Sleep-disordered breathing, particularly the obstructive sleep apnea syndrome, is common during childhood. Complications include neurocognitive deficits, growth failure, and pulmonary hypertension. Nevertheless, sleep-disordered breathing is often unrecognized in children. New syndromes, such as the upper airway resistance syndrome, have recently been described. Polysomnography is invaluable for the evaluation of sleep-disordered breathing. Advances in diagnosis and management can alleviate much of the morbidity previously associated with sleep-related respiratory disorders.

Sleep-disordered breathing in children.

Central Sleep Apnea: Pathophysiology and Treatment

Background: Congenital central hypoventilation syndrome (CCHS) is characterized by alveolar hypoventilation and autonomic dysregulation.Purpose: (1) To demonstrate the importance of PHOX2B testing in diagnosing and treating patients with CCHS, (2) to summarize recent advances in understanding how mutations in the PHOX2B gene lead to the CCHS phenotype, and (3) to provide an update on recommendations for diagnosis and treatment of patients with CCHS.Methods: Committee members were invited on the basis of their expertise in CCHS and asked to review the current state of the science by independently completing literature searches. Consensus on recommendations was reached by agreement among members of the Committee.Results: A review of pertinent literature allowed for the development of a document that summarizes recent advances in understanding CCHS and expert interpretation of the evidence for management of affected patients.Conclusions: A PHOX2B mutation is required to confirm the diagnosis of CCHS. Knowled...

An Official ATS Clinical Policy Statement: Congenital Central Hypoventilation Syndrome: Genetic Basis, Diagnosis, and Management

CO2, brainstem chemoreceptors and breathing

Idiopathic congenital central hypoventilation syndrome (CCHS) has been linked to autonomic nervous system dysregulation and/or dysfunction (ANSD) since it was first described in 1970 A genetic basis of CCHS has been proposed because of the reports of four families with two affected children, because of mother-child transmission, and because of a recent report of a polyalanine expansion mutation in PHOX2b in a subset of CCHS subjects We, therefore, studied genes pertinent to early embryologic development of the ANS including mammalian achaete-scute homolog-1 (MASH1), bone morphogenic protein-2 (BMP2), engrailed-1 (EN1), TLX3, endothelin converting enzyme-1 (ECE1), endothelin-1 (EDN1), PHOX2a, and PHOX2b in 67 probands with CCHS, and gender- and ethnicity-matched controls No disease-defining mutations were identified in MASH1, BMP2, EN1, TLX3, ECE1, EDN1, or PHOX2a The 65/67 CCHS probands (97%) were found to be heterozygous for the exon 3 polyalanine expansion mutation identified previously in PHOX2b Further, there was an association between repeat mutation length and severity of the CCHS/ANSD phenotype Of the two probands who did not carry the expansion mutation, one had a nonsense mutation in exon 3 which truncated the protein and the other had no mutation in PHOX2b but had a previously reported EDN3 frameshift point mutation The polyalanine expansion mutation was not found in any of 67 matched controls Of 54 available families (including 97 unaffected parents), whose child carried the PHOX2b mutation, 4 parents demonstrated mosaicism for an expansion mutation identical to that seen in the CCHS cases, suggesting that not all mutations in affected probands with unaffected parents are de novo We also studied four women with CCHS who were heterozygous for the PHOX2b mutation, each with one child Three of the four children were also affected and had the same mutation, demonstrating autosomal dominant inheritance of the mutation Assay of the PHOX2b polyalanine repeat mutation represents a highly sensitive and specific technique for confirming the diagnosis of CCHS Identification of the CCHS mutation will lead to clarification of the phenotype, allow for prenatal diagnosis for parents of CCHS probands and adults with CCHS in future pregnancies, and potentially direct intervention strategies for the treatment of CCHS

Idiopathic congenital central hypoventilation syndrome: Analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b

Lisa J. Menzies

Papers

Congenital central hypoventilation syndrome: Diagnosis, management, and long-term outcome in thirty-two children