NORD gratefully acknowledges Frances Smith, PhD, Chief Scientific Officer, Pachyonychia Congentia Project, for assistance in the preparation of this report.
Pachyonychia congenita (PC) is a rare keratinizing skin disorder inherited in an autosomal dominant fashion. The predominant characteristics are severe plantar pain, palmoplantar keratoderma (PPK) including calluses with underlying blisters and variable hypertrophic nail dystrophy, often accompanied by oral leukokeratosis, cysts of various types, follicular hyperkeratosis, palmoplantar hyperhydrosis and sometimes natal teeth.Introduction
Historically, PC was subdivided into PC-1 (caused by mutations in KRT6A or KRT16) and PC-2 (due to mutations in KRT6B or KRT17). However, based on clinical and molecular data collected by the International Pachyonychia Congenita Research Registry (IPCRR; www.pachyonychia.org ) the nomenclature was revised in 2011. Those with mutations in KRT6A are named PC-K6a, those with mutations in KRT16 are PCK16 etc.
The symptoms and severity of pachyonychia congenita can vary widely, even among individuals in the same family or among individuals with the same disease-causing gene mutation.
The most predominant feature, palmoplantar keratoderma usually begins when a child starts weight bearing and walking. Blisters develop beneath the calluses causing extreme pain. This can lead to the use of crutches, canes or wheelchairs. Nail dystrophy (fingernails and toenails) is typically noted within the first few months/year of life. Nails tend to either (a) grow to full length with an upward slant caused by prominent distal hyperkeratosis or (b) have a nail plate that terminates prematurely to leave a gently sloping distal region of hyperkeratosis and exposed distal finger tip. Infections can occur under the nails and be painful.
Cysts of various types including vellus hair cysts and steatocystomas usually develop at puberty and continue into adulthood. In some cases of PC, particularly PC-K17, cysts can be the most painful and problematic characteristic. Multiple milia (particularly on the face) often occur in young children with PC-K17. Follicular keratoses occur in some patients on the trunk, elbows and knees, usually in early childhood. Oral leukokeratosis (white patches on the tongue and cheek) is more common in those with PC-K6a. It is often present at birth or within the first few months of life and can be misdiagnosed as Candida albicans if no other symptoms of PC are apparent. Natal or prenatal teeth are more commonly seen in those with mutations in KRT17. Palmoplantar hyperhydrosis occurs in about 50% of cases with PC.
Other less common features include angular cheilitis, laryngeal involvement resulting in a hoarse cry or hoarse voice and ‘first bite syndrome’. First bite syndrome is more common in young children and is intense pain near the jaw or ears that lasts about 15-25 seconds when beginning to eat or swallow.
Variants of PC:
There are several autosomal dominant disorders that are classified as variants of pachyonychia congenita.
Focal non-epidermolytic palmoplantar keratoderma (FNEPPK): keratoderma of varying severity is present on the palms and soles with no/very mild nail changes, caused by mutations in KRT16 or KRT6C.
Steatocystoma multiplex (SM): widespread pilosebaceous cysts develop at puberty, but there is little or no nail involvement or palmoplantar keratoderma, due to mutations in KRT17.
Pachyonychia congenita is caused by a mutation in one of five keratin genes, KRT6A, KRT6B, KRT6C, KRT16 or KRT17. These mutations are inherited in an autosomal dominant manner, although approximately 40% of cases are the result of new spontaneous mutations with no previous family history. In an autosomal dominant disorder, only one copy of an abnormal gene is necessary to produce clinical symptoms. The risk of an affected individual passing the abnormal gene to offspring is 50 percent for each pregnancy.
The majority of the mutations are heterozygous single base pair changes resulting in an amino acid change (missense mutations) with a small number of deletion/insertion mutations, splice site mutations and nonsense mutations. Some mutations are found in a number of families (recurrent mutations), while other more rare mutations have only been observed in single families to date. All keratins share a similar protein structure consisting of an alpha helical central rod domain (subdivided into 4 domains connected by nonhelical linker regions). The majority of mutations causing PC are within the helix boundary domains at either end of the alpha helical rod domain. These regions are thought to play a vital role during end to end overlap interactions during keratin filament assembly.
The variants of PC are also caused by mutations in the same keratin genes associated with PC (see Diagnosis, below).
PC affects both males and females. No ethnic differences have been reported. Prevalence is estimated at between 5,000 and 10,000 worldwide.
PC is normally diagnosed by clinical examination, which can now be confirmed at the molecular level. Molecular diagnosis (from a blood sample or saliva sample), of PC patients is available to identify the exact gene defect (mutation) in KRT6A, KRT6B, KRT6C, KRT16 or KRT17 and to confirm the clinical diagnosis. See PC Project website (www.pachyonychia.org) for details about genetic testing.
At present there is no cure or specific treatment for PC. Patients manage their symptoms in a variety of ways either at home or with professional care. The main issue of plantar hyperkeratosis is dealt with by paring/trimming/grinding/filing and, thickened nails by filing/grinding/clipping. Topical agents including keratolytics (eg. salicylic acid, urea) and moisturizers provide limited benefit in softening the skin. For some patients, retinoids can help in thinning the callus but may lead to increased pain. A soft nipple with an enlarged opening on a feeding bottle can help young infants with oral leukokeratosis that are failing to thrive and may also have ‘first bite syndrome’. Cysts do not usually require treatment but if infected or painful can be incised and drained. Wicking socks and ventilated footwear can help with hyperhidrosis. For further information on patient care and tools see www.pachyonychia.org.
Several different therapeutic strategies to develop more specific and effective treatment for PC have recently been investigated. These include siRNAs, rapamycin, topical rapamycin and simvastatin. A number of studies are ongoing and several clinical trials are planned for 2016.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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