Gorlin-Goltz Syndrome: A Father and Son With Clinical Abnormalities

A 17-year-old white adolescent boy presented with multiple asymptomatic pits on the palms and soles of approximately 5 to 6 years’ duration. There was no history of trauma in those areas. According to the patient, immersing the hands and feet in water would make the pits more obvious. His past health was unremarkable. His 40-year-old father also had palmar pits and multiple skin lesions on the face, back, and chest. 

On examination, multiple brownish pits were seen on the palms and soles. The pits measured 1 to 2 mm in diameter and depth. Two skin-colored papules were noted on the abdomen and another 2 skin-colored papules on his back. In addition, frontal bossing and hypertelorism were noted. The rest of the physical examination findings were normal.

The patient was suspected to have Gorlin-Goltz syndrome. The papules of the patient and the skin lesions of the father were surgically removed and were found to be basal cell carcinomas (BCCs) on histopathology. Therefore, a diagnosis of Gorlin-Goltz syndrome was made in the patient and his father.

Discussion

Gorlin-Goltz syndrome, also known as Gorlin syndrome, nevoid basal cell carcinoma syndrome, and basal cell nevus syndrome, has an autosomal dominant mode of inheritance with a high level of penetrance and variable expressivity.¹ It is characterized by palmar and/or plantar pits, BCCs, odontogenic keratocysts, ectopic calcification of the falx cerebri, and a propensity to multiple neoplasms and developmental abnormalities.² The condition was first described by Jarisch and White^3,4 in 1894. The spectrum of disease associated with this syndrome was subsequently described in detail by Gorlin and Goltz in 1960⁵; the disease now bears their names.

The incidence is estimated to be 1 in 50,000 to 235,800 in the general population.^6-8 Although the syndrome arises in all ethnic groups, most reported cases are in the white population.^8,9 Males and females are equally affected.^1,8 

The syndrome occurs mainly due to a germline inactivating mutation in the human homologue of the Drosophila patched (PTCH1) tumor suppressor gene that encodes the receptor for sonic hedgehog protein.² The gene has been mapped to chromosome 9q22.3.² An inactivating mutation in PTCH1 results in unregulated stimulation of sonic hedgehog signaling, which leads to abnormal proliferation of cells and carcinogenesis.⁶ Occasionally, the syndrome may result from a germline heterozygous loss of function mutation in the suppressor of fused gene (SUFU), which encodes a component of the sonic hedgehog/patched signaling pathway.¹⁰ The SUFU gene has been mapped to chromosome 10q24.32.¹⁰ Affected individuals without a family history of Gorlin-Goltz syndrome are the result of new mutations.

Clinical Manifestations and Diagnosis

A variety of clinical abnormalities have been described. The diagnostic criteria were first put forth by Evans and colleagues¹¹ and later modified by Kimonis and colleagues.¹² Diagnosis of Gorlin-Goltz syndrome can be established when 2 major criteria or 1 major and 2 minor criteria are present.^11,12

The major criteria are as follows:

• Multiple BBCs or 1 occurring younger than 20 years

• Histologically proven odontogenic keratocyst of the jaw

• 3 or more palmar or plantar pits

• Bilamellar calcification of the falx cerebri

• Bifid, fused, or markedly splayed ribs

• First-degree relative with the syndrome

The minor criteria are as follows:

• Macrocephaly determined after adjustment for height

• Congenital malformations (cleft lip or palate, frontal bossing, coarse face, moderate or severe hypertelorism)

• Other skeletal abnormalities (Sprengel deformity, marked pectus deformity, marked syndactyly of the digits)

• Radiologic abnormalities (bridging of the sella turcica, vertebral anomalies such as hemivertebrae, fusion or elongation of the vertebral bodies, modeling defects of the hands and feet, or flame-shaped hands or feet)

• Ovarian fibroma

• Medulloblastoma

Other clinical findings include brachycephaly, low positioning of occiput, tentorium cerebelli calcification, agenesis of the corpus callosum, high-arched palate, prognathism, microphthalmia, exophthalmos, rotatory nystagmus, strabismus, orbital cyst, chalazion, coloboma, cataract, glaucoma, otosclerosis, conductive hearing loss, scoliosis, spina bifida occulta, polydactyly, shortened fourth metacarpal, ovarian cyst, ovarian fibrosarcoma, ovarian leiomyosarcoma, hypogonadotropic hypogonadism, cryptorchidism, gynecomastia, horseshoe kidney, unilateral renal agenesis, renal cyst, duplication of the renal pelvis and ureter, fetal rhabdomyoma, lymphomesentric cysts, and cardiac fibroma.^1,2,13

Differential Diagnosis

In our patient, the diagnosis was suspected based on the presence of palmoplantar pits, frontal bossing, hypertelorism, and a potential paternal history. The diagnosis was confirmed when the excised skin lesions showed BCCs. The patient and his father had not previously received a diagnosis of the syndrome in spite of an array of clinical features having been present for years. Therefore, when palmoplantar pits are discovered, a search for the underlying cause is essential. Early diagnosis of Gorlin-Goltz syndrome is important to reduce the severity of complications such as BCC and other tumors.⁸

Palmar and/or plantar pits are highly characteristic of Gorlin-Goltz syndrome and are readily identifiable. Soaking the hands and feet in warm water for approximately 10 minutes can make their appearance more pronounced.² They are asymmetric and range from 2 to 3 mm in diameter and 1 to 3 mm in depth.^1,9 They usually develop by 10 years of age, and the percentage of pits increases to more than 85% by 20 years of age.⁹ Pits are caused by partial or complete absence of stratum corneum in sharply defined areas.^1,9 

Palmoplantar pits can be seen in other conditions such as pitted keratolysis,¹⁴ punctate palmoplantar keratoderma,¹⁵ keratotic pits of the palmar creases,¹⁶ Darier disease,¹⁷ Dupuytren contracture,¹⁸ epidermodysplasia verruciformis,¹⁹ multiple trichoepitheliomas,²⁰ Alagille syndrome,²¹ and reticulate acropigmentation of Kitamura.²² The distinctive features of each condition allow for a straightforward diagnosis.

Diagnostic Investigations

In patients with suspected Gorlin-Goltz syndrome, the following tests should be done to diagnose the syndrome: radiographs of the skull, chest, spine, hands and feet; panoramic films; computed tomography; abdominal ultrasonography; echocardiography; and biopsy of any suspicious skin lesions.

Management

Management requires a multidisciplinary approach and may require care from an ear, nose, and throat surgeon, pediatrician/internist, dermatologist, plastic surgeon, dentist, geneticist, ophthalmologist, gynecologist, orthopedic surgeon, cardiologist, urologist, and neurosurgeon depending on the specific manifestations that need to be addressed. Screening of family members and genetic counseling are indicated. Patients should be advised to practice sun-protective behaviors to reduce the risk of BCCs.² Lifelong integrated multispecialty follow-up is essential, aiming particularly at the early detection and progression of any life-threatening lesions.

Alexander K. C. Leung, MD, is a clinical professor of pediatrics at the University of Calgary and a pediatric consultant at the Alberta Children’s Hospital in Calgary, Alberta, Canada.

Benjamin Barankin, MD, is a dermatologist and the medical director and founder of the Toronto Dermatology Centre in Toronto, Ontario, Canada.

References

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