Debra E Weese-Mayer

Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United States

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Publications (160)558.49 Total impact

  • Sleep Medicine Clinics 09/2014; 9(3):425-439.
  • Casey M. Rand, Michael S. Carroll, Debra E. Weese-Mayer
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    ABSTRACT: Congenital central hypoventilation syndrome (CCHS), a rare neurocristopathy with disordered respiratory control, is characterized by alveolar hypoventilation and diffuse autonomic nervous system (ANS) dysregulation. Mutations in the paired-like homeobox 2B (PHOX2B) are causative, leading to physiologic ANS dysregulation and pathologic abnormalities. Presentation is typically during the newborn period with alveolar hypoventilation during sleep, or in more severely affected individuals, during sleep and wakefulness. Breathing complications occur despite the lungs and airways being normal. Disordered respiratory control demonstrated by absent or severely attenuated ventilatory, behavioral, and arousal responses to both endogenous and exogenous hypoxemia and hypercarbia results in severe physiologic compromise.
    Clinics in Chest Medicine. 01/2014;
  • Sleep Medicine Clinics 01/2014;
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    ABSTRACT: Congenital central hypoventilation syndrome is a neurodevelopmental disorder characterized by life-threatening hypoventilation, possibly resulting from disruption of central chemosensory integration. However, animal models suggest the possibility of residual chemosensory function in the human disease. Cardioventilatory function in a large cohort with congenital central hypoventilation syndrome and verified paired-like homeobox 2B (PHOX2B) mutations was assessed to determine the extent and genotype-dependence of any residual chemosensory function in these patients. As part of inpatient clinical care and evaluation, 64 distinct studies from 32 infants, children and young adults with the disorder were evaluated for physiological response to 3 different inspired steady-state gas exposures of 3 minutes each: hyperoxia (100% O2); hyperoxic hypercapnia (95% O2 and 5% CO2); hypoxic hypercapnia (14% O2, 7% CO2, balanced with N2). These were followed by a hypoxia challenge consisting of 5 or 7 breaths of nitrogen (100% N2). In addition, a control group of 15 young adults was exposed to all but the hypoxic challenge. Comprehensive monitoring was used to derive breath-to-breath and beat-to-beat measures of ventilatory, cardiovascular and cerebrovascular function. On average, patients showed residual awake ventilatory response to chemosensory challenge independent of the specific patient PHOX2B genotype. Graded dysfunction in cardiovascular regulation was found to associate with genotype, suggesting differential effects on different autonomic subsystems. In addition, differences between cases and controls in cerebrovascular response to chemosensory challenge may indicate alterations in cerebral autoregulation. Thus, residual cardiorespiratory responses suggest partial preservation of central nervous system networks that could provide a fulcrum for potential pharmacological interventions.
    Journal of Applied Physiology 12/2013; · 3.43 Impact Factor
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    ABSTRACT: Stress peptide, pituitary adenylate cyclase activating polypeptide (PACAP), has been implicated in sudden infant death syndrome (SIDS). The aim of this exploratory study was to determine whether variants in the gene encoding the PACAP-specific receptor, PAC1, are associated with SIDS in Caucasian and African-American infants. Polymerase chain reaction and Sanger DNA sequencing was used to compare variants in the 5'-untranslated region, exons and intron-exon boundaries of the PAC1 gene in 96 SIDS cases and 96 race- and gender-matched controls. The intron 3 variant, A/G: rs758995 (variant 'h'), and the intron 6 variant, C/T: rs10081254 (variant 'n'), were significantly associated with SIDS in Caucasians and African-Americans, respectively (p<0.05). Also associated with SIDS were interactions between the variants rs2302475 (variant 'i') in PAC1 and rs8192597 and rs2856966 in PACAP among Caucasians (p<0.02) and rs2267734 (variant 'q') in PAC1 and rs1893154 in PACAP among African-Americans (p<0.01). However none of these differences survived post hoc analysis. Overall, this study does not support a strong association between variants in the PAC1 gene and SIDS, however, a number of potential associations between race-specific variants and SIDS were identified that warrant targeted investigations in future studies. Keywords: genetic variants, PAC1 receptor, pituitary adenylate cyclase activating polypeptide, sudden infant death syndrome This article is protected by copyright. All rights reserved.
    Acta Paediatrica 08/2013; · 1.97 Impact Factor
  • Debra E Weese-Mayer, Casey M Rand, Diego Ize-Ludlow
    Journal of the Canadian Academy of Child and Adolescent Psychiatry = Journal de l'Academie canadienne de psychiatrie de l'enfant et de l'adolescent 08/2013; 22(3):238-9.
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    ABSTRACT: Long considered a rare and unique disorder of respiratory control, congenital central hypoventilation syndrome has recently been further distinguished as a disorder of autonomic regulation. Similarly, more recent evidence suggests that sudden infant death syndrome is also a disorder of autonomic regulation. Congenital central hypoventilation syndrome typically presents in the newborn period with alveolar hypoventilation, symptoms of autonomic dysregulation and, in a subset of cases, Hirschsprung disease or tumors of neural crest origin or both. Genetic investigation identified PHOX2B, a crucial gene during early autonomic development, as disease defining for congenital central hypoventilation syndrome. Although sudden infant death syndrome is most likely defined by complex multifactorial genetic and environmental interactions, it is also thought to result from central deficits in the control of breathing and autonomic regulation. The purpose of this article is to review the current understanding of these autonomic disorders and discuss the influence of this information on clinical practice and future research directions.
    Seminars in pediatric neurology 03/2013; 20(1):44-55.
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    ABSTRACT: Down syndrome (DS) is recognized by characteristic facial features, intellectual disability, and an increased risk for cardiac malformations and duodenal atresia. Recently, Hirschsprung disease (HSCR), or congenital aganglionic megacolon, has been seen more often among patients with DS. Given the systemic nature of DS-related features, it is natural to attribute neonatal complications to the chromosomal aberration. We describe a biracial male infant with DS who had significantly delayed defecation and required continuous ventilator support, but had no primary cardiac or lung disease. Subsequent evaluations confirmed total colonic aganglionosis. Because we were unable to safely extubate the infant, a diagnosis of congenital central hypoventilation syndrome (CCHS) was considered and confirmed by molecular analysis of the PHOX2B gene, revealing a heterozygous polyalanine repeat-expansion mutation containing 27 repeats (normal gene contains 20 repeats). HSCR coexisting with CCHS is known as Haddad syndrome. This is the first reported case with co-occurrence of DS, CCHS, and HSCR.
    PEDIATRICS 10/2012; · 5.30 Impact Factor
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    ABSTRACT: Congenital central hypoventilation syndrome (CCHS), a rare disorder characterized by alveolar hypoventilation and autonomic dysregulation, is caused by mutations in the PHOX2B gene. Most mutations occur de novo, but recent evidence suggests that up to 25% are inherited from asymptomatic parents with somatic mosaicism for these mutations. However, to date, germline mosaicism has not been reported. This report describes a family with recurrence of PHOX2B mutation-confirmed CCHS due to germline mosaicism. The first occurrence was a baby girl, noted on day 2 of life to have multiple episodes of apnea, bradycardia, and cyanosis while breathing room air. PHOX2B gene testing confirmed the diagnosis of CCHS with a heterozygous polyalanine repeat expansion mutation (PARM); genotype 20/27 (normal 20/20). Both parents tested negative for this mutation using fragment analysis (limit of detection<1%). Upon subsequent pregnancy [paternity confirmed using short tandem repeat (STR) analysis], amniocentesis testing identified the PHOX2B 20/27 genotype, confirmed with repeat testing. Elective abortion was performed at 21.5 weeks gestation. Testing of abortus tissue confirmed amniocentesis testing. The PHOX2B 20/27 expansion was not observed in a paternal sperm sample. This case represents the first reported family with recurrence of PHOX2B mutation-confirmed CCHS without detection of a parental carrier state or mosaicism, confirming the previously hypothesized possibility of germline mosaicism for PHOX2B mutations. This is an important finding for genetic counseling of CCHS families, suggesting that even if somatic mosaicism is not detected in parental samples, there is still reason for careful genetic counseling and consideration of prenatal testing during subsequent pregnancies.
    American Journal of Medical Genetics Part A 07/2012; 158A(9):2297-301. · 2.30 Impact Factor
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    ABSTRACT: The study aims were twofold: 1) identify the localization and the cytoarchitecture of the retrotrapezoid nucleus (RTN) in the human fetus and infant and 2) ascertain if the RTN, given its essential role in animal studies for the maintenance of breathing and chemoreception, showed abnormalities in victims of sudden perinatal and infant death (sudden intrauterine unexplained death/SIUD - and sudden infant death syndrome/SIDS). We examined SIDS and SIUD cases and Controls (n=58) from 34 gestational weeks to 8 months of postnatal age by complete autopsy, in-depth autonomic nervous system histological examination, and immunohistochemical analysis of the PHOX2B gene, a transcriptional factor involved in Congenital Central Hypoventilation Syndrome that has been defined as a marker of rat RTN neurons. We identified a group of PHOX2B-immunopositive neurons within the caudal pons, contiguous to the facial/parafacial complex, in 90% of Controls, likely the homologous human RTN (hRTN). We observed structural and/or PHOX2B-expression abnormalities of the hRTN in 71% of SIUD/SIDS cases vs 10% of Controls (p<0.05). In conclusion we suggest that developmental abnormalities of the hRTN may seriously compromise chemoreception control, playing a critical role in the pathogenesis of both SIUD and SIDS.
    Autonomic neuroscience: basic & clinical 07/2012; 170(1-2):12-9. · 1.82 Impact Factor
  • Casey M Rand, Debra E Weese-Mayer
    Journal of Human Genetics 05/2012; 57(6):345-6. · 2.53 Impact Factor
  • American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
  • American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
  • American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Congenital central hypoventilation syndrome (CCHS) is characterized by alveolar hypoventilation, autonomic nervous system (ANS) dysregulation (ANSD), and mutations in the paired-like homeobox 2B (PHOX2B) gene. ANSD in CCHS affects multiple systems and includes ophthalmologic abnormalities. We hypothesized that quantitative pupil measures, obtained using pupillometry, would vary between cases with CCHS and controls and within those with CCHS by PHOX2B genotype. Measures known to be illustrative of sympathetic and parasympathetic response (prestimulus, maximum pupil diameter, percentage of pupil constriction after light stimulus, and average constriction and dilation velocities) were significantly reduced in those with CCHS as compared with controls (all P < 0.05). These reductions are indicative of both sympathetic and parasympathetic deficits in CCHS, which is in keeping with the role of PHOX2B in ANS development. An inverse linear relationship was apparent in pupil diameter and velocity measurements among the cases with CCHS with the most common heterozygous PHOX2B polyalanine expansion repeat mutations, suggesting a graded phenotype/genotype dose response based on polyalanine repeat length. These results confirm our central hypotheses while offering the first objective measures of pupillary dysfunction and ophthalmologic-specific ANSD in CCHS. A total of 316 monocular measurements were taken under dark-adapted conditions with a fixed light stimulus from 22 PHOX2B mutation-confirmed cases with CCHS and 68 healthy controls.
    Pediatric Research 03/2012; 71(3):280-5. · 2.84 Impact Factor
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    ABSTRACT: Familial dysautonomia (FD) is a profound sensory and autonomic nervous system disorder associated with an increased risk for sudden death. While bradycardia resulting from loss of sympathetic tone has been hypothesized to play a role in this mortality, extended in-home monitoring has failed to find evidence of low heart rates in children with FD. In order to better characterize the specific cardio-respiratory pathophysiology and autonomic dysregulation in patients with FD, 25 affected children and matched controls were studied with in-home technology, during day and night. Respiratory and heart rate timing and variability metrics were derived from inductance plethysmography and electrocardiogram signals. Selective shortening of inspiratory time produced an overall increase in respiratory frequency in children with FD, with higher daytime respiratory variability (vs. controls), suggesting alterations in central rhythm generating circuits that may contribute to the heightened risk for sudden death. Overall heart rate was increased and variability reduced in FD cases, with elevated heart rates during 20% of study time. Time and frequency domain measures of autonomic tone indicated lower parasympathetic drive in FD patients (vs. controls). These results suggest withdrawal of vagal, rather than sympathetic tone, as a cause for the sustained increase and dramatic lability in respiration and heart rates that characterize this disorder.
    Pediatric Pulmonology 12/2011; 47(7):682-91. · 2.38 Impact Factor
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    ABSTRACT: Clinical testing for PHOX2B mutations is widely used for patients with any symptoms suggestive of hypoventilation (with/without anatomic/physiologic autonomic dysregulation), though not necessarily with the congenital central hypoventilation syndrome (CCHS) phenotype. Consequently, a multitude of referrals for clinical PHOX2B testing (fragment analysis of the 20 polyalanine repeat region and/or sequencing of entire coding region) have no identifiable mutation. Whole gene deletions/duplications have recently been identified as a common disease-causing mechanism, but have not been reported in a clinical population referred for PHOX2B testing. The objective of this study was to determine if PHOX2B exon or whole gene deletion/duplication would be identified in a subset of patients referred for PHOX2B testing. We hypothesized that PHOX2B exon or whole gene deletion or duplication would be identified in a subset of cases who were referred for genetic testing but not found to have a PHOX2B mutation with currently available clinical PHOX2B testing. Genomic DNA samples from patients that tested negative for PHOX2B mutations using fragment analysis and/or sequencing, and control samples, were screened for PHOX2B exon deletions/duplications by multiplex ligation-dependent probe amplification with confirmation by array comparative genomic hybridization. Deletions of/in PHOX2B were identified in 4/250 patients and 0/261 controls. The deletions ranged from 6,216 base pairs (involving only PHOX2B exon 3) to 2.6 megabases (involving all of PHOX2B and 12 other genes). The case with PHOX2B partial exon 3 deletion had a CCHS-compatible phenotype (hypoventilation, Hirschsprung disease). Phenotypes for the other three cases, all PHOX2B whole-gene deletions, were varied including: (1) apparent life threatening event, (2) full CCHS necessitating artificial ventilation with ganglioneuroblastoma, and (3) hypoventilation during sleep. Family studies of two of the four probands showed these deletions to be maternally inherited; the mothers also had phenotypic findings of autonomic dysfunction. PHOX2B exon or whole gene deletion should be considered as another mechanism of disease which may include CCHS, Hirschsprung disease, and/or tumors of neural crest origin, although the genotype-phenotype relationship requires further clarification. Pediatr Pulmonol. 2012; 47:153-161. © 2011 Wiley Periodicals, Inc.
    Pediatric Pulmonology 08/2011; 47(2):153-61. · 2.38 Impact Factor
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    ABSTRACT: Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) falls within a group of pediatric disorders with both respiratory control and autonomic nervous system dysregulation. Children with ROHHAD typically present after 1.5 years of age with rapid weight gain as the initial sign. Subsequently, they develop alveolar hypoventilation, autonomic nervous system dysregulation, and, if untreated, cardiorespiratory arrest. To our knowledge, this is the first report of discordant presentation of ROHHAD in monozygotic twins. Twin girls, born at term, had concordant growth and development until 8 years of age. From 8 to 12 years of age, the affected twin developed features characteristic of ROHHAD including obesity, alveolar hypoventilation, scoliosis, hypothalamic dysfunction (central diabetes insipidus, hypothyroidism, premature pubarche, and growth hormone deficiency), right paraspinal/thoracic ganglioneuroblastoma, seizures, and autonomic dysregulation including altered pain perception, large and sluggishly reactive pupils, hypothermia, and profound bradycardia that required a cardiac pacemaker. Results of genetic testing for PHOX2B (congenital central hypoventilation syndrome disease-defining gene) mutations were negative. With early recognition and conservative management, the affected twin had excellent neurocognitive outcome that matched that of the unaffected twin. The unaffected twin demonstrated rapid weight gain later in age but not development of signs/symptoms consistent with ROHHAD. This discordant twin pair demonstrates key features of ROHHAD including the importance of early recognition (especially hypoventilation), complexity of signs/symptoms and clinical course, and importance of initiating comprehensive, multispecialty care. These cases confound the hypothesis of a monogenic etiology for ROHHAD and indicate alternative etiologies including autoimmune or epigenetic phenomenon or a combination of genetic predisposition and acquired precipitant.
    PEDIATRICS 08/2011; 128(3):e711-5. · 5.30 Impact Factor
  • Source
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    ABSTRACT: Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is a rare and complex pediatric disorder. Despite increased identification and advancing knowledge of the disease course, the variable onset and timing of phenotypic features in ROHHAD often result in delayed or missed diagnosis, potentially leading to fatal central hypoventilation, cardiorespiratory arrest, and impaired neurocognitive development. The 5-hydroxytryptamine receptor 1A (HTR1A), orthopedia (OTP), and pituitary adenylate cyclase activating polypeptide (PACAP) genes were targeted in the etiology of ROHHAD based on their roles in the embryologic development of the hypothalamus and autonomic nervous system. We hypothesized that variations of HTR1A, OTP, and/or PACAP would be associated with ROHHAD. All coding regions and intron-exon boundaries of the HTR1A, OTP, and PACAP genes, in addition to the promoter region of the HTR1A gene, were analyzed by standard sequencing in 25 ROHHAD cases and 25 matched controls. Thirteen variations, including six protein-changing mutations, were identified. None of these variations were significantly correlated with ROHHAD. This report provides evidence that variation of the HTR1A, OTP, and PACAP genes are not responsible for ROHHAD. These results represent a further step in the investigation of the genetic determinants of ROHHAD.
    Pediatric Research 06/2011; 70(4):375-8. · 2.84 Impact Factor
  • American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011

Publication Stats

4k Citations
558.49 Total Impact Points


  • 2012–2014
    • Ann & Robert H. Lurie Children's Hospital of Chicago
      Chicago, Illinois, United States
    • Children's Memorial Medical Center
      Chicago, Illinois, United States
  • 1987–2012
    • Children's Memorial Hospital
      Chicago, Illinois, United States
  • 1992–2011
    • Rush Medical College
      Chicago, Illinois, United States
  • 1990–2010
    • Northwestern University
      • • Department of Pediatrics
      • • Feinberg School of Medicine
      Evanston, IL, United States
    • McGill University
      • Faculty of Medicine
      Montréal, Quebec, Canada
  • 1991–2009
    • Rush University Medical Center
      • • Department of Pediatrics
      • • Department of Neurological Sciences
      Chicago, Illinois, United States
  • 2008
    • University of Desarrollo
      • Human Genetics Centre
      CiudadSantiago, Santiago, Chile
  • 2007
    • Vanderbilt University
      • Division of Clinical Pharmacology
      Nashville, MI, United States
  • 2001–2007
    • University of Pittsburgh
      • • Department of Pediatrics
      • • School of Dental Medicine
      Pittsburgh, PA, United States
  • 2006
    • Repatriation General Hospital
      Tarndarnya, South Australia, Australia
    • New York University
      New York City, New York, United States
  • 2005
    • University of Southern California
      • Department of Pediatrics
      Los Angeles, CA, United States
  • 2003
    • Children's National Medical Center
      • Division of General and Community Pediatrics
      Washington, Washington, D.C., United States
  • 1990–2003
    • University of Chicago
      • Department of Pediatrics
      Chicago, Illinois, United States
  • 1996
    • Case Western Reserve University
      • Department of Genetics and Genome Sciences
      Cleveland, OH, United States