A novel mutation in IGFALS , c.380 T > C (p.L127P), associated with short stature, delayed puberty, osteopenia and hyperinsulinaemia in two siblings: insights into the roles of insulin growth factor‐1 ( IGF 1)

Summary Background The acid‐labile subunit ( ALS ) protein is crucial for maintaining the circulating IGF / IGFBP system. Inactivating mutations of IGFALS result in IGF 1 deficiency associated with growth retardation. Although the first IGFALS mutation in humans was described in 2004, only 16 mutations have been reported since. Moreover, the phenotype of affected patients as a consequence of ALS deficiency is still highly variable. We assessed whether children with idiopathic short stature ( ISS ) harbour mutations in IGFALS and characterized affected patients' phenotype. Design Sixty‐five children with ISS were enrolled in the study. Serum ALS levels were measured by ELISA , and IGFALS was sequenced. Results A novel homozygous mutation in IGFALS , c.380 T > C (p.L127 P ), was identified in two siblings of a consanguineous family. The proband, a 17·75‐year‐old male, was −1·9 SDS in height and −4·5 SDS in weight. Exaggerated stimulated GH (38 ng/ml) and extremely low IGF 1 and IGFBP 3 (<25 and <500 ng/ml, respectively) indicated GH insensitivity. Both affected siblings had low or no ALS (43 and 0  mU /ml, respectively). They were also mildly small for gestational age, severely underweight and showed osteopenia, insulin insensitivity and delayed and slow puberty progression. Conclusions Acid‐labile subunit deficiency due to IGFALS mutations is a rare cause of growth retardation in children. The unique combination of features presented by the two affected siblings emphasizes the important role of IGF 1 in bone formation, insulin regulation and the pubertal process, in addition to its crucial effect on growth. Long‐term follow‐up is indicated since the clinical outcome with respect to osteoporosis, diabetes mellitus and fertility has not been recognized.