Pachyonychia Congenita
Pachyonychia congenita is a group of rare genetically inher- ited diseases characterized by nail dystrophy and by varying features of ectodermal dysplasias. There are two major clinical subtypes recognized: type I with oral leukokeratosis and type II with multiple pilosebaceous cysts.
GENETICS/BIRTH DEFECTS
1. Inheritance
a. Type I pachyonychia congenita (Jadassohn-Lewandowsky type)
i. Autosomal dominant inheritance ii. Possible autosomal recessive inheritance b. Type II pachyonychia congenita (Jackson-Lawler
type): autosomal dominant 2. Etiology
a. Type I: caused by mutations in genes encoding one of the paired keratins of specialized epidermis, K6a/
K16, resulting in:
i. Fragility of specific epithelia
ii. Phenotypes of pachyonychia congenita I or focal non-epidermolytic palmoplantar keratoderma with insignificant nail changes
b. Type II: caused by mutations in genes encoding one of the paired keratins of specialized epidermis, K6b/K17 i. Linkage analysis mapped pachyonychia congenita type II phenotype within the type I keratin gene cluster on chromosome 17q12-21
ii. A germline mutation has been identified in ker- atin 17 gene (K17)
iii. Colocalization of K17 with keratin 6b 3. Genotype-phenotype correlation
a. Differences in type I and type II phenotypes: largely explainable by the difference in expression patterns between the K6a/K16 and k6b/K17 expression pairs b. K6b/K17 expresses at higher levels in the piloseba-
ceous unit than K6a/K16: responsible for the pilose- baceous cysts in type II
c. Conversely, K6a/K16 more widely expressed in oral epithelia: responsible for the greater predominance of oral leukokeratosis in type I
CLINICAL FEATURES
1. Presence of intra- and interfamilial phenotypic variation 2. Pachyonychia congenita type I (56.2% of cases)
a. The most common subtype b. Onset in infancy
c. Severe nail dystrophy affecting all the nails symmet- rically
i. The best hallmark of the disease ii. Thickened wedge-shaped nails
iii. Proximal portions of the nails: smooth and nor- mally attached to the lateral nail folds
iv. Distal portions of the nails: may increase to many times the normal thickness, producing a subungual keratinous mass that pushes the nail plate upward, arching it transversally, folding it longitudinally, and elevating it distally
v. Nails commonly shed and regrow with similar but more severe changes
vi. Projections from the nail beds make the nails susceptible to trauma with consequent chronic paronychial infections
d. With or without following associated anomalies i. Focal nonepidermolytic palmoplantar keratoderma
(predominantly a feature of type I) ii. Follicular keratoses observed on:
a) Temple b) Eyebrows
c) Extensor aspect of the proximal parts of the extremities
iii. Hyperkeratosis of palms, soles, knees and elbows
iv. Localized foot blistering
v. Oral leukokeratosis: a prominent sign vi. Neonatal teeth
vii. Blister formation on palms and soles
viii. Hoarse voice due to laryngeal involvement (leukokeratosis)
ix. Plantar hyperhidrosis
3. Pachyonychia congenita type II (24.9% of cases) a. Nail dystrophy
b. Less pronounced or absent palmoplantar keratoderma and oral changes
c. Follicular keratoses d. Oral leukokeratosis
e. Multiple pilosebaceous cysts (most useful distin- guishing feature for type II but usually occurring at puberty)
i. Epidermoid or infundibular cysts (arising from the hair follicle infundibulum)
ii. Eruptive vellus hair cysts and multiple steatocys- tomas (characteristic of type II) (arising from the sebaceous duct epithelium)
f. Bullae of palms and soles g. Palmar and plantar hyperhidrosis h. Natal or neonatal teeth
i. Pili torti in children j. Bushy eyebrows k. Hidradenitis suppurativa
4. Pachyonychia congenita type III (Schafer-Brunauer type) (11.7%)
a. Features of type I and type II b. Angular cheilosis
c. Leukokeratosis of the cornea d. Cataracts
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782 PACHYONYCHIA CONGENITA
5. Pachyonychia congenita tarda (type IV) (7.2%) a. A rare form of pachyonychia congenita b. Features of type I, type II, and type III c. Laryngeal lesions
d. Hoarseness e. Mental retardation
f. Hair anomalies g. Alopecia
h. Nail changes occurring in the second or third decade i. Abnormal painful nails
j. Palmoplantar kertoderma
6. Pachyonychia congenita with early onset nail changes in the absence of other associated features
DIAGNOSTIC INVESTIGATIONS
1. Histology and ultrastructure of cutaneous and oral lesions: suggest a keratin disorder
2. Molecular analyses of mutations in genes encoding one of the paired keratins of specialized epidermis, K6a/K16 and K6b/K17
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. Autosomal dominant inheritance: not increased unless a parent is affected
ii. Autosomal recessive inheritance: 25%
b. Patient’s offspring
i. Autosomal dominant inheritance: 50%
ii. Autosomal recessive inheritance: not increased unless the spouse is a carrier
2. Prenatal diagnosis: genomic mutation detection possible in prenatal diagnosis of pachyonychia congenita type I (K6a/K16) or type II (K6b/K17) by CVS or amniocentesis 3. Management
a. No ideal treatment for the thickened nail plate available b. Vigorous use of topical lubricants and keratolytics c. Antiseptic wet dressings for secondarily infected
areas
d. Systemic treatment with acitretin producing variable and inconsistent results with caution of side effects (teratogenicity and hyperostosis)
e. Custom-fitted footwear for protective support of painful fissures and blisters on the soles
f. Simple avulsion of the distorted nails inadequate because the dystrophic nail regrows
g. Curettage and electrofulguration or surgical excision of the nail matrix and bed can improve function and appearance
h. Surgical excision of a focal, hyperplastic epithelial mass results in improvement of hoarseness due to laryngeal obstruction by laryngeal lesions. Additional microsurgery may be necessary for the recurrence of the laryngeal lesions
REFERENCES
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Smith FJD, Corden LD, Rugg EL, et al.: Missense mutations in keratin 17 cause either pachyonychia congenita type 2 or a phenotype resembling steatocystoma multiplex. J Invest Dermatol 108:220–223, 1997.
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Smith FJD, McKenna KE, Irvine AD, et al.: A mutation detection strategy for the human K6A gene and novel mutations in two cases of pachyonychia congenita type 1. Exp Dermatol 8:109–114, 1999.
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PACHYONYCHIA CONGENITA 783
Fig. 1. Characteristic nail changes in a 8-month-old girl with pachyony- chia congenita type I showing smooth proximal ends and thick distal ends of the nails, producing a subungual keratinous mass that pushes the nail bed upward, arching it transversally, folding it longitudinally, and elevating it distally. The patient also has oral leukokeratosis.
