Expanding the phenotype of congenital central hypoventilation syndrome impacts management decisions

Byers, Heather M.; Chen, Maida; Gelfand, Andrew; Ong, Bruce A.; Jendras, Marisa; Glass, Ian A.

doi:10.1002/ajmg.a.38726

Cited by 14 publications

(6 citation statements)

References 28 publications

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“…They are in general considered more pathogenic than PARMs and are highly associated with HD and NCT ( 10 , 28 , 29 ). However, there are several reports of NPARM genotypes with relatively mild phenotypes ( 28 , 30 , 31 ). It was speculated that the severity of NPARM depends on the PHOX2B exon with severe variants linked to exon 3, while pathogenic variants in exon 1 present with mild phenotype ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: A novel PHOX2B p.Ala248_Ala266dup variant causing congenital central hypoventilation syndrome

Artamonova

Zlotina²,

Ismagilova³

et al. 2023

Front. Pediatr.

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IntroductionCongenital central hypoventilation syndrome (CCHS) is a rare disease characterized by central alveolar hypoventilation and impaired autonomic regulation, caused by pathogenic variants of PHOX2B gene. More than 90% of patients have a polyalanine repeat mutation (PARM) in the heterozygous state, characterized by the expansion of GCN repeats and an increase in the number of alanine repeats, so that genotypes 20/24–20/33 are formed (the normal genotype is 20/20). The remaining 10% of patients harbor non-PARMs.Case descriptionWe present a clinical case of a girl with a novel PHOX2B heterozygous genetic variant in the exon 3: NM_003924.4: c.735_791dup, p.Ala248_Ala266dup. The duplication includes 16 GCN (alanine) repeats and 3 adjacent amino acids. Both clinically healthy parents demonstrated a normal PHOX2B sequence. In addition, the girl has a variant of unknown significance in RYR1 gene and a variant of unknown significance in NKX2-5 gene. The child's phenotype is quite special. She needs ventilation during sleep, and has Hirschsprung's disease type I, arteriovenous malformation S4 of the left lung, ventricular and atrium septal defects, coronary right ventricular fistula, hemodynamically nonsignificant, episodes of sick sinus and atrioventricular dissociation with bradycardia, divergent alternating strabismus, and oculus uterque (both eyes) (OU) retinal angiopathy. Two episodes of hypoglycemic seizures were also registered. Severe pulmonary hypertension resolved after appropriate ventilation adjustment. Diagnostic odyssey was quite dramatic.ConclusionDetection of a novel PHOX2B variant expands the understanding of molecular mechanisms of CCHS and genotype–phenotype correlations.

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Section: Discussionmentioning

confidence: 99%

Case Report: A novel PHOX2B p.Ala248_Ala266dup variant causing congenital central hypoventilation syndrome

Artamonova

Zlotina²,

Ismagilova³

et al. 2023

Front. Pediatr.

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“…Diagnosis requires a high index of suspicion and exclusion of cardiac, respiratory, metabolic, and neurological causes of central apnea or hypoventilation. 6 CCHS is a lifelong disease with no response to pharmacologic therapies. Management is extremely challenging with need for lifelong home ventilation and tracheostomy in the severe phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Recurrent apnea in an infant: Lessons for the clinician

Karmani¹,

Pandey

Shridhar

et al. 2020

Medical Journal Armed Forces India

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“…Patients with NPARMs manifest a wide spectrum of phenotypes, some of whom may have only mild hypoventilation, while others have extensive gut involvement, need for continuous ventilatory support, and increased tumour risk over 1 year of age [15]. Hypoventilation may not be the main feature in some PHOX2B mutations [19].…”

Section: Do the Phox2b Anomalies Predict The Clinical Presentation?mentioning

confidence: 99%

Guidelines for diagnosis and management of congenital central hypoventilation syndrome

Trang

Samuels

Ceccherini

et al. 2020

Orphanet J Rare Dis

137

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Background Congenital Central Hypoventilation Syndrome (CCHS) is a rare condition characterized by an alveolar hypoventilation due to a deficient autonomic central control of ventilation and a global autonomic dysfunction. Paired-like homeobox 2B (PHOX2B) mutations are found in most of the patients with CCHS. In recent years, the condition has evolved from a life-threatening neonatal onset disorder to include broader and milder clinical presentations, affecting children, adults and families. Genes other than PHOX2B have been found responsible for CCHS in rare cases and there are as yet other unknown genes that may account for the disease. At present, management relies on lifelong ventilatory support and close follow up of dysautonomic progression. Body This paper provides a state-of-the-art comprehensive description of CCHS and of the components of diagnostic evaluation and multi-disciplinary management, as well as considerations for future research. Conclusion Awareness and knowledge of the diagnosis and management of this rare disease should be brought to a large health community including adult physicians and health carers.

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Expanding the phenotype of congenital central hypoventilation syndrome impacts management decisions

Cited by 14 publications

References 28 publications

Case Report: A novel PHOX2B p.Ala248_Ala266dup variant causing congenital central hypoventilation syndrome

Case Report: A novel PHOX2B p.Ala248_Ala266dup variant causing congenital central hypoventilation syndrome

Recurrent apnea in an infant: Lessons for the clinician

Guidelines for diagnosis and management of congenital central hypoventilation syndrome

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