A rare disease due to a severely impaired central autonomic control of breathing and dysfunction of the autonomous nervous system. The incidence is estimated to be at 1 of 200 000 livebirths. A heterozygous mutation of the PHOX-2B gene is found in 90% of the patients. Association with Hirschsprung's disease is observed in 16% of the cases (adapted from Mondo)¹. Hyperinsulinism has been observed in patients².

Prevalence

Incidence is 1:148000-200000 births (Estimated, may include mild/undiagnosed or be overestimated globally)³. Rare, but reported worldwide⁴.

Age of Onset

Typical: 0-2^3,4; Range: 0-36⁵.

HPO Terms

–

Association

Mendelian

Locus

hg19 chr4:41747989-41748049

hg38 chr4:41745972-41746032

t2t chr4:41719745-41719805

Details

Alleles of 24 repeats (and sometimes 25 repeats) correspond to delayed disease onset and/or milder phenotype; alleles above benign range (9-20 repeats) and below the pathogenic range (26-33 repeats) have uncertain significance³.

Mechanism

LoF/GoF

Polyalanine expansion leading to loss or gain of function, dependent on altered protein product^6,3. Correlation between length and reduced transcriptional activity⁷.

Detection

Short-read sequencing and exome sequencing are reportedly unable to accurately detect these expansions. Fragment analysis is the standard detection method, while Sanger sequencing determines the exact repeat size [@genereviews:NBK1427].

Year

2003⁸

Location in Gene

Coding Exon 3

Gene Strand

Alleles

Ref. Motif

GCN

Ranges

Benign (ref.)

–

Benign (gene)

–

Pathogenic (ref.)

GCN

Pathogenic (gene)

CNG

Unknown (ref.)

–

Unknown (gene)

–

Interruption (ref.)

–

Interruption (gene)

–

gnomAD

Pathogenic genotype frequency data is not displayed for this locus because a substantial number of large alleles failed manual review by the gnomAD team.

References

Direct supporting references for info on this page.

Ontology Lookup Service (OLS)

mondo:0800026

Paired-Like Homeobox 2B (PHOX2B) Mutation and the Hidden Endocrine Puzzle: Hyperinsulinism in Congenital Central Hypoventilation Syndrome.

Mohamad,Sabsabee, Manal,Mustafa

Cureus · 2025-12-13

pmid:41531556

Congenital Central Hypoventilation Syndrome

Debra E.,Weese-Mayer, Casey M.,Rand, Ilya,Khaytin, Susan M.,Slattery, Kai Lee,Yap, Mary L.,Marazita, Elizabeth M.,Berry-Kravis

GeneReviews® · 1993-01-01

genereviews:NBK1427

PHOX2B mutations and polyalanine expansions correlate with the severity of the respiratory phenotype and associated symptoms in both congenital and late onset Central Hypoventilation syndrome.

I,Matera, T,Bachetti, F,Puppo, M,Di Duca, F,Morandi, G M,Casiraghi, M R,Cilio, R,Hennekam, R,Hofstra, J G,Schöber, R,Ravazzolo, G,Ottonello, I,Ceccherini

Journal of medical genetics · 2004-05-01

pmid:15121777

PHOX2B mutation-confirmed congenital central hypoventilation syndrome: presentation in adulthood.

Nick A,Antic, Beth A,Malow, Neale,Lange, R Doug,McEvoy, Amy L,Olson, Peter,Turkington, Wolfram,Windisch, Martin,Samuels, Cathy A,Stevens, Elizabeth M,Berry-Kravis, Debra E,Weese-Mayer

American journal of respiratory and critical care medicine · 2006-07-27

pmid:16873766

Sequence composition changes in short tandem repeats: heterogeneity, detection, mechanisms and clinical implications.

Indhu-Shree,Rajan-Babu, Egor,Dolzhenko, Michael A,Eberle, Jan M,Friedman

Nature reviews. Genetics · 2024-03-11

pmid:38467784

Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in congenital central hypoventilation syndrome.

Tiziana,Bachetti, Ivana,Matera, Silvia,Borghini, Marco,Di Duca, Roberto,Ravazzolo, Isabella,Ceccherini

Human molecular genetics · 2005-05-11

pmid:15888479

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

Jeanne,Amiel, Béatrice,Laudier, Tania,Attié-Bitach, Ha,Trang, Loïc,de Pontual, Blanca,Gener, Delphine,Trochet, Heather,Etchevers, Pierre,Ray, Michel,Simonneau, Michel,Vekemans, Arnold,Munnich, Claude,Gaultier, Stanislas,Lyonnet

Nature genetics · 2003-03-17

pmid:12640453

Additional Literature

Additional literature related to this locus.

Raw PubMed search results
(All PubMed results returned by searching for this gene, tandem repeats, and disease, in medline format)

Generation of iPSC lines (UMILi032-A, UMILi033-A, UMILi034-A, UMILi035-A, UMILi036-A) from five Congenital Central Hypoventilation Syndrome patients carrying different poly-alanine expansion mutations in the PHOX2B gene.

Ana Lucia,Cuadros Gamboa, Filippo,Chiesa, Paride,Pelucchi, Martina,Bertocchi, Anna,Ripepi, Eleonora,Piscitelli, Marta,Peruzzi, Niccolò,Nassi, Cinzia,Arzilli, Monica,Annunziata, Amelia,Morrone, Viviana,Tritto, Paola,Riva, Giuseppe,Santamaria, Isabella,Ceccherini, Roberta,Benfante, Simona Di,Lascio, Diego,Fornasari

Stem cell research · 2025-12-15

pmid:41420984

PHOX2B deletion in congenital central hypoventilation syndrome: is this sufficient for pathogenesis?

Kiyoshi,Hayasaka, Ayako,Sasaki, Yumiko,Kishikawa, Yu,Abiko, Haruka,Arakaki, Madoka,Yasukohchi, Jun,Takayama, Gen,Tamiya, Hisaya,Hasegawa, Atsushi,Ueda, Motoki,Osawa, Tetsuo,Mitsui

Journal of human genetics · 2025-11-05

pmid:41188450

Recurrence of CCHS-associated PHOX2B Poly-Alanine expansion variant due to paternal mosaicism.

Huling,Jiang, Zepeng,Ping, Suping,Li, Jianjun,Zhu

Gene · 2024-03-11

pmid:38467313

Pulmonary hypertension in an adult patient with congenital central hypoventilation syndrome: a case report.

Yosuke,Terui, Shoko,Ohura, Tetsuji,Nozaki, Takuya,Yagi

European heart journal. Case reports · 2024-02-26

pmid:38454954

Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions.

Rosa,Antón, Miguel Á,Treviño, David,Pantoja-Uceda, Sara,Félix, María,Babu, Eurico J,Cabrita, Markus,Zweckstetter, Philip,Tinnefeld, Andrés M,Vera, Javier,Oroz

Nature communications · 2024-03-02

pmid:38431667

Characteristics and outcomes in children with congenital central hypoventilation syndrome on long-term mechanical ventilation in the Netherlands.

E E,Evers-Bikker, W,de Weerd, P J,Wijkstra, L,Corel, L P,Verweij, B A H,Vosse

European journal of pediatrics · 2023-11-25

pmid:38001308

Caroline B,Ferreira, Talita M,Silva, Phelipe E,Silva, Claudio L,Castro, Catherine,Czeisler, José J,Otero, Ana C,Takakura, Thiago S,Moreira

eLife · 2022-11-17

pmid:36394266

Generation of two hiPSC lines (UMILi027-A and UMILi028-A) from early and late-onset Congenital Central hypoventilation Syndrome (CCHS) patients carrying a polyalanine expansion mutation in the PHOX2B gene.

Ana Lucia,Cuadros Gamboa, Roberta,Benfante, Monica,Nizzardo, Tiziana,Bachetti, Paride,Pelucchi, Valentina,Melzi, Cinzia,Arzilli, Marta,Peruzzi, Rolland A,Reinbold, Silvia,Cardani, Amelia,Morrone, Renzo,Guerrini, Ileana,Zucchi, Stefania,Corti, Isabella,Ceccherini, Raffaele,Piumelli, Niccolò,Nassi, Simona,Di Lascio, Diego,Fornasari

Stem cell research · 2022-04-07

pmid:35421844

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

Reihaneh,Khorasanian, Marzieh,Mojbafan, Nastaran,Khosravi

Molecular biology reports · 2021-10-09

pmid:34626313

Locus CCHS PHOX2B

Disease

Locus

Alleles

gnomAD

References

Additional Literature