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).

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. 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.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.

Interferon treatment in children with chronic hepatitis B: an Israeli experience.

OBJECTIVE: To summarize the experience of two pediatric gastroenterology centers in northern Israel using interferon alpha to treat children with chronic hepatitis B. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 59 children with chronic HBV. Forty-nine children were treated with subcutaneous IFN alpha at dosages of 10 MU/m (n = 12) or 5 MU/m (n = 37) three times a week for 6 months. Children treated with 5 MU/m IFN alpha were a heterogeneous group with regard to their alanine aminotransferases levels: 11/37 (group 1) had ALT twice above the upper limit of normal and 26/37 (group 2) had normal or less than twice ULN elevations of ALT. Ten children were observed without treatment. RESULTS: Sustained biochemical and virologic response occurred in 9/12 children (75%) treated with 10 MU/m IFN alpha, 3/11 (27%) in group 1 given 5 MU/m (P = 0.0315) and 4% (1/26) in group 2 treated with 5 MU/m. After 4 years follow-up, similar seroconversion rates were present in children who had baseline ALT higher than twice ULN, whether they were treated with 10 or 5 MU/m IFN alpha (83 vs. 73%). Children with normal or slightly abnormal baseline ALT also had a similar anti-hepatitis B e antigen seroconversion rate at the end of follow-up, whether they had been treated with IFN alpha or not (2/26, 8%, in group 2 and 4/10, 40%, in the untreated children, not significantly different). CONCLUSIONS: The results of IFN alpha treatment in this group of Israeli children are similar to these reported in the literature and reinforce the current consensus, which recommends INF alpha only for children with chronic HBV and significantly elevated liver enzymes.