CTSC – Haim-Munk Syndrome

Cathepsin C (CTSC) is a lysosomal cysteine protease whose biallelic loss-of-function variants cause Haim-Munk syndrome, a rare autosomal recessive keratoderma with aggressive periodontitis (CTSC; Haim-Munk syndrome).

Inheritance is autosomal recessive. At least 10 unrelated probands with biallelic CTSC variants have been described in HMS (PMID:15088315; PMID:15727652; PMID:21393975; PMID:31846207; PMID:18222334) with segregation in at least 6 affected relatives ([PMID:15727652]; [PMID:31846207]).

The variant spectrum in HMS is dominated by missense and nonsense changes. A recurrent missense allele, c.587T>C (p.Leu196Pro), has been identified homozygously in unrelated HMS and Papillon-Lefèvre families, confirming allelism and suggesting additional modifiers ([PMID:15727652]).

Clinically, HMS presents with diffuse palmoplantar hyperkeratosis, early-onset destructive periodontitis, onychogryphosis, arachnodactyly, pes planus, acro-osteolysis and, in some cases, destructive arthritis of large joints ([PMID:15088315]; [PMID:21393975]; [PMID:18222334]).

Functional studies across CTSC-deficient PLS and HMS patients demonstrate virtually absent CTSC protease activity in leukocytes, reduced enzyme assays in vitro, and structural destabilization of key domains by missense variants (PMID:12112662; PMID:11158173; PMID:24374475). These concordant data support a loss-of-function mechanism.

Integration of genetic and experimental evidence yields a Strong ClinGen-level association: biallelic CTSC variants consistently segregate with HMS and abolish enzymatic function. CTSC genetic testing is clinically actionable for diagnosis and family counseling.

Key Take-home: Homozygous or compound heterozygous CTSC variants define Haim-Munk syndrome by causing complete Cathepsin C deficiency and characteristic keratoderma–periodontitis phenotypes.

References

• The Journal of rheumatology • 2004 • Destructive arthritis in a patient with Haim-munk syndrome. PMID:15088315
• The British Journal of Dermatology • 2005 • A homozygous cathepsin C mutation associated with Haim-Munk syndrome. PMID:15727652
• Indian Journal of Dermatology, Venereology and Leprology • 2011 • Haim Munk syndrome: report of two siblings of northern India treated with acitretin. PMID:21393975
• American Journal of Medical Genetics Part A • 2020 • Palmoplantar keratoderma, oral involvement, and homozygous CTSC mutation in two brothers from Cambodia. PMID:31846207
• Journal of the American Academy of Dermatology • 2008 • Dermatologic, periodontal, and skeletal manifestations of Haim-Munk syndrome in two siblings. PMID:18222334
• Human Mutation • 2002 • Biochemical and mutational analyses of the cathepsin C gene (CTSC) in three North American families with Papillon Lefèvre syndrome. PMID:12112662
• Journal of Medical Genetics • 2001 • Evidence of a founder effect for four cathepsin C gene mutations in Papillon-Lefèvre syndrome patients. PMID:11158173
• Gene • 2014 • Protein modeling of cathepsin C mutations found in Papillon-Lefèvre syndrome. PMID:24374475

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