COL1A1 – Caffey disease

Infantile cortical hyperostosis (Caffey disease) is a rare pediatric skeletal disorder characterized by acute inflammation with subperiosteal new bone formation, soft tissue swelling, fever, pain, and irritability. The autosomal dominant form has been linked to type I collagen abnormalities, implicating COL1A1 in disease pathogenesis.

The first pathogenic COL1A1 variant in Caffey disease was reported in a 7-month-old Indian boy who harbored a heterozygous c.3040C>T (p.Arg1014Cys), confirming collagenopathy in sporadic and familial presentations (PMID:21249479).

A recurrence of cortical hyperostosis in a 12-year-old female—mirroring her infantile presentation—and identification of the identical c.3040C>T (p.Arg1014Cys) variant in this familial form underscored the mutation’s persistence and phenotypic consistency (PMID:23389580).

Reduced penetrance was demonstrated in a Turkish kindred: an affected infant and asymptomatic mother, grandmother, aunt, and cousin all carried the c.3040C>T (p.Arg1014Cys) variant, with complete resolution following anti-inflammatory therapy (PMID:29090879).

A genome-wide linkage study in a large pedigree (LOD 6.78) and two smaller families confirmed heterozygosity for c.3040C>T (p.Arg1014Cys), while a second Japanese familial case lacked COL1A1/COL1A2 mutations, indicating genetic heterogeneity (PMID:15864348; PMID:24390061).

In a cohort of 28 families, p.Arg1014Cys was identified in 23 and a novel c.2752C>T (p.Arg918Cys) in five, both arginine-to-cysteine substitutions within the proα1(I) triple helix. Patient fibroblasts produced disulfide-linked proα1(I) chains; dermal collagen fibrils exhibited increased diameter variability and packing defects, substantiating a dominant-negative mechanism (PMID:34272483).

Although COL1A1 arginine substitutions are highly penetrant, the existence of mutation-negative pedigrees suggests alternative loci contribute to phenocopies and underscores allelic heterogeneity.

Taken together, autosomal dominant COL1A1 missense substitutions, particularly p.Arg1014Cys and p.Arg918Cys, definitively cause Caffey disease. Genetic testing enables molecular confirmation, guides prognosis, and informs family counseling.

References

• Indian Journal of Pediatrics • 2011 • COL1A1 mutation in an Indian child with Caffey disease. PMID:21249479
• Journal of Pediatric Orthopedics • 2013 • Recurrence of infantile cortical hyperostosis: a case report and review of the literature. PMID:23389580
• The Turkish Journal of Pediatrics • 2016 • Familial mutation in Caffey disease with reduced penetrance: A case report. PMID:29090879
• The Journal of Clinical Investigation • 2005 • A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders. PMID:15864348
• European Journal of Pediatrics • 2014 • Two Japanese familial cases of Caffey disease with and without the common COL1A1 mutation and normal bone density, and review of the literature. PMID:24390061
• Genetics in Medicine • 2021 • Caffey disease is associated with distinct arginine to cysteine substitutions in the proα1(I) chain of type I procollagen. PMID:34272483

Evidence Based Scoring (AI generated)