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PHOX2B Germline and Somatic Mutations in Late-Onset Central Hypoventilation Syndrome

¹ INSERM U781 and Département de Génétique, Hôpital Necker-Enfants Malades, Université Paris 5–René Descartes, Paris, France; ² Université Pierre et Marie Curie–Paris 6, UPRES EA2397, Service Central d'Explorations Fonctionnelles Respiratoires, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; ³ Division of Pediatric Sleep Medicine, Department of Pediatrics, and Kosair Children's Hospital Research Institute, University of Louisville, Louisville, Kentucky; ⁴ Service de Physiologie, INSERM E9935, Hôpital Robert Debré, Université Paris VII, Paris, France; and ⁵ Service de Neuropédiatrie, Hôpital Bicêtre, Bicêtre, France

Correspondence and requests for reprints should be addressed to Jeanne Amiel, M.D., Ph.D., Département de Génétique, Hôpital Necker–Enfants Malades 149, rue de Sèvres, 75743 Paris Cedex 15, France. E-mail: amiel{at}necker.fr

Rationale: Late-onset central hypoventilation syndrome (LO-CHS) is a rare disorder that may manifest as early as infancy or as late as during adulthood. The potential overlap of LO-CHS with congenital CHS is under debate, even though both disorders can result from heterozygous PHOX2B gene mutations.

Objectives: To characterize the PHOX2B status in a series of 25 patients with LO-CHS referred from 3 months of age to adulthood. Whenever a PHOX2B mutation was identified, we ascertained its germline or somatic origin in both patients with LO-CHS and in 15 parents of probands with congenital CHS found to harbor a PHOX2B mutation.

Methods: The PHOX2B gene was analyzed by direct DNA sequencing and origin of the mutation evaluated by fluorescent PCR.

Measurements and Main Results: We have identified a heterozygous PHOX2B gene mutation in 17 of 25 patients with LO-CHS. The far most frequent mutation results in a germline +5 alanine expansion in the series of 20 alanines (15 cases) that show incomplete penetrance and variable expressivity, possibly resulting from combined environmental and genetic factors. PHOX2B frameshift and missense mutations have also been identified in patients with LO-CHS. Importantly, one parent found to harbor a somatic mosaic for a +8 alanine expansion developed alveolar hypoventilation in his 40s.

Conclusions: These data indicate that PHOX2B gene mutations should be systematically examined in any adult with unexplained central hypoventilation and raise the question of follow-up for apparently healthy parents found to harbor a somatic mosaic for the PHOX2B mutation identified in their child.

Key Words: late-onset central hypoventilation • PHOX2B • somatic mosaic

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Late-onset central hypoventilation syndrome (LO-CHS) is a clinically and genetically heterogeneous group for which a subgroup is ascribed to PHOX2B gene mutations. What This Study Adds to the Field PHOX2B mutations leading to LO-CHS are not always polyalanine expansions. PHOX2B mutations can be in a mosaic state. Patients carrying a mosaic are at risk to develop the disease.