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

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.

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

Journal of Medical Genetics ◽

10.1136/jmedgenet-2017-104885 ◽

2017 ◽

Vol 55 (6) ◽

pp. 403-407 ◽

Cited By ~ 4

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.

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

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2010-1689 ◽

2011 ◽

Vol 96 (2) ◽

pp. E404-E412 ◽

Cited By ~ 41

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 > 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.

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Foramen Magnum Stenosis in Achondroplasia

Austin Journal of Radiology ◽

10.26420/austinjradiol.2021.1136 ◽

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].

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

PEDIATRICS ◽

10.1542/peds.88.2.334 ◽

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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Clinical and Radiologic Evaluation of an Individual with Hypochondroplasia and a Novel FGFR3 Mutation

Journal of Pediatric Genetics ◽

10.1055/s-0039-1695056 ◽

2019 ◽

Vol 09 (01) ◽

pp. 048-052

Author(s):

Rosario Ramos Mejía ◽

Miriam Aza-Carmona ◽

Mariana del Pino ◽

Karen E. Heath ◽

Virginia Fano ◽

...

Keyword(s):

Short Stature ◽

Skeletal Dysplasia ◽

Fibroblast Growth Factor Receptor ◽

Growth Factor Receptor ◽

Missense Variant ◽

Radiologic Evaluation ◽

Radiologic Findings ◽

Fgfr3 Gene ◽

Fgfr3 Mutation ◽

Fgfr3 Mutations

AbstractHypochondroplasia (HCH), a skeletal dysplasia caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, is characterized by disproportionate short stature. The p.Asn540Lys (p.N540K) mutation accounts for ∼50 to 70% of cases of HCH, but novel FGFR3 mutations are described. We present a family with disproportionately short stature and mild radiologic findings seen in a major public pediatric hospital in Argentina. A previously undescribed heterozygous missense variant in FGFR3, NM_000142.4:667C > T; p.(Arg223Cys) was identified. The predicted phenotype correlates well with the mild auxologic and radiologic characteristics observed. In this case, disproportionately short stature raised the suspicion of skeletal dysplasia.

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HISTOPATHOLOGICAL ANALYSIS OF LERI-WEILL DYSCHONDROSTEOSIS: DISORDERED GROWTH PLATE

Hand Surgery ◽

10.1142/s0218810401000424 ◽

2001 ◽

Vol 06 (01) ◽

pp. 13-23 ◽

Cited By ~ 29

Author(s):

C. F. J. Munns ◽

I. A. Glass ◽

R. LaBrom ◽

M. Hayes ◽

S. Flanagan ◽

...

Keyword(s):

Short Stature ◽

Growth Plate ◽

Distal Radius ◽

Skeletal Dysplasia ◽

Endochondral Ossification ◽

Homeobox Gene ◽

Histopathological Study ◽

Molecular Testing ◽

Histopathological Analysis ◽

Triangular Fibrocartilage

Leri-Weill syndrome (LWS) is a dominant (pseudoautosomal) skeletal dysplasia with mesomelic short stature and bilateral Madelung deformity, due to dyschondrosteosis of the distal radius. It results from the loss of one copy of the Short Stature Homeobox Gene (SHOX) from the tip of the short arm of the X or Y chromosome. SHOX molecular testing enabled us to evaluate the histopathology of the radial physis in LWS patients with a documented SHOX abnormality. A widespread disorganisation of physeal anatomy was revealed with disruption of the normal parallel columnar arrangement of chondrocytes. Tandem stacking of maturing chondrocytes within columns was replaced by a side-by-side arrangement. The presence of hypertrophic osteoid with micro-enchondromata in the radial metaphysis suggests abnormal endochondral ossification. The Vickers' ligament was confirmed to blend with the triangular fibrocartilage complex (TFCC). This histopathological study demonstrates that the zone of dyschondrosteosis in LWS is characterised by marked disruption of normal physeal chondrocyte processes and that a generalised physeal abnormality is present.

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