Congenital Central Hypoventilation Syndrome: a Bedside- To-Bench Success Story for Advancing Early Diagnosis and Treatment and Improved Survival and Quality of Life
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Review nature publishing group Congenital central hypoventilation syndrome: a bedside- to-bench success story for advancing early diagnosis and treatment and improved survival and quality of life Debra E. Weese-Mayer1,2, Casey M. Rand1, Amy Zhou1, Michael S. Carroll1,2 and Carl E. Hunt3,4 The “bedside-to-bench” Congenital Central Hypoventilation Nonetheless, they maintain the ability to consciously alter the Syndrome (CCHS) research journey has led to increased phe- rate and depth of breathing. Historically, CCHS was diagnosed notypic-genotypic knowledge regarding autonomic nervous in the newborn period, yet we now know that cases can be system (ANS) regulation, and improved clinical outcomes. diagnosed later in infancy, childhood or adulthood (3–11). CCHS is a neurocristopathy characterized by hypoventila- Hirschsprung disease (HSCR) and tumors of neural crest ori- tion and ANS dysregulation. Initially described in 1970, timely gin present in varied combinations with CCHS, in addition to diagnosis and treatment remained problematic until the first a spectrum of symptoms compatible with autonomic nervous large cohort report (1992), delineating clinical presentation system dysregulation (ANSD) (1,12–29). While the spectrum and treatment options. A central role of ANS dysregulation and variability of CCHS-associated symptoms have made (2001) emerged, precipitating evaluation of genes critical to diagnosis and treatment complex, these very complexities led ANS development, and subsequent 2003 identification of to the discovery of its etiology and the consequent successes Paired-Like Homeobox 2B (PHOX2B) as the disease-defining in diagnosis and treatment. Here we describe some of these gene for CCHS. This breakthrough engendered clinical genetic discoveries and advances, which over the last five decades have testing, making diagnosis exact and early tracheostomy/arti- transformed diagnosis, treatment, and quality of life for CCHS ficial ventilation feasible. PHOX2B genotype-CCHS phenotype patients. relationships were elucidated, informing early recognition and timely treatment for phenotypic manifestations includ- THE EARLY STORY OF CCHS ing Hirschsprung disease, prolonged sinus pauses, and neural The 1970 report of an infant with “failure of automatic control crest tumors. Simultaneously, cellular models of CCHS-causing of ventilation” (30) was the first to describe the CCHS control PHOX2B mutations were developed to delineate molecular of breathing deficit, including extraordinary details regarding mechanisms. In addition to new insights regarding genet- the child’s autonomic dysregulation. Over the next few years, ics and neurobiology of autonomic control overall, new four additional CCHS patients were reported with clinical knowledge gained has enabled physicians to anticipate and courses complicated by cor pulmonale, seizures, neurologic delineate the full clinical CCHS phenotype and initiate timely abnormalities and high mortality, but no identifiable neuropa- effective management. In summary, from an initial guarantee thology on autopsy (31,32). of early mortality or severe neurologic morbidity in survivors, Three cases reported by Hunt and colleagues in 1978 and CCHS children can now be diagnosed early and managed 1979 (33,34) introduced two important strategies: (i) medical effectively, achieving dramatically improved quality of life as management to prevent or reverse cor pulmonale, and decrease adults. risk for hypoxic encephalopathy, permanent disability or death, and (ii) successful introduction of diaphragm pacing. These infants proved unresponsive to respiratory stimulants, ongenital Central Hypoventilation Syndrome (CCHS) and one developed bilateral ganglioneuroblastomas, suggest- Cpatients characteristically present with diminutive tidal ing a phenotype not limited to the brainstem. Two of the three volumes and monotonous respiratory rates asleep and awake, cases died before age two, in part due to the cor pulmonale and with more profound alveolar hypoventilation typically associated hypoxic encephalopathy, and the third died sud- occurring during sleep (1,2). These individuals thus become denly and unexpectedly as a young adult. hypoxemic and hypercarbic, with diminished or absent venti- In 1978, Haddad and colleagues reported three additional latory and arousal responses to these endogenous challenges. CCHS infants (35). This report highlighted an association 1Center for Autonomic Medicine in Pediatrics (CAMP), Ann & Robert H. Lurie Children’s Hospital of Chicago and Stanley Manne Children’s Research Institute, Chicago, Illinois; 2Feinberg School of Medicine, Northwestern University, Chicago, Illinois; 3Pediatrics, F. Edward Hébert School of Medicine, Uniformed Services University, Bethesda, Maryland; 4Pediatrics, George Washington University, Washington, D.C. Correspondence: Debra E. Weese-Mayer ([email protected]) Received 18 May 2016; accepted 15 August 2016; advance online publication 2 November 2016. doi:10.1038/pr.2016.196 192 Pediatric REsEarch Volume 81 | Number 1 | January 2017 Copyright © 2017 International Pediatric Research Foundation, Inc. CCHS: bedside-to-bench success story Review of CCHS with HSCR and tumors of neural crest origin. The CCHS that suggested a Mendelian codominant transmission report described an infant who exhibited postnatal cyanosis, (12,38). Thus, researchers began to search for CCHS-causing improved ventilation in rapid eye movement (REM) sleep, mutations, focusing primarily on genes implicated in HSCR. attenuated ventilatory response to hypercarbia, lack of heart While these studies provided interesting candidates for CCHS rate variability, HSCR and multiple ganglioneuroblastomas. etiology, results were inconclusive and no single gene emerged Additionally, this report described CCHS in sisters, the first as a clear causative factor (39–41). suggestion that CCHS is familial. While the pathophysiology remained quite unclear, linking CCHS to HSCR and neural THE BREAKTHROUGH: PHOX2B AS THE DISEASE-DEFINING crest tumors, and identifying familial recurrence were essential GENE FOR CCHS steps in understanding these entities. A New Suspect In the following decades, additional CCHS cases were The Paired-Like Homeobox 2B (PHOX2B) gene encodes a reported, though still totaling fewer than 100. These reports, highly conserved homeodomain transcription factor. Early combined with the first large cohort studies appearing in the work indicated PHOX2B may play a key role in embryologic early 1990s (13), resulted in a broad understanding of the development of the ANS, including circuits thought to under- phenotype and provided hints to the varying organ systems lie chemosensory functions (42,43). PHOX2B was further involved, the need for early diagnosis and referral, for vigilant implicated in intestinal innervation, linking this gene to the ventilatory management, and for vigorous efforts to support gastrointestinal phenotype as well. Recognizing the overlap an age-appropriate quality of life. These early cases collectively in phenotypic manifestations of CCHS with PHOX2B devel- made it clear that CCHS is far more than a simple orphan opmental roles, work began to evaluate PHOX2B in CCHS disorder of respiratory control. While CCHS-related morbid- cohorts. ity and mortality had decreased, major gaps in knowledge remained—in particular, the underlying cause of the disease. A Link is Identified In 2003, Amiel and colleagues reported mutations in PHOX2B UNCOVERING CLUES TO THE CAUSE: AUTONOMIC in 20 of 29 (69%) mainly French CCHS cases (44). The major- DYSFUNCTION AND FAMILIAL RECURRENCE ity of these mutations (18 of 20) were in-frame expansions of a In response to increasing identification of CCHS, specialized 20-alanine repeat region found in exon 3 of PHOX2B between centers were established to advance CCHS care. These centers 25 and 29 alanines (now termed as polyalanine repeat expan- would aggregate the rare disease patients needed for research sion mutations, PARMs). The two remaining patients had analysis, allowing elucidation of CCHS-associated symptoms, frameshift mutations, part of a group of rarer mutations in uncovering of fundamental systems involved, and defining PHOX2B now termed non-PARMs (NPARMs). Neither muta- familial inheritance. Together, these advances would form the tion type was found in any controls, nor in parents of the CCHS basis of future inquiry and discovery. cases. Similarly, a 2003 report identified PHOX2B PARM and NPARM mutations in 5 of 10 Japanese CCHS cases (41). These Dysfunction of the ANS studies implicated PHOX2B in CCHS pathogenesis, but the The effects of the ANS are expansive (Figure 1), thus diag- full story was not yet clear. nosing and delineating symptoms associated with ANSD is complicated, particularly in a rare disease with variable expres- Mounting Evidence of PHOX2B as the Disease-Defining Gene for sion. In 1999, the American Thoracic Society published the CCHS first official statement on CCHS (1). This statement reported Concurrently, Weese-Mayer and colleagues (39) evaluated can- 160–180 known living cases of CCHS, describing symptoms of didate CCHS genes in a larger cohort of US cases and controls. and conditions associated with CCHS, and recognized critical Surprisingly, PHOX2B mutations were identified in 100% of 67 diagnosis of abnormal respiratory control and related cardio- CCHS cases in this cohort. Sixty-six of these patients had hetero- respiratory and autonomic symptoms. This report expanded zygous PHOX2B PARMs,