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Test Information Sheet
CTSC Gene Analysis in Papillon- Lefèvre Syndrome (PLS) and
Haim-Munk Syndrome (HMS)
Mendelian Inheritance in Man Numbers: 24500 (Papillon-Lefevre Syndrome); 245010 (Haim-Munk Syndrome);
602365 (CTSC gene)
Clinical features:
Papillon-Lefèvre Syndrome (PLS) is characterized by two main features: palmoplantar keratoderma (PPK) with
thickening (hyperkeratosis) of the skin of palms and soles, and severe, early-onset periodontitis leading to the
premature loss of dentition. The destruction of the periodontium results in loss of primary teeth usually by age 5 and
loss of permanent teeth by about age 20 (Hart et al., 1999; Khan et al., 2012). The PPK can range from mild or
psoriasiform scaling to severe hyperkeratosis, which usually develops before age 3. Hyperkeratotic plaques may also
develop over elbows and knees (Khan et al, 2012). Other symptoms of PLS may include pyogenic skin infections, nail
dystrophy, hyperhidrosis, increased susceptibility to infection, and ectopic cranial calcifications (Laass et al., 1997;
Hart et al., 2000b).
Haim-Munk Syndrome (HMS) is also associated with PPK similar to PLS, but features additional abnormalities,
including arachnodactyly, acro-osteolysis, nail deformities (onychogryphosis), and more severe skin involvement
(Hart et al., 1997; Hart et al., 2000a, Cury et al., 2005). HMS has only been seen in descendants of an isolated nonAshkenazi Jewish isolate from Cochin, India (Hart et al., 2000a; Cury et al., 2005). PLS and HMS are both syndromic
forms of PPK, and can be distinguished from other types of PPK by the characteristic severe, early-onset periodontitis
(Cury et al., 2005).
Inheritance pattern: Autosomal recessive
Reasons for referral:
1. Confirmation of clinical diagnosis
2. Genetic counseling and recurrence risk assessment
3. Prenatal diagnosis in families with a known mutation in the CTSC gene
Genetics:
Mutations in the CTSC gene cause Papillon- Lefèvre Syndrome and Haim-Munk Syndrome. The gene is located on
chromosome 11q14.2 and contains seven exons. CTSC encodes cathepsin C, a lysosomal cysteine protease with four
identical subunits that are important for intracellular protein degradation and activation of serine proteases in immune
inflammatory cells. CTSC is highly expressed in lung, kidney, placenta, myeloid, and immune cells (Hart et al., 1999;
Hart et al., 2000a).
Mutation spectrum:
To date, more than 50 mutations have been reported in the CTSC gene. Missense and nonsense mutations are the
most commonly identified types of mutations in affected individuals, although splice site changes and frame-shift
mutations have also been reported (Hart et al., 2000a). There is one report of a larger deletion spanning exons 3-7
(Jouary et al, 2008). Most affected individuals are homozygous for cathepsin C mutations inherited from a common
ancestor, reflecting consanguinity (Hart et al., 2000a; Khan et al., 2012).
Information Sheet Papillon- Lefèvre and Haim-Munk Syndromes
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GeneDx 05/2013
Test method:
Using genomic DNA from a submitted specimen, bi-directional sequence analysis of the complete coding region
(exons 1-7) and splice sites of the CTSC gene is performed. If no mutation is found by sequencing, targeted array
CGH analysis is available to evaluate for a deletion or duplication of one or more exons in the CTSC gene. The
presence of a mutation or deletion is confirmed by repeat analysis using sequencing, restriction fragment analysis, or
another appropriate method.
Test sensitivity:
One study (Hart et al., 2000b) identified pathogenic CTSC mutations in 30 out of 36 families with PLS, indicating a
clinical sensitivity of ~83%. In the majority of reported patients with PLS and HMS, mutations in both CTSC alleles
were identified by gene sequencing (Hart et al., 1997; Toomes et al., 1999; Hart et al., 2000a; Hart et al., 2000b; Cury
et al., 2005). However, one study did identify a large deletion (Jouary et al., 2008), which would not be identifiable by
sequencing.
Specimen Requirements and Shipping/Handling:
 Blood: A single tube with 1-5 mL whole blood in EDTA (1-2mL for infants). Ship overnight at ambient
temperature, using a cool pack in hot weather. Specimens may be refrigerated for one week prior to shipping.
 Buccal Brushes: Can be used as an alternative to blood for CTSC sequencing only. Gene
deletion/duplication testing requires submission of a venous blood sample. When sending a
buccal sample, use a GeneDx buccal kit (others not accepted). Submit by mail. Buccal brushes are
not accepted on children under 6 months of age.

Prenatal Diagnosis: For prenatal testing for a known mutation in the CTSC gene, please refer to the specimen
requirements table on our website at: http://www.genedx.com/test-catalog/prenatal/. Ship specimen overnight
at ambient temperature, using a cool pack in hot weather.
Required Forms:
 Sample Submission (Requisition) Form – complete all pages, including
 Payment Options Form or Institutional Billing Instructions
For test codes, CPT codes, and turn-around-time, please refer to the “Papillon- Lefèvre Syndrome
(PLS) and Haim-Munk Syndrome (HMS)” page on our website: www.genedx.com
References:
Cury et al., (2005) Brit J of Dermatology 152: 353-356; Hart et al., (1997) J Periodont Res 32:81-89; Hart et al.,
(1999) J Med Genet 36:881-887; Hart et al., (2000a) J Med Genet 37:88-94; Hart et al., (2000b) J Med Genet 37:927932; Jouary et al., (2008) 128:322-325; Khan et al., (2012) J Indian Soc Periodontol 16(2):261-265; Laass et al.,
(1997) Hum Genet 101:376-382; Toomes et al., (1999) Nat Genet 23:421-424.
Information Sheet Papillon- Lefèvre and Haim-Munk Syndromes
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GeneDx 05/2013