Nevoid basal-cell carcinoma syndrome

Overview

Nevoid Basal-Cell Carcinoma Syndrome (NBCCS), also known as Gorlin syndrome, is a rare, inherited disorder characterized by the development of multiple basal cell carcinomas (a type of skin cancer), jaw cysts, skeletal abnormalities, and a predisposition to various tumors. It is a multisystem disorder affecting the skin, bones, nervous system, and other organs. The syndrome was first described by Drs. Robert J. Gorlin and Robert W. Goltz in the 1960s.

NBCCS often presents in childhood or early adulthood and can vary significantly in severity even among affected members of the same family. Early diagnosis is critical to initiate appropriate surveillance and treatment, reduce cancer risk, and manage complications.

Causes

Nevoid Basal-Cell Carcinoma Syndrome is caused by mutations in the PTCH1 gene located on chromosome 9q22.3. This gene encodes the patched-1 protein, a key component of the Hedgehog signaling pathway, which plays a critical role in cell growth, development, and differentiation.

Mutations in PTCH1 lead to unregulated cell proliferation and tumor formation. In some cases, mutations in other genes such as SUFU and PTCH2 have also been implicated, particularly in patients with medulloblastomas.

The syndrome is inherited in an autosomal dominant pattern, meaning only one mutated copy of the gene is sufficient to cause the condition. However, about 20–30% of cases are due to new (de novo) mutations, with no prior family history.

Symptoms

The symptoms of NBCCS vary widely among individuals. Some may have only a few signs, while others may experience numerous complications. The most common and defining features include:

Cutaneous Manifestations

• Multiple basal cell carcinomas (BCCs): Typically develop during adolescence or early adulthood; may occur on sun-exposed and non-sun-exposed areas

• Palmar and plantar pits: Small depressions in the skin of the hands and feet, often visible by adolescence

• Skin tags or milia: Common, especially in children

Craniofacial and Skeletal Abnormalities

• Keratocystic odontogenic tumors (KCOTs): Benign but locally aggressive cysts in the jaw, often requiring surgical removal

• Macrocephaly: Enlarged head circumference

• Frontal bossing: Prominent forehead

• Hypertelorism: Widely spaced eyes

• Rib anomalies: Bifid, fused, or missing ribs

• Scoliosis: Curvature of the spine

Neurologic and Tumor-Related Features

• Medulloblastoma: A malignant brain tumor, particularly in children with SUFU mutations

• Intracranial calcifications: Especially of the falx cerebri (midline brain structure)

Other Features

• Ovarian fibromas: Benign tumors in females

• Cardiac fibromas: Rare but potentially serious heart tumors

• Cleft lip or palate: Less common but observed in some cases

Diagnosis

NBCCS is diagnosed based on clinical criteria, family history, and confirmed through genetic testing. Diagnosis typically requires the presence of two major criteria or one major plus two minor criteria.

Major Diagnostic Criteria

• More than two basal cell carcinomas or one BCC before age 20

• Keratocystic odontogenic tumors of the jaw (confirmed histologically)

• Palmar or plantar pits (three or more)

• Bilamellar calcification of the falx cerebri

• Medulloblastoma (especially in children)

• First-degree relative with NBCCS

Minor Diagnostic Criteria

• Congenital skeletal anomalies (e.g., bifid ribs, scoliosis)

• Macrocephaly

• Cleft lip or palate

• Ovarian or cardiac fibromas

• Lymphomesenteric cysts

• Ocular abnormalities (e.g., cataracts, coloboma, strabismus)

Confirmatory Testing

• Genetic testing: Detection of a pathogenic mutation in PTCH1, SUFU, or PTCH2 confirms the diagnosis

• Imaging: X-rays, CT, or MRI to detect jaw cysts, rib abnormalities, or brain calcifications

• Dermatologic examination: For early identification of BCCs and skin pits

• Dental panoramic X-rays: Recommended by age 8 to detect jaw cysts early

Treatment

There is no cure for NBCCS, so treatment focuses on surveillance, early detection of complications, and symptom management. A multidisciplinary team including dermatologists, dentists, geneticists, and surgeons is often required.

Skin Cancer Management

• Excision of basal cell carcinomas: Standard treatment for accessible or problematic lesions

• Topical therapies: Imiquimod or 5-fluorouracil for superficial BCCs

• Photodynamic therapy: A non-invasive option for multiple lesions

• Systemic hedgehog pathway inhibitors: Such as vismodegib or sonidegib for patients with advanced or multiple BCCs

Jaw Cyst Management

• Surgical removal: Often necessary due to recurrence and potential for bone destruction

• Regular dental surveillance: Panoramic X-rays every 12–18 months

Tumor Surveillance

• Brain MRI: Especially in children at risk for medulloblastoma

• Pelvic ultrasound: To monitor for ovarian fibromas in females

• Echocardiogram: If cardiac fibromas are suspected

Genetic Counseling

• Essential for affected individuals and family members

• Discusses inheritance risks and prenatal testing options

Prognosis

The prognosis for individuals with Nevoid Basal-Cell Carcinoma Syndrome is generally favorable, especially with early diagnosis and regular surveillance. Most basal cell carcinomas are slow-growing and treatable, although the potential for multiple lesions throughout life can significantly impact quality of life and cosmetic appearance.

Patients with SUFU mutations have a higher risk of developing medulloblastomas during childhood, which may influence overall prognosis and treatment strategy. Early detection and treatment of complications particularly jaw cysts, skin cancers, and tumors, are critical to maintaining good long-term outcomes.

With appropriate medical care, many individuals with NBCCS can lead full, productive lives. Lifelong follow-up and preventive strategies play a key role in minimizing morbidity associated with this multisystem disorder.