Genetic and Developmental Disorders of the Oral Mucosa: Epidemiology; Molecular Mechanisms; Diagnostic Criteria; Management

Home , Black hairy tongue, Cutis laxa, Dyskeratosis congenita, Enamel hypoplasia, Enchondromatosis, Fissured tongue

DOI: 10.1111/prd.12261

REVIEW ARTICLE

Genetic and developmental disorders of the oral mucosa: Epidemiology; molecular mechanisms; diagnostic criteria; management

1Department of Surgery, Medicine and Experimental Sciences, University of Sassari, Sassari, Italy 2WHO Collaboration Centre for Epidemiology and Community Dentistry, University of Milan, Milan, Italy 3Klinik für Zahnerhaltung, Präventiv-und Kinderzahnmedizin Zahnmedizinische Kliniken (ZMK), University of Bern, Switzerland 4IRCCS “Ca Granda-Ospedale Maggiore”, University of Milan, Milan, Italy 5Department of Biomedical, Surgical and Dental Science, University of Milan, Milan, Italy

Correspondence Guglielmo Campus, Prof Guglielmo Campus Klinik für Zahnerhaltung, Präventiv-und Kinderzahnmedizin Zahnmedizinische Kliniken (ZMK) University of Bern, Freiburgstrasse 7, Bern, Switzerland. Emails: [email protected]; [email protected]

1 | INTRODUCTION exact prevalence is unknown, but the syndrome seems more common among the Amish community. This rare condition is inherited as an Oral mucosal lesions may appear as ulcers, color changes and altera- autosomal recessive trait with a variable expression. Mutations of the tions in size and configuration of oral anatomy. This review presents Ellis van Creveld protein 1 and 2 genes, located in a head-to-head con- a broad overview of genetic and developmental disorders of the figuration on chromosome 4p16, have been identified as causative.6,7 oral mucosa that might be recognized in children, adults and the el- The mutations of Ellis van Creveld belong to the short rib-polydactyly derly.1-3 A number of genetic disorders (Table 1) have specific mani- group and especially type III (Verma-Naumoff syndrome). festations of the oral mucosa caused by a derangement of one or Chondro-ectodermal dysplasia is characterized by the presence of several of the components of the tissue. Many of them follow the short ribs, polydactyly, growth retardation and ectodermal and cardiac skin or systemic signs of the underlying genetic disease, but in a few defects. The most constant oral findings are fusion of the upper or cases, oral signs represent the first manifestation of the disorder. lower lip to the gingiva and hypertrophy of the labiogingival fraenum, Disorders during embryonic development (Table 2) might lead to resulting in the disappearance of the mucolabial fold, or the presence of a wide range of abnormalities in the oral cavity; some of them are multiple fibrous bands. Oligodontia and small conical teeth with enamel quite common but of negligible concern, whereas others are rare but hypoplasia are also present.8 The differential diagnosis from similar serious, affecting not only the oral mucosa, but also other structures chondrodystrophies, such as Jeune dystrophy, McKusick-Kaufman of the oral cavity (ie palate, tongue and gingiva). syndrome, includes oro-facial-digital syndrome, and Weyers acroden- tal dysostosis.5,9-11 The oral dental management is quite complex and often requires a multidisciplinary approach to correct the dental de- 2 | GENETIC DISORDERS fects. Orthodontics and maxillofacial oral surgery are often involved in the treatment; moreover, comprehensive restorative treatment is fun- 2.1 | Genodermatoses damental to manage enamel hypoplasia and to replace missing teeth.10

2.1.1 | Chondro-ectodermal dysplasia 2.1.2 | Dyskeratosis congenita Chondro-ectodermal dysplasia, also termed Ellis-van Creveld syndrome, is a rare disease first described in 1940 by Ellis & van Creveld.4 Dyskeratosis congenita or Zinsser-Engman-Cole syndrome is a multi- Approximately 150 cases have been reported worldwide to date.5 The system disorder,12 first described by Zinsser in 1906 and recognized

TABLE 1 Genetic disorders 2.1.3 | Ehlers-Danlos syndrome Genodermatoses Other genetic disorders Ehlers-Danlos syndrome is a group of connective tissue disor- • Chondro-ectodermal dysplasia • Acanthosis nigricans ders20 inherited as an autosomal dominant, autosomal recessive • Dyskeratosis congenita • Angio-osteo-hypertrophic or X-linked recessive trait. It was first described by Edvard Ehlers, • Ehlers-Danlos syndrome syndrome • Hereditary benign intraepithelial • Encephalotrigeminal a Danish dermatologist, in 1901 and a few years later in 1908 by dyskeratosis angiomatosis Henri-Alexandre Danlos, a French dermatologist.21 The preva- • Keratosis follicularis • Familial adenomatous lence is between 1:5000 and 1:10 000, but the epidemiology of • Lipoid proteinosis polyposis the specific types is largely unknown.20 The various types of the • Multiple hamartoma syndrome • Focal dermal hypoplasia • Pachyonychia congenita • Focal palmoplantar and syndromes are clinically and genetically heterogeneous, result- • Peutz-Jeghers syndrome oral mucosa hyperkerato- ing from defects in either the synthesis or the structure of fibril- • Tuberous sclerosis sis syndrome lar collagen.22,23 Although the basic defect is not well known, the • White sponge nevus • Gingival fibromatosis three fundamental mechanisms of disease include deficiencies of • Maffucci’s syndrome • Neurofibromatosis (type collagen-processing enzymes, dominant negative effects of mu- 1) tant collagen chains and haploinsufficiency.24 Defects in either • Oro-facial-digital collagen-processing enzymes or collagen structure are ubiquitous syndrome (type 1) in all subtypes of the disease, leading to collagen fragility through- out the body. The oral mucosa is excessively fragile and subject TABLE 2 Developmental disorders to bruising. Gingival bleeding and periodontitis are common.25 Wound healing may only be slightly delayed. Tooth mobility is not Oral mucosa Gingiva Tongue increased,26 although a hypermobility of the temporomandibular • Cysts of the • Retrocuspid • Geographic tongue joint may occur.21,27 Approximately 50% of patients have the abil- oral mucosa in papilla • Fissured tongue newborns • Median rhomboid ity to touch their nose with the tip of the tongue (Gorlin's sign) • Fordyce′s glossitis compared with 10% of the normal population.25,28 The differential granules • Hairy tongue diagnosis includes cutis laxa, Marfan's syndrome, Marfanoid hy- • Leukoedema • Lingual varices permobility syndrome and osteogenesis imperfecta. Oral manifes- • Lingual thyroid nodule tation includes periodontitis and oral mucosal ulceration. There is no definitive treatment for the syndrome. as a clinical entity by Engman & Cole.13 Dyskeratosis congenita is a rare disease with an estimated annual incidence of less than one per 2.1.4 | Hereditary benign intraepithelial million population.14 The most common mode of inheritance is the dyskeratosis X-linked recessive form, which affects mainly males and is caused by mutation of the DKC1 gene at the Xq28 site.15 It is characterized Hereditary benign intraepithelial dyskeratosis is a rare autosomal by hyperpigmentation, telangiectasias and atrophic areas of the skin dominant disorder that was first described by Von Sallmann & Paton (usually on the face, neck and chest), dystrophic nails, hyperhidrosis, in 1959. 29,30 The disorder occurs almost exclusively in members of dermal and mucosal bullae, blepharitis, ectropion, aplastic anemia, the Native American Haliwa-Saponi tribe (formerly referred to as mental handicap and oral manifestations.12,13,15 The oral lesions con- Haliwa Indians) or descendants of them. Several additional cases sist of aggregates or recurrent blisters that rupture, leaving a raw ul- were described in persons who reside in the northeastern part of cerated surface mainly on the tongue and buccal mucosa.16 Atrophy North Carolina.31 Some cases were also reported in Italy, England, of the oral mucosa is the result of repeated episodes. Leukoplakia is Germany and Brazil.32,33 generally seen in the oral mucosa.17,18 These lesions are considered to A segment of DNA localized at 4q35 is duplicated, resulting be potentially malignant, with a malignant transformation rate of up in triple alleles for two linked markers, suggesting that gene du- to 35% of the cases in 10-30 years.16 Differential diagnosis includes plication is responsible for the disorder. The disease affects the palmoplantar keratoderma-spastic paralysis syndrome, nail-patella oral mucosa and bulbar conjunctiva, with onset usually at birth or syndrome, twenty-nail dystrophy, poikiloderma with neutropenia, early childhood.32 The oral lesions usually appear as thick, soft, Fanconi anemia, Diamond-Blackfan anemia, Shwachman-Diamond white, asymptomatic papules and plaques with varying sizes and anemia, idiopathic aplastic anemia, idiopathic pulmonary fibrosis, can involve any part of the oral cavity.34 Milder cases may ex- Coats plus syndrome.19 hibit the opalescent appearance of leukoedema. Some of these Dental management is supportive, but the leukoplakic lesions appearances may be due to a superimposed Candida spp. infec- require frequent close monitoring (usually once every 3 months) and tion.33 The differential diagnosis includes white sponge nevus a biopsy of suspicious areas in order to detect possible oral cancer. due to the similarity of the clinical appearance of lesions. No Surgical removal of dysplastic lesions may reduce the risk of malig- treatment is recommended because of the nonmalignant nature nant transformation. of the disease. 14 | PINNA et al.

is unknown, it is estimated at 1:200 000.52,53 Mutation of the phos- 2.1.5 | Keratosis follicularis phatase and tensin homolog tumor-suppressor genes has been im- Keratosis follicularis, also known as Darier disease or dyskeratosis plicated in its pathogenesis. The chromosomal locus of this gene is follicularis, is a rare keratinization disorder.35 It is an inherited auto- on band 10q23.3.54,55 Inherited mutation in the phosphatase and somal dominant genodermatosis with complete penetrance.36 The tensin homolog gene has been found in about 80% of affected disease was first described by Prince Marrow in 1886 and shortly patients, whereas in the remaining 20% the etiology remains un- after by Darier & White in 1889.37 The estimated prevalence is be- known.56 Oral findings are present in 80% of patients and are con- tween 1:36 000 and 1:100 000 of the population, most often af- sidered the major diagnostic criteria, especially for early clinical fecting males.36,38 It is caused by mutations in the ATP2A2 gene identification.52,57 Oral lesions usually consist of small multiple (12q23-q24.1) encoding a Ca2+ pump of the endoplasmic reticulum whitish or pink papules or nodules, around 1-3 mm, that affect the of the epithelial cells, resulting in abnormal organization or matura- gingiva, dorsal tongue and buccal mucosa.58 These lesions may be tion of complexes responsible for cell adhesion.39,40 Mucosal lesions isolated or coalesce in a characteristic cobblestone pattern, usu- may affect the mouth, pharynx and female genitalia. The oral mu- ally on the gingiva.58 Other possible oral findings include a high cosae are affected in 13%-50% of cases.41 The typical oral lesions arched palate, periodontitis (Figure 1), extensive dental caries and are small, whitish confluent papules of varying size with a central xerostomia.56,59,60 The differential diagnosis includes tuberous depression, which may occasionally coalesce into plaques and be- sclerosis, juvenile polyposis syndrome, Peutz-Jeghers syndrome, come hypertrophic, assuming a cobblestone appearance.42 The pal- Birt-Hogg-Dubé syndrome, Gorlin syndrome and neurofibromato- ate, gingiva, buccal mucosa and tongue are the most frequent sites sis type 1.52 As the malignancy of oral lesions is not described and of localization.41,43 The differential diagnosis includes acanthosis the lesions are asymptomatic, no treatment of the oral lesions is nigricans, papillary hyperplasia of the palate, warty dyskeratoma generally required.60 and familial benign pemphigus. The oral lesions of Darier disease are asymptomatic, thus no special dental management is required, and 2.1.8 | Pachyonychia congenita systemic retinoids used to treat severe cutaneous involvement do not improve oral disease.41 Pachyonychia congenita, or Jadassohn-Lewandowsky syndrome, is a rare group of genodermatosis usually inherited as an autosomal dominant trait.61 Since it was initially reported in 1906 by 2.1.6 | Lipoid proteinosis Jadassohn & Lewandowsky,62 approximately 1000 patients have Lipoid proteinosis, also known as Urbach-Wiethe syndrome or hya- been registered to date worldwide, but the prevalence is still not linosis cutis et mucosae, is a rare autosomal recessive genodermato- known.63,64 The disease is caused by the mutation of five keratin sis. It was first described by Urbach & Wiethe in 1929.44 Incidence genes KRT6A (OMIM 148041), KRT6B (OMIM 148042), KRT6C and prevalence are not known. More than 300 cases (age range (OMIM 612315), KRT16 (OMIM 148067) and KRT17 (OMIM 6-67 years) have been reported worldwide. This condition is more 148069).65,66 Keratins play a key role in epidermal cell integrity common in Europe (the Netherlands or Germany) and South African and mechanical strength. These genes are expressed in the nail regions, particularly among children of consanguineous marriages.45 bed, palmoplantar epidermis, oral and laryngeal mucosa and hair The etiology remains uncertain. Mutations in the gene encoding for follicles. Disruption of the cytoskeletal system due to the keratin extracellular protein 1 on band 1q21 are found.45,46 The most com- gene mutations leads to extreme fragility of the epithelial cells and mon mutations are located on exons 6 and 7 of extracellular protein tissues, which appears clinically as epidermolysis and compensa- 1.47 tory hyperkeratosis at these sites.51 Onset is variable, with most The mouth is extensively involved, most frequently affecting cases manifesting soon after birth, others becoming clinically ap- the palate, gingiva, buccal mucosa, lingual frenulum and tongue.48 parent only in late childhood and rarely in adulthood.67 It is char- The mucosa has a nodular and thick aspect and seems to be related acterized by symmetrical thickening of the nails, palmoplantar to hyaline deposition, especially in the gingival tissues.49 The main hyperkeratosis with hyperhidrosis, blister formation and follicular differential diagnoses are hydroa vacciniforme and erythropoietic keratosis.68 protoporphyria, but also include xanthomas, leprosy and lichen am- The oral mucosal lesions appear as leukokeratosis, which yloidosis.26 No specific treatment is available for this uncommon are sometimes painful. These usually appear with a striated disorder. hyperkeratotic aspect and are present as thick and white or greyish-white areas that are usually located on the palate, dorsum of the tongue, the gingiva and the buccal mucosa.51,66 The 2.1.7 | Multiple hamartoma syndrome differential diagnosis should include leukoplakia, lichen planus, Multiple hamartoma syndrome, also known as Cowden disease, is white sponge nevus, dyskeratosis congenita, hereditary benign a multisystem disorder inherited as an autosomal dominant trait intraepithelial dyskeratosis and focal palmoplantar and oral mu- showing a high degree of penetrance and a range of expressivity cosa hyperkeratosis syndrome. No treatment is required for the with a predisposition to cancer.50,51 Although the exact prevalence oral lesions. PINNA et al. | 15

population in Europe was estimated to be 8.8:100 000.77 Many patients die by the age of 20 years. Two major mutation loci have been identified: one in TSC1 and the other in TSC2, tumor-suppressor genes located in chromosome 9q34 and 16p13.77 The TSC1 gene codes for hamartin protein and TSC2 gene is responsible for encoding for tuberin. The loss of the complex created by these proteins, an important inhibitor of neoplasia, pro- motes an uncontrolled cell proliferation and migration.76 It is characterized by epilepsy, mental handicap, paraventricular calcifications, multiple small gliomas, mucocutaneous manifestations, skeletal disorders and, rarely, ophthalmic tumors.76,78 Characteristic skin lesions occur on the face, principally along the nasolabial fold and cheeks (facial angiofibromas), peri-ungual fibroma (Koenen tumors) and fibrous FIGURE 1 Cowden disease. Multiple lesions of the gums, which plaques on the forehead and scalp. Other lesions include renal angio- appears rounded, nodular and sessile. The gingivae look globally myolipomas, subependymal nodules and retinal hamartoma.77 hyperplastic The oral cavity is frequently involved.79 The oral mucosa may present fibromas, especially affecting the anterior gingiva. Other sites less frequently involved include labial mucosa, superior labial 2.1.9 | Peutz-Jeghers syndrome frenulum, palate and tongue.51 The gingiva or other parts of the oral Peutz-Jeghers syndrome is an autosomal dominant condition char- mucosa may exhibit confluent nodules a few millimeters to less than acterized by the association of gastrointestinal polyposis, mucocu- 1 cm in diameter, which are of whitish or normal color. Enamel pits 69 taneous pigmentation and cancer predisposition. The exact global also occur. The differential diagnosis of oral lesions should include prevalence is unknown, but is estimated to be in the range of 1:25 000 multiple fibromas, multiple condylomata acuminata, focal epithelial 70 to 1:300 000 births in the USA. The syndrome is inherited in an au- hyperplasia and neurofibromatosis. Frequent dental examinations tosomal dominant manner and is caused by a mutation of the LKB1/ are needed in order to eliminate potential irritative factors. STK11 gene (19p13), which encodes for a serine/threonine kinase.71 This syndrome is characterized by intestinal polyposis (hamarto- 2.1.11 | White sponge nevus mas) and blue and/or dark brown mucocutaneous pigmented spots.72,73 Polyps, present from childhood, may lead to intussusception or gastro- White sponge nevus is rare autosomal dominant disorder with a high de- intestinal bleeding. The disease is associated with an increased risk of gree of penetrance and varied expressivity. It was first described in 1909 gastrointestinal cancer. In addition, extracolonic manifestations, both by Cannon80 and the prevalence is less than 1:200 000.81 Mutations of malignant and nonmalignant lesions, may also be present. the keratin 4 or keratin 13 genes have been reported.82 Clinically, the Orally, the pigmented maculae are typically placed in peri-oral disease is characterized by the presence of white, corrugated and dif- and/or intra-oral areas, which could be present at birth and become fuse plaques on the oral mucosa. The clinical manifestations tend to ap- 73,74 more extensive in early childhood. These constitute the most im- pear at an early age. The lesions are benign, asymptomatic and usually portant diagnostic finding and appear as spots 1-10 mm in diameter, bilateral. The oral manifestations are found in the buccal mucosa and always found on the lower lip and the buccal mucosa, but rarely on the ventral surface of the tongue mostly, but they may occur anywhere 71,74 the upper lip, tongue, palate and gingiva. The presence in child- on the oral mucosa (Figure 2). Extra-oral sites, such as esophageal, la- hood of pigmented spots on the lips, buccal mucosa and peri-oral ryngeal, nasal and anogenital mucosa, might also be affected.80 tissues should alert the clinician to investigate for Peutz-Jeghers The differential diagnosis includes oral leukoplakia and dyskerato- syndrome. sis congenita and, rarely, other genodermatoses associated with white The differential diagnosis includes Addison's disease, Albright's hyperkeratotic lesions of the oral mucosa. No standard treatment pro- syndrome, Gardner's syndrome, simple freckles and normal pigmen- tocol is reported for this condition; nevertheless, partial remissions tation. The surgical excision of intestinal polyps is recommended. No have been documented with the use of tetracycline mouth rinse; long- treatment is required for the pigmented lesions, except for aesthetic term low-dose treatment of systemic antibiotic therapy maintained the reasons, and good results are reported with the use of potassium remission, suggesting that a bacterial overgrowth may be associated.83 titanyl phosphate laser ablation.75

2.2 | Other genetic disorders 2.1.10 | Tuberous sclerosis 2.2.1 | Acanthosis nigricans Tuberous sclerosis, also known as epiloia or Bourneville-Pringle syndrome, is transmitted as an autosomal dominant neurocutane- Acanthosis nigricans was first reported in 1890 by Pollitzer.84 76 ous syndrome with high penetrance. The prevalence in the general The condition involves skin and mucosa, characterized by dark 16 | PINNA et al. discoloration and papillary lesions.85 There are two forms of acan- confirmed by Weber. The incidence is unknown but around 1000 thosis nigricans, benign and malignant. The benign form is quite cases have been reported in the literature.91 The etiology remains common, with a prevalence in the general population of 1%-13%; unknown; however, it has been suggested that the syndrome may racial differences are reported (Figure 3). The malignant form is a result from a mesodermal abnormality between the third and sixth rare disease of unclear origin. The disease seems to be most common weeks of gestation during vascular differentiation, probably due to in Native Americans, followed by African Americans, Hispanics and an intrauterine insult.92,93 Caucasians.86 The disease is most commonly associated with disor- The syndrome consists of a classical triad of clinical features ders related to insulin resistance, including obesity, type 2 diabetes, represented by cutaneous hemangiomas, such as nevus flammeus, and polycystic ovary syndrome. Elevated insulin concentrations re- lymphangiomas, arteriovenous fistulas or varicosities (or both), cutis sult in direct and indirect activation of insulin-like growth factor-1 marmorata and unilateral hypertrophy of hard and soft tissues with receptors on keratinocytes and fibroblasts, leading to proliferation. different localizations.94 Some drugs, such as insulin, fusidic acid, nicotinic acid, systemic cor- In the oro-facial region, patients with this condition may present ticosteroids and estrogens, may precipitate the signs of this condi- a unilateral increase of facial dimensions in both the hard and soft tion. The form associated with malignant neoplasms is less common, tissues,95 especially in the lips, cheeks, tongue, teeth and periodontal although the lesions themselves are not malignant.85 tissues.94 Sometimes, there is also a unilateral increase of the dimen- Skin alterations are one of the most characteristic features of sions of fungiform papillae and palate anomalies like petecchiae.96,97 this disease; they are thick with small velvety papillary lesions, tags The oral hemangiomas are usually located on the lips, buccal mu- and dark pigmentation. The most common sites of involvement are cosa, soft and hard palates and gingiva and oropharynx.98 Premature the axillae, neck, groin, umbilicus, peri-anal area and the genitalia.87 tooth eruption, marked displacement of teeth on the affected side The genetic type of benign acanthosis nigricans involves the oral and jawbone overgrowth may produce asymmetry, malocclusion mucosa in about 10%-15% of cases. The tongue and lips are very and anterior open bite.99 The differential diagnosis includes Sturge- often involved, but rarely the gingiva, buccal mucosa or palate. The Weber syndrome, Maffucci's syndrome and large isolated hemangi- lips may be enlarged and covered by papillomatous growths, partic- omas. Dental management is supportive, but severe asymmetry of ularly at the commissures. There is hypertrophy and elongation of the face requires an interdisciplinary approach, including corrective the filiform papillae, resulting in a shaggy appearance of the tongue. surgery.94 Hyperplasia of the interdental papilla and pseudo-pocket formation have also been described.88 The differential diagnosis includes hairy 2.2.3 | Encephalotrigeminal angiomatosis tongue. No treatment is required for the benign form and oral cavity manifestations. The malignant form is a rare condition always asso- Encephalotrigeminal angiomatosis, also known as Sturge-Weber ciated with neoplasms. Eight cases of malignant acanthosis nigricans syndrome, Sturge-Weber disease, Sturge-Weber-Dimitri syndrome have been reported globally.89 and meningofacial angiomatosis,100 is a rare, congenital, neuro- oculo-cutaneous dysplasia. It was initially described by Schirmer in 1869 and later in much more detail by Sturge & Weber.101 In 2.2.2 | Angio-osteo-hypertrophic syndrome Europe, the birth prevalence is estimated to be around 1:20 000 and Angio-osteo-hypertrophic syndrome, also known as Klippel- 1:50 000.102 No ethnicity predilection is described. It has been theo- Trénaunay-Weber syndrome, is a rare congenital vascular bone syn- rized that the disease originates from a somatic mutation in GNAQ drome first described by Klippel & Trénaunay in 190090 and later

FIGURE 2 White sponge nevus. Buccal mucosa shows white FIGURE 3 Achantosis nigricans benign form. lesions with multiple furrows and a spongy texture Hyperpigmentation of the tongue PINNA et al. | 17

(9q21), during the early stages of cerebral vascularization,102,103 as impacted teeth, odontomas and, rarely, benign fibrous soft-tissue a developmental anomaly of embryonic origin because of errors in tumors.109,113 The differential diagnosis includes exostoses, other mesodermal and ectodermal development. There is failure of regres- bone tumors, Peutz-Jeghers syndrome, Cowden's syndrome and sion of a vascular plexus around the cephalic portion of the neural other syndromes associated with multiple intestinal polyposis. The tube that is destined to become facial skin.104 treatment of osteomas, epidermoid cysts and other soft-tissue tu- The common clinical features are angioma of the leptomeninges, mors consists of surgical excision if they are large enough to cause dermal angiomas resulting in port wine stains, due to the deep pur- functional or cosmetic problems.75 ple hue that they leave on the skin or mucosa, abnormal findings in skull radiographs, mental retardation, epilepsy, ocular involve- 2.2.5 | Focal dermal hypoplasia ment and hemiplegia.100,105 Hemangiomas of the oral mucosa have a bright red or purple color and are placed unilaterally, rarely cross Focal dermal hypoplasia is a rare congenital dysplastic disorder the midline and may involve the upper gingiva, buccal mucosa, lips, affecting tissues of ectodermal and mesodermal origin.114 It also tongue and floor of the mouth.106 In gingivae, these lesions present known as Goltz syndrome, first described in 1962.115 The preva- as unilateral hyperplasia due to an increased vascular component. lence is unknown and only 200-300 cases have been reported in Other oral abnormalities reported are pyogenic granulomas, unilat- the literature.114 eral hypertrophy of the alveolus, ipsilateral premature eruption or It is caused by a mutation in the porcupine homolog (Drosophila) delayed eruption of teeth and malocclusion (Figure 4A,B).100,107 The (PORCN) gene of the X chromosome (Xp11.23).116,117 It is a multisys- differential diagnosis includes large disseminated hemangiomas and tem disorder characterized by dermatologic, skeletal, ocular, urinary, Klippel-Trenaunay-Weber syndrome. Treatment is variable and de- gastrointestinal, neurological and oral abnormalities. The skin and the pends on the nature or intensity of the clinical features; dentists and skeleton are the most common sites affected; oral findings are less fre- oral surgeons need to be aware of serious bleeding risks. quently reported.40 The frequently observed oral mucosal (Figure 5) manifestations are multiple papillomas on the tongue, buccal mucosa, palate, gingiva or lips and are considered characteristic.118,119 Similar 2.2.4 | Familial adenomatous polyposis papillomas may be found at junctions between the mucosa and the Familial adenomatous polyposis is an autosomal dominant disorder skin on the vulva, peri-anal and peri-oral areas.118 Other oral mani- characterized by the development of hundreds to thousands of in- festations are oligodontia or hypodontia of both deciduous and per- testinal adenomatous polyps, mainly of the colon and rectum.108 manent dentitions; dysplastic enamel, microdontia, taurodontism and Extra-intestinal manifestations are frequently observed, involv- malocclusion are not rare.118,120 The differential diagnosis of oral le- ing a variety of systems, including the skin, skeleton and soft tis- sions should include multiple papillomas and condylomata acuminate sues.71 This combination has been called Gardner's syndrome.109 due to human papillomaviruses, focal epithelial hyperplasia and incon- Worldwide, this disorder is a major cause of cancer-associated tinentia pigmenti. Oral papillomas typically require surgical excision, morbidity and mortality. Its prevalence varies considerably among especially in the gingiva if they limit the normal tooth eruption. different populations, with the highest reported from Western and industrialized countries; it is quite rare: 1:10 000 subjects in the 2.2.6 | Focal palmoplantar and oral mucosa USA110 and 1:11 300 to 1:37 590 in Europe.111 hyperkeratosis syndrome It is caused by a mutation in the adenomatous polyposis coli gene. Adenomatous polyposis coli is a tumor-suppressor gene that Focal palmoplantar and oral mucosa hyperkeratosis syndrome was is located on chromosome 5q21-q22.112 The gene has 15 exons and first described by Gorlin in 1936.100 It is inherited as an autosomal is involved in cell proliferation, migration, adhesion and cytoskeletal dominant trait and is also referred to as hyperkeratosis palmo- stabilization.109 plantaris and attached gingival hyperkeratosis and by many other A very high risk of malignant transformation of intestinal pol- names.121 It is a very rare disease and belongs to the heterogeneous yps into colonic adenocarcinoma is reported.108 Oral manifesta- group of inherited palmoplantar keratoderma with associated ecto- tions include multiple osteomas of the jaws, supernumerary and dermal manifestations.122 The prevalence is unknown. Only a few

FIGURE 4 Encephalotrigeminal angiomatosis. A, Port wine stain on the left side of the face. B, Intra-oral examination shows red/magenta areas on the left side of upper and lower maxilla without gingival overgrowth 18 | PINNA et al. cases have been reported in the literature, including some families The enlarged tissues result in both functional and esthetic prob- affected by the disease in several consecutive generations.100,123 lems: it may partially or totally cover the dental crowns, pseudo- Palms, soles and attached gingiva, areas bearing mechanical pres- pocketing, delay or impede tooth eruption and can cause diastemas, sure or friction, are the most common sites where the disorder ap- malpositioning of teeth, cross and open bites, prominent lips and pears as focal painful hyperkeratosis.121 Adult patients additionally open lip posture.126,128 The differential diagnosis should include gin- demonstrate hyperhidrosis, hyperkeratosis, slight peri-ungual kerato- gival hyperplasia due to phenytoin, nifedipine and cyclosporine and ses at several toe- and fingernails and thickening of the nails.100,121,124 gingival fibromatosis, which may occur as part of other genetic syn- Marked hyperkeratosis of the attached gingiva presenting as leu- dromes. Treatments vary according to the degree of severity of gin- koplakia is a constant finding.121 However, other oral sites, such as gival enlargement and different types of treatment modality could be the palate, alveolar mucosa, lateral border of the tongue, retromolar employed for the excision, including conventional surgery, electro- pad mucosa and the buccal mucosa along the occlusal line may be surgery, apically positioned flap and lasers.129,130 The maintenance involved due to mechanical stress during normal oral function.100,121 of good oral hygiene and plaque control is fundamental. Attempts The differential diagnosis should include pachyonychia congen- at improving oral hygiene are of limited benefit in severe gingival ita, dyskeratosis congenita, Papillon-Lefevre syndrome and oral enlargement; in this case, surgical gingival resection is indicated. leukoplakia and esophageal carcinoma syndrome. Regarding the treatment, unfortunately, no reliably successful treatment exists, 2.2.8 | Maffucci's syndrome but aromatic retinoids, usually topical keratolytics, such as 6% salicylic acid in white soft paraffin or a gel of 6% salicylic acid in 70% Maffucci's syndrome is a rare congenital nonhereditary meso- propylene glycol, may occasionally be helpful. Dental management dermal dysplasia, first reported by Angelo Maffucci in 1881.131 The is only supportive. prevalence is unknown. About 250 cases have been reported so far in the world literature. The exact etiology is still unknown. No fa- 132,133 2.2.7 | Gingival fibromatosis milial pattern, sexual or racial predilection has been reported. However, somatic mosaic mutations in isocitrate dehydrogenase 1 125 Gingival fibromatosis, first reported by Goddard & Gross in 1856, and 2 genes have been identified.134 The syndrome is character- is a rare disease characterized by proliferative fibrous overgrowth of ized by multiple enchondromas, principally in the small bones of the the gingival tissue caused by an increase in the subepithelial connec- hands and feet. These abnormalities are usually asymmetric and can 118 tive tissue elements. The prevalence is unknown; the incidence is cause secondary fractures and lead to significant deformity.133,135 126 1:750 000 in live births. It is transmitted as an autosomal domi- Other findings are multiple hemangiomas localized on the skin, mu- nant or autosomal recessive trait and can occur in either dominant cosae and viscera including the oropharynx, intra-abdominal and 127 (common) or recessive forms. Clinically it is a slowly progressive gastrointestinal tract.135,136 They are typically located in the subcu- disease involving excessive collagen deposition. There is generalized taneous tissues and appear as blue nodules, which can be emptied enlargement of the gingiva, which is usually firm, smooth and oc- by manual compression.137 Due to these clinical signs, some authors casionally nodular, with minimal or no inflammation and normal or consider the disease as a variant of Ollier's disease, which has only 126 pale in color. The upper gingiva is more severely affected and may enchondromatosis.138 Thrombi may form, calcify and give a charac- prevent the eruption of the teeth (Figure 6). teristic appearance of phleboliths on plain X-rays.135

A B

FIGURE 5 Focal dermal hypoplasia. A, Polysyndactyly of the hand in a child with focal dermal hypoplasia. B, Enamel hypoplasia of an inferior incisor from the same patient PINNA et al. | 19

The oral mucosa is rarely affected and the oral lesions are usu- nodular neurofibromas that vary in size.146 Common sites include ally multiple hemangiomas.139 The tongue is the most frequent site the tongue (26%), buccal mucosa (8%), alveolar ridge (2%), labial mu- of hemangiomas, but the buccal mucosa, lips, soft palate and other cosa (8%), palate (8%), gingiva (2%), nasopharynx, paranasal sinuses, oral regions can also be involved. This disease is associated with an larynx, floor of the mouth and salivary gland. Oral neurofibromas increased risk of malignant transformation, especially chondrosar- usually present as fibrous, uninflamed, submucosal discrete masses. comas and hemangiosarcomas.133,137,140 The overall prevalence of Tumors generally tend to grow slowly and patients are usually as- malignancies associated with Maffucci's syndrome is 23%-100% in ymptomatic. However, symptoms may arise due to trauma to the different studies.135,137 The differential diagnosis includes heman- swellings, especially depending on the oral location (eg tongue, pal- giomas, Ollier's disease, the blue rubber bleb nevus syndrome and ate).147,148 The most commonly reported finding is enlargement of Klippel-Trenaunay-Weber syndrome. Overall management aims at the fungiform papillae of the tongue.142 Gingival neurofibromas can the relief of symptoms, early detection of malignancies and long- enhance periodontal disease, as tissue growth limits routine oral hy- term follow-up. Management of the oral lesions is usually surgical giene measures.149 and depends on the size and location of the lesions. Patients may present with absent, impacted and/or malpositioned teeth.150 Tumors may also arise within the jaws and other bones.151 Individuals with neurofibromatosis type 1 demonstrate 2.2.9 | Neurofibromatosis (type 1) an increased incidence of benign tumors, with the risk of malignant Neurofibromatosis, also known as von Recklinghausen's disease, is transformation being 3%-5%.152 The differential diagnosis should a group of genetic disorders inherited as an autosomal dominant include multiple mucosal neuromas, multiple endocrine neoplasia trait, characterized by multiple cutaneous lesions and tumors of the type III syndrome and Klippel-Trenaunay-Weber syndrome. Oral central and peripheral nervous system.141 Neurofibromatosis type neurofibromas, especially when accessible and a small size, are most 1 is the most common, affecting approximately 1:3500 individu- frequently treated by surgical excision.147 A good oral health status als worldwide.141 It is due to a mutation of the neurofibromatosis in patients with neurofibromatosis type 1 must be achieved through type 1 gene, which is a tumor-suppressor gene located in the long oral hygiene maintenance and regular dental check-ups.145 arm of chromosome 17q11.2,142 and rarely by 17q11 microdeletion (only 5%).143 The cardinal features of the disease are the “cafe-au- 2.2.10 | Oro-facial-digital syndrome (type 1) lait” spots (more than six spots, >5 mm in diameter in children or >15 mm in adults) and the skin neurofibromas.144 Other clinical Oro-facial-digital syndromes constitute a heterogeneous group signs are nervous system manifestations, skeletal disorders, iris of embryonic development disorders first described by Mohr in Lisch nodules (melanocytic hamartomas that appear as well-defined, 1941.153 Thirteen types of this syndrome have been described dome-shaped elevations projecting from the surface of the iris) and based on clinical manifestations and inheritance patterns, char- multiple neurofibromas.145 acterized by malformations of the face, oral cavity, hands and Neurofibromatosis type 1 may present oral symptoms in up to feet.154,155 Oro-facial-digital syndrome type 1, also known as the 72% of affected patients, who exhibit multiple or, rarely, isolated Papillon-League- Psaume syndrome, or oro-facio- digital dysostosis, was first described in 1954,156 and it is the most common among all types. The other types are extremely rare.157 The prevalence of oro-facial-digital syndrome type 1 is unknown, but the annual incidence is estimated to be between 1:250 000 and 1:50 000 live births.158 It is transmitted as an X-linked dominant trait, which occurs mostly in females; the disease has lethal effects in males.159,160 The other types of oro-facial-digital syndrome show autosomal recessive inheritance.159 Oro-facial-digital syndrome type 1 is caused by mutations in the CXORF5 gene, later renamed oro-facial-digital syndrome I, which is found on the short arm of X-chromosome (Xp22.2-Xp22.3). 161,162 This is characterized by a number of heterogeneous clinical features involving malformations of the digits, face and oral cavity. The cardinal clinical manifestations are digital malformations of hands (50%-70%) and feet (25%), such as clinodactyly, brachydactyly or syndactyly of the hands and polydactyly of the feet.162,163 Other common conditions are polycystic kidney disease, which can be the most determining feature in this syndrome, cutaneous lesions, such as milia, xeroderma, alopecia, sparse hair and FIGURE 6 Gingival fibromatosis. A 20-year-old female patient 161,164 with gingival overgrowth without displacement of teeth. The dermatoglyphic abnormalities. Central nervous system disease gingiva is pink, firm, nodular, painless and nonhemorrhagic occurs in 40% of oro-facial-digital syndrome type 1 individuals, with 20 | PINNA et al. mental retardation, seizures, hydrocephalus, cerebellar anomalies, porencephaly and agenesis of corpus callosum.165,166 Facial features include frontal bossing, facial asymmetry, hypertelorism and a broadened nasal bridge.167 Regarding the intra-oral lesions, constant oral mucosal findings are multiple hyperplastic frenula traversing the upper and lower gingivolabial folds; accessory gingival frenula are common.168,169 The tongue appears multilobed or bifid and often exhibits multiple hamartomas and ankylosis. Clefts of the lips and the soft and hard palate are common. Mandibular lateral incisors are often missing, supernumerary teeth are common and upper canines are often malpositioned.168-170 The differential diagnosis should include oro-facial-digital syndrome type II (Mohr syndrome), chondro-ectodermal dysplasia and oculo-dento-digital syndrome. A multidisciplinary approach is necessary in the treatment of this syndrome. Maxillofacial surgery and orthodontics are often needed to treat the oral manifestations. FIGURE 7 Fordyce's granules (also known as Fordyce's spots). Fordyce granules are small raised, yellow-white spots that appear in 3 | DEVELOPMENTAL DISORDERS the cheek oral mucosa or in the labial mucosa

3.1 | Oral mucosa 3.1.3 | Leukoedema 3.1.1 | Cysts of the oral mucosa in newborns Leukoedema is a benign and asymptomatic condition that probably Nodules or cysts of the oral mucosa occur with a high incidence represents a variation of normal mucosa. Sandstead & Lowe first de- (about 80%) in infants.171 These cysts can be classified as gingi- scribed this exclusively in adults. However, Martin & Crump also rec- 175,176 val cysts (dental lamina cysts) and median palatal mucosal cysts ognized it in children and young adults. Leukoedema appears (Epstein's pearls).171 Epstein's pearls are considered to be the result as a grayish-white lesion located on the buccal mucosa, frequently of the entrapment of the epithelial cells in the median palatal raphe. bilaterally. Analogous mucosal changes have been found on vaginal Pearls are small white or yellow vesicles (1-3 mm diameter) in the and laryngeal mucosae. The etiology is unknown, but associations median area of the palate, but these disorders can also affect other with tobacco use, local irritation from sodium lauryl sulphate- 177 structures of the oral cavity, the tongue and lips. They do not require containing toothpaste and malocclusion have been suggested. treatment as they resolve spontaneously over the first few weeks The prevalence differs in adults depending on the population ex- of life. amined: very high in Black adults (almost 90%) and quite frequent in White adults, who show much less pronounced forms (prevalence rate: 3:1000 in White adults).176 Histologically, the lesions show hy- 3.1.2 | Fordyce′s granules perparakeratosis and are frequently elongated with irregular rete- 176 Fordyce's granules, also termed Fordyce's spots or disease, are het- pegs and intracellular edema of the Malpighian layer. Leukoedema erotopic/ectopic sebaceous glands that are considered to be a nor- differs from leukoplakia as there is no loss of pliability or flexibility mal variation of the oral mucosa. These spots were first described of the involved tissues (Figure 8). Differential diagnosis from lichen by Kölliker in 1861, but are named after Fordyce, who reported on planus is realized by stretching the mucosa: leukoedema will either them in 1896.172,173 They appear as multiple, small, milia-like, yel- disappear or persist, whereas lichen planus will become more evi- lowish structures with a 1-2 mm diameter that occasionally might dent. Leukoedema should also be differentiated from white sponge 176 form confluent plaques. Granules are also described on the genital nevus and habitual cheek-biting. Fordyce's spots do not require mucosa and on the skin of the face. They are found in the major- any treatment. However, anxious patients require reassurance. ity of adults, with an estimated prevalence of about 80%, which in- creases with age.173 In the oral cavity, the granules are found on the 3.1.4 | Retrocuspid papilla vestibular mucosa, but the upper lip, gingiva and anterior pillars of 178 fauces may also be involved (Figure 7). The composition of granules Retrocuspid papilla was first described in 1947 by Hirschfeld ; it is identical to that of sebaceous glands on the skin and about 50% of is a 2-4 mm nodule located, more commonly, bilateral on the lingual the sebum composition is triglycerides.174 They appear to be a more attached gingiva in proximity of mandibular canines. It is considered frequent finding in people with greasy skin types, with some rheu- a developmental anomaly as it appears bilaterally and in a predict- matic disorders and in hereditary nonpolyposis colorectal cancer.67 able location. It is observed more frequently in young children and 179 No treatment is required. seems to regress or disappear during their growth. Histologically, PINNA et al. | 21

FIGURE 9 Geographic tongue. Left side of the dorsum of the tongue with typical appearance of geographic tongue. There is a map-like aspect with small red patches, surrounded by a serpiginous, white, hyperkeratotic border

FIGURE 8 Leukoedema. The buccal mucosa is characterized by a grayish-white, opalescent pattern and a slightly wrinkled surface is present tongue can sometimes cause tongue discomfort; to manage this it is possible to treat patients with pain relievers and mouth rinses the lesions are composed mainly of loosely arranged delicate fibrous with an anesthetic and/or antihistamine and/or corticosteroid connective tissue with occasional mature, dense collagenous areas; ointments or rinses. papillae could be classified into two different types by the presence or absence of stellate and occasionally multinucleated fibroblasts.180 3.1.6 | Fissured tongue It should be differentiated from pyogenic granuloma, peripheral giant cell granuloma, irritation fibroma, gingival cyst or a metastatic After geographic tongue, fissured or “scrotal” tongue is the second neoplasm to the gingiva.181 No treatment is required. most common developmental malformation of unknown cause of the tongue, even if in recent years a polygenic mode of transmission was proposed. Many authors have observed a relationship 3.1.5 | Geographic tongue between scrotal tongue and geographic tongue, as a genetic as- Geographic tongue, or benign migratory glossitis, is a disorder of sociation between these lesions was supposed.184 Its prevalence unknown etiology and pathogenesis, although an inherited pattern has been suggested with a polygenic mode of transmission. Changes in the lingual microbiota profiles were noted; however, it remains unknown if this finding is a consequence of the lesions or of factors associated with the initiation and progression of the disease.182 The prevalence ranges from 1.0% to 2.5% and it is more frequent in adults than in children.183 Clinically, the lesions appear as a central atrophic area bounded by a raised white circinate line with multiple tongue sites affected. The circinate, irregular erythe- matous lesions are caused by loss of filiform papillae, whereas the fungiform papillae remain unchanged. The most common locations are the lateral margins and tip of the tongue. Lesions vary in size from several millimeters to several centimeters. These lesions persist for a short time in an area of the tongue and then disappear and reappear in another area (Figure 9). The finding of an association between fissured tongue and geographic tongue supports a genetic basis for the two conditions.184 The fissures may act as stag- nation areas on the tongue surface in which glossitis may begin. Geographic tongue presents with clinical, histological and genetic FIGURE 10 Fissured tongue. Fissured tongue characterized by grooves that vary in depth and are noted along the dorsal and patterns similar to those of psoriasis, suggesting that it may rep- lateral aspects of the tongue. Fissured tongue and geographic 184 resent an oral manifestation of the disease. Geographic tongue tongue (see Figure 5) have been reported in association with typically does not require any medical treatment. Geographic chronic granulomatous disease 22 | PINNA et al. ranges from 0.5% to 5%. It has been associated with more advanced ages, whereas the prevalence of geographic tongue was higher in younger subjects.185 Clinically fissured tongue is characterized by multiple fissures or grooves on the dorsal surface varying in depth, size and number; usually, the fissures have a symmetrical distribution (Figure 10). The condition is asymptomatic. Local irritation of the fissures might occur if food debris, microorganisms and fungi are retained in the deeper fissures. Fissured tongue is a characteristic of Down's syndrome and Melkersson-Rosenthal syndrome (also noted as “Miescher-Melkersson-Rosenthal syndrome”), a rare neurological disorder characterized by recurring facial paralysis and swelling of the face and lips.186-188 Treatment is not required.

3.1.7 | Median rhomboid glossitis FIGURE 11 Median rhomboid glossitis. Area of the dorsum of the tongue, around the midline, well-demarcated, depapillated and Median rhomboid glossitis was commonly referred to as a developmen- quite lobulated tal defect with a starting point during embryogenesis, caused by the failure of the tuberculum impar to be covered completely by the lateral processes of the tongue. It is found anterior to the circumvallate papillae. As this defect is not observed in children,189-191 a developmental etiology has largely been discounted; furthermore, median rhomboid glossitis is also described as a form of hyperplastic candidiasis and the term is only used when lesions are found on the central portion of the tongue. Other predisposing factors include smoking, denture wearing, use of corticosteroid sprays or inhalers and HIV infection. The prevalence of this lesion was reported as 2.4% in the Israeli population. This tongue disorder is sometimes not clearly diagnostic to the clinician. Hyperplastic candidiasis may be present in other areas of the mouth as well, such as the commissures and the hard and soft palate (Figure 11). Associations with Actinomyces spp. have also been proposed.71 FIGURE 12 Hairy tongue. Hair-like appearance to the top of the tongue with typical hypertrophied and elongated filiform papillae 3.1.8 | Hairy tongue on the dorsal surface of the tongue. The accumulation of bacteria, food and/or yeasts result in various colors, usually black (“black Hairy tongue is a relatively common disorder affecting the filiform hairy tongue”) papillae.192 Its prevalence varies geographically, ranging from 0.6% to 11.3%. The etiology is not clear, although several predisposing factors are advocated, such as oral antibiotics, oxidizing agents, met- 3.1.9 | Lingual varices ronidazole, smoking, radiation, poor oral hygiene and Candida albi- cans infection.193 Clinically, it is characterized by hypertrophy and Lingual varices, also referred to as lingual or sublingual varicosities, elongation of the filiform papillae of the dorsum of the tongue, which are dilated veins on the ventral surface of the tongue. These lesions take on a hairy appearance (Figure 12). Papillae, which normally are may appear as part of the normal aging process. It is normal for there about 1 mm in length, may become as long as 12 mm.100 to be veins visible underneath the tongue, partly because the mu- Papillae may vary from yellowish-white to brown or black when cous membrane is so thin and translucent in this region, but where pigments produced by oral bacteria colonize them. Hairy tongue should these vessels become dilated and tortuous, they may appear round not be confused with oral hairy leukoplakia, a condition characterized by and black like caviar. Age and an increase in venous pressure are vertical white striations typically affecting the lateral tongue bilaterally predisposing factors;194 prevalence is quite large (20%-80% of the and caused by Epstein-Barr virus, occurring usually in immunocompro- population) in the elderly population.195 mised patients.84 Hairy tongue is usually asymptomatic, but it may cause significant distress to the patient for esthetic reasons. Brushing of the 3.1.10 | Lingual thyroid nodule tongue may promote desquamation and reduce the length of the papillae. In severe cases, with very long filiform papillae, topical application of The prevalence of ectopic thyroid tissue ranges between 7% and keratolytic agents such as 30%-50% trichloroacetic acid or salicylic acid 10%. Lingual thyroid nodule is the most common ectopic thy- in alcohol or 40% urea in water destroys the elongated papillae. roid, accounting for 90% of all cases with a prevalence between PINNA et al. | 23

1:100 000 and 1:300 000.196 The molecular mechanisms involved 2. Scully C. Oral and Maxillofacial Medicine: The Basis of Diagnosis and in thyroid dysgenesis are not fully known; nevertheless, muta- Treatment. Edinburgh: Churchill Livingstone; 2013:392. 3. Shulman JD. Prevalence of oral mucosal lesions in children and tions in regulatory genes expressed in the developing thyroid are youths in the USA. Int J Paediatr Dent. 2005;15(2):89-97. 197 speculated. Clinically, an enlargement of the posterior base of 4. Muensterer OJ, Berdon W, McManus C, et al. Ellis-van Creveld the tongue is evident as a firm, midline mass. The color can range syndrome: its history. Pediatr Radiol. 2013;43(4):1030-1036. from light pink to bright red and the surface may be smooth or 5. Baujat G, Le Merrer M. Ellis-van Creveld syndrome. Orphanet J Rare Dis. 2007;2:27. irregular. Ectopic thyroid can be associated with clinically evident 6. D'Asdia MC, Torrente I, Consoli F, et al. Novel and recurrent EVC thyroid dysfunction, which can be either hypofunction or hyper- and EVC2 mutations in Ellis-van Creveld syndrome and Weyers function. Benign or malignant neoplastic changes can also occur in acrofacial dyostosis. Eur J Med Genet. 2013;56(4):80-87. ectopic thyroid nodules.196 Nodules are often asymptomatic, but 7. Sasalawad SS, Hugar SM, Poonacha KS, Mallikarjuna R. Ellis-van Creveld syndrome. BMJ Case Rep. 2013;2013. symptoms may be related to size and location as well as associ- 8. Cahuana A, Palma C, Gonzales W, Gean E. Oral manifestations ated endocrine dysfunction. Symptoms of lingual thyroid nodules in Ellis-van Creveld syndrome: report of five cases. Pediatr Dent. include cough, pain, dysphagia, dysphonia, dyspnea and hemor- 2004;26(3):277-282. rhage. Asymptomatic nodules do not require therapy but they 9. Ghosh S, Setty S, Sivakumar A, Pai KM. Report of a new syn- must be kept under observation. For those with symptoms, treat- drome: focus on differential diagnosis and review of Ellis- van Creveld, Curry-Hall, acrofacial dysostosis, and orofacial ment depends on the size, nature of symptoms, thyroid function digital syndromes. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 198 status and histological findings. 2007;103(5):670-676. 10. Hassona Y, Hamdan M, Shqaidef A, Abu Karaky A, Scully C. Ellis-Van Creveld syndrome: dental management considerations and description of a new oral finding. Spec Care Dentist. 4 | CONCLUSIONS 2015;35(6):312-315. 11. Pedro RL, Andrade LH, Maia LC. The importance of oral-clinical Oral medicine and pathology is a clinical specialty encompassing the findings for the correct diagnosis of Ellis-van Creveld syndrome. diagnosis and treatment of patients with a wide spectrum of disor- Gen Dent. 2011;59(5):e206-209. 12. Dokal I. Dyskeratosis congenita. Hematology Am Soc Hematol Educ ders involving the oral cavity. Dentists, dental hygienists, general Program. 2011;2011(4):480-486. internists, pediatricians and so on need to broaden their knowledge 13. Mason PJ, Bessler M. The genetics of dyskeratosis congenita. bases and practice their clinical skills. A large variety of disorders af- Cancer Genet. 2011;204(12):635-645. fect the oral cavity, including genetic diseases, infections, cancers, 14. Fernandez Garcia MS, Teruya-Feldstein J. The diagnosis and treatment of dyskeratosis congenita: a review. J Blood Med. blood diseases, skin diseases, endocrine and metabolic disorders, au- 2014;5:157-167. toimmune and rheumatologic diseases, local lesions, to name a few. 15. Baran I, Nalcaci R, Kocak M. Dyskeratosis congenita: clinical re- The oral mucosa shows considerable variation in its normal structure port and review of the literature. Int J Dent Hyg. 2010;8(1):68-74. and can be affected by a wide range of conditions. They can be harm- 16. Karunakaran A, Ravindran R, Arshad M, Ram MK, Laxmi MK. Dyskeratosis congenita: a report of two cases. Case Rep Dent. less, minor primary conditions and secondary indications of systemic 2013;2013:845125. disease. Several of them are quite rare and their diagnosis not easy. 17. Pindborg JJ, Kalapessi HK, Kale SA, Singh B, Talyerkhan BN. Frequency of oral leukoplakias and related conditions among 10,000 Bombayites. Preliminary report. J All India Dent Assoc. 5 | SUMMARY 1965;37:228-229. 18. Solder B, Weiss M, Jager A, Belohradsky BH. Dyskeratosis congenita: multisystemic disorder with special consideration of im- The review describes the main oral mucosa disease manifestations. munologic aspects. A review of the literature. Clin Pediatr (Phila). The review may be useful to the oral care specialties in the develop- 1998;37:521-530. ment of a differential diagnosis. In several circumstances, the sever- 19. Savage S. Dyskeratosis congenita. http://www.ncbi.nlm.nih.gov/ books/NBK22301. Accessed February 18, 2018. ity or prognosis of the disease needs to be monitored. 20. Abel MD, Carrasco LR. Ehlers-Danlos syndrome: classifications, oral manifestations, and dental considerations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;102:582-590. ACKNOWLEDGMENT 21. Steinmann B, Royce P, Superti-Furga A. The Ehlers-Danlos syndrome. In: Royce PM, Steinmann B, eds. Connective Tissue and its The authors thank all the colleagues who helped to complete this Heritable Disorders: Molecular, Genetic, and Medical Aspects. New review and provided the clinical photographs – Professor Charanjit York, NY: Wiley-Liss; 2002:431-523. Singh Saimbi, Professor Gianfranco Favia, Professor Olga di Fede. 22. Kumar V, Abbas A, Fausto N. Robbins and Cotran Pathologic Basis of Disease, 7th edn. Philadelphia, PA: WB Saunders; 2004. 23. Rombaut L, Malfait F, De Wandele I, et al. Medication, sur- REFERENCES gery, and physiotherapy among patients with the hypermobility type of Ehlers-Danlos syndrome. Arch Phys Med Rehabil. 1. Gonsalves WC, Chi AC, Neville BW. Common oral lesions: Part 2011;92:1106-1112. I. Superficial mucosal lesions. Am Fam Physician. 2007;75(4): 24. Mao JR, Bristow J. The Ehlers-Danlos syndrome: on beyond colla- 501-507. gens. J Clin Invest. 2001;107:1063-1069. 24 | PINNA et al.

25. Letourneau Y, Perusse R, Buithieu H. Oral manifestations 47. Ravi Prakash SM, Verma S, Sumalatha MN, Chattopadhyay S. Oral of Ehlers-Danlos syndrome. J Can Dent Assoc. 2001;67(6): manifestations of lipoid proteinosis: a case report and literature 330-334. review. Saudi Dent J. 2013;25(2):91-94. 26. Orpha.net a. http://www.orpha.net/consor/cgi-bin/Disease_Search. 48. Gutte R, Sanghvi S, Tamhankar P, Khopkar U. Lipoid proteinosis: php?lng=EN&data_id=8650&Disease_Disease_Search_disease histopathological characterization of early papulovesicular lesions. Group=Lipoidproteinosis&_Disease_Disease_Search_disease- Indian Dermatol Online J. 2012;3(2):148-149. Type=Pat&Disease(s)/group%20of%20diseases=Lipoid-proteino- 49. Sargenti Neto S, Batista JD, Durighetto AF Jr. A case of oral recur- sis&title=Lipoid-proteinosis&search=Disease_Search_Simple. rent ulcerative lesions in a patient with lipoid proteinosis (Urbach- Accessed February 20, 2019. Wiethe disease). Br J Oral Maxillofac Surg. 2010;48(8):654-655. 27. Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. 50. Farooq A, Walker LJ, Bowling J, Audisio RA. Cowden syndrome. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Cancer Treat Rev. 2010;36(8):577-583. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos 51. Nico MM, Hammerschmidt M, Lourenco SV. Oral mucosal man- Support Group (UK). Am J Med Genet. 1998;77(1):31-37. ifestations in some genodermatoses: correlation with cutaneous 28. Norton LA, Assael LA. Orthodontic and temporomandibular joint lesions. Eur J Dermatol. 2013;23(5):581-591. considerations in treatment of patients with Ehlers-Danlos syn- 52. Orpha.net e. http://www.orpha.net/consor/cgi-bin/Disease_Search. drome. Am J Orthod Dentofacial Orthop. 1997;111(1):75-84. php?lng=EN&data_id=243&Disease_Disease_Search_diseaseGroup= 29. Cai R, Zhang C, Chen R, Bi Y, Le Q. Clinicopathological features of cowden-syndrom&Disease_Disease_Search_diseaseType=Pat&Dis- a suspected case of hereditary benign intraepithelial dyskerato- ease%28s%29/group%20of%20diseases=Cowden-syndrome&ti- sis with bilateral corneas involved: a case report and mini review. tle=Cowden-syndrome&search=Disease_Search_Simple. Cornea. 2011;30(12):1481-1484. Accessed February 20, 2019. 30. von Sallmann L, Paton D. Hereditary dyskeratosis of the perilimbal 53. Tripathi AK, Kumar V, Dwivedi R, Saimbi CS. Sturge-Weber conjunctiva. Trans Am Ophthalmol Soc. 1959;57:53-62. syndrome: oral and extra-oral manifestations. BMJ Case Rep. 31. Allingham RR, Seo B, Rampersaud E, et al. A duplication in chro- 2015;2015. mosome 4q35 is associated with hereditary benign intraepithelial 54. Eng C, Hampel H, de la Chapelle A. Genetic testing for cancer pre- dyskeratosis. Am J Hum Genet. 2001;68(2):491-494. disposition. Annu Rev Med. 2001;52(6):371-400. 32. Baroni A, Palla M, Aiello FS, et al. Hereditary benign intraepithelial 55. Marsh DJ, Coulon V, Lunetta KL, et al. Mutation spectrum and dyskeratosis: case report. Int J Dermatol. 2009;48(6):627-629. genotype-phenotype analyses in Cowden disease and Bannayan- 33. Jham BC, Mesquita RA, Aguiar MC, Carmo MA. Hereditary be- Zonana syndrome, two hamartoma syndromes with germline nign intraepithelial dyskeratosis: a new case? J Oral Pathol Med. PTEN mutation. Hum Mol Genet. 1998;7(3):507-515. 2007;36(1):55-57. 56. Woo VL, Abdelsayed R. Oral manifestations of internal ma- 34. Witkop CJ Jr, Shankle CH, Graham JB, Murray MR, Rucknagel lignancy and paraneoplastic syndromes. Dent Clin North Am. DL, Byerly BH. Hereditary benign intraepithelial dyskeratosis. 2008;52(1):203-230. II. Oral manifestations and hereditary transmission. Arch Pathol. 57. Hand JL, Rogers RS 3rd. Oral manifestations of genodermatoses. 1960;70:696-711. Dermatol Clin. 2003;21(1):183-194. 35. Takagi A, Kamijo M, Ikeda S. Darier disease. J Dermatol. 58. Amer M, Mostafa FF, Attwa EM, Ibrahim S. Cowden's syndrome: a 2016;43(3):275-279. clinical, immunological, and histopathological study. Int J Dermatol. 36. Ringpfeil F, Raus A, DiGiovanna JJ, et al. Darier disease – novel 2011;50(5):516-521. mutations in ATP2A2 and genotype-phenotype correlation. Exp 59. Babu NA, Rajesh E, Krupaa J, Gnananandar G. Genodermatoses. J Dermatol. 2001;10(1):19-27. Pharm Bioallied. 2015;7(1):S203-206. 37. Prindiville DE, Stern D. Oral manifestations of Darier's disease. J 60. Segura Saint-Gerons R, Ceballos Salobrena A, Toro Rojas M, Oral Surg. 1976;34(11):1001-1006. Gandara Rey JM. Oral manifestations of Cowden's disease. 38. Jalil AA, Zain RB, van der Waal I. Darier disease: a case report. Br J Presentation of a clinical case. Med Oral Patol Oral Cir Bucal. Oral Maxillofac Surg. 2005;43(4):336-338. 2006;11(5):E421-E424. 39. Onozuka T, Sawamura D, Yokota K, Shimizu H. Mutational analysis 61. Leachman SA, Kaspar RL, Fleckman P, et al. Clinical and patholog- of the ATP2A2 gene in two Darier disease families with intrafamil- ical features of pachyonychia congenita. J Investig Dermatol Symp ial variability. Br J Dermatol. 2004;150(4):652-657. Proc. 2005;10(1):3-17. 40. Seoane J, Gibson RL, Almagro M, Pintos E. Oral manifesta- 62. Jadassohn J, Lewandowski F. In: Neisser A, Jacobi E, eds. Konographia tions associated with focal dermal hypoplasia. Dermatology. Dermatologica. Berlin, Germany: Urban fr Schwarzenberg; 1906:3. 2009;219(3):368-370. 63. Rittie L, Kaspar RL, Sprecher E, Smith FJD. Report of the 13th 41. Macleod RI, Munro CS. The incidence and distribution of oral Annual International Pachyonychia Congenita Consortium lesions in patients with Darier's disease. Br Dent J. 1991;171(1): Symposium. Br J Dermatol. 2017;176(5):1144-1147. 133-136. 64. van Steensel MAM, Coulombe PA, Kaspar RL, et al. Report of the 42. Dolci M, Favia G, Scully C, Di Alberti L. Keratosis follicularis of 10th Annual International Pachyonychia Congenita Consortium the oral mucosa with oral squamous cell carcinoma. Oral Oncol. Meeting. J Invest Dermatol. 2014;134(3):588-591. 2004;40(8):856-858. 65. Cogulu O, Onay H, Aykut A, et al. Pachyonychia congenita type 43. Ferris T, Lamey PJ, Rennie JS. Darier's disease: oral features and 2, N92S mutation of keratin 17 gene: clinical features, muta- genetic aspects. Br Dent J. 1990;168(2):71-73. tion analysis and pathological view. Eur J Pediatr. 2009;168(10): 44. Suresh K, Venkat K, Prem M, Karthik P. A rare case report of lipoid 1269-1272. proteinosis. Int J Recent Trends Sci Technol. 2014;10:275-277. 66. McLean WH, Hansen CD, Eliason MJ, Smith FJ. The phenotypic 45. Hamada T. Lipoid proteinosis. Clin Exp Dermatol. 2002;27(8): and molecular genetic features of pachyonychia congenita. J Invest 624-629. Dermatol. 2011;131(5):1015-1017. 46. Naha K, Shastry AB, Saravu K, Bhatia S. Lipoid proteinosis mimick- 67. Shah S, Boen M, Kenner-Bell B, Schwartz M, Rademaker A, Paller ing congenital immunodeficiency: a case report. Australas Med J. AS. Pachyonychia congenita in pediatric patients: natural history, 2011;4:155-159. features, and impact. JAMA Dermatol. 2014;150(2):146-153. PINNA et al. | 25

68. da Silva Santos PS, Mannarino F, Lellis RF, Osorio LH. Oral manifes- 91. Orpha.netf. http://www.orpha.net/consor/cgi-bin/Disease_Search. tations of pachyonychia congenita. Dermatol Online J. 2010;16(10):3. php?lng=EN&data_id=523&Disease_Disease_Search_diseaseG- 69. McGarrity T, Amos C, Baker M. Peutz-Jeghers Syndrome. roup=Klippel-Trenaunay-Weber-syndrome&Disease_Disease_ GeneReviews® https://www.ncbi.nlm.nih.gov/books/NBK481802/. Search_diseaseType=Pat&Disease%28s%29/group%20of%20 Accessed July 14, 2016. diseases=Angioosteohypertrophic-syndrome&title=Angioosteohy- 70. Orpha.net h. http://www.orpha.net/consor/cgibin/Disease_Search.php? pertrophic-syndrome&search=Disease_Search_Simple. Accessed lng=EN&data_id=233&Disease_Disease_Search_diseaseGroup= February 20, 2019. Peutz-Jeghers-Syndrome&Disease_Disease_Search_disease- 92. Leiber B. Klippel-Trenaunay-Symptomencomplex. In: Altmeyer P, Type=Pat&Disease(s)/group%20of%20diseases=Peutz-Jeghers-syn- ed. Therapielexikon Die Klinischen Syndrome. München: Urban and drome&title=Peutz-Jeghers-syndrome&search=Disease_Search_ Schwarzemberg; 2005:459-463. Simple. Accessed February 20, 2019. 93. You CK, Rees J, Gillis DA, Steeves J. Klippel-Trenaunay syndrome: 71. Neville B, Damm D, Allen C, Bouquot J. Oral & Maxillofacial a review. Can J Surg. 1983;26(5):399-403. Pathology, 2nd edn. Philadelphia, PA: WB Saunders; 2002. 94. Defraia E, Baccetti T, Marinelli A, Tollaro I. Biometric and magnetic 72. Campos FG, Figueiredo MN, Martinez CA. Colorectal cancer risk resonance imaging assessment of dentofacial abnormalities in a in hamartomatous polyposis syndromes. World J Gastrointest Surg. case of Klippel-Trenaunay-Weber syndrome. Oral Surg Oral Med 2015;7:25-32. Oral Pathol Oral Radiol Endod. 2004;97(1):127-132. 73. Kitagawa S, Townsend BL, Hebert AA. Peutz-Jeghers syndrome. 95. Bathi RJ, Agarwal N, Burde KN. Klippel-Trenaunay syndrome Dermatol Clin. 1995;13(1):127-133. (angio osteohypertrophy syndrome): a report of 3 cases. Oral Surg 74. Zaheri S, Chong SK, Harland CC. Treatment of mucocutaneous Oral Med Oral Pathol Oral Radiol Endod. 2002;93(3):276-280. pigmentation in Peutz-Jeghers syndrome with potassium titanyl 96. Bolan M, Ferreira MC, Almeida IC, D'Agostini Derech C, Ribeiro phosphate (KTP) laser. Clin Exp Dermatol. 2005;30(6):710-712. GL. Palatal expansion and the Klippel-Trenaunay-Weber syn- 75. Daley TD, Armstrong JE. Oral manifestations of gastrointestinal drome. Am J Orthod Dentofac Orthop. 2005;128(3):385-387. diseases. Can J Gastroenterol. 2007;21(4):241-244. 97. Sciubba JJ, Brown AM. Oral-facial manifestations of Klippel- 76. Schwartz RA, Fernandez G, Kotulska K, Jozwiak S. Tuberous scle- Trenaunay-Weber syndrome. Report of two cases. Oral Surg Oral rosis complex: advances in diagnosis, genetics, and management. J Med Oral Pathol. 1977;43(2):227-232. Am Acad Dermatol. 2007;57(2):189-202. 98. Hallett KB, Bankier A, Chow CW, Bateman J, Hall RK. Gingival 77. Wolkenstein P. Neurofibromatoses and tuberous sclerosis. J fibromatosis and Klippel-Trenaunay-Weber syndrome. Case Neuroradiol. 2005;32(3):174-179. report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 78. Curatolo P, Bombardieri R. Tuberous sclerosis. Handb Clin Neurol. 1995;79(5):578-582. 2008;87:129-151. 99. Huang WJ, Creath CJ. Klippel-Trenaunay-Weber syndrome: litera- 79. Martelli H, Lima LS, Bonan PR, Coletta RD. Oral manifestations ture review and case report. Pediatr Dent. 1994;16(3):231-235. leading to the diagnosis of familial tuberous sclerosis. Indian J Dent 100. Gorlin R, Cohen M, Hennekam R. Syndromes of Head and Neck. 4th Res. 2010;21(1):138-140. ed. New York, NY: Oxford University Press Inc; 2001:456. 80. Jorgenson RJ, Levin S. White sponge nevus. Arch Dermatol. 101. Sudarsanam A, Ardern-Holmes SL. Sturge-Weber syndrome: from 1981;117(1):73-76. the past to the present. Eur J Paediatr Neurol. 2014;18(3):257-266. 81. Shibuya Y, Zhang J, Yokoo S, Umeda M, Komori T. Constitutional 102. Orpha.netd. http://www.orpha.net/consor/cgi-bin/Disease_Search. mutation of keratin 13 gene in familial white sponge nevus. Oral php?lng=EN&data_id=591&Disease_Disease_Search_diseaseG- Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;96:561-565. roup=Sturge-Weber&Disease_Disease_Search_diseaseType=Pat& 82. Kimura M, Nagao T, Machida J, Warnakulasuriya S. Mutation of Disease(s)/group%20of%20diseases=Sturge-Weber-syndrome&ti- keratin 4 gene causing white sponge nevus in a Japanese family. tle=Sturge-Weber-syndrome&search=Disease_Search_Simple. Int J Oral Maxillofac Surg. 2013;42:615-618. Accessed February 20, 2019. 83. Otobe IF, de Sousa SO, Matthews RW, Migliari DA. White sponge 103. Parsa CF. Focal venous hypertension as a pathophysiologic naevus: improvement with tetracycline mouth rinse: report of four mechanism for tissue hypertrophy, port-wine stains, the Sturge- cases. Clin Exp Dermatol. 2007;32:749-751. Weber syndrome, and related disorders: proof of concept with 84. Pollitzer S. In: Unna P, Morris M, Besnier E, eds. International Atlas novel hypothesis for underlying etiological cause (an American of Rare Skin Disease. London: HK Lewis & Company; 1891(18):1-3. Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 85. Schwartz RA. Acanthosis nigricans. J Am Acad Dermatol. 2013;111:180-215. 1994;31(1):1-19. 104. Shaikh SM, Goswami M, Singh S, Singh D. Sturge-Weber syndrome 86. Orpha.netg. http://www.orpha.net/consor/cgi-bin/Disease_Search. – a case report. J Oral Biol Craniofac Res. 2015;5(1):53-56. php?lng=EN&data_id=396&Disease_Disease_Search_diseaseG- 105. Caiazzo A, Mehra P, Papageorge MB. The use of preoperative roup=acanthosis-nigricans&Disease_Disease_Search_diseaseType= percutaneous transcatheter vascular occlusive therapy in the Pat&Disease%28s%29/group%20of%20diseases=Acanthosis-nigri- management of Sturge-Weber syndrome: report of a case. J Oral cans&title=Acanthosis-nigricans&search=Disease_Search_Simple. Maxillofac Surg. 1998;56(6):775-778. Accessed February 20, 2019. 106. Royle HE, Lapp R, Ferrara ED. The Sturge-Weber syndrome. Oral 87. Cairo F, Rubino I, Rotundo R, Prato GP, Ficarra G. Oral Acanthosis Surg Oral Med Oral Pathol. 1966;22(4):490-497. nigricans as a marker of internal malignancy. A case report. J 107. Manivannan N, Gokulanathan S, Ahathya RS, Gubernath D, Periodontol. 2001;72(9):1271-1275. Shanmugasundaram R. Sturge-Weber syndrome. J Pharm Bioallied 88. Tyler MT, Ficarra G, Silverman S Jr, Odom RB, Regezi JA. Malignant Sci. 2012;4(s2):S349-S352 acanthosis nigricans with florid papillary oral lesions. Oral Surg Oral 108. Waller A, Findeis S, Lee MJ. Familial adenomatous polyposis. J Med Oral Pathol Oral Radiol Endod. 1996;81(4):445-449. Pediatr Genet. 2016;5(2):78-83. 89. Canjuga I, Mravak-Stipetic M, Kopic V, Galic J. Oral acanthosis ni- 109. Wijn MA, Keller JJ, Giardiello FM, Brand HS. Oral and maxillofa- gricans: case report and comparison with literature reports. Acta cial manifestations of familial adenomatous polyposis. Oral Dis. Dermatovenerol Croat. 2008;16(2):91-95. 2007;13(4):360-365. 90. Klippel M, Trenaunay P. Du naevus variquex osteohypertrophique. 110. Galiatsatos P, Foulkes WD. Familial adenomatous polyposis. Am J Arch Gen Med. 1900;3(4):641-672. Gastroenterol. 2006;101(2):385-398. 26 | PINNA et al.

111. Half E, Bercovich D, Rozen P. Familial adenomatous polyposis. 136. Kondo T. Hemangioma related to Maffucci syndrome in a man: a Orphanet J Rare Dis. 2009;4:22. case report. J Med Case Rep. 2011;5:224. 112. Leoz ML, Carballal S, Moreira L, Ocana T, Balaguer F. The ge- 137. Zwenneke Flach H, Ginai AZ, Wolter Oosterhuis J. Best cases netic basis of familial adenomatous polyposis and its implica- from the AFIP. Maffucci syndrome: radiologic and pathologic tions for clinical practice and risk management. Appl Clin Genet. findings. Armed Forces Institutes of Pathology. Radiographics. 2015;8:95-107. 2001;21(6):1311-1316. 113. Ida M, Nakamura T, Utsunomiya J. Osteomatous changes and 138. Southwell-Keely JP, Sira S, Cohen A. Maffucci syndrome: a rare tooth abnormalities found in the jaw of patients with adenomato- and important differential diagnosis for lumpy hands. Hand Surg. sis coli. Oral Surg Oral Med Oral Pathol. 1981;52(1):2-11. 2007;12(1):51-53. 114. Murakami C, de Oliveira Lira Ortega A, Guimaraes AS, Goncalves- 139. Moorthy AP. Oral manifestations in Maffucci syndrome. Br Dent J. Bittar D, Bonecker M, Ciamponi AL. Focal dermal hypoplasia: a 1983;155:160-161. case report and literature review. Oral Surg Oral Med Oral Pathol 140. Miyake M, Tateishi U, Maeda T, Arai Y, Hasegawa T, Sugimura K. Oral Radiol Endod. 2011;112(2):e11-e18. MR features of angiosarcoma in a patient with Maffucci's syn- 115. Goltz RW, Peterson WC, Gorlin RJ, Ravits HG. Focal dermal hypo- drome. Radiat Med. 2005;23(7):508-512. plasia. Arch Dermatol. 1962;86:708-717. 141. Gerber PA, Antal AS, Neumann NJ, et al. Neurofibromatosis. Eur J 116. Paller AS. Wnt signaling in focal dermal hypoplasia. Nat Genet. Med Res. 2009;14(3):102-105. 2007;39(6):820-821. 142. Bongiorno MR, Pistone G, Arico M. Manifestations of the tongue 117. Wang X, Reid Sutton V, Omar Peraza-Llanes J, et al. Mutations in in Neurofibromatosis type 1. Oral Dis. 2006;12(2):125-129. X-linked PORCN, a putative regulator of Wnt signaling, cause focal 143. Orpha.netc. http://www.orpha.net/consor/cgi-bin/Disease_Search. dermal hypoplasia. Nat Genet. 2007;39(6):836-838. php?lng=EN&data_id=185&Disease_Disease_Search_disease 118. Bittencourt LP, Campos V, Moliterno LF, Ribeiro DP, Sampaio RK. Group=neurofibromatosis&Disease_Disease_Search_disease- Hereditary gingival fibromatosis: review of the literature and a Type=Pat&Disease(s)/group%20of%20diseases=Neurofibroma- case report. Quintessence Int. 2000;31(6):415-418. tosis-type-1&title=Neurofibromatosis-type-1&search=Disease_ 119. Tejani Z, Batra P, Mason C, Atherton D. Focal dermal hypoplasia: Search_Simple. Accessed February 20, 2019. oral and dental findings. J Clin Pediatr Dent. 2005;30(1):67-72. 144. Chen W, Fan PC, Happle R. Partial unilateral lentiginosis with 120. McNamara T, Trotman CA, Hahessy AM, Kavanagh P. Focal dermal ipsilateral Lisch nodules and axillary freckling. Dermatology. hypoplasia (Goltz-Gorlin) syndrome with taurodontism. Spec Care 2004;209(4):321-324. Dentist. 1996;16(1):26-28. 145. Javed F, Ramalingam S, Ahmed HB, et al. Oral manifestations in pa- 121. Laskaris G, Vareltzidis A, Avgerinou G. Focal palmoplantar and oral tients with neurofibromatosis type-1: a comprehensive literature mucosa hyperkeratosis syndrome: a report concerning five mem- review. Crit Rev Oncol Hematol. 2014;91(12):123-129. bers of a family. Oral Surg Oral Med Oral Pathol. 1980;50(3):250-253. 146. Geist JR, Gander DL, Stefanac SJ. Oral manifestations of neu- 122. Kolde G, Hennies HC, Bethke G, Reichart PA. Focal palmoplantar rofibromatosis types I and II. Oral Surg Oral Med Oral Pathol. and gingival keratosis: a distinct palmoplantar ectodermal dyspla- 1992;73:376-382. sia with epidermolytic alterations but lack of mutations in known 147. Joseph B, Nath SG, Sheejith B. An unusual case of multiple intra- keratins. J Am Acad Dermatol. 2005;52(3):403-409. oral manifestations of neurofibromatosis type 1: case report with 123. Young WG, Newcomb GM, Daley TJ. Focal palmoplantar and gin- literature review. J Clin Diagn Res. 2014;8(3):Zd20-22. gival hyperkeratosis syndrome: report of a family, with cytologic, 148. Mahajan A, Dixit J, Bhardwaj A. Gingival enlargement in neurofi- ultrastructural, and histochemical findings. Oral Surg Oral Med Oral bromatosis type 1: a case report and literature review. J Contemp Pathol. 1982;53(5):473-482. Dent Pract. 2010;11:57-63. 124. Fred HL, Gieser RG, Berry WR, Eiband JM. Keratosis palmaris et 149. Shekar V, Rangdhol V, Baliah WJ, Thirunavukarasu S. An unusual plantaris. Arch Intern Med. 1964;113:866-871. oral manifestation of type 1 neurofibromatosis: a case report and 125. Goddard W, Gross S. Case of hypertrophy of the gums. Dent Regist review of literature. J Nat Sci Biol Med. 2015;6(1):261-263. West. 1856;9:7. 150. Doufexi A, Mina M, Ioannidou E. Gingival overgrowth in children: 126. Coletta RD, Graner E. Hereditary gingival fibromatosis: a system- epidemiology, pathogenesis, and complications. A literature re- atic review. J Periodontol. 2006;77(5):753-764. view. J Periodontol. 2005;76(1):3-10. 127. Nayak PA, Nayak UA, Khandelwal V, Ninave N. Idiopathic gingival 151. NIH CDPO. 1987. https://consensus.nih.gov/1987/1987Neurofi- fibromatosis. Int J Clin Pediatr Dent. 2011;4(1):77-81. bramatosis064html.htm. Accessed February 19, 2018. 128. Goldblatt J, Singer SL. Autosomal recessive gingival fibromatosis 152. Garcia de Marcos JA, Dean Ferrer A, Alamillos Granados F, et al. with distinctive facies. Clin Genet. 1992;42:306-308. Gingival neurofibroma in a neurofibromatosis type 1 patient. Med 129. Danesh-Meyer MJ, Holborow DW. Familial gingival fibromatosis: a Oral Patol Oral Cir Bucal. 2007;12(4):E287-291. report of two patients. N Z Dent J. 1993;89:119-122. 153. Mohr O. A hereditary subletal syndrome in man. Skr Norske Vidensk 130. Srinivasa T, Kaushik R, Manjunath Shiva RG. Elephantiasis gingiva Akad. 1941;14:1-18. in 13 year old boy – a case report. J Int Dent Med Res. 2011;4:30-44. 154. Gurrieri F, Franco B, Toriello H, Neri G. Oral-facial-digital syn- 131. Maffucci A. A case of enchondroma and multiple hemangioma. dromes: review and diagnostic guidelines. Am J Med Genet A. Med Chir Napoli. 1881;3:399-412. 2007;143a(21):3314-3323. 132. Desai S, Kubeyinje EP, Belagavi CS, Desai S. Maffucci's syndrome. 155. King NM, Sanares AM. Oral-facial-digital syndrome, type I: a case Ann Saudi Med. 1997;17(4):451-453. report. J Clin Pediatr Dent. 2002;26(2):211-215. 133. Kuwahara RT, Skinner RB Jr. Maffucci syndrome: a case report. 156. Papillon L, Psaume J. [Hereditary abnormality of the buccal mucosa: Cutis. 2002;69(1):21-22. abnormal bands and frenula]. Revue Stomatol. 1954;55:209-227. 134. Amary MF, Damato S, Halai D, et al. Ollier disease and Maffucci 157. Rakkolainen A, Ala-Mello S, Kristo P, Orpana A, Jarvela I. Four syndrome are caused by somatic mosaic mutations of IDH1 and novel mutations in the OFD1 (Cxorf5) gene in Finnish patients with IDH2. Nat Genet. 2011;43:1262-1265. oral-facial- digital syndrome 1. J Med Genet. 2002;39(4):292-296. 135. Dini LI, Isolan GR, Saraiva GA, Dini SA, Gallo P. Maffucci's syn- 158. Orpha.netb. http://www.orpha.net/consor/cgi-bin/Disease_Search. drome complicated by intracranial chondrosarcoma: two new il- php?lng=EN&data_id=2506&Disease_Disease_Search_dis lustrative cases. Arq Neuropsiquiatr. 2007;65(38):816-821. easeGroup=OFD1&Disease_Disease_Search_disease- PINNA et al. | 27

Type=Pat&Disease(s)/group%20of%20diseases=Orofaciodigi- 179. D'Aoust P, Landry R, Ganske R, Carrier J. The prevalence of the tal-syndrome-type-1&title=Orofaciodigital-syndrome-type1&- retrocuspid papilla among three indigenous groups of patients. search=Disease_Search_Simple http://www.orpha.net/consor/cgi Study of the subjects in Ecuador, Honduras and Nicaragua. Ont -bin/Disease_Search.php?lng=EN&data_id=2506&Disease_ Dent. 1991;68(8):39, 43, 45. Disease_Search_diseaseGroup=OFD1&Disease_Disease_ 180. Buchner A, Merrell PW, Hansen LS, Leider AS. The retrocus- Search_diseaseType=Pat&Disease(s)/group%20of%20 pid papilla of the mandibular lingual gingiva. J Periodontol. diseases=Orofaciodigital-syndrome-type-1&title=Orofaciodig- 1990;61(9):585-589. ital-syndrome-type-1&search=Disease_Search_Simple. Accessed 181. Al-Shawaf M. Retrocuspid papilla in a sample of Saudi dental pa- February 20, 2019. tients. PODJ. 2008;1(1):33-36. 159. Kennedy SM, Hashida Y, Malatack JJ. Polycystic kidneys, pancre- 182. Dafar A, Bankvall M, Cevik-Aras H, Jontell M, Sjoberg F. Lingual atic cysts, and cystadenomatous bile ducts in the oral-facial-digital microbiota profiles of patients with geographic tongue. J Oral syndrome type I. Arch Pathol Lab Med. 1991;115(2):519-523. Microbiol. 2017;9(1):1355206. 160. Mihci E, Tacoy S, Ozbilim G, Franco B. Oral-facial digital syndrome 183. Jainkittivong A, Langlais RP. Geographic tongue: clinical charac- type 1. Indian Pediatr. 2007;44(11):854-856. teristics of 188 cases. J Contemp Dent Pract. 2005;6(1):123-135. 161. Feather SA, Woolf AS, Donnai D, Malcolm S, Winter RM. The oral- 184. Goswami M, Verma A, Verma M. Benign migratory glossitis with facial-digital syndrome type 1 (OFD1), a cause of polycystic kidney fissured tongue. J Indian Soc Pedod Prev Dent. 2012;30(2):173-175. disease and associated malformations, maps to Xp22.2-Xp22.3. 185. Banoczy J, Rigo O, Albrecht M. Prevalence study of tongue le- Hum Mol Genet. 1997;6(7):1163-1167. sions in a Hungarian population. Community Dent Oral Epidemiol. 162. Ferrante MI, Giorgio G, Feather SA, et al. Identification of the 1993;21(4):224-226. gene for oral-facial-digital type I syndrome. Am J Hum Genet. 186. Giudici N, Bianchetti MG, Ramelli GP, Milani GP. Recurrent epi- 2001;68(3):569-576. sodes of peripheral facial nerve palsy and fissured tongue. J 163. Hsieh YC, Hou JW. Oral-facial-digital syndrome with Y-shaped Paediatr Child Health. 2017;53(6):609. fourth metacarpals and endocardial cushion defect. Am J Med 187. Liu R, Yu S. Melkersson-Rosenthal syndrome: a review of seven Genet. 1999;86(3):278-281. patients. J Clin Neurosci. 2013;20(7):993-995. 164. Habib K, Fraitag S, Couly G, de Prost Y. Cutaneous lesions in the 188. Viswanath V, Nair S, Chavan N, Torsekar R. Caviar tongue. Indian J orofaciodigital syndrome. Ann Pediatr (Paris). 1992;39(7):449-452. Dermatol Venereol Leprol. 2011;77(1):78-79. 165. Connacher AA, Forsyth CC, Stewart WK. Orofaciodigital syn- 189. Baughman R. Median rhomboid glossitis: a developmental anom- drome type I associated with polycystic kidneys and agenesis of aly? Oral Surg Oral Med Oral Pathol. 1971;31(1):56-65. the corpus callosum. J Med Genet. 1987;24(1):116-118. 190. Nowak K. Szyfter W [Median rhomboid glossitis–change of in- 166. Termote B, Verswijvel G, Palmers Y. Oro-facio-digital syn- flammation origin or developmental anomaly?]. Otolaryngol Pol. drome type 1: imaging findings in an 11-year-old girl. JBR-BTR. 2005;59(6):857-860. 2007;90(1):47-50. 191. Ugar-Cankal D, Denizci S, Hocaoglu T. Prevalence of tongue le- 167. Tuli A, Sachdev V, Singh A, Kumar A. Physical and dental mani- sions among Turkish schoolchildren. Saudi Med J. 2005;26(12): festations of oral-facial-digital syndrome type I. J Indian Soc Pedod 1962-1967. Prev Dent. 2011;29(6):S83-S86. 192. Gurvits GE, Tan A. Black hairy tongue syndrome. World J 168. Gonzalez MG, Castro MP, Nieto DV, Bouzan JC. Oral-facial-digital Gastroenterol. 2014;20(31):10845-10850. syndrome type I: surgical approach and a case report. J Plast 193. Schlager E, St Claire C, Ashack K, Khachemoune A. Black hairy Reconstr Aesthet Surg. 2014;67(3):396-398. tongue: predisposing factors, diagnosis, and treatment. Am J Clin 169. Ozturk F, Doruk C. Orthodontic treatment of a patient with Dermatol. 2017;18(4):563-569. oral-facial- digital syndrome. Am J Orthod Dentofacial Orthop. 194. Hedstrom L, Albrektsson M, Bergh H. Is there a connection between 2012;141(4):S110-S118. sublingual varices and hypertension? BMC Oral Health. 2015;15:78. 170. Thauvin-Robinet C, Cossee M, Cormier-Daire V, et al. Clinical, 195. Gomes CC, Gomez RS, do Carmo MA, Castro WH, Gala-Garcia molecular, and genotype-phenotype correlation studies from 25 A, Mesquita RA. Mucosal varicosities: case report treated cases of oral-facial-digital syndrome type 1: a French and Belgian with monoethanolamine oleate. Med Oral Patol Oral Cir Bucal. collaborative study. J Med Genet. 2006;43(1):54-61. 2006;11(1):E44-E46. 171. Ikemura K, Kakinoki Y, Nishio K, Suenaga Y. Cysts of the oral mu- 196. Ibrahim NA, Fadeyibi IO. Ectopic thyroid: etiology, pathology and cosa in newborns: a clinical observation. J Uoeh. 1983;5(2):163-168. management. Hormones (Athens). 2011;10(4):261-269. 172. Fordyce J. A peculiar affection of the mucous membrane of the lip 197. De Felice M, Di Lauro R. Thyroid development and its disorders: ge- and oral cavity. J Cutan Genito-Urin Dis. 1896;14(11):7. netics and molecular mechanisms. Endocr Rev. 2004;25(5):722-746. 173. Monteil RA. Fordyce's spots: disease, heterotopia or ade- 198. Mussak EN, Kacker A. Surgical and medical management of midline noma? Histological and ultrastructural study. J Biol Buccale. ectopic thyroid. Otolaryngol Head Neck Surg. 2007;136(6):870-872. 1981;9(2):109-128. 174. Nordstrom KM, McGinley KJ, Lessin SR, Leyden JJ. Neutral lipid composition of Fordyce's granules. Br J Dermatol. How to cite this article: Pinna R, Cocco F, Campus G, et al. 1989;121(5):669-670. Genetic and developmental disorders of the oral mucosa: 175. Martin JL, Crump EP. Leukoedema of the buccal mucosa in Negro children and youth. Oral Surg Oral Med Oral Pathol. 1972;34(1):49-58. Epidemiology; molecular mechanisms; diagnostic criteria; 176. Martin JL. Leukoedema: a review of the literature. J Natl Med management. Periodontol 2000. 2019;80:12–27. https://doi. Assoc. 1992;84(11):938-940. org/10.1111/prd.12261 177. Macdonald JB, Tobin CA, Hurley MY. Oral leukoedema with mucosal desquamation caused by toothpaste containing sodium lauryl sulfate. Cutis. 2016;97(1):E4-E5. 178. Hirschfeld I. The retrocuspid papillae. Oral Surg Oral Med Oral Pathol. 1947;33(6):447-457.