eMedicine Specialties > Pediatrics: General Medicine > Oncology

Gorlin Syndrome

Author: Andrew W Walter, MS, MD, Associate Professor of Pediatrics, Department of Pediatrics, Division of Hematology/Oncology, Jefferson Medical College; Director of Pediatric Neuro-oncology, AI duPont Hospital for Children
Contributor Information and Disclosures

Updated: Mar 23, 2009

Introduction

Background

Gorlin syndrome (basal cell nevus syndrome or nevoid basal cell carcinoma syndrome) is a rare, autosomal dominant cancer syndrome.¹  Patients with this syndrome often have anomalies of multiple organs, many of which are subtle. Study of patients with this rare but important syndrome has yielded important information about neurodevelopment and carcinogenesis. 

Clinicians should be familiar with Gorlin syndrome because of the propensity of these patients to develop multiple neoplasms, including basal cell carcinomas and medulloblastoma, and because of the their extreme sensitivity to ionizing radiation including sunlight.

The presence of multiple abnormalities of the skin, skeleton, and nervous system have led some to call Gorlin syndrome the fifth phakomatosis. The term nevus, as in basal cell nevus syndrome, is an archaic term referring to any circumscribed lesion believed to arise under genetic influence. However, the nevi in the basal cell nevus syndrome are true basal cell carcinomas.^2,3

Pathophysiology

The genetic locus for Gorlin syndrome is 9q22.3-q31, as determined with linkage analysis.^4,5 Germline mutations in the patched gene (PTCH) have been found in patients with Gorlin syndrome and are thought to cause the disorder. More than 50 germline mutations in PTCH are described. About 40% of cases of Gorlin syndrome represent new mutations.^6,7

The molecular biology of cancers in Gorlin syndrome is similar to that of patients with inherited mutations in the Rb, the retinoblastoma gene. Studies of patients with retinoblastoma have provided clinical evidence supporting the Knudson hypothesis, a theory of oncogenesis that states that normal cells require at least 2 mutagenic hits (2 distinct episodes of DNA damage) to produce a cancer. Patients with retinoblastoma, Gorlin syndrome, and similar syndromes have a constitutional (germline) defect in the DNA sequence in 1 of the 2 gene copies. 

The presence of a defect in 1 of the 2 gene copies is not sufficient to cause a cancer. If a second DNA injury, or loss of the normal remaining allele, occurs at the same gene (the second hit), the cell may become malignant. These tumor suppressor genes act normally by suppressing growth and limiting the emergence of malignant clones. Loss or inactivation of such a gene can lead to an increased risk for malignancies and/or overgrowth syndromes such as Gorlin syndrome.⁸

The mechanism of oncogenesis mediated by ionizing irradiation in patients with Gorlin syndrome is unknown. WBCs from patients with Gorlin syndrome are not exquisitely sensitive to irradiation as are cells from patients with another sun-sensitive disorder, xeroderma pigmentosum. 

An important and interesting aspect of the study of Gorlin syndrome is that some of the developmental defects (such as jaw cysts) also appear to have undergone a “transformation” following 2 hits, without developing into a malignancy. In some patients, cells comprising the lining of the jaw cysts have lost the normal Gorlin syndrome gene while retaining the mutant allele. This may explain the behavior of the jaw cysts, which may behave more like low-grade neoplasms than congenital malformations.^9,10,11

Study of the genetics of Gorlin syndrome has led to important basic discoveries in developmental biology. DNA analysis from patients with Gorlin syndrome led to the realization that the genetic defect that causes Gorlin syndrome is homologous to a sequence in the fruit fly Drosophila called the segment polarity gene (PTCH). The PTCH gene is known to be important in developmental abnormalities, growth regulation, and segmentation in Drosophila. The PTCH gene analogue in humans codes for a transmembrane protein, which represses transcription of genes encoding members of the tumor growth factor (TGF) beta and WNT families of signaling proteins.

Basal cell carcinomas from patients with Gorlin syndrome have abnormalities of the PTCH sequence, reinforcing the importance of the Gorlin mutation in oncogenesis and suggesting a potential role of this gene as a tumor suppressor gene. DNA from sporadic basal cell carcinomas (ie, from tumors in patients who were otherwise healthy and who did not have Gorlin syndrome) also had allelic loss in the nevoid basal cell carcinoma syndrome region with inactivating mutations of the remaining allele, suggesting that the gene may play a role in a final common pathway to oncogenesis in basal cell carcinomas.

Gailani et al showed that inactivation of patched is probably a necessary step in basal cell carcinoma development, even in patients without the Gorlin syndrome.⁴  As many as one third of patients with medulloblastoma and Gorlin syndrome have lost the wild type allele on chromosome 9q, implying that this site may code for tumor suppressor activity.

The exact genetic defects in patients with Gorlin syndrome are multiple. One group identified 28 mutations distributed throughout the entire gene. They concluded that the preponderance of truncation mutations in the germ line of patients with Gorlin syndrome suggested that the developmental defects are likely due to haploinsufficiency.⁷

Frequency

International

Incidence of Gorlin syndrome is estimated to be 1 case per 50,000-150,000 population. The perceived incidence may vary by region. For example, the apparent incidence may be highest in Australia. This may be a result of demographics because a large percentage of the Australian population is made up of fair-skinned peoples transplanted from Europe to the intense solar climate in parts of Australia.

Mortality/Morbidity

Early death from Gorlin syndrome is rare. Important potential causes of early death include the effects of medulloblastoma, which is a malignant brain tumor of the posterior fossa that develops in 10% of patients with Gorlin syndrome.

In rare cases, patients die from progressively invasive basal cell carcinomas that are treated with irradiation, which causes further damage and carcinogenesis.

Morbidity from the complications of Gorlin syndrome can be substantial, as outlined in Physical.

Race

Gorlin syndrome has been described in whites and in blacks.

Sex

This disorder is inherited in an autosomal dominant fashion and appears to occur with equal frequency in men and women.

Age

One of the challenges of Gorlin syndrome is recognizing its presence. Although quite distinctive when fully expressed, many of the physical findings are absent in early childhood. Several of the developmental anomalies accumulate with age with median time of diagnosis in the second or third decades. This makes definitive diagnosis in childhood difficult in many cases. The most important reason for recognizing Gorlin syndrome is, as with other cancer syndromes, patients can develop multiple neoplasms at an early age. The most common neoplasms seen are basal cell carcinomas of the skin, occurring in more than 90% of patients, especially with advancing age (>40 y).

Clinical

History

Patients with Gorlin syndrome most commonly present with either dental cysts or basal cell carcinomas in the third or fourth decade of life. Rare patients present with medulloblastoma in childhood. In a considerable number of patients, the syndrome is probably never diagnosed.

Physical

Numerous anomalies have been described in patients with Gorlin syndrome. These include abnormalities of the skin, head and neck, spine and bony skeleton, genitourinary system, CNS, heart, and ovaries. The most common abnormalities include calcification of the cerebral falx, distinctive pits of the palms and soles, macrocephaly, odontogenic keratocysts of the jaw,¹² one or more basal cell carcinomas (especially at a young age), rib abnormalities, and having a first degree relative with Gorlin syndrome. Less common findings include thoracic or cervical vertebral anomalies, short fourth metacarpals, pectus excavatum or pectus carinatum, cleft lip or palate,¹³ moderate or severe hypertelorism, Sprengel deformity, ovarian fibroma, or medulloblastoma. Kimonis has proposed that the diagnosis of Gorlin syndrome can be made in the presence of 2 major or 1 majorand2minorcriteriaasdiscussed below.^14,15

The diagnostic criteria may not all be present at an early age. For example, in one series of patients with Gorlin syndrome described by Shanley et al.¹⁶ The mean age of onset of basal cell carcinomas was 20 years. In this same series, jaw cysts were first noted at a mean age of 15 years. Similarly, palmar pits are not uniformly present at an early age. Therefore, these 3 major criteria are only variably present at a young age, making definitive diagnosis difficult in many young patients.

Kimonis et al proposed that Gorlin syndrome can be diagnosed when 2 major or 1 major and 2 minor criteria are present.¹⁴

• Major criteria
  • Two or more basal cell carcinomas in persons younger than 20 years
  • Odontogenic keratocysts of the jaw
  • Three or more palmar or plantar pits
  • Bilamellar calcification of the falx cerebri
  • Bifid, fused, or markedly splayed ribs
  • First-degree relative with Gorlin syndrome
• Minor criteria
  • Macrocephaly
  • Congenital malformations (eg, cleft lip or palate, frontal bossing, coarse face, hypertelorism)
  • Other skeletal abnormalities (eg, Sprengel deformity, marked pectus deformity, or syndactyly of the digits)
  • Radiologic abnormalities (eg, bridging of the sella turcica, vertebral anomalies [eg, hemivertebrae, fusion or elongation of the vertebral bodies], modeling defects of the hands and feet, or flame-shaped lucencies of the hands or feet)
  • Ovarian fibroma
  • Medulloblastoma

The nevi in the basal cell nevus syndrome are true basal cell carcinomas. Patients may present with multiple fleshy pigmented or nonpigmented nevi that may appear to be typical moles. However, biopsies of these lesions uniformly result in the diagnosis of basal cell carcinoma. The pits of the palms and soles are tiny epidermal defects in keratin production. Although these are often not present in young children, they are highly specific to Gorlin syndrome. The keratoses of the jaw, although benign abnormalities, require surgical intervention. They can also recur after surgery, mimicking more a low-grade neoplasm than a congenital anomaly.

Causes

See Pathophysiology.

• Search for CME/CE on This Topic »

• Basal Cell Carcinoma (Dermatology)
• Benign Cardiac Tumors (Cardiology)
• Nevoid Basal Cell Carcinoma Syndrome (Dermatology)
• Intestinal Polyposis Syndromes (Pediatrics: General Medicine)

• Celecoxib Effective in Inhibiting Genetic Basal Cell Carcinoma

• The Asian Dermatologic Patient: Review of Common Pigmentary Disorders and Cutaneous Diseases
• UV Radiation, Vitamin D and Epidermal Carcinogenesis