GHinsensitive

Growth hormone insensitivity (GHI), also called GH insensitivity, refers to a set of rare disorders in which tissues fail to respond properly to growth hormone (GH). In these conditions, circulating GH is often normal or elevated, while the downstream signal to produce insulin-like growth factor 1 (IGF‑1) is blunted, resulting in deficient IGF‑1 activity and impaired growth. The most well characterized form is Laron syndrome, caused by mutations in the growth hormone receptor (GHR) gene and inherited in an autosomal recessive manner. Other causes include post‑receptor defects in GH signaling and defects in IGF‑1 action, which produce a similar biochemical profile of high GH and low IGF‑1.

In GH insensitivity, the liver and other tissues fail to produce IGF‑1 in response to GH, leading to disproportionately short stature and skeletal growth impairment. Clinically, individuals typically present with severe short stature beginning in early childhood, often with distinctive facial features and relatively normal or increased GH levels. Hypoglycemia in infancy can occur in some forms.

Diagnosis relies on biochemical and genetic evidence. Laboratory findings show elevated GH with low or inappropriately normal IGF‑1 and IGF‑binding protein‑3 levels; confirmation is usually achieved by genetic testing for GHR mutations or other components of the GH–IGF axis, and by assessing IGF‑1 generation in response to GH.

Treatment centers on replacing IGF‑1 with recombinant human IGF‑1 (mecasermin), which can improve growth velocity. Growth hormone therapy is ineffective in GH insensitivity and is not recommended. Management includes monitoring for hypoglycemia during IGF‑1 therapy and addressing metabolic and developmental needs.

Prognosis varies with early recognition and treatment; final adult height remains limited in many cases. GH insensitivity is rare, with Laron syndrome being most extensively documented, and is estimated to occur in only a small fraction of individuals with short stature.