SHOX Haploinsufficiency as a Cause of Syndromic and Nonsyndromic Short Stature

Fukami, Maki; Seki, Atsuhito; Ogata, Tsutomu

doi:10.1159/000444596

Cited by 78 publications

(79 citation statements)

References 77 publications

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“…It is assumed that the heterozygous loss of the SHOX gene is responsible for Leri-Weill dyschondrosteosis (OMIM 127300), whereas homozygous loss leads to Langer mesomelic dysplasia (OMIM 249700), both being characterized by disproportionate short stature [29, 30]. Defects on the SHOX gene have also been identified in idiopathic short stature [31, 32]. Patients with identified Xp22.33 rearrangements usually had some additional features of disproportionate short stature that mask the suspicion of heterozygous loss of the SHOX gene.…”

Section: Discussionmentioning

confidence: 99%

Recurrent Copy Number Variants Associated with Syndromic Short Stature of Unknown Cause

et al. 2017

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Background/Aims: Genetic imbalances are responsible for many cases of short stature of unknown etiology. This study aims to identify recurrent pathogenic copy number variants (CNVs) in patients with syndromic short stature of unknown cause. Methods: We selected 229 children with short stature and dysmorphic features, developmental delay, and/or intellectual disability, but without a recognized syndrome. All patients were evaluated by chromosomal microarray (array-based comparative genomic hybridization/single nucleotide polymorphism array). Additionally, we searched databases and previous studies to recover recurrent pathogenic CNVs associated with short stature. Results: We identified 32 pathogenic/probably pathogenic CNVs in 229 patients. By reviewing the literature, we selected 4 previous studies which evaluated CNVs in cohorts of patients with short stature. Taken together, there were 671 patients with short stature of unknown cause evaluated by chromosomal microarray. Pathogenic/probably pathogenic CNVs were identified in 87 patients (13%). Seven recurrent CNVs, 22q11.21, 15q26, 1p36.33, Xp22.33, 17p13.3, 1q21.1, 2q24.2, were observed. They are responsible for about 40% of all pathogenic/probably pathogenic genomic imbalances found in short stature patients of unknown cause. Conclusion: CNVs seem to play a significant role in patients with short stature. Chromosomal microarray should be used as a diagnostic tool for evaluation of growth disorders, especially for syndromic short stature of unknown cause.

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Section: Discussionmentioning

confidence: 99%

Recurrent Copy Number Variants Associated with Syndromic Short Stature of Unknown Cause

et al. 2017

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“…For example, SHOX abnormalities account for 1-17% of ISS cases [4,5]. Mutations in ACAN, a gene encoding an essential component of cartilage extracellular matrix aggrecan, lead to autosomal dominant ISS accompanied by advanced bone age, midface hypoplasia, and joint problems [6][7][8].…”

Section: Sequence Analysismentioning

confidence: 99%

Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature

et al. 2017

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Abstract. Although mutations in ACAN, FGFR3, NPR2, and SHOX typically lead to skeletal dysplasia, and mutations in GHRHR, GH1, GHR, STAT5B, IGF1, IGFALS, and IGF1R usually underlie hormonal defects of the growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis, such mutations have also been identified in patients with idiopathic short stature (ISS). Of these, SHOX abnormalities are known to account for a certain percentage of ISS cases, whereas the frequency of mutations in the other 10 genes in ISS cohorts remains unknown. Here, we performed next-generation sequencing-based mutation screening of the 10 genes in 86 unrelated Japanese ISS patients without SHOX abnormalities. We searched for rare protein-altering variants. The functional significance of the identified variants was assessed by in silico analyses. Consequently, we identified 18 heterozygous rare variants in 19 patients, including four probable damaging variants in ACAN, six pathogenicity-unknown variants in FGFR3, GHRHR, GHR, and IGFALS, and eight possible benign variants. Pathogenic variants in NPR2, GH1, and IGF1 were absent from our cohort. Unlike previously reported patients with ACAN mutations, our four patients with ACAN variants manifested non-specific short stature with age-appropriate or mildly delayed bone ages, and had parents of normal stature. These results indicate that ACAN mutations can underlie ISS without characteristic skeletal features, and that such mutations are possibly associated with de novo occurrence or low penetrance. In addition, our data imply that mutations in FGFR3, NPR2, and GH-IGF1 axis genes play only limited roles in the etiology of ISS.

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“…Subsequently, the 2 copies are requested for normal skeletal development. Clinically, a wide range of short stature phenotypes are ascribed to SHOX gene deficiency, namely idiopathic short stature, Turner syndrome, LWD characterized by mesomelic short stature and Madelung deformity as well as Langer mesomelic dysplasia (the homozygous form of LWD) recognized by severe disproportionate short stature with noticeable mesomelic and rhizomelic limb shortening [Fukami et al, 2016]. The classical clinical triad of LWD was not obvious in our patient, except for the short stature.…”

Section: Resultsmentioning

confidence: 62%

Familial X/Y Translocation Encompassing <b><i>ARSE</i></b> in Two Moroccan Siblings with Sensorineural Deafness

Amasdl¹,

Smaili²,

Natiq³

et al. 2017

Cytogenet Genome Res

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Unbalanced translocations involving X and Y chromosomes are rare and associated with a contiguous gene syndrome. The clinical phenotype is heterogeneous including mainly short stature, chondrodysplasia punctata, ichthyosis, hypogonadism, and intellectual disability. Here, we report 2 brothers with peculiar gestalt, short stature, and hearing loss, who harbor an X/Y translocation. Physical examination, brainstem acoustic potential evaluation, bone age, hormonal assessment, and X-ray investigations were performed. Because of their dysmorphic features, karyotyping, FISH, and aCGH were carried out. The probands had short stature, hypertelorism, midface hypoplasia, sensorineural hearing loss, normal intelligence as well as slight radial and ulnar bowing with brachytelephalangy. R-banding identified a derivative X chromosome with an abnormally expanded short arm. The mother was detected as a carrier of the same aberrant X chromosome. aCGH disclosed a 3.1-Mb distal deletion of chromosome region Xp22.33pter. This interval encompasses several genes, especially the short stature homeobox (SHOX) and arylsulfatase (ARSE) genes. The final karyotype of the probands was: 46,Y,der(X),t(X;Y)(p22;q12).ish der(X)(DXYS129-,DXYS153-)mat.arr[hg19] Xp22.33(61091_2689408)×1mat,Xp22.33(2701273_3258404)×0mat,Yq11.222q12 (21412851_59310245)×2. Herein, we describe a Moroccan family with a maternally inherited X/Y translocation and discuss the genotype-phenotype correlations according to the deleted genes.

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SHOX Haploinsufficiency as a Cause of Syndromic and Nonsyndromic Short Stature

Cited by 78 publications

References 77 publications

Recurrent Copy Number Variants Associated with Syndromic Short Stature of Unknown Cause

Recurrent Copy Number Variants Associated with Syndromic Short Stature of Unknown Cause

Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature

Familial X/Y Translocation Encompassing <b><i>ARSE</i></b> in Two Moroccan Siblings with Sensorineural Deafness

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