Pachyonychia Congenita 1

A number sign (#) is used with this entry because pachyonychia congenita-1 (PC1) is caused by heterozygous mutation in the keratin-16 gene (KRT16; 148067) on chromosome 17q21.

Description

Pachyonychia congenita (PC) is an autosomal dominant genodermatosis with the main clinical features of hypertrophic nail dystrophy, painful and highly debilitating plantar keratoderma, oral leukokeratosis, and a variety of epidermal cysts. Although the condition had previously been subdivided clinically into Jadassohn-Lewandowsky PC type 1 and Jackson-Lawler PC type 2, patients with PC were later found to have a mixed constellation of both types, leading to a classification of PC based on genotype (summary by Sybert, 2010; Eliason et al., 2012; McLean et al., 2011).

Historical Classification of Pachyonychia Congenita

Gorlin et al. (1976) suggested that 2 distinct syndromes are subsumed under the designation pachyonychia congenita. PC type 1, the Jadassohn-Lewandowsky type, shows oral leukokeratosis. PC type 2, the Jackson-Lawler type, has natal teeth and epidermoid cysts (cylindromas), but no oral leukoplakia. Corneal dystrophy may be a feature exclusively of the Jackson-Lawler type.

Smith et al. (1998) stated that PC type 2, in contrast to PC type 1, has minimal oral involvement and milder keratoderma, and multiple steatocystomas (184500) is a major clinical feature. Steatocystoma, also known as eruptive vellus cyst, is a cystic hamartoma lined by sebaceous ductal epithelium.

On the basis of a study of 13 patients with PC type 1 or type 2, Terrinoni et al. (2001) concluded that the presence of pilosebaceous cysts following puberty is the best indicator of PC type 2; prepubescent patients are more difficult to classify due to the lack of cysts. Natal teeth are indicative of PC type 2, although their absence does not preclude the PC type 2 diagnosis.

Genetic Heterogeneity of Pachyonychia Congenita

See pachyonychia congenita-2 (PC2; 167210), caused by mutation in the KRT17 gene (148069) on chromosome 17; PC3 (615726), caused by mutation in the KRT6A gene (148041) on chromosome 2; and PC4 (615728), caused by mutation or in the KRT6B gene (148042) on chromosome 12.

See 260130 for a possible autosomal recessive form of pachyonychia congenita.

Nomenclature

The form of PC caused by mutation in the KRT16 gene, here designated PC1, has also been designated PC-16 (Eliason et al., 2012) and PC-K16 (Shah et al., 2014).

Clinical Features

Pachyonychia congenita is characterized by oral leukokeratosis, onychogryposis, hyperkeratosis of the palms and soles, follicular keratosis, especially of the knees and elbows, and hyperhidrosis of the hands and feet. Occasionally dystrophic changes are also observed in the hair or cornea (Witkop and Gorlin, 1961).

Laryngeal changes requiring tracheostomy for respiratory distress during childhood were reported by Stieglitz and Centerwall (1983) in father and son. Feinstein et al. (1988) classified 168 reported cases into 4 types, of which type IV, present in 7.2% of the cases, had laryngeal lesions, hoarseness, mental retardation, hair anomalies, and alopecia.

Leachman et al. (2005) analyzed clinical, pathologic, and genetic data from the literature in 2 research registries. They found that more than 97% of PC cases exhibited fingernail and toenail thickening, and painful plantar keratoderma. Prospective evaluation of 57 PC patients from 41 families revealed variable clinical findings: hyperhidrosis (79%), oral leukokeratosis (75%), follicular keratosis (65%), palmar keratoderma (60%), cutaneous cysts (35%), hoarseness or laryngeal involvement (16%), coarse or twisted hair (26%), early primary tooth loss (14%), and presence of natal or prenatal teeth (2%). Stratification of these data by keratin mutation confirmed the increased incidence of cyst formation and natal teeth among PC2 patients, although cysts were more commonly seen in PC1 patients than had previously been reported (25-33%). Previously unreported clinical features of PC included development of painful oral and nipple lesions during breastfeeding, copious production of waxy material in ears, and inability to walk without an ambulatory aid (50%).

Pachyonychia Congenita, Late-Onset

Pachyonychia congenita with late onset of symptoms has been described by several authors (Paller et al., 1991; Iraci et al., 1993; Lucker and Steijlen, 1995; Mouaci-Midoun et al., 1996; Hannaford and Stapleton, 2000) and has been referred to as pachyonychia congenita tarda. Paller et al. (1991) described a late-onset form in which typical subungual hyperkeratoses began during the teenage years. Leukokeratosis and keratoderma of the palms and soles were associated. The family history of 3 of the 5 patients was consistent with autosomal dominant inheritance.

Connors et al. (2001) described a young girl with clinical features of pachyonychia congenita type 1 in whom the typical skin and nail changes were not noted until the age of 6 years. Direct sequencing of the KRT16 gene revealed a novel lys354 to asn mutation (K354N; 148067.0008) in the central 2B domain of the KRT16 polypeptide. Mutations in this region of KRT16 had not been described, but had been described in homologous regions of KRT14 (148066) in the milder Koebner (131900) and Weber-Cockayne (131800) variants of epidermolysis simplex. It was unclear whether the position of the mutation was sufficient to explain the late-onset phenotype.

Inheritance

Pachyonychia congenita is inherited as an autosomal dominant trait (Gorlin et al., 1976). Murray (1921) found 7 affected in 3 generations. Kumer and Loos (1935) found 24 affected in 5 generations. McKusick (1971) observed an apparent new mutation with transmission from father to son in a Jewish family.

Diagnosis

Prenatal Diagnosis

Using a genomic PCR system, Smith et al. (1999) carried out the first prenatal diagnosis of Jadassohn-Lewandowsky syndrome using CVS material, correctly predicting a normal fetus.

Molecular Genetics

In a sporadic case of pachyonychia congenita-1, described as the Jadassohn-Lewandowsky type, McLean et al. (1995) identified heterozygosity for a missense mutation (L132P; 148067.0001) in the helix initiation motif of KRT16.

In affected members of a 5-generation Dutch family with the Jadassohn-Lewandowsky type of PC, Smith et al. (1999) identified heterozygosity for a missense mutation (R127P; 148067.0005) in the KRT16 gene. In a sporadic case of pachyonychia congenita-1, they identified heterozygosity for a 3-bp deletion in KRT16 (148067.0004).

Smith et al. (2005) identified keratin mutations in 30 probands from the International Pachyonychia Congenita Research Registry, including 8 patients with mutations in the KRT16 gene (see, e.g., 148067.0001-148067.0003 and 148067.0012). Smith et al. (2005) noted that the probands from 2 families with the same mutation, N125S (148067.0003), had different phenotypes: 1 proband, who had complete lack of thickening and only minor splinter hemorrhages of the nails, was given a diagnosis of FNEPPK (613000), whereas the other proband had typical hypertrophic dystrophy involving 17 of 20 nails. The authors suggested that in keratin disorders, a combination of factors, genetic and environmental, might be involved in determining the overall clinical phenotype.

In a 36-year-old Chinese woman with severe hypertrophic dystrophy of the toenails and diffuse painful plantar keratoderma, with subtle focal palmar hyperkeratoses and normal nails of the hands, Du et al. (2012) identified heterozygosity for a KRT16 missense mutation (N125G; 148067.0013). Her 5-year-old daughter, who had only focal plantar hyperkeratosis at pressure points, without nail or hand involvement, was also heterozygous for the mutation. Both patients reported hyperhidrosis of the hands and feet. The mutation was not found in unaffected family members or in 100 controls.