Published ahead of print on July 27, 2006, doi:10.1164/rccm.200605-607CR
© 2006 American Thoracic Society doi: 10.1164/rccm.200605-607CR
PHOX2B Mutation–confirmed Congenital Central Hypoventilation SyndromePresentation in AdulthoodAdelaide Institute for Sleep Health, Repatriation General Hospital, Daw Park, South Australia, Australia; Sleep Disorders Division, Department of Neurology, Vanderbilt University Medical Center, Nashville; Department of Pediatrics, T.C. Thompson Children's Hospital, Chattanooga, Tennessee; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado; Department of Pediatrics, Neurology, and Biochemistry, and Division of Pediatric Respiratory Medicine, Department of Pediatrics, Rush University Medical Center, Chicago, Illinois; Salford Royal Hospitals NHS Trust Hope Hospital, Salford; Department of Pediatrics, University Hospital of North Staffordshire, Stoke on Trent, United Kingdom; and Department of Respiratory Medicine, University Hospital, Freiburg, Germany Correspondence and requests for reprints should be addressed to Debra E. Weese-Mayer, M.D., Division of Pediatric Respiratory Medicine, Department of Pediatrics, Rush University Medical Center, Chicago, IL 60612. E-mail: Debra_E_Weese-Mayer{at}rsh.net
Congenital central hypoventilation syndrome (CCHS) typically presents in the newborn period. A case series of five adults is presented, each heterozygous for a documented polyalanine expansion mutation in the PHOX2B gene and evidence of nocturnal alveolar hypoventilation. All cases had symptoms in childhood, but survived to adulthood without ventilatory support. After identification of physiologic compromise, artificial ventilation was initiated. These adults have the mildest of the CCHS-related PHOX2B polyalanine expansion mutations, coding for only five extra alanines; three of the adults have affected offspring. Report of these cases should lead to a more rapid identification of CCHS presenting in adulthood.
Key Words: congenital central hypoventilation syndrome • PHOX2B gene This case series demonstrates that adults may present with a PHOX2B mutation–confirmed late-onset form of congenital central hypoventilation syndrome (CCHS), having survived childhood without artificial ventilatory support. All cases had apparent symptoms, though often mild, in childhood. It is hoped that increased awareness of this condition among adult-medicine physicians across a number of specialties will lead to earlier clinical and genetic diagnosis and treatment of unexplained cases of hypoventilation in adulthood. CCHS (MIM number: 209880) is a disorder of respiratory control with related autonomic nervous system dysregulation/dysfunction (ANSD) (1). The most commonly cited associations include Hirschsprung disease and/or tumors of neural crest origin (neuroblastoma, ganglioneuroblastoma, ganglioneuroma), reported in approximately 20 and 6% of CCHS cases, respectively (1). Other symptoms of diffuse ANSD are seen frequently in CCHS and include decreased heart rate variability, attenuated heart rate response to exercise, severe constipation, esophageal dysmotility/dysphagia, decreased perception of discomfort, pupillary abnormalities, decreased perception of anxiety, sporadic profuse sweating, and decreased basal body temperature (1). PHOX2B, located on chromosome 4p12 and coding for a highly conserved transcription factor known to play a key role in the development of ANS reflex circuits in mice (2), is the disease-defining gene for CCHS (2–7). Approximately 92% of individuals with CCHS are heterozygous for a polyalanine repeat expansion mutation involving the second polyalanine repeat sequence in exon 3 of the PHOX2B gene (2–7). Expansions are in-frame and range from 15 to 39 nucleotide insertions, resulting in expansion of the normal 20-repeat polyalanine tract to 25 to 33 alanine repeats to produce genotypes of 20/25 to 20/33 (the normal genotype would be referred to as 20/20) (3, 5, 6). The remaining 8% of patients with the CCHS phenotype have unique mutations in the PHOX2B gene (2–7). More than 90% of PHOX2B expansion mutations occur de novo in CCHS probands, with up to 10% of unaffected parents showing somatic mosaicism for the expansion mutation seen in her/his child (3). In these families, as well as in offspring of a proband with PHOX2B mutation–confirmed CCHS, the mutation and the phenotype are inherited as an autosomal dominant trait (3). Polyalanine expansion size has been associated with severity of autonomic dysfunction (number of ANSD symptoms) (3, 5), increased R-R interval on Holter monitoring (8), and severity of ventilatory dependence (3, 5). Although individuals with CCHS typically present in the newborn period (1), we recently described an individual who presented in adulthood (9). Just as with the newborns, the adult was diagnosed in the absence of primary lung, cardiac, or neuromuscular disease, or an identifiable brainstem lesion that could account for the alveolar hypoventilation. The diagnosis in the reported adult was expedited because of prior diagnosis of CCHS in his daughter, and by application of the clinically available PHOX2B test for the CCHS-related polyalanine expansion mutation. We subsequently identified four more adult cases presenting after age 21, all of whom survived into adulthood without artificial ventilatory support until the time of diagnosis, and all with a documented polyalanine expansion mutation in the PHOX2B gene (genotype 20/25 in all cases, meaning one normal allele with 20 alanine repeats and one mutated expanded allele with 25 alanine repeats). The purpose of this report is to review the medical history and clinical presentation of these five adult cases to more clearly characterize the adult presentation of CCHS and to alert the adult practitioner to the possibility of CCHS presenting in adulthood.
Case Identification and Case Report Preparation All cases were identified by positive test results for the CCHS-related PHOX2B polyalanine expansion mutation through the CCHS Center and Molecular Diagnostics Laboratory at Rush University Medical Center (Chicago, IL). Cases 1 and 2 had been published as unexplained alveolar hypoventilation, so PHOX2B testing was sought to clarify the diagnosis. Cases 3 and 4 were referred for clinical recommendations and genetic testing. Case 5 was identified after enrollment in the Rush University CCHS Center research program. All described cases consented to inclusion in the institutional review board–approved CCHS/PHOX2B research project. Medical records from each proband were collected and reviewed by two authors (D.E.W.-M. and N.A.A.). One to two investigators familiar with each case were invited to prepare a case report based on the medical records and clinical evaluation. Additional testing or records were requested on a case-by-case basis in an aim for uniform clinical assessment. The case report format was standardized and prepared to convey the available test results, with areas of overlap and variance (D.E.W.-M. and N.A.A.).
Genetic Testing: DNA Preparation
Genotyping of PHOX2B Polyalanine Repeat Sequence
Case 1 Case 1 (Adelaide, Australia) presented to the emergency department (ED) at age 22 with symptoms of a minor upper respiratory tract infection. An arterial blood gas measurement, taken because of an unexpectedly low pulse oximetry reading, revealed a PO2 of 36 mm Hg, a PCO2 of 63 mm Hg, an HCO3 of 37 mmol/L, and a pH of 7.42 while awake breathing room air. The admission hematocrit was 55% and the echocardiogram revealed right heart dilatation. Pulmonary function testing, complete neurologic examination, and muscle biopsy were normal. Magnetic resonance imaging (MRI) of the brain/brainstem was normal. Body mass index (BMI) was 28. Holter recording revealed sinus rhythm with a rate of 29 to 122 beats/min with occasional ventricular ectopic beats. One hundred eighteen sinus pauses were noted, exclusively during wakefulness, and all were asymptomatic, with the longest R-R interval measured at 8.4 s. Polysomnography (PSG) revealed severe hypoxemia (nadir SpO2, 71%) and hypercarbia (peak transcutaneous CO2 [TcpCO2], 82 mm Hg) in non-REM sleep. No REM sleep was documented on the first or subsequent PSGs. Voluntary breath-hold lasted more than 2 min despite hemoglobin desaturation to 65%, without any perception of dyspnea. Nasal mask bilevel positive airway pressure was initiated with confirmed compliance, but with further deterioration in arterial blood gases. Subsequently, almitrine bismesylate (Vectarion; Servier, Gidy, France) was initiated (50 mg twice daily), producing a sustained improvement in PCO2 measurements (decline from 80 to 49 mm Hg over 6 mo without any change in bilevel ventilation compliance or body weight). Case 1 is now 35 yr old and he remains adequately ventilated during sleep with bilevel nasal mask positive pressure, although almitrine therapy has been complicated by a nonprogressive peripheral neuropathy requiring a dosage reduction. There has been no recurrence of seizures previously noted in childhood since he has been adequately oxygenated and ventilated. His hypoventilation remains during sleep only, with normal PCO2 documented while awake. Case 1 is heterozygous for the PHOX2B polyalanine expansion mutation, with genotype 20/25. This case was described in the literature several years ago (10) as having unexplained respiratory failure.
Evidence for apparent symptoms before adulthood and evidence for chronicity.
Case 2
Evidence for apparent symptoms before adulthood and evidence for chronicity.
Case 3
Evidence for apparent symptoms before adulthood and evidence for chronicity.
Case 4
Evidence for apparent symptoms before adulthood and evidence for chronicity.
Case 5
Evidence for apparent symptoms before adulthood and evidence for chronicity.
This report of five adults with PHOX2B mutation–confirmed CCHS indicates that individuals with the shortest of the PHOX2B polyalanine expansion mutations known to cause CCHS can survive into adulthood without manifesting the early respiratory failure classically associated with the CCHS phenotype. Although these cases were not diagnosed until adulthood, it is apparent that these adults had subtle symptoms indicative of CCHS during childhood and even adulthood, including unexplained "epilepsy" resistant to anticonvulsants and with a normal EEG, cyanotic apnea spells, and the ability to breath-hold for prolonged periods. Likewise, many of these adults had laboratory evidence for chronicity of symptoms, including hypercarbia, polycythemia, and right heart changes. Furthermore, two of the cases presented with significant cognitive impairment, suggesting the possibility that these adults suffered neurocognitively from sequelae of the hypoxemia and hypercarbia. Taken together, these cases indicate that there are likely other adults with yet undiagnosed CCHS. These adults may present to the sleep laboratory, epilepsy clinic, pulmonary clinic, emergency room, or the intensive care unit. Because most emergency room physicians and adult intensivists will not be familiar with CCHS, the diagnosis of CCHS will depend on a heightened level of suspicion and on careful medical history for diseases among offspring. It will be essential to assess hemoglobin saturation and, ideally, end tidal carbon dioxide levels before administering drugs that depress ventilation. It is hoped that increased awareness and the clinically available genetic testing for CCHS might lead to earlier diagnosis, earlier therapeutic intervention, and avoidance of inadvertent respiratory depression. The 25-repeat polyalanine expansion mutation in PHOX2B is the smallest expansion known to cause CCHS. The results presented here indicate that individuals with the 25-repeat expansion in their mutated allele (20/25 genotype) can show variable penetrance. Specifically, the described adults did not present until between age 22 and 36 yr. Some of the children with CCHS born to these adults also had a delayed age at presentation, although all within the first year of life. Because no mutations larger than 25 repeats have been identified in adult-onset cases, it appears that longer expansions containing 26 to 33 alanine repeats (genotypes 20/26 to 20/33) cause typical CCHS and are not associated with variable penetrance or adult-onset presentations. As such, cellular impairment in PHOX2B transcriptional activity (12, 13), mislocalization of PHOX2B to the cell cytoplasm (normally present only in the nucleus) (12), and a tendency to PHOX2B protein misfolding with multimer formation (13) have been found to be increasingly severe with increasing repeat size for polyalanine repeat mutations. PHOX2B-containing cellular aggregates are identifiable only for mutations larger than 25 repeats (13). Thus, the relatively milder cellular defects associated with the small 25-repeat expansion mutations may not always reach a threshold required for clinical disease or may have milder phenotypic consequences. Although repeat expansions larger than 25 repeats always cause CCHS evident in infancy, repeat expansions smaller than 25 repeats have not been identified in association with CCHS, and it is likely that such small expansions do not impair function of PHOX2B enough to cause disease. The variable clinical penetrance associated with the 25-repeat mutation thus reflects the molecular effect of this mutation, which operates near the threshold of PHOX2B impairment necessary to result in disease. Three of the adults described in this report have two affected children each, consistent with the expected autosomal dominant inheritance pattern for CCHS (3). Given the possibility of incomplete and variable penetrance and subtle to moderate clinical symptoms in adults carrying the 25-repeat mutation, it would be advised that parents of any CCHS proband with a 25-repeat mutation have PHOX2B testing performed, both for counseling regarding recurrence of the condition in future children and because the parent carrier may have undiagnosed symptoms of alveolar hypoventilation requiring evaluation and intervention. There is a range of presentation associated with the 25-repeat expansion mutation, which extends from the newborn period to adulthood, raising the possibility that some individuals may remain asymptomatic throughout life. The explanation for this is not clear but most likely involves genetic modifiers or environmental cofactors acting in concert with a level of PHOX2B impairment balanced at the threshold for disease, such that an acute stressor or even aging could result in decompensation and symptomatic presentation. In summary, we believe there are likely to be many other adults with the PHOX2B 20/25 genotype who are yet to be diagnosed with CCHS. Through increased awareness, the diagnosis of these adults and of parents of children with the 20/25 genotype can be expedited. Through prompt intervention with noninvasive nasal mask ventilation during sleep, and comprehensive follow-up as provided to children with CCHS, further physiologic compromise can be prevented.
The authors thank Dr. Kay Metcalfe and Dr. Ian Ballin for their involvement in Case 5, and all unnamed physicians who helped to identify the five cases.
Originally Published in Press as DOI: 10.1164/rccm.200605-607CR on July 27, 2006 Conflict of Interest Statement: N.A.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.A.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. N.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.D.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.L.O. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.T. has received a research grant from Pfizer for a clinical trial to be conducted on the early diagnosis of chronic obstructive pulmonary disease, and has also received $3,500 for lectures at meetings sponsored by various pharmaceutical companies (GlaxoSmithKline, AstraZeneca, Pfizer). W.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.A.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.M.B.-K. donated the patent for the PHOX2B assay to the Chicago Community Trust and has not received any income from this patent. D.E.W.-M. donated the patent for the PHOX2B assay to the Chicago Community Trust and has not received any income from this patent. Received in original form May 4, 2006; accepted in final form July 27, 2006
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