Clinical characteristics.

Pachyonychia congenita (PC) is characterized by hypertrophic nail dystrophy, painful palmoplantar keratoderma and blistering, oral leukokeratosis, pilosebaceous cysts (including steatocystoma and vellus hair cysts), palmoplantar hyperhydrosis, and follicular keratoses on the trunk and extremities.

Diagnosis/testing.

PC is diagnosed by clinical findings and/or by the identification of a heterozygous pathogenic variant in one of the five keratin genes known to cause PC: KRT6A, KRT6B, KRT6C, KRT16, and KRT17.

Management.

Treatment of manifestations: Pain from the palmoplantar keratoderma may be reduced somewhat by limiting friction and trauma to the feet by minimizing walking or standing, reducing hydration of the stratum corneum by using wicking socks and ventilated footwear, selecting comfortable shoes, and maintaining ideal body weight. Foot care includes paring down of hyperkeratotic areas and topical therapies for hyperkeratosis (emollients and lotions containing keratolyics). Care of thickened nails often requires the use of surgical or razor blades or sanders such as a Dremel^® tool. Troublesome nails removed surgically frequently grow back in some form. Good oral hygiene and brushing gently with a soft toothbrush can improve thick, white patches on the tongue and oral mucosa. Secondary fungal and bacterial infections that require treatment are common; cysts usually do not require treatment but can be incised and drained if infected or painful. Bottle-fed infants with leukokeratosis may need a soft nipple with an enlarged opening. Rarely, young children with laryngeal thickening/growths need emergency surgery to reestablish the airway; however, surgery may exacerbate the condition.

Prevention of secondary complications: Attention to pre- and post-grooming hygiene to prevent infection; a "bleach bath" regimen using a mild bleach solution can help prevent infections.

Agents/circumstances to avoid: High temperatures and high humidity may worsen the condition.

Genetic counseling.

Pachyonychia congenita is inherited in an autosomal dominant manner. Approximately 30% of cases appear to be caused by a de novo pathogenic variant. A single case of germline mosaicism has been reported. The offspring of an affected individual have a 50% chance of inheriting the disorder. If the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk is possible.

Suggestive Findings

Pachyonychia congenita (PC) should be suspected in individuals with the following clinical features and/or family history findings.

Clinical features

• Plantar keratoderma including callus with underlying blisters
• Plantar pain
• Hypertrophic nail dystrophy, which may be limited to the toenails or to a few toenails or fingernails (See Figure 1 and Table 2.)
• Pilosebaceous cysts including widespread steatocystomas/steatocysts (benign lesions) and vellus hair cysts which usually develop at puberty and continue throughout adulthood
• Oral leukokeratosis
• Follicular keratoses on the trunk and extremities usually present by early childhood
• Palmoplantar hyperhydrosis (<50%)
• Natal or prenatal teeth (i.e., present at birth or by age 1 month in some affected individuals)

Figure 1.

Common findings of pachyonychia congenita include: thickened and dystrophic nails (both fingernails and toenails) (a-c); bullae (usually on the pressure points of the heels and soles); hyperkeratosis (d-e); cysts (f); and oral leukokeratosis (g).

Family history consistent with autosomal dominant inheritance

Note: (1) Approximately 70% of individuals with PC, enrolled in the International Pachyonychia Congenita Research Registry, inherited the condition from an affected parent; therefore, lack of a family history of PC does not preclude the diagnosis. (2) If the family history suggests autosomal recessive inheritance, a condition other than PC should be considered (see Differential Diagnosis).

Establishing the Diagnosis

The diagnosis of PC is established in a proband with the triad of toenail thickening, plantar keratoderma, and plantar pain and/or by the identification of a heterozygous pathogenic variant in one of the five genes listed in Table 1.

Note: Histologic, immunohistologic, or electron microscopic examination of the nails or skin from individuals with PC is not helpful in confirming the diagnosis of PC but can be performed to rule out other diagnoses.

Molecular genetic testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Serial single-gene testing

• For individuals who have focal non-epidermolytic palmoplantar keratoderma (FNEPPK), sequence analysis of KRT6C and KRT16 may be considered first.
• For individuals who have steatocystoma multiplex (SM) or a history of natal teeth, sequence analysis of KRT17 may be considered first.

A multigene panel that includes KRT6A, KRT6B, KRT6C, KRT16, KRT17, and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene varies by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

In all types of pachyonychia congenita (PC) most characteristics are visible by age ten years [Shah et al 2014] and typically include toenail thickening, plantar keratoderma, and plantar pain (see Suggestive Findings). However, the absence or presence of certain features as well as the age at onset varies according the gene that is mutated (see Table 2 for phenotypic features of PC). The most recent classification of the condition also incorporates the genetic cause (see Nomenclature).

The severity of findings can differ both within a family and among families with the same pathogenic variant.