Donohue syndrome

Donohue syndrome, also known as leprechaunism, is an extremely rare and severe autosomal recessive disorder caused by mutations in the insulin receptor gene (INSR) located on chromosome 19. It represents the most severe form of insulin resistance syndrome. The condition is characterized by intrauterine and postnatal growth restriction, distinctive facial features (including large, low-set ears, flattened nasal bridge, thick lips, and wide nostrils that historically led to the now-outdated term 'leprechaunism'), and profound insulin resistance with paradoxical fasting hypoglycemia and postprandial hyperglycemia. The disease affects multiple body systems. Endocrine abnormalities are central, with markedly elevated circulating insulin levels (hyperinsulinemia) despite severe insulin resistance. Affected infants typically display decreased subcutaneous fat, loose and rugose (wrinkled) skin, hirsutism (excessive body hair), acanthosis nigricans (darkened, thickened skin folds), and enlarged external genitalia or ovarian cysts in females. Musculoskeletal features include muscle wasting and reduced body fat. The liver, pancreas, kidneys, and heart may also be affected, with organomegaly reported in some cases. Failure to thrive is a hallmark feature, and affected infants are highly susceptible to recurrent infections. The prognosis for Donohue syndrome is very poor, with most affected children dying within the first one to two years of life, often from intercurrent infections or cardiac complications. There is currently no curative treatment. Management is largely supportive and may include nutritional optimization, glucose monitoring, and treatment of infections. Recombinant insulin-like growth factor 1 (rhIGF-1, mecasermin) has been used in some cases to partially bypass the defective insulin receptor signaling, though its efficacy in significantly altering the disease course remains limited. Genetic counseling is recommended for affected families.

Common questions about Donohue syndrome