Pachyonychia congenita (often abbreviated as "PC") is a rare group of
autosomal
An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosome ...
dominant skin disorders that are caused by a mutation in one of five different keratin genes. Pachyonychia congenita is often associated with thickened toenails, plantar keratoderma, and plantar pain.
Signs and symptoms
Pachyonychia congenita is characterized by a clinical triad present in 97% of people with PC by the time they turn 10 years old:
# Thickened toenails
# Plantar
keratoderma
Keratoderma is a hornlike skin condition.
Classification
The keratodermas are classified into the following subgroups:Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. .
Congenital
* Simple kera ...
# Plantar pain that may require some patients to use wheelchairs, canes, crutches, and pain medications due to its severity
Other signs and symptoms found in PC include:
* Thickened fingernails
* Palmar keratoderma
* Oral
leukokeratosis
* Cysts, including
steatocystoma multiplex
Steatocystoma multiplex is a benign, autosomal dominant congenital condition resulting in multiple cysts on a person's body. Steatocystoma simplex is the solitary counterpart to steatocystoma multiplex.
In steatocystoma multiplex, the tendency to ...
*
Follicular hyperkeratosis
*
Natal or prenatal teeth
* Blisters
* Excessive sweating of the palms and soles
* Excess earwax production
* Ear pain
* Hoarseness
*
Angular chelitis
Angular cheilitis (AC) is inflammation of one or both corners of the mouth. Often the corners are red with skin breakdown and crusting. It can also be itchy or painful. The condition can last for days to years. Angular cheilitis is a type of chei ...
* Fingernail and toenail infections
Cause
The condition is caused by
genetic mutations
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...
in one of five
genes
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
that encode
keratin
Keratin () is one of a family of structural fibrous proteins also known as ''scleroproteins''. It is the key structural material making up Scale (anatomy), scales, hair, Nail (anatomy), nails, feathers, horn (anatomy), horns, claws, Hoof, hoove ...
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s. Three keratin genes were identified to have a role PC in 1995
with a fourth keratin gene's role in PC identified in 1998.
Inheritance
Pachyonychia congenita follows an autosomal dominant pattern of inheritance, which means the defective gene is located on an
autosome
An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosomes ...
, and only one copy of the gene is required to inherit the disorder from a parent who has the disorder. On average, 50% of the offspring of an affected person will inherit the disorder, regardless of sex.
Occasionally, however, a solitary case can emerge in a family with no prior history of the disorder due to the occurrence of a new
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
(often referred to as a sporadic, spontaneous or de novo mutation).
Diagnosis
Classification
ILDS: Q84.520
ICD-10: Q84.5
Pachyonychia congenita consists of five sub-types, each named after its corresponding genetic mutation and each associated with distinguishing clinical features:
# PC-K6a is caused by a mutation in the
''KRT6A'' gene and more often associated with oral
leukokeratosis and poor feeding in infants.
# PC-K6b is caused by a mutation in the
''KRT6B'' gene and more commonly associated with an increased age of onset (>14 years).
# PC-K6c is caused by a mutation in the
''KRT6C'' gene and is the least common sub-type. It is not often associated with the additional features of oral leukokeratosis, cysts, follicular
hyperkeratosis
Hyperkeratosis is thickening of the stratum corneum (the outermost layer of the epidermis, or skin), often associated with the presence of an abnormal quantity of keratin,Kumar, Vinay; Fausto, Nelso; Abbas, Abul (2004) ''Robbins & Cotran Pathol ...
, and
natal teeth.
# PC-K16 is caused by a mutation in the
''KRT16'' gene and is more commonly associated with severe plantar pain.
# PC-K17 is caused by a mutation in the
''KRT17'' gene and more commonly associated with the presence of cysts, follicular kyperkeratosis, and natal teeth.
Before the genetic basis of Pachyonychia congenita was identified and described, the disease was historically divided into the following sub-types:
[Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. .]
* Pachyonychia congenita type I (also known as "Jadassohn–Lewandowsky syndrome"
) is an
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
keratoderma
Keratoderma is a hornlike skin condition.
Classification
The keratodermas are classified into the following subgroups:Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. .
Congenital
* Simple kera ...
that principally involves the plantar surfaces, but also with nails changes that may be evident at birth, but more commonly develop within the first few months of life.
[James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. .]
* Pachyonychia congenita type II (also known as "Jackson–Lawler pachyonychia congenita" and "Jackson–Sertoli syndrome") is an autosomal dominant keratoderma presenting with a limited focal plantar keratoderma that may be very minor, with nails changes that may be evident at birth, but more commonly develop within the first few months of life.
Clinical Diagnosis
In order to clinically diagnose pachyonychia congenita, the clinical triad of toenail thickening, plantar keratoderma, and plantar pain must be present. This triad is present in 97% of individuals with PC by the age of 10 years old.
Pachyonychia congenita can be suspected in patients who do not have the complete clinical triad but who exhibit other symptoms such as cysts, oral leukokeratosis, follicular hyperkeratosis, palmoplantar
hyperhidrosis
Hyperhidrosis is a medical condition in which a person exhibits excessive perspiration, sweating, more than is required for the Thermoregulation, regulation of body temperature. Although it is primarily a physical burden, hyperhidrosis can deterio ...
, or natal teeth. Since PC is inherited in an autosomal dominant fashion in 70% of individuals, it should especially be suspected in patients with symptoms who also have a parent with similar symptoms. Histopathological analysis of skin or nail tissue is not helpful in diagnosis of PC, but can be used to rule out some related diseases. If there is a clinical suspicion for PC,
genetic testing
Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
can confirm the diagnosis.
Genetic Diagnosis
The diagnosis of PC can be confirmed by the identification of a mutation in one of the five genes responsible for the condition: ''KRT6A, KRT6B, KRT6C, KRT16, KRT17.'' Pachyonychia Congenita Project is a non-profit dedicated to finding a cure for PC. The organization houses a genetic registry (the International PC Research Registry) and offers free genetic testing for individuals suspected to have PC.
Treatment
There is currently no cure for pachyonychia congenita. Treatment focuses on symptom relief for any plantar pain, hyperkeratoses, cysts, leukokeratosis, hyperhidrosis, or secondary infections.
Palmoplantar keratoderma can be treated with consistent grooming, including trimming back the callus, applying emollients, and draining blisters. Plantar pain is often treated by reducing pressure on the feet by minimizing walking, wearing cushioned footwear, or using wheelchairs or crutches. Hyperkeratosis can be treated with keratolytic emollients while cysts may be treated with incision and drainage. Patients with hyperhidrosis may need to wear moisture-wicking socks and ventilated shoes. Any secondary infection may need to be treated with antibiotics, though infection can often be prevented with appropriate grooming and vinegar or bleach baths.
Epidemiology
Pachyonychia congenita is a rare disorder with an unknown prevalence. As of 2018, the International PC Research Registry has identified approximately 774 individuals with the disease, but prevalence is estimated to be 5,000–10,000 worldwide.
The disease affects both males and females.
Research
There are several ongoing investigational therapies for pachyonychia congenita, including topical
sirolimus
Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis ...
,
siRNA
Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded non-coding RNA molecules, typically 20–24 base pairs in length, similar to microRNA (miRNA), and operating within the RN ...
,
botulinum toxin
Botulinum toxin, or botulinum neurotoxin (commonly called botox), is a neurotoxic protein produced by the bacterium ''Clostridium botulinum'' and related species. It prevents the release of the neurotransmitter acetylcholine from axon en ...
,
statin
Statins (or HMG-CoA reductase inhibitors) are a class of medications that lower cholesterol. They are prescribed typically to people who are at high risk of cardiovascular disease.
Low-density lipoprotein (LDL) carriers of cholesterol play ...
s, and
anti-TNF biologics.
Pachyonychia Congenita Project houses a list of clinical trials and assists with clinical trial recruitment from patients enrolled in their International PC Research Registry.
See also
*
Unilateral palmoplantar verrucous nevus
A Unilateral palmoplantar verrucous nevus is a cutaneous condition that has features of pachyonychia congenita.
See also
* Unilateral nevoid telangiectasia
* List of cutaneous conditions
Many skin conditions affect the human integumentary ...
*
List of cutaneous conditions
Many skin conditions affect the human integumentary system—the organ system covering the entire surface of the Human body, body and composed of Human skin, skin, hair, Nail (anatomy), nails, and related muscle and glands. The major function o ...
References
External links
GeneReviews/NCBI/NIH/UW entry on Pachyonychia Congenita*
{{Authority control
Genodermatoses
Autosomal dominant disorders
Conditions of the skin appendages
Papulosquamous hyperkeratotic cutaneous conditions