Basal cell nevus syndrome Q82.8

Kaposi, 1872; Robert W. Goltz and Robert J.Gorlin, 1960.

Note: Although Gorlin described many syndromes, several of which received his name, none is so closely associated with his name as the nevoid basal cell carcinoma syndrome.

Nevoid basal cell carcinoma syndrome, also known as Gorlin-Goltz syndrome, is an autosomaldominant multisystem disorder characterized by the occurrence of numerous basal cell carcinomas at an early age, as well as multiple other malformations, particularly of the skeletal system, the central nervous system, the urogenital system, and the heart. 

The main symptoms are:

• (prematurely developing) basal cell carcinomas
• jaw cysts
• Pits
• Calcifications of the falx cerebri and
• medulloblastomas.   

Prevalence (Europe) about 1/57,000 - 1:256,000 patients. It is lower in East Asia, where it is between 1:235,800 and 1:13,939,393.

In up to 40% of cases, the family history is negative, so that a correspondingly high rate of new mutations can be assumed.

Autosomal dominant inheritance with incomplete penetrance of mutations of the gene loci 9q22.3(PTCH1 tumor suppressor gene), 9q31 and 1p32 (see below Hedgehog signaling pathway).

The autosomal dominant inherited nevoid basal cell carcinoma syndrome (BCNS) can be caused by mutations in 3 different genes:

• PTCH1 gene (PTCH = tumor suppressor gene, 601309) on chromosome 9q22
• PTCH2 gene (603673) on chromosome 1p32
• SUFU gene (607035) on chromosome 10q24-q25.

Somatic mutations in the PTCH2 gene have also been identified in solitary basal cell carcinoma (605462) and medulloblastoma (155255). Both malignancies are characteristics of the nevoid basal cell carcinoma syndrome.

More than 70 germline mutations have now been found in patients with Gorlin-Goltz syndrome. The PTCH gene encodes a transmembrane protein (PTCH) that acts as a receptor in the Sonic-Hedgehog signaling cascade. This activation usually occurs through the binding of SHH to PTCH. This removes the inhibitory effect of PTCH on the cell membrane protein Smoothened (SMO). This allows signals to be transmitted into the intercellular space up to the cell nucleus. In the cell nucleus, further activation of transcription factors (e.g. Gli1 = glioma-associated onogenic homolog) occurs, which in turn induce genes in the cell nucleus that lead to cell cycle progression and cell proliferation (Hübner L 2014).

Linear basal cell carcinomas: Basal cell carcinomas in a linear arrangement are regarded as a special form of nevoid basal cell carcinoma syndrome (Gorlin-Goltz syndrome).

Can occur at any age. Mostly occurring in early adulthood.

Skin: Multiple, closely spaced basal cell carcinomas (mostly of the nodulo-ulcerative type, some of which are pigmented), primarily on the face, but also on the trunk and extremities. The first basal cell carcinomas can appear even before the age of 20. Slow growth; the tumor size may remain stable for years. Some individual tumors may experience sudden, expansive growth accompanied by ulcerations and tissue destruction. In nearly 90% of cases, pitted palmoplantar keratoses (pits) are present. In addition, lipomas, epidermal cysts, and milia are present on the skin.

Skeletal system: odontogenic jaw cysts, rib cysts, dental malformations, forked ribs, spina bifida, scoliosis, frontal bossing, broadened nasal bridge, shortened metacarpal bones (4th and 5th metacarpals), syndactyly.

CNS: macrocephaly, agenesis of the corpus callosum (10% of cases), calcifications of the falx cerebri, cataracts, congenital amaurosis, and occasionally mental retardation; 5% of affected individuals develop a cerebellar medulloblastoma as early as childhood.

Genital tract: Optional calcifications of the ovary, ovarian fibromas. In male patients, optional hypogonadism.

Case reports compiled from the literature:

• Gorlin and Goltz (1960) described a familial syndrome characterized by multiple nevoid basal cell epitheliomas, jaw cysts, and bifid ribs. The inheritance pattern was autosomal dominant.
• Herzberg and Wiskemann (1963) described what they termed the “fifth phakomatosis,” a basal cell nevus syndrome with medulloblastoma. They reported on a family in which both the father and the son had basal cell carcinomas, with the son additionally having a medulloblastoma and congenital thoracic scoliosis.
• Cawson and Kerr (1964) described a syndrome characterized by jaw cysts, basal cell carcinomas, and skeletal anomalies. One of the patients also had an astrocytoma with severe hydrocephalus. Additional features included pits on the palms and soles.
• Lile et al. (1968) observed 4 cases across 3 generations of a family. Two of the patients had a short terminal phalanx of the thumb.
• Berlin et al. (1966) observed an ovarian carcinoma associated with this syndrome.
• Holubar et al. (1970) found basal cell epitheliomas in multiple palmar pits in an 8-year-old girl with BCNS.
• Schwartz (1978) identified hamartomatous polyps of the stomach and mesenteric cysts as features of basal cell nevus syndrome. Totten (1980) observed a large congenital pulmonary cyst occupying the left thoracic cavity in an affected patient.
• Cramer and Niederdellmann (1983) described 9 individuals from 3 families with cerebral gigantism syndrome (117550); 7 of the patients also had signs of nevoid basal cell carcinoma syndrome. In one family, the elderly father and son had jaw cysts and other signs of nevoid basal cell carcinoma syndrome. A second son suffered from macrocephaly, mild hydrocephalus, intracranial calcifications, and EEG abnormalities.
• Koch et al. (2002) described a 13-year-old boy with NBCCS and a mesenchymal liver tumor. At the age of 3, he had been treated for a medulloblastoma with resection and radiation therapy.

• Diagnosis of clinical complications according to Evans:
  • Major criteria:
    • More than 2 basal cell carcinomas or 1 basal cell carcinoma before LJ 30
    • Jaw cysts before the 20th LJ
    • Palmare or plantar dimples (> 3)
    • Calcification of the falx cerebri
    • Medulloblastoma, especially desmoplastic type
    • Positive family history (1st degree relatives with BZNS)
  • Secondary criteria:
    • Congenital skeletal anomalies:
      • Split, fused or missing ribs
      • Split or fused vertebral bodies
    • Frontooccipital head circumference (> 97th percentile, with frontal bumps)
    • Cardiac or ovarian fibroids
    • Congenital malformation: cleft lip, jaw, palate, polydactyly, cataract, iriscoloboma.

Notice! A diagnosis is made when 2 major criteria or 1 major criterion and 2 minor criteria are met.

Prophylaxis with acitretin (neotigason) 0.5 mg/kg bw/day p.o.

New studies show good results with pembrolizumab.

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