PHOX2B – Congenital Central Hypoventilation Syndrome

Autosomal dominant mutations in the paired-like homeobox 2B (PHOX2B) gene underlie congenital central hypoventilation syndrome (CCHS), a rare disorder of autonomic control characterized by alveolar hypoventilation particularly during sleep. PHOX2B mutations were first identified in 18 unrelated CCHS probands as heterozygous de novo frameshifts and polyalanine expansions (±5–13 alanines) within a 20-alanine tract, accounting for ~60%–90% of cases (PMID:12640453).

Genetically, CCHS follows an autosomal dominant inheritance with most mutations arising de novo; polyalanine repeat expansion mutations (PARMs) predominate (~90%), whereas non-polyalanine repeat mutations (NPARMs) including missense, nonsense, and frameshift variants occur in ~10% of cases. A recurrent heterozygous in-frame duplication, c.753_767dup (p.Ala256_Ala260dup), has been reported in multiple unrelated individuals and produces a 5-alanine expansion within exon 3 (PMID:14566559). Clinical penetrance varies, with some PARM carriers presenting in childhood or adulthood (late-onset CCHS). Case series have described additional features such as Hirschsprung disease in ~20% and neural crest tumors in ~2%–3% of patients.

Segregation evidence is provided by a large extended Caucasian kindred in which 10 affected relatives across four generations harbored a heterozygous non-polyalanine PHOX2B mutation, demonstrating autosomal dominant transmission and variable expressivity (PMID:23622117). No healthy carriers beyond the proband generation were reported, supporting a high penetrance of pathogenic alleles.

Functional studies in neuronal progenitor models and animal systems confirm that PHOX2B mutations disrupt transcriptional regulation and neuronal differentiation. In vitro assays show that both PARMs and NPARMs impair PHOX2B transactivation of target genes (e.g., DBH, PHOX2A) and alter subcellular localization, with longer expansions forming cytoplasmic aggregates and frameshifts sequestering proteins in the nucleolus. Conditional expression of a human NPARM in mouse brainstem progenitors abrogates locus coeruleus specification and yields respiratory lethality, recapitulating the human phenotype (PMID:14532329).

No convincing evidence disputes the PHOX2B–CCHS association, and genotype-phenotype correlations are consistent across multiple cohorts. Detailed mapping of variant effects has shown that NPARMs often confer more severe, syndromic presentations (e.g., Hirschsprung disease, neural crest tumors), whereas shorter PARMs more frequently underlie isolated CCHS.

Key take-home: Genetic testing for PHOX2B mutations is essential for the accurate diagnosis of CCHS, informs prognosis of associated features such as Hirschsprung disease and neural crest tumors, and guides anticipatory management including ventilatory support and family counseling.

References

• Nature genetics • 2003 • Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. PMID:12640453
• Human genetics • 2003 • Molecular analysis of congenital central hypoventilation syndrome. PMID:14566559
• Human molecular genetics • 2003 • Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome. PMID:14532329
• Journal of medical case reports • 2013 • Extreme intra-familial variability of congenital central hypoventilation syndrome: a case series. PMID:23622117

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