Growth hormone insensitivity with immunodeficiency

Other Names: Growth hormone insensitivity due to postreceptor defect; Laron syndrome due to postreceptor defect

Definition

Growth hormone insensitivity syndrome (GHIS) is a group of diseases characterized by marked short stature associated with normal or elevated growth hormone (GH) concentrations, which fail to respond to exogenous GH administration.GHIS comprises growth delay due to IGF-1 deficiency, growth delay due to IGF-1 resistance, Laron syndrome, short stature due to STAT5b deficiency and primary acid-labile subunit (ALS) deficiency

Intrauterine growth and birth size are usually subnormal. Postnatal growth is slowed. Facial dysmorphism is common and includes microcephaly, thin upper and everted lower lips and small chin. Disproportional growth, delayed motor development and delayed puberty have been described in some cases and relative obesity may occur in young adults. Intellectual development varies from normal intelligence to intellectual deficiency. Despite sharing short stature and the classical biochemical features of GH insensitivity, affected individuals present heterogeneous clinical features depending on the genetic condition. Hearing loss has been described in some cases of IGF-1.

Epidemiology

A few cases of IGF-1 deficiency, IGF-1 resistance, STAT5B and ALS deficiencies, and more than 250 cases of Laron syndrome have been reported in the literature so far. Males and females are equally affected.

Cause

GHIS is due to mutations in the growth hormone receptor (GHR) gene (Laron syndrome) or to post receptor defects due to mutations in the IGF-1 (IGF-1 deficiency and IGF-1 resistance), IGFALS (short stature due to primary ALS deficiency) or STAT5B genes (STAT5b deficiency).

Inheritance

GHIS is inherited in autosomal recessive pattern.

Symptoms

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

• Abnormal facial shape(Unusual facial appearance)
• Everted lower lip vermilion(Drooping lower lip)
• Failure to thrive(Faltering weight)
• Hypercholesterolemia(Elevated serum cholesterol)
• Insulin resistance(Body fails to respond to insulin)
• Microcephaly(Abnormally small skull)
• Short stature(Decreased body height)

30%-79% of people have these symptoms

• Delayed eruption of teeth(Delayed eruption)
• Delayed skeletal maturation(Delayed bone maturation)
• Fine hair(Fine hair shaft)
• Hypoglycemia(Low blood sugar)
• Hypoplasia of penis(Underdeveloped penis)
• Type II diabetes mellitus(Noninsulin-dependent diabetes)

5%-29% of people have these symptoms

• Abnormality of the nail
• Diabetes insipidus
• Hearing impairment(Deafness)
• High pitched voice
• Hypogonadism(Decreased activity of gonads)
• Immunodeficiency(Decreased immune function)
• Intellectual disability(Mental deficiency)
• Large fontanelles(Wide fontanelles)
• Truncal obesity

Diagnosis

Hormonal tests reveal normal or high serum concentrations of GH. IGF-1 and growth hormone binding protein (GHBP) levels depend on the disease-causing mutations. IGF-1 levels are low in cases ofGHR defects, STAT5b, IGF-1 and ALS deficiencies, and high in cases of IGF-1 resistance. Genetic tests should be performed to make a precise etiological diagnosis.

Treatment

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Mecasermin (Brand name: Increlex®)Long-term treatment of growth failure in children with severe primary IGF-1 deficiency (Primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to growth hormone.
• Mecasermin rinfabate (Brand name: Iplex®) Treatment of growth failure in children with severe primary IGF-1 deficiency (Primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to growth hormone.

NIH genetic and rare disease info

• NIH info on Growth hormone insensitivity with immunodeficiency

Growth hormone insensitivity with immunodeficiency is a rare disease.

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