Abstract
Hirschsprung disease, neuroblastomas, and congenital central hypoventilation syndrome can occur in combination, and familial cases have been reported in all three conditions. This suggests variable expression of a single genetic abnormality as the common cause to these neural crest disorders. Because the PHOX2B gene is pivotal in the development of most relays of the autonomic nervous system, including all autonomic neural crest derivatives, it was considered a candidate gene for the above conditions. Recent studies have shown that 1) PHOX2B is the main disease-causing gene for congenital central hypoventilation syndrome, an autosomal dominant disorder with incomplete penetrance; 2) PHOX2B is the first gene for which germline mutations have been demonstrated to predispose to neuroblastoma; and 3) Hirschsprung disease was associated with an intronic single-nucleotide polymorphism of the PHOX2B gene in a case-control study. For clarifying the variable clinical expression of the autonomic nervous system dysfunction observed in neural crest disorders, international databases of clinical symptoms and molecular test results should be established. Furthermore, the development of genetic mouse models should help to improve our understanding of the molecular mechanisms underlying neural crest disorders.
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Abbreviations
- ANS:
-
autonomic nervous system
- CCHS:
-
congenital central hypoventilation syndrome
- HASH-1:
-
human achaete-scute homologous 1 gene
- HSCR:
-
Hirschsprung disease
- LO-CHS:
-
late-onset central hypoventilation syndrome
- MASH-1:
-
mammalian achaete-scute homologous 1 gene
- PHOX2B:
-
paired-like homeobox 2b gene
- RET:
-
rearranged after transfection gene
- SIDS:
-
sudden infant death syndrome
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Acknowledgements
We are grateful to Jean-François Brunet (CNRS UMR 8542, Ecole Normale Supérieure, Paris, France) and to Jeanne Amiel (INSERM U393 and Département de Génétique Médicale, Hôpital Necker-Enfants Malades, Paris, France) for critical reading of the manuscript.
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Gaultier, C., Trang, H., Dauger, S. et al. Pediatric Disorders with Autonomic Dysfunction: What Role for PHOX2B?. Pediatr Res 58, 1–6 (2005). https://doi.org/10.1203/01.PDR.0000166755.29277.C4
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DOI: https://doi.org/10.1203/01.PDR.0000166755.29277.C4
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