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Gorlin Syndrome - PTCH1

Clinical Features

Gorlin Syndrome or Basal Cell Nevus Syndrome (BCNS) is characterized by the development of multiple basal cell carcinomas (usually manifesting between the 2nd and 4th decade) and / or multiple jaw keratocyst. However, multiple basal cell carcinomas can already develop in childhood / adolescence. 

A large number of patients have a characteristic appearance with macrocephaly, frontal bossing, hypertelorism, and palmar-plantar pits.  Skeletal malformation - such as fused or bifid ribs, scoliosis- are common.

Further findings include ectopic calcification of the central nervous system (esp. falx cerebri); ocular anomalies; increased risk for medulloblastoma ( 5 %); and additional skin findings (facial milia, epidermoid cysts, multiple nevi); and ovarian / cardiac fibromas.

Diagnostic criteria:

The clinical diagnosis of Gorlin syndrome can be established in individuals fulfilling two major diagnostic criteria and one minor diagnostic criterion or one major and three minor diagnostic criteria [Evans, 1993]:

Major criteria:

• Multiple BCCs (>5 in a lifetime) or a BCC before age 30 years
• Jaw keratocyst (odontogenic keratocyst histologically)
• Palmar/plantar pits (two or more); pits may appear as white "punched-out" or pink "pin-prick" lesion
• Calcification of the falx cerebri; Falx calcification is nearly always present and visible on anteroposterior (AP) x-rays of the skull after age 20 years
• First-degree relative with BCNS

Minor criteria:

• Childhood medulloblastoma (also called primitive neuroectodermal tumor [PNET])
• Lympho-mesenteric or pleural cysts
• Macrocephaly
• Cleft lip/palate
• Vertebral/rib anomalies
• Preaxial or postaxial polydactyly
• Ovarian / cardiac fibromas
• Ocular anomalies (cataract, developmental defects, and pigmentary changes of the RPE)

Genetic Information

BCNS is inherited in an autosomal dominant manner. Germline mutations in PTCH1 (9q22.3-q31) can be found in up to 85% of patients with the clinical diagnosis of BCNS (70 – 80 % inherited from one parent; 20 – 30 % de novo mutations). BCNS is considered to be fully penetrant, however, there is variable inter- and intrafamilial expression. The PTCH1-gene comprises 23 exons and encodes an integral membrane protein functioning as a receptor for sonic hedgehog (SHH).

Diagnostic