High prevalence of variants in skeletal dysplasia associated genes in individuals with short stature and minor skeletal anomalies

2021 ◽  
Author(s):  
Lucia Sentchordi-Montané ◽  
Sara Benito-Sanz ◽  
Miriam Aza-Carmona ◽  
Francisca Díaz-González ◽  
Silvia Modamio-Høybjør ◽  
...  
Keyword(s):  
Short Stature ◽  
Skeletal Dysplasia ◽  
Genetic Defect ◽  
Radiological Feature ◽  
Molecular Defect ◽  
Skeletal Dysplasias ◽  
Skeletal Anomalies ◽  
Radiological Data ◽  
High Prevalence ◽  
Next Generation Sequencing Ngs

Objective: Next generation sequencing (NGS) has expanded the diagnostic paradigm turning the focus to the growth plate. The aim of the study was to determine the prevalence of variants in genes implicated in skeletal dysplasias in probands with short stature and mild skeletal anomalies. Design: Clinical and radiological data were collected from 108 probands with short stature and mild skeletal anomalies. Methods: A customized skeletal dysplasia NGS panel was performed. Variants were classified using ACMG recommendations and Sherloc. Anthropometric measurements and skeletal anomalies were subsequently compared in those with or without an identified genetic defect. Results: Heterozygous variants were identified in 21/108 probands (19.4%). Variants were most frequently identified in ACAN (n=10) and IHH (n=7) whilst one variant was detected in COL2A1, CREBBP, EXT1 and PTPN11. Statistically significant differences (p<0.05) were observed for sitting height/height (SH/H) ratio, SH/H ratio SDS and the SH/H ratio SDS >1 in those with an identified variant compared to those without. Conclusions: A molecular defect was elucidated in a fifth of patients. Thus, the prevalence of mild forms of skeletal dysplasias is relatively high in individuals with short stature and mild skeletal anomalies, with variants in ACAN and IHH accounting for 81% of the cases. An elevated SH/H ratio appears to be associated with a greater probability in detecting a variant, but no other clinical or radiological feature has been found determinant to finding a genetic cause. Currently, we cannot perform extensive molecular studies in all short stature individuals so detailed clinical and radiological phenotyping may orientate which are the candidate patients to obtain worthwhile results. In addition, detailed phenotyping of probands and family members will often aid variant classification.

scholarly journals Acromesomelic Dysplasia with Interstitial Lung Disease: A Unique Association

2018 ◽  
Vol 04 (01) ◽  
pp. 029-031
Author(s):  
Chinnu Sasikumar ◽  
Ketaki Utpat ◽  
Unnati Desai ◽  
Jyotsna M Joshi
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Skeletal Dysplasia ◽  
Autosomal Recessive ◽  
Autosomal Recessive Inheritance ◽  
Recessive Inheritance ◽  
Skeletal Dysplasias ◽  
Skeletal Anomalies ◽  
Unique Association

ABSTRACTAcromesomelic dysplasia is an extremely uncommon skeletal dysplasia with an autosomal recessive inheritance. It is characterized by a constellation of skeletal anomalies. Respiratory impediments have been sporadically reported earlier in various skeletal dysplasias. However, respiratory affection in acromesomelic dysplasia has not been elucidated earlier. We herein report a case of acromesomelic dysplasia associated with interstitial lung disease (ILD). Diagnosis of acromesomelic dysplasia was based on radiographs of whole skeleton.

Level of the conus in pediatric patients with skeletal dysplasia

2010 ◽  
Vol 5 (5) ◽  
pp. 455-459 ◽  
Author(s):  
Deanna M. Sasaki-Adams ◽  
Jeffrey W. Campbell ◽  
Gela Bajelidze ◽  
Marcelo C. Assis ◽  
William G. Mackenzie ◽  
...  
Keyword(s):  
Short Stature ◽  
Vertebral Body ◽  
Skeletal Dysplasia ◽  
Pediatric Patients ◽  
Bone Development ◽  
Tertiary Care ◽  
Tethered Cord ◽  
Retrospective Chart Review ◽  
Conus Medullaris ◽  
Skeletal Dysplasias

Object Skeletal dysplasias are a heterogeneous group of disorders that affect bone development and can result in reduced vertebral body growth and short stature. The level of the conus medullaris is unknown in this population. The purpose of this review was to determine the level of the conus in a population of pediatric patients with skeletal dysplasia. Methods A retrospective chart review of a 7-year period was undertaken at a tertiary care pediatric hospital to identify patients in whom skeletal dysplasia had been diagnosed. Radiographs and MR imaging studies were evaluated to discern the level of the conus with respect to the bony vertebral column. Results Four hundred sixty-seven patients with skeletal dysplasia were identified. One hundred eleven patients had quality MR images. Forty-seven different skeletal dysplasias were observed. The mean conus level was found at the L-1 vertebral body. No difference was noted with respect to the age of the patients or the type of skeletal dysplasia. Two patients (1.7%) had a conus level lower than L-2. Conclusions Skeletal dysplasia leads to abnormal bone formation and can result in short stature. The location of the conus with respect to the vertebral bodies appears to be stable at the L-1 level regardless of patient age or the type of skeletal dysplasia involved. However, the appearance of a low-level conus and associated tethered cord syndrome may be slightly increased in this population.

scholarly journals Autosomal recessive chondrodysplasia with severe short stature caused by a biallelic COL10A1 variant

2017 ◽  
Vol 55 (6) ◽  
pp. 403-407 ◽  
Author(s):  
Noor ul Ain ◽  
Outi Makitie ◽  
Sadaf Naz
Keyword(s):  
Short Stature ◽  
Skeletal Dysplasia ◽  
In Silico ◽  
Autosomal Recessive ◽  
Limb Deformity ◽  
Mild Phenotype ◽  
Whole Exome ◽  
New Type ◽  
Severe Short Stature ◽  
Amino Acid Conservation

BackgroundHeterozygous mutations in COL10A1 underlie metaphyseal chondrodysplasia, Schmid type (MCDS), an autosomal dominant skeletal dysplasia.ObjectiveTo identify the causative variant in a large consanguineous Pakistani family with severe skeletal dysplasia and marked lower limb deformity.MethodsWhole exome sequencing was completed followed by Sanger sequencing to verify segregation of the identified variants. In silico variant pathogenicity predictions and amino acid conservation analyses were performed.ResultsA homozygous c.133 C>T (p.Pro45Ser) variant was identified in COL10A1 in all six severely affected individuals (adult heights 119–130 cm, mean ~−6.33 SD). The individuals heterozygous for the variant had mild phenotype of short stature (adult heights 140–162 cm, mean ~−2.15 SD) but no apparent skeletal deformities. The variant was predicted to be pathogenic by in silico prediction tools and was absent from public databases and hundred control chromosomes. Pro45 is conserved in orthologues and is located in the non-collagenous 2 domain of COL10A1, variants of which have never been associated with skeletal dysplasia.ConclusionsThis first report of individuals with a homozygous variant in COL10A1 defines a new type of autosomal recessive skeletal dysplasia. The observations in COL10A1 variant carriers suggest a phenotypic overlap between the mildest forms of MCDS and idiopathic short stature.

scholarly journals Clinical and Molecular Evaluation of SHOX/PAR1 Duplications in Léri-Weill Dyschondrosteosis (LWD) and Idiopathic Short Stature (ISS)

2011 ◽  
Vol 96 (2) ◽  
pp. E404-E412 ◽  
Author(s):  
S. Benito-Sanz ◽  
E. Barroso ◽  
D. Heine-Suñer ◽  
A. Hisado-Oliva ◽  
V. Romanelli ◽  
...  
Keyword(s):  
Short Stature ◽  
Skeletal Dysplasia ◽  
Copy Number ◽  
Clinical Manifestations ◽  
Idiopathic Short Stature ◽  
Pseudoautosomal Region ◽  
Height Gain ◽  
Multiple Copies ◽  
Copy Number Changes ◽  
Design And Methods

abstract Context: Léri-Weill dyschondrosteosis (LWD) is a skeletal dysplasia characterized by disproportionate short stature and the Madelung deformity of the forearm. SHOX mutations and pseudoautosomal region 1 deletions encompassing SHOX or its enhancers have been identified in approximately 60% of LWD and approximately 15% of idiopathic short stature (ISS) individuals. Recently SHOX duplications have been described in LWD/ISS but also in individuals with other clinical manifestations, thus questioning their pathogenicity. Objective: The objective of the study was to investigate the pathogenicity of SHOX duplications in LWD and ISS. Design and Methods: Multiplex ligation-dependent probe amplification is routinely used in our unit to analyze for SHOX/pseudoautosomal region 1 copy number changes in LWD/ISS referrals. Quantitative PCR, microsatellite marker, and fluorescence in situ hybridization analysis were undertaken to confirm all identified duplications. Results: During the routine analysis of 122 LWD and 613 ISS referrals, a total of four complete and 10 partial SHOX duplications or multiple copy number (n &gt; 3) as well as one duplication of the SHOX 5′ flanking region were identified in nine LWD and six ISS cases. Partial SHOX duplications appeared to have a more deleterious effect on skeletal dysplasia and height gain than complete SHOX duplications. Importantly, no increase in SHOX copy number was identified in 340 individuals with normal stature or 104 overgrowth referrals. Conclusion: MLPA analysis of SHOX/PAR1 led to the identification of partial and complete SHOX duplications or multiple copies associated with LWD or ISS, suggesting that they may represent an additional class of mutations implicated in the molecular etiology of these clinical entities.

scholarly journals Foramen Magnum Stenosis in Achondroplasia

2021 ◽  
Vol 8 (4) ◽  
Author(s):  
Choayb S ◽  
◽  
Adil H ◽  
El Haddad S ◽  
◽  
...  
Keyword(s):  
Sudden Death ◽  
Skull Base ◽  
Short Stature ◽  
Skeletal Dysplasia ◽  
Endochondral Ossification ◽  
Foramen Magnum ◽  
Severe Complication ◽  
Occipital Bone ◽  
Severe Morbidity ◽  
Cervicomedullary Junction

Achondroplasia is the most common hereditary skeletal dysplasia and is characterized by disproportionately short stature with rhizomelic short extremities [1]. The skull features include a narrowed foramen magnum, short skull base, and clivus [2]. Foramen magnum stenosis is a characteristic funding, secondary to an abnormal placement and premature fusion of the posterior synchondroses [1]. The second factor responsible for stenosis is a defect in endochondral ossification in the basiocciput that may result in an extension of the squamous occipital bone [2]. It can cause hydrocephalus and prominent emissary and meningeal veins (Figure 1). Figure 1: Sagittal T1WI revealing a narrowed stenosis of the foramen magnum and compression of the cervicomedullary junction. The most severe complication is the compression of the cervicomedullary junction, associated with severe morbidity and sudden death in younger children [1].

scholarly journals SUN-LB008 Clinical Phenotype and Genotype Analysis of Short Stature Patients with Skeletal Dysplasia

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Hui Miao ◽  
Huijuan Zhu ◽  
Fengying Gong ◽  
Hongbo Yang ◽  
Linjie Wang ◽  
...  
Keyword(s):  
Short Stature ◽  
Skeletal Dysplasia ◽  
Clinical Phenotype ◽  
Genotype Analysis

The Weismann-Netter Syndrome: A Cause of Bowed Legs in Childhood

PEDIATRICS ◽  
1991 ◽  
Vol 88 (2) ◽  
pp. 334-337
Author(s):  
GARY L. FRANCIS ◽  
JAMES J. JELINEK ◽  
KATHLEEN MCHALE ◽  
MEGAN ADAMSON ◽  
SONDRA W. LEVIN
Keyword(s):  
Case Report ◽  
Short Stature ◽  
Skeletal Dysplasia ◽  
Full Term ◽  
Pediatric Age ◽  
Uncomplicated Pregnancy ◽  
Age Range

The Weismann-Netter syndrome is a rare, heritable skeletal dysplasia which often presents as asymptomatic bowing of the lower legs or short stature.1 Although more than 40 cases have been described, there is mention of only 8 cases in patients who were younger than 16 years of age.1-9 In retrospect, most of the affected adults reported symptoms during childhood. We recently had the opportunity to evaluate a 4-year-old boy, whom we believe to have the Weismann-Netter syndrome. This case served to heighten our awareness of this condition, which should be recognizable in the pediatric age range. CASE REPORT The proband (Fig 1), a four-year-old Arabic boy, was the product of a full-term, uncomplicated pregnancy.

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