To the Editor: In their letter to the editor (1), Latorraca and Palli raise questions about the article titled “Progressive gray matter changes in patients with congenital central hypoventilation syndrome” (2). Specifically, Latorraca and Palli suggest that we neglected critical aspects of congenital central hypoventilation syndrome (CCHS) diagnosis and patient management in this study.

The first concern was related to genetic assessment of the CCHS subjects. The study used high-resolution T1-weighted magnetic resonance images to assess gray matter changes in CCHS subjects after a 4-y interval from initial scans, and evaluated those changes with voxel-based-morphometry procedures. All CCHS subjects were diagnosed based on American Thoracic Society 1999 criteria (3), since only limited PHOX2B mutation information was available at study design (2002 to 2003). The characteristics are well known to any CCHS researcher; all subjects showed early onset of the condition, hypoventilation during sleep, ventilatory insensitivity to hypercapnia and hypoxia, and severe autonomic characteristics, typically including failed temperature regulation, recurrent syncope, and frequently, asymmetric parasympathetic signs. However, we realize the importance of genetic evaluation for the syndrome, and have specifically emphasized that necessity elsewhere (4). We made repeated efforts to gather additional genetic information from our CCHS subjects, but to no avail, despite the obvious medical benefits. The reasons for declining a request varied, but included statements often found in response to testing for other life-threatening diseases, and included parental refusal. We had genetic information from a limited number of CCHS subjects (two positive (20/27 and 20/25 polyalanine expansions), one negative, and four untested); based on other published studies, from 62 to 97% of CCHS subjects show PHOX2B mutations (5,6), and we believe that the majority of our CCHS subjects also have such mutations, along with the primary CCHS characteristics described above. However, a small proportion of CCHS subjects in the literature shows an absence of PHOX2B mutation, despite presence of characteristics positive for the syndrome (5). Although handicapped by largely absent specific genetic information, we used the obvious clinical presentation here.

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