A young man with multiple basal cell carcinomas was referred to Oslo University Hospital on suspicion of a rare syndrome. Rare disorders can be difficult to diagnose correctly, as illustrated in this case report.
Figure 1 The patient at first visit to the dermatologist. a) Weeping sore in a basal cell carcinoma behind the ear. b) Overview showing basal cell carcinomas on the scalp. c) Large basal cell carcinoma on the scalp with central ulceration and pigmented ridges
The medical records do not describe how this conclusion was reached, but the case illustrates that macrocephaly does not always reflect hydrocephalus. It could be familial, or part of a rare syndrome, for example Sotos syndrome, Gorlin syndrome, Cowden syndrome, Fragile X syndrome, neurofibromatosis type 1, metabolic disorders or other conditions.
Sotos syndrome is characterised by extreme growth in height and/or macrocephaly, learning disabilities of varying severity and characteristic facial features, such as a long, narrow face. Cardiac anomalies, renal anomalies and other congenital malformations may be present. Mutations in the NSD1 gene cause Sotos syndrome (1 ).
Rare disorders should, whenever possible, be confirmed genetically to allow conclusions to be drawn about prognosis, inheritance and recurrence risk. Incorrect diagnosis can have serious consequences.
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 ).
BOX 1
Clinical diagnostic criteria for Gorlin syndrome (6 ). The diagnosis is made clinically if the patient fulfils two major criteria and one minor criterion, or one major criterion and three minor criteria.
Major criteria
Multiple basal cell carcinomas (more than five in lifetime) or one basal cell carcinoma before 30 years of age
Jaw cysts
Palmar or plantar pits
Meningeal calcification
First-degree relative with the disorder
Minor criteria
Vertebral/rib malformation
Macrocephaly (> 97th percentile) with prominent forehead
Cardiovascular or ovarian fibroma
Medulloblastoma
Lymphomesenteric cysts or pleural cysts
Cleft lip/palate
Preaxial or postaxial polydactyly
Ocular anomalies (cataracts, developmental abnormalities, pigment changes in the retina)
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.
Figure 2 Illustrative image showing jaw cysts. Orthopantomography (OPG) of a boy diagnosed with Gorlin syndrome. In the image mixed dentition can be seen together with two large cystic radiolucencies in the mandible (arrows). Histological examination revealed keratocysts (keratocystic odontogenic tumours). Consent has been given for publication of the image
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.
BOX 2
«Hedgehog inhibitors» inhibit the hedgehog signalling pathway in cells. The name «hedgehog» stems from experiments in which fruit flies were given a specific mutation. The mutation led to the fly larvae becoming small and hairy, such that they resembled hedgehogs. The signalling pathway has subsequently been shown to be central to the development of conditions including basal cell carcinoma. Inhibition of this signalling pathway has therapeutic efficacy in basal cell carcinoma (20 ).
Summary
Gorlin syndrome is a rare genetic condition in which patients may develop medulloblastomas, jaw cysts and basal cell carcinomas and show congenital skeletal malformations. If left undiagnosed, Gorlin syndrome can have a number of negative consequences. Early diagnosis and good follow-up is important for all patients with rare disorders.
We wish to make doctors and dentists aware of Gorlin syndrome so that, whenever the syndrome is suspected or a patient has been diagnosed, the patient is referred for assessment, treatment and follow-up by specialists who know the disorder well. Dermatology departments at university hospitals and departments of medical genetics have a key role to play in assessment and follow-up.
A national support group for Gorlin syndrome has been established, consisting of a dermatologist, oncologist, geneticist, paediatrician, specialist dentist, ophthalmologist, orthopaedic surgeon, plastic surgeon, oral and maxillofacial surgeon and counsellors. Patients, relatives and health professionals can contact the Centre for Rare Disorders directly for information about Gorlin syndrome, or to be put in touch with members of the group.
