Case Report: A novel PHOX2B p.Ala248_Ala266dup variant causing congenital central hypoventilation syndrome
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...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-02-01
|
| Series: | Frontiers in Pediatrics |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fped.2022.1070303/full |
| _version_ | 1797924541399302144 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Irina N. Artamonova |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T15:02:35Z |
| format | Article |
| id | doaj.art-f0990813c2d842c782f7b82dfa2399d0 |
| institution | Directory Open Access Journal |
| issn | 2296-2360 |
| language | English |
| last_indexed | 2024-04-10T15:02:35Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pediatrics |
| spelling | doaj.art-f0990813c2d842c782f7b82dfa2399d02023-02-15T09:48:39ZengFrontiers Media S.A.Frontiers in Pediatrics2296-23602023-02-011010.3389/fped.2022.10703031070303Case Report: A novel PHOX2B p.Ala248_Ala266dup variant causing congenital central hypoventilation syndromeIrina N. Artamonova0Anna M. Zlotina1Olga R. Ismagilova2Tatyana A. Levko3Natalia Yu Kolbina4Aleksandr V. Bryzzhin5Andrey P. Smorodin6Alexandr V. Borodin7Ekaterina A. Mamaeva8Anna A. Sukhotskaya9Ilya M. Kagantsov10Daria A. Malysheva11Elena S. Vasichkina12Tatiana M. Pervunina13Natalia A. Petrova14Institute of Perinatology and Pediatrics, Almazov National Medical Research Centre, Saint-Petersburg, RussiaInstitute of Molecular Biology and Genetics, Almazov National Medical Research Centre, Saint-Petersburg, RussiaFederal State Budgetary Scientific Institution, Research Centre for Medical Genetics (RCMG), Moscow, RussiaDepartment of Pediatric and Medical Rehabilitation, Almazov National Medical Research Centre, Saint-Petersburg, RussiaDepartment of Pediatric and Medical Rehabilitation, Almazov National Medical Research Centre, Saint-Petersburg, RussiaPediatric Anesthesiology and Intensive Care Unit, Almazov National Medical Research Centre, Saint-Petersburg, RussiaPediatric Surgery Anesthesiology and Intensive Care Unit Almazov National Medical Research Centre, Saint-Petersburg, RussiaWorld-Class Research Centre for Personalized Medicine, Research Centre of Unknown, Rare and Genetically Determined Diseases, Almazov National Medical Research Centre, Saint-Petersburg, RussiaInstitute of Perinatology and Pediatrics, Almazov National Medical Research Centre, Saint-Petersburg, Russia0Department of Pediatric Surgery for Congenital Malformations, Almazov National Medical Research Centre, Saint-Petersburg, Russia1Department of Pediatric Surgery for Congenital Malformations, Institute of Perinatology and Pediatrics, Almazov National Medical Research Centre, Saint-Petersburg, Russia2Department of Pediatric Surgery for Congenital Malformations, Almazov National Medical Research Centre, Saint-Petersburg, Russia3World-Class Research Centre for Personalized Medicine, Research Centre of Unknown, Rare and Genetically Determined Diseases, Almazov National Medical Research Centre, Saint-Petersburg, Russia4Institute of Perinatology and Pediatrics, World-Class Research Centre for Personalized Medicine, Research Centre of Unknown, Rare and Genetically Determined Diseases, Almazov National Medical Research Centre, Saint-Petersburg, Russia5World-Class Research Centre for Personalized Medicine, Research Centre of Unknown, Rare and Genetically Determined Diseases, Institute of Perinatology and Pediatrics, Almazov National Medical Research Centre, Saint-Petersburg, RussiaIntroductionCongenital 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.https://www.frontiersin.org/articles/10.3389/fped.2022.1070303/fullgenotype–phenotype correlationcongenital central hypoventilation syndrome (CCHS)PHOX2Bnovel mutationHirschsprung diseasepolyalanine sequence |
| spellingShingle | 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 Case Report: A novel PHOX2B p.Ala248_Ala266dup variant causing congenital central hypoventilation syndrome Frontiers in Pediatrics genotype–phenotype correlation congenital central hypoventilation syndrome (CCHS) PHOX2B novel mutation Hirschsprung disease polyalanine sequence |
| title | Case Report: A novel PHOX2B p.Ala248_Ala266dup variant causing congenital central hypoventilation syndrome |
| title_full | Case Report: A novel PHOX2B p.Ala248_Ala266dup variant causing congenital central hypoventilation syndrome |
| title_fullStr | Case Report: A novel PHOX2B p.Ala248_Ala266dup variant causing congenital central hypoventilation syndrome |
| title_full_unstemmed | Case Report: A novel PHOX2B p.Ala248_Ala266dup variant causing congenital central hypoventilation syndrome |
| title_short | Case Report: A novel PHOX2B p.Ala248_Ala266dup variant causing congenital central hypoventilation syndrome |
| title_sort | case report a novel phox2b p ala248 ala266dup variant causing congenital central hypoventilation syndrome |
| topic | genotype–phenotype correlation congenital central hypoventilation syndrome (CCHS) PHOX2B novel mutation Hirschsprung disease polyalanine sequence |
| url | https://www.frontiersin.org/articles/10.3389/fped.2022.1070303/full |
| work_keys_str_mv | AT irinanartamonova casereportanovelphox2bpala248ala266dupvariantcausingcongenitalcentralhypoventilationsyndrome AT annamzlotina casereportanovelphox2bpala248ala266dupvariantcausingcongenitalcentralhypoventilationsyndrome AT olgarismagilova casereportanovelphox2bpala248ala266dupvariantcausingcongenitalcentralhypoventilationsyndrome AT tatyanaalevko casereportanovelphox2bpala248ala266dupvariantcausingcongenitalcentralhypoventilationsyndrome AT nataliayukolbina casereportanovelphox2bpala248ala266dupvariantcausingcongenitalcentralhypoventilationsyndrome AT aleksandrvbryzzhin casereportanovelphox2bpala248ala266dupvariantcausingcongenitalcentralhypoventilationsyndrome AT andreypsmorodin casereportanovelphox2bpala248ala266dupvariantcausingcongenitalcentralhypoventilationsyndrome AT alexandrvborodin casereportanovelphox2bpala248ala266dupvariantcausingcongenitalcentralhypoventilationsyndrome AT ekaterinaamamaeva casereportanovelphox2bpala248ala266dupvariantcausingcongenitalcentralhypoventilationsyndrome AT annaasukhotskaya casereportanovelphox2bpala248ala266dupvariantcausingcongenitalcentralhypoventilationsyndrome AT ilyamkagantsov casereportanovelphox2bpala248ala266dupvariantcausingcongenitalcentralhypoventilationsyndrome AT dariaamalysheva casereportanovelphox2bpala248ala266dupvariantcausingcongenitalcentralhypoventilationsyndrome AT elenasvasichkina casereportanovelphox2bpala248ala266dupvariantcausingcongenitalcentralhypoventilationsyndrome AT tatianampervunina casereportanovelphox2bpala248ala266dupvariantcausingcongenitalcentralhypoventilationsyndrome AT nataliaapetrova casereportanovelphox2bpala248ala266dupvariantcausingcongenitalcentralhypoventilationsyndrome |