Paired-Like Homeobox Gene PHOX2B Non-Polyalanine Repeat Expansion Mutations: Genotype-Phenotype Correlation in Congenital Central Hypoventilation Syndrome and Later Onset-CCHS

Abstract Background: Congenital central hypoventilation syndrome (CCHS) is a rare autosomal dominant disorder caused by pathogenic variants in PHOX2B gene. Characteristics of neonatal-onset CCHS cases have not been well assessed. Our study aimed to expand current knowledge of clinical and genetic features of neonates with CCHS and provide data on the genotype-phenotype correlation.Methods: We made a retrospective analysis of 14 neonates carrying PHOX2B pathogenic variants from 2014 to 2019 and we reviewed previously published neonatal-onset cases. Clinical and genetic data were analyzed. Moreover, genotype-phenotype correlation analysis was performed.Results: We identified a total of 60 cases with neonatal-onset CCHS including 14 novel cases from our local cohort. Nearly 20% (18.2%, 10/55) of the patients were born prematurely. Nearly half (46.2%, 18/39) of the patients had abnormal family history. Polyhydramnios was observed in 21.3% (10/47) of the patients. About 90% of the patients manifested hypoventilation in the first week. Forty-six (76.7%) patients were classified as severer-CCHS. Gastrointestinal manifestations were observed in 71.7% of the patients. Approximately twofold more males than females were affected by Hirschprung disease (HSCR)/variant HSCR (75.8% vs 35%, P=0.003). Neural crest tumor occurred in 9.1% (4/44) patients. Half patients had PARMs in PHOX2B and the left had 23 distinct non-PARMs (NPARMs) with one novel variant (c.684dup). The prevalence of HSCR and mild-CCHS among patients with NPARMs was significantly greater than that of the patients with PARMs.Conclusions: This report provides a large cohort of neonatal-onset CCHS cases. The results indicate that severe hypoventilation and HSCR are frequently observed in this group. NPARMs accounted for half of the cohort with some genotypes tend to be associated with mild phenotype. Molecular testing in suspicious neonates and genetic counseling for CCHS families are highly recommended.

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Clinical PHOX2B Testing In Congenital Central Hypoventilation Syndrome (CCHS): Genotype/Phenotype Correlation

10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a3705 ◽

2011 ◽

Author(s):

Casey M. Rand ◽

Michael S. Carroll ◽

Elizabeth M. Berry-Kravis ◽

Lili Zhou ◽

Lawrence Jennings ◽

...

Keyword(s):

Congenital Central Hypoventilation Syndrome ◽

Phenotype Correlation ◽

Genotype Phenotype Correlation ◽

Central Hypoventilation ◽

Hypoventilation Syndrome

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Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome

Nature Genetics ◽

10.1038/ng1130 ◽

2003 ◽

Vol 33 (4) ◽

pp. 459-461 ◽

Cited By ~ 543

Author(s):

Jeanne Amiel ◽

Béatrice Laudier ◽

Tania Attié-Bitach ◽

Ha Trang ◽

Loïc de Pontual ◽

...

Keyword(s):

Homeobox Gene ◽

Congenital Central Hypoventilation Syndrome ◽

Frameshift Mutations ◽

Central Hypoventilation ◽

Polyalanine Expansion ◽

Hypoventilation Syndrome

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How the Management of Children With Congenital Central Hypoventilation Syndrome Has Changed Over Time: Two Decades of Experience From an Italian Center

Frontiers in Pediatrics ◽

10.3389/fped.2021.648927 ◽

2021 ◽

Vol 9 ◽

Author(s):

Federica Porcaro ◽

Maria Giovanna Paglietti ◽

Claudio Cherchi ◽

Alessandra Schiavino ◽

Maria Beatrice Chiarini Testa ◽

...

Keyword(s):

Mechanical Ventilation ◽

Invasive Mechanical Ventilation ◽

Repeat Expansion ◽

Breath Holding ◽

Congenital Central Hypoventilation Syndrome ◽

Invasive Ventilation ◽

Number Of Patients ◽

Central Hypoventilation ◽

Hypoventilation Syndrome ◽

Over Time

Background: Congenital central hypoventilation syndrome (CCHS) is a rare disorder whose clinical phenotype is closely related to genotype.Methods: A retrospective analysis has been conducted on 22 patients with CCHS, who were referred to the Pediatric Pulmonology and Respiratory Intermediate Care Unit of Bambino Gesù Children's Hospital (Italy) for a multidisciplinary follow-up program between 2000 and 2020.Results: Apnea and cyanosis were the most frequent symptoms at onset (91%). Overall, 59% of patients required tracheostomy and invasive mechanical ventilation (IMV) in the first months of life. Thirty-two percent of patients had Hirschsprung disease (HSCR) that was associated with longer polyalanine repetitions or non-polyalanine repeat expansion mutations (NPARMs). Polyalanine repeat expansion mutations (PARMs) were more frequent and two novel NPARMs (c.780dupT and C.225–256delCT) were described in 14% of patients. Focal epilepsy was first described in 14% of patients and neurocognitive and neuromotor impairment involved 27% and 23% of children, respectively. Symptoms due to autonomic nervous system dysfunction/dysregulation (ANSD)—including strabismus (27%), dysphagia (27%), abnormal heart rhythm (10%), breath-holding spells (9%), and recurrent seizures due to hypoglycemia (9%)—were associated with an increased number of polyalanine repetitions of exon 3 or NPARMs of PHOX2B gene. Overall, the number of patients with moderate to severe phenotype initially treated with non-invasive ventilation (NIV) increased over time, and the decannulation program was concluded with 3 patients who started with IMV.Conclusions: Our study confirms that more severe phenotypes of CCHS are related to the number of polyalanine repetitions or to NPARMs. Although invasive ventilation is often required by patients with severe genotype/phenotype, gradual acquisition of specific skills in the management of patients with CCHS and technological improvements in mechanical ventilation allowed us to improve our therapeutic approach in this population.

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Genetic study of apatient with congenital central hypoventilation syndrome in Iran: a case report

10.21203/rs.3.rs-305918/v1 ◽

2021 ◽

Author(s):

Reihaneh Khorasanian ◽

Marzieh Mojbafan ◽

Nastaran Khosravi

Keyword(s):

Genetic Analysis ◽

Genetic Study ◽

Genetic Disorder ◽

Repeat Expansion ◽

Congenital Central Hypoventilation Syndrome ◽

The Family ◽

Central Hypoventilation ◽

Genetics And Genomics ◽

Hypoventilation Syndrome ◽

Expansion Mutation

Abstract I. Background: Congenital central hypoventilation syndrome (CCHS) is an extremely rare genetic disorder characterized by autonomic nervous system (ANS) dysregulation caused by mutations in the PHOX2B gene. Here we introduce the first genetic analysis of a CCHS patient in Iran.II. Methods and Results: Genetic analysis of the PHOX2B gene was performed by Sanger sequencing and interpreted using the American College of Medical Genetics and Genomics (ACMG) guideline. The results showed a heterozygous duplication in the exon 3 causing a polyalanine repeat expansion mutation (PARMs) to 27 repeats in the PHOX2B gene (20/27 genotype). The patient’s parents were normal for this mutation.III. Conclusions: According to the ACMG guideline, the mutation is a pathogenic one, and it was a denovo mutation in the family. The genetic study can help the family for prenatal diagnosis or pre-implantation diagnosis if the parents have gonadal mosaicism.

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