Upcoming Website Maintenance Notification

On Sunday October 20th, 2019 from 5:00 am cst to 8:00 am cst there will be approximately 3 hours of scheduled downtime while we make upgrades to our servers. During this time-window the JCSM website will be unavailable. Thank you for your patience.


Issue Navigator

Volume 13 No. 07
Earn CME
Accepted Papers

Case Reports

Three-Generation Family With Congenital Central Hypoventilation Syndrome and Novel PHOX2B Gene Non-Polyalanine Repeat Mutation

Ajay S. Kasi, MD1; Taryn J. Jurgensen, BA1; Stephanie Yen, MD2; Sheila S. Kun, RN, MS1; Thomas G. Keens, MD1,2; Iris A. Perez, MD1,2
1Division of Pediatric Pulmonology and Sleep Medicine, Children's Hospital Los Angeles, Los Angeles, California; 2Keck School of Medicine of the University of Southern California, Los Angeles, California


PHOX2B non-polyalanine repeat mutation (NPARM) in patients with congenital central hypoventilation syndrome (CCHS) is generally considered to be associated with full-time ventilator dependence and severe autonomic nervous system dysfunction. We report a three-generation family with four individuals possessing a novel PHOX2B NPARM (c.245C > T) with variable phenotypes. This mutation was inherited in an autosomal dominant pattern with variable penetrance. The affected family members with CCHS have a milder phenotype than is typically expected with a NPARM. Two family members are ventilator dependent only during sleep and do not have Hirschsprung disease or neural crest tumors. One family member was asymptomatic until systemic hypertension developed during adulthood and another family member remains asymptomatic as an adult. Our findings emphasize the importance of monitoring adults with a PHOX2B NPARM who are considered asymptomatic in childhood.


Kasi AS, Jurgensen TJ, Yen S, Kun SS, Keens TG, Perez IA. Three-generation family with congenital central hypoventilation syndrome and novel PHOX2B gene non-polyalanine repeat mutation. J Clin Sleep Med. 2017;13(7):925–927.


Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder of the autonomic nervous system caused by a mutation in the PHOX2B gene. Most patients with CCHS (90%) have a polyalanine repeat mutation (PARM) in the PHOX2B gene in the range of 24 to 33 repeats. Approximately 10% of patients have a non-polyalanine repeat mutation (NPARM) in the PHOX2B gene, which is generally reported to be associated with a more severe phenotype.1 Only a few familial cases of CCHS with confirmed PHOX2B gene mutations have been previously reported in the literature,27 only two of which involve the PHOX2B NPARM mutation.4,5 In these two familial cases, Hirschsprung disease as well as respiratory control symptoms were prominent.

We report a three-generation family with four individuals possessing a novel PHOX2B NPARM (c.245C > T) who have variable, less severe phenotypes.


The patient in the index case, II:7 (Figure 1), 31 years of age at the time of this writing, was born at term by cesarean section. She was asymptomatic at birth but at 2 weeks of age, she became dusky, apneic, and difficult to arouse. She required cardiopulmonary resuscitation and was hospitalized. After extensive inpatient evaluation, the clinical diagnosis of CCHS was made. There was no family history of respiratory or cardiac disease. She was initially treated with doxapram, a respiratory stimulant that seemed effective, and the patient was discharged home at 3 months of age on this medication. However, she had recurrent apneic events and at 4 months of age, she returned to the hospital where mechanical-assisted ventilation was initiated and a tracheostomy was performed. She was discharged home at 6 months of age on positive pressure ventilation (PPV) via tracheostomy only during sleep. She was able to sustain adequate ventilation spontaneously while awake.

Novel PHOX2B NPARM c.245C > T in a three-generation family with CCHS.

CCHS = congenital central hypoventilation syndrome, NPARM = non-polyalanine repeat mutation.


Figure 1

Novel PHOX2B NPARM c.245C > T in a three-generation family with CCHS.

(more ...)

Subsequently, she did not require hospitalization until 18 years of age, when she had several episodes of vomiting and dehydration. This was thought to be a manifestation of autonomic dysfunction. Strabismus developed, but the condition resolved without surgical therapy. Periodic Holter monitoring and echocardiograms were normal. The patient did not have Hirschsprung disease. At 21 years of age, she was noted to have bradycardia during sleep and even during wakefulness. Palpitations and dizziness with exercise developed in this patient. Holter monitoring showed bradycardia and sinus pauses, and a cardiac pacemaker was implanted at 22 years of age. Later that year, PHOX2B gene mutation analysis showed a novel variant, c.245C > T (p.P82L), a missense mutation in exon 2, confirming the diagnosis of CCHS. She continues to use PPV via tracheostomy only during sleep. Periodic imaging throughout her life has not revealed neural crest tumors.

III:6, the niece of the patient described in the index case, 5 years of age at the time of this writing, had respiratory distress at birth following a term cesarean section. She had severe apnea, bradycardia, and hypoxemia in the neonatal intensive care unit that required intubation and mechanical ventilation. Blood gas showed partial pressure of carbon dioxide of 89 mm Hg. She had three episodes of supraventricular tachycardia, one of which required adenosine. Echocardiogram showed a small patent foramen ovale. She had emesis after feedings and gastroesophageal reflux disease requiring medical therapy was diagnosed. It was initially thought that CCHS was an unlikely diagnosis because her mother (II:5) was healthy. However, PHOX2B gene mutation analysis was requested by her mother because of a family history of CCHS. CCHS was diagnosed at 2 months of age when PHOX2B gene mutation analysis showed the same NPARM, c.245C > T, as II:7. Tracheostomy was performed and she was discharged home on full-time PPV the following month. At 1 year of age, she was weaned to PPV via tracheostomy only during sleep. However, during illness, she requires full-time ventilatory support. She does not have strabismus, Hirschsprung disease, or neural crest tumors. Recent echocardiogram and Holter monitoring results were normal.

Following the diagnosis of CCHS in III:6, her mother, II:5, was tested for the PHOX2B gene mutation at 33 years of age. Even though she did not report any symptoms, her PHOX2B gene mutation analysis showed the same NPARM, c.245C > T, as both II:7 and III:6. Quantitative polymerase chain reaction reported the mutant allele burden to be 50% and that the lack of symptoms was not caused by low-level mosaicism. Polysomnogram did not show any apnea or hypoxemia. However, capnography was not performed during the study. Echocardiogram and Holter monitoring tests were normal. Systemic hypertension requiring medication later developed at 36 years of age. Blood tests showed elevated serum bicarbonate of 33 mEq/L. She has been referred to a pulmonologist for further testing.

Following the diagnosis of II:5, PHOX2B gene mutation analysis was performed on I:2 (mother of the index case) at 65 years of age. Even though she did not report any respiratory or sleep issues, she was positive for the same NPARM, c.245C > T, as II:5, II:7 and III:6. Quantitative polymerase chain reaction reported the mutant allele burden to be 16.7%, indicating that approximately 33% of the nucleated peripheral blood cells were heterozygous for this mutation. The lack of phenotypic findings was attributed to low-level mosaicism, which is strong evidence that this mutation first occurred in this patient. Subsequently, echocardiogram and Holter monitoring were performed and results were normal. At 69 years of age, she was intubated for a hip surgery and recovered without any complications. She has been referred for a polysomnography.

The siblings of I:2 tested negative for PHOX2B gene mutations. II:2 and II:3 later tested negative for PHOX2B gene mutations as well.


This family demonstrates a novel PHOX2B gene NPARM, c.245C > T, in four individuals across three generations with highly variable phenotypes. The PHOX2B gene mutation c.245C > T is a missense mutation in exon 2. This mutation results in a cytosine to thymine substitution at nucleotide position 245, changing the amino acid at codon 82 from proline to leucine.

NPARMs (approximately 10% CCHS cases) include frame-shift, nonsense, and missense mutations. Most NPARMs occur de novo and have been reported to produce severe phenotypes with the need for continuous ventilatory support, Hirschsprung disease, and increased neural crest tumor risk.1 However, in this family, the affected individuals in whom CCHS was diagnosed (II:7 and III:6) have less severe phenotypes. They require ventilatory support only during sleep and do not have Hirschsprung disease or neural crest tumors. This suggests that the NPARM c.245C > T is associated with milder phenotypes. It is important to note that in II:7, cardiac rhythm abnormalities developed in her second decade of life, indicating that this mutation may cause delayed manifestations of autonomic dysfunction. This novel finding supports continued monitoring for cardiac dysrhythmia in CCHS adults with NPARM.

In this family, there is autosomal dominant inheritance, incomplete penetrance, and variability in phenotype. Previous reports also show autosomal dominant inheritance patterns and highly variable phenotypes in PHOX2B NPARMs.4,5 The first family member (I:2) with the NPARM c.245C > T is asymptomatic. This is most likely caused by low-level mosaicism. In II:5, the absence of characteristic CCHS phenotype is not due to low-level mosaicism but likely due to variable penetrance or expressivity. Our findings support the hypothesis that the phenotypic variability may be caused by unknown gene modifiers.5,8,9 Environmental factors may also play a role in the phenotypic variability.10

The late-onset elevated serum bicarbonate seen in II:5 demonstrates that asymptomatic individuals with PHOX2B gene mutations can develop symptoms later in life. Thus, asymptomatic individuals who are known to carry PHOX2B gene mutations should undergo continued observation for respiratory and cardiac disturbances.9

In summary, we report a novel PHOX2B NPARM, c.245C > T, in four family members across three generations with both increased variability and decreased severity in phenotype than previously reported patients with CCHS NPARM. Our study highlights the importance of screening family members of patients with CCHS for PHOX2B gene mutations as well as continued surveillance of asymptomatic individuals with documented PHOX2B gene mutation.


Work for this study was performed at Children's Hospital Los Angeles. All authors have reviewed and approved the manuscript. All authors have no conflicts of interest to disclose.


The authors thank Sally L. Davidson Ward, MD for her comments on the manuscript.



Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, Trang H. An official ATS clinical policy statement: congenital central hypoventilation syndrome - genetic basis, diagnosis, and management. Am J Respir Crit Care Med. 2010;181(6):626–644. [PubMed]


Chuen-im P, Marwan S, Carter J, Kemp J, Rivera-Spoljaric K. Heterozygous 24-polyalanine repeats in the PHOX2B gene with different manifestations across three generations. Pediatr Pulmonol. 2014;49(2):E13–E16. [PubMed]


Meguro T, Yoshida Y, Hayashi M, et al. Inheritance of polyalanine expansion mutation of PHOX2B in congenital central hypoventilation syndrome. J Hum Genet. 2012;57(5):335–337. [PubMed]


Bygarski E, Paterson M, Lemire EG. Extreme intra-familial variability of congenital central hypoventilation syndrome: a case series. J Med Case Rep. 2013;7:117. [PubMed Central][PubMed]


Low KJ, Turnbull AR, Smith KR, et al. A case of congenital central hypoventilation syndrome in a three-generation family with non-polyalanine repeat PHOX2B mutation. Pediatr Pulmonol. 2014;49(10):E140–E143. [PubMed]


Trivedi A, Waters K, Suresh S, Nair R. Congenital central hypoventilation syndrome: four families. Sleep Breath. 2011;15(4):785–789. [PubMed]


Klaskova E, Drabek J, Hobzova M, et al. Significant phenotype variability of congenital central hypoventilation syndrome in a family with polyalanine expansion mutation of the PHOX2B gene. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2016;160(4):495–498. [PubMed]


Trochet D, Mathieu Y, Pontual Ld, et al. In vitro studies of non poly alanine PHOX2B mutations argue against a loss-of-function mechanism for congenital central hypoventilation. Hum Mutat. 2009;30(2):E421–E431. [PubMed]


Trochet D, de Pontual L, Straus C, et al. PHOX2B germline and somatic mutations in late-onset central hypoventilation syndrome. Am J Respir Crit Care Med. 2008;177(8):906–911. [PubMed]


Amin R, Riekstins A, Al-Saleh S, Massicotte C, Coates AL, MacLusky I. Presentation and treatment of monozygotic twins with congenital central hypoventilation syndrome. Can Respir J. 2011;18(2):87–89. [PubMed Central][PubMed]