Genetic Disorders Predisposing to Skin Malignancy

Introduction

Basal cell nevus syndrome (BCNS, MIM #109400; nevoid basal cell carcinoma syndrome; Gorlin or Gorlin–Goltz syndrome), a rare autosomal dominant condition, is characterized by the presence of multiple basal cell carcinomas (BCCs), palmoplantar pits, odontogenic keratocysts, and skeletal abnormalities.

History

In 1960, Gorlin and Goltz described a syndrome of multiple basal cell epitheliomas, jaw cysts, and bifid ribs. Since then, numerous additional clinical findings, including medulloblastoma, palmoplantar pits, ovarian carcinoma, and frontal bossing, have been reported.

Epidemiology

Prevalence estimates range from 1:56,000 to 1:164,000.

Pathogenesis and etiology

The BCNS gene, a tumor suppressor gene, was mapped to chromosome 9q22.3-q31 in 1992. Subsequent studies identified the gene as PATCHED (PTCH), a transmembrane receptor in the sonic hedgehog pathway, similar to Drosophila patched involvement in fly development. The hedgehog pathway is fundamental in human growth and development, including neural tube, skeleton, limbs, craniofacial structures, and skin. Loss of heterozygosity for genetic markers in this region has been detected in 50% of sporadic BCCs, supporting its role as a tumor suppressor gene. Mutations in PTCH1 and PTCH2 have been identified in BCNS. The PTCH protein inhibits the smoothened protein in the absence of hedgehog. With hedgehog binding, smoothened is released, and through the transcription factor Gli, multiple downstream target genes involved in cell proliferation are expressed. With PTCH mutations, loss of negative autoregulation leads to increased transcription of non-functional PTCH mRNA, in addition to a constitutively active smoothened.

Clinical features

The characteristic skin finding in this syndrome, BCCs, typically appears between puberty and age 35. These may occur as early as 2 years of life, and are influenced by ethnicity. In one study, 38% of black patients developed BCCs versus 80% of Caucasians. BCCs can number from a few to thousands ( Fig. 33.1 ) and can be mistaken for skin tags, nevi, hemangiomas, or molluscum contagiosum. Most involve the face, back, or chest. Although only rarely invasive, they may occur following radiation for medulloblastoma and lead to death. A major cutaneous finding is palmoplantar pitting ( Figs 33.2 and 33.3 ), seen in up to 87% of patients and as early as 5 months of life. Milia may also be intermixed with BCCs, and epidermal cysts are seen in a majority of patients.

Odontogenic keratocysts of the jaw usually develop during the first decade and peak in the second or third decades. They are most often detected on routine dental check-ups and can be seen in over 80% of patients, more often in the mandible. While they almost never cause symptoms unless secondarily infected, they can displace developing permanent teeth and affect expansion of the jaws.

Musculoskeletal abnormalities are quite common and include fused, splayed, hypoplastic, or bifid ribs (in approximately 60%), kyphoscoliosis, spina bifida occulta, malformations of the occipitovertebral junction, and enlarged occipitofrontal circumference with frontal bossing and macrocephaly ( Fig. 33.4 ). Other features include highly arched eyebrows, high arched palate, narrow sloping shoulder, immobile thumbs, cleft lip and palate, and low pitched voice.

Medulloblastoma has been reported in very young children with BCNS, with an incidence estimated as 3.5%. Radiation therapy for this tumor can markedly affect the onset, number, and biological aggressiveness of BCCs. Other reported brain tumors include meningiomas, craniopharyngioma, astrocytoma, and cysts in the brain. Falx cerebri calcification occurs relatively early in life and is detectable in at least 85% of patients.

Patient evaluation, diagnosis, and differential diagnosis

Major and minor diagnostic criteria for BCNS are summarized in Table 33.1 . In a patient with multiple BCCs, other diagnoses to consider include Bazex–Dupré–Christol and Rombo syndromes (see below).

Dermatological evaluation of patients with BCNS is recommended every 2–3 months, particularly during adolescence. Beginning at age 8, patients should have a panoramic radiograph of the jaws every year, with complete removal of any odontogenic keratocysts. Other tests to consider are annual magnetic resonance imaging from infancy through age 8, to evaluate for medulloblastoma; periodic chest radiography to screen for cardiac fibromas; and radiographic studies to detect calcification of the falx cerebri and rib anomalies.

Pathology

BCCs seen in BCNS are indistinguishable from those seen sporadically.

Treatment

There is a paucity of studies evaluating treatment of the numerous BCCs in BCNS. It has been recommended that superficial BCCs without follicular involvement be managed by total body application of 0.1% tretinoin cream and 5% 5-fluorouracil cream twice daily. More invasive lesions should be curetted or excised, with Mohs micrographic surgery employed for indicated lesions. One report of four patients with BCNS described successful treatment of the majority of superficial and nodular BCCs with imiquimod when used five times a week for 8–14 weeks.

A randomized placebo-controlled trial of 981 patients with a history of BCC (not BCNS) evaluated the daily use of 10 mg isotretinoin versus placebo in the prevention of BCCs. Patients enrolled had a history of at least two previous BCCs and were treated for 36 months. No difference was seen in the development of subsequent BCCs. No trials have evaluated isotretinoin in patients with BCNS. One case report showed a decrease in the number of new BCCs in a patient treated with 0.4 mg/kg/day of isotretinoin over 4 years, compared to 0.2 mg/kg/day. A case report on the combined use of isotretinoin and intralesional interferon alfa failed to demonstrate synergism or effective clearance of BCCs in one patient.

Case reports of the use of carbon dioxide laser resurfacing and topical and systemic photodynamic therapy have reported some efficacy.

Introduction

Inherited epidermolysis bullosa (EB) encompasses over 30 different diseases, each of which has a distinctive phenotype and/or genotype. This heterogeneous group of genodermatoses has as its unifying feature the development of blisters following minimal or seemingly insignificant traction on the skin. Four major EB types – EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), Kindler syndrome – are separated on the basis of the ultrastructural level in which blisters form.

History

The name epidermolysis bullosa was first used by Köbner in 1886, although individual cases were previously reported under other names, based on confusion with several other unrelated acquired blistering diseases, including pemphigus.

Epidemiology

The overall incidence and prevalence of EB, based on data from the American National EB Registry, is 19 per 1 million live births and 8 per 1 million individuals, respectively. With rare exceptions, similar rates have been observed elsewhere in the world. There are no gender or racial predilections.

Pathogenesis and etiology

With rare exceptions, EBS is transmitted as an autosomal dominant disease (as is dominant dystrophic EB), whereas JEB (with only one possible exception) and recessive dystrophic EB are autosomal recessive disorders. Each EB type and subtype results from mutations in genes encoding specific structural proteins within keratinocytes or the dermoepidermal junction (DEJ). Their presence leads to mechanical instability within specific structures (i.e. keratin filaments; hemidesmosomes; anchoring fibrils) residing within the skin. Mutations in the genes ( KRT5 ; KRT14 ) encoding keratins 5 and 14 account for all but a few EBS subtypes. Most JEB subtypes are associated with mutations in laminin 332, a three-chained macromolecule present in both the hemidesmosome and the underlying anchoring filaments. Other genes that may result in JEB phenotypes are those encoding type XVII collagen, plectin, and integrin, mutations in the latter of which are accompanied by pyloric atresia. All subtypes of DEB are caused by mutations within the type VII collagen gene ( COL7A ). Although strong phenotype–genotype correlations do not exist for every EB subtype, in general those autosomal recessive EB patients having the most severe cutaneous and extracutaneous disease manifestations possess mutations that result in homozygous or compound heterozygous premature termination codons. Mouse models of JEB and recessive DEB (RDEB) suggest that mutations in the genes encoding laminin 332 and type VII collagen play an important role in promotion and invasiveness of SCCs.