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.

Autosomal-dominantly inherited multisystemic disease with the occurrence of numerous basal cell carcinomas in early life and multiple other malformations, especially of the skeletal system, the CNS, the urogenital system and the heart.

Leitymptoms are (prematurely developing) basal cell carcinomas, jaw cysts, pits, calcifications of the falx cerebri and medulloblastomas.

Incidence: about 1/57.000 - 1:256.000 patients. 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 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 features of 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 functions as a receptor in the Sonic-Hedgehog signaling cascade. Typically, this activation occurs through the binding of SHH to PTCH. This abolishes the inhibitory effect of PTCH on the cell membrane protein Smoothened (SMO). This allows signals to be propagated into the intercellular space up to the nucleus. In the nucleus, further activation of transcription factors (e.g. Gli1 = glioma-associated onogenic homolog) occurs, which in turn induce genes in the nucleus that lead to cell cycle progression and cell proliferation (Hübner L 2014).

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

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

Skin: Multiple, dense basal cell carcinomas (mostly nodulo-ulcerous type, partly pigmented) mainly on the face, but also on the trunk and extremities. First basal cell carcinomas may appear before the age of 20. Slow growth; tumour size may remain stationary for years. Possibly sudden, expansive growth of individual tumors accompanied by ulceration and destruction. In almost 90% of cases dimpled palmoplantar keratoses (pits) are found. Lipomas, epidermal cysts and milia can also be found on the skin.

Skeletal system: Odontogenic jaw cysts, rib cysts, dental malformations, forked ribs, spina bifida, scoliosis, frontal humps, widened nasal bridge, shortened metacarpal bones (4th and 5th rays), syndactyls.

CNS: Macrocephaly, agenesis of the corpus callosum (10% of cases), calcifications of the falx cerebri, cataract, congenital amaurosis, facultative mental retardation; 5% of affected individuals have medulloblastoma of the cerebellum in childhood.

Genital tract: Optional calcifications of the ovary, ovarian fibroids. In male patients, facultative hypogonadism.

Casuistics compiled from the literature:

• Gorlin and Goltz (1960) described a familial syndrome with multiple nevoid basal cell epitheliomas, maxillary cysts, and bifid rib. The inheritance was autosomal dominant.
• Herzberg and Wiskemann (1963) described what they called the "fifth phakomatosis," a basal cell nevus syndrome with medulloblastoma. They reported on a family in which both the father and son had basal cell carcinomas, with the son also having medulloblastoma and congenital thoracic scoliosis.
• Cawson and Kerr (1964) described a syndrome with mandibular cysts, basal cell carcinomas, and skeletal abnormalities. One of the patients also suffered from astrocytoma with severe hydrocephalus. Other features included pits on the palms and soles.
• Lile et al (1968) observed 4 cases in 3 generations of one family. Two of the patients had a short terminal phalanx of the thumb.
• Berlin et al (1966) observed 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) noted hamartomatous polyps of the stomach and mesenteric cysts as features of basal cell nevus syndrome. Totten (1980) observed a large congenital lung 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, aged 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 mesenchymal liver tumor. At the age of 3 years, he had been treated for medulloblastoma by resection and radiation.

• 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.

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