OVERVIEW

What is Rabson-Mendenhall syndrome?

Rabson-Mendenhall syndrome is a rare genetic disorder caused by mutations in the insulin receptor gene, leading to insulin resistance and a range of symptoms. First identified in 1956 by Rabson and Mendenhall, the condition was named after them.

The syndrome is primarily characterized by severe insulin resistance, accompanied by hirsutism, acanthosis nigricans, distinctive facial features, reduced subcutaneous fat, abnormal tooth development, pineal hyperplasia, thickened nails, genital hypertrophy, abdominal distension, and precocious thoughts. Some children may experience fasting hypoglycemia and postprandial hyperglycemia.

Currently, there is no effective treatment for this syndrome, and it cannot be cured. Management focuses on symptom control. Most patients survive only until adolescence.

Is Rabson-Mendenhall syndrome common?

Rabson-Mendenhall syndrome is extremely rare, with only a few dozen cases reported worldwide to date.

SYMPTOMS

What are the common symptoms and manifestations of Rabson-Mendenhall syndrome?

The common manifestations of Rabson-Mendenhall syndrome mainly include:

Acanthosis nigricans (dark brown skin with velvety, papillomatous growths in areas like the armpits, neck, groin, and vulva, often mistaken for "poor hygiene"), hirsutism, reduced subcutaneous fat, dry skin, thickened skin, growth retardation, abnormal facial features, arched lips, premature but underdeveloped teeth, fissured tongue, thickened nails, joint hyperextensibility, enlarged external genitalia or precocious puberty. Some children may also exhibit kidney malformations or cardiac abnormalities.

All affected children have severe hyperinsulinemia, and some may progress to diabetes, leading to diabetic ketoacidosis or death. Insulin levels gradually decline with age, sometimes dropping to zero. Most children survive to 5–15 years of age.

How does Rabson-Mendenhall syndrome progress?

The progression of Rabson-Mendenhall syndrome can be divided into three stages:

• 0–1 year: High insulin levels suppress hepatic glucose output, but peripheral glucose utilization is severely impaired. Infants primarily exhibit fasting hypoglycemia and postprandial hyperglycemia.

• 3–4 years: As insulin levels decline, hepatic glucose suppression weakens, leading to persistent hyperglycemia.

• 6–7 years and beyond: A sharp drop in insulin reduces its inhibition of fatty acid oxidation, eventually causing diabetic ketoacidosis. Survival depends on residual insulin receptor binding capacity.

What diseases can Rabson-Mendenhall syndrome cause?

The most common complication of Rabson-Mendenhall syndrome is diabetic ketoacidosis.

CAUSES

What causes Rabson-Mendenhall syndrome?

Rabson-Mendenhall syndrome is a genetic disorder caused by mutations in the insulin receptor gene. These mutations lead to insulin resistance.

Who is most likely to develop Rabson-Mendenhall syndrome?

Individuals whose parents carry mutations in the insulin receptor gene have a higher risk of inheriting the condition.

Is Rabson-Mendenhall syndrome contagious?

No, it is not contagious.

Is Rabson-Mendenhall syndrome hereditary?

Yes, it is hereditary and follows an autosomal recessive inheritance pattern. If both parents carry the mutated insulin receptor gene, their offspring have a higher likelihood of inheriting the disease.

DIAGNOSIS

How is Rabson-Mendenhall syndrome diagnosed?

When diagnosing Rabson-Mendenhall syndrome, doctors primarily consider the patient's distinctive clinical manifestations:

• Onset in childhood, coarse facial skin, pineal hyperplasia, dental abnormalities, growth retardation, genital hypertrophy, and abdominal distension;

• Hyperinsulinemia with or without impaired glucose tolerance;

• Acanthosis nigricans, hyperandrogenism, polycystic ovaries, and absence of obesity;

• No detection of insulin receptor antibodies or other diabetes-specific antibodies in blood tests;

• No response to insulin or oral hypoglycemic therapy.

Additionally, doctors need to perform genetic testing for mutations in the insulin receptor gene to confirm the diagnosis.

What tests are needed for Rabson-Mendenhall syndrome?

Generally, blood tests, oral examinations, and genetic mutation testing are required.

• Blood tests: An oral glucose tolerance test (OGTT) with simultaneous insulin release testing can indicate abnormal blood sugar levels and hyperinsulinemia. Negative results for diabetes autoantibodies (e.g., anti-islet cell antibodies and anti-insulin antibodies) support the diagnosis.

• Oral examination: Early tooth replacement, extensive dental caries, crowded teeth, skeletal crossbite tendency, and residual roots—all indicative of dental abnormalities—support the diagnosis.

• Genetic mutation testing: Analysis of mutations in the insulin receptor gene can confirm the diagnosis.

Which diseases are easily confused with Rabson-Mendenhall syndrome? How to differentiate them?

Mutations in the insulin receptor gene can cause severe insulin resistance syndromes, which are classified into Donohue syndrome (leprechaunism), Rabson-Mendenhall syndrome, and Type A insulin resistance syndrome based on symptoms. These syndromes differ significantly in disease severity and outcomes.

Donohue syndrome is the most severe, often fatal in infancy. Rabson-Mendenhall syndrome patients typically survive until adolescence, while Type A insulin resistance syndrome is milder, with patients often living into adulthood and eventually succumbing to diabetic complications or experiencing symptom improvement over time.

Due to shared insulin resistance, Rabson-Mendenhall syndrome must also be distinguished from lipodystrophy syndromes and Type B insulin resistance.

Key differences include:

• Type A insulin resistance: Caused by insulin receptor gene mutations, characterized by severe insulin resistance, acanthosis nigricans, and hyperandrogenism. It primarily affects young women without obesity, usually involving only one mutated allele. Diabetes is generally mild, and patients often survive into adulthood.

• Leprechaunism: Results from homozygous or compound heterozygous mutations in the insulin receptor gene, inherited autosomal recessively. Features include "elfin" facial traits (wide-set eyes, low-set ears, thick lips, flat nose), intrauterine and postnatal growth retardation, and early mortality (90% die before age 2), often before diabetes or ketoacidosis develops.

• Lipodystrophy syndromes: Can be genetic or acquired. Genetic forms involve insulin receptor gene mutations, while acquired forms have unknown causes. Symptoms include insulin-resistant diabetes, widespread symmetric or complete subcutaneous fat loss, hypertriglyceridemia, low leptin levels, and hepatosplenomegaly.

• Type B insulin resistance: Caused by autoimmune insulin receptor antibodies, primarily affecting middle-aged women. Nearly all patients have other autoimmune diseases (e.g., systemic lupus erythematosus, Sjögren's syndrome).

TREATMENT

Which department should I visit for Rabson-Mendenhall syndrome?

You should go to pediatric endocrinology or endocrinology.

Can Rabson-Mendenhall syndrome resolve on its own?

Rabson-Mendenhall syndrome is a congenital genetic disorder and will not recover on its own.

How is Rabson-Mendenhall syndrome treated?

Currently, there is no effective treatment for Rabson-Mendenhall syndrome, especially for severe insulin resistance. The primary goals of treatment are to manage metabolic disorders caused by insulin resistance (such as hyperglycemia) and actively address complications (such as ketoacidosis).

Generally, treatment for this syndrome can be divided into three aspects:

• First, lifestyle interventions, including calorie restriction and increased aerobic exercise.

• Second, improving blood glucose levels. Medications such as biguanides, sulfonylureas, and insulin sensitizers have been reported, but the results are unsatisfactory. In the absence of effective therapies, oral medications combined with high-dose insulin therapy may be used. Recombinant human insulin-like growth factor 1 (rhIGF-1) can also be tried. One case report showed that a patient with this syndrome achieved good results by combining rhIGF-1 with high doses of metformin, pioglitazone, vildagliptin, and acarbose.

• Finally, for patients with lipodystrophy, improving adipose tissue metabolism with recombinant leptin therapy may reduce food intake and improve fatty liver and hyperglycemia.

Currently, neither recombinant human insulin-like growth factor 1 nor recombinant leptin is available in China.

Does Rabson-Mendenhall syndrome require hospitalization?

Hospitalization is necessary when the syndrome is first suspected or when the condition changes.

Can Rabson-Mendenhall syndrome be cured?

Rabson-Mendenhall syndrome cannot be cured, and most patients only survive until adolescence.

DIET & LIFESTYLE

Does Rabson-Mendenhall syndrome affect fertility?

Patients with Rabson-Mendenhall syndrome typically only survive until adolescence and cannot reproduce.

PREVENTION

How to prevent Rabson-Mendenhall syndrome?

Screening and monitoring family members of patients can help detect the disease early and initiate treatment promptly.

Genetic mutation testing for family members of patients can predict disease occurrence and prevent offspring from being affected.