title: A novel mutation in IGFALS, c.380T>C (p.L127P), associated with short stature, delayed puberty, osteopenia and hyperinsulinaemia in two siblings: insights into the roles of insulin growth factor-1 (IGF1).
abstract: BACKGROUND
  The acid-labile subunit (ALS) protein is crucial for maintaining the circulating IGF/IGFBP system. Inactivating mutations of IGFALS result in IGF1 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.
  
  
  METHODS
  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.380T>C (p.L127P), 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 IGF1 and IGFBP3 (<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 IGF1 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.
authors.affiliation: Pediatric Endocrine Institute, Ha'Emek Medical Center, Afula, Israel.
authors.forename: Ora
authors.initials: O
authors.lastname: Hess
authors.forename: Morad
authors.initials: M
authors.lastname: Khayat
authors.forename: Vivian
authors.initials: V
authors.lastname: Hwa
authors.forename: Karen E
authors.initials: KE
authors.lastname: Heath
authors.forename: Amnon
authors.initials: A
authors.lastname: Teitler
authors.forename: Yifat
authors.initials: Y
authors.lastname: Hritan
authors.forename: Stavit
authors.initials: S
authors.lastname: Allon-Shalev
authors.forename: Yardena
authors.initials: Y
authors.lastname: Tenenbaum-Rakover
mesh_terms: D000293:Adolescent; D019943:Amino Acid Substitution; D001851:Bone Diseases, Metabolic / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003241:Consanguinity; D004393:Dwarfism, Pituitary / Q000235:genetics*; D005260:Female; D006023:Glycoproteins / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics*; D007223:Infant; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008297:Male; D020125:Mutation, Missense; D011628:Puberty, Delayed / Q000235:genetics*; D035781:Siblings; D013577:Syndrome
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; C075944:insulin-like growth factor binding protein, acid labile subunit; D007334:Insulin-Like Growth Factor I