PHOX2B – Haddad syndrome

Haddad syndrome (congenital central hypoventilation syndrome with Hirschsprung disease) is a rare neurocristopathy characterized by alveolar hypoventilation and intestinal aganglionosis. Heterozygous mutations in the paired-like homeobox 2 b gene (PHOX2B) underlie this autosomal dominant disorder, leading to impaired development of autonomic and enteric neurons. De novo expansions of the C-terminal polyalanine tract and non-polyalanine repeat mutations (NPARMs) have been reported in multiple unrelated patients, establishing a clear genotype–phenotype correlation.

Clinical validity is supported by at least 14 unrelated probands with de novo PHOX2B mutations (4 single‐patient reports [PMID:15930201][PMID:21286029][PMID:23572305][PMID:24135798] and a 10-patient series [PMID:30850150]), consistent AD inheritance, and concordant functional evidence from in vitro and in vivo models. Segregation analysis reveals no familial transmission, as most cases arise de novo.

Inheritance is autosomal dominant. Variant spectrum includes polyalanine expansions of +5 to +13 alanines and frameshift or nonsense NPARMs. A representative pathogenic allele is c.741_758dup (p.Ala255_Ala260dup) ([PMID:30850150]).

Functional studies demonstrate that PHOX2B encodes a transcription factor essential for autonomic nervous system development. Polyalanine expansions cause protein misfolding, cytoplasmic aggregation, dominant-negative effects on transcriptional activation of targets such as PHOX2A and DBH, and impaired DNA binding ([PMID:15888479]). The E3 ubiquitin ligase TRIM11 mediates clearance of expanded PHOX2B, rescuing transcriptional activity in cell models ([PMID:22307522]).

Mouse models confirm that PHOX2B loss of function disrupts neural crest–derived neuronal lineages, with knockout mice dying in utero and conditional expression of NPARMs impairing locus coeruleus development and respiratory rhythm, paralleling human pathology ([PMID:14532329]).

In summary, robust genetic and functional data classify the PHOX2B–Haddad syndrome association as Strong. PHOX2B mutation screening is clinically actionable for early diagnosis, genetic counseling, and guiding ventilatory and surgical management in affected neonates.

Key Take-home: PHOX2B heterozygous mutations are a definitive molecular marker for Haddad syndrome, enabling precise diagnosis and personalized treatment strategies.

References

• Pediatrics • 2005 • Congenital central hypoventilation syndrome and Hirschsprung's disease in an extremely preterm infant. PMID:15930201
• Journal of Korean medical science • 2011 • Haddad syndrome with PHOX2B gene mutation in a Korean infant. PMID:21286029
• Anaesthesiology intensive therapy • 2013 • Haddad syndrome. PMID:23572305
• European journal of pediatrics • 2014 • An unusual cause of fetal hypomobility: congenital central hypoventilation syndrome associated with Hirschsprung disease. PMID:24135798
• Journal of pediatric surgery • 2020 • Clinical features of children with Haddad syndrome: A single-center experience. PMID:30850150
• American journal of human genetics • 2005 • PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome. PMID:15657873
• Human molecular genetics • 2005 • Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in congenital central hypoventilation syndrome. PMID:15888479
• Journal of molecular medicine • 2012 • The E3 ubiquitin ligase TRIM11 mediates the degradation of congenital central hypoventilation syndrome-associated polyalanine-expanded PHOX2B. PMID:22307522

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