Donohue syndrome

Alternate names

Donohue's syndrome;leprechaunism;leprechaunism syndrome

Definition

Donohue syndrome is a rare disorder characterized by severe insulin resistance, a condition in which the body's tissues and organs do not respond properly to the hormone insulin.

Summary

Insulin normally helps regulate blood sugar levels by controlling how much sugar (in the form of glucose) is passed from the bloodstream into cells to be used as energy. Severe insulin resistance leads to problems with regulating blood sugar levels and affects the development and function of organs and tissues throughout the body. Donohue syndrome is one of a group of related conditions described as inherited severe insulin resistance syndromes. These disorders, which also include Rabson-Mendenhall syndrome and type A insulin resistance syndrome, are considered part of a spectrum. Donohue syndrome represents the most severe end of the spectrum; most children with this condition do not survive beyond age 2.

Epidemiology

Donohue syndrome is estimated to affect less than 1 per million people worldwide. Several dozen cases have been reported in the medical literature.

Cause

Donohue syndrome results from mutations in the INSR gene. This gene provides instructions for making a protein called an insulin receptor, which is found in many types of cells. Insulin receptors are embedded in the outer membrane surrounding the cell, where they attach (bind) to insulin circulating in the bloodstream. This binding triggers signaling pathways that influence many cell functions.

The INSR gene mutations that cause Donohue syndrome greatly reduce the number of insulin receptors that reach the cell membrane or disrupt the function of these receptors. Although insulin is present in the bloodstream, without functional receptors it cannot exert its effects on cells and tissues. This severe resistance to the effects of insulin impairs blood sugar regulation and affects many aspects of development in people with Donohue syndrome.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

Severe insulin resistance underlies the varied signs and symptoms of Donohue syndrome. Individuals with Donohue syndrome are unusually small starting before birth, and affected infants experience failure to thrive, which means they do not grow and gain weight at the expected rate. Additional features that become apparent soon after birth include a lack of fatty tissue under the skin (subcutaneous fat); wasting (atrophy) of muscles; excessive body hair growth (hirsutism); multiple cysts on the ovaries in females; and enlargement of the nipples, genitalia, kidneys, heart, and other organs.

Most affected individuals also have a skin condition called acanthosis nigricans, in which the skin in body folds and creases becomes thick, dark, and velvety. Distinctive facial features in people with Donohue syndrome include bulging eyes, thick lips, upturned nostrils, and low-set ears. Affected individuals develop recurrent, life-threatening infections beginning in infancy.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Fasting hypoglycemia(Low blood sugar when fasting)
• Hyperkeratosis
• Insulin resistance(Body fails to respond to insulin)
• Postnatal growth retardation(Growth delay as children)
• Postprandial hyperglycemia
• Reduced subcutaneous adipose tissue(Reduced fat tissue below the skin)
• Severe intrauterine growth retardation(Severe prenatal growth deficiency)

30%-79% of people have these symptoms

• Abdominal distention(Abdominal bloating)
• Acanthosis nigricans(Darkened and thickened skin)
• Clitoral hypertrophy(Enlarged clitoris)
• Enlarged kidney(Large kidneys)
• Facial hypertrichosis(Increased facial hair growth)
• Failure to thrive(Faltering weight)
• Hepatomegaly(Enlarged liver)
• Hyperinsulinemia
• Hypertrophic cardiomyopathy(Enlarged and thickened heart muscle)
• Intellectual disability(Mental deficiency)
• Labial hypertrophy(Enlargement of the labia)
• Long penis(Enlarged penis)
• Overgrowth of external genitalia
• Prominent nipples
• Recurrent infantile hypoglycemia(Recurrent low blood sugar in infant)
• Severe global developmental delay
• Skeletal muscle atrophy(Muscle degeneration)

Diagnosis

Clinical Findings

• Progressive intrauterine growth restriction (IUGR) from the early third trimester and postnatal failure to thrive
• Dysmorphic facial features characterized by proptosis; infra-orbital folds; large, low-set, posteriorly rotated ears; thick vermilion of the upper and lower lips; and gingival hypertrophy [Grasso et al 2013]
• Hypotonia
• Developmental delay

Other:

• Dry skin and reduced subcutaneous fat
• Hypertrichosis
• Acanthosis nigricans
• Prominent nipples
• Abdominal distention
• Organomegaly
• Genital enlargement (males and females)
• Rectal hypertrophy and prolapse

Laboratory Findings Severe hyperinsulinemia: extremely high plasma insulin and C-peptide levels with fluctuating blood glucose levels (typically fasting hypoglycemia and postprandial hyperglycemia) Ketoacidosis not reported.

Imaging Findings Hypertrophic cardiomyopathy

• Enlarged kidneys, liver, and spleen
• Nephrocalcinosis
• Enlarged polycystic ovaries

The diagnosis of INSR-related severe syndromic insulin resistance is established in a proband with the characteristic findings described above and identification of biallelic INSR pathogenic variants on molecular genetic testing.

Treatment

There are currently no effective treatments for the insulin resistance or other manifestations of DS. Postprandial hyperglycemia does not respond to insulin treatment or glucose-lowering therapies such as metformin.

Frequent feedings (e.g., breastfeeding, nasogastric tube, and/or intravenous glucose) are used to prevent hypoglycemia .

NIH genetic and rare disease info

• NIH info on Donohue syndrome

Donohue syndrome is a rare disease.

Donohue syndrome Resources
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