Phenotypic Effects of Null and Haploinsufficiency of Acid-Labile Subunit in a Family with Two Novel<i>IGFALS</i>Gene Mutations

Context: Acid-labile subunit (ALS) deficiency due to homozygous inactivation of the ALS gene (IGFALS) is associated with moderate short stature, and in few cases pubertal delay. The clinical expression of heterozygosity is unknown. Objective: To investigate the clinical, laboratory, and radiological features of homozygous and heterozygous carriers of a novel mutation in the ALS gene in comparison with non-carriers. Subjects: Three short Kurdish brothers and their relatives. Results: The index cases presented with short stature, microcephaly, and low circulating IGF-I and IGFbinding protein-3 (IGFBP-3), and undetectable ALS levels. Two were known with a low bone mineral density and one of them had suffered from two fractures. We found a novel homozygous ALS gene mutation resulting in a premature stop codon (c.1490dupT, p.Leu497PhefsX40). The IGF-I, IGFBP-3, and ALS 150 kDa ternary complex was absent, and ALS proteins in serum were not detected with western blot. IGFPB-1 and IGFPB-2 were low and there was a mild insulin resistance. Five heterozygous carriers tended to have a lower height and head circumference than five non-carriers, and had low plasma ALS and IGFBP-3 levels. Bone mineral (apparent) density was low in two out of three homozygous carriers, and also in four out of nine relatives. Conclusions: The clinical presentation of homozygous ALS mutations may, besides short stature, include microcephaly. Heterozygous carriers may have less statural and head growth, suggestive for a gene dosage effect.

Section: Introductionmentioning

confidence: 99%

Homozygous and heterozygous expression of a novel mutation of the acid-labile subunit

Duyvenvoorde

Kempers²,

Twickler³

et al. 2008

“…The third child reported, a 17-year-old boy with a heterozygous IGFALS mutation had the phenotype of short stature (height SDS K2.0), normal weight (56 kg at 15.3 years, weight SDS K0.3) and severe pubertal delay (Tanner stage 1 at age 16.1 years, onset of puberty 16.9 years), similar to CDGP (11). His father and mother were relatively tall with height measurements of C1.5 SDS and K0.9 SDS respectively.…”

Section: Discussionmentioning

confidence: 89%

“…The absence of mutations in our wellcharacterised cohort indicates that IGFALS mutations are not a common occurrence in CDGP. However, such variants should nonetheless be considered, in particular if the short stature-delayed puberty phenotype co-exists with clinical markers atypical of CDGP, such as learning disabilities, evidence of dysmorphism or a history of frequent fractures (8)(9)(10)(11)(12)(13).…”

Section: Discussionmentioning

confidence: 99%

“…Another study reported a point mutation in IGFALS at nucleotide position 1318 in a child presenting with short stature and relatively mild pubertal delay (9,10). Three other children, two with pubertal delay and one with significant short stature, have been reported in a family with novel compound heterozygous mutations in exon 2 of IGFALS (11). There are also recent reports of IGFALS mutations in three males with idiopathic short stature (12) and in two other males with short stature and osteoporosis (13).…”

Section: Introductionmentioning

confidence: 99%

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Constitutional delay of growth and puberty is not commonly associated with mutations in the acid labile subunit gene.

Banerjee

Hanson

Perveen

et al. 2008

Objectives: Constitutional delay of growth and puberty (CDGP) is a common clinical condition that may be inherited as an autosomal dominant, recessive or X-linked trait. However, single-gene defects underlying CDGP have not yet been identified. A small number of children (to date 10) with modest growth failure and in the majority delayed puberty, a phenotype similar to that of CDGP, have been reported to carry mutations in the IGF acid labile subunit (IGFALS) gene which encodes the ALS, a part of the ternary complex carrying IGF-I in the circulation. The aim of our study was to screen a wellcharacterised CDGP cohort exhibiting a range of growth retardation and pubertal delay for pathogenic sequence variants in IGFALS. Design and methods: We used denaturing high performance liquid chromatography (dHPLC) to screen for IGFALS mutations in DNA samples from 90 children (80 males) with CDGP of predominantly White European origin. DNA fragments generating abnormal waveforms were directly sequenced. Results: No IGFALS mutation was identified in the coding sequences or exon-intron boundaries in our CDGP cohort. One abnormal waveform pattern in dHPLC in 15 children with CDGP was found to represent a recognised synonymous single-nucleotide polymorphism of the coding transcript in the second exon in residue 210 of IGFALS. Conclusions: IGFALS sequence variants are unlikely to be a common association with pubertal delay in children with CDGP.

“…The adult male patient with STAT5B mutation previously described had normal LH, FSH, and testosterone despite elevation of PRL levels (7,8), suggesting a lack of action of circulating PRL. The pubertal delay observed in patients with STAT5B defects can be explained by the state of chronic illness or related to the low levels of circulating IGF1 (20)(21)(22). For this reason, at this moment, we did not recommend any specific treatment for the mild hyperprolactinemia observed in these patients.…”

Section: Discussionmentioning

confidence: 92%

A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings

Pugliese-Pires

Tonelli

Dora

et al. 2010

Background: GH insensitivity (GHI) syndrome caused by STAT5B mutations was recently reported, and it is characterized by extreme short stature and immune dysfunction. Treatment with recombinant human IGF1 (rhIGF1) is approved for patients with GHI, but the growth response to this therapy in patients with STAT5B mutations has not been reported. Objectives: To report the clinical features, molecular findings, and the short-term growth response to rhIGF1 therapy in patients with STAT5B mutation. Subjects and methods: Hormonal and immunological evaluations were performed in two male siblings with GHI associated with atopic eczema, interstitial lung disease, and thrombocytopenic purpura. STAT5B genes were directly sequenced. The younger sibling was treated with rhIGF1 at a dose of 110 mg/kg BID. Results: Both siblings had laboratory findings compatible with GHI associated with hyperprolactinemia. Lymphopenia and reduced number of natural killer cells without immunoglobulin abnormalities were observed. STAT5B sequence revealed a homozygous frameshift mutation (p.L142fsX161) in both siblings. The younger sibling (9.9 years of age) was treated with rhIGF1 at appropriate dosage, and he did not present any significant change in his growth velocity (from 2.3 to 3.0 cm/year after 1.5 years of therapy). The presence of a chronic illness could possibly be responsible for the poor result of rhIGF1 treatment. Further studies in patients with STAT5B defects are necessary to define the response to rhIGF1 treatment in this disorder. Conclusion: GHI associated with immune dysfunction, especially interstitial lung disease, and hyperprolactinemia is strongly suggestive of a mutation in STAT5B in both sexes.