Donohue syndrome is a rare autosomal recessive disorder with an incidence of 1 in 4 million live births [1,2] caused by mutations of the insulin receptor gene on chromosome 19p13 . It was initially termed ‘dysendocrinism’ and ‘leprechaunism’ (owing to elf-like features of those affected) ; these terms have since been discarded in favour of Donohue syndrome.
The primary pathology is insulin resistance due to defective binding of insulin to its mutant receptor. These insulin receptor mutations are often collectively termed ‘loss of function’ mutations. Multiple mutations have been identified and the natural history of the disease depends on the degree of insulin resistance . While patients with milder forms (the most common of which is Rabson-Mendelhall syndrome) can live into adulthood, a severe disease results in death during infancy. Clinical features include growth retardation (intrauterine growth restriction, low birth weight, marasmus, failure to thrive), organomegaly (liver, spleen, kidneys, genitals), abnormal facies (pointed chin, microcephaly, prominent low set ears), skin features (pachyderma, hypertrichosis, acanthosis nigricans), hypotonia and relatively large hands/feet. Accelerated fasting states cause muscle wasting and low subcutaneous fat. They may also have hyperplasia of the islets of Langerhans, nephrocalcinosis, atrophic adrenal glands, bile duct cholestasis, lymphoid hypoplasia and cystic gonadal appearances. Cardiac involvement in the form of hypertrophic cardiomyopathy, which occurs early in infancy, is attributed to the effects of IGF-1 . A pathognomonic biochemical triad includes hyperinsulinism, fasting hypoglycaemia and postprandial hyperglycaemia .
Infants with the severe variant have a poor prognosis, succumbing to sepsis due to immunodeficiency. There is no established curative treatment, but exogenous administration of IGF-1 can be used in all insulin resistance syndromes to improve glycaemic control, to reduce levels of hyperinsulinaemia and the secondary effects of hyperinsulinism.