Congenital Central Hypoventilation Syndrome

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DESCRIPTION

  • Congenital central hypoventilation syndrome (CCHS), also known as Ondine’s curse, is a rare genetic disorder characterized by sleep-related hypoventilation in the absence of hypoventilation due to an alternate cause.
  • There is a wide spectrum of disease ranging from mild hypoventilation in sleep to severe apnea with sleep and hypoventilation when awake.
  • Requires a mutation in the paired-like homeobox 2B (PHOX2B) gene for diagnosis
  • Commonly associated with autonomic nervous system (ANS) dysfunction (Hirschsprung disease and tumors of neural crest origin)
  • Lifelong disease requiring some degree of ventilatory support (ranging from only with time of sleep to 24-hour ventilation) with a generally good prognosis

EPIDEMIOLOGY

  • Most commonly seen in the newborn period but can present in childhood and even adulthood
  • Estimated to occur in 1 in every 150,000 to 200,000 live births
  • Males and females are affected equally.
  • Estimated 1,000 to 1,200 cases of CCHS worldwide
  • With new screening methods of the PHOX2B gene identification, CCHS is now found to be more common than previously thought.

ETIOLOGY

Mutation in the PHOX2B gene which results in ANS dysfunction, leading to impaired ventilation

RISK FACTORS

Genetics

  • Autosomal dominant inheritance
  • Caused by mutation in the PHOX2B gene located on chromosome 4p12, which encodes a transcription factor for central and peripheral nervous system development
    • About 90% of cases are due to heterozygous polyalanine repeat expansion of the normal 20 alanine repeat located on exon 3.
    • CCHS can be classified by two different genotypes.
    • Most cases are heterozygous for a polyalanine repeat expansion mutations (PARMs) increasing the number of alanine repeats from 20 to 24 to 33.
    • Nonpolyalanine repeat mutations (NPARMs) account for about 10% of cases caused by mutations such as missense, nonsense, frameshift, or stop codon mutations.
    • Both genotypes lead to impaired functioning of the PHOX2B protein.
  • Knowing the specific mutation can help predict the phenotype. Increased number of PARMs and NPARMs is associated with more severe disease.
  • Genetic counseling is advised for parents of children with CCHS.

PATHOPHYSIOLOGY

  • The PHOX2B gene is located throughout the central and peripheral nervous systems, and a defect in this gene leads to impaired ventilatory response to hypoxemia and hypercarbia.
  • Persistent hypercapnia and hypoventilation without proper feedback and intervention can lead to respiratory and cardiac failure.

COMMONLY ASSOCIATED CONDITIONS

  • Hirschsprung disease (a.k.a. Haddad syndrome)
    • Associated with about 20–30% of cases of CCHS; due to failure of neural crest cells to innervate the distal intestine
  • Neural crest tumors
    • Primarily neuroblastoma; due to the association of neural crest development with the PHOX2B gene
  • Autonomic dysfunction
    • May include dysrhythmias or alterations in blood pressure and/or altered temperature regulation
  • Ophthalmologic
    • May include altered pupil response, strabismus, anisocoria, absent or reduced depth perception
  • Facial dysmorphology
    • “Box-shaped” face with deep philtrum with downturned lips

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