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

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Association of germline mutations and polymorphisms of the RET proto-oncogene with idiopathic congenital central hypoventilation syndrome in 33 patients
  1. G Fitze1,
  2. E Paditz2,
  3. M Schläfke3,
  4. E Kuhlisch4,
  5. D Roesner1,
  6. H K Schackert5
  1. 1Department of Paediatric Surgery, University of Technology Dresden, 01307 Dresden, Germany
  2. 2Department of Paediatrics, University of Technology Dresden, 01307 Dresden, Germany
  3. 3Department of Applied Physiology, Ruhr-University Bochum, 44780 Bochum, Germany
  4. 4Institute of Medical Informatics and Biometry, University of Technology Dresden, 01307 Dresden, Germany
  5. 5Department of Surgical Research, University of Technology Dresden, 01307 Dresden, Germany
  1. Correspondence to:
 Dr G Fitze, Department of Paediatric Surgery, University of Technology Dresden, Fetscherstrasse 74, D-01307 Dresden, Germany;
 Guido.Fitze{at}mailbox.tu-dresden.de

https://doi.org/10.1136/jmg.40.2.e10

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    The idiopathic congenital central hypoventilation syndrome (CCHS) was first described by Mellins et al1 and is characterised by an alteration of the ventilatory response to hypercapnia and hypoxia.1 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.2 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.3 The first extensive series of CCHS patients was described by Weese-Mayer et al4 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.5 Specifically, CCHS has been reported in association with neoplastic as well as dysgenetic neurocristopathies, such as neuroblastomas6 and ganglioneuromas,7 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.6,8–16

    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 …

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