Pachyonychia Congenita Clinical Presentation

Pachyonychia congenita type 1 (Jadassohn-Lewandowski syndrome)

Pachyonychia congenita type 1 is the more common variant.

Hypertrophic nail dystrophy (pachyonychia) is the characteristic feature of pachyonychia congenita and affects 90-98% of patients.^[5] All 20 nails are usually affected, with thickening and discoloration present at birth or developing within the first few months of life. Although the pachyonychia is usually striking, pachyonychia congenita may present with very subtle nail changes.^[10] A strict phenotype-genotype correlation between mutations and clinical severity has not been established, and members of the same family may express varying degrees of nail involvement.^[11] The thickened nails often require constant paring and grooming to prevent overgrowth and trauma, and they may be accompanied by painful paronychia (both pressure related and infectious). The nail dystrophy also often results in difficulty with fine motor tasks such as handling or picking up small objects.

Symmetric focal palmoplantar keratoderma is another characteristic finding of the disorder and occurs in 91-96% of patients.^[5] It usually develops in early childhood, after the nail changes, and with the start of walking and weight bearing. The keratoderma is characteristically exquisitely painful. Quality-of-life assessments in patients with pachyonychia congenita point to it as the most disabling feature of the disease. The keratoderma is generally worse on plantar surfaces than on palmar surfaces and is often preceded or accompanied by blistering. Fissuring and secondary infection may also occur. Although some degree of keratoderma is seen in most pachyonychia congenita patients, the severity of the keratoderma—similar to the nail changes—is highly variable.^[10]

Oral leukokeratosis (non–premalignant) is another prominent feature of pachyonychia congenita, especially pachyonychia congenita type 1. Similar to the nail changes, it is often present at or soon after birth and may be one of the earliest sign of pachyonychia congenita. The leukokeratotic plaques occur most commonly on the tongue and buccal surfaces of the mouth. In newborns, the leukokeratoses may lead to difficulties in suckling and breastfeeding.^[5]

Palmoplantar hyperhidrosis is frequently observed and may lead to exacerbations of blister formation and pain.

Follicular keratoses (seen in 65-79% patients) may develop on extensor surfaces of the extremities and in areas of friction such as along the waist. They are generally more severe in childhood, and they improve with age.^[5]

Laryngeal involvement, primarily in young children, may occur and usually manifests as hoarseness. Respiratory stridor requiring emergent tracheotomy is a rare but life-threatening complication that has been reported. Laryngoscopic evaluation has revealed laryngeal changes that range from thickening to exophytic masses.^{[12, 13, 14, 15]}

Pachyonychia congenita type 1 patients do not develop the numerous steatocystomas or vellus hair cysts associated with pachyonychia congenita type 2. Cysts may occur in pachyonychia congenita type 1 but they are generally typical epidermal inclusion cysts. They often develop in intertriginous areas and may be numerous enough to mimic hidradenitis suppurativa.^{[5] [16]}

Pachyonychia congenita type 2 (Jackson-Lawler syndrome)

The key clinical features of pachyonychia congenita type 1 are also seen in pachyonychia congenita type 2, although the palmoplantar keratoderma may be milder and oral leukokeratoses less frequently seen in pachyonychia congenita type 2. The distinguishing features of pachyonychia congenita type 2 are natal teeth, steatocystomas, and pili torti.

Natal or prenatal teeth are associated with pachyonychia congenita type 2 and are present at birth or within the first 30 days of life.^{[5, 17, 18]} They are typically lost in infancy and replaced with normal permanent teeth during childhood. Natal teeth may lead to trauma or lacerations of the infant’s tongue or mother’s breast during breastfeeding and can pose an aspiration risk in infancy. The occurrence of natal teeth in a patient with nail findings of pachyonychia congenita is highly suggestive of pachyonychia congenita type 2, but their absence does not confirm a pachyonychia congenita type 1 phenotype because the teeth are not a consistently penetrant feature of pachyonychia congenita type 2, even within the same family.

Pachyonychia congenita type 2 is classically characterized by the development of numerous steatocystomas, although a variety of cysts, including epidermal inclusion cysts, pilosebaceous cysts, and vellus hair cysts, may be seen.^{[5, 18, 19, 20]} Although steatocystomas and vellus hair cysts appear to be a reliable distinguishing feature of pachyonychia congenita type 2, their onset at or after puberty makes them less helpful in establishing a diagnosis of pachyonychia congenita type 2 over pachyonychia congenita type 1 in childhood.

Pili torti, or twisted hair, has been reported as a rare occurrence in some patients with pachyonychia congenita type 2.^{[19, 16]}

Pachyonychia congenita type 1 (Jadassohn-Lewandowski syndrome)

The hypertrophic nail dystrophy usually affects all 20 nails. The nails may grow to full length and have an upward-slanted or heaped-up appearance due to a progressive distal thickening, or the plate may terminate prematurely with a gently sloped distal edge of hyperkeratosis and exposed distal finger tip. The surface of the plate can be smooth or rough and is often discolored. Note the image below.

The palmoplantar keratoderma of pachyonychia congenita is symmetric and focal, developing particularly in areas of friction, trauma, and weight bearing. Blisters often develop within or adjacent to the calloused areas.

Follicular hyperkeratoses are reminiscent of severe keratosis pilaris and are most frequently found on the elbows and knees and along the waistband area. Note the image below.

Leukokeratosis of the oral mucosa, as shown below, is a prominent sign, especially of pachyonychia congenita type 1. Patchy whitish areas are most commonly seen on the tongue and buccal mucosa. The gingival mucosa is rarely involved. The clinical appearance of the lingual and buccal leukokeratosis can resemble candidiasis and premalignant leukoplakia, respectively. Buccal lesions are often accentuated at areas of trauma such as along the bite line.

Pachyonychia congenita type 2 (Jackson-Lawler syndrome)

Physical examination findings associated with the distinguishing features of pachyonychia congenita type 2 are natal teeth, steatocystomas, and pili torti.

Natal or prenatal teeth can generally be seen in a frontal position and are often friable and prone to caries. Steatocystomas present as numerous small skin- to yellow-colored cysts that range from a few millimeters to a few centimeters and typically occur in sebaceous gland–dense areas such as the chest, arms, armpit, and neck. Pili torti presents as short and brittle hairs.

Pachyonychia congenita results from autosomal dominant mutations occurring in 1 of 4 genes encoding keratins. Keratins are key proteins that form the cytoskeletal intermediate filament network within all epithelial cells. Various epithelial cell types express a different range of keratins based on cell function.

The mutations in pachyonychia congenita type 1 are found in the genes encoding keratin 6A (KRT6A) or its expression partner keratin 16 (KRT16).The mutations in pachyonychia congenita type 2 occur in the keratin gene KRT6B or its expression partner KRT17.^{[11, 21, 22]} These keratins are constitutively expressed in keratinocytes of the nail, palmoplantar skin, mucosa, and hair, leading to the manifestations of the disorder in these sites. The basic protein structure of a keratin filament consists of an alpha-helical rod that is divided into 4 domains (1A, 1B, 2A, 2B) linked together by nonhelical linkers (L1, L12, L2). A helix initiation motif and a helix termination motif segment can be found at the either end of the alpha-helical rod and are highly conserved in sequence between keratins.

As with most other keratin disorders, the majority of mutations in pachyonychia congenita occur in these highly conserved helix boundary domains at the end of the rod domain. Proper function of these highly conserved domains appears to be critical for normal keratin filament assembly and cytoskeletal integrity; mutations result in cell fragility.

Keratin mutations associated with the delayed-onset form of pachyonychia congenita, or pachyonychia congenita tarda, have been found outside the helix boundary motif regions of the K16 and K17 proteins.^{[23, 24]}