CHUK – Cocoon Syndrome

Cocoon syndrome is a severe, autosomal recessive pterygium disorder characterized by extensive cutaneous webbing, syndactyly (HP:0001159), and craniofacial malformations. The gene CHUK (CHUK) encodes IKKα, a kinase essential for NF-κB signaling and epidermal development. Mutations in CHUK have been implicated in a spectrum of disorders including Bartsocas-Papas syndrome and Cocoon syndrome. The association between CHUK and Cocoon syndrome is supported by multiple unrelated cases and functional studies.

Genetic evidence for CHUK in Cocoon syndrome arises from a cohort study of six pedigrees where three unrelated probands harbored homozygous predicted loss-of-function variants in CHUK. These include c.427C>T (p.Arg143Ter), c.934-2A>G, and c.1249C>T (p.Gln417Ter) in homozygosity, segregating with a consistent autosomal recessive phenotype of severe syndactyly and cutaneous webbing (PMID:25691407). No additional affected relatives beyond probands were reported, but parental carrier status was confirmed.

The mode of inheritance for Cocoon syndrome due to CHUK is autosomal recessive. All three probands exhibited biallelic loss-of-function alleles and were born to carrier parents, consistent with recessive transmission. The absence of the phenotype in heterozygous carriers further supports a loss-of-function mechanism.

Functional studies demonstrate that CHUK encodes IKKα, which forms part of the canonical IKK complex regulating NF-κB activation. A heterozygous kinase-domain variant, c.425A>G (p.His142Arg), exerts a dominant-negative effect on IKK complex assembly and NF-κB signaling in vitro, disrupting epidermal lineage commitment (PMID:28513979). Additional work shows that nuclear IKKα stabilizes p73 to promote apoptotic responses, highlighting IKKα’s role in epidermal and craniofacial development pathways (PMID:17452332).

Mechanistically, CHUK loss-of-function impairs NF-κB–dependent transcriptional programs essential for epidermal differentiation and limb morphogenesis. This disruption manifests clinically as extensive pterygia, syndactyly, and craniofacial defects characteristic of the Cocoon syndrome spectrum observed in homozygous cases.

Based on multiple unrelated probands, consistent biallelic pathogenic variants, and concordant functional data, the clinical validity of CHUK for Cocoon syndrome is classified as Moderate. Molecular diagnosis enables accurate genetic counseling and carrier screening. Future functional assays and animal models could further elucidate CHUK’s developmental roles and inform therapeutic strategies.

References

• American journal of medical genetics. Part A • 2015 • Expanding the genetic and phenotypic spectrum of popliteal pterygium disorders. PMID:25691407
• American journal of medical genetics. Part A • 2017 • Identification of a de novo variant in CHUK in a patient with an EEC/AEC syndrome-like phenotype and hypogammaglobulinemia. PMID:28513979
• The Journal of biological chemistry • 2007 • Stabilization of p73 by nuclear IkappaB kinase-alpha mediates cisplatin-induced apoptosis. PMID:17452332

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