pachyonychia congenita
TRANSCRIPT
Pachyonychia Congenita
1/31/2015 Prepared by Dixi Dawn F. Apigo
DESCRIPTION
• Etymology
– Greek
• Pachy = “thick”
• Onyx = “nail”
– Latin
• Congenita = “born with”
1/31/2015 Prepared by Dixi Dawn F. Apigo
What is Pachyonychia
Congenita?• An autosomal dominant condition that
primarily affects the nails & skin.
• Signs & symptoms usually become apparent within few months of life
• Pachyonichia congenita tarda – a rare form of the condition
– Appears in adolescence or early adulthood.
• This disorder does not affect lifespan, but patients do experience constant pain.
1/31/2015 Prepared by Dixi Dawn F. Apigo
CLINICAL MANIFESTATIONS
• Hypertrophic nail dystrophy: A hallmark of this disorder is thickened & abnormally shaped fingernails & toenails.
• Painful calluses & blisters: Palms & the feet will have painful blisters & calluses. makes it almost impossible for the child to walk
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CLINICAL MANIFESTATIONS
• Palmoplantar keratoderma
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CLINICAL MANIFESTATIONS
• Follicular hyperkeratosis: Bumps around
hair follicles in areas that get lots of
friction: waist, hips, knees, elbows
• Oral leukokeratosis: thick, white patches
inside the mouth and on the tongue
• Palmoplantar hyperhidrosis: excessive
sweating on the palms & soles
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CLINICAL MANIFESTATIONS
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Less common features
• Angular cheilitis: sores at the corner of the mouth
• Teeth at or before birth
• Laryngeal involvement with a white keratin film on the larynx causing hoarseness or breathing difficulties
• Intense pain on first bite: The pain is near the jaw or ears & lasts 15-25 seconds when beginning to eat or swallow– More common in younger children & often
confused with ear problems.
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GENETIC CAUSES OF
PACHYONYCHIA CONGENITA
Etiology & Pathogenesis
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Loci
• The keratin genes are located in two clusters
• Keratins are a family of related proteins with about 54 members.
• Keratins are proteins that form tough fibersthat strengthen skin, hair and finger nails.
• Only mutations in keratins 6a, 6b, 16, and 17 are linked to PC
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• Normal keratin filaments form a strong structuralnetwork (left) that enables cells to withstandpressure and stretching. Mutant keratin proteinsform clumps (right), resulting in weak cells thatbreak open under pressure. Images courtesy Prof. W.H. Irwin McLean,University of Dundee, Scotland. Keratin filaments are green, and cell nuclei are blue.
1/31/2015 Prepared by Dixi Dawn F. Apigo
KRT6A
KRT6 a gene provides
instructions for making
Keratin 6a
The keratin that gives the tough framework to skin of the
palms & feet, nails, & the mucous lining inside the mouth
K6A teams with K16
To create dense networks
Give strength & residency to the skin & nails
K6A is also involved in wound healing
KRT6A is located on the long arm (q) of chromosome
12 at position 13.13
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KRT6A Mutation
Over 20 mutations in PC-
1.
Most mutations involve only a single AA protein building block
A few add or delete genetic material
Change structure of K6A & disrupt the creation of keratin filament network
Without functional keratin
Skin & nails are easily damaged
Painful & distorted nails, skin, & other
symptoms
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KRT16
• Long arm (q) of chromosome 16 at position 21.2
KRT16
• Provides instruction for K16
K16
• Works with K6
• To make strong, tough keratin intermediate filaments
Keratin intermediate
filaments
• Provide strength & resiliency to the nails, skin & other tissues
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KRT16 Mutations
Over 13 mutations in KRT16 cause PC-1
Most cases: the condition is present at
birth or recognized soon after
Most mutations occur in the exchange of only 1 amino acid
building block
A few mutations may delete a few amino
acids
The changes disrupt the assembly
pathways of keratin
1/31/2015 Prepared by Dixi Dawn F. Apigo
KRT6B
• Long arm (q) of chromosome 12 at position 13.13
KRT6B instructs
K6b
K6b
- is found in the tough fibrous framework of cells that form skin, hair, & nails
- Also found in the sweat glands
K6b joins with keratin 7 to form keratin intermediate filaments
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KRT6B Mutations
Without proper keratin structure
Soles of the feet become very fragile & blister easily, & nails do not function
properly
Sweat glands are also affected & leads to the development of cysts
Mutations disrupt
the work with keratin 17 the creation of the keratin network
2 mutations in KRT6B cause PC-2
Change only 1 amino acid building block Delete the genetic material
1/31/2015 Prepared by Dixi Dawn F. Apigo
KRT17
• Locus 17q21.2
KRT17 instructs for the protein K17
Produced in the nails, hair follicles, skin on the palms & soles, sweat glands or sebaceous glands
K17 partners with K6 to make the proper keratin structure that are tough & resilient
1/31/2015 Prepared by Dixi Dawn F. Apigo
KRT17 Mutations
About 16 mutations in KRT17 cause PC-2
Most mutations are the result of only 1 amino
acid building block
Alteration in the structure of K-17 keeps
it from working effectively with K-6b
Mutations disrupt the filament network
Leading to a breakdown in the skin cells, formation of cysts, & malfunction of the nails
& hair follicle cells
1/31/2015 Prepared by Dixi Dawn F. Apigo
Diagnosis & Management
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Diagnosis
• Usually by its clinical appearance
• Skin biopsy of affected tissue show only
nonspecific changes
• Molecular genetic testing – to detect the
affected keratin genes
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Classification of PC based on clinical
manifestations
PC-1 PachyonychiaCongenita Type 1
• Has most of the features
listed
• Related to mutations in
two genes:
1. KRT6A
2. KRT16
PC-2 PachyonychiaCongenita Type 2
• Has additional features
• Development of cysts, called steatocytomas, all over the body.
• Coarse, twisted & brittle hair
• Some babies may be born with prenatal teeth
1. KRT6B
2. KRT17
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Classification of PC based on keratin
gene with specific mutation
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Treatment
• Effectiveness of treatment depends on the severity of the specific problem
• Treatment might include: – Emollients – soften the skin
– Keratolytics eg salicylic acid ointment (for treatment of scaly skin diseases), urea cream (a natural moisturizing factor) or other forms of heel balm
– Mechanical debridement
– Pain relief
– Oral retinoids eg acitretin
1/31/2015 Prepared by Dixi Dawn F. Apigo
References
• Genetic Learning Center. Pachyonychia congenita. Retrieved from http://learn.genetics.utah.edu/content/disorders/singlegene/pc/
• Kelly, E.B. (2013). Encyclopaedia of human genetics and disease. Santa Barbara, California: ABC-CLIO, LLC
• Pachyonychia Congenita Project: What is pachyonychia congenita? Retrieved from http://www.pachyonychia.org/what_is_pc.php
• DermNet NZ. (2014). Pachyonychia congenita. Retrieved from http://www.dermnetnz.org/scaly/pachyonychia.html
1/31/2015 Prepared by Dixi Dawn F. Apigo