Irina N. Artamonova, Anna M. Zlotina, Olga R. Ismagilova, Tatyana A. Levko, Natalia Yu Kolbina, Aleksandr V. Bryzzhin, Andrey P. Smorodin, Alexandr V. Borodin, Ekaterina A. Mamaeva, Anna A. Sukhotskaya, Ilya M. Kagantsov, Daria A. Malysheva, Elena S. Vasichkina, Tatiana M. Pervunina, Natalia A. Petrova
Almazov National Medical Research Centre. Research Centre for Medical Genetics.
Russia
Frontiers in Pediatrics
Front Pediatr 2023; 10:
DOI: 10.3389/fped.2022.1070303
Abstract
Introduction: Congenital 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 description: We 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.
Conclusion: Detection of a novel PHOX2B variant expands the understanding of molecular mechanisms of CCHS and genotype-phenotype correlations.
Category
Class III. Pulmonary Hypertension Associated with Airway Disease, Apnea or Hypoventilation
Genetic Factors Associated with Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes