CCHS WITH HIRSCHSPRUNG DISEASE, INCLUDED
HADDAD SYNDROME, INCLUDED
OHD, INCLUDED
AUTONOMIC CONTROL, CONGENITAL FAILURE OF ONDINE CURSE, CONGENITAL ONDINE-HIRSCHSPRUNG DISEASE, INCLUDED
CCHS
Ondine curse
Central congenital hypoventilation syndrome
Congenital central alveolar hypoventilation syndrome
Idiopathic congenital central hypoventilation syndrome, 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. ... Idiopathic congenital central hypoventilation syndrome, 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. 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. These patients typically present in the first hours of life with cyanosis and increased carbon dioxide during sleep. 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. 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 ... 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 patients of whom 2 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 (megacolon) (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) also described a case in a male infant. 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. A heterogeneous group of patients with late-onset central hypoventilation syndrome (LO-CHS) was described by Katz et al. (2000). 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.
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 ... - Mutation in the PHOX2B Gene 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 (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. 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. - Mutations in Other Genes To test the hypothesis that CCHS and HSCR share a common molecular pathology, Bolk et al. (1996) conducted mutation analysis of potential candidate genes in pediatric patients with CCHS and HSCR or isolated CCHS. They identified a frameshift mutation in the gene encoding endothelin-3 (131242.0003). 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). 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. Identification of mutations in RET-GDNF pathway and the endothelin pathway in Ondine curse shed light on the genetic bases of this life-threatening condition and supports the view that CCHS is a neural crest cell disorder. Nevertheless, mutations had been reported in a minority of patients tested to that time. Amiel et al. (1998) stated that the involvement of at least 3 genes belonging to distinct signaling pathways, the incomplete penetrance of the mutation in carrier parents, and the variable expression of the respiratory control defect observed in Ret -/- homozygous mice exposed to hypercapnia (Burton et al., 1997) support the view that an interactive polygenic inheritance is involved in Ondine curse. 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 (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. In 2 patients with CCHS and 1 with Haddad syndrome, de Pontual et al. (2003) identified mutations in the ASCL1 gene (100790.0001-100790.0003).