SPR Unknown #49 -- FINAL

Erin Happ

Midwestern University

Francis Prendergast



A 16 month old male with known Congenital Central Hypoventilation Syndrome and associated Hirschprungs presented to an outside hospital with seizure activity. At that time an MRI of the brain, abdomen and pelvis was performed. A large mass was found in the right upper abdomen, and biopsy was taken. Pathology confirmed neuroblastoma. CCHS is characterized by alveolar hypoventilation and autonomic dysregulation. PHOX2B gene mutation is required for diagnosis of CCHS. Normal genotype is 20/20 with multiple genotypes produced ranging from 20/24 to 20/33. Knowledge of the specific PHOX2B mutation can aid can predict disease severity and comorbidities.


1693, Congenital Central Hypoventilation Syndrome, Neuroblastoma, abdominal mass, PHOX2B gene, neural crest tumor spr unknown 49

Publication Date: 2011-03-29


16 month old male with known Congenital Central Hypoventilation Syndrome and associated Hirschprungs disease.


CT of the abdomen and pelvis reveals a large, heterogeneous right suprarenal mass with areas of calcification.


Neuroblastoma, associated with PHOX2B gene mutation in CCHS.




Congenital Central Hypoventilation Syndrome (also known as Ondine's Curse) is multisystem disorder of the central nervous system where, most dramatically, there is autonomic dysregulation of ventilation. A CCHS patient’s respiratory response to hypoxia and hypercapnea is sluggish during awake hours and absent to varying degrees during sleep, serious illness, and/or stress. These patients either require full ventilatory support, or at the least, night-time ventilatory support.

The PHOX2B gene mutation is required for the diagnosis of CCHS. Normal genotype is 20/20 with multiple polyalanine repeat expansion mutations (PARM)possible ranging from 20/24 to 20/33. CCHS is associated with a heterozygous expansion of the polyalanine-coding region to give 24-33 repeats. More rarely CCHS is caused by other heterozygous mutations in the coding sequence of PHOX2B, or nonpolyalanine repeat expansion mutations (NPARM). DNA from the tumor of this patient showed a 20/33 PARM.

Tumors of neural crest origin occur more frequently among the NPARM cases of CCHS (50%), and only occur in the PARM variety 1%. All NPARM neural crest tumors recorded to date have been neuroblastomas. More notable, only 20/29 and 20/33 PARM genotypes have been identified to have tumors of neural crest origin. According to one paper, only ganglioneuromas and ganglioneuroblastomas have been associated with the PARM genotypes mentioned above. This case would be the first time a neuroblastoma was associated with a PHOX2B gene PARM, and raises the question of how frequently CCHS patients should be screened for such tumors, and if screening should be based on genotype/mutation. Current recommendations only state that serial abdominal imaging should be performed, but at what time interval has yet to be determined. Of note, 20/24 and 20/28 genotypes have never been shown to be associated with tumors of neural crest origin, and thus the value of serial imaging in these patients is of unknown value. However, given that our patient had a novel association of 20/33 genotype association with neuroblastoma, perhaps more importance will be placed on serial imaging of all CCHS patients in the near future.


  1. Weese-Mayer, Debra E. et al. An Official ATS Clinical Policy Statement: Congenital Central Hypoventilation Syndrome Genetic basis, Diagnosis and Management. Am J Respir Crit Care Med 2010;181:626-644.
  2. Weese-Mayer, Debra E. Congenital Central Hypoventilation Syndrome. National Institutes of Health books. www.ncbi.nlm.nih.gov/books/NBK1427/
  3. Maris JM, et al. Neuroblastoma. Lancet 2007;369:2106-2120

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