Pachyonychia congenita Q84.9

Jadassohn and Lewandowsky, 1906

Pachyonychia congenita" is a group of ectodermal dysplasia syndromes with mostly autosomal dominant inheritance and varying degrees of focal palmoplantar keratoses(keratosis palmoplantaris) as well as keratoses of the mucous membranes and pronounced nail dystrophies. Mutations in the keratin genes KRT6b and KRT17 have been detected. The combination with diffuse alopecia has been described (Nikoo A 2012).

According to current knowledge, Pachyonychia congenita is divided into 4(5) clinical subgroups (PC1-4):

• Type I: Jadassohn-Lewandowsky type (PC-1; OMIM 167200) - autosomal dominant mutations in the genes KRT16 or KRT6A (chromosome 17q12-q21). To date, 25 mutations in KRT16 have been associated with PC. 21 mutations are located on exon 1 and 4 mutations on exon 6 (Xu Q et al. 2019)
• Type II: Jackson-Lawler type (PC-2; OMIM 167210) - mutations in KRT6b and KRT17, genes coding for the respective keratins, located on chromosome 17q12-q21 and 12q13.
• Type III: (PC-3; OMIM 615726)- mutations in KRT6a, a gene localized on chromosome 12q13.13.
• Type IV: (PC-4; OMIM 61528) - mutations in KRT6b, a gene located on chromosome 12q13.13.
• Type V: PC-K6c, a milder form of PC with mutations in KRT6C, a gene located on chromosome 12 at q13.13, the rarest form. Keratin 6C (KRT6C) may be a heterodimer partner for KRT9, a keratin gene associated with epidermolytic palmoplantar keratoderma (EPPK) (Li P et al. 2023). The model representation for KRT6C/KRT9 shows a typical coiled-coil structure in their 2B domains.

There is also a late-manifesting type (Pachyonychia congenita tarda) that resembles either the PC-1 type or the PC-2 type.

The keratins affected in this syndrome are preferentially formed in the skin layers of the palm, the skin appendages such as nails and in the oral mucosa, which explains the lesional structures.

Predominantly autosomal-dominantly inherited mutations in the keratin genes KRT6a, 6b (gene locus: 12q13) and KTR16, 17 (gene locus: 17q12-q21); less frequent autosomal-recessive inheritance and spontaneous mutations.

The described mutations of the keratin genes KRT16 and KRT17 affect the helix initiation motif, a functionally important section at the beginning of the helical structure of the keratin monomers. These are of crucial importance for the undisturbed formation of keratin filaments. The result is clumped keratin filaments. These can no longer interact with other cytoskeletal structures. This results in a reduced mechanical load-bearing capacity of the epithelial layer.

Congenital claw-like, thickened finger and toe nails. Insular or striate palmar, rarely plantar keratoses (PC1), often hyperhidrosis. Circumscribed keratoses on toes, soles, heels, elbows, and knees. Sebostasis and blistering are possible.

• Mucosal changes: Whitish, streaky plaques on the tongue, corners of the mouth, oral mucosa and larynx (leukokeratoses especially PC1 - see oral leukoplakia).

Congenital Onychogrypose

Nail changes caused by trauma

Twenty-Nail Dystrophy

Steatocystoma multiplex

Palmoplantar keratoses

epidermolysis bullosa hereditaria

white mucosal nevus

Treat circumscribed keratoses, especially palmar and plantar keratoses with salicylic acid-containing patches (e.g. Guttaplast patches) in combination with corneal shavers or salicylic acid-containing or urea-containing formulations such as R215 or R105. For onycholysis, use highly concentrated urea-containing topical preparations (e.g. 40% urea paste, Onychomal cream, urea paste 40% (NRF 11.30.). Use orthopaedic footwear if necessary according to the German Ordinance on Medical Devices.

Good results are described under acitretin (neotigason), initial 0.5-1 mg/kg bw/day, maintenance dose 0.2-0.5 mg/kg bw/day. Relatively high dosage seems necessary.

Hyperkeratoses on the skin are better reduced than nail changes.

Rapamycin (m-TOR inhibitor) showed an improvement of the symptoms with regard to keratoses.

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2. Connors JB et al. (2001) Delayed-onset pachyonychia congenita associated with a novel mutation in the central 2B domain of keratin 16. Br J Dermatol 144: 1058-1062
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6. Li P et al. (2023) Proteomic profiling reveals KRT6C as a probable hereterodimer partner for KRT9: New insights into re-classifying epidermolytic palmoplantar keratoderma (EPPK) and a milder form of pachyonychia congenita (PC-K6c) as a group of genetic cutaneous disorders. J Proteomics 287:104971.

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