Short Stature Associated with a Novel Heterozygous Mutation in theInsulin-Like Growth Factor 1Gene

The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFkB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T 3 /T 4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in w3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.

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“…Heterozygous carriers of IGF1 mutations or deletions are w1 S.D. shorter than non-carriers (71,73,74,76).…”

Section: Gh Deficiencymentioning

confidence: 96%

“…Patients with a homozygous hypomorphic mutation (72) or specific heterozygous mutations (73,74) presented with less severe growth failure and normal hearing (reviewed in (75)). Heterozygous carriers of IGF1 mutations or deletions are w1 S.D.…”

Section: Gh Deficiencymentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Wit

Oostdijk

Losekoot

et al. 2016

European Journal of Endocrinology

150

132

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“…Furthermore, heterozygosity for the same gene defect may be associated with a mild negative effect on growth (approx. 1 SD), as observed for mutations in IGF1 [9,13,14] and IGFALS [15,16,17]. On the other hand, some cases of heterozygosity for a GHR mutation are associated with pronounced growth failure [12,18].…”

Section: Introductionmentioning

confidence: 97%

Genetic Analysis of Short Children with Apparent Growth Hormone Insensitivity

Wit

Duyvenvoorde²,

Scheltinga³

et al. 2012

Horm Res Paediatr

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Background/Aims: In short children, a low IGF-I and normal GH secretion may be associated with various monogenic causes, but their prevalence is unknown. We aimed at testing GH1, GHR, STAT5B, IGF1, and IGFALS in children with GH insensitivity. Subjects and Methods: Patients were divided into three groups: group 1 (height SDS <–2.5, IGF-I <–2 SDS, n = 9), group 2 (height SDS –2.5 to –1.9, IGF-I <–2 SDS, n = 6) and group 3 (height SDS <–1.9, IGF-I –2 to 0 SDS, n = 21). An IGF-I generation test was performed in 11 patients. Genomic DNA was used for direct sequencing, multiplex ligation-dependent probe amplification and whole-genome SNP array analysis. Results: Three patients in group 1 had two novel heterozygous STAT5B mutations, in two combined with novel IGFALS variants. In groups 2 and 3 the association between genetic variants and short stature was uncertain. The IGF-I generation test was not predictive for the growth response to GH treatment. Conclusion: In severely short children with IGF-I deficiency, genetic assessment is advised. Heterozygous STAT5B mutations, with or without heterozygous IGFALS defects, may be associated with GH insensitivity. In children with less severe short stature or IGF-I deficiency, functional variants are rare.

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“…All pathological mutations were present in the homozygous state with heterozygous carriers of normal stature but below the means for age and sex. Interestingly, a putative dominantly transmitted heterozygous frameshift mutation of the IGF1 gene was recently reported as the cause of short stature in a family [7], although subsequent functional studies did not support this hypothesis [8]. …”

Section: Introductionmentioning

confidence: 99%

Identification of a Novel Heterozygous IGF1 Splicing Mutation in a Large Kindred with Familial Short Stature

et al. 2012

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Background/Aims: Insulin-like growth factor (IGF)-I is critical for normal human growth. Extremely rare homozygous mutations of the IGF1 gene severely impair intrauterine growth, intellectual development and postnatal growth. Case/Method: A young male presented with postnatal growth retardation (–4.0 height SDS). His serum IGF-I concentration was low (115 µg/l, –2.21 SDS) and increased minimally to 130 µg/l (–1.82 SDS) on GH therapy, and he was analyzed for defect(s) in the GH-IGF-I axis. Severe short stature could be traced back several generations. Results: From the proband and 4 other severely short-statured family members, two novel, heterozygous, variants were identified in the IGF1 gene: c.207G>A in exon 3 and c.402+1G>C in the donor splice site of intron 4. The IGF1 gene was normal in 11 normal stature family members, and, interestingly, in 5 other short-statured family members. Study of IGF1 mRNA indicated c.402+1G>A induced splicing out of exon 4, leading to a predicted frameshift and protein truncation. Conclusions: A novel heterozygous IGF1 splicing variant is associated with familial short stature in an extended family. Although it remains unclear whether this heterozygous mutation is the cause of the growth failure, the extreme rarity of IGF1 gene defects makes these cases of considerable interest.

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Short Stature Associated with a Novel Heterozygous Mutation in theInsulin-Like Growth Factor 1Gene

Abstract: Heterozygosity for this novel IGF1 mutation in children born from a mother with the same mutation, presumably in combination with other genetic factors for short stature, leads to severe short stature, which can be successfully treated with GH.

Cited by 59 publications

References 17 publications

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Genetic Analysis of Short Children with Apparent Growth Hormone Insensitivity

Identification of a Novel Heterozygous <b><i>IGF1</i></b> Splicing Mutation in a Large Kindred with Familial Short Stature

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