Donohue syndrome

Overview

Donohue syndrome, also known as leprechaunism, is an extremely rare and severe genetic disorder characterized by insulin resistance, growth retardation, and distinctive facial and bodily features. It is a congenital condition that affects infants from birth and is typically fatal within the first year of life. The syndrome is named after Dr. William L. Donohue, who first described it in the 1940s. The term "leprechaunism" was originally used to describe the unique facial appearance of affected individuals, though it is now considered outdated and insensitive.

Causes

Donohue syndrome is caused by mutations in the INSR gene, which encodes the insulin receptor protein. This receptor is critical for allowing insulin—a hormone that regulates glucose metabolism—to bind to cells and initiate glucose uptake. In Donohue syndrome, mutations result in either a complete absence or severe malfunction of insulin receptors, leading to extreme insulin resistance and impaired growth and metabolism. The condition is inherited in an autosomal recessive pattern, meaning both parents must carry one copy of the faulty gene.

Symptoms

Symptoms of Donohue syndrome are apparent at or shortly after birth and affect multiple body systems. Key features include:

• Intrauterine growth retardation (IUGR): Poor fetal growth resulting in very low birth weight.

• Dysmorphic facial features: Including large, low-set ears, flared nostrils, thick lips, and a wide mouth.

• Hypertrichosis: Excessive hair growth on the face and body.

• Abdominal distension: Often due to enlarged organs or gastrointestinal issues.

• Enlarged genitalia: Common in both males and females.

• Lipoatrophy: Near-complete loss of subcutaneous fat.

• Hyperinsulinemia: Extremely elevated insulin levels due to insulin resistance.

• Feeding difficulties and failure to thrive: Ongoing nutritional challenges due to metabolic dysfunction.

Diagnosis

Diagnosis of Donohue syndrome is based on clinical presentation, biochemical tests, and genetic analysis. Steps include:

• Physical examination: Identifying characteristic dysmorphic features and growth abnormalities.

• Blood tests: Reveal extremely high levels of insulin and elevated blood glucose or paradoxical hypoglycemia.

• Glucose tolerance test: Often shows an impaired response to insulin.

• Genetic testing: Confirms mutations in the INSR gene.

• Family history assessment: May show a pattern of consanguinity or recurrence in siblings.

Treatment

There is no cure for Donohue syndrome, and treatment is largely supportive and symptomatic. Management may include:

• Nutritional support: High-calorie feedings, sometimes requiring tube feeding to manage failure to thrive.

• Insulin-sensitizing agents: Experimental use of medications like recombinant human insulin-like growth factor 1 (rhIGF-1) to bypass defective insulin receptors.

• Monitoring and managing metabolic complications: Including blood sugar fluctuations and electrolyte imbalances.

• Multidisciplinary care: Including endocrinologists, geneticists, nutritionists, and palliative care specialists.

Research into potential gene therapies and other novel interventions is ongoing but has not yet yielded a definitive treatment.

Prognosis

The prognosis for Donohue syndrome is extremely poor. Most affected individuals do not survive beyond the first year of life due to complications such as severe hypoglycemia, cardiac failure, or infections. Rare cases have been reported where children survived into early childhood with intensive medical care, but long-term survival remains exceedingly rare. Early diagnosis and supportive care can help improve comfort and quality of life, even though the overall outlook remains grim.