Novel XRCC4 Mutations in an Infant With Microcephalic Primordial Dwarfism, Dilated Cardiomyopathy, Subclinical Hypothyroidism, and Early Death: Expanding the Phenotype Of XRCC4 Mutations

Novel XRCC4 Mutations in an Infant With Microcephalic Primordial Dwarfism, Dilated Cardiomyopathy, Subclinical Hypothyroidism, and Early Death: Expanding the Phenotype Of XRCC4 Mutations

ABSTRACT: Objective: Microcephalic primordial dwarfism (MPD) is a group of clinically and genetically heterogeneous disorders which result in severe prenatal and postnatal growth failure. X-ray repair cross-complementing protein 4 (XRCC4) is a causative gene for an autosomal recessive form of MPD....

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Main Authors: Meghan E. Fredette, MD, Kristin C. Lombardi, MD, Angela L. Duker, MS, LCGC, Catherine O. Buck, MD, Chanika Phornphutkul, MD, Michael B. Bober, MD, PhD, Jose Bernardo Quintos, MD
Format: Article
Language:English
Published: Elsevier 2020-01-01
Series:AACE Clinical Case Reports
Online Access:http://www.sciencedirect.com/science/article/pii/S2376060520300675
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spelling doaj-fdfa917c44de448da1bb99dbd3fb11f92021-04-30T07:23:24ZengElsevierAACE Clinical Case Reports2376-06052020-01-0161e1e4Novel XRCC4 Mutations in an Infant With Microcephalic Primordial Dwarfism, Dilated Cardiomyopathy, Subclinical Hypothyroidism, and Early Death: Expanding the Phenotype Of XRCC4 MutationsMeghan E. Fredette, MD0Kristin C. Lombardi, MD1Angela L. Duker, MS, LCGC2Catherine O. Buck, MD3Chanika Phornphutkul, MD4Michael B. Bober, MD, PhD5Jose Bernardo Quintos, MD6Address correspondence to Dr. Meghan E. Fredette, 111 Plain Street, 3rd Floor, Providence, RI 02903.; From the Warren Alpert Medical School of Brown University, Providence, Rhode Island; Divisions of Pediatric Endocrinology Hasbro Children's Hospital, Providence, Rhode IslandFrom the Warren Alpert Medical School of Brown University, Providence, Rhode Island; Pediatric Cardiology, Hasbro Children's Hospital, Providence, Rhode IslandDivision of Orthogenetics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DelawareFrom the Warren Alpert Medical School of Brown University, Providence, Rhode Island; Division of Neonatology, Women and Infants Hospital, Providence, Rhode IslandFrom the Warren Alpert Medical School of Brown University, Providence, Rhode Island; Division of Genetics and Metabolism, Hasbro Children's Hospital, Providence, Rhode Island.Division of Orthogenetics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DelawareFrom the Warren Alpert Medical School of Brown University, Providence, Rhode Island; Divisions of Pediatric Endocrinology Hasbro Children's Hospital, Providence, Rhode IslandABSTRACT: Objective: Microcephalic primordial dwarfism (MPD) is a group of clinically and genetically heterogeneous disorders which result in severe prenatal and postnatal growth failure. X-ray repair cross-complementing protein 4 (XRCC4) is a causative gene for an autosomal recessive form of MPD. The objective of this report is to describe novel XRCC4 mutations in a female infant with MPD, dilated cardiomyopathy, and subclinical hypothyroidism. Methods: Genetic testing was performed using a comprehensive next generation sequencing panel for MPD, followed by targeted XRCC4 gene sequencing. Results: We report the case of a 970-gram, 35-cm, female infant (weight z score -5.05, length z score -4.71) born at 36 weeks and 3 days gestation. Physical examination revealed triangular facies, micrognathism, clinodactyly, and second and third toe syndactyly. Initial echocardiogram at birth was normal. Follow-up echocardiogram at 60 days of life revealed dilated cardiomyopathy with moderate left ventricular systolic dysfunction (ejection fraction was 40 to 45%), and anticongestive therapy was initiated. Thyroid testing revealed subclinical hypothyroidism with elevated thyroid-stimulating hormone of 13.0 μIU/mL (reference range is 0.3 to 5.0 μIU/mL) and normal free thyroxine by dialysis of 1.6 ng/dL (reference range is 0.8 to 2.0 ng/dL). Levothyroxine was initiated. Postnatal growth remained poor (weight z score at 3 months -4.93, length z score at 3 months -6.48), including progressive microcephaly (head circumference z score at 3 months -10.94). Genetic testing revealed novel compound heterozygous XRCC4 variants in trans: c.628A>T and c.638+3A>G. The child ultimately had cardiopulmonary arrest and died at 6 months of life. Conclusion: Molecular diagnosis in MPD is key to defining the natural history, management, and prognosis for patients with these rare disorders.http://www.sciencedirect.com/science/article/pii/S2376060520300675
collection DOAJ
language English
format Article
sources DOAJ
author Meghan E. Fredette, MD
Kristin C. Lombardi, MD
Angela L. Duker, MS, LCGC
Catherine O. Buck, MD
Chanika Phornphutkul, MD
Michael B. Bober, MD, PhD
Jose Bernardo Quintos, MD
spellingShingle Meghan E. Fredette, MD
Kristin C. Lombardi, MD
Angela L. Duker, MS, LCGC
Catherine O. Buck, MD
Chanika Phornphutkul, MD
Michael B. Bober, MD, PhD
Jose Bernardo Quintos, MD
Novel XRCC4 Mutations in an Infant With Microcephalic Primordial Dwarfism, Dilated Cardiomyopathy, Subclinical Hypothyroidism, and Early Death: Expanding the Phenotype Of XRCC4 Mutations
AACE Clinical Case Reports
author_facet Meghan E. Fredette, MD
Kristin C. Lombardi, MD
Angela L. Duker, MS, LCGC
Catherine O. Buck, MD
Chanika Phornphutkul, MD
Michael B. Bober, MD, PhD
Jose Bernardo Quintos, MD
author_sort Meghan E. Fredette, MD
title Novel XRCC4 Mutations in an Infant With Microcephalic Primordial Dwarfism, Dilated Cardiomyopathy, Subclinical Hypothyroidism, and Early Death: Expanding the Phenotype Of XRCC4 Mutations
title_short Novel XRCC4 Mutations in an Infant With Microcephalic Primordial Dwarfism, Dilated Cardiomyopathy, Subclinical Hypothyroidism, and Early Death: Expanding the Phenotype Of XRCC4 Mutations
title_full Novel XRCC4 Mutations in an Infant With Microcephalic Primordial Dwarfism, Dilated Cardiomyopathy, Subclinical Hypothyroidism, and Early Death: Expanding the Phenotype Of XRCC4 Mutations
title_fullStr Novel XRCC4 Mutations in an Infant With Microcephalic Primordial Dwarfism, Dilated Cardiomyopathy, Subclinical Hypothyroidism, and Early Death: Expanding the Phenotype Of XRCC4 Mutations
title_full_unstemmed Novel XRCC4 Mutations in an Infant With Microcephalic Primordial Dwarfism, Dilated Cardiomyopathy, Subclinical Hypothyroidism, and Early Death: Expanding the Phenotype Of XRCC4 Mutations
title_sort novel xrcc4 mutations in an infant with microcephalic primordial dwarfism, dilated cardiomyopathy, subclinical hypothyroidism, and early death: expanding the phenotype of xrcc4 mutations
publisher Elsevier
series AACE Clinical Case Reports
issn 2376-0605
publishDate 2020-01-01
description ABSTRACT: Objective: Microcephalic primordial dwarfism (MPD) is a group of clinically and genetically heterogeneous disorders which result in severe prenatal and postnatal growth failure. X-ray repair cross-complementing protein 4 (XRCC4) is a causative gene for an autosomal recessive form of MPD. The objective of this report is to describe novel XRCC4 mutations in a female infant with MPD, dilated cardiomyopathy, and subclinical hypothyroidism. Methods: Genetic testing was performed using a comprehensive next generation sequencing panel for MPD, followed by targeted XRCC4 gene sequencing. Results: We report the case of a 970-gram, 35-cm, female infant (weight z score -5.05, length z score -4.71) born at 36 weeks and 3 days gestation. Physical examination revealed triangular facies, micrognathism, clinodactyly, and second and third toe syndactyly. Initial echocardiogram at birth was normal. Follow-up echocardiogram at 60 days of life revealed dilated cardiomyopathy with moderate left ventricular systolic dysfunction (ejection fraction was 40 to 45%), and anticongestive therapy was initiated. Thyroid testing revealed subclinical hypothyroidism with elevated thyroid-stimulating hormone of 13.0 μIU/mL (reference range is 0.3 to 5.0 μIU/mL) and normal free thyroxine by dialysis of 1.6 ng/dL (reference range is 0.8 to 2.0 ng/dL). Levothyroxine was initiated. Postnatal growth remained poor (weight z score at 3 months -4.93, length z score at 3 months -6.48), including progressive microcephaly (head circumference z score at 3 months -10.94). Genetic testing revealed novel compound heterozygous XRCC4 variants in trans: c.628A>T and c.638+3A>G. The child ultimately had cardiopulmonary arrest and died at 6 months of life. Conclusion: Molecular diagnosis in MPD is key to defining the natural history, management, and prognosis for patients with these rare disorders.
url http://www.sciencedirect.com/science/article/pii/S2376060520300675
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