Pachyonychia congenita Q84.9

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

Jadassohn-Lewandowsky Syndrome; Keratosis congenita multiplex; keratosis disseminata circumscripta; leukokeratosis linguae; MIM 167200; Pachyonychia ichthyosiformis; Pachyonychia Syndrome; polyceratosis congenita

History
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Jadassohn and Lewandowsky, 1906

Definition
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A group of ectodermal dysplasia syndromes, with mostly autosomal dominant inheritance and variously pronounced cornification disorders of the skin(keratosis palmoplantaris) and mucous membranes as well as pronounced nail dystrophies, is summarized under this name.

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

  • Type I: Jadassohn-Lewandowsky type (PC-1; OMIM 167200) - mutation in the genes KRT17 or KRT6B (chromosome 17q12-q21)
  • Type II: Jackson-Lawler type (PC-2; OMIM 167210) - Mutations in KRT6b and KRT17, genes coding for the respective keratins and located on chromosome 17q12-q21 and 12q13.
  • Type III: (PC-3; OMIM 615726) mutations in KRT6a, a gene located on chromosome 12q13.13.
  • Type IV: (PC-4; OMIM 61528) - Mutations in KRT6b, a gene located on chromosome 12q13.13.

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

Occurrence/Epidemiology
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Incidence: 0.5-1/100,000 inhabitants/year.

Etiopathogenesis
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Predominantly autosomal-dominantly inherited mutations in the keratin genes KRT6a, 6b (gene locus: 12q13) and KTR16, 17 (gene locus: 17q12-q21); more rarely 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 keratin monomers. These are crucial for an undisturbed formation of keratin filaments. This leads to functional deficits of the keratinocytes, e.g. to normal mechanical stress.

Due to keratin mutations, the keratin filaments clump together and can no longer interact with other cytoskeletal structures. This results in a reduced mechanical load capacity of the epithelial dressing.

Manifestation
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Mostly congenital. Late manifestations between 10-30 LJ are described according to casuistics.

Clinical features
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Congenital claw-shaped, thickened finger and toe nails. Island-shaped or stripy palmar, more rarely plantar keratoses (PC1), often hyperhidrosis. Circumscribed keratoses on toes, soles, heel, elbows and knees. Sebostasis and blistering are possible.

  • Mucous membrane changes: Whitish, streaky plaques on the tongue, corners of the mouth, oral mucosa and larynx (leukokeratoses mainly PC1 - see oral leukoplakia).
  • Eye changes: thickening and clouding of the cornea, cataract.
  • Multiple cysts (PC2), which develop after puberty
  • Accompanying symptoms: Spina bifida occulta, diverticulitis, heart anomalies, tooth anomalies = indicator for PC2 (see below Dentes connat). Pili torti can be detected in some patients with PC-2.

Differential diagnosis
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External therapy
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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.

Internal therapy
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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.

Operative therapie
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Sanding the nails. If necessary, surgical removal of the nails including the nail bed.

Note(s)
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Associations with eruptive vellus hair cysts and steatocystoma multiplex were observed (also mutations of the K17 gene).

Literature
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  1. Bondeson J (1993) Pachyonychia congenita. A historical note. On J Dermatopathy 15: 594-599
  2. Connors JB et al (2001) Delayed-onset pachyonychia congenita associated with a novel mutation in the central 2B domain of keratin 16th Br J Dermatol 144: 1058-1062
  3. Feng YG et al (2003) Keratin 17 mutation in pachyonychia congenita type 2 with early onset of sebaceous cysts. Br J Dermatol 148: 452-455
  4. Hoting E et al (1985) Systemic retinoid therapy with etretinate in Pachyonychia congenita. Dermatologist 36: 526-528
  5. Jadasson J, Lewandowski F (1906) Pachyonychia congenita. Keratosis disseminata circumscripta (follicularis), tylomata. Leukokeratosis linguae. In: Neisser A, Jakobi E (eds) Ikonographia Dermatologica, vol 1, Urban & Schwarzenberg, Berlin, pp. 29-31
  6. Müller C (1904) On the causes of congenital onychogryphosis. Munich Med Weekly 49: 2180-2182
  7. Scholz IM et al (2011) Pachyonychia congenita type 2 JDDG 9: 144-145
  8. Smith F (2003) The molecular genetics of keratin disorders. At J Clin Dermatol 4: 347-364
  9. Swensson O (1999) Pachyonychia congenita. dermatologist 50: 483-490
  10. van Steensel MA et al. (2001) A new type of pachyonychia congenita. Eur J Dermatol 11: 188-190
  11. Ward KM et al (2003) Identification of a recurrent mutation in keratin 6a in a patient with overlapping clinical features of pachyonychia congenita types 1 and 2 Clin Exp Dermatol 28: 434-436
  12. Wilson AG (1905) Three cases of hereditary hyperkeratosis of the nail bed. Br J Dermatol 17: 13-14

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Last updated on: 29.10.2020