENG) gene on chromosome 9q34.1. For HHT2, the mutation is in the activin receptor gene on chromosome 12q1 [35]. Currently, only researchbased genetic testing is available.
[7]
[8]
[9]
[10]
[11]
Summary Many genodermatoses have distinct oral features that may help identify or confirm a genetic diagnosis. Oral features of the disorders described here are summarized in Table 1. These conditions provide clear examples of rapid progress in the field of genetic technology relevant to patient care. Less than a decade ago, the exact genetic locus of most of these disorders was unknown. Today, for many of these disorders, the exact location of the disease-causing mutation is known and clinical genetic testing is available for patients. This information has impact not only for genetic counseling and anticipatory medical care, but also provides insight into the mechanisms of disease. How this rapid progress will impact care, and ultimately treatment of patients, remains to be seen.
[12]
[13] [14]
[15]
[16]
[17]
References [18] [1] Morrison PJ, Nevin NC. Multiple endocrine neoplasia type IIB (mucosal neuroma syndrome, WagenmannFroboese syndrome). J Med Genet 1996;33:779 – 82. [2] Rimoin DL, Connor JM, Pyeritz RE. Emery and Rimoin’s principles and practices of medical genetics. 3rd edition. New York: Churchill Livingstone; 1996. p. 1383 – 5. [3] Wiesner GL, Snow K. Multiple endocrine neoplasia type 2. Available at: www.geneclinics.org. Accessed September 20, 1999. [4] Schenberg ME, Zajac JD, Lim-Tio S, et al. Multiple endocrine neoplasia syndrome-type 2b. Int J Oral Maxillofac Surg 1992;21:110 – 4. [5] Quintal MC, Tabet JC, Oligny L, et al. Oral soft tissue myxoma: report of a case and review of the literature. J Otolaryngol 1994;23:42 – 5. [6] Raff SB, Carney JA, Krugman D, et al. Prolactin secretion abnormalities in patients with the ‘‘syndrome of
[19] [20]
[21]
[22] [23]
[24]
193
spotty skin pigmentation, myxomas, endocrine overactivity and Schwannomas’’ (Carney complex). J Pediatr Endocrinol Metab 2000;13:373 – 9. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet 2000;37: 828 – 30. Eng C, Hampel H, de la Chapelle A. Genetic testing for cancer predisposition. Annu Rev Med 2001;52: 371 – 400. Chaudhry SI, Shirlaw PJ, Morgan PR, Challacombe SJ. Cowden’s syndrome (multiple hamartoma and neoplasia syndrome): diagnostic dilemmas in three cases. Oral Dis 2000;6:248 – 52. Hildebrand C, Burgdorf WHC, Lautenschlager S. Cowden syndrome: diagnostic skin signs. Dermatology 2001;202:362 – 6. Thyresson HN, Doyle JA. Cowden’s disease (multiple hamartoma syndrome). Mayo Clin Proc 1981;56: 179 – 84. 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; 90:430 – 5. Gomez MR. History of the tuberous sclerosis complex. Brain Dev 1995;17:55 – 7. Northrup H, Kit-Sing A. Tuberous sclerosis complex. Available at: www.geneclinics.org. Accessed April 13, 2002. Rogers RS, O’Connor WJ. Dermatologic manifestations. In: Gomez MR, Sampson JR, Whittemore VH, editors. Tuberous sclerosis complex. 3rd edition. Oxford: Oxford University Press; 1999. p. 160 – 80. Tillman HH, DeCaro F. Tuberous sclerosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1991;71: 301 – 2. Gomez MR. Liver, digestive tract, spleen, arteries, thymus, and lymphatics. In: Gomez MR, Sampson JR, Whittemore VH, editors. Tuberous sclerosis complex. 3rd edition. Oxford: Oxford University Press; 1999. p. 228 – 39. Flanagan N, O’Connor WJ, McCartan B, et al. Developmental enamel defects in tuberous sclerosis: a clinical genetic marker? J Med Genet 1997;34:637 – 9. Kitagawa S, Townsend BL, Hebert AA. Peutz-Jeghers syndrome. Dermatol Clin 1995;13:127 – 31. Boardman LA, Thibodeau SN, Schaid DJ, et al. Increased risk for cancer in patients with Peutz-Jeghers syndrome. Ann Intern Med 1998;128:896 – 9. Amos CI, Frazier ML, McGarrity TJ. Peutz-Jeghers syndrome. Available at: www.geneclinics.org. Accessed February 23, 2001. Mallory SB, Stough DB. Genodermatoses with malignant potential. Dermatol Clin 1987;5:221 – 30. Andrews NC, Fleming MD. Dyskeratosis congenita: recent advances and future directions. J Pediatr Hematol Oncol 1999;21:344 – 55. Solder B, Weiss M, Jager A, et al. Dyskeratosis congenita: multisystemic disorder with special consideration of immunologic aspects. Clin Pediatr 1998;37:521 – 30.
194
J.L. Hand, R.S. Rogers III / Dermatol Clin 21 (2003) 183–194
[25] Dahl PR, Daoud MS, Su WPD. Jadassohn-Lewandowsky syndrome (pachyonychia congenita). Semin Dermatol 1995;14:129 – 34. [26] Hannaford RS, Stapleton K. Pachyonychia congenital tarda. Australas J Dermatol 2000;41:175 – 7. [27] Smith FJD, Coleman CM, Bayoumy NM, et al. Novel keratin 17 mutations in pachyonychia congenita type 2. J Invest Derm 2001;116:806 – 8. [28] Kupietzky A, Houpt M. Hypohidrotic ectodermal dysplasia: characteristics and treatment. Oral Pathol 1995; 26:285 – 91. [29] Ohno K, Ohmori I. Anondontia with hypohidrotic ectodermal dysplasia in a young female: a case report. Pediatr Dent 2000;22:49 – 52. [30] Kobielak K, Kobeilak A, Roszkiewicz J, et al. Mutations in the EDA gene in three unrelated families reveal no correlation between phenotype and genotype in the patients with an X-linked anhydrotic ectodermal dysplasia. Am J Med Genet 2001;100:191 – 7.
[31] Zhang Y, Lundgren T, Renvert S, et al. Evidence of a founder effect for four cathepsin C gene mutations in Papillon-Lefe`vre syndrome patients. J Med Genet 2001;38:96 – 101. [32] Wiebe CB, Hakkinen L, Putnins EE, et al. Successful periodontal maintenance of a case with PapillonLefe`vre syndrome:12-year follow-up and review of the literature. J Periodontol 2001;72:824 – 30. [33] Austin GB, Quart AM, Nvak B. HHT with oral manifestations. Oral Med 1981;51:245 – 51. [34] Bartolucci EG, Swan RH, Hurt WC. Oral manifestations of hereditary hemorrhagic telangiectasia (Osler-WeberRendu disease). Review and case reports. J Periodontol 1982;53:163 – 7. [35] McDonald J, Guttmacher AE. Hereditary hemorrhagic telangiectasia. Available at: www.geneclinics.org. Accessed June 26, 2000.