Background Congenital Central Hypoventilation Syndrome (CCHS) is a rare condition characterized by an alveolar hypoventilation due to a deficient autonomic central control of ventilation and a global autonomic dysfunction. Paired-like homeobox 2B (PHOX2B) mutations are found in most of the patients with CCHS. In recent years, the condition has evolved from a life-threatening neonatal onset disorder to include broader and milder clinical presentations, affecting children, adults and families. Genes other than PHOX2B have been found responsible for CCHS in rare cases and there are as yet other unknown genes that may account for the disease. At present, management relies on lifelong ventilatory support and close follow up of dysautonomic progression. Body This paper provides a state-of-the-art comprehensive description of CCHS and of the components of diagnostic evaluation and multi-disciplinary management, as well as considerations for future research. Conclusion Awareness and knowledge of the diagnosis and management of this rare disease should be brought to a large health community including adult physicians and health carers.
HMV programs provide necessary and safe assistance for children with severe chronic respiratory failure. As shown in our series, it is possible to be kept on this respiratory support modality for long periods with good compliance and a small number of hospitalizations.
Homozygosity for a dominant allele is relatively rare and preferentially observed in communities with high inbreeding. According to the definition of true dominance, similar phenotypes should be observed in patients heterozygous and homozygous for a dominant mutation. However, the homozygous phenotype usually tends to be more severe than the heterozygous one. In these cases, the wild-type and mutant alleles are semi-dominant. Here we report a patient with a Congenital Central Hypoventilation Syndrome (CCHS) phenotype and homozygosity for a PHOX2B gene mutation leading to an alanine expansion shorter than the threshold hitherto observed in CCHS patients with a heterozygous mutation. This observation adds the concept of mutational threshold per se to the discussion about dominant and recessive alleles. © 2008 Wiley-Liss, Inc.KEY WORDS: PHOX2B, CCHS, homozygous alanine expansion INTRODUCTIONHomopolymeric tracts of amino acids are extremely abundant in eukaryotic proteins (Green and Wang, 1994). In humans, 20% of proteins contain at least one such tract (Karlin et al., 2002). They have recently been proposed to be a major source of phenotypic variation in evolution (Fondon and Garner, 2004). Polyalanine tracts varying in length from 5 to 20 repeats have been predicted in roughly 500 human proteins, with over-representation among transcription factors (Lavoie et al., 2003). Alanine tracts are encoded by imperfect tri-nucleotide repeats (GCN) and length polymorphisms can be observed in controls (Lavoie et al., 2003). Unequal allelic homologous recombination and/or DNA loop formation during meiosis and mitosis may cause alanine expansions and contractions (Trochet et al., 2007;Warren, 1997). The function of polyalanine stretches is still unknown. In all cases but one (PABPN1), polyalanine expansion mutations in human diseases have involved transcription factors Trochet et al. PHOX2B, HOXA13, HOXD13, RUNX2, ZIC2, FOXL2, ARX, and SOX3) (Table1). The mechanisms by which alanine expansion lead to disease may include loss-of-function, a dominant negative effect, or a gain of toxic function (Albrecht and Mundlos, 2005). (Congenital Central Hypoventilation Syndrome (CCHS) is a life-threatening condition that results from abnormal autonomic control of breathing and is ascribed to heterozygous PHOX2B (MIM# 603851) gene mutations. Various mutations have been described, i.e. polyalanine expansions, missense and frameshift mutations Weese-Mayer et al., 2003;Matera et al., 2004). Polyalanine expansions are by far the most frequent mutations with an expansion ranging from +5 to +13 alanines. Genotype/phenotype correlations on large series showed that i) patients with a +5 alanine expansion do not present Hirschsprung disease as an associated feature (Trochet et al., 2005b), ii) the longer the expansion, the more severe the ventilatory phenotype (Matera et al., 2004) and, iii) tumours of the sympathetic nervous system are rarely found with alanine expansions (Trochet et al., 2005b). Polyalanine contractions of -5, -7 and -13 alanines...
A greater awareness is required to diagnose late-onset CCHS. A respiratory infection can trigger the disease, with a significant difference in CO2 between sleep and wakefulness as the warning signal. Given the clinical suspicion, a genetic study should be performed. Polysomnography is essential for patient characterization. Follow-up and ventilator support adjustment prevent serious hypoxia and hypercapnia, which impair cardiovascular and neurocognitive functions. This patient's mutation has not been previously described; hence, clinical evolution cannot be predicted.
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