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Volume 13 No. 08
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Case Reports

A Case of “Abnormally Abnormal” Hypoxic Ventilatory Responses: A Novel NPARM PHOX 2B Gene Mutation

Stefan A. Unger, PhD, MRCPCH1,2; Maude Guillot, MBChB1; Donald S. Urquhart, MD, FRCPCH1,2
1Department of Respiratory and Sleep Medicine, Royal Hospital for Sick Children Edinburgh, Edinburgh, United Kingdom; 2University of Edinburgh, Department of Child Life and Health, Edinburgh, United Kingdom


Congenital central hypoventilation syndrome (CCHS) is a rare disorder associated with dysregulation of the autonomic ventilatory response to hypoxia and hypercarbia usually caused by polyalanine repeat expansion mutations in the PHOX 2B gene. Non-polyalanine repeat mutations (NPARM) represent approximately 10% of cases, and usually require continuous ventilation during sleep, although our knowledge of disease progression is limited. Here we present a case with a novel NPARM CCHS mutation associated with a premature stop codon for the PHOX 2B protein. Despite the type of the mutation, patient management with supplementary oxygen has been sufficient. Experience from our case may help when counseling parents.


Unger SA, Guillot M, Urquhart DS. A case of “abnormally abnormal” hypoxic ventilatory responses: a novel NPARM PHOX 2B gene mutation. J Clin Sleep Med. 2017;13(8):1013–1015.


Congenital central hypoventilation syndrome (CCHS) is a rare disorder associated with a failure in the autonomic ventilatory response to hypoxia and hypercarbia and usually presents in the neonatal period with features of hypoventilation.1


We report the case of a patient born at term by emergency cesarean section as a result of pregnancy-induced hypertension. There were no immediate postnatal complications but the baby subsequently had three dusky episodes on the maternity ward, associated with feeding and vomiting after feeding. He continued to struggle with feedings in the neonatal unit, and was unable to tolerate more than 10 mL at a time. On the patient's second day of life, bilious emesis developed and was associated with abdominal distension and delayed passage of meconium.

The patient's care was transferred to the surgical team. His initial barium enema results showed a large-caliber rectum and distal colon with prominent filling defects throughout the large bowel. A significant quantity of meconium was passed immediately after rectal examination, and the abdominal distension was thought to be the result of a retained meconium plug. Unfortunately, the patient's stool pattern remained irregular and was associated with episodic vomiting. He underwent rectal biopsy, which confirmed Hirschsprung disease, and was discharged from the hospital with a plan for daily rectal washouts.

During surgical admission the patient was noted to have several mild episodes of desaturations in room air during sleep. A sleep study revealed central apneas associated with decreases in arterial oxygen saturation measured by pulse oximetry (SpO2) to the low 90s, and these decreases were at the time believed to be consistent with an immature breathing pattern. There was no evidence of hypoventilation; pCO2 (5.5 kPa) measured on blood gas testing was normal. Chest x-ray, electrocardiography, and four-limb blood pressures were also normal. Supplemental oxygen was started at 0.2 L/min via nasal cannulae with restoration of normoxemia, and the baby was discharged from the hospital.

A repeat sleep study at 2 months of age showed persistent central apneas during sleep in air and in 0.2 L/min of oxygen with no desaturation while the patient was awake. Oxygen supplementation was titrated to 0.3 L/min to obliterate events. Genetic analysis included blood tests for Prader-Willi syndrome and myotonic dystrophy, and the PHOX 2B CCHS mutation study was performed. A sleep study was repeated at 5 months of age, which again demonstrated persistent central apneas even in oxygen. Caffeine injections were started and oxygen supplementation was increased to 0.5 L/min.

From a surgical standpoint the patient continued to require regular rectal washouts. At 6 months of age he had a proximal bowel pull-through (Soave procedure) after it was discovered intraoperatively that the agangliosis extended up to the splenic flexure. He made a good recovery and is currently stable on laxatives with regular surgical follow-up.

Results from the patient's genetic studies were initially negative for classic CCHS, with normal numbers of polyalanine repeats within the PHOX 2B region of chromosome 7 on each allele (20/20). However, subsequent analysis showed a nonpolyalanine repeat mutation (NPARM) with a deletion at position 481 on exon 3 within this homeobox gene not previously described. The position of the deletion would be associated with a premature stop codon and as a consequence, halt the production of the PHOX 2B protein. Hence, this NPARM mutation was expected to lead to alterations in respiratory control with central apneas and abnormal respiratory drive.

Sleep studies were arranged initially at 3-month intervals, then 6-month intervals, with a low threshold for commencing noninvasive ventilation should the patient's respiratory control deteriorate. However, the patient continues to be stable in 0.5 L/min of oxygen with only a mild increase in CO2 (Figure 1). Central apneas continued when in air during sleep. Caffeine injection was stopped at 22 months of age. The patient has remained well, with adequate growth and development.

Excerpts from a cardiorespiratory sleep study in room air and 0.5 L/min nasal cannulae oxygen.

A slight rise in average pCO2 in 0.5 L/min was noted. CO2 = transcutaneous carbon dioxide, ECG = echocardiograph, Ext. Po = sleeping position of patient, Flow Th = thermistor flow signal, RIP Abdomen = abdomen effort belt, RIP Thorax = thorax effort belt, SPO2 = pulse oximetry.


Figure 1

Excerpts from a cardiorespiratory sleep study in room air and 0.5 L/min nasal cannulae oxygen.

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Because of the comorbidities associated with CCHS, our patient has required a variety of regular investigations as part of disease surveillance. These include: 6-monthly abdominal ultrasonography until age 7 years with urinary catecholamine testing, annual 72-hour Holter cardiac monitoring and echo-cardiograms, neurocognitive assessments, and ophthalmologic review. Thus far, these investigations have been satisfactory.


CCHS is known to result from polyalanine repeat expansion mutations in the paired-like homeobox PHOX 2B gene, located on the chromosome 4p12, in more than 90% of cases.2 In the remaining 10% there is a non-polyalanine mutation that includes missense, nonsense, and frameshift types in the PHOX 2B gene. A relationship between genotype for polyalanine repeat mutations (PARM) and the need for ventilatory support exists, especially for those with a 20/25 repeat mutation.3 In contrast, more than 67% of NPARM mutations reported thus far require continuous ventilatory support.1,4 Almost all NPARMs are located at the 3′ end of exon 2 or in exon 3, with the mutation in our case situated at a different location and no requirement for continuous ventilatory support to this point apart from supplemental oxygen during sleep.

CCHS is also associated with cardiac conduction abnormalities and other manifestations of neurocristopathy, such as Hirschsprung disease and tumors of neural crest origin, including neuroblastomas, ganglioneuromas, and ganglioneuroblastomas.1,5 It has been shown that there is a higher incidence of neural crest tumors and Hirschsprung disease in NPARM mutations.4 Whereas up to 80% of cases with NPARM CCHS have a history of Hirschsprung disease, only 2% overall of those with the Hirschsprung disease have a type of CCHS.1

NPARM CCHS is a rare condition and our understanding of disease progression is limited as demonstrated by our case. Despite a mutation related to a premature stop codon for the PHOX 2B gene, our patient shows limited signs of hypoventilation and remains stable in nasal cannula oxygen only during sleep. This case report may help provide more information to parents during counseling in the neonatal period with regard to the spectrum of existing disease patterns. The question regarding the longitudinal evolution of this case remains unanswered and close follow-up is required.


Work for this study was performed at the Department of Respiratory and Sleep Medicine, Royal Hospital for Sick Children Edinburgh, Sciennes Road, Edinburgh, EH9 1LF. All authors have written, seen, and approved the manuscript. All authors declare no conflicts of interest. There was no financial support for this case study. The guardian of the patient described has provided written consent for the publication of this case report.


The authors thank the family for providing consent to publish this case report. We thank Professor Cunningham, Dr. Marshall, Dr. McDougall, and Dr. MacLeod who were involved in the management of this patient. We also thank Laura Hill and David Fynn (Respiratory Physiology Laboratory) for their help with the figure.



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Amiel J, Laudier B, Attie-Bitach T, et al. Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet. 2003;33(4):459–461. [PubMed]


Matera I, Bachetti T, Puppo F, et al. PHOX2B mutations and polyalanine expansions correlate with the severity of the respiratory phenotype and associated symptoms in both congenital and late onset central hypoventilation syndrome. J Med Genet. 2004;41(5):373–380. [PubMed Central][PubMed]


Berry-Kravis EM, Zhou L, Rand CM, Weese-Mayer DE. Congenital central hypoventilation syndrome: PHOX2B mutations and phenotype. Am J Respir Crit Care Med. 2006;174(10):1139–1344. [PubMed]


Gronli JO, Santucci BA, Leurgans SE, Berry-Kravis EM, Weese-Mayer DE. Congenital central hypoventilation syndrome: PHOX2B genotype determines risk for sudden death. Pediatr Pulmonol. 2008;43(1):77–86. [PubMed]