Association of germline mutations and polymorphisms of the RET proto-oncogene with idiopathic congenital central hypoventilation syndrome in 33 patients.

The idiopathic congenital central hypoventilation syndrome (CCHS) was first described by Mellins et al and is characterised by an alteration of the ventilatory response to hypercapnia and hypoxia. Whereas normal ventilation is adequate in many of the patients during wakefulness, the alveolar hypoventilation observed during sleep seems attributable to a failure of the central autonomic control of ventilation in the brainstem. CCHS is a rare entity in which affected children show symptoms typically in the newborn period. These symptoms include a period of cyanosis upon sleep induction, a decrease of oxyhaemoglobin saturation with simultaneous life threatening increase of the partial pressure of CO2 in arterial blood (PaCO2), which yields no respiratory response, and no arousal reflex by the infants. Primary neuromuscular, lung, or cardiac disorders or an identifiable brainstem lesion are absent. The first extensive series of CCHS patients was described by Weese-Mayer et al in 1992. The apparent functional defect possibly stems from an abnormal migration or differentiation of neural crest derived cells into the autonomic ventilatory control system. Therefore, idiopathic congenital central hypoventilation syndrome may be regarded as a feature of complex neurocristopathies, as confirmed by the observation of a combination of CCHS and other neurocristopathies. Specifically, CCHS has been reported in association with neoplastic as well as dysgenetic neurocristopathies, such as neuroblastomas and ganglioneuromas, but the frequency of such cases is lower than 5%. Furthermore, in 16-20% of the patients, CCHS is combined with Hirschsprung disease (HSCR), a developmental disorder characterised by congenital absence of ganglion cells in the myoenteric and submucosal plexuses of the bowel. 8–16 Although most CCHS cases are sporadic, a putative genetic origin for CCHS has also been considered because of the familial occurrence in several reported cases, such as monozygotic female twins, female sibs, 18 male-female sibs, and male-female half sibs. Moreover, a case-control family study showed that CCHS patients and their parents are more likely to be affected with symptoms of autonomic nervous system dysfunction (ANSD) than controls and parents of controls. Thus, CCHS is also considered as the most severe manifestation of ANSD. The segregation analysis of ANSD symptoms in families with CCHS affected subjects was consistent with the familial association hypothesis and fits almost equally two genetic models, the major locus model and the multifactorial model. 20 21 In addition to the frequently reported association of CCHS with Hirschsprung disease in humans, a similar phenotype has also been observed in the ret knockout mouse model. Whereas heterozygous animals did not show any histopathological signs of aganglionosis, animals with a homozygous functional ret deletion showed severe aganglionosis extending to the stomach and also variable defects of the kidneys. Interestingly, ret -/mice died within the first 16-24 hours of life, probably not as a result of the above mentioned malformations but rather from altered respiratory CO2 sensitivity and responsiveness. In addition, reports of patients with HSCR who harbour germline mutations of the RET proto-oncogene have shown that they were primarily point mutations scattered throughout the extracellular domain and within the intracellular tyrosine kinase domain of RET in up to 20% of sporadic cases and in up to 50% of familial cases. However, a population based study of Swedish HSCR patients showed a low mutation rate of only 3.2%. The RET mutations found in HSCR result in either RET protein truncation, decreased presentation on cell surface, or functional inactivation of the molecule. Based on these observations, the RET proto-oncogene may also be considered as a candidate gene for idiopathic congenital central hypoventilation syndrome, although previous analyses of the coding region of RET showed no causative mutation (apart from common gene variants at positions c.1296G/A, c.2071G/A, c.2307T/G, and c.2712C/G) in 17 CCHS patients, of whom seven showed a combination with Key points