Generic selectors
Exact matches only
Search in title
Search in content
Post Type Selectors
Search in posts
Search in pages
Filter by Categories
15th National Conference of the IAOMFP, Chennai, 2006
Abstract
Abstracts from current literature
Acne in India: Guidelines for management - IAA Consensus Document
Addendum
Announcement
Art & Psychiatry
Article
Articles
Association Activities
Association Notes
Award Article
Book Review
Brief Report
Case Analysis
Case Letter
Case Letters
Case Notes
Case Report
Case Reports
Clinical and Laboratory Investigations
Clinical Article
Clinical Studies
Clinical Study
Commentary
Conference Oration
Conference Summary
Continuing Medical Education
Correspondence
Corrigendum
Cosmetic Dermatology
Cosmetology
Current Best Evidence
Current Issue
Current View
Derma Quest
Dermato Surgery
Dermatopathology
Dermatosurgery Specials
Dispensing Pearl
Do you know?
Drug Dialogues
e-IJDVL
Editor Speaks
Editorial
Editorial Remarks
Editorial Report
Editorial Report - 2007
Editorial report for 2004-2005
Errata
Erratum
Focus
Fourth All India Conference Programme
From Our Book Shelf
From the Desk of Chief Editor
General
Get Set for Net
Get set for the net
Guest Article
Guest Editorial
History
How I Manage?
IADVL Announcement
IADVL Announcements
IJDVL Awards
IJDVL AWARDS 2015
IJDVL Awards 2018
IJDVL Awards 2019
IJDVL Awards 2020
IJDVL International Awards 2018
Images in Clinical Practice
In Memorium
Inaugural Address
Index
Knowledge From World Contemporaries
Leprosy Section
Letter in Response to Previous Publication
Letter to Editor
Letter to the Editor
Letter to the Editor - Case Letter
Letter to the Editor - Letter in Response to Published Article
LETTER TO THE EDITOR - LETTERS IN RESPONSE TO PUBLISHED ARTICLES
Letter to the Editor - Observation Letter
Letter to the Editor - Study Letter
Letter to the Editor - Therapy Letter
Letter to the Editor: Articles in Response to Previously Published Articles
Letters in Response to Previous Publication
Letters to the Editor
Letters to the Editor - Letter in Response to Previously Published Articles
Letters to the Editor: Case Letters
Letters to the Editor: Letters in Response to Previously Published Articles
Medicolegal Window
Messages
Miscellaneous Letter
Musings
Net Case
Net case report
Net Image
Net Images
Net Letter
Net Quiz
Net Study
New Preparations
News
News & Views
Obituary
Observation Letter
Observation Letters
Oration
Original Article
ORIGINAL CONTRIBUTION
Original Contributions
Pattern of Skin Diseases
Pearls
Pediatric Dermatology
Pediatric Rounds
Perspective
Presedential Address
Presidential Address
Presidents Remarks
Quiz
Recommendations
Regret
Report
Report of chief editor
Report of Hon : Treasurer IADVL
Report of Hon. General Secretary IADVL
Research Methdology
Research Methodology
Resident page
Resident's Page
Resident’s Page
Residents' Corner
Residents' Corner
Residents' Page
Retraction
Review
Review Article
Review Articles
Reviewers 2022
Revision Corner
Self Assessment Programme
SEMINAR
Seminar: Chronic Arsenicosis in India
Seminar: HIV Infection
Short Communication
Short Communications
Short Report
Snippets
Special Article
Specialty Interface
Studies
Study Letter
Study Letters
Supplement-Photoprotection
Supplement-Psoriasis
Symposium - Contact Dermatitis
Symposium - Lasers
Symposium - Pediatric Dermatoses
Symposium - Psoriasis
Symposium - Vesicobullous Disorders
SYMPOSIUM - VITILIGO
Symposium Aesthetic Surgery
Symposium Dermatopathology
Symposium-Hair Disorders
Symposium-Nails Part I
Symposium-Nails-Part II
Systematic Review and Meta-Analysis
Systematic Reviews and Meta-analyses
Systematic Reviews and Meta-analysis
Tables
Technology
Therapeutic Guideline-IADVL
Therapeutic Guidelines
Therapeutic Guidelines - IADVL
Therapeutics
Therapy
Therapy Letter
Therapy Letters
View Point
Viewpoint
What’s new in Dermatology
Generic selectors
Exact matches only
Search in title
Search in content
Post Type Selectors
Search in posts
Search in pages
Filter by Categories
15th National Conference of the IAOMFP, Chennai, 2006
Abstract
Abstracts from current literature
Acne in India: Guidelines for management - IAA Consensus Document
Addendum
Announcement
Art & Psychiatry
Article
Articles
Association Activities
Association Notes
Award Article
Book Review
Brief Report
Case Analysis
Case Letter
Case Letters
Case Notes
Case Report
Case Reports
Clinical and Laboratory Investigations
Clinical Article
Clinical Studies
Clinical Study
Commentary
Conference Oration
Conference Summary
Continuing Medical Education
Correspondence
Corrigendum
Cosmetic Dermatology
Cosmetology
Current Best Evidence
Current Issue
Current View
Derma Quest
Dermato Surgery
Dermatopathology
Dermatosurgery Specials
Dispensing Pearl
Do you know?
Drug Dialogues
e-IJDVL
Editor Speaks
Editorial
Editorial Remarks
Editorial Report
Editorial Report - 2007
Editorial report for 2004-2005
Errata
Erratum
Focus
Fourth All India Conference Programme
From Our Book Shelf
From the Desk of Chief Editor
General
Get Set for Net
Get set for the net
Guest Article
Guest Editorial
History
How I Manage?
IADVL Announcement
IADVL Announcements
IJDVL Awards
IJDVL AWARDS 2015
IJDVL Awards 2018
IJDVL Awards 2019
IJDVL Awards 2020
IJDVL International Awards 2018
Images in Clinical Practice
In Memorium
Inaugural Address
Index
Knowledge From World Contemporaries
Leprosy Section
Letter in Response to Previous Publication
Letter to Editor
Letter to the Editor
Letter to the Editor - Case Letter
Letter to the Editor - Letter in Response to Published Article
LETTER TO THE EDITOR - LETTERS IN RESPONSE TO PUBLISHED ARTICLES
Letter to the Editor - Observation Letter
Letter to the Editor - Study Letter
Letter to the Editor - Therapy Letter
Letter to the Editor: Articles in Response to Previously Published Articles
Letters in Response to Previous Publication
Letters to the Editor
Letters to the Editor - Letter in Response to Previously Published Articles
Letters to the Editor: Case Letters
Letters to the Editor: Letters in Response to Previously Published Articles
Medicolegal Window
Messages
Miscellaneous Letter
Musings
Net Case
Net case report
Net Image
Net Images
Net Letter
Net Quiz
Net Study
New Preparations
News
News & Views
Obituary
Observation Letter
Observation Letters
Oration
Original Article
ORIGINAL CONTRIBUTION
Original Contributions
Pattern of Skin Diseases
Pearls
Pediatric Dermatology
Pediatric Rounds
Perspective
Presedential Address
Presidential Address
Presidents Remarks
Quiz
Recommendations
Regret
Report
Report of chief editor
Report of Hon : Treasurer IADVL
Report of Hon. General Secretary IADVL
Research Methdology
Research Methodology
Resident page
Resident's Page
Resident’s Page
Residents' Corner
Residents' Corner
Residents' Page
Retraction
Review
Review Article
Review Articles
Reviewers 2022
Revision Corner
Self Assessment Programme
SEMINAR
Seminar: Chronic Arsenicosis in India
Seminar: HIV Infection
Short Communication
Short Communications
Short Report
Snippets
Special Article
Specialty Interface
Studies
Study Letter
Study Letters
Supplement-Photoprotection
Supplement-Psoriasis
Symposium - Contact Dermatitis
Symposium - Lasers
Symposium - Pediatric Dermatoses
Symposium - Psoriasis
Symposium - Vesicobullous Disorders
SYMPOSIUM - VITILIGO
Symposium Aesthetic Surgery
Symposium Dermatopathology
Symposium-Hair Disorders
Symposium-Nails Part I
Symposium-Nails-Part II
Systematic Review and Meta-Analysis
Systematic Reviews and Meta-analyses
Systematic Reviews and Meta-analysis
Tables
Technology
Therapeutic Guideline-IADVL
Therapeutic Guidelines
Therapeutic Guidelines - IADVL
Therapeutics
Therapy
Therapy Letter
Therapy Letters
View Point
Viewpoint
What’s new in Dermatology
View/Download PDF

Translate this page into:

Case Letter
90 (
1
); 102-105
doi:
10.25259/IJDVL_1138_2021
pmid:
37317743

PLACK syndrome associated with alopecia areata and a novel homozygous base pair insertion in exon 18 of CAST gene

Department of Dermatology, Government Medical College, Kozhikode, Kerala, India
Corresponding author: Dr. Anza Khader, Department of Dermatology, Government Medical College, Kozhikode, Kerala, India. anzashaan@gmail.com
Licence
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Vidya AS, Khader A, Devi K, Archana GA, Reeshma J, Reshma NJ. PLACK syndrome associated with alopecia areata and a novel homozygous base pair insertion in exon 18 of CAST gene. Indian J Dermatol Venereol Leprol. 2023;90:102-5. doi: 10.25259/IJDVL_1138_2021

Dear Editor,

Peeling skin syndromes (PSS) are rare autosomal recessive genodermatoses characterised by superficial painless shedding of stratum corneum.1,2 Traupe classified PSS into Type A and B in which the former presents without skin blistering and the latter is a form of exfoliative ichthyosis.3 Lin et al in 2015 first reported four cases with generalised peeling, leukonychia, acral punctate keratoses, cheilitis, knuckle pads and proposed an acronym PLACK syndrome.2

An 11-year-old boy born to nonconsanguinous parents presented with a history of recurrent bullae and peeling of skin subsiding with hyperpigmentation since 3 months of age. Peeling of skin with or without bullae developed spontaneously or following trauma. It was generalised till 7 years of age and later remained confined to extremities. The child also had recurrent episodes of patchy hair loss in the scalp. The child had no significant systemic illnesses. There was no history of similar lesions in the family.

Clinical examination revealed generalised xerosis, peeling of skin over dorsae of hands and feet, forearm, elbows, knees and lower legs, punctate palmoplantar keratoderma, hyperkeratotic papules over knuckles and dorsae of feet and multiple hyperkeratotic follicular papules over both lower limbs. Though all nails showed proximal leukonychia and distal onycholysis, partial nail dystrophy was seen only on toe nails [Figures 1a, 1b, 1c and 1d]. A single patch of non scarring alopecia over the vertex of scalp was noted and the dermoscopy of this patch revealed yellow dots, black dots, short vellus hair and exclamation mark sign [Figures 2a and 2b].

Skin biopsy from peeled area showed subcorneal blister and from the hyperkeratotic papule showed hyperkeratosis and acanthosis [Figures 3a and 3b].

Figure 1a
Peeling of skin over the extensor aspect of left leg.
Figure 1b
Hyperkeratotic papules over knuckles and proximal leukonychia.
Figure 1c
Angular cheilitis.
Figure 1d
Multiple hyperkeratotic follicular papules overthe right knee joint.
Figure 2a
A patchy area of hair loss over the vertex of scalp.
Figure 2b
Scalp dermoscopy showing yellow dots, black dots, short vellus hairs and exclamation mark sign (Dino-Lite premier AM4113T, 200X, polarized).
Figure 3a
Skin biopsy from peeled area showing subcorneal separation with neutrophils, acanthosis and perivascular neutrophilic infiltrate (H&E, 400x).
Figure 3b
Skin biopsy from hyperkeratotic papule showing hyperkeratosis, irregular acanthosis, perifollicular and perivascular neutrophilic infiltration (H&E, 400x).

Genomic DNA was isolated from the patient’s blood sample (Qiagen). The specific exon regions from CAST gene were PCR amplified and sequenced using Sanger sequencer (ABI 3500, Thermo Scientific). The chromatogram was analysed for variants but all the previously reported mutations were absent in our patient.

Further whole exome sequencing and subsequent analysis of genomic DNA was performed (MedGenome Labs Ltd).A homozygous single base pair insertion in exon 18 of the CAST gene (chr5:g.96748570_96748571insT; Depth: 33x) encoding calpastatin that resulted in a frameshift mutation and premature truncation of the protein at codon 441 (p.Glu441Ter; ENST00000510756.5) was detected. As the patient had alopecia areata we also looked for the variant of PTPN22 (Protein tyrosine phosphatase non-receptor type 22) encoding Lyp phosphatase (Lyp R620W) and this was detected while doing whole exome sequencing.

PLACK syndrome is an autosomal recessive condition with a prevalence of 1:10,00,000. The onset occurs in infancy and does not affect the life expectancy of the individual.2

PLACK syndrome is characterised by superficial blisters predominantly over the extremities, either of spontaneous onset or induced by trauma. Other features include asymptomatic peeling of skin, generalised xerosis, fissuring of lips and perioral region, white nails and keratotic papules over knuckles and dorsa of hands and feet.2

Six mutations reported till date are loss of function mutations in c.607dup (p.Ile203Asnfs*8), c.424A > T (p.Lys142*), c.1750delG (p.Val584Trpfs*37), c.461dupGCAT (p.Ser154Cysfs*6), c.544G > T (p.Glu182*) and (c.507_508insA).2,46 To the best of our knowledge, ours is probably the seventh case and the first from India which is associated with a novel homozygous mutation in the CAST gene and an unreported clinical association of alopecia areata.

CAST gene encodes calpastatin, a specific inhibitor of calpain, an intracellular cysteine protease. Calpains which are expressed normally in human skin are activated by calcium ions and play an important role in cell proliferation, migration, apoptosis, cell survival, epidermal differentiation, cornification and keratinocyte apoptosis.57 Mutation in Cast gene leads to decreased calpastatin which results in increased activity of calpains and impairs intracellular adhesion leading to peeling of skin and also affects cell cycle regulation and keratinocyte apoptosis causing hyperkeratosis.5

The gene encoding for Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is exclusively expressed in immune cells. Its non synonymous C1858T substitution in codon 620 (LypR620W) is considered as a risk factor in many autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus and thyroid diseases.8,9 This LypR620W variant with arginine to tryptophan substitution causes Lyp/Pep (Lymphoidphosphatase/PEST–enriched phosphatase) more susceptible to calpain and proteosome mediated cleavage and degradation. The increased activity of calpains as in our case lowers Lyp/Pep levels and decreases the inhibitory effects on immunological activation result in many autoimmune disorders including alopecia areata.811 We report the seventh case of PLACK syndrome with a new variant mutation in CAST gene and a clinical association of alopecia areata hitherto unreported in literature. The CAST gene mutation and its effects on calpain calpastatin system and calpain mediated degradation of Lyp/Pep resulting in lymphocyte and dendritic cell hyper responsiveness might have resulted in alopecia areata in our case. We would like to propose that the individuals with PLACK syndrome may present with various autoimmune diseases if there is associated Lyp/Pep polymorphism although the direct effect of CAST gene on Lyp/Pep requires further studies.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

  1. , , , , , . A case of late-onset peeling skin syndrome likely triggeredby irritation. Ann Dermatol. 2017;29:119-20.
    [CrossRef] [PubMed] [Google Scholar]
  2. , , , , , , et al. Loss-of-Function Mutations in CAST Cause Peeling Skin, Leukonychia, Acral Punctate Keratoses, Cheilitis, and Knuckle Pads. Am J Hum Genet. 2015;96:440-7.
    [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
  3. . Peeling‐skin syndrome: Clinical and morphological evidence for two types. In: , ed. The Ichthyoses: a guide to clinical diagnosis, genetic counselling, and therapy. Berlin: Springer; . p. :207-10.
    [Google Scholar]
  4. , , , , , , et al. PLACK syndrome resulting from a new homozygous insertion mutation in CAST. J Dermatol Sci. 2017;88:256-8.
    [CrossRef] [PubMed] [Google Scholar]
  5. , , , , , , et al. A novel homozygous nonsense mutation in CAST associated with PLACK syndrome. Cell Tissue Res. 2019;378:267-77.
    [CrossRef] [PubMed] [Google Scholar]
  6. , , , , , . PLACK syndrome shows remarkable phenotypic homogeneity. Clin Exp Dermatol. 2019;44:580-3.
    [PubMed] [PubMed Central] [Google Scholar]
  7. , , . Role of Calpain in Pathogenesis of Human Disease Processes. J Nat Sci. 2016;2:218.
    [PubMed] [PubMed Central] [Google Scholar]
  8. , . Tyrosine phosphatase PTPN22: multifunctional regulator of immune signaling, development, and disease. Annu Rev Immunol. 2014;32:83-119.
    [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
  9. , , , , , , et al. Association between PTPN22 C1858T polymorphism and alopecia areata risk. Exp Ther Med 2015:1953-58.
    [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
  10. , , , , , , et al. The autoimmune disease-associated PTPN22 variant promotes calpain-mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness. Nat Genet. 2011;43:902-7.
    [CrossRef] [PubMed] [Google Scholar]
  11. , , , , , , et al. Roles of calpain-calpastatin system (CCS) in human T cell activation. Oncotarget. 2016;47:76479-95.
    [CrossRef] [PubMed] [PubMed Central] [Google Scholar]

Fulltext Views
3,555

PDF downloads
1,272
View/Download PDF
Download Citations
BibTeX
RIS
Show Sections