Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 399040002, 719972004; ICD10CM: G47.35; ICD9CM: 327.25; ORPHA: 661, 99803; DO: 0060731;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4p13 | Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease | 209880 | Autosomal dominant | 3 | PHOX2B | 603851 |
A number sign (#) is used with this entry because of evidence that congenital central hypoventilation syndrome-1 (CCHS1) with or without Hirschsprung disease is caused by heterozygous mutation in the PHOX2B gene (603851) on chromosome 4p13.
Idiopathic congenital central hypoventilation syndrome (CCHS), also known as 'Ondine's curse' (Deonna et al., 1974), is a rare disorder characterized by abnormal control of respiration in the absence of neuromuscular, lung or cardiac disease, or an identifiable brainstem lesion. Affected individuals typically present in the first hours of life with cyanosis and increased carbon dioxide during sleep. Patients breathe normally while awake, but hypoventilate with normal respiratory rates and shallow breathing during sleep; more severely affected patients hypoventilate both awake and asleep. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia (reviewed by Weese-Mayer et al., 1999).
Congenital central hypoventilation syndrome has been associated with several disorders classified as neurocristopathies, that is, aberrant phenotypes arising from a defect of migration or differentiation of neural crest cells. These include neuroblastoma (Haddad et al., 1978), ganglioneuroma (Swaminathan et al., 1989), and most frequently Hirschsprung disease (HSCR) which appears in 16% of CCHS patients. The association of CCHS and HSCR is referred to as Haddad syndrome.
Genetic Heterogeneity of CCHS
See also CCHS2 (619482), caused by mutation in the MYOH1 gene (614636) on chromosome 12q24, and CCHS3 (619483), caused by mutation in the LBX1 gene (604255) on chromosome 10q24.
Congenital central hypoventilation can be a feature of other developmental disorders, such as those caused by mutation in the MECP2 gene (300005).
The syndrome of congenital central hypoventilation was first reported by Mellins et al. (1970). Cases were reported also by Deonna et al. (1974), Yasuma et al. (1987), O'Dell et al. (1987), Oren et al. (1987), and Weese-Mayer et al. (1988).
Haddad et al. (1978) described 3 female patients, 2 of whom were sisters. All 3 died in the first few months of life. They showed a combination of Ondine curse (failure of autonomic control of ventilation during sleep) and Hirschsprung disease (aganglionic megacolon; see 142623). Esophageal motility and control of heart rate were also markedly reduced. Neuropathologic studies postmortem showed no anatomic defect. The authors postulated a developmental defect of serotonergic neurons. Stern et al. (1980) described a case in a male infant; see also Stern et al. (1981).
Minutillo et al. (1989) described a patient and pointed out possibly distinctive facial features (antimongoloid slanting eyes, triangular mouth, small nose, and low-set, posteriorly rotated ears). Familial depression of ventilatory response to hypoxia and hypercapnia (267480) and familial lethal sleep apnea (207720) are disorders of possibly related nature.
Folgering et al. (1979) found absence of the arcuate nucleus at autopsy in an infant with congenital central hypoventilation syndrome. Decreased muscarinic receptor binding in the arcuate nucleus has been implicated in the sudden infant death syndrome (SIDS; 272120) by Kinney et al. (1995).
Weese-Mayer et al. (1999) prepared a comprehensive statement concerning CCHS for the American Thoracic Society. They stated that approximately 100 cases had been reported. They estimated that 160 to 180 children with CCHS are living worldwide, but considered these numbers to be an underestimate. Extensive information was given concerning long-term comprehensive management. In addition to the clinical features of alveolar hypoventilation, patients with CCHS often manifest a spectrum of clinical symptoms reflecting dysfunction of the autonomic nervous system. These include Hirschsprung disease and/or severe constipation, feeding difficulty, decreased perception of discomfort, pupillary abnormalities, decreased perception of anxiety, profuse sweating, and decreased basal body temperature.
Antic et al. (2006) reported 5 unrelated patients with onset of central hypoventilation after age 21 years. All survived into adulthood without artificial ventilatory support until the time of diagnosis, although all reported respiratory symptoms since childhood when a detailed history was taken. Presentations included unexpected hypoxemia during respiratory infection, sleep abnormalities, and seizures. Some of the patients had evidence of chronic symptoms, such as hypercarbia, polycythemia, and right heart changes. Two patients had cognitive impairment, which may have resulted from chronic hypoxemia. Molecular analysis identified an expansion of +5 alanine repeats in exon 2 of the PHOX2B gene (603851.0001). Some of the patients' children inherited the same expansion but showed onset within the first year of life, indicating incomplete penetrance associated with this relatively short expansion.
Lombardo et al. (2018) evaluated 20 patients from Cincinnati Children's Hospital from January 2003 through June 2016 with CCHS and molecularly proven pathogenic variants in PHOX2B. Six (30%) had cardiac anomalies. There were 5 girls and 1 boy; 4 patients were African American and 2 were of European descent. One African American female had a moderate secundum atrial septal defect (ASD) with deficient retroaortic rim, moderate right atrial and ventricular enlargement, and a patent ductus arteriosus (PDA) requiring surgical closure at age 5 years. A white female had separate origin of the left vertebral artery off the aortic arch. An African American female had an anomalous left coronary artery. A white male had a moderate PDA requiring surgical closure at age 3 years. An African American female had a complete vascular ring. The last patient was an African American female with a secundum ASD. Two of the patients, both African American females, had Hirschsprung disease, and 1 white female had an adrenal ganglioneuroma. Five of the patients required BiPAP, and 1 required tracheostomy with continuous ventilatory support.
Sivan et al. (2019) reported a full-term male infant, born to Ashkenazi Jewish parents, who developed central apneas and bradypneas consistent with CCHS, requiring ventilator support during sleep. When awake, the child did not hypoventilate, except during bottle feedings. A tracheostomy was performed to allow for assisted ventilation during sleep and when feeding. At the age of 3 years, the child continued to require ventilator support when sleeping and with intercurrent illnesses. He had no symptoms consistent with Hirschsprung disease, no neural crest tumors on chest radiography and abdominal and pelvic ultrasound, and no arrhythmias on 72-hour Holter monitoring.
Guzoglu et al. (2020) reported a male infant with Haddad syndrome. He developed respiratory distress after birth, and on initial examination was found to have mild hypotonia, flat facies, and mild hypertelorism. He was intubated due to recurrent bradypnea on the first day of life and subsequently failed to wean from the ventilator. He developed seizures, dilated pupils that did not react to light, and intermittent episodes of fever and hypotension. He had bilious vomiting at 7 days of life. Subsequent ileum and colonic biopsies showed total intestinal aganglionosis, confirming a diagnosis of Hirschsprung disease. He died from an infection and respiratory failure at 41 days of life.
CCHS caused by mutation in the PHOX2B gene is transmitted in an autosomal dominant pattern with incomplete penetrance (summary by Parodi et al., 2010).
Sivan et al. (2019) reported a case of cooccurrence of 2 minimally or non-penetrant PHOX2B variants, with a classic presentation of CCHS inherited in an autosomal recessive manner.
Rutishauser and Feldges (1977) reported the disorder in a mother and daughter. Khalifa et al. (1988) reported affected monozygotic twins.
Hamilton and Bodurtha (1989) described black brother and sister with the association of Hirschsprung disease and CCHS. Curiously, they were half sibs (same father, different mothers). Since there was no known relationship of the mothers, the possibility of autosomal dominant inheritance with reduced penetrance (or paternal gonadal mosaicism) might be considered.
From segregation analyses, Weese-Mayer et al. (1993) concluded that multifactorial and major-locus models are almost equally likely in CCHS.
Hypothesizing that CCHS is the most severe manifestation of general autonomic nervous system dysfunction (ANSD), Marazita et al. (2001) investigated the genetics of ANSD. They performed major locus segregation analysis utilizing regressive models in 52 probands with CCHS and 52 age-, race-, and gender-matched controls. CCHS probands were assumed to be affected; controls and relatives were designated as affected if they had 2 or more relevant symptoms. They found that case families were consistent with transmission of a major effect; control families were not. In the total data set, the best-fitting model was considered to be codominant mendelian inheritance of a major gene for ANSD.
In a case-control family study of autonomic nervous system dysfunction in idiopathic CCHS, Weese-Mayer et al. (2001) found that, under each of 2 arbitrary definitions of ANSD affection, 16% of CCHS sibs had the ANSD phenotype with 2 or more symptoms, compared to 4% of control sibs. Aunts and uncles of CCHS cases were also significantly more likely to have 2 or more ANSD symptoms than were aunts and uncles of the controls.
Silvestri et al. (2002) reported offspring born to 4 women with idiopathic CCHS. One of the children was diagnosed with CCHS, 1 had recurrent and apparently life-threatening events, 1 was born prematurely with severe chronic lung disease and diminished ventilatory responses to carbon dioxide, and 1 was apparently healthy with no clinical manifestations suggestive of disordered respiratory control at 25 months of age. Thus, 2 and possibly 3 of these patients illustrated transmission of altered respiratory control from a CCHS mother.
Parodi et al. (2010) performed polysomnography in 3 apparently healthy parents of a child with CCHS due to an expanded alanine allele in the PHOX2B gene. One mother, with a 5-alanine expansion, was found to have significant sleep breathing control anomalies. The other 2 parents had normal sleep breathing patterns and were found to be somatic mosaic for 6-alanine expansions. These findings confirmed variable expressivity and incomplete penetrance of PHOX2B mutations, and suggested that polysomnography and assessment of the degree of somatic mosaicism should be conducted in asymptomatic mutation carriers.
Among 45 unrelated Japanese families in which a child had congenital central hypoventilation syndrome, Meguro et al. (2012) found that 1 patient (2%) inherited a 5-alanine expansion mutation from a parent with late-onset central hypoventilation syndrome. In this family, the maternal grandmother and maternal uncle, who carried the same expansion, also had late-onset central hypoventilation syndrome. In addition, 9 patients (20%) inherited a 5- to 7-alanine expansion mutation from apparently asymptomatic parents with somatic mosaicism. The level of mosaicism in these parents ranged from 5 to 62%, and 3 patients had affected sibs. Meguro et al. (2012) postulated that the expansion in somatic mosaicism results from a replication error, rather than unequal crossing over, since contracted alleles were not identified. These findings had implications for genetic counseling.
In mice, the development of reflex circuits of the autonomic nervous system is dependent on the paired-like homeobox gene Phox2b (603851). For that reason, Amiel et al. (2003) investigated the human ortholog, PHOX2B, as a candidate gene in CCHS. They found heterozygous de novo mutations in PHOX2B in 18 of 29 affected individuals. Most mutations consisted of 5 to 9 alanine expansions within a 20-residue polyalanine tract, probably resulting from nonhomologous recombination (603851.0001). They showed that PHOX2B is expressed in both the central and the peripheral autonomic nervous system during human embryonic development.
Sasaki et al. (2003) studied 7 patients with isolated CCHS and 3 CCHS patients with Hirschsprung disease. In 4 patients they detected polyalanine expansions in the PHOX2B gene and in 1 patient a novel frameshift mutation in PHOX2B. They could not reject the possibility that mutations in the RET (164761), GDNF, PHOX2A, and HASH1 (ASCL1; 100790) genes may also be involved in the pathogenesis of CCHS.
In 65 of 67 CCHS probands (97%), Weese-Mayer et al. (2003) found heterozygosity for the exon 3 polyalanine expansion mutation in PHOX2B. There was an association between repeat mutation length and severity of the CCHS/ANSD phenotype. Of the 2 probands who did not carry the expansion mutation, one had a nonsense mutation in exon 3 that truncated the protein, and the other had no mutation in PHOX2B but had a previously reported EDN3 frameshift point mutation of unknown significance.
Matera et al. (2004) screened the PHOX2B gene in 27 patients with CCHS, including 3 with associated Hirschsprung disease and 3 with late-onset CCHS, and identified 3 heterozygous frameshift mutations and 22 polyalanine expansions ranging from 5 to 13 residues. The authors noted that phenotype severity increased with increasing polyalanine expansion size. Polyalanine triplet expansions were also detected in the affected sibs of 2 familial cases and in 2 asymptomatic parents. Matera et al. (2004) concluded that their findings demonstrated autosomal dominant inheritance with reduced penetrance.
Trochet et al. (2005) reported the clinical and molecular assessments of a cohort of 188 probands with CCHS, either isolated or associated with Hirschsprung disease and/or tumors of the sympathetic nervous system (TSNS). The mutation detection rate was 92.6% (174/188), and the most prevalent mutation was an in-frame duplication leading to an expansion of +5 to +13 alanines in the 20-alanine stretch of the carboxy terminal of the PHOX2B protein (603851.0001). Analysis of genotype-phenotype interactions strongly supported the contention that patients with CCHS who develop malignant TSNS harbor either a missense or a frameshift heterozygous mutation of the PHOX2B gene. These data pointed to another link between congenital malformations and tumor predisposition when a master gene in development is mutated.
De Pontual et al. (2006) genotyped the RET locus in 143 patients with CCHS who were known to have mutations in the PHOX2B gene. The odds ratios of HSCR for patients heterozygous and homozygous for the nonsyndromic HSCR-predisposing RET haplotype (ATA), which contained the hypomorphic intron 1 allele (164761.0050), were 2.39 and 4.74, respectively; 16 patients with a PHOX2B alanine expansion and no predisposing RET haplotype also had HSCR. De Pontual et al. (2006) concluded that there are both RET-dependent and RET-independent HSCR cases and suggested that at least 1 more modifier gene must be involved.
Lombardo et al. (2018) reported 6 patients with CCHS and cardiac anomalies who had heterozygous mutations in the PHOX2B gene. Only 1 had an expansion of the polyalanine tract (603851.0001), and this patient required tracheostomy with continuous mechanical ventilation and had Hirschsprung disease. One had a whole-gene deletion. Two patients had missense mutations involving the homeobox domain (R141Q, 603851.0009; R149L, 603851.0010). Two had a recurrent premature termination codon (Y78X; 603851.0011).
Sivan et al. (2019) reported a male infant with CCHS who had compound heterozygous mutations in the PHOX2B gene: a polyalanine repeat expansion (24 alanine repeats; 603851.0001) and a missense mutation (G262V; 603851.0012). The polyalanine repeat expansion was seen in the father, paternal grandfather, and 2 out of 5 of the father's sibs, and the missense mutation was seen in the mother, maternal grandfather, and 3 out of 9 of the mother's sibs. All family members, other than the proband, were phenotypically normal. The authors concluded that this was the first reported case of compound heterozygosity for variants in the PHOX2B gene in a proband with CCHS in which neither variant alone was sufficient to cause disease in multiple family members. The authors noted the importance of PHOX2B testing in parents of all probands with CCHS to identify mosaicism in a parent, confirm allele pathogenicity, determine inheritance, and provide information for future pregnancy planning. The authors also suggested sequencing of PHOX2B if a polyalanine repeat expansion has been identified, especially when the phenotype is more severe than expected.
Reclassified Variants
The 1-bp insertion in the EDN3 gene (131242.0003) reported by Bolk et al. (1996) has been reclassified as a variant of unknown significance. In a patient with isolated congenital central hypoventilation syndrome, Bolk et al. (1996) identified a 1-bp insertion of an adenosine (131242.0003) in exon 4 of the EDN3 gene, which caused a frameshift and a premature stop codon in exon 5.
There have been reports of mutations in 4 other genes (RET, 164761; BDNF, 113505; GDNF, 600837; ASCL1, 100790) as a cause of CCHS or Haddad syndrome (Bolk et al., 1996; Amiel et al., 1998; de Pontual et al., 2003; Weese-Mayer et al., 2002; Weese-Mayer et al., 2003). However, all of the identified mutations in these genes have been reclassified as variants of unknown significance.
Bolk et al. (1996) used SSCP analysis to study mutations of the RET gene in 14 patients with CCHS. All detected nucleotide changes in the RET gene were classified as polymorphic variants. Cytogenetic study did not reveal chromosomal abnormalities (except a familial inv(2)(p11.2q13) in 1 case).
Weese-Mayer et al. (2002) studied 19 children with CCHS, 5 of whom also had Hirschsprung disease, for mutations in the brain-derived neurotrophic factor gene. They identified a mutation (T2I; 113505.0001) in the BDNF gene in 1 child with isolated CCHS as well as in his father, who did not have CCHS but had symptoms of postural hypotension and vasovagal syncope. However, the T2I variant in the BDNF gene was later reclassified as a variant of unknown significance.
Amiel et al. (1998) reviewed the mutations in the RET-GDNF signaling pathway in Ondine curse. They failed to detect EDNRB or EDN3 mutations in their series. By contrast, screening the coding sequence of the RET (164761) and GDNF (600837) genes in 5 unrelated cases of isolated CCHS and in 2 cases of CCHS-HSCR association, they found mutations in children with isolated CCHS (1 in 7) and the CCHS-HSCR association (1 in 7), respectively. However, the patients with CCHS in whom Amiel et al. (1998) identified mutations in the GDNF and RET genes were later found by Amiel et al. (2003) to also carry the pathogenic polyalanine expansion in the PHOX2B gene (603851.0001).
Shimokaze et al. (2015) studied the relationship between PHOX2B mutations and the CCHS phenotype in 92 Japanese patients, including 2 pairs of sibs. Nineteen patients had a 25-polyalanine repeat expansion mutation (PARM), 67 patients had 26 or more PARMs, and 6 patients had non-PARM (nPARM) mutations. In the 19 patients with 25 PARMs, the male-to-female ratio was approximately 3 to 1. None of the patients had Hirschsprung disease. Seven of the 19 patients presented after the neonatal period, and 8 of 19 cases had impaired intellectual development. Additional genetic and/or epigenetic factors were thought to play a role in the development of CCHS in patients with 25 PARMs, and male sex was considered likely to be a predisposing factor for clinical expression in this group. Additionally, it was thought that impaired intellectual development was likely seen in the 25 PARM cohort because of inappropriate ventilatory support. Shimokaze et al. (2015) reported that in the 73 cases of CCHS with 26 or more PARMs or nPARMs, the male-to-female ratio was equal, all patients presented with hypoventilation in the newborn period, and Hirschsprung disease and constipation were frequently seen.
Shirasawa et al. (2000) disrupted the Rnx (604640) locus in mouse embryonic stem cells. The phenotype of Rnx-deficient mice resembled that of congenital central hypoventilation.
De Pontual et al. (2006) generated doubly heterozygous (Phox2b +/- and Ret +/-) mice and observed that the intestine of the mutant mice was indistinguishable from wildtype littermates; the authors concluded that a greater than 50% loss of function for each gene must be necessary in the mouse for an enteric phenotype to occur.
Demartini et al. (2020) provided a historical review of the mythic tale of Ondine, from which the name 'Ondine Curse' was derived to describe loss of autonomic breath control in general, and later associated with CCHS. In the tale, Ondine was a nymph who cursed her husband to remain awake in order to control his own breathing.
Katz et al. (2000) described a heterogeneous group of patients with late-onset central hypoventilation syndrome (LO-CHS). These patients had rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD).
Amiel, J., Laudier, B., Attie-Bitach, T., Trang, H., de Pontual, L., Gener, B., Trochet, D., Etchevers, H., Ray, P., Simmoneau, M., Vekemans, M., Munnich, A., Gaultier, C., Lyonnet, S. Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nature Genet. 33: 459-460, 2003. [PubMed: 12640453] [Full Text: https://doi.org/10.1038/ng1130]
Amiel, J., Salomon, R., Attie, T., Pelet, A., Trang, H., Mokhtari, M., Gaultier, C., Munnich, A., Lyonnet, S. Mutations of the RET-GDNF signaling pathway in Ondine's curse. (Letter) Am. J. Hum. Genet. 62: 715-717, 1998. [PubMed: 9497256] [Full Text: https://doi.org/10.1086/301759]
Antic, N. A., Malow, B. A., Lange, N., McEvoy, R. D., Olson, A. L., Turkington, P., Windisch, W., Samuels, M., Stevens, C. A., Berry-Kravis, E. M., Weese-Mayer, D. E. PHOX2B mutation-confirmed congenital central hypoventilation syndrome: presentation in adulthood. Am. J. Resp. Crit. Care Med. 174: 923-927, 2006. [PubMed: 16873766] [Full Text: https://doi.org/10.1164/rccm.200605-607CR]
Bolk, S., Angrist, M., Schwartz, S., Silvestri, J. M., Weese-Mayer, D. E., Chakravarti, A. Congenital central hypoventilation syndrome: mutation analysis of the receptor tyrosine kinase RET. Am. J. Med. Genet. 63: 603-609, 1996. [PubMed: 8826440] [Full Text: https://doi.org/10.1002/(SICI)1096-8628(19960628)63:4<603::AID-AJMG14>3.0.CO;2-M]
Bolk, S., Angrist, M., Xie, J., Yanagisawa, M., Silvestri, J. M., Weese-Mayer, D. E., Chakravarti, A. Endothelin-3 frameshift mutation in congenital central hypoventilation syndrome. Nature Genet. 13: 395-396, 1996. [PubMed: 8696331] [Full Text: https://doi.org/10.1038/ng0896-395]
Burton, M. D., Kawashima, A., Brayer, J. A., Kazemi, H., Shannon, D. C., Schuchardt, T., Costantini, F., Pachnis, V., Kinane, T. B. RET proto-oncogene is important for the development of the respiratory CO(2) sensitivity. J. Auton. Nerv. Syst. 63: 137-143, 1997. [PubMed: 9138245] [Full Text: https://doi.org/10.1016/s0165-1838(97)00002-7]
de Pontual, L., Nepote, V., Attie-Bitach, T., Al Halabiah, H., Trang, H., Elghouzzi, V., Levacher, B., Benihoud, K., Auge, J., Faure, C., Laudier, B., Vekemans, M., Munnich, A., Perricaudet, M., Guillemot, F., Gaultier, C., Lyonnet, S., Simonneau, M., Amiel, J. Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse). Hum. Molec. Genet. 12: 3173-3180, 2003. [PubMed: 14532329] [Full Text: https://doi.org/10.1093/hmg/ddg339]
de Pontual, L., Pelet, A., Trochet, D., Jaubert, F., Espinosa-Parrilla, Y., Munnich, A., Brunet, J.-F., Goridis, C., Feingold, J., Lyonnet, S., Amiel, J. Mutations of the RET gene in isolated and syndromic Hirschsprung's disease in human disclose major and modifier alleles at a single locus. J. Med. Genet. 43: 419-423, 2006. [PubMed: 16443855] [Full Text: https://doi.org/10.1136/jmg.2005.040113]
Demartini, Z., Jr., Maranha Gatto, L. A., Koppe, G. L., Francisco, A. N., Guerios, E. E. Ondine's curse: myth meets reality. Sleep Med. X 2: 100012, 2020. [PubMed: 33870169] [Full Text: https://doi.org/10.1016/j.sleepx.2020.100012]
Deonna, T., Arczynska, W., Torrado, A. Congenital failure of automatic ventilation (Ondine's curse). J. Pediat. 84: 710-714, 1974. [PubMed: 4522725] [Full Text: https://doi.org/10.1016/s0022-3476(74)80013-2]
Folgering, H., Kuyper, F., Kille, J. F. Primary alveolar hypoventilation (Ondine's curse syndrome) in an infant without external arcuate nucleus: case report. Bull. Europ. Physiopath. Resp. 15: 659-665, 1979. [PubMed: 497494]
Guzoglu, N., Aslan, M. K., Gunay, Y. D., Atasoy, P. Ceylaner, S., Aliefendioglu, D. A novel mutation which causes a frameshift in the PHOX2B gene causes Haddad syndrome. Clin. Dysmorph. 29: 152-154, 2020. [PubMed: 32073407] [Full Text: https://doi.org/10.1097/MCD.0000000000000317]
Haddad, G. G., Mazza, N. M., Defendini, R., Blanc, W. A., Driscoll, J. M., Epstein, M. A. F., Epstein, R. A., Mellins, R. B. Congenital failure of automatic control of ventilation, gastrointestinal motility and heart rate. Medicine 57: 517-526, 1978. [PubMed: 713831] [Full Text: https://doi.org/10.1097/00005792-197811000-00003]
Hamilton, J., Bodurtha, J. N. Congenital central hypoventilation syndrome and Hirschsprung's disease in half sibs. J. Med. Genet. 26: 272-274, 1989. [PubMed: 2654399] [Full Text: https://doi.org/10.1136/jmg.26.4.272]
Katz, E. S., McGrath, S., Marcus, C. L. Late-onset central hypoventilation with hypothalamic dysfunction: a distinct clinical syndrome. Pediat. Pulmonol. 29: 62-68, 2000. [PubMed: 10613788] [Full Text: https://doi.org/10.1002/(sici)1099-0496(200001)29:1<62::aid-ppul10>3.0.co;2-m]
Khalifa, M. M., Flavin, M. A., Wherrett, B. A. Congenital central hypoventilation syndrome in monozygotic twins. J. Pediat. 113: 853-855, 1988. [PubMed: 3183842] [Full Text: https://doi.org/10.1016/s0022-3476(88)80016-7]
Kinney, H. C., Filiano, J. J., Sleeper, L. A., Mandell, F., Valdes-Dapena, M., White, W. F. Decreased muscarinic receptor binding in the arcuate nucleus in sudden infant death syndrome. Science 269: 1446-1450, 1995. [PubMed: 7660131] [Full Text: https://doi.org/10.1126/science.7660131]
Lombardo, R. C., Porollo, A., Cnota, J. F., Hopkin, R. J. Congenital heart disease and aortic arch variants associated with mutations in PHOX2B. Genet. Med. 20: 1538-1543, 2018. [PubMed: 29543228] [Full Text: https://doi.org/10.1038/gim.2018.34]
Marazita, M. L., Maher, B. S., Cooper, M. E., Silvestri, J. M., Huffman, A. D., Smok-Pearsall, S. M., Kowal, M. H., Weese-Mayer, D. E. Genetic segregation analysis of autonomic nervous system dysfunction in families of probands with idiopathic congenital central hypoventilation syndrome. Am. J. Med. Genet. 100: 229-236, 2001. [PubMed: 11343309] [Full Text: https://doi.org/10.1002/ajmg.1284]
Matera, I., Bachetti, T., Puppo, F., Di Duca, M., Morandi, F., Casiraghi, G. M., Cilio, M. R., Hennekam, R., Hofstra, R., Schober, J. G., Ravazzolo, R., Ottonello, G., Ceccherini, I. 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. (Letter) J. Med. Genet. 41: 373-380, 2004. [PubMed: 15121777] [Full Text: https://doi.org/10.1136/jmg.2003.015412]
Meguro, T., Yoshida, Y., Hayashi, M., Toyota, K., Otagiri, T., Mochizuki, N., Kishikawa, Y., Sasaki, A., Hayasaka, K. Inheritance of polyalanine expansion mutation of PHOX2B in congenital central hypoventilation syndrome. J. Hum. Genet. 57: 335-337, 2012. [PubMed: 22437207] [Full Text: https://doi.org/10.1038/jhg.2012.27]
Mellins, R. B., Balfour, H. H., Jr., Turino, G. M., Winters, R. W. Failure of automatic control of ventilation (Ondine's curse): report of an infant born with this syndrome and review of the literature. Medicine 49: 487-504, 1970. [PubMed: 5286083]
Minutillo, C., Pemberton, P. J., Goldblatt, J. Hirschsprung's disease and Ondine's curse: further evidence for a distinct syndrome. Clin. Genet. 36: 200-203, 1989. [PubMed: 2791333] [Full Text: https://doi.org/10.1111/j.1399-0004.1989.tb03189.x]
O'Dell, K., Staren, E., Bassuk, A. Total colonic aganglionosis (Zuelzer-Wilson syndrome) and congenital failure of automatic control of ventilation (Ondine's curse). J. Pediat. Surg. 22: 1019-1020, 1987. [PubMed: 3430302] [Full Text: https://doi.org/10.1016/s0022-3468(87)80504-3]
Oren, J., Kelly, D. H., Shannon, D. C. Long term follow up of children with congenital central hypoventilation syndrome. Pediatrics 80: 375-380, 1987. [PubMed: 2442698]
Parodi, S,, Vollono, C., Baglietto, M. P., Balestri, M., Di Duca, M., Landri, P. A., Ceccherini, I., Ottonello, G., Cilio, M. R. Congenital central hypoventilation syndrome: genotype-phenotype correlation in parents of affected children carrying a PHOX2B expansion mutation. Clin. Genet. 78: 289-293, 2010. [PubMed: 20236122] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01383.x]
Rutishauser, M., Feldges, A. Familiaere primaere chronische Hypoventilation. Schweiz. Med. Wschr. 107: 722-726, 1977. [PubMed: 867015]
Sasaki, A., Kanai, M., Kijima, K., Akaba, K., Hashimoto, M., Hasegawa, H., Otaki, S., Koizumi, T., Kusuda, S., Ogawa, Y., Tuchiya, K., Yamamoto, W., Nakamura, T., Hayasaka, K. Molecular analysis of congenital central hypoventilation syndrome. Hum. Genet. 114: 22-26, 2003. [PubMed: 14566559] [Full Text: https://doi.org/10.1007/s00439-003-1036-z]
Shimokaze, T., Sasaki, A., Meguro, T., Hasegawa, H., Hiraku, Y., Yoshikawa, T., Kishikawa, Y., Hayasaka, K. Genotype-phenotype relationship in Japanese patients with congenital central hypoventilation syndrome. J. Hum. Genet. 60: 473-477, 2015. [PubMed: 26063465] [Full Text: https://doi.org/10.1038/jhg.2015.65]
Shirasawa, S., Arata, A., Onimaru, H., Roth, K. A., Brown, G. A., Horning, S., Arata, S., Okumura, K., Sasazuki, T., Korsmeyer, S. J. Rnx deficiency results in congenital central hypoventilation. Nature Genet. 24: 287-290, 2000. [PubMed: 10700185] [Full Text: https://doi.org/10.1038/73516]
Silvestri, J. M., Chen, M. L., Weese-Mayer, D. E., McQuitty, J. M., Carveth, H. J., Nielson, D. W., Borowitz, D., Cerny, F. Idiopathic congenital central hypoventilation syndrome: the next generation. Am. J. Med. Genet. 112: 46-50, 2002. [PubMed: 12239719] [Full Text: https://doi.org/10.1002/ajmg.10819]
Sivan, Y., Zhou, A., Jennings, L. J., Berry-Kravis, E. M., Yu, M., Zhou, L., Rand, C. M., Weese-Mayer, D. E. Congenital central hypoventilation syndrome: severe disease caused by co-occurrence of two PHOX2B variants inherited separately from asymptomatic family members. Am. J. Med. Genet. 179A: 503-506, 2019. [PubMed: 30672101] [Full Text: https://doi.org/10.1002/ajmg.a.61047]
Stern, M., Erttmann, R., Helwege, H. H., Kuhn, N. Total aganglionosis of the colon and Ondine's curse. (Letter) Lancet 315: 877-878, 1980. Note: Originally Volume I. [PubMed: 6103232] [Full Text: https://doi.org/10.1016/s0140-6736(80)91375-6]
Stern, M., Hellwege, H. H., Gravinghoff, L., Lambrecht, W. Total aganglionosis of the colon (Hirschsprung's disease) and congenital failure of automatic control of ventilation (Ondine's curse). Acta Paediat. Scand. 70: 121-124, 1981. [PubMed: 7211372] [Full Text: https://doi.org/10.1111/j.1651-2227.1981.tb07184.x]
Swaminathan, S., Gilsanz, V., Atkinson, J., Keenes, T. G. Congenital central hypoventilation syndrome associated with multiple ganglioneuromas. Chest 96: 423-424, 1989. [PubMed: 2752827] [Full Text: https://doi.org/10.1378/chest.96.2.423]
Trochet, D., O'Brien, L. M., Gozal, D., Trang, H., Nordenskjold, A., Laudier, B., Svensson, P.-J., Uhrig, S., Cole, T., Niemann, S., Munnich, A., Gaultier, C., Lyonnet, S., Amiel, J. PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome. Am. J. Hum. Genet. 76: 421-426, 2005. Note: Erratum: Am. J. Hum. Genet. 76: 715 only, 2005. [PubMed: 15657873] [Full Text: https://doi.org/10.1086/428366]
Weese-Mayer, D. E., Berry-Kravis, E. M., Zhou, L., Maher, B. S., Silvestri, J. M., Curran, M. E., Marazita, M. L. Idiopathic congenital central hypoventilation syndrome: analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b. Am. J. Med. Genet. 123A: 267-278, 2003. [PubMed: 14608649] [Full Text: https://doi.org/10.1002/ajmg.a.20527]
Weese-Mayer, D. E., Bolk, S., Silvestri, J. M., Chakravarti, A. Idiopathic congenital central hypoventilation syndrome: evaluation of brain-derived neurotrophic factor genomic DNA sequence variation. Am. J. Med. Genet. 107: 306-310, 2002. [PubMed: 11840487] [Full Text: https://doi.org/10.1002/ajmg.10133]
Weese-Mayer, D. E., Brouillette, R. T., Naidich, T. P., McLone, D. G., Hunt, C. E. Magnetic resonance imaging and computerized tomography in central hypoventilation. Am. Rev. Resp. Dis. 137: 393-398, 1988. [PubMed: 3341630] [Full Text: https://doi.org/10.1164/ajrccm/137.2.393]
Weese-Mayer, D. E., Shannon, D. C., Keens, T. G., Silvestri, J. M. Idiopathic congenital central hypoventilation syndrome: diagnosis and management. Am. J. Resp. Crit. Care Med. 160: 368-373, 1999. [PubMed: 10390427] [Full Text: https://doi.org/10.1164/ajrccm.160.1.16010]
Weese-Mayer, D. E., Silvestri, J. M., Huffman, A. D., Smok-Pearsall, S. M., Kowal, M. H., Maher, B. S., Cooper, M. E., Marazita, M. L. Case/control family study of autonomic nervous system dysfunction in idiopathic congenital central hypoventilation syndrome. Am. J. Med. Genet. 100: 237-245, 2001. [PubMed: 11343310] [Full Text: https://doi.org/10.1002/ajmg.1249]
Weese-Mayer, D. E., Silvestri, J. M., Marazita, M. L., Hoo, J. J. Congenital central hypoventilation syndrome: inheritance and relation to sudden infant death syndrome. Am. J. Med. Genet. 47: 360-367, 1993. [PubMed: 8135282] [Full Text: https://doi.org/10.1002/ajmg.1320470313]
Yasuma, F., Nomura, H., Sotobata, I., Ishihara, H., Saito, H., Yasuura, K., Okamoto, H., Hirose, S., Abe, T., Seki, A. Congenital central alveolar hypoventilation (Ondine's curse): a case report and a review of the literature. Europ. J. Pediat. 146: 81-83, 1987. [PubMed: 3582411] [Full Text: https://doi.org/10.1007/BF00647295]