A Novel Mutation in IGFALS, c.380T>C (p.L127P), Associated with Short Stature, Delayed Puberty, Osteopenia and Hyperinsulinemia in Two Siblings: Insights into the Roles of Insulin Growth Factor-1 (IGF1)

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 632-648-Pediatric Growth Case Reports
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-633
Ora Hess1, Vivian Hwa2, Morad Khayat1, Stavit Allon Shalev1, Amnon Teitler1, Yifat Hritan1, Karen E Heath3 and Yardena Tenenbaum Rakover*1
1Ha'Emek Medical Center, Afula, Israel, 2Oregon Hlth Sci Univ, Portland, OR, 3Hospital Universitario La Paz, Madrid, Spain
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 mutation of IGFALS in humans was described in 2004, only 16 mutations have been reported since. Moreover, the phenotype of affected patients and its relation to ALS deficiency are still inconclusive. The aim of the present study was to assess whether children with idiopathic short stature (ISS) harbor mutations in IGFALS and to characterize the phenotype of the affected patients.

Patients & Methods: 65 children with ISS were enrolled. Serum ALS levels were measured by ELISA and IGFALS was sequenced.

Results: A novel mutation in IGFALS, c.380T>C in exon 2, resulted in substitution of leucine with proline in position 127 (p.L127P); the mutation was identified in the homozygous state in two siblings of a consanguineous family and in the heterozygous state in the parents. The proband, a 17.75-year-old, was -2.9 SDS in height and -4.5 SDS in weight. Exaggerated stimulated GH 38 ng/ml, and extremely low IGF1 and IGFBP3 (<25 ng/ml, <500 ng/ml; respectively) indicated GH insensitivity. His 13.8-year-old sister was -2.8 SDS in height and -3.75 SDS in weight and had very low IGF1 and IGFBP3 (44.5 ng/ml and <500 ng/ml, respectively) and exaggerated peak GH 29 ng/ml in response to stimulation test. A low concentration of ALS was found in both siblings (0 and 43 mU/ml, respectively, mean ± SDS of the control group was 1180 ± 389 mU/ml). Both were mildly small for gestational age, severely underweight, and showed delayed and slow progress in puberty, osteopenia and insulin insensitivity.

Conclusions: ALS deficiency due to IGFALS mutations is a rare cause of growth retardation in children. Our finding of a unique phenotype in 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.

Nothing to Disclose: OH, VH, MK, SAS, AT, YH, KEH, YTR

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: The described project was supported by an award from the Legacy Heritage Fund Limited (HLMH, Inc.).