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Mild Phenotype in Nonpolyalanine Repeat Mutations of PHOX2B in Congenital Central Hypoventilation Syndrome
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A1990 - Mild Phenotype in Nonpolyalanine Repeat Mutations of PHOX2B in Congenital Central Hypoventilation Syndrome
Author Block: A. Kasi1, A. T. Wang2, T. J. Jurgensen3, S. S. Kun3, T. G. Keens3, I. A. Perez3; 1Emory University, Atlanta, GA, United States, 2Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States, 3Children's Hospital Los Angeles, Los Angeles, CA, United States.
INTRODUCTION: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder of the autonomic nervous system due to a mutation in the PHOX2B gene. ~10% of patients have nonpolyalanine repeat mutations (NPARM). NPARMs are reported to cause severe phenotypes with need for full-time ventilatory support, Hirschsprung’s disease, and increased tumor risk. However, we follow NPARM patients with milder phenotypes.
METHODS: Retrospective chart review of CCHS patients with NPARM was conducted to evaluate their phenotype. The analyzed data included the following: PHOX2B mutation; age at diagnosis; type and duration of ventilatory support; echocardiogram and Holter monitor tests; Hirschsprung’s disease; neurodevelopmental delays; ophthalmologic abnormalities; and neural crest tumors.
RESULTS: We identified five CCHS patients with PHOX2B NPARM aged 3-31 years, 3 females. Four patients were diagnosed during infancy and one patient at two years of age. All patients had signs of respiratory depression within the first two months of life.
The patient with the most severe phenotype requires continuous ventilator support with positive pressure ventilation via tracheostomy (PPV) during sleep (~10 hours/day) and diaphragm pacing when awake. This patient also has Hirschsprung’s disease and a neural crest tumor (adrenal ganglioneuroma), which was later resected.
Three patients require PPV only during sleep. One patient has a cardiac pacemaker due to a bradyarrhythmia and strabismus, which resolved without surgical correction. One patient has Hirschsprung’s disease. One patient has speech delay.
One patient does not require ventilator support. He had an ALTE at 6 weeks of age and was diagnosed with obstructive sleep apnea treated with adenotonsillectomy. A subsequent polysomnogram showed mild central sleep apnea, without hypoventilation, requiring only supplemental oxygen. He was diagnosed with CCHS at 2 years of age by PHOX2B testing due to recurrent apneas.
None of the patients have echocardiographic abnormalities.
CONCLUSIONS: CCHS patients with PHOX2B NPARM can have mild phenotypes. We speculate that the type of NPARM and its respective location on the PHOX2B gene play a critical role in the severity of phenotypes displayed by each CCHS patient.
Author Block: A. Kasi1, A. T. Wang2, T. J. Jurgensen3, S. S. Kun3, T. G. Keens3, I. A. Perez3; 1Emory University, Atlanta, GA, United States, 2Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States, 3Children's Hospital Los Angeles, Los Angeles, CA, United States.
INTRODUCTION: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder of the autonomic nervous system due to a mutation in the PHOX2B gene. ~10% of patients have nonpolyalanine repeat mutations (NPARM). NPARMs are reported to cause severe phenotypes with need for full-time ventilatory support, Hirschsprung’s disease, and increased tumor risk. However, we follow NPARM patients with milder phenotypes.
METHODS: Retrospective chart review of CCHS patients with NPARM was conducted to evaluate their phenotype. The analyzed data included the following: PHOX2B mutation; age at diagnosis; type and duration of ventilatory support; echocardiogram and Holter monitor tests; Hirschsprung’s disease; neurodevelopmental delays; ophthalmologic abnormalities; and neural crest tumors.
RESULTS: We identified five CCHS patients with PHOX2B NPARM aged 3-31 years, 3 females. Four patients were diagnosed during infancy and one patient at two years of age. All patients had signs of respiratory depression within the first two months of life.
The patient with the most severe phenotype requires continuous ventilator support with positive pressure ventilation via tracheostomy (PPV) during sleep (~10 hours/day) and diaphragm pacing when awake. This patient also has Hirschsprung’s disease and a neural crest tumor (adrenal ganglioneuroma), which was later resected.
Three patients require PPV only during sleep. One patient has a cardiac pacemaker due to a bradyarrhythmia and strabismus, which resolved without surgical correction. One patient has Hirschsprung’s disease. One patient has speech delay.
One patient does not require ventilator support. He had an ALTE at 6 weeks of age and was diagnosed with obstructive sleep apnea treated with adenotonsillectomy. A subsequent polysomnogram showed mild central sleep apnea, without hypoventilation, requiring only supplemental oxygen. He was diagnosed with CCHS at 2 years of age by PHOX2B testing due to recurrent apneas.
None of the patients have echocardiographic abnormalities.
CONCLUSIONS: CCHS patients with PHOX2B NPARM can have mild phenotypes. We speculate that the type of NPARM and its respective location on the PHOX2B gene play a critical role in the severity of phenotypes displayed by each CCHS patient.
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