Congenital central hypoventilation syndrome in neonates: report of fourteen new cases and a review of the literature

Mei, Mei; Yang, Lin; Lu, Yulan; Wang, Laishuan; Cheng, Guoqiang; Cao, Yun; Chen, Chao; Qian, Liling; Zhou, Wenhao

doi:10.21037/tp-20-303

Cited by 7 publications

(10 citation statements)

References 52 publications

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“…CHDs were found in five children with NPARMs (multiple atrial septal defect (ASD), patent ductus arteriosus, vertebral, coronary arteries anomalies, complete vascular ring), and a secundum ASD in a patient with a 20/33 PARM ( 39 ). Similar prevalence of CHD was found in the study of Mei et al; however, exact CHD types were not provided and patent ductus arteriosus and atrial septal defect were prevalent ( 40 ).…”

Section: Discussionsupporting

confidence: 64%

“…Our case seems to combine clinical features of both nonsevere PARMs and NPARMs: the girl has HD, ANSD, and structural cardiovascular abnormalities, like severe NPARM cases do ( 24 , 40 , 46 ), but her hypoventilation is relatively mild, requiring non-invasive lung ventilation (NLV) only during sleep. It was proposed that PHOX2B pathogenic variants have variable penetrance depending on unknown epigenetic factors ( 28 , 46 ), and further evaluation is needed.…”

Section: Discussionmentioning

confidence: 93%

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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: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 93%

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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“…Central hypoventilation is not usually associated with hypotonia. Most commonly it results from heterozygous polyalanine expansion mutations in PHOX2B [ 10 ], which may not be reliably detected in exome based testing. Specific testing for PHOX2B polyalanine expansion mutations in this patient was normal and no other variants in PHOX2B or other genes known to be associated with central hypoventilation were identified by WGS.…”

Section: Discussionmentioning

confidence: 99%

Biallelic P4HTM variants associated with HIDEA syndrome and mitochondrial respiratory chain complex I deficiency

et al. 2021

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We report a patient with profound congenital hypotonia, central hypoventilation, poor visual behaviour with retinal hypopigmentation, and significantly decreased mitochondrial respiratory chain complex I activity in muscle, who died at 7 months of age having made minimal developmental progress. Biallelic predicted truncating P4HTM variants were identified following trio whole-genome sequencing, consistent with a diagnosis of hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy and eye abnormalities (HIDEA) syndrome. Very few patients with HIDEA syndrome have been reported previously and mitochondrial abnormalities were observed in three of four previous cases who had a muscle biopsy, suggesting the possibility that HIDEA syndrome represents a primary mitochondrial disorder. P4HTM encodes a transmembrane prolyl 4-hydroxylase with putative targets including hypoxia inducible factors, RNA polymerase II and activating transcription factor 4, which has been implicated in the integrated stress response observed in cell and animal models of mitochondrial disease, and may explain the mitochondrial dysfunction observed in HIDEA syndrome.

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“…44 Most studies concentrated in Asia focused on post-test counselling considerations. 35,95,99,134,161 There was a significant focus on counselling for recurrence risk and future pregnancy. In India, genetic testing followed by genetic counselling was considered essential in ensuring caregivers are aware of the possibility that etiology may not be established despite genetic testing, to inform recurrence, as well as…”

Section: Geography and Ethnicitymentioning

confidence: 99%

“…Studies of neurologic disorders identified the need for early identification of genetic biomarkers for brain injury 153 and timely genetic testing and diagnosis. 99,143 A study that focused on global developmental delay outlined the need for families to be counselled regarding anticipated comorbidities and the possibility of no diagnosis/etiology in spite of utilizing many types of genetic tests. 111…”

Section: Neurologic Disordersmentioning

confidence: 99%

Genetic counselling considerations with genetic/genomic testing in Neonatal and Pediatric Intensive Care Units: A scoping review

Kim,

Pistawka,

Langlois

et al. 2023

Clinical Genetics

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Genetic and genomic technologies can effectively diagnose numerous genetic disorders. Patients benefit when genetic counselling accompanies genetic testing and international guidelines recommend pre‐ and post‐test genetic counselling with genome‐wide sequencing. However, there is a gap in knowledge regarding the unique genetic counselling considerations with different types of genetic testing in the Neonatal Intensive Care Unit (NICU) and the Pediatric Intensive Care Unit (PICU). This scoping review was conducted to identify the gaps in care with respect to genetic counselling for infants/pediatric patients undergoing genetic and genomic testing in NICUs and PICUs and understand areas in need of improvement in order to optimize clinical care for patients, caregivers, and healthcare providers. Five databases (MEDLINE [Ovid], Embase [Ovid], PsycINFO [Ebsco], CENTRAL [Ovid], and CINHAL [Ebsco]) and grey literature were searched. A total of 170 studies were included and used for data extraction and analysis. This scoping review includes descriptive analysis, followed by a narrative account of the extracted data. Results were divided into three groups: pre‐test, post‐test, and comprehensive (both pre‐ and post‐test) genetic counselling considerations based on indication for testing. More studies were conducted in the NICU than the PICU. Comprehensive genetic counselling was discussed in only 31% of all the included studies demonstrating the need for both pre‐test and post‐test genetic counselling for different clinical indications in addition to the need to account for different cultural aspects based on ethnicity and geographic factors.

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Congenital central hypoventilation syndrome in neonates: report of fourteen new cases and a review of the literature

Cited by 7 publications

References 52 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

Biallelic P4HTM variants associated with HIDEA syndrome and mitochondrial respiratory chain complex I deficiency

Genetic counselling considerations with genetic/genomic testing in Neonatal and Pediatric Intensive Care Units: A scoping review

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