Hamartoneoplastic Syndromes

Key points

  • Hamartomas are benign malformations presenting as an excess of normal tissue within the tissue of origin.

  • Although some syndromes show a clear genetic transmission, the underlying reasons for many of these abnormalities are not fully understood.

  • The hamartomatous syndromes are usually associated with other neural, cutaneous, skeletal, or developmental malformations.

  • The orofacial signs and symptoms often precede systemic displays of the syndromes. Thus, oral and maxillofacial surgeons are in a unique position to identify and aid in diagnosing many of the hamartoneoplastic syndromes.

Gorlin syndrome (nevoid basal cell carcinoma syndrome)

  • Genetics

    • Nevoid basal cell carcinoma syndrome (NBCCS) includes more than 100 signs and symptoms involving the skin, central nervous system, and skeletal system. The inheritance pattern is autosomal dominant. It is caused by a chromosome 9q22 microdeletion. Forty percent of new mutations arise spontaneously and the trait has complete penetrance with a widely varied expressivity. In general, this syndrome and many others are noted to support the double-hit theory, the first hit being genetics and the second hit being some environmental insult.

  • Clinical features

    • Also known as Gorlin-Goltz syndrome, NBCCS includes multiple symptoms of the skeletal system, central nervous system, and skin. Manifestations commonly include nevoid basal cell carcinomas, odontogenic keratocysts (OKCs), skeletal anomalies, and bifid ribs.

    • People affected with NBCCS tend to be very tall, and 70% of patients have a characteristic facies caused by enlarged occipitofrontal circumference. Ocular hypertelorism is also, along with prominent supraorbital ridges, a broad nasal base, and mandibular prognathism. Cleft lip and/or palate occur in about 5% of cases. Congenital blindness may also occur.

    • Skin involvement includes nevoid basal cell carcinomas. In contrast with classic basal cell carcinomas, these lesions tend to appear at an early age (before 35 years old), in multiples, and on areas of skin not exposed to the sun. Palmar/planar pits present along the ventral surfaces of hands and feet in more than half of cases, with a higher frequency among elderly affected individuals.

    • Reproductive system abnormalities can occur, such as bilateral calcifying ovarian fibromas or ovarian fibrosarcoma.

    • Calcification of the falx cerebri and tentorium cerebelli is common, as well as calcification of the dura and the pia mater and the choroid plexus. Although neurologic abnormalities are frequent, the incidence of intellectual disability is around 3%.

    • Common skeletal abnormalities include bifid, missing, splayed, fused, or hypoplastic ribs. Kyphoscoliosis may be present along with spinal bifida occulta. Lytic pseudocystic bone lesions are usually seen in the bones of the feet and hands. They can also affect the arms, legs, pelvis, and skull.

    • As mentioned earlier, odontogenic keratocysts of the jaw are often the first clinically detected feature, and 85% of cases are affected before the third decade of life. Originating from the remnants of the dental lamina, the OKCs are large, expansile, and generally asymptomatic. However, the cysts may be associated with an unerupted tooth causing cortical expansion, tooth mobility, and displacement and invasion of nearby structures. The mandible is 3 times more likely to be affected than the maxilla, but OKCs can occur in both jaws simultaneously. The posterior molar/ramus area is the most common site to be affected in the mandible and the second molar region is the most common site of the maxilla. OKCs may present as multilocular or unilocular lesions, and the recurrence rate after surgical treatment is high, ranging from 30% to 60%.

    • Diagnosis of the OKC is normally done from a histologic sample of the lining. Two types of stratified squamous epithelium can line OKCs: parakeratinized or, more rarely, the orthokeratinized type. Also typically displayed are a well-defined basal epithelial layer, palisaded nuclei, no rete ridges, and prominent epithelial rests. Inflammatory cells are commonly found in the underlying connective tissue. Syndromic OKCs have a higher rate of satellite cysts. Ameloblastoma and squamous cell carcinomas of the jaw can, rarely, arise from OKCs.

  • Differential diagnosis

    • Diffuse osteoma cutis, basaloid follicular hamartomas (associated with myasthenia gravis), Bazex syndrome, Rombo syndrome, multiple seborrheic keratoses in patients with adenocarcinoma. Multiple jaw cysts may be mistaken for dentigerous cysts or isolated OKCs. Severe calcifications of many organs may also suggest pseudohypoparathyroidism.

  • Treatment considerations for the oral and maxillofacial surgeon

    • OKCs are typically the first presenting feature of the syndrome so radiographic examination of skull and jaws is indicated. Biopsy of the skin lesions confirms clinical presentation of nevoid basal cell carcinomas, whereas OKCs may be distinguished histologically. OKCs associated with NBCCS tend to develop multiple new cysts and may be confused with recurrence of previous lesions. Because syndromic OKCs present at an earlier age than sporadic cysts, with the multiplicity of lesions and potential for recurrence, management by the maxillofacial surgeon continues into adulthood because lifelong follow-up is anticipated ( Figs. 1 and 2 ).

      Fig. 1
      ( A , B ) Panoramic radiographs of siblings with multiple OKCs as seen in Gorlin-Goltz syndrome.

      Fig. 2
      Multiple basal cell nevi in a patient with Gorlin syndrome.
      ( Courtesy of D. DeLuke, DDS, MBA, Richmond, VA.)

Gorlin syndrome (nevoid basal cell carcinoma syndrome)

  • Genetics

    • Nevoid basal cell carcinoma syndrome (NBCCS) includes more than 100 signs and symptoms involving the skin, central nervous system, and skeletal system. The inheritance pattern is autosomal dominant. It is caused by a chromosome 9q22 microdeletion. Forty percent of new mutations arise spontaneously and the trait has complete penetrance with a widely varied expressivity. In general, this syndrome and many others are noted to support the double-hit theory, the first hit being genetics and the second hit being some environmental insult.

  • Clinical features

    • Also known as Gorlin-Goltz syndrome, NBCCS includes multiple symptoms of the skeletal system, central nervous system, and skin. Manifestations commonly include nevoid basal cell carcinomas, odontogenic keratocysts (OKCs), skeletal anomalies, and bifid ribs.

    • People affected with NBCCS tend to be very tall, and 70% of patients have a characteristic facies caused by enlarged occipitofrontal circumference. Ocular hypertelorism is also, along with prominent supraorbital ridges, a broad nasal base, and mandibular prognathism. Cleft lip and/or palate occur in about 5% of cases. Congenital blindness may also occur.

    • Skin involvement includes nevoid basal cell carcinomas. In contrast with classic basal cell carcinomas, these lesions tend to appear at an early age (before 35 years old), in multiples, and on areas of skin not exposed to the sun. Palmar/planar pits present along the ventral surfaces of hands and feet in more than half of cases, with a higher frequency among elderly affected individuals.

    • Reproductive system abnormalities can occur, such as bilateral calcifying ovarian fibromas or ovarian fibrosarcoma.

    • Calcification of the falx cerebri and tentorium cerebelli is common, as well as calcification of the dura and the pia mater and the choroid plexus. Although neurologic abnormalities are frequent, the incidence of intellectual disability is around 3%.

    • Common skeletal abnormalities include bifid, missing, splayed, fused, or hypoplastic ribs. Kyphoscoliosis may be present along with spinal bifida occulta. Lytic pseudocystic bone lesions are usually seen in the bones of the feet and hands. They can also affect the arms, legs, pelvis, and skull.

    • As mentioned earlier, odontogenic keratocysts of the jaw are often the first clinically detected feature, and 85% of cases are affected before the third decade of life. Originating from the remnants of the dental lamina, the OKCs are large, expansile, and generally asymptomatic. However, the cysts may be associated with an unerupted tooth causing cortical expansion, tooth mobility, and displacement and invasion of nearby structures. The mandible is 3 times more likely to be affected than the maxilla, but OKCs can occur in both jaws simultaneously. The posterior molar/ramus area is the most common site to be affected in the mandible and the second molar region is the most common site of the maxilla. OKCs may present as multilocular or unilocular lesions, and the recurrence rate after surgical treatment is high, ranging from 30% to 60%.

    • Diagnosis of the OKC is normally done from a histologic sample of the lining. Two types of stratified squamous epithelium can line OKCs: parakeratinized or, more rarely, the orthokeratinized type. Also typically displayed are a well-defined basal epithelial layer, palisaded nuclei, no rete ridges, and prominent epithelial rests. Inflammatory cells are commonly found in the underlying connective tissue. Syndromic OKCs have a higher rate of satellite cysts. Ameloblastoma and squamous cell carcinomas of the jaw can, rarely, arise from OKCs.

  • Differential diagnosis

    • Diffuse osteoma cutis, basaloid follicular hamartomas (associated with myasthenia gravis), Bazex syndrome, Rombo syndrome, multiple seborrheic keratoses in patients with adenocarcinoma. Multiple jaw cysts may be mistaken for dentigerous cysts or isolated OKCs. Severe calcifications of many organs may also suggest pseudohypoparathyroidism.

  • Treatment considerations for the oral and maxillofacial surgeon

    • OKCs are typically the first presenting feature of the syndrome so radiographic examination of skull and jaws is indicated. Biopsy of the skin lesions confirms clinical presentation of nevoid basal cell carcinomas, whereas OKCs may be distinguished histologically. OKCs associated with NBCCS tend to develop multiple new cysts and may be confused with recurrence of previous lesions. Because syndromic OKCs present at an earlier age than sporadic cysts, with the multiplicity of lesions and potential for recurrence, management by the maxillofacial surgeon continues into adulthood because lifelong follow-up is anticipated ( Figs. 1 and 2 ).

      Fig. 1
      ( A , B ) Panoramic radiographs of siblings with multiple OKCs as seen in Gorlin-Goltz syndrome.

      Fig. 2
      Multiple basal cell nevi in a patient with Gorlin syndrome.
      ( Courtesy of D. DeLuke, DDS, MBA, Richmond, VA.)

Gardner syndrome

  • Genetics

    • Gardner syndrome (GS) has been found to be associated with the extracolonic manifestations of adenomatous polyposis of the colon (APC). The germline mutation associated with GS is localized to a gene on the long arm of chromosome 5. GS is present with APC with an incidence of 1 in 4000 to 1 in 12,000. Although the wide spectrum of extracolonic manifestations depicts the variable expressivity of the genotypic abnormality, GS represents a more complete phenotypic expression of the APC genotype. Spontaneous mutations can arise, because 30% of cases occur because of a new dominant mutation.

  • Clinical features

    • The classic presentation of GS is a collection of multiple intestinal polyps (adenomatosis), widespread osteomas and abnormalities of the facial skeleton, epidermoid cysts, and desmoid soft tissue tumors. Extracolonic features typically precede the intestinal polyposis. Although the early symptoms of APC are not well defined, soft tissue and other benign tumors in a child or adolescent may indicate the possible onset of GS followed by adenomas in the colorectal region.

    • Osteomas of the jaw are most often found throughout the facial bones and are slow growing and reach a limited size. Appearing with well-developed haversian systems on radiograph, the enostotic lesions may coalesce with other lesions. Other bones, such as the radius, ulna, and tibia, may be affected, and lesions appear as small osteomas with cortical hyperostosis.

    • Approximately 58% to 88% of all individuals affected by ACP-GS have characteristic bilateral lesions of the retina, known as congenital hypertrophy of the retinal pigment epithelium.

    • Skin lesions include epidermoid cysts, desmoid tumors, and fibrous hyperplasia. Epidermoid cysts are generally small, always benign, and occur in about half of cases of GS. They occur most often on the extremities, face, and scalp, typically manifesting in adolescence, and they precede the intestinal polyposis. Often unnoticed by patients, development of skin cysts may serve as an indication for further investigation for intestinal abnormalities. Desmoid tumors appear in 3.5% to 5.7% of patients, typically near other surgical sites such as the abdominal cavity. Desmoid tumors are rare in the general population, so discovery in a patient should lead to an investigation of the colon for other signs of GS.

    • Gastrointestinal system manifestations are required for diagnosis, and these multiple intestinal adenomatous polyps are at high risk for malignant transformation. By 30 years of age, 50% of patients show malignancy of a polyp, and as age advances the likelihood of malignancy is expected to reach 100%.

    • Beside multiple osteomas, other dental-osseous abnormalities occur in ∼17% of patients and include supernumerary teeth and impacted teeth, hypercementosis, root resorption, dentigerous cysts, and multiple complex odontomas. Odontomas tend to be in both the mandible and the maxilla, most frequently in the incisal-premolar area.

  • Differential diagnosis:

    • Multiple polyps of the colon can raise suspicion for juvenile polyposis of the colon, Turcot syndrome, Peutz-Jeghers syndrome (PJS), Cronkite-Canada syndrome, Torre-Muir syndrome, Cowden syndrome (CS), and Bannayan-Riley-Ruvalcaba syndrome.

  • Treatment considerations for the oral and maxillofacial surgeon

    • The role of the oral and maxillofacial surgeon is for early detection of GS. Extraintestinal manifestations are common, and 70% of all affected individuals have significant abnormalities detectable on a dental panoramic radiograph. Because intestinal lesion polyposis is often a late sequela, multiple facial bone and dental abnormalities should prompt further investigation for predictive testing of at-risk individuals to predict and identify children who may have inherited the GS or APC gene. Computed tomography images provide the necessary details of the osteomas, and are the preferred radiologic examination for the assessment of bone abnormalities. Osteomas that restrict mandibular function or affect cosmesis may require resection with risk for recurrence. Necessary exodontia should be approached with care because increased density of alveolar bone and possible loss of the periodontal space caused by hypercementosis may complicate the procedure ( Fig. 3 ).

      Fig. 3
      ( A ) Panoramic radiograph of multiple odontomas of the jaws. ( B ) Large bilateral osteomas in a patient with Garner syndrome. ( C ) Dense, compact bone from an osteoma of the mandible in a patient with Garner syndrome.
      ( Courtesy of [ A ] O. Erdoğan, DDS, PhD, Adana, Turkey; and [ B ] L. Eisenbud, DDS.)

Klippel-Trénaunay-Weber syndrome

  • Genetics

    • First reported in France in 1900, Klippel-Trénaunay syndrome (KTS) is a rare congenital disorder characterized by multiple large venous varicosities and malformations, capillary malformations, and cutaneous nevi and lymphatic abnormalities with hard and soft tissue hypertrophy. The diagnosis can be made by identification of two of the fundamental features of varicose veins, capillary malformation and hypertrophy of the affected limb. Although a genetic basis is suggested because of cases being reported occurring within particular families, the cause of this syndrome remains unknown. There are no direct hereditary factors, suggesting an inheritance on a multifactorial basis. One hypothesis states that the syndrome could result from a lethal gene that survives by mosaicism. The presumed disorder suggested is a developmental derangement of mesoderm, lending to arteriovenous malformations, intrauterine injury to the sympathetic ganglia and intermediolateral tract, and resultant dilation of microscopic arteriovenous anastomoses.

  • Clinical features

    • The classic presentation of KTS is a triad of abnormalities that includes varicose veins, capillary malformations, and hypertrophy of affected limbs. In addition, malformations of the venous valves may be seen. The vascular irregularities typically occur in the lower extremities because gravity assists venous drainage from the head and neck. These deep vein abnormalities can result in obstruction of normal venous flow and can lead to venous hypertension, development of varices, and hypertrophy of the limb.

    • Capillary malformations typically present as port-wine stains (PWSs). They are usually purple, macular, endothelium-lined vascular channels located in the superficial dermis. These lesions are nonproliferative, do not blanch, and typically do not resolve.

    • Limb hypertrophy in KTS is always associated with limb elongation leading to limb discrepancy. Excessive limb growth is both in length and girth, with hard tissue and soft tissue hypertrophy, and the growth rate is unpredictable, without regular rate or form. The soft tissues include increases in vascular tissue, muscle, and skin. Associated with the soft tissue hypertrophy is vascular hyperplasia and arteriovenous malformations.

    • Approximately 5% of KTS anomalies affect the head and neck and appear as orofacial anomalies with hard and soft tissue hypertrophy. As with the hypertrophy of the extremities, the tissues appear to be increased unilaterally and may spread throughout the maxilla, mandible, tongue, lips, cheek, and palate.

    • The excessively large varicosities seen in KTS are congenital lesions, and appear earlier than usual varicose veins, typically being seen when patients begin to ambulate. These abnormalities may be painful and tender, and can lead to fatigue, heaviness, and ulcerations. Aneurysms of deep veins may occur as a result of high pressure or vessel wall fragility. Other vascular deformities such as aplasia, phlebitis, and valvular incompetence can manifest.

    • Patients may have lymphatic abnormalities such as aplasia, hypoplasia, and extremity edema from congestion of the lymphatic system. Associated additional findings such as abdominal hemangioma, heart defects, syndactyly, polydactyly, oligodactyly, and macrodactyly have been reported in the literature. Complications from KTS can include cellulitis, thrombosis, emboli, disseminated intravascular coagulation, and neurologic disease.

  • Differential diagnosis

    • KTS should be distinguished from other congenital vascular anomalies like Parkes Weber syndrome, which is limb enlargement with a malformation and arteriovenous fistula.

    • Sturge-Weber syndrome (SWS) commonly presents with facial hemangiomas along with focal seizures, sensory and motor paralysis, calcifications of vessel walls, and visual field defects. Also included are neurofibromatosis, Beckwith-Wiedemann syndrome, and Maffucci syndrome.

  • Treatment considerations for the oral and maxillofacial surgeon

    • Addressing the facial asymmetry and esthetics is the main goal for the oral and maxillofacial surgeon. Lesions associated with KTS are associated with capillary fragility and tend to bleed easily. Prolonged bleeding may be expected, and significant preoperative hematological testing should be performed in patients with KTS to avoid possible postoperative bleeding problems. Lesions of KTS occur in the head and neck as unilateral enlargement, and may disrupt the dentoalveolar segment presenting as displaced teeth with malocclusion. Beyond the abnormal blood vessels, the literature also suggests defects in platelets, coagulation factors, and fibrin degradation products (FDP) contributing as systemic causes of bleeding. Thus, the preoperative tests requested should include FDP, antithrombin III, and specific factor XIII assay before performing any oral surgical procedures ( Figs. 4 and 5 ).

      Fig. 4
      Exophytic pedunculated growth arising from the gingiva on buccal side of the upper right molar teeth.
      ( From Bathi RJ, Agarwal N, Burde KN. Klippel-Trenaunay syndrome (angio osteohypertrophy syndrome): a report of 3 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;93(3):276–80; with permission.)

      Fig. 5
      Cutaneous and subcutaneous hemangioma of the lower third of the face with swelling of the lower lip and increased lower facial height.
      ( From Bathi RJ, Agarwal N, Burde KN. Klippel-Trenaunay syndrome (angio osteohypertrophy syndrome): a report of 3 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;93(3):276–80; with permission.)

Sturge-Weber syndrome

  • Genetics (including inheritance patterns and frequency)

    • Sturge-Weber Syndrome (SWS) is a neurocutaneous syndrome characterized by port-wine staining (PWS) in the skin of the face and leptomeningeal angiomatosis. SWS is generally proposed to be a result of genetic mosaicism; therefore, it arises spontaneously without family history. Precise population-based data do not exist for the prevalence or incidence of SWS, but the incidence of a PWS is estimated to be 0.3% in newborns, without evidence of a sex predilection. SWS is an embryologic anomaly and arises in utero when a vascular plexus fails to regress from the portion of neural tube that is destined to become facial skin, thereby causing angiomatosis of the leptomeninges.

  • Clinical features (including histology if relevant)

    • Dermal capillarovenous malformations, called PWSs, are made up of postcapillary venules within the dermis. They appear at birth on the face in 90% of patients, but may spread to neck, chest, and back. They start out as pink macules, but tend to darken and increase in thickness with age. As a disruption in the development of cephalic neuroectoderm, a distribution among the trigeminal nerve is seen, particularly the ophthalmic (V 1 ) division. These cutaneous abnormalities never regress spontaneously.

    • Congenital glaucoma is the most common presentation in a patient with a PWS with V 1 division involvement. Other ocular abnormalities include strabismus and choroidal vascular lesions. They show angiomatosis vascular hyperplasia, blanch with pressure, and can present in the oral cavity affecting the buccal mucosa, lips, and even the alveolar process, which can result in changes to the eruption pattern of teeth and malocclusion.

    • The characteristic angioma of the leptomeninges generally affects the temporal, parietal, or occipital areas and even possible involvement of the cerebral vascular system. If cutaneous lesions are lacking, the diagnosis of SWS is made from radiologic findings, including intracranial calcifications, which are likely to be caused by decreased blood flow in areas of pial angiomatosis.

    • Progressive neurologic deficits are present in 40% of patients. The presence of calcifications, atrophy, or seizures may suggest cognitive decline and need for surgical intervention. Other symptoms associated with SWS include hemiparesis, hemiplegia, cerebral atrophy, and angiomatosis of various other organs.

  • Differential diagnosis

    • KTS often occurs with SWS, suggesting a similar underlying disorder.

    • Coats disease involves telangiectasias of the retinal blood vessels and may involve other areas of the face. Congenital hemangiomas typically do not present as large as the PWS. A rare, hereditary form of vascular malformation presenting intraorally is the Osler-Weber-Rendu syndrome. Neurofibromatosis, Bannayan-Riley-Ruvalcaba syndrome, and Beckwith-Wiedemann syndrome should also be considered in a differential diagnosis.

  • Treatment considerations for the oral and maxillofacial surgeon

Jan 23, 2017 | Posted by in Oral and Maxillofacial Surgery | Comments Off on Hamartoneoplastic Syndromes
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