An ultra-rare case of immunoskeletal dysplasia with neurodevelopmental abnormalities in an Indian patient with homozygous c.953C > T variant in EXTL3 gene: a case report

Abstract Background Immunoskeletal dysplasia with neurodevelopmental abnormalities (ISDNA) is an ultra-rare genetic condition that belongs to the group of spondyloepimetaphyseal dysplasias. It is caused due to presence of biallelic variants in the EXTL3 gene. The encoded exostosin like glycosyltrans...

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Main Authors: Shruti Bajaj, Purnima Satoskar, Aadhira Nair, Frenny Sheth, Jayesh Sheth, Harsh Sheth
Format: Article
Language:English
Published: BMC 2022-02-01
Series:BMC Pediatrics
Subjects:
Online Access:https://doi.org/10.1186/s12887-022-03143-2
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author Shruti Bajaj
Purnima Satoskar
Aadhira Nair
Frenny Sheth
Jayesh Sheth
Harsh Sheth
author_facet Shruti Bajaj
Purnima Satoskar
Aadhira Nair
Frenny Sheth
Jayesh Sheth
Harsh Sheth
author_sort Shruti Bajaj
collection DOAJ
description Abstract Background Immunoskeletal dysplasia with neurodevelopmental abnormalities (ISDNA) is an ultra-rare genetic condition that belongs to the group of spondyloepimetaphyseal dysplasias. It is caused due to presence of biallelic variants in the EXTL3 gene. The encoded exostosin like glycosyltransferase 3 (EXTL3) protein plays a key role in heparan sulfate synthesis. The skeletal and nervous systems are prominently affected in ISDNA with variability in immunological manifestations. Here, we report the 15th case of ISDNA (third patient of an Indian ancestry) in the world, along with a review of literature. Case presentation A 15-month-old female child with clinical indications of global developmental delay, short stature, coarse facial features, and hypotonia was referred to our clinic. Spondyloepimetaphyseal dysplasias associated with extra-skeletal manifestations was suspected based on clinic-radiological correlation. Whole exome sequencing analysis revealed the presence of a homozygous known pathogenic variant c.953C > T (p. Pro318Leu) in exon 3 of the EXTL3 gene, thereby confirming diagnosis of ISDNA. Conclusion We present an ultra-rare case of ISDNA- third patient of Indian ancestry and only the 15th reported case in the literature. On review of all cases in the literature, we find that the affected individuals show abnormalities primarily in three systems namely- skeletal, nervous and immune system. Notably, patients harbouring the same variant in EXTL3 gene show phenotypic variability especially with respect to presence or absence of immunological manifestations, suggesting a role of unknown modifiers. Hence, it is currently not possible to correlate the variant position in the EXTL3 gene with disease severity.
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spelling doaj.art-dc71625c01eb43c8a34645948e77eaa52022-12-22T04:10:58ZengBMCBMC Pediatrics1471-24312022-02-012211910.1186/s12887-022-03143-2An ultra-rare case of immunoskeletal dysplasia with neurodevelopmental abnormalities in an Indian patient with homozygous c.953C > T variant in EXTL3 gene: a case reportShruti Bajaj0Purnima Satoskar1Aadhira Nair2Frenny Sheth3Jayesh Sheth4Harsh Sheth5The Purple Gene Clinic, Simplex KhushaanganDepartment of Obstetrics and Gynaecology, Nowrosjee Wadia Maternity Hospital and Seth G. S. Medical College, Acharya Donde MargFRIGE’s Institute of Human Genetics, FRIGE HouseFRIGE’s Institute of Human Genetics, FRIGE HouseFRIGE’s Institute of Human Genetics, FRIGE HouseFRIGE’s Institute of Human Genetics, FRIGE HouseAbstract Background Immunoskeletal dysplasia with neurodevelopmental abnormalities (ISDNA) is an ultra-rare genetic condition that belongs to the group of spondyloepimetaphyseal dysplasias. It is caused due to presence of biallelic variants in the EXTL3 gene. The encoded exostosin like glycosyltransferase 3 (EXTL3) protein plays a key role in heparan sulfate synthesis. The skeletal and nervous systems are prominently affected in ISDNA with variability in immunological manifestations. Here, we report the 15th case of ISDNA (third patient of an Indian ancestry) in the world, along with a review of literature. Case presentation A 15-month-old female child with clinical indications of global developmental delay, short stature, coarse facial features, and hypotonia was referred to our clinic. Spondyloepimetaphyseal dysplasias associated with extra-skeletal manifestations was suspected based on clinic-radiological correlation. Whole exome sequencing analysis revealed the presence of a homozygous known pathogenic variant c.953C > T (p. Pro318Leu) in exon 3 of the EXTL3 gene, thereby confirming diagnosis of ISDNA. Conclusion We present an ultra-rare case of ISDNA- third patient of Indian ancestry and only the 15th reported case in the literature. On review of all cases in the literature, we find that the affected individuals show abnormalities primarily in three systems namely- skeletal, nervous and immune system. Notably, patients harbouring the same variant in EXTL3 gene show phenotypic variability especially with respect to presence or absence of immunological manifestations, suggesting a role of unknown modifiers. Hence, it is currently not possible to correlate the variant position in the EXTL3 gene with disease severity.https://doi.org/10.1186/s12887-022-03143-2Bone dysplasiaDevelopmental delayHeparan sulphateImmunoskeletal dysplasia with neurodevelopmental abnormalitiesEXTL3
spellingShingle Shruti Bajaj
Purnima Satoskar
Aadhira Nair
Frenny Sheth
Jayesh Sheth
Harsh Sheth
An ultra-rare case of immunoskeletal dysplasia with neurodevelopmental abnormalities in an Indian patient with homozygous c.953C > T variant in EXTL3 gene: a case report
BMC Pediatrics
Bone dysplasia
Developmental delay
Heparan sulphate
Immunoskeletal dysplasia with neurodevelopmental abnormalities
EXTL3
title An ultra-rare case of immunoskeletal dysplasia with neurodevelopmental abnormalities in an Indian patient with homozygous c.953C > T variant in EXTL3 gene: a case report
title_full An ultra-rare case of immunoskeletal dysplasia with neurodevelopmental abnormalities in an Indian patient with homozygous c.953C > T variant in EXTL3 gene: a case report
title_fullStr An ultra-rare case of immunoskeletal dysplasia with neurodevelopmental abnormalities in an Indian patient with homozygous c.953C > T variant in EXTL3 gene: a case report
title_full_unstemmed An ultra-rare case of immunoskeletal dysplasia with neurodevelopmental abnormalities in an Indian patient with homozygous c.953C > T variant in EXTL3 gene: a case report
title_short An ultra-rare case of immunoskeletal dysplasia with neurodevelopmental abnormalities in an Indian patient with homozygous c.953C > T variant in EXTL3 gene: a case report
title_sort ultra rare case of immunoskeletal dysplasia with neurodevelopmental abnormalities in an indian patient with homozygous c 953c t variant in extl3 gene a case report
topic Bone dysplasia
Developmental delay
Heparan sulphate
Immunoskeletal dysplasia with neurodevelopmental abnormalities
EXTL3
url https://doi.org/10.1186/s12887-022-03143-2
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