Heterozygous IGFALS gene variants in idiopathic short stature and normal children: impact on height and the IGF system.

BACKGROUND: In acid-labile subunit (ALS)-deficient families, heterozygous carriers of IGFALS gene mutations are frequently shorter than their wild-type relatives, suggesting that IGFALS haploinsufficiency could result in short stature. We have characterized IGFALS gene variants in idiopathic short stature (ISS) and in normal children, determining their impact on height and the IGF system. PATIENTS AND METHODS: In 188 normal and 79 ISS children levels of IGF-1, IGFBP-3, ALS, ternary complex formation (TCF) and IGFALS gene sequence were determined. RESULTS: In sum, 9 nonsynonymous or frameshift IGFALS variants (E35Gfs*17, G83S, L97F, R277H, P287L, A330D, R493H, A546V and R548W) were found in 10 ISS children and 6 variants (G170S, V239M, N276S, R277H, G506R and R548W) were found in 7 normal children. If ISS children were classified according to the ability for TCF enhanced by the addition of rhIGFBP-3 (TCF+), carriers of pathogenic IGFALS gene variants were shorter and presented lower levels of IGF-1, IGFBP-3 and ALS in comparison to carriers of benign variants. In ISS families, subjects carrying pathogenic variants were shorter and presented lower IGF-1, IGFBP-3 and ALS levels than noncarriers. CONCLUSIONS: These findings suggest that heterozygous IGFALS gene variants could be responsible for short stature in a subset of ISS children with diminished levels of IGF-1, IGFBP-3 and ALS.

A novel missense mutation in the SH2 domain of the STAT5B gene results in a transcriptionally inactive STAT5b associated with severe IGF-I deficiency, immune dysfunction, and lack of pulmonary disease.

CONTEXT: Signal transducer and activator of transcription 5b (STAT5b) deficiency, first reported in a patient who carried a p.Ala630Pro missense mutation in the Src homology 2 (SH2) domain, results in a rare clinical condition of GH insensitivity (GHI), IGF-I deficiency (IGFD), and severe immune dysregulation manifesting as progressive worsening of pulmonary function. PATIENT: The new patient presented with severe cutaneous eczema, episodic infections in the first years of life, and autoimmune thyroiditis. Immunological evaluation revealed T lymphopenia, but severe pulmonary symptoms were notably absent. She concomitantly exhibited pronounced growth failure, reaching an adult height of 124.7 cm [-5.90 SD score (SDS)]. Endocrine evaluations (normal provocative GH tests; low serum IGF-I, -3.7 SDS, and IGF-binding protein-3, -4.5 SDS) were consistent with GHI and IGFD. RESULTS: Analysis of the STAT5B gene revealed a novel homozygous missense mutation, p.Phe646Ser, located within the ßD' strand of the SH2 domain. Reconstitution studies demonstrated expression of the p.Phe646Ser variant was less robust than wild type but, in contrast to the previously described STAT5B p.Ala630Pro SH2 mutation, could be phosphorylated in response to GH and interferon-γ. The phosphorylated p.Phe646Ser, however, could not drive transcription. CONCLUSION: A novel STAT5B p.Phe646Ser mutation has been identified in a patient with clinical characteristics of STAT5b deficiency. Only the second STAT5B missense mutation identified, its lack of transcriptional activities despite GH-induced phosphorylation, confirms the crucial role of STAT5b for regulating the expression of IGF1 and provides insights into the importance of the SH2 ßD' strand for full STAT5b transcriptional activities. Whether the phosphorylated p.Phe646Ser variant retained functions that prevented pulmonary distress remains unresolved.

Normal growth spurt and final height despite low levels of all forms of circulating insulin-like growth factor-I in a patient with acid-labile subunit deficiency.

BACKGROUND: In a recently described patient with acid-labile subunit (ALS) deficiency, the inability to form ternary complexes resulted in a marked reduction in circulating total insulin-like growth factor (IGF)-I, whereas skeletal growth was only marginally affected. To further study the role of circulating versus locally produced IGF-I in skeletal growth in this patient, we now describe in detail growth changes and their relationship with several components of the circulating IGF system. DESIGN AND METHODS: We followed growth and development up to the final height in a patient with complete ALS deficiency and determined both spontaneous and growth hormone (GH)-stimulated changes in the IGF system, including measurements of total, free and bioactive IGF-I, total IGF-II and insulin-like growth factor binding protein (IGFBP)-1, IGFBP-2 and IGFBP-3. RESULTS: The patient had a delayed growth and pubertal onset. Six months of GH treatment had no effect on growth. At the age of 19.3 years, he spontaneously completed puberty and had a normal growth spurt for a late adolescent (peak height velocity of 8.4 cm/year). A normal final height was attained at 21.3 years (167.5 cm; -0.78 SDS). During as well as after puberty, basal levels of total, free and bioactive IGF-I were low, as were total IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3. GH treatment for 6 months normalized free IGF-I and increased bioactive IGF-I, but had no effect on growth velocity. CONCLUSIONS: This case story shows that in the presence of complete ALS deficiency, a height within normal limits can be obtained despite low levels of all forms of circulating IGF-I. Furthermore, the patient presented a delayed but normal growth spurt without any marked increment of circulating IGF-I.