Cargando…

A novel homozygous mutation in POLR3A gene causing 4H syndrome: a case report

BACKGROUND: 4H syndrome is a congenital hypomyelinating leukodystrophy characterized by hypodontia, hypomyelination and hypogonadotropic hypogonadism belonging to the Pol III-related leukodystrophies which arise due to mutations in the POLR3A or POLR3B gene. The clinical presentation is of neurodeve...

Descripción completa

Detalles Bibliográficos
Autores principales: Tewari, Vishal V., Mehta, Ritu, Sreedhar, C. M., Tewari, Kunal, Mohammad, Akbar, Gupta, Neerja, Gulati, Sheffali, Kabra, Madhulika
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883641/
https://www.ncbi.nlm.nih.gov/pubmed/29618326
http://dx.doi.org/10.1186/s12887-018-1108-9
_version_ 1783311688146092032
author Tewari, Vishal V.
Mehta, Ritu
Sreedhar, C. M.
Tewari, Kunal
Mohammad, Akbar
Gupta, Neerja
Gulati, Sheffali
Kabra, Madhulika
author_facet Tewari, Vishal V.
Mehta, Ritu
Sreedhar, C. M.
Tewari, Kunal
Mohammad, Akbar
Gupta, Neerja
Gulati, Sheffali
Kabra, Madhulika
author_sort Tewari, Vishal V.
collection PubMed
description BACKGROUND: 4H syndrome is a congenital hypomyelinating leukodystrophy characterized by hypodontia, hypomyelination and hypogonadotropic hypogonadism belonging to the Pol III-related leukodystrophies which arise due to mutations in the POLR3A or POLR3B gene. The clinical presentation is of neurodevelopmental delay or regression with ataxia, dystonia, nystagmus, delayed deciduous dentition and abnormal order of eruption of teeth. MRI brain shows a characteristic hypomyelination pattern. Several mutations have been described in the implicated genes but there are no reports on mutations seen in patients from India. CASE PRESENTATION: We report a 1½ year old girl, only child of a non-consanguinous couple who presented with delayed developmental milestones and delayed dentition. On physical examination she had downward slanting palpebral fissures, low set ears, smooth philtrum, hypodontia, prominent body hair and clitoromegaly. There was prominent horizontal nystagmus, hypertonia of both upper and lower limbs, exaggerated deep tendon jerks and flexor planter response. She had not attained complete head control and required support to sit. She showed absent waves on brainstem evoked response audiometry and her fundus examination showed bilateral optic atrophy with prolongation of P100 latencies on visual evoked potentials. MRI Brain showed hyperintensity of entire white matter with involvement of the internal and external capsule, frontal deep white matter and corpus callosum. Her karyotype was 46 XX and her endocrinal profile was unremarkable. Clinical exome sequencing identified an unreported mutation in the POLR3A gene. The same mutation was identified by Sanger sequencing in heterozygous state in both parents. The child is being managed with physiotherapy and developmental therapy. She has been provided with hearing aids and started on speech therapy. Parents were provided anticipatory guidance and genetic counselling about autosomal recessive nature of inheritance, risk of recurrence and need for follow-up. CONCLUSION: 4H syndrome is a rare congenital hypomyelinating leukodystrophy inherited as an autosomal recessive disorder due to mutations in the POLR3A and POLR3B gene. Delay or regression of milestones, abnormalities in dentition and endocrinal perturbations are its hallmark. A novel mutation in the POLR3A gene resulting in amino acid substitution of arginine for glutamine at codon 808 (p.R808Q) was detected in exon 18 in our case. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12887-018-1108-9) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-5883641
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-58836412018-04-09 A novel homozygous mutation in POLR3A gene causing 4H syndrome: a case report Tewari, Vishal V. Mehta, Ritu Sreedhar, C. M. Tewari, Kunal Mohammad, Akbar Gupta, Neerja Gulati, Sheffali Kabra, Madhulika BMC Pediatr Case Report BACKGROUND: 4H syndrome is a congenital hypomyelinating leukodystrophy characterized by hypodontia, hypomyelination and hypogonadotropic hypogonadism belonging to the Pol III-related leukodystrophies which arise due to mutations in the POLR3A or POLR3B gene. The clinical presentation is of neurodevelopmental delay or regression with ataxia, dystonia, nystagmus, delayed deciduous dentition and abnormal order of eruption of teeth. MRI brain shows a characteristic hypomyelination pattern. Several mutations have been described in the implicated genes but there are no reports on mutations seen in patients from India. CASE PRESENTATION: We report a 1½ year old girl, only child of a non-consanguinous couple who presented with delayed developmental milestones and delayed dentition. On physical examination she had downward slanting palpebral fissures, low set ears, smooth philtrum, hypodontia, prominent body hair and clitoromegaly. There was prominent horizontal nystagmus, hypertonia of both upper and lower limbs, exaggerated deep tendon jerks and flexor planter response. She had not attained complete head control and required support to sit. She showed absent waves on brainstem evoked response audiometry and her fundus examination showed bilateral optic atrophy with prolongation of P100 latencies on visual evoked potentials. MRI Brain showed hyperintensity of entire white matter with involvement of the internal and external capsule, frontal deep white matter and corpus callosum. Her karyotype was 46 XX and her endocrinal profile was unremarkable. Clinical exome sequencing identified an unreported mutation in the POLR3A gene. The same mutation was identified by Sanger sequencing in heterozygous state in both parents. The child is being managed with physiotherapy and developmental therapy. She has been provided with hearing aids and started on speech therapy. Parents were provided anticipatory guidance and genetic counselling about autosomal recessive nature of inheritance, risk of recurrence and need for follow-up. CONCLUSION: 4H syndrome is a rare congenital hypomyelinating leukodystrophy inherited as an autosomal recessive disorder due to mutations in the POLR3A and POLR3B gene. Delay or regression of milestones, abnormalities in dentition and endocrinal perturbations are its hallmark. A novel mutation in the POLR3A gene resulting in amino acid substitution of arginine for glutamine at codon 808 (p.R808Q) was detected in exon 18 in our case. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12887-018-1108-9) contains supplementary material, which is available to authorized users. BioMed Central 2018-04-04 /pmc/articles/PMC5883641/ /pubmed/29618326 http://dx.doi.org/10.1186/s12887-018-1108-9 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Case Report
Tewari, Vishal V.
Mehta, Ritu
Sreedhar, C. M.
Tewari, Kunal
Mohammad, Akbar
Gupta, Neerja
Gulati, Sheffali
Kabra, Madhulika
A novel homozygous mutation in POLR3A gene causing 4H syndrome: a case report
title A novel homozygous mutation in POLR3A gene causing 4H syndrome: a case report
title_full A novel homozygous mutation in POLR3A gene causing 4H syndrome: a case report
title_fullStr A novel homozygous mutation in POLR3A gene causing 4H syndrome: a case report
title_full_unstemmed A novel homozygous mutation in POLR3A gene causing 4H syndrome: a case report
title_short A novel homozygous mutation in POLR3A gene causing 4H syndrome: a case report
title_sort novel homozygous mutation in polr3a gene causing 4h syndrome: a case report
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883641/
https://www.ncbi.nlm.nih.gov/pubmed/29618326
http://dx.doi.org/10.1186/s12887-018-1108-9
work_keys_str_mv AT tewarivishalv anovelhomozygousmutationinpolr3agenecausing4hsyndromeacasereport
AT mehtaritu anovelhomozygousmutationinpolr3agenecausing4hsyndromeacasereport
AT sreedharcm anovelhomozygousmutationinpolr3agenecausing4hsyndromeacasereport
AT tewarikunal anovelhomozygousmutationinpolr3agenecausing4hsyndromeacasereport
AT mohammadakbar anovelhomozygousmutationinpolr3agenecausing4hsyndromeacasereport
AT guptaneerja anovelhomozygousmutationinpolr3agenecausing4hsyndromeacasereport
AT gulatisheffali anovelhomozygousmutationinpolr3agenecausing4hsyndromeacasereport
AT kabramadhulika anovelhomozygousmutationinpolr3agenecausing4hsyndromeacasereport
AT tewarivishalv novelhomozygousmutationinpolr3agenecausing4hsyndromeacasereport
AT mehtaritu novelhomozygousmutationinpolr3agenecausing4hsyndromeacasereport
AT sreedharcm novelhomozygousmutationinpolr3agenecausing4hsyndromeacasereport
AT tewarikunal novelhomozygousmutationinpolr3agenecausing4hsyndromeacasereport
AT mohammadakbar novelhomozygousmutationinpolr3agenecausing4hsyndromeacasereport
AT guptaneerja novelhomozygousmutationinpolr3agenecausing4hsyndromeacasereport
AT gulatisheffali novelhomozygousmutationinpolr3agenecausing4hsyndromeacasereport
AT kabramadhulika novelhomozygousmutationinpolr3agenecausing4hsyndromeacasereport