eMedicine Specialties > Dermatology > Malignant Neoplasms

Nevoid Basal Cell Carcinoma Syndrome

Author: Daniel Berg, MD, FRCP(C), Professor of Dermatology, Director of Dermatologic Surgery, University of Washington School of Medicine
Contributor Information and Disclosures

Updated: Mar 12, 2009

Introduction

Background

The autosomal dominant nevoid basal cell carcinoma syndrome (NBCCS) represents a series of multiorgan abnormalities known to be the consequence of abnormalities in the PTCH gene. The syndrome has been documented for 50 years, but more recent developments in molecular genetics have dramatically increased understanding of its pathophysiology (see Causes).

Pathophysiology

Multiple organ systems may be impacted in nevoid basal cell carcinoma syndrome (NBCCS). Abnormalities of the skin, the skeletal system, the genitourinary system, and the CNS are the most common. A variety of less common neoplasms are also associated.

Frequency

International

The approximate prevalence is reported to be 1 case per 56,000-164,000 population. The prevalence is likely to be considerably higher in individuals younger than 20 years who present with basal cell carcinomas (BCCs).

Mortality/Morbidity

Morbidity and premature mortality are primarily related to the development of skin cancers and other tumors associated with the syndrome. Actual mortality rates are unavailable; morbidity from multiple skin cancers and their treatment may be severe.

Race

The syndrome is found in all races. However, a definite but smaller percentage of African Americans present with skin cancer and have fewer skin cancers than whites who are affected. This decreased number of skin cancers, a diagnostic hallmark, may account for the comparatively fewer African Americans ascertained in reviews of the syndrome. Full expression of the non – skin cancer features of the syndrome is found in African Americans.

Sex

Men and women are affected equally. The male-to-female ratio is estimated to be 1:1.3.

Age

The disease is present (inherited) at birth and most commonly manifests itself with either BCCs (usually multiple) occurring at a young age (third decade or earlier) or odontogenic keratocysts presenting in the second or third decade.

Other incidental findings, such as cleft lip, or asymptomatic findings, such as hypertelorism, may be noticed earlier, but these features may not lead to the diagnosis until the development of more specific findings. Findings usually seen in the syndrome, such as jaw cysts, BCCs, calcification of the falx, and ovarian fibromas, develop more commonly with increasing age in the individual who is affected. Some findings are present earlier in childhood. Medulloblastoma, though a relatively less common manifestation of NBCCS, is a tumor of early childhood. Radiologic abnormalities, such as bifid ribs, or asymptomatic findings, such as palmar pits, may be present at a higher frequency in childhood; these findings may be helpful in making an early diagnosis.¹

Clinical

History

Many of the features of nevoid basal cell carcinoma syndrome (NBCCS) present as signs rather than symptoms. Symptoms are most likely related to the major findings.

• Cutaneous symptoms: Local invasion of an aggressive BCC may lead to pain or symptoms (eg, neurologic) related to local invasion. Metastasis is extremely rare.
• Neurologic symptoms: Medulloblastoma, a cerebellar tumor of young childhood, may present with neurologic symptoms in a child who is affected.
• Genitourinary symptoms: Ovarian fibromas are usually asymptomatic, but they may present with pain secondary to torsion.
• Dental symptoms: Odontogenic keratocysts (also called keratocystic odontogenic tumors) may be asymptomatic, or they may manifest as jaw pain or abnormal dentition.

Physical

Despite the recent understanding of the underlying genetic basis of nevoid basal cell carcinoma syndrome (NBCCS), the diagnosis remains clinical. Kimonis et al have suggested the following diagnostic criteria to help the clinician. Although not absolute, these criteria help guide the clinician in choosing laboratory evaluation for both diagnostic purposes and ongoing surveillance. Clinicians must remember that some of the findings listed may present at different ages; therefore, ongoing surveillance with respect to diagnosis may be needed.

Diagnosis of NBCCS is made in the presence of 2 major criteria or 1 major and 2 minor criteria. The major criteria consist of the following: (1) more than 2 BCCs or 1 BCC in patients younger than 20 years; (2) odontogenic keratocysts of the jaw (proven by histologic analysis); (3) 3 or more palmar or plantar pits; (4) bilamellar calcification of the falx cerebri; (5) bifid, fused, or markedly splayed ribs; and (6) first-degree relative with NBCCS.

The minor criteria include the following: (1) macrocephaly; (2) congenital malformations, such as cleft lip or palate, frontal bossing, coarse facies, and moderate or severe hypertelorism; (3) other skeletal abnormalities, such as Sprengel deformity, marked pectus deformity, and marked syndactyly of the digits; (4) radiologic abnormalities, such as bridging of the sella turcica, vertebral anomalies, modeling defects of the hands and feet, or flame-shaped lucencies of the hands and the feet; and (5) ovarian fibroma or medulloblastoma.

Several studies have documented the incidence of the various features found in the syndrome.^2,3,4,5,6

• Characteristic facies occur due to increased calvarial size. Other contributing features include a broadened nasal root, frontal and biparietal bossing, mild hypertelorism, and an exaggerated length of the mandible.
• Ocular findings include congenital blindness due to corneal opacity and cataract or glaucoma, occurring in as many as 10-15% of patients. Strabismus (exotropia) may be seen.
• Cleft lip or palate occurs in 3-5% of patients.
• BCCs are the most common finding in the syndrome. Of whites older than 40 years, 97% had BCCs. Tumors are usually multiple. BCCs are most common on the face, the neck, and the upper part of the trunk, that is, in sun-exposed areas, but they are also increased in relatively sun-protected areas. Although some lesions may become aggressive, most are not. Tumors largely begin to appear between puberty and age 35 years, but they may appear at a younger age. In 1997, Kimonis et al found that 50% of whites had their first BCC by age 21.5 years and 90% had it by age 35 years.⁶ Lesions may present as any kind of clinical or histologic BCC; however, some lesions may be small and resemble milia, small nevi, tags, or hemangiomas. Milia may be seen in as many as 30% of patients with NBCCS.

• Asymmetric palmar and/or plantar pits are seen in 65-87% of all people with NBCCS. When they do develop, they often do so early in life, being found in as many as 80% of patients younger than 10 years. Thus, they may be a helpful early criterion for the diagnosis of NBCCS. More than 3 pits should be noted because the relevance of 1 or 2 pits may not be diagnostic.
• Odontogenic keratocysts are seen in 74-80% of patients. They usually begin to develop in the first decade (after age 7 y), with the peak incidence in the second and third decades, which is younger than seen with isolated odontogenic cysts. They are more common in the mandible than in the maxilla. They are usually asymptomatic, but they may cause pathologic fracture, swelling, loose teeth, or displacement of developing permanent teeth.
• Medulloblastoma (malignant tumors of the cerebellum) occur in 1-4% of patients. They present in childhood, with the greatest risk from birth to 3 years, although cases have been reported as late as 7 years.
• Skeletal abnormalities include polydactyly of the hands or the feet, hallux valgus, pectus excavatum or pectus carinatum, and syndactyly of the second and third fingers. Kyphoscoliosis may also be more common or more severe in NBCCS. Sprengel deformity of the shoulder occurs in 5-10% of patients. A short fourth metacarpal may be seen with increased frequency, although as many as 10% of healthy persons also have this sign.
• Genitourinary system findings include bilateral calcified ovarian fibromas, which are found in 14-24% of women; these are often asymptomatic and rarely become malignant. Men may have associated cryptorchidism or gynecomastia and reduced body hair, although these findings have not been confirmed by recent studies.
• Cardiac findings are less common, but an increased risk of cardiac fibroma may be present. Cardiac fibroma usually presents in children or young adults.
• Other tumors, including fibrosarcoma, rhabdomyosarcoma, and meningioma, may be increased in frequency in persons with NBCCS.

Causes

Nevoid basal cell carcinoma syndrome (NBCCS), also known as basal cell nevus syndrome (BCNS), is an autosomal dominant syndrome caused by mutations in the PTCH (patched) gene found on chromosome arm 9q. The disease has complete penetrance and variable expressivity. Although clinical features vary more among families than within families, no clear-cut link exists between specific mutations and phenotype. Approximately one third of cases are new mutations.

• Genetics of NBCCS^7,8,9,10,11
  • First elucidated in fruit flies, the protein product of the patched gene is important in determining segment polarity of wings and limbs (anterior-posterior relationships in developing embryos). In mammals, the patched gene (PTCH) is an important inhibitor in the so-called hedgehog (HH) signaling pathway, whose downstream proteins can lead to cell growth. PTCH is frequently mutated on 1 allele in sporadic BCCs, and, according to Epstein, "upregulation of HH signaling is the pivotal abnormality in all BCCs."¹² .
  • Its wide-reaching activity accounts for the myriad of findings in patients with NBCCS.
  • Ultraviolet (UV) light exposure appears to be an important cofactor. BCCs are much more common in sun-exposed areas and are much more common in whites with the syndrome. Nevertheless, molecular genetic studies looking for UV-related mutations in BCCs obtained from patients with NBCCS leave the possibility that agents other than UV-B may cause alterations to the gene.¹³
  • Patients are particularly sensitive to ionizing radiation (XRT), and reports of multiple BCCs in the radiation portal developing in patients treated with XRT for medulloblastoma exist. Reports of more aggressive BCCs occurring in sites of previous XRT for BCC also exist. Radiobiologic studies on fibroblasts suggest an abnormal response to radiation in fibroblasts obtained from patients with NBCCS.

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