Raras
Buscar doenças, sintomas, genes...
Síndrome de hipoventilação central congênita
ORPHA:661CID-10 · G47.3CID-11 · 7A42.1OMIM 209880DOENÇA RARA

É uma doença rara causada por uma falha grave no controle automático da respiração feito pelo cérebro e também por um mau funcionamento do sistema nervoso autônomo (aquele que comanda funções que não controlamos, como a própria respiração). Estima-se que afete 1 em cada 200.000 nascidos vivos. Uma alteração (mutação) no gene PHOX-2B é encontrada em 90% dos pacientes. Em 16% dos casos, a doença está associada à doença de Hirschsprung. Apesar da alta taxa de mortalidade e da necessidade de ventilação mecânica por toda a vida, o resultado a longo prazo para pacientes com CCHS pode melhorar muito com um acompanhamento médico coordenado e feito por várias especialidades.

Mantido por Agente Raras·Colaborar como especialista →

Introdução

O que você precisa saber de cara

📋

É uma doença rara causada por uma falha grave no controle automático da respiração feito pelo cérebro e também por um mau funcionamento do sistema nervoso autônomo (aquele que comanda funções que não controlamos, como a própria respiração). Estima-se que afete 1 em cada 200.000 nascidos vivos. Uma alteração (mutação) no gene PHOX-2B é encontrada em 90% dos pacientes. Em 16% dos casos, a doença está associada à doença de Hirschsprung. Apesar da alta taxa de mortalidade e da necessidade de ventilação mecânica por toda a vida, o resultado a longo prazo para pacientes com CCHS pode melhorar muito com um acompanhamento médico coordenado e feito por várias especialidades.

Pesquisas ativas
6 ensaios
13 total registrados no ClinicalTrials.gov
Publicações científicas
659 artigos
Último publicado: 2026 Apr

Escala de raridade

CLASSIFICAÇÃO ORPHANET · BRASIL 2024
Unknown
Ultra-rara
<1/50k
Muito rara
1/20k
Rara
1/10k
Pouco freq.
1/5k
Incomum
1/2k
Prevalência
0.0
Worldwide
Início
Infancy
+ neonatal
🏥
SUS: Cobertura mínimaScore: 35%
Centros em: MG, PR, SC, RS, ES +10CID-10: G47.3
🇧🇷Dados SUS / DATASUS
PROCEDIMENTOS SIGTAP (2)
0202010694
Sequenciamento completo do exoma (WES)genetic_test
0301070040
Atendimento em reabilitação — doenças rarasrehabilitation
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Entender a doença

Do básico ao detalhe, leia no seu ritmo

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Sinais e sintomas

O que aparece no corpo e com que frequência cada sintoma acontece

Partes do corpo afetadas

🧠
Neurológico
6 sintomas
🫃
Digestivo
3 sintomas
🫁
Pulmão
2 sintomas
👂
Ouvidos
2 sintomas
📏
Crescimento
1 sintomas
❤️
Coração
1 sintomas

+ 15 sintomas em outras categorias

Características mais comuns

100%prev.
Hipoventilação
Frequência: 20/20
100%prev.
Hipoventilação central
Frequência: 27/27
100%prev.
Hipoventilação noturna
Frequência: 10/10
90%prev.
Insuficiência respiratória
Muito frequente (99-80%)
90%prev.
Anormalidade do sistema nervoso autônomo
Muito frequente (99-80%)
89%prev.
HP:0003577
Frequência: 24/27
30sintomas
Muito frequente (8)
Frequente (1)
Ocasional (10)
Sem dados (11)

Os sintomas variam de pessoa para pessoa. Abaixo estão as 30 características clínicas mais associadas, ordenadas por frequência.

HipoventilaçãoHypoventilation
Frequência: 20/20100%
Hipoventilação centralCentral hypoventilation
Frequência: 27/27100%
Hipoventilação noturnaNocturnal hypoventilation
Frequência: 10/10100%
Insuficiência respiratóriaRespiratory insufficiency
Muito frequente (99-80%)90%
Anormalidade do sistema nervoso autônomoAbnormality of the autonomic nervous system
Muito frequente (99-80%)90%

Linha do tempo da pesquisa

Publicações por ano — veja quando o interesse científico cresceu
Anos de pesquisa1desde 2026
Total histórico659PubMed
Últimos 10 anos200publicações
Pico202439 papers
Linha do tempo
2026Hoje · 2026🧪 2009Primeiro ensaio clínico📈 2024Ano de pico
Publicações por ano (últimos 10 anos)

Encontrou um erro ou informação desatualizada? Sugira uma correção →

Genética e causas

O que está alterado no DNA e como passa nas famílias

Genes associados

6 genes identificados com associação a esta condição. Padrão de herança: Autosomal dominant, Not applicable.

MYO1HUnconventional myosin-IhDisease-causing germline mutation(s) inTolerante
FUNÇÃO

Myosins are actin-based motor molecules with ATPase activity. Unconventional myosins serve in intracellular movements. Their highly divergent tails are presumed to bind to membranous compartments, which would be moved relative to actin filaments (By similarity)

LOCALIZAÇÃO

MECANISMO DE DOENÇA

Central hypoventilation syndrome, congenital, 2, and autonomic dysfunction

An autosomal recessive form of congenital central hypoventilation syndrome, a rare disorder characterized by abnormal control of respiration in the absence of neuromuscular, lung or cardiac disease, or an identifiable brainstem lesion. CCHS2 is characterized by shallow breathing and apneic spells apparent in the neonatal period. Some patients have other features of autonomic dysfunction, including bladder dysfunction, sinus bradycardia, and temperature dysregulation.

EXPRESSÃO TECIDUAL(Baixa expressão)
Testículo
3.2 TPM
Tireoide
0.5 TPM
Cervix Ectocervix
0.4 TPM
Esôfago - Mucosa
0.3 TPM
Pulmão
0.3 TPM
OUTRAS DOENÇAS (2)
central hypoventilation syndrome, congenital, 2, and autonomic dysfunctioncentral hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease
HGNC:13879UniProt:Q8N1T3
LBX1Transcription factor LBX1Disease-causing germline mutation(s) inRestrito
FUNÇÃO

Transcription factor required for the development of GABAergic interneurons in the dorsal horn of the spinal cord and migration and further development of hypaxial muscle precursor cells for limb muscles, diaphragm and hypoglossal cord

LOCALIZAÇÃO

Nucleus

MECANISMO DE DOENÇA

Central hypoventilation syndrome, congenital, 3

A form of congenital central hypoventilation syndrome, a rare disorder characterized by abnormal control of respiration in the absence of neuromuscular, lung or cardiac disease, or an identifiable brainstem lesion. CCHS3 is an autosomal recessive, neonatal form characterized by slow and shallow breathing due to a deficiency in autonomic control of respiration. Affected individuals present with respiratory insufficiency and absence of the hypercapnic reflex that stimulates breathing. Additional features include gastrointestinal problems, poor heat tolerance and paroxysmal hypertension.

EXPRESSÃO TECIDUAL(Tecido-específico)
Músculo esquelético
9.7 TPM
Cerebelo
3.0 TPM
Cérebro - Hemisfério cerebelar
2.5 TPM
Brain Spinal cord cervical c-1
0.3 TPM
Pulmão
0.3 TPM
OUTRAS DOENÇAS (2)
central hypoventilation syndrome, congenital, 3central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease
HGNC:16960UniProt:P52954
PHOX2BPaired mesoderm homeobox protein 2BDisease-causing germline mutation(s) inAltamente restrito
FUNÇÃO

Involved in the development of several major noradrenergic neuron populations, including the locus coeruleus. Transcription factor which could determine a neurotransmitter phenotype in vertebrates. Enhances second-messenger-mediated activation of the dopamine beta-hydrolase and c-fos promoters, and of several enhancers including cAMP-response element and serum-response element

LOCALIZAÇÃO

Nucleus

MECANISMO DE DOENÇA

Central hypoventilation syndrome, congenital, 1

An autosomal dominant form of congenital central hypoventilation syndrome, a rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia.

EXPRESSÃO TECIDUAL(Baixa expressão)
Cólon sigmoide
4.1 TPM
Cólon transverso
1.5 TPM
Intestino delgado
0.8 TPM
Esôfago - Muscular
0.5 TPM
Esôfago - Junção
0.4 TPM
OUTRAS DOENÇAS (5)
neuroblastoma, susceptibility to, 2central hypoventilation syndrome, congenital, 1, with or without Hirschsprung diseaseHirschsprung disease-ganglioneuroblastoma syndromeneuroblastoma
HGNC:9143UniProt:Q99453
BDNFNeurotrophic factor BDNF precursor formCandidate gene tested inAltamente restrito
FUNÇÃO

Important signaling molecule that activates signaling cascades downstream of NTRK2 (PubMed:11152678). During development, promotes the survival and differentiation of selected neuronal populations of the peripheral and central nervous systems. Participates in axonal growth, pathfinding and in the modulation of dendritic growth and morphology. Major regulator of synaptic transmission and plasticity at adult synapses in many regions of the CNS. The versatility of BDNF is emphasized by its contribu

LOCALIZAÇÃO

Secreted

VIAS BIOLÓGICAS (10)
PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingPIP3 activates AKT signalingConstitutive Signaling by Aberrant PI3K in CancerActivated NTRK2 signals through PI3KActivated NTRK2 signals through PLCG1
OUTRAS DOENÇAS (2)
WAGR syndromecentral hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease
HGNC:1033UniProt:P23560
EDN3Endothelin-3Candidate gene tested inModerado
FUNÇÃO

Endothelins are endothelium-derived vasoconstrictor peptides

LOCALIZAÇÃO

Secreted

VIAS BIOLÓGICAS (3)
G alpha (q) signalling eventsPeptide ligand-binding receptorsTranscriptional and post-translational regulation of MITF-M expression and activity
MECANISMO DE DOENÇA

Hirschsprung disease 4

A disorder of neural crest development characterized by absence of enteric ganglia along a variable length of the intestine. It is the most common cause of congenital intestinal obstruction. Early symptoms range from complete acute neonatal obstruction, characterized by vomiting, abdominal distention and failure to pass stool, to chronic constipation in the older child.

EXPRESSÃO TECIDUAL(Ubíquo)
Vagina
141.1 TPM
Tireoide
34.8 TPM
Glândula salivar
26.3 TPM
Esôfago - Mucosa
24.2 TPM
Intestino delgado
19.7 TPM
OUTRAS DOENÇAS (5)
Waardenburg syndrome type 4BWaardenburg-Shah syndromecentral hypoventilation syndrome, congenital, 1, with or without Hirschsprung diseaseHirschsprung disease
HGNC:3178UniProt:P14138
GDNFGlial cell line-derived neurotrophic factorCandidate gene tested inRestrito
FUNÇÃO

Neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake (PubMed:8493557). Acts by binding to its coreceptor, GFRA1, leading to autophosphorylation and activation of the RET receptor (PubMed:10829012, PubMed:25242331, PubMed:31535977). Involved in the development of the neural crest (PubMed:15242795)

LOCALIZAÇÃO

Secreted

VIAS BIOLÓGICAS (4)
RAF/MAP kinase cascadeRET signalingFormation of the ureteric budNCAM1 interactions
MECANISMO DE DOENÇA

Hirschsprung disease 3

A disorder of neural crest development characterized by absence of enteric ganglia along a variable length of the intestine. It is the most common cause of congenital intestinal obstruction. Early symptoms range from complete acute neonatal obstruction, characterized by vomiting, abdominal distention and failure to pass stool, to chronic constipation in the older child.

EXPRESSÃO TECIDUAL(Tecido-específico)
Cólon sigmoide
11.6 TPM
Esôfago - Muscular
6.2 TPM
Fibroblastos
5.7 TPM
Esôfago - Junção
4.9 TPM
Cólon transverso
4.6 TPM
OUTRAS DOENÇAS (3)
central hypoventilation syndrome, congenital, 1, with or without Hirschsprung diseaseHirschsprung diseaseHirschsprung disease, susceptibility to, 3
HGNC:4232UniProt:P39905

Variantes genéticas (ClinVar)

113 variantes patogênicas registradas no ClinVar.

🧬 GDNF: GRCh38/hg38 5p13.3-11(chr5:30831208-46273389)x3 ()
🧬 GDNF: GRCh38/hg38 5p13.3-12(chr5:29299893-45899898)x3 ()
🧬 GDNF: GRCh37/hg19 5p13.3-11(chr5:29348753-46389339)x3 ()
🧬 GDNF: GRCh37/hg19 5p13.2-11(chr5:36053583-46389339)x3 ()
🧬 GDNF: GRCh37/hg19 5p14.1-11(chr5:26382110-46389339) ()
Ver todas no ClinVar

Classificação de variantes (ClinVar)

Distribuição de 1 variantes classificadas pelo ClinVar.

1
Patogênica (100.0%)
VARIANTES MAIS SIGNIFICATIVAS
PHOX2B: NM_003924.4(PHOX2B):c.325del (p.Gln109fs) [Likely pathogenic]

Diagnóstico

Os sinais que médicos procuram e os exames que confirmam

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Tratamento e manejo

Remédios, cuidados de apoio e o que precisa acompanhar

Pipeline de tratamentos
Pipeline regulatório — de medicamentos já aprovados a drogas em pesquisa exploratória.
2Fase 21
·Pré-clínico11
Medicamentos catalogadosEnsaios clínicos· 0 medicamentos · 12 ensaios
Carregando informações de tratamento...

Onde tratar no SUS

Hospitais de referência no Brasil e o protocolo oficial do SUS (PCDT)

🇧🇷 Atendimento SUS — Síndrome de hipoventilação central congênita

Centros de Referência SUS

24 centros habilitados pelo SUS para Síndrome de hipoventilação central congênita

Centros para Síndrome de hipoventilação central congênita

Detalhes dos centros

Hospital Universitário Prof. Edgard Santos (HUPES)

R. Dr. Augusto Viana, s/n - Canela, Salvador - BA, 40110-060 · CNES 0003808

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Hospital Infantil Albert Sabin

R. Tertuliano Sales, 544 - Vila União, Fortaleza - CE, 60410-794 · CNES 2407876

Serviço de Referência

Rota
Anomalias CongênitasDeficiência Intelectual

Hospital de Apoio de Brasília (HAB)

AENW 3 Lote A Setor Noroeste - Plano Piloto, Brasília - DF, 70684-831 · CNES 0010456

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Estadual Infantil e Maternidade Alzir Bernardino Alves (HIABA)

Av. Min. Salgado Filho, 918 - Soteco, Vila Velha - ES, 29106-010 · CNES 6631207

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital das Clínicas da UFG

Rua 235 QD. 68 Lote Área, Nº 285, s/nº - Setor Leste Universitário, Goiânia - GO, 74605-050 · CNES 2338424

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Hospital Universitário da UFJF

R. Catulo Breviglieri, Bairro - s/n - Santa Catarina, Juiz de Fora - MG, 36036-110 · CNES 2297442

Atenção Especializada

Rota
Anomalias Congênitas

Hospital das Clínicas da UFMG

Av. Prof. Alfredo Balena, 110 - Santa Efigênia, Belo Horizonte - MG, 30130-100 · CNES 2280167

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Universitário Julio Müller (HUJM)

R. Luis Philippe Pereira Leite, s/n - Alvorada, Cuiabá - MT, 78048-902 · CNES 2726092

Atenção Especializada

Rota
Anomalias Congênitas

Hospital Universitário João de Barros Barreto

R. dos Mundurucus, 4487 - Guamá, Belém - PA, 66073-000 · CNES 2337878

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Universitário Lauro Wanderley (HULW)

R. Tabeliao Estanislau Eloy, 585 - Castelo Branco, João Pessoa - PB, 58050-585 · CNES 0002470

Atenção Especializada

Rota
Anomalias Congênitas

Instituto de Medicina Integral Prof. Fernando Figueira (IMIP)

R. dos Coelhos, 300 - Boa Vista, Recife - PE, 50070-902 · CNES 0000647

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Pequeno Príncipe

R. Des. Motta, 1070 - Água Verde, Curitiba - PR, 80250-060 · CNES 3143805

Serviço de Referência

Rota
Anomalias CongênitasDeficiência Intelectual

Hospital Universitário Regional de Maringá (HUM)

Av. Mandacaru, 1590 - Parque das Laranjeiras, Maringá - PR, 87083-240 · CNES 2216108

Atenção Especializada

Rota
Anomalias Congênitas

Hospital de Clínicas da UFPR

R. Gen. Carneiro, 181 - Alto da Glória, Curitiba - PR, 80060-900 · CNES 2364980

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Universitário Pedro Ernesto (HUPE-UERJ)

Blvd. 28 de Setembro, 77 - Vila Isabel, Rio de Janeiro - RJ, 20551-030 · CNES 2280221

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira (IFF/Fiocruz)

Av. Rui Barbosa, 716 - Flamengo, Rio de Janeiro - RJ, 22250-020 · CNES 2269988

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital São Lucas da PUCRS

Av. Ipiranga, 6690 - Jardim Botânico, Porto Alegre - RS, 90610-000 · CNES 2232928

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Hospital de Clínicas de Porto Alegre (HCPA)

Rua Ramiro Barcelos, 2350 Bloco A - Av. Protásio Alves, 211 - Bloco B e C - Santa Cecília, Porto Alegre - RS, 90035-903 · CNES 2237601

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital Universitário da UFSC (HU-UFSC)

R. Profa. Maria Flora Pausewang - Trindade, Florianópolis - SC, 88036-800 · CNES 2560356

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo

Hospital das Clínicas da FMUSP

R. Dr. Ovídio Pires de Campos, 225 - Cerqueira César, São Paulo - SP, 05403-010 · CNES 2077485

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital de Base de São José do Rio Preto

Av. Brg. Faria Lima, 5544 - Vila Sao Jose, São José do Rio Preto - SP, 15090-000 · CNES 2079798

Atenção Especializada

Rota
Anomalias Congênitas

Hospital de Clínicas da UNICAMP

R. Vital Brasil, 251 - Cidade Universitária, Campinas - SP, 13083-888 · CNES 2748223

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

Hospital de Clínicas de Ribeirão Preto (HCRP-USP)

R. Ten. Catão Roxo, 3900 - Vila Monte Alegre, Ribeirão Preto - SP, 14015-010 · CNES 2082187

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do MetabolismoDeficiência Intelectual

UNIFESP / Hospital São Paulo

R. Napoleão de Barros, 715 - Vila Clementino, São Paulo - SP, 04024-002 · CNES 2688689

Serviço de Referência

Rota
Anomalias CongênitasErros Inatos do Metabolismo
Sobre os centros SUS: Estes centros são habilitados pelo Ministério da Saúde como Serviços de Referência em Doenças Raras ou Serviços de Atenção Especializada. O atendimento é pelo SUS, com encaminhamento da rede de atenção básica.

Dados de DATASUS/CNES, SBGM, ABNeuro e Ministério da Saúde. Sempre confirme a disponibilidade diretamente com o estabelecimento.

Pesquisa ativa

Ensaios clínicos abertos e novidades científicas recentes

🟢 Recrutando agora

4 pesquisas recrutando participantes. Converse com seu médico sobre a possibilidade de participar.

Outros ensaios clínicos

13 ensaios clínicos encontrados, 6 ativos.

Distribuição por fase
Ver todos no ClinicalTrials.gov
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Publicações mais relevantes

Timeline de publicações
299 papers (10 anos)
#1

Generation of iPSC lines (UMILi032-A, UMILi033-A, UMILi034-A, UMILi035-A, UMILi036-A) from five Congenital Central Hypoventilation Syndrome patients carrying different poly-alanine expansion mutations in the PHOX2B gene.

Stem cell research2026 Feb

Congenital Central Hypoventilation Syndrome (CCHS) is a rare, life-threatening genetic disorder of the autonomic nervous system characterized by alveolar hypoventilation and generalized dysautonomia. CCHS is caused by heterozygous PHOX2B mutations, predominantly polyalanine repeat expansion (95% of cases) and, less frequently, frameshift mutations (5%). To address the lack of disease models, we generated five human induced pluripotent stem cell (hiPSC) lines derived from patients carrying +5Ala, +6Ala and +11Ala expansion mutations. These hiPSC lines exhibited undifferentiated hPSC phenotype, pluripotency, normal karyotype, and retention of the pathogenic genotype, providing a reliable in vitro platform for elucidating CCHS molecular mechanisms and disease pathogenesis.

#2

Hirschsprung Disease on Fetal Autopsy Leading to the Diagnosis of Congenital Central Hypoventilation Syndrome in a Stillborn Fetus.

Clinical genetics2026 Mar

Hirschsprung disease (HD) can be associated with congenital central hypoventilation syndrome (CCHS). CCHS is mostly due to PHOX2B pathogenic variants. First report of HD on fetal autopsy leading to CCHS diagnosis. Highlights the role of fetal autopsy in stillborn babies, to guide genetic investigation and refine genetic counseling.

#3

Sex Differences in the Effects of Etonogestrel on Respiratory Recovery in an In Vivo Rat Model of Central Chemoreflex Impairment.

Acta physiologica (Oxford, England)2026 Apr

Rhythmic breathing movements driven by the brainstem rely on chemosensory inputs to homeostatically adjust motor output to the prevailing metabolic demand. The central CO2 chemoreflex is a critical component of this neural circuitry, as defects in these sensors cause hypoventilation syndromes, which are typically difficult to manage pharmacologically. Progesterone has long been known to stimulate breathing in both sexes, and remarkably the progestinic metabolite, etonogestrel (ETO), enhances CO2 chemosensitivity in animal models and female patients affected by congenital central hypoventilation syndrome. However, ETO's mechanisms and sites of action remain unknown, and the experimental use of synthetic progestins has been met with mixed respiratory outcomes. In our recent work, we demonstrated that chronic ETO treatment improved the CO2 chemoreflex in female rats in which < 80% of chemoreceptor neurons comprising the retrotrapezoid nucleus (RTN) were eliminated. Since the progesterone receptor is widely expressed in both the male and female brain, we investigated whether ETO-induced CO2 chemoreflex recovery can be replicated in male rats in which RTN neurons are partially eliminated by the use of substance P-saporin toxin. Our results confirm dose-dependent impairment of the CO2 chemoreflex in both sexes following chemoreceptor lesion and corroborate the findings that ETO treatment restores ventilation in female rats with moderate-sized lesions. Interestingly, female respiratory recovery was associated with increased expression of the pH-sensing genes Gpr4 and Task2 in the RTN. In contrast, male rats failed to show significant recovery with ETO treatment, suggesting a sex-specific mechanism through which ETO promotes CO2 chemoreflex recovery.

#4

Recognition of a Critical Functional Domain and Improved PHOX2B Missense Variant Interpretation by Utilization of In Silico Prediction Tools.

Human mutation2026

Pathogenic heterozygous variants in PHOX2B are associated with congenital central hypoventilation syndrome (CCHS), which is characterized by autonomic nervous system dysregulation severely affecting respiratory control. The interpretation of PHOX2B missense variation is challenging due to their rarity and the lack of available functional evidence. Consequently, most PHOX2B missense variants are classified as variants of uncertain significance (VUSs), complicating the timely diagnosis and clinical management of the condition. To generate an improved model for assessments of PHOX2B missense variants, a methodology was derived to evaluate all PHOX2B missense variants in the literature and public/private databases according to a consensus classification framework and assigned pathogenicity classifications. Pathogenicity prediction scores from the in silico prediction tools CADD, REVEL, BayesDel, and AlphaMissense were obtained for all variants. A weighted logistic regression in a multiple imputation framework was performed to assess the strength of evidence supporting application of ACMG/AMP guidelines' PP3/BP4 criteria. CADD, REVEL, and BayesDel meet the predictive strengths for PP3/BP4 recommended by the Clinical Genome Resource (ClinGen). Based on their areas under the curve and low proportions of variants with indeterminate pathogenicity predictions, BayesDel and REVEL were the strongest predictive tools and should be utilized for routine PHOX2B missense variant assessment with this study's calculated score thresholds for PP3/BP4 strength levels. Furthermore, the positional distribution of pathogenic and benign variants was analyzed to assess potential hotspots or critical functional domains in PHOX2B, and pathogenic variants were found to cluster in the homeodomain. The enrichment of pathogenic variation was substantiated by the prediction tools, supporting the use of the PM1 criterion for variants in the homeodomain. This calibration of existing computational prediction tools for PHOX2B missense variant classification and recognition of the homeodomain variants will enable fewer VUS classifications in favor of conclusive results, aiding in these individuals' care.

#5

Heart Rate Variability: Longitudinal Cardioautonomic Physiomarker in Congenital Central Hypoventilation Syndrome.

Annals of the American Thoracic Society2026 Feb 21

Congenital Central Hypoventilation Syndrome (CCHS) is caused by PHOX2B gene variants, resulting in highly variable cardiac autonomic dysregulation, including abrupt sinus pauses and risk of sudden unexpected death. The relationship between age, PHOX2B genotype, and cardiac autonomic dysfunction remains unknown, and CCHS-related physiomarkers are lacking. To assess the impact of age and genotype-severity on longitudinal heart rate variability (HRV), a non-invasive measure of cardiovascular autonomic function, in CCHS. Longitudinal HRV measures were calculated from continuous overnight electrocardiography during polysomnography during clinical evaluation with provided artificial ventilation. PHOX2B variants were divided into moderate and severe groupings based on clinical, cellular, and in-silico PHOX2B data. Linear mixed-effects models were used to examine demographic and clinical differences in HRV by age and PHOX2B variant grouping. 226 overnight recordings from 52 unique individuals with CCHS were included. PHOX2B variant severity was associated with decreased vagal tone, baroreflex activity, and total HRV. Increasing age was associated with reduced parasympathetic and baroreflex activity with increased sympathetic dominance. Our findings suggest parasympathetic withdrawal with advancing age in CCHS and, potentially in response, increasing sympathetic contribution to cardiac autonomic control. Reduced baroreflex sensitivity with age, potentially due to cumulative physiological stress, may contribute to this sympathetic dominance, offering insight into the heightened cardiovascular risk observed clinically with age. This novel relationship between PHOX2B variant severity, age and HRV suggests that HRV may be a sensitive, easy-to-obtain physiomarker of CCHS phenotype severity and progression, providing an opportunity to predict and anticipate increasing cardioautonomic dysregulation and risk in CCHS.

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Ainda não existe comunidade no Raras para Síndrome de hipoventilação central congênita

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Doenças relacionadas

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Ordenadas pelo número de sintomas em comum.

Referências e fontes

Bases de dados externas citadas neste artigo

Publicações científicas

Artigos indexados no PubMed ligados a esta doença no grafo RarasNet — título, periódico e PMID direto da fonte, sem intermediação de IA.

  1. Generation of iPSC lines (UMILi032-A, UMILi033-A, UMILi034-A, UMILi035-A, UMILi036-A) from five Congenital Central Hypoventilation Syndrome patients carrying different poly-alanine expansion mutations in the PHOX2B gene.
    Stem cell research· 2026· PMID 41420984mais citado
  2. Hirschsprung Disease on Fetal Autopsy Leading to the Diagnosis of Congenital Central Hypoventilation Syndrome in a Stillborn Fetus.
    Clinical genetics· 2026· PMID 41253684mais citado
  3. Sex Differences in the Effects of Etonogestrel on Respiratory Recovery in an In&#xa0;Vivo Rat Model of Central Chemoreflex Impairment.
    Acta physiologica (Oxford, England)· 2026· PMID 41823358mais citado
  4. Recognition of a Critical Functional Domain and Improved PHOX2B Missense Variant Interpretation by Utilization of In Silico Prediction Tools.
    Human mutation· 2026· PMID 41809564mais citado
  5. Heart Rate Variability: Longitudinal Cardioautonomic Physiomarker in Congenital Central Hypoventilation Syndrome.
    Annals of the American Thoracic Society· 2026· PMID 41721744mais citado
  6. International Congenital Central Hypoventilation Syndrome (CCHS) Registry: Analysis of Patient-Reported Symptoms by PHOX2B Variant.
    Pediatr Pulmonol· 2026· PMID 41981969recente
  7. PHOX2B Tyr14Ter Mutation Might Be Associated with Sustained Diurnal Hypertension: Case Report and Review of the Literature.
    Children (Basel)· 2026· PMID 41897137recente

Bases de dados e fontes oficiais

Identificadores e referências canônicas usadas para montar este verbete.

  1. ORPHA:661(Orphanet)
  2. OMIM OMIM:209880(OMIM)
  3. MONDO:0800026(MONDO)
  4. GARD:8535(GARD (NIH))
  5. Variantes catalogadas(ClinVar)
  6. Busca completa no PubMed(PubMed)
  7. Artigo Wikipedia(Wikipedia)
  8. Q979129(Wikidata)

Dados compilados pelo RarasNet a partir de fontes abertas (Orphanet, OMIM, MONDO, PubMed/EuropePMC, ClinicalTrials.gov, DATASUS, PCDT/MS). Este conteúdo é informativo e não substitui avaliação médica.

Conteúdo mantido por Agente Raras · Médicos e pesquisadores podem colaborar

Síndrome de hipoventilação central congênita
Compêndio · Raras BR

Síndrome de hipoventilação central congênita

ORPHA:661 · MONDO:0800026
Prevalência
Unknown
Herança
Autosomal dominant, Not applicable
CID-10
G47.3 · Apnéia de sono
CID-11
Ensaios
6 ativos
Início
Infancy, Neonatal
Prevalência
0.0 (Worldwide)
MedGen
UMLS
C1275808
EuropePMC
Wikidata
Wikipedia
Papers 10a
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