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Case report: The cardio-facio-cutaneous syndrome due to a novel germline mutation in MAP2K1: A multifaceted disease with immunodeficiency and short stature

Cardio-facio-cutaneous syndrome (CFCS) belongs to the group of RASopathies, clinical disorders defined by disruptions in the RAS/MAPK signaling pathway. It is caused by heterozygous gain-of-function germline mutations in genes encoding protein kinases: BRAF, MAP2K1 (MEK1), MAP2K2 (MEK2), and in the...

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Autores principales: Szczawińska-Popłonyk, Aleksandra, Popłonyk, Natalia, Niedziela, Marek, Sowińska-Seidler, Anna, Sztromwasser, Paweł, Jamsheer, Aleksander, Obara-Moszyńska, Monika
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9614356/
https://www.ncbi.nlm.nih.gov/pubmed/36313893
http://dx.doi.org/10.3389/fped.2022.990111
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author Szczawińska-Popłonyk, Aleksandra
Popłonyk, Natalia
Niedziela, Marek
Sowińska-Seidler, Anna
Sztromwasser, Paweł
Jamsheer, Aleksander
Obara-Moszyńska, Monika
author_facet Szczawińska-Popłonyk, Aleksandra
Popłonyk, Natalia
Niedziela, Marek
Sowińska-Seidler, Anna
Sztromwasser, Paweł
Jamsheer, Aleksander
Obara-Moszyńska, Monika
author_sort Szczawińska-Popłonyk, Aleksandra
collection PubMed
description Cardio-facio-cutaneous syndrome (CFCS) belongs to the group of RASopathies, clinical disorders defined by disruptions in the RAS/MAPK signaling pathway. It is caused by heterozygous gain-of-function germline mutations in genes encoding protein kinases: BRAF, MAP2K1 (MEK1), MAP2K2 (MEK2), and in the GTPase-encoding gene KRAS. CFCS is characterized by craniofacial dysmorphic features, congenital heart defects, severe malnutrition, proportionate short stature, anomalies within the structure of skin and hair, and psychomotor disability. The pathophysiology of growth impairment is multifactorial with feeding difficulties, growth hormone deficiency, and insensitivity. Immunodeficiency has not been hitherto reported as an integral part of CFCS yet an increased activation of the RAS/MAPK signaling pathway may contribute to explaining the causal relationship between RASopathy and the dysfunctions within the B and T lymph cell compartments resulting in a deficiency in T cell costimulation and B cell maturation with impaired class switch recombination, somatic hypermutation, and high-affinity antibody production. We report on a boy born prematurely at 32 WGA, with the perinatal period complicated by pneumonia, respiratory distress syndrome, and valvular pulmonary stenosis. The boy suffered from recurrent pneumonia, obstructive bronchitis, sepsis, urinary tract infection, and recurrent fevers. He presented with severe hypotrophy, psychomotor disability, short stature, craniofacial dysmorphism, dental hypoplasia, sparse hair, and cryptorchidism. Whole genome sequencing showed a novel heterozygous pathogenic germline missense variant: c.364A > G; p.Asn122Asp in the MAP2K1 gene, supporting the diagnosis of CFCS. The immunological workup revealed hypogammaglobulinemia, IgG subclass, and specific antibody deficiency accompanied by decreased numbers of T helper cells and naive and memory B cells. Replacement immunoglobulin therapy with timely antibiotic prophylaxis were instituted. At the age of six years, growth hormone deficiency was diagnosed and the rGH therapy was started. The ever-increasing progress in genetic studies contributes to establishing the definitive CFCS diagnosis and sheds the light on the interrelated genotype-phenotype heterogeneity of RASopathies. Herein, we add new phenotypic features of predominating humoral immunodeficiency to the symptomatology of CFCS with a novel mutation in MAP2K1. While CFCS is a multifaceted disease, increased pediatricians’ awareness is needed to prevent the delay in diagnostics and therapeutic interventions.
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spelling pubmed-96143562022-10-29 Case report: The cardio-facio-cutaneous syndrome due to a novel germline mutation in MAP2K1: A multifaceted disease with immunodeficiency and short stature Szczawińska-Popłonyk, Aleksandra Popłonyk, Natalia Niedziela, Marek Sowińska-Seidler, Anna Sztromwasser, Paweł Jamsheer, Aleksander Obara-Moszyńska, Monika Front Pediatr Pediatrics Cardio-facio-cutaneous syndrome (CFCS) belongs to the group of RASopathies, clinical disorders defined by disruptions in the RAS/MAPK signaling pathway. It is caused by heterozygous gain-of-function germline mutations in genes encoding protein kinases: BRAF, MAP2K1 (MEK1), MAP2K2 (MEK2), and in the GTPase-encoding gene KRAS. CFCS is characterized by craniofacial dysmorphic features, congenital heart defects, severe malnutrition, proportionate short stature, anomalies within the structure of skin and hair, and psychomotor disability. The pathophysiology of growth impairment is multifactorial with feeding difficulties, growth hormone deficiency, and insensitivity. Immunodeficiency has not been hitherto reported as an integral part of CFCS yet an increased activation of the RAS/MAPK signaling pathway may contribute to explaining the causal relationship between RASopathy and the dysfunctions within the B and T lymph cell compartments resulting in a deficiency in T cell costimulation and B cell maturation with impaired class switch recombination, somatic hypermutation, and high-affinity antibody production. We report on a boy born prematurely at 32 WGA, with the perinatal period complicated by pneumonia, respiratory distress syndrome, and valvular pulmonary stenosis. The boy suffered from recurrent pneumonia, obstructive bronchitis, sepsis, urinary tract infection, and recurrent fevers. He presented with severe hypotrophy, psychomotor disability, short stature, craniofacial dysmorphism, dental hypoplasia, sparse hair, and cryptorchidism. Whole genome sequencing showed a novel heterozygous pathogenic germline missense variant: c.364A > G; p.Asn122Asp in the MAP2K1 gene, supporting the diagnosis of CFCS. The immunological workup revealed hypogammaglobulinemia, IgG subclass, and specific antibody deficiency accompanied by decreased numbers of T helper cells and naive and memory B cells. Replacement immunoglobulin therapy with timely antibiotic prophylaxis were instituted. At the age of six years, growth hormone deficiency was diagnosed and the rGH therapy was started. The ever-increasing progress in genetic studies contributes to establishing the definitive CFCS diagnosis and sheds the light on the interrelated genotype-phenotype heterogeneity of RASopathies. Herein, we add new phenotypic features of predominating humoral immunodeficiency to the symptomatology of CFCS with a novel mutation in MAP2K1. While CFCS is a multifaceted disease, increased pediatricians’ awareness is needed to prevent the delay in diagnostics and therapeutic interventions. Frontiers Media S.A. 2022-10-14 /pmc/articles/PMC9614356/ /pubmed/36313893 http://dx.doi.org/10.3389/fped.2022.990111 Text en © 2022 Szczawińska-Popłonyk, Popłonyk, Niedziela, Sowińska-Seidler, Sztromwasser, Jamsheer and Obara-Moszynska. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (https://creativecommons.org/licenses/by/4.0/) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pediatrics
Szczawińska-Popłonyk, Aleksandra
Popłonyk, Natalia
Niedziela, Marek
Sowińska-Seidler, Anna
Sztromwasser, Paweł
Jamsheer, Aleksander
Obara-Moszyńska, Monika
Case report: The cardio-facio-cutaneous syndrome due to a novel germline mutation in MAP2K1: A multifaceted disease with immunodeficiency and short stature
title Case report: The cardio-facio-cutaneous syndrome due to a novel germline mutation in MAP2K1: A multifaceted disease with immunodeficiency and short stature
title_full Case report: The cardio-facio-cutaneous syndrome due to a novel germline mutation in MAP2K1: A multifaceted disease with immunodeficiency and short stature
title_fullStr Case report: The cardio-facio-cutaneous syndrome due to a novel germline mutation in MAP2K1: A multifaceted disease with immunodeficiency and short stature
title_full_unstemmed Case report: The cardio-facio-cutaneous syndrome due to a novel germline mutation in MAP2K1: A multifaceted disease with immunodeficiency and short stature
title_short Case report: The cardio-facio-cutaneous syndrome due to a novel germline mutation in MAP2K1: A multifaceted disease with immunodeficiency and short stature
title_sort case report: the cardio-facio-cutaneous syndrome due to a novel germline mutation in map2k1: a multifaceted disease with immunodeficiency and short stature
topic Pediatrics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9614356/
https://www.ncbi.nlm.nih.gov/pubmed/36313893
http://dx.doi.org/10.3389/fped.2022.990111
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