Abstract
Congenital central hypoventilation syndrome (CCHS) is an autonomic nervous system dysfunction due to PHOX2B gene mutation. Little is known about gastrointestinal motility disorders in CCHS patients. This study aims to describe the spectrum of gastrointestinal motility disorders in CCHS and provide PHOX2B genotype-phenotype correlation with Hirschsprung Disease (HD). We reviewed the records of 72 CCHS patients seen at Children’s Hospital Los Angeles from 1999 to 2019. Data collected included demographics, PHOX2B genotype, ventilator dependence, medical and surgical history, and gastrointestinal motility studies. Of the 72 patients, 31% had HD, 50% females, and 60% had 20/27 PARM. Rectosigmoid HD formed 73% of the cases whereas long segment (up to splenic flexure involvement) forms represented 23%. Four patients had total colonic aganglionosis, including one patient with 20/25 PARM genotype. One HD patient was identified with colonic myopathy in the residual segment. One patient was found to have achalasia type 1.
Conclusion: Nearly one third of our CCHS patients had HD. Although most had 20/27 PARM, 2 patients had 20/25 PARM. Thus, CCHS patients with constipation are at risk for HD regardless of genotype. Colonic myopathy may coexist in treated HD with refractory constipation. Achalasia may occur in patients with CCHS.
What is Known: • Patients with CCHS have motility disorders and present with esophageal dysmotility and constipation as a manifestation of their autonomic nervous system dysfunction. • About 20% of patients with CCHS have Hirschsprung disease and previously described to be associated with NPARM and 20/27 PARM genotype. | |
What is New: • Thirty-one percent of CCHS patients in our series have Hirschsprung disease (HD). • HD, including the more severe total colonic aganglionosis was found in a patient with 20/25 PARM genotype suggesting that CCHS patients with constipation should be screened for HD regardless of genotype. |
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05 January 2021
A correction to this paper has been published: <ExternalRef><RefSource>https://doi.org/10.1007/s00431-020-03922-y</RefSource><RefTarget Address="10.1007/s00431-020-03922-y" TargetType="DOI"/></ExternalRef>
Abbreviations
- CCHS:
-
Congenital central hypoventilation syndrome
- HD:
-
Hirschsprung disease
References
Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, Trang H, ATS Congenital Central Hypoventilation Syndrome Subcommittee (2010) An official ATS clinical policy statement: congenital central hypoventilation syndrome: genetic basis, diagnosis, and management. Am J Respir Crit Care Med 181(6):626–644. https://doi.org/10.1164/rccm.200807-1069ST
Kapur RP (2000) Developmental disorders of the enteric nervous system. Gut 47(Suppl 4):iv81–iv87. https://doi.org/10.1136/gut.47.suppl_4.iv81
Butler Tjaden NE, Trainor PA (2013) The developmental etiology and pathogenesis of Hirschsprung disease. Transl Res: J Lab Clin Med 162(1):1–15. https://doi.org/10.1016/j.trsl.2013.03.001
Vanderlaan M, Holbrook CR, Wang M, Tuell A, Gozal D (2004) Epidemiologic survey of 196 patients with congenital central hypoventilation syndrome. Pediatr Pulmonol 37(3):217–229. https://doi.org/10.1002/ppul.10438
Trang H, Dehan M, Beaufils F, Zaccaria I, Amiel J, Gaultier C, French CCHS Working Group (2005) The French Congenital Central Hypoventilation Syndrome Registry: general data, phenotype, and genotype. Chest 127(1):72–79
Croaker GD, Shi E, Simpson E, Cartmill T, Cass DT (1998) Congenital central hypoventilation syndrome and Hirschsprung's disease. Arch Dis Child 78(4):316–322. https://doi.org/10.1136/adc.78.4.316
Haddad GG, Mazza NM, Defendini R, Blanc WA, Driscoll JM, Epstein MA, Epstein RA, Mellins RB (1978) Congenital failure of automatic control of ventilation, gastrointestinal motility and heart rate. Medicine 57(6):517–526. https://doi.org/10.1097/00005792-197811000-00003
Amiel J, Laudier B, Attié-Bitach T, Trang H, de Pontual L, Gener B, Trochet D, Etchevers H, Ray P, Simonneau M, Vekemans M, Munnich A, Gaultier C, Lyonnet S (2003) Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet 33(4):459–461. https://doi.org/10.1038/ng1130
Broch A, Trang H, Montalva L, Berrebi D, Dauger S, Bonnard A (2019) Congenital central hypoventilation syndrome and Hirschsprung disease: a retrospective review of the French National Registry Center on 33 cases. J Pediatr Surg 54(11):2325–2330
Trochet D, O'Brien LM, Gozal D, Trang H, Nordenskjöld A, Laudier B, Svensson PJ, Uhrig S, Cole T, Niemann S, Munnich A, Gaultier C, Lyonnet S, Amiel J (2005) PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome. Am J Hum Genet 76(3):421–426. https://doi.org/10.1086/428366
Berry-Kravis EM, Zhou L, Rand CM, Weese-Mayer DE (2006) Congenital central hypoventilation syndrome: PHOX2B mutations and phenotype. Am J Respir Crit Care Med 174(10):1139–1144. https://doi.org/10.1164/rccm.200602-305OC
Kasi AS, Perez IA, Kun SS, Keens TG (2016) Congenital central hypoventilation syndrome: diagnostic and management challenges. Pediatr Health, Med Therap 7:99–107. https://doi.org/10.2147/PHMT.S95054
Faure C, Viarme F, Cargill G, Navarro J, Gaultier C, Trang H (2002) Abnormal esophageal motility in children with congenital central hypoventilation syndrome. Gastroenterology 122(5):1258–1263. https://doi.org/10.1053/gast.2002.33062
Miura Y, Watanabe T, Uchida T, Nawa T, Endo N, Fukuzawa T, Ohkubo R, Takeyama J, Sasaki A, Hayasaka K (2019) A novel PHOX2B gene mutation in an extremely low birth weight infant with congenital central hypoventilation syndrome and variant Hirschsprung’s disease. Eur J Med Genet 62(9):103541. https://doi.org/10.1016/j.ejmg.2018.09.008
Ambartsumyan L, Rodriguez L (2014) Gastrointestinal motility disorders in children. Gastroenterol Hepatol 10(1):16–26
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KB, IP, TK, TD: substantial contributions to conception/design of work and to acquisition, analysis, interpretation of data for the work, drafting and revising manuscript critically for important intellectual content, final approval of manuscript.
KB, IP, TK, AS, JP, TD: substantial contributions to acquisition, analysis, interpretation of data for the work, drafting and revising manuscript critically for important intellectual content, final approval of manuscript.
AS: substantial contributions to conception/design of work, revising manuscript critically for important intellectual content, final approval of manuscript.
JP: Substantial contributions to conception/design of work, revising manuscript critically for important intellectual content, final approval of manuscript.
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Balakrishnan, K., Perez, I.A., Keens, T.G. et al. Hirschsprung disease and other gastrointestinal motility disorders in patients with CCHS. Eur J Pediatr 180, 469–473 (2021). https://doi.org/10.1007/s00431-020-03848-5
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DOI: https://doi.org/10.1007/s00431-020-03848-5