Man with macrocephaly, learning disability and multiple basal cell carcinomas

Discussion

Gorlin syndrome, also known as nevoid basal cell carcinoma syndrome, was first described in 1960. The clinical findings were a basal cell carcinoma, jaw cysts and bifid rib (2). In 1968, the condition was described in a Norwegian family (3). The Centre for Rare Disorders is the Norwegian national centre of excellence for this disorder, and about 40 people with the syndrome are registered with the centre. Gorlin syndrome is probably underdiagnosed in Norway. The incidence is estimated to be around 1 : 30,000 (4), which would indicate that there are about 170 cases nationwide.

The diagnosis is made clinically if the patient fulfils two major criteria and one minor criterion, or one major criterion and three minor criteria (Box 1) (5, 6). This is one of several classifications (7, 8). Patients may have a variety of congenital malformations (8). Mutation in the PTCH1 gene is found in 85% (6), and inheritance is autosomal dominant. The disorder has high penetrance and variable expressivity (6, 9). The de novo mutation rate is over 50% (4). Life expectancy is believed to be over 70 years (10).

The GP observed that the original diagnosis did not fully capture the symptoms of the patient, who was by then in his late 20s. He made the referral to a specialist, who suspected Gorlin syndrome and referred the patient on to Oslo University Hospital, where this diagnosis was confirmed. A review of the case history illustrates the challenges of recognising and diagnosing a rare disorder. A disorder is regarded as rare when there are fewer than 100 known cases per million inhabitants (11). In Norway, approximately 30,000 people are living with rare disorders (12), so taken as a whole, they make up a significant group.

Macrocephaly, skeletal malformations, ocular changes, learning disabilities and jaw cysts are unlikely to occur together by coincidence. The boy had been diagnosed with a rare disorder, Sotos syndrome. The oral and maxillofacial surgeon who operated on the jaw cysts was aware of this diagnosis and therefore did not link the jaw cysts to what later proved to be the correct diagnosis in this case. Unfortunately the patient did not attend a follow-up appointment with the oral and maxillofacial surgeon.

The patient had a learning disability. To our knowledge, there are no published studies describing learning disabilities in patients with Gorlin syndrome (6). The fact that the patient had already been diagnosed with a rare disorder and had a learning disability may have led to Gorlin syndrome not being considered earlier. For rare disorders where the diagnosis cannot be confirmed by mutation analysis or clinical criteria, the patient should be reassessed after a few years. An incorrect diagnosis can have serious consequences for the patient in terms of follow-up and prognosis, and for the family with regard to inheritance and recurrence risk.

There are no national assessment, treatment or follow-up procedures for patients with Gorlin syndrome in Norway, but there are international guidelines that we recommend should be followed (6, 13). The GP should assist with the coordination of follow-up.

Treatment is symptomatic. There is an increased risk of medulloblastoma in the first three years of life (14). A paediatric neurologist should monitor the patient’s psychomotor development and assess the need for MRI. Children and newly diagnosed adults should be examined for possible ocular defects. The heart and ovaries should be examined for fibromas and operated on or monitored as required. A dermatologist should also monitor the patient, as basal cell carcinoma is a common symptom. Standard treatment of basal cell carcinoma consists of surgery, cryotherapy, photodynamic therapy (PDT), topical immunomodulatory agents or laser ablation.

Radiotherapy should not be used in patients with Gorlin syndrome, if it can be avoided, as it is associated with an increased risk of radiation-induced tumours and new basal cell carcinomas. Diagnostic x-ray or CT scans are also associated with this risk (15) and must be used with caution. Radiotherapy for medulloblastoma in children with the syndrome has led to radiation-induced brain tumours and innumerable basal cell carcinomas (16, 17). Sun exposure without adequate protection increases the risk of basal cell carcinoma. Little exposure to sunlight leads to low vitamin D levels (18).

Patients should be monitored periodically for jaw cysts. Such cysts can become large and can displace teeth (6, 8). We recommend that examinations are carried out using a digital orthopantomogram (OPG) (Fig. 2) by a maxillofacial radiologist or dentist who is familiar with performing and interpretating this test. The National Resource Centre for Oral Health in Rare Medical Conditions at Lovisenberg Diakonale Hospital can be contacted for questions relating to the teeth and jaws.

The need for psychosocial support must be considered (19). The patient and their family should be offered a referral for genetic counselling and informed about the Centre for Rare Disorders. In families in which the genetic defect is known, predictive testing of first-degree relatives, including children, is recommended, because the results will have consequences for further follow-up, prevention and treatment (6, 13).

A pharmaceutical alternative has recently become available for the treatment of basal cell carcinomas when standard treatment is no longer sufficient. These drugs are called «hedgehog inhibitors» (Box 2) (20). They work by blocking the signalling pathway that, because of mutations in PTCH1, is activated upon development of basal cell carcinomas in all patients – not just those with Gorlin syndrome (21, 22). The drug is available in capsule form (vismodegib) and was approved for clinical use in locally advanced basal cell carcinoma in Norway in August 2013.