Rabson–Mendenhall syndrome

Overview

Rabson–Mendenhall syndrome is a rare and severe genetic disorder characterized by extreme insulin resistance, meaning the body's tissues are unable to respond properly to the hormone insulin. This syndrome is classified as a subtype of congenital insulin resistance syndromes, often presenting in infancy or early childhood. It is named after Drs. Rabson and Mendenhall, who first described the condition in 1956.

Individuals with Rabson–Mendenhall syndrome typically exhibit a range of physical abnormalities, endocrine dysfunctions, and metabolic disturbances. The condition is progressive and often life-threatening due to complications arising from persistent hyperglycemia and associated hormonal imbalances. It is inherited in an autosomal recessive manner, making it more prevalent in populations with consanguineous marriages.

Causes

The primary cause of Rabson–Mendenhall syndrome is a mutation in the INSR gene, which encodes the insulin receptor protein. This mutation leads to the production of defective insulin receptors that cannot effectively bind or respond to insulin. As a result, cells fail to absorb glucose from the bloodstream, leading to chronic high blood sugar levels and widespread insulin resistance.

The inheritance pattern is autosomal recessive, meaning that both parents must carry and pass on a defective copy of the gene for a child to be affected. Carriers usually do not show symptoms themselves.

Symptoms

The symptoms of Rabson–Mendenhall syndrome are typically evident early in life, often in infancy. Common clinical features include:

• Severe insulin resistance and hyperinsulinemia

• Acanthosis nigricans (dark, velvety patches of skin, especially in body folds)

• Hypertrichosis (excessive hair growth)

• Dental anomalies (early eruption of teeth, widely spaced teeth)

• Enlarged genitalia in both sexes

• Pineal hyperplasia (leading to abnormal development of the pineal gland)

• Dysmorphic facial features (prominent eyes, large jaw, broad nose)

• Growth abnormalities, including failure to thrive or short stature

• Postprandial hyperglycemia and fasting hypoglycemia

As the disease progresses, affected individuals may develop signs of diabetes mellitus, ketoacidosis, and other endocrine imbalances due to the body's inability to regulate blood glucose effectively.

Diagnosis

Diagnosis of Rabson–Mendenhall syndrome involves a combination of clinical evaluation, laboratory testing, and genetic analysis:

• Clinical assessment: Noting early-onset insulin resistance, characteristic physical features, and growth abnormalities

• Laboratory tests: Extremely elevated insulin levels, abnormal glucose tolerance tests, and signs of hyperglycemia or hypoglycemia

• Genetic testing: Identification of mutations in the INSR gene confirms the diagnosis

• Imaging: May reveal pineal gland abnormalities or other endocrine gland changes

Early genetic counseling is advised for families with a history of the condition or known consanguinity.

Treatment

There is no cure for Rabson–Mendenhall syndrome, and treatment focuses on managing symptoms, improving quality of life, and delaying disease progression. Therapeutic options include:

• High-dose insulin therapy: Often required, but typically ineffective due to extreme insulin resistance

• Recombinant insulin-like growth factor 1 (IGF-1): May help in some patients by bypassing the defective insulin receptor pathway

• Metformin and other insulin-sensitizing agents: Sometimes used to improve glucose control

• Dietary management: Strict control of carbohydrate intake to manage blood sugar levels

• Supportive care: Includes endocrinology follow-up, management of skin and dental issues, and monitoring for complications

Due to the severity of the condition, treatment is typically multidisciplinary and involves endocrinologists, geneticists, dermatologists, and pediatricians.

Prognosis

The prognosis of Rabson–Mendenhall syndrome is generally poor. Most affected individuals do not survive beyond the first or second decade of life due to complications such as diabetic ketoacidosis, severe infections, or multi-organ failure. However, early diagnosis and aggressive supportive care may help in temporarily improving quality of life and slowing disease progression.

Ongoing research into gene therapy and novel insulin-sensitizing agents offers hope for improved future outcomes, but at present, management remains primarily symptomatic and palliative.