Genotype-Phenotype Relationship in Patients and Relatives with &lt;b&gt;&lt;i&gt;SHOX&lt;/i&gt;&lt;/b&gt; Region Anomalies in the French Population

Auger, Julie; Baptiste, Amandine; Benabbad, Imane; Thierry, Gaëlle; Costa, Jean‐Marc; Amouyal, Mélanie; Kottler, Marie Laure; Leheup, Bruno; Touraine, Renaud; Schmitt, Sébastien; Lebrun, Marine; Cormier‐Daire, Valérie; Bonnefont, Jean‐Paul; Roux, Nicolas de; Elie, Caroline; Rosilio, Myriam

doi:10.1159/000448282

Cited by 5 publications

(3 citation statements)

References 36 publications

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“…On the other side of the spectrum, one can encounter individuals with only mild body disproportions, and in some cases, even a height in the lower half of the height distribution of the population growth charts with normal body proportions. Even within the same family, considerable phenotypic and radiologic heterogeneity exist [10][11][12][13][14][15]. Causes of SHOX haploinsufficiency include heterozygous deletions or variants in the SHOX gene itself, heterozygous deletions of (part of) one of the 5′ or 3′ enhancer regions regulating SHOX expression, or duplications in these regions inhibiting proper expression [16].…”

Section: Introductionmentioning

confidence: 99%

Novel Clinical Criteria Allow Detection of Short Stature Homeobox-Containing Gene Haploinsufficiency Caused by Either Gene or Enhancer Region Defects

et al. 2019

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Introduction: Short stature homeobox-containing gene (SHOX) haploinsufficiency is associated with short stature, Madelung deformity and mesomelia. Current clinical screening tools are based on patients with intragenic variants or deletions. However, recent discoveries showed that deletions of the enhancer elements are quite common. The majority of these patients show less body disproportion and respond better to recombinant human growth hormone treatment. We redefined clinical criteria for genetic analysis to facilitate detection of the full spectrum of SHOX haploinsuf-ficiency. Methods: We analyzed 51 children with SHOX variants or deletions and 25 children with a deletion in its enhancer region. Data were compared to 277 children referred for suspicion of growth failure without endocrine or genetic pathology. Results: Only half of the patients with an enhancer region deletion fulfilled any of the current screening criteria. We propose new clinical criteria based on sitting height to height ratio > 1 SDS or arm span ≥3 cm below height, with a sensitivity of 99%. When these criteria are combined with obligatory short stature, the sensitivity to detect SHOX haploinsufficiency is 68.1%, the specificity 80.6%, and the number needed to screen 21 patients. Conclusion: Novel clinical criteria for screening for SHOX haploinsufficiency allow the detection of patients within the full genetic spectrum, that is, intragenic variants and enhancer region deletions.

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Section: Introductionmentioning

confidence: 99%

Novel Clinical Criteria Allow Detection of Short Stature Homeobox-Containing Gene Haploinsufficiency Caused by Either Gene or Enhancer Region Defects

et al. 2019

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“…The phenotype associated with heterozygous SHOX mutations is a continuum from milder short stature without radiological findings to disproportionately short stature with Madelung deformity. The clinical symptoms can be markedly different even among the affected members of the same family who have the same genetic defects ( 1 , 3 , 9 – 12 ). This case describes a novel SHOX mutation in a Moroccan boy with disproportionate short stature and his mother with disproportionate short stature and LWD.…”

Section: Introductionmentioning

confidence: 99%

Report of a Novel SHOX Missense Variant in a Boy With Short Stature and His Mother With Leri–Weill Dyschondrosteosis

et al. 2018

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Heterozygous mutations in the SHOX gene or in the upstream and downstream enhancer elements are associated with 2–22% of cases of idiopathic short stature (OMIM #300582) and with 60% of cases of Leri–Weill dyschondrosteosis (OMIM #127300) with which female subjects are generally more severely affected. Approximately 80–90% of SHOX pathogenic variants are deletions or duplications, and the remaining 10–20% are point mutations that primarily give rise to missense variants. The clinical interpretation of novel variants, particularly missense variants, can be challenging and can remain of uncertain significance. Here, we describe a novel missense variant (c.1044 G>T, p.Arg118Met) in a Moroccan boy with a disproportionately short stature and without any radiological traits or bone deformities and in his mother, who had a disproportionately short stature and a Madelung deformity. This variant has not been reported to date in the updated SHOX allelic variant or Human Gene Mutation Databases nor is it listed as a polymorphism in the ExAC browser, dbSNP, or 1000G. This mutation was predicted to be deleterious by three different bioinformatics tools since it modifies an amino acid in a highly conserved DNA-binding domain of the SHOX protein. Based on this evidence, the patient was treated with recombinant human growth hormone.

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“…A hipoplasia da mandíbula também é observada. A prevalência de haploinsuficiência do SHOX é 1: 2.000, e a alteração é mais frequentemente de origem materna, sugerindo transmissão preferencial de mãe para filho (LERI;WEILL, 1929;LANGER, 1965;AUGER et al, 2016).…”

Section: Introdução E Revisão De Literaturaunclassified

Microrrearranjos cromossômicos em síndromes craniofaciais complexas

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A Deus por cuidar de cada detalhe da minha vida, não me deixar desanimar e me carregar no colo nos momentos mais difíceis. Aos meus filhos, Maria Clara e João Gabriel, a melhor parte de mim, por seus sorrisos, beijos e abraços, por compreenderem a importância do meu trabalho e minha ausência em muitos momentos que precisaram de mim. Meu amor infinito. Aos meus pais, Adelone e Irma, pelo amor incondicional e por terem me ensinado valores como a humildade, responsabilidade, ética, respeito, gratidão, persistência e por cuidarem com todo amor dos meus filhos na minha ausência. Aos meus irmãos Ellen, Lilian, Marlon e Marcos, pela presença nos momentos difíceis, pelo apoio e pelas palavras de incentivo.

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Genotype-Phenotype Relationship in Patients and Relatives with <b><i>SHOX</i></b> Region Anomalies in the French Population

Cited by 5 publications

References 36 publications

Novel Clinical Criteria Allow Detection of Short Stature Homeobox-Containing Gene Haploinsufficiency Caused by Either Gene or Enhancer Region Defects

Novel Clinical Criteria Allow Detection of Short Stature Homeobox-Containing Gene Haploinsufficiency Caused by Either Gene or Enhancer Region Defects

Report of a Novel SHOX Missense Variant in a Boy With Short Stature and His Mother With Leri–Weill Dyschondrosteosis

Microrrearranjos cromossômicos em síndromes craniofaciais complexas

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