Genetics

Cyclic Neutropenia: The inheritance pattern of cyclic neutropenia is autosomal dominant; the responsible gene has been identified and is called ELA-2 (neutrophil elastase gene). This gene is located on the short arm of chromosome 19. In the chromosome mapping system its location is designated as 19p13.3. The disorder is characterized by a cyclic decrease in the number of circulating neutrophilic leukocytes (neutrophils); a decrease in the number of circulating neutrophils is called neutropenia. The cycles usually occur in intervals of 21 to 27 days, but in some patients the interval may be extended to several months. These episodes of neutropenia generally persist for 2 to 3 days.

The clinical manifestations are related to the decrease in neutrophils. Systemic manifestations of cyclic neutropenia include fever, malaise, sore throat, and occasional cutaneous infections. Oral manifestations consist of severe ulcerative gingivitis or gingivostomatitis (Figure 6-14). In addition to the gingiva, areas of ulceration can also occur on the tongue and surfaces of the oral mucosa. The ulcers are of variable size and have a craterlike appearance. They are very painful and have a bleeding base. Generally the oral lesions are infected secondarily. When neutrophils return to normal, the oral lesions tend to improve.

Patients with cyclic neutropenia are usually managed by first determining the frequency of the cycles through periodic neutrophil counts and then instituting preventive antibiotic therapy to protect against secondary opportunistic infections. Over time episodes of neutropenia and associated ulcerative gingivitis lead to severe periodontal disease, with loss of alveolar bone, tooth mobility, and exfoliation of teeth. Treatment should be initiated when the circulating neutrophil count is normal to reduce the risk of complications such as gingival hemorrhage and secondary infection. Dental hygiene care, including frequent appointments for removal of local irritants and maintenance of optimal oral hygiene, reduces the risk of opportunistic infections in patients with cyclic neutropenia.

Patients with cyclic neutropenia are treated with periodic granulocyte colony-stimulating factor (G-CSF) that reduces the symptoms and results in substantial clinical improvement.

Chronic neutropenia, also known as Kostmann syndrome, is another variety of neutropenia that is inherited as an autosomal recessive. The intraoral manifestations are similar to those of the cyclic variety but are constant. The responsible gene is still unknown, and it is also treated with periodic G-CSF.

Papillon-Lefèvre Syndrome: Papillon-Lefèvre syndrome has an autosomal-recessive inheritance pattern and is composed of marked destruction of the periodontal tissues (periodontoclasia) of both dentitions with premature loss of teeth and hyperkeratosis of the palms of the hands and soles of the feet (palmar and plantar hyperkeratosis).

The gene for this syndrome has been mapped to the long arm of chromosome 11 regions 14-21 (11q14-21). These patients are normal at birth except for a reddening of the palms of the hands and soles of the feet. Teeth erupt in normal sequence, position, and time. At about 1½ to 2 years of age, a marked gingivoperiodontal inflammatory process develops characterized by edema, bleeding, alveolar bone resorption, and mobility of teeth with consequent exfoliation. A red, scaly keratosis develops on the palms and soles concurrent with these oral lesions and occasionally extends to the dorsal surfaces of the hands and feet. The oral lesions are complicated by superimposed inflammation, and radiographs reveal marked alveolar bone resorption with vertical pockets. Teeth are lost in the same sequence in which they erupted. When the last tooth is lost, the gingiva regains a normal appearance.

The lesions on the hands and feet remain as reddish-white, scaly, thick areas of hyperkeratinization (Figure 6-15). The permanent dentition begins to erupt at the proper time. At about 8 or 9 years of age the gingivoperiodontal destruction is repeated in the same manner as occurred in the primary dentition (Figure 6-16). All permanent teeth are lost before 14 years of age. The gingiva again resumes a normal appearance.

Peripheral blood neutrophil is depressed in all patients with Papillon-Lefèvre syndrome. This suggests that the neutrophils may be an important factor in the pathogenesis of severe periodontal disease in these patients. Retinoid therapy markedly improves the skin condition but has no effect on the periodontal disease in patients with this syndrome. To date all therapeutic attempts at preventing the gingival and periodontal destruction and subsequent loss of teeth have been unsuccessful. The basic defect that causes the condition is unknown. Peripheral blood neutrophil chemotaxis has been reported to be depressed in patients with Papillon-Lefèvre syndrome. This decreased chemotaxis suggests that neutrophils may play a role in periodontal destruction in patients with this syndrome. Current research suggests bacterial and viral involvement as the initiating factors for the periodontal destruction. It has been suggested that the genetic component of Papillon-Lefèvre syndrome is a predisposition rather than the main determinant of periodontal disease.

The skin manifestations remain for life, but treatment with retinol (oral etretinate) has proven somewhat effective in controlling the hyperkeratinization. These patients do not have any other abnormalities.

Focal Palmoplantar and Gingival Hyperkeratosis: Areas of hyperkeratinization of the palms and soles and marked hyperkeratinization of the labial and lingual gingiva characterize focal palmoplantar and gingival hyperkeratosis. This syndrome has an autosomal-dominant inheritance pattern. The palmar and plantar hyperkeratosis starts at the tips of the fingers and toes and extends to the surface of the palms and soles. This process increases with age and also becomes localized, with calluses forming on the weight-bearing areas.

The oral hyperkeratinization is bandlike and a few millimeters in width (Figure 6-17). It follows the normal festooned contour of the gingiva. The free gingiva is not affected. Palatal and lingual mucosa occasionally can be affected with areas of hyperkeratinization. These changes start in childhood and increase with age. The rest of the oral cavity is normal.

Gingival Fibromatosis: Gingival fibromatosis is a component of several inherited syndromes. The gingival hypertrophy generally develops early in life, and within a few years the teeth are completely covered. The fibromatosis is composed of very firm tissue with a granular corrugated surface. Generally the color is paler than that of the normal gingiva and results from the marked collagenization of the fibrous connective tissue. The extensive gingival enlargement leads to protrusion of the lips.

In addition to isolated gingival fibromatosis (Figure 6-18), which has an autosomal-dominant inheritance pattern and no other associated abnormalities, gingival fibromatosis is a component of a number of syndromes. Because of the gingival involvement, several of these syndromes, although rare, are described here. However, only those that are well known and occur most frequently are included.

Dental hygiene care can reduce the risk of secondary inflammation and infection in patients with gingival fibromatosis.

Laband Syndrome: The inheritance pattern of Laband syndrome is autosomal dominant. In addition to gingival fibromatosis, patients have dysplastic or absent nails and malformed nose and ears because of soft and pliable cartilage formation, hepatosplenomegaly (enlarged liver and spleen), and hypoplasia of terminal phalanges of the fingers and toes with a resultant froglike appearance.

Gingival Fibromatosis With Hypertrichosis, Epilepsy, and Mental Retardation Syndrome: Gingival fibromatosis with hypertrichosis, epilepsy, and mental retardation syndrome has an autosomal-dominant inheritance pattern. Hypertrichosis (excessive growth of hair), especially of the eyebrows, extremities, genitals, and sacral region, characterize gingival fibromatosis with hypertrichosis, epilepsy, and mental retardation. Epilepsy and mental retardation can also occur in this syndrome but are inconsistent features.

Gingival Fibromatosis With Multiple Hyaline Fibromas: Gingival fibromatosis with multiple hyaline fibromas has an autosomal-dominant inheritance pattern and is also known as the Murray-Puretíc Drescher syndrome. In addition to gingival fibromatosis, it is characterized by hypertrophy of the nail beds and multiple hyaline fibrous tumors developing on the nose, chin, head, back, fingers, thighs, and legs. These tumors on the extremities can produce contractures of various joints, including hips, knees, shoulders, and elbows.

Cherubism: The inheritance pattern of cherubism is autosomal dominant with marked penetrance (when the gene is present, the clinical manifestations are usually seen) in males and variable expressivity and incomplete penetrance in females. The gene for cherubism has been mapped to the short arm of chromosome 4 region 16 (4p16). The first clinical manifestation is a progressive bilateral facial swelling that appears when the patient is between 1½ and 4 years of age. This change can affect either the mandible or the maxilla, but involvement of the mandible is most common. Displacement of the eyes is evident when the maxilla is affected. This, added to the bilateral deformity, produces the characteristic cherubic facial appearance that is responsible for the name of the syndrome. Increased distance between the eyes (ocular hypertelorism) is always present in affected patients. Radiographs of the jaws show a typical “soap-bubble” or multilocular appearance (Figure 6-19), which usually occupies the ascending ramus of the mandible and extends into the molar and premolar areas. Severe cases can involve the full mandible, but the condyle is always spared. When the maxilla is affected, the changes are observed at the level of the tuberosity and involve the antrum.

These areas of bone radiolucency are occupied by fibrous connective tissue containing multinucleated giant cells. The microscopic appearance resembles the central giant cell granuloma (described in Chapter 2). The bone lesions interfere with tooth development and eruption. Most of these patients have pseudoanodontia (teeth falsely appear to be lacking), especially of molars and premolars, because of delayed eruption.

The size of the jaws tends to increase rapidly until about puberty and then generally remains stable. After the individual reaches age 20 or 30 years, radiographs show an almost normal bone appearance, with a few areas of increased bone density. The facial deformity remains for life, and in some patients it can be quite striking.

Ellis–Van Creveld Syndrome: Ellis–van Creveld syndrome has an autosomal-recessive inheritance pattern. The gene for this has been mapped to the short arm of chromosome 4 region 16 (4p16). Affected individuals are dwarfs because of distal shortening of the extremities. One third of these patients are mildly mentally handicapped. The hands show polydactyly (supernumerary digits) on the ulnar side, and fingernails and toenails are hypoplastic and deformed. Other skeletal anomalies include curvature of the legs and feet. Fifty percent of affected individuals have congenital heart defects. Anomalies of the external genitals, especially in males, are also observed.

The oral manifestations are constant and characteristic and include fusion of the anterior portion of the maxillary gingiva to the upper lip from canine to canine. Thus the anterior maxillary vestibular sulcus is lacking (Figure 6-20). This anomaly induces a V-notch appearance in the midline of the upper lip. The anterior lower alveolar ridge presents a serrated appearance caused by thick frenula, which start at the vestibular sulcus and traverse the alveolar ridge. The central incisors of both maxilla and mandible are generally lacking and are replaced by a centrally located abnormal tooth. Most of the teeth have a conical shape and exhibit enamel hypoplasia. More than 50% of newborns with this syndrome have natal teeth.

Cleidocranial Dysplasia: The inheritance pattern of cleidocranial dysplasia is autosomal dominant; however, about half of the cases are isolated examples caused by either spontaneous mutation or a gene with poor penetrance. The gene for this syndrome has been mapped to the short arm of chromosome 6 region 21 (6p21). The cranium develops a mushroom shape because the fontanelles remain open. This makes the face appear small. Frontal, parietal, and occipital enlargement is quite noticeable. Skull radiographs reveal the open fontanelles, which are often open for life. The paranasal sinuses are lacking or hypoplastic. The neck is long and narrow because of unilateral or bilateral aplasia (lack of development) or hypoplasia of the clavicles. Affected individuals are able to approximate their shoulders to the midline because of this clavicular alteration. Various other bone anomalies can also be present.

The premaxilla is generally underdeveloped, resulting in pseudoprognathism. These patients have many supernumerary teeth, sometimes even simulating a third dentition (Figure 6-21). They are crowded in the jaws and do not erupt. They also interfere with the eruption of normal teeth, resulting in pseudoanodontia. A lack of cellular cementum has been reported in patients with this syndrome. Multiple cysts can develop in association with the impacted teeth. About 1% of affected patients have cleft lip, cleft palate, or both.

Gardner Syndrome: Gardner syndrome, also known as familial colorectal polyposis, has an autosomal-dominant inheritance pattern with variable expressivity and marked penetrance. The adenomatous polyposis coli gene is responsible for Gardner syndrome and is located on the long arm of chromosome 5 regions 21-22 (5q21-22). One of the basic components is the presence of osteomas in various bones, especially the frontal bones, mandible, and maxilla. When they expand, osteomas of the facial skeleton obliterate the sinuses and induce facial asymmetry. Osteomas can also occur in the long bones of the skeleton but with less frequency than in the bones of the face.

In addition to osteomas, multiple odontomas can occur in the jawbones, especially the mandible (Figure 6-22). Teeth can exhibit hypercementosis and fail to erupt.

The most serious component of this syndrome is the presence of intestinal polyps, which become malignant at age 30 and after. Polyposis primarily affects the colon and rectum and generally develops before puberty. Some authors advocate intestinal resection when the polyps appear because their malignant transformation into adenocarcinoma is invariable, especially with increasing age.

Mandibulofacial Dysostosis: The inheritance pattern of mandibulofacial dysostosis is autosomal dominant with incomplete penetrance and variable expressivity. The gene for this syndrome has been mapped to the long arm of chromosome 5 regions 32-33.1 (5q32-33.1). The facies shows downward sloping of the palpebral fissures, a hypoplastic nose, hypoplastic malar bones with hypoplasia or absence of the zygomatic process, abnormal and misplaced ears, and a receding chin. The mouth appears fishlike, with downward sloping of the lip commissures. The lower eyelids show a cleft (coloboma) of the outer third, with a lack of lashes medial to it. The ears may exhibit tags, which on occasion can also be seen near the angle of the mouth.

Deafness is a constant feature resulting from a lack of otic ossicles. Mental development is within normal limits; difficulty in learning arises from deafness. Oral manifestations include a markedly hypoplastic mandible with flattened condyles and coronoid processes and an obtuse mandibular angle. Teeth are malposed, and malocclusion with open bite is quite evident. The palate is high, or a cleft is present in about 30% of affected patients (Figure 6-23). Gingival disease is common and is related to the dental abnormalities.

Nevoid Basal Cell Carcinoma Syndrome: The nevoid basal cell carcinoma syndrome, also known as Gorlin syndrome, has an autosomal-dominant inheritance pattern with high penetrance and variable expressivity. The gene for this syndrome maps to the long arm of chromosome 9 region 22.3 (9q22.3). The facies is characterized by mild hypertelorism (increased distance between the eyes) and mild prognathism, with frontal and parietal enlargement and a broad nasal root.

The cutaneous manifestations, which are called nevi, typically are basal cell carcinomas. The term nevus (plural, nevi), as defined here, is a congenital lesion characterized by skin pigmentation. These basal cell carcinomas appear early in life and continue to develop over the nose, eyelids, cheeks, neck, arms, and trunk. They can be flesh colored or pale brown and develop singly or in clusters. Histologically they are basal cell carcinomas. The palms and soles show small pits that become filled with dirt and appear as dark spots on those surfaces.

The oral manifestations of this syndrome consist of multiple cysts of the jaws (Figure 6-24) that (histologically) are odontogenic keratocysts (see Chapter 5). These cysts vary in size; they can be very large and have a marked tendency to recur after surgical removal. Occasionally an ameloblastoma arises in these cysts as part of this syndrome. The cysts develop as early as 5 to 6 years of age in some affected patients and interfere with normal development of the jawbones and teeth.

A great variety of skeletal anomalies have been reported in association with the nevoid basal cell carcinoma syndrome, the most constant being bifurcation or splaying of one or more ribs. Other frequent abnormalities of bone include shortening of the metacarpals, spina bifida occulta (defective closure of the bone encasement of the spinal cord), and kyphoscoliosis (a combination of scoliosis, which is a lateral curving of the spine, and kyphosis, which is an abnormal vertical curvature of the spine or “hunchback”).

Many different neoplasms have been reported in association with this syndrome. Medulloblastoma (brain tumor) has been seen in many cases. Children surviving the medulloblastoma eventually present other manifestations of the syndrome. Other less frequent findings include calcified ovarian fibromas and mesenteric cysts.

Osteogenesis Imperfecta: Osteogenesis imperfecta is known to have an autosomal-dominant inheritance pattern with variable expressivity. However, only 30% of patients have a family history of this condition. The remaining 70% represent sporadic cases and cases suggesting autosomal-recessive inheritance. The basic defect is produced by different mutations affecting the genes that encode for type I collagen, resulting in abnormally formed bones that fracture easily. The genes responsible for the inherited varieties of osteogenesis imperfecta are mapped as follows: collagen type I alpha 2 is in the long arm of chromosome 7 region 22.1 (7q22.1); collagen type I alpha 1 is in the long arm of chromosome 17 region 21.31-22.05 (17q21.31-22.05). Osteogenesis imperfecta occurs in about 1 in 20,000 births, and major syndromes have been classified in four types: I, II, III, and IV.

The clinical manifestations vary markedly from patient to patient. The sporadic cases tend to be more severe than those with an autosomal-dominant inheritance pattern. The basic defect involves collagen and results in abnormally formed bones that fracture easily. Multiple bone fractures are the main clinical complication of this syndrome. In the congenital form newborns can have several fractured bones at birth. Infants with this condition have experienced fractures just by being moved. In the most severe cases all bones can be affected, presenting a plethora of abnormalities, including bowing of the legs, curvature of the spine (kyphosis and scoliosis), deformity of the skull, shortening of arms and legs, and other abnormalities. In the mildest cases individuals show only blue sclerae (a blue appearance of the white of the eye).

The oral manifestation of this syndrome is a dentinogenesis imperfecta–like condition (a description of dentinogenesis imperfecta follows later in this chapter). Primary teeth are affected in 80% of patients, whereas permanent teeth are affected in only 35% of these individuals (Figure 6-25). The crowns, roots, and pulp chambers generally are smaller than normal. Teeth appear opalescent or translucent at time of eruption, but they darken with age. The enamel is lost because the abnormal dentin cannot provide adequate support.

Torus Mandibularis: Mandibular tori (singular, torus) have an autosomal-dominant inheritance pattern with variable expressivity and marked penetrance. This anomaly can be unilateral or bilateral. These tori occur on the lingual aspect of the mandible in the area of the premolar teeth (Figure 6-26). Occurrence before age 15 years is extremely rare. The size of the torus is variable, and occasionally it can be multilobulated. Mandibular tori are symptomless and generally require no treatment. Surgical removal may be necessary if the patient needs a denture. Intraoral radiographs usually show a radiopacity in the area of the mandibular premolars if mandibular tori are present. (Mandibular tori are also discussed in Chapters 1 and 7.)

Torus Palatinus: Autosomal dominance with variable expressivity and almost 100% penetrance characterizes torus palatinus. A bony overgrowth occurs at the midline of the hard palate (Figure 6-27). A marked predilection exists for women (2:1), and a higher prevalence exists among Native Americans, including Inuits. Torus palatinus becomes evident around the time of puberty and is only rarely seen in children younger than 14 years of age. The size of this anomaly varies from nearly undetectable to large masses that occupy almost the entire hard palate. Some palatal tori are multilobular. Torus palatinus is symptomless. However, the surface mucosa is thin and easily traumatized. The torus may need to be removed if the patient needs a full denture. (Torus palatinus is also described in Chapters 1 and 7.)

Maxillary Exostosis: Exostoses have an autosomal-dominant inheritance pattern. Maxillary exostoses represent tori that generally develop on the buccal aspect of the maxillary alveolar ridge, usually in the molar and premolar area (Figure 6-28). They are generally symptomless unless traumatized. They may be single, multiple, unilateral, and bilateral and occur less frequently than either palatal or mandibular tori. (Exostoses are also described in Chapter 7.)

Isolated Cleft Palate and Cleft Lip With or Without Cleft Palate: The majority of cases of facial clefting are multifactorial in origin; they occur in about 1 in 800 births. A large number of inherited syndromes can include cleft lip and palate or isolated cleft palate as a component. When clefting is part of an inherited syndrome, its occurrence within affected families will be in accordance with the inheritance pattern of the syndrome. Most of these syndromes are very rare. Cleft lip-palate and congenital lip pits (Van der Woude syndrome) is the syndrome that is considered to occur most frequently; therefore it is the only one described here. It has an autosomal-dominant inheritance pattern with 80% penetrance for any of its components. In the majority of cases the gene has been mapped to the long arm of chromosome 1 regions 32 to 41 (1q32-41). The labial pits (Figure 6-29) are bilateral and are located near the midline of the vermilion border of the lower lip. They may be 3 mm or more in diameter and generally finish in a blind end. Occasionally they exude saliva because of their association with a labial minor salivary gland. These pits are rarely unilateral, and the clefting is bilateral in about 80% of patients. Some patients without clefting have agenesis (lack of development) of the maxillary lateral incisors or peg lateral incisors. Other oral findings that have been seen include fibrous adhesions between the maxilla and mandible, a cleft uvula, and ankyloglossia.

Hereditary Hemorrhagic Telangiectasia: The inheritance pattern of hereditary hemorrhagic telangiectasia, also known as Osler-Rendu–Parkes Weber syndrome, is autosomal dominant. Recent studies indicate that this syndrome may have two different responsible loci: one at the long arm of chromosome 9 (9q3) and the other in chromosome 12. It is characterized by multiple capillary dilations of the skin and mucous membranes (Figure 6-30). The skin of the face shows numerous pinpoint and spiderlike telangiectases, especially on the lips, eyelids, and around the nose. The scalp and ears are also affected. Similar lesions are present in the nasal mucosa and are responsible for frequent and sometimes serious nosebleeds (epistaxis) that can last for several days. Any organ or mucous membrane can be the site of telangiectasia.

Telangiectases of the oral mucosa are especially prominent on the tip and anterior dorsum of the tongue. The palate, gingiva, and buccal mucosa are often affected but to a lesser degree. Hemorrhage from sites in the oral cavity, mainly the lips and tongue, is second in frequency to epistaxis. Gingival bleeding has been reported and is a possible complication of dental hygiene treatment. The risk of gingival hemorrhage should be a concern of the dental hygienist when treating a patient with this syndrome.

Multiple Mucosal Neuroma Syndrome: The combination of multiple mucosal neuromas, medullary carcinoma of the thyroid gland, and pheochromocytoma is identified as multiple endocrine neoplasia, type 2B (MEN 2B). The inheritance pattern is autosomal dominant with decreased penetrance. This syndrome is the result of mutations in the receptor tyrosine kinase that maps to chromosome 10q11.2. Patients are tall with characteristic thick, large lips and often everted upper eyelids. The mucosal neuromas are prominent on the lips and anterior dorsal surface of the tongue (Figure 6-31). They generally appear in the first few years of life. In addition, neuromas can occur on the buccal mucosa and the eyelids. The mucosal neuromas are seen as multiple, mobile, firm lumps covered by normal mucosa. Histologically they are aggregates of nerve tissue.

Medullary carcinoma of the thyroid has been diagnosed in more than 75% of patients with this syndrome; it generally develops in the second decade of life. Metastatic lesions develop frequently, and about 20% of patients die as a consequence of metastasis. The thyroid carcinoma produces calcitonin (a hormone normally produced by the C cells of the thyroid gland). The carcinoma can be detected by evaluating plasma levels of this hormone.

Pheochromocytoma is a benign neoplasm that generally develops in ganglia around the adrenal glands. The tumor is often bilateral and is responsible for night sweats, high blood pressure, and episodes of severe diarrhea. It generally develops in the second or third decade of life. The pheochromocytoma induces increased urinary levels of epinephrine and other substances. Other findings in this syndrome have included cutaneous pigmentation and a host of skeletal abnormalities.

Early diagnosis of this syndrome is imperative because of the high malignant potential of the thyroid carcinoma. Some authors recommend preventive thyroidectomy when this syndrome is diagnosed so that the development of carcinoma is avoided. The neuromas of the oral mucosa may be the earliest visible manifestation of this syndrome.

Neurofibromatosis of Von Recklinghausen: Neurofibromatosis of von Recklinghausen, also called von Recklinghausen disease, has an autosomal-dominant inheritance pattern and is probably a disorder of neural crest origin. The gene for this syndrome maps to the long arm of chromosome 17 region 11.2 (17q11.2). Several varieties exist; however, only the classic form is described here.

Multiple neurofibromas, which appear as papules and growths of various sizes, are seen on the facial skin, especially the eyelids. The tumors can arise anywhere, including the oral cavity, and can be present at birth or develop early in life, increasing in number and size at puberty. Malignant transformation of the neurofibromas occurs in an estimated 3% to 15% of patients with neurofibromatosis. Neurofibromas also develop in the central nervous system, eyes, ears, viscera, and intraosseous locations. Mental disability is observed occasionally, and multiple skeletal anomalies are common.

Oral involvement is seen in about 10% of patients and is characterized by single or multiple tumors at any location in the oral mucosa, the most frequent being the lateral borders of the tongue. Gingival neurofibromas can also occur in these patients (Figure 6-32), and intramandibular neurofibromas have been reported and present as radiolucencies in the mandible.

Café au lait (the color of coffee with milk) pigmentation of skin is present from the first decade of life in 90% of patients with neurofibromatosis. This pigmentation is quite marked in the axilla and can also affect other areas of the skin. Café au lait skin pigmentation generally precedes the development of the neurofibromas.

Peutz-Jeghers Syndrome: Autosomal-dominant inheritance characterizes the Peutz-Jeghers syndrome. The gene for this syndrome maps to the short arm of chromosome 19 region 13.3 (19p13.3). It consists of multiple melanotic macular pigmentations of the skin and mucosa, which are associated with gastrointestinal polyposis. The pigmentations occur around the eyes, nose, and mouth (Figure 6-33). These macules are a few millimeters in diameter and vary in number and degree of pigmentation. They tend to diminish with age. Intraorally larger areas of pigmentation are observed on the lips and buccal mucosa of about 98% of affected patients.

Pigmentation of the hands, nasal mucosa, and eyes can also occur. The intestinal polyps are hamartomas (an abnormal growth of normal tissue in its normal location). They develop mostly in the small intestine; only rarely do they undergo malignant transformation.

White Sponge Nevus: Autosomal-dominant inheritance with complete penetrance characterizes white sponge nevus (also called Cannon disease, or familial white folded mucosal dysplasia). The cause of white sponge nevus is a mutation in the mucosal keratin pair K4 or K13. The disorder can be present at birth or develop around puberty. Clinically it is characterized by a white, corrugated, soft, folding oral mucosa. The buccal mucosa is always affected, and in most patients the lesions are bilateral. A thick layer of keratin, which at times desquamates and leaves a raw mucosal surface, produces the whitening. Other areas of the oral mucosa can also be affected, but the free gingiva is spared.

Amelogenesis Imperfecta: A group of inherited conditions affecting the enamel of teeth and having no associated systemic defects characterizes amelogenesis imperfecta. Witkop and Sauk classified amelogenesis imperfecta into four types:

The hypoplastic type of amelogenesis imperfecta is characterized by tooth enamel that does not develop to a normal thickness because of failure of the ameloblasts to lay down enamel matrix properly. On radiographs the abnormal enamel contrasts normally with dentin. Several varieties of this type of amelogenesis imperfecta are further classified according to their clinical presentation: pitted, local, smooth, rough, and enamel agenesis. Combined with the clinical appearance, the classification also includes the inheritance pattern. Thus an autosomal-dominant and an autosomal-recessive variety exist for the local hypoplastic type. Among this group of enamel defects, the most frequent one is the pitted autosomal-dominant variety (Figure 6-34), which is characterized by teeth that have random pits on the enamel. The size of these pits varies from pinpoint to pinhead, and the pits are observed mostly on the labial and buccal surfaces of the permanent teeth. The pits are frequently arranged in rows or columns or both. Occasionally more than one tooth has a normal clinical appearance. The gene for the local hypoplastic autosomal-dominant type of amelogenesis imperfecta maps to the long arm of chromosome 4 (4q11-13).

An enamel of normal thickness that is poorly calcified characterizes the hypocalcified type of amelogenesis imperfecta (Figure 6-35). Two varieties of hypocalcified amelogenesis imperfecta exist: (1) an autosomal-dominant variety, and (2) an autosomal-recessive variety. The autosomal-recessive pattern is more severe in its clinical manifestations. At eruption teeth present yellow-to-orange enamel that is very soft and rapidly lost, leaving exposed dentin. On radiographs the enamel has a moth-eaten appearance and is less radiopaque than dentin. Cervical enamel is better calcified and generally remains on the crown. This type of amelogenesis imperfecta is frequently associated with an anterior open bite.

An enamel of mottled appearance but normal thickness characterizes the hypomaturation type of amelogenesis imperfecta. This type of amelogenesis imperfecta is composed of large amounts of enamel matrix; therefore the enamel is softer than normal. With pressure the tip of an explorer will penetrate the enamel. The basic defect seems to be in the enamel rod sheath. The enamel chips easily from the crown. On radiographs it has almost the same radiodensity as dentin. Four varieties of the hypomaturation type of amelogenesis imperfecta exist; however, only the snowcapped type is discussed here.

A type of hypomaturation amelogenesis imperfecta, called snow-capped amelogenesis imperfecta, apparently has an X-linked recessive inheritance pattern in some families and an autosomal-dominant pattern in others. Clinically both varieties are identical and are characterized by a hypomaturation of the surface enamel of the occlusal third of all the teeth of both dentitions. The maxillary teeth are more severely affected with this whitish discoloration (Figure 6-36). The enamel in these areas is of regular hardness and smooth. It does not fracture or chip from the crown.

Its association with taurodontic teeth (described later in this chapter and also in Chapter 5) characterizes the hypoplastic-hypomaturation type of amelogenesis imperfecta. The thin enamel is yellow to brown and pitted. On radiographs the enamel has a radiodensity similar to dentin, and single-rooted teeth have large pulp chambers.

It is generally not easy to diagnose the exact type of amelogenesis imperfecta clinically because of the frequent similarity among different varieties. The mode of inheritance must be kept in mind, and an accurate family history should always be taken. Recently different mutations in several genes have been identified as responsible for some types of amelogenesis imperfecta; the genes are: AMELX, AMELY, ENAM, AMELOBLASTIN, TUFTELIN, ENAMELYSIN, KALLIKREIN, and DLX3.

The prevalence of all forms of amelogenesis imperfecta in the United States has been estimated at 1:15000.

Dentinogenesis Imperfecta: Dentinogenesis imperfecta is usually subdivided into three types. Type one is dentinogenesis imperfecta associated with osteogenesis imperfecta (previously described in this chapter). The other two types are not associated with osteogenesis imperfecta. The teeth in all three types have a similar clinical appearance.

Dentinogenesis imperfecta type II is also known as hereditary opalescent dentin. The inheritance pattern is autosomal dominant, and the gene maps to the long arm of chromosome 4 (4q13-21). Teeth have bulbous crowns with a color that varies from opalescent brown to brownish-blue (Figure 6-37). The primary teeth are usually affected more severely than the permanent teeth. Twenty percent of patients have enamel hypoplasia as well. The dentin is very soft, which produces chipping of enamel that results in tooth attrition. Occasionally this attrition can cause the teeth to be worn down to the alveolar process. Radiographically no pulp chambers or root canals are seen (Figure 6-38). Roots are short and thin with periapical radiolucencies. Patients may lose teeth prematurely because of complications produced by the attrition and the short roots. The basic defect lies with the odontoblasts, which lay down an abnormal matrix and then degenerate. Cells derived from the dental pulp, which lay down abnormal dentin, later replace these odontoblasts.

Dentin Dysplasia: Dentin dysplasia is subdivided into type I (radicular dentin dysplasia) and type II (coronal dentin dysplasia).

Hypohidrotic Ectodermal Dysplasia: Hypohidrotic ectodermal dysplasia represents a genetic heterogeneity. Although in the majority of families it is inherited as an X-linked recessive trait, in some families it is inherited as an autosomal-recessive trait. The clinical manifestations for both the X-linked and autosomal-recessive forms are identical. The gene for the X-linked variety of this syndrome maps to the long arm of the X chromosome region 12-13.1 (Xq12-13.1). The autosomal-recessive variety maps to the long arm of chromosome 2 (2q11-q13).

This entity represents the most severe form of ectodermal dysplasia. Its major components are hypodontia (partial anodontia), hypotrichosis (less than the normal amount of hair), and hypohidrosis (abnormally diminished secretion of sweat). Affected children are born without lanugo (body hair present at birth), and many have episodes of fevers of unknown causes because of the almost complete lack of sweat glands. Some patients die of hyperthermia (greatly increased body temperature) after prolonged exposure to the sun or heavy exercise. The clinical characteristics may not be apparent until the second year of life.

The facies is quite typical, with marked frontal bossing, depressed nasal bridge (saddle nose), protuberant lips, and almost complete lack of scalp hair. The hair that is present is usually blond, short, fine, and stiff. The skin is soft, thin, and very dry. Sebaceous glands are also lacking. Linear wrinkles and increased pigmentation are seen around the eyes and mouth. The eyelashes and eyebrows are often missing entirely. After puberty the beard generally is normal, but axillary and pubic hair is scanty.

The oral manifestations of hypohidrotic ectodermal dysplasia consist of hypodontia or rarely anodontia. When present, incisors and canines have small, conical crowns (Figure 6-41). The alveolar bone is formed only when teeth are present; therefore patients lacking alveolar processes have loss of vertical dimension with markedly protruding lips. There may also be partial lack and aplasia of minor salivary glands in the buccal, labial, and lower respiratory tract mucosa.

Female carriers of the X-linked form of hypohidrotic ectodermal dysplasia have minor clinical manifestations such as thin and slightly sparse hair, cone-shaped teeth, hypodontia, and variable degrees of reduced sweating. This is in accordance with the Lyon hypothesis of variability of expression.

Hypophosphatasia: The inheritance pattern of hypophosphatasia is autosomal recessive. The gene for this syndrome maps to the short arm of chromosome 1 regions 36.1-34 (1p36.1-34). The basic defect in this condition is a decrease in serum alkaline phosphatase levels with increased urinary and plasma levels of phosphoethanolamine. Alkaline phosphatase participates in the process of calcification of bone and cementum; therefore these two tissues will be altered in patients with hypophosphatasia. Agenesis or abnormal formation of cementum in these patients leads to spontaneous premature shedding of primary teeth, especially mandibular incisors (Figure 6-42). Teeth are exfoliated without evidence of periodontal or gingival disease. The primary molars and permanent teeth are rarely if ever affected, which is probably associated with the greater mechanical fixation resulting from the larger size of their roots. The total lack of cementum observed in exfoliated teeth implies a lack of periodontal fiber attachment, with consequent exfoliation of single-rooted teeth. The most important alteration in this syndrome is the improper formation of mature bone. Therefore individuals who survive the neonatal period experience rachitic-like changes such as bowing of legs and multiple fractures.

Hypophosphatemic Vitamin D–Resistant Rickets: Hypophosphatemic vitamin D–resistant rickets, which is quite common, has an X-linked dominant inheritance pattern and is the result of a mutation in the PHEX gene. It consists of low serum levels of phosphorus, which are produced by low absorption of inorganic phosphate in the renal tubules, rickets or osteomalacia, resistance to treatment with usual doses of vitamin D, and a lack of other abnormalities. Affected individuals generally are of short stature and have bowlegs, especially if the condition is present from childhood. Adult-onset forms also exist, and the clinical manifestations in these patients are minor or even lacking, with the exception of low serum levels of inorganic phosphate.

The characteristic radiographic oral findings are large pulp chambers with very long pulp horns. In addition, the dentin exhibits pronounced cracks that extend to the dentinoenamel junction. These cracks induce fracture of the enamel with microexposure of the pulp and subsequent pulpal infection. Eventually, with the progress of the infectious inflammatory pulpal disease, periapical abscess formation occurs. Gingival abscesses are also frequent. Regional lymphadenitis accompanies these processes.

Pegged Or Absent Maxillary Lateral Incisors: The inheritance pattern of pegged or absent maxillary lateral incisors is generally autosomal dominant with variable expressivity. The lateral incisor can be small, peg shaped, or congenitally lacking, either unilaterally or bilaterally (Figure 6-43). Both primary and secondary dentitions can be affected, but mostly the latter. This condition has a prevalence of 1% to 3% in the white population and about 7% in Asians. In addition, the premolar teeth are congenitally lacking in 10% to 20% of affected individuals.

Taurodontism: Taurodontism is a genetic heterogeneous condition with dominant and recessive inheritance. It is characterized by very large, pyramid-shaped molars with large pulp chambers (Figure 6-44). (Taurodontic teeth [bull teeth] are also described in Chapter 5.) Taurodontism is most frequent among Native Americans, including Inuits. The furcation of the roots is displaced apically, and these teeth are classified according to the degree of furcation displacement. It is frequently found in Klinefelter syndrome (XXY) and is associated with many other syndromes as well.