Generic selectors
Exact matches only
Search in title
Search in content
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 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 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
Revision Corner
Self Assessment Programme
SEMINAR
Seminar: Chronic Arsenicosis in India
Seminar: HIV Infection
Short Communication
Short Communications
Short Report
Special Article
Specialty Interface
Studies
Study Letter
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
Tables
Technology
Therapeutic Guidelines
Therapeutic Guidelines - IADVL
Therapeutics
Therapy
Therapy Letter
View Point
Viewpoint
What’s new in Dermatology
View/Download PDF
Observation Letter
87 (
3
); 410-416
doi:
10.25259/IJDVL_374_19
pmid:
33666035
CROSSMARK LOGO Buy Reprints
PDF

A novel homozygous frameshift mutation in DSG1 gene in an Indian consanguineous family with severe dermatitis, multiple allergies and metabolic wasting syndrome

Department of Pediatric Dermatology Indira Gandhi Institute of Child Health, Bengaluru, Karnataka, India
Department of Biochemistry, Indira Gandhi Institute of Child Health, Bengaluru, Karnataka, India
Corresponding author: Dr. Sahana M. Srinivas, Department of Pediatric Dermatology, Indira Gandhi Institute of Child Health, Bengaluru, Karnataka, India. sahana.bmc@gmal.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, tweak, 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: Srinivas SM, Basavanaik P, Gowdra A. A novel homozygous frameshift mutation in DSG1 gene in an Indian consanguineous family with severe dermatitis, multiple allergies and metabolic wasting syndrome. Indian J Dermatol Venereol Leprol 2021;87:410-6.

Sir,

Severe dermatitis, multiple allergies and metabolic wasting syndrome (OMIM #615508), also known as congenital erythroderma with palmoplantar keratoderma, hypotrichosis and hyper-immunoglobulin E, is a recently recognized autosomal recessive genodermatosis caused by homozygous or compound heterozygous loss of function mutation in desmoglein1 gene (DSG1) or heterozygous missense mutation in desmoplakin gene (DSP). 1,2 It was first described in 2013 by Samuelov et al.1 It is clinically characterized by congenital ichthyosiform erythroderma, palmoplantar keratoderma, failure to thrive, multiple allergies, increased serum immunoglobulin E levels, hypotrichosis, recurrent infections and other systemic abnormalities like metabolic wasting, malabsorption, esophagitis, cardiac defects, microcephaly and developmental delay. Till date, approximately 14 cases of severe dermatitis, multiple allergies and metabolic wasting syndrome from 10 families have been reported in literature with varying phenotypes. Herein, we describe a rare case of severe dermatitis, multiple allergies and metabolic wasting syndrome in an Indian consanguineous family with a novel homozygous frameshift mutation, in exon 15 of DSG1gene and identical mutation in a heterozygous state in the parents.

A 4-year-old term boy, first born to a second degree consanguineously married couple of Indian origin, presented with erythema and scaling all over the body from 7thday of life with recurrent respiratory infections, failure to thrive, metabolic wasting and developmental delay. Both the parents had mild palmoplantar keratoderma. He had Cushingoid features, short stature with height less than 3rd percentile (69.6cm) and bone age of 2 years along with infantile face, voice and microphallus with a stretch penile length of 2.5 cm (<2 standard deviation for age) which were suggestive of growth hormone deficiency. Cutaneous examination showed diffuse erythema with scaling all over the body [Figure 1a]. Well-defined hyperkeratotic scaly plaques were present on the extensor aspect of both the knee joints, upper and lower limbs [Figure 1b]. Ill-defined hyperkeratosis with accentuation was present on the flexures and perianal region [Figure 1c]. Scalp showed mild scaling and hypotrichosis [Figure 1a]. Diffuse palmoplantar keratoderma was present [Figures 2a and b]. Investigations revealed increased serum immunoglobulin E levels (>2000 IU/mL) and growth hormone stimulation test confirmed severe growth hormone deficiency. Light microscopy of the hair shaft was normal. Histopathological examination revealed orthokeratosis, hypergranulosis, subtle acantholysis and a few scattered dyskeratotic cells in the epidermis [Figure 3]. Differential diagnoses considered were Netherton syndrome, non-bullous ichthyosiform erythroderma, trichothiodystrophy, ichthyosis hypotrichosis syndrome and epidermal growth factor receptor deficiency.

Genetic testing was done in the proband and his parents after taking written informed consent. Clinical exome sequencing report of the proband revealed homozygous 2 base pair (AG) deletion in exon 15 of DSG1 gene located on chromosome 18,c.2601_2602delAG (NM_001942.3:g. 28934754_28934755delAG) where amino acid arginine was replaced by serine at 867th codon position that resulted in a frameshift mutation and premature truncation of protein 9 amino acids downstream to codon 867 (p.Arg867Serfs*9; ENST00000257192.4) [Figure 4]. This DSG1 variant has not been reported in Human Gene Mutation Database Professional 2018.4, Single Nucleotide Polymorphism Database, 1000 genomes, Exome Aggregation Consortium and our internal databases. We also excluded it from 300 normal healthy Indians.The in-silico prediction of the variant is damaging by MutationTaster (www.mutationtaster.org). Protein Variation Effect Analyzer, (http://provean.jcvi.org) predicted it to be deleterious with a score of -4.3. This variant is not associated with nonsense-mediated mRNA decay and it is highly conserved across species.3 This mutant variant of the index case was validated by Sanger sequencing [Figure 5a].The Sanger sequence report of both father and mother revealed an identical mutation in a heterozygous state [Figures 5b and c]. Fortunately, his asymptomatic sister did not have the mutation.

Figure 1a:: Diffuse erythema with scaling on face and chest along with scant hair on the scalp
Figure 1b:: Well-defined hyperkeratotic plaques present on the knee joint
Figure 1c:: Perianal scaling with hyperkeratosis
Figure 2a:: Diffuse keratoderma present on palms
Figure 2b:: Diffuse plantar keratoderma
Figure 3:: Epidermis showing orthokeratosis, hypergranulosis, subtle acantholysis and a few scattered dyskeratotic cells (H and E,×100)
Figure 4:: Excerpt of next-generation sequencing data of the proband visualized with the integrative genomic viewer showing homozygous 2 base pair deletion in exon 15 of desmoglein1 gene located on chromosome 18 compared with two control sequences
Figure 5a:: Sequence chromatogram and alignment to the reference sequence showing the variation in exon 15 of the desmoglein1 gene (chr18:28934754_28934755delAG; c.2601_2602delAG; p.Arg867SerfsTer9) in the proband
Figure 5b:: Sequence chromatogram and alignment to the reference sequence showing the identical variation in heterozygous carrier father indicated by the red arrow
Figure 5c:: Sequence chromatogram and alignment to the reference sequence showing the identical variation in heterozygous carrier mother indicated by the red arrow

Desmosomal cadherin DSG1 is a component of intercellular desmosome junctions; it has a central role in the pathogenesis of pemphigus foliaceus, bullous impetigo, staphylococcal scalded skin syndrome and an inherited skin disorder – striate palmoplantar keratoderma (OMIM #148700).1 Monoallelic DSG1 mutation results in striate palmoplantar keratoderma whereas biallelic loss of function mutation results in severe life-threatening severe dermatitis, multiple allergies and metabolic wasting syndrome.4 This mutation results in complete loss of protein function by the cytoplasmic accumulation of the abnormal protein which cannot be transported to the cell surface. Heritable barrier abnormality with subsequent immune cascade is a possible cause.This results in increased expression of various genes coding for cytokines associated with allergic diseases.5 The role of atopy and allergies in the pathogenesis of severe dermatitis, multiple allergies and metabolic wasting syndrome is not well-established. Hence, further investigations are required to know the exact etiology and pathomechanism in producing this phenotypic heterogeneity.

The clinical phenotype and genotype of all 10 families reported in the literature have been described in Table 1.1,2,4-7 Currently, 10 pathogenic variants in 14 cases in two genes DSG1 and DSP have been described in literature: homozygous nonsense-2, splice site-4 and frameshift mutations-3 in DSG1 gene and heterozygous missense-1 in DSP gene [Figure 6].1,2,4-7 Cardiac abnormality, food allergies, hypoalbuminemia, microcephaly and esophageal abnormalities were not seen in our case. The differential diagnosis of severe dermatitis, multiple allergies and metabolic wasting syndrome with salient features has been tabulated in Table 2. Several therapeutic approaches like topical corticosteroids, topical tacrolimus and oral retinoids (acitretin 0.5mg/kg) have been tried with partial improvement of ichthyosis and palmoplantar keratoderma. Our case was treated with bland emollients and wet wrap therapy. Parents were not willing to start oral retinoids. Long-term prognosis depends on the systemic involvement.

Figure 6:: Mutation spectrum of recessive mutations in the desmoglein1gene causing severe dermatitis, multiple allergies and metabolic wasting syndrome as described in literature till date.The novel mutation in our study is represented in red
Table 1:: Phenotype and genotype of all 10 reported families of severe dermatitis, multiple allergies and metabolic wasting syndrome
Study Samuelov L, et al. Has C, et al. McAleer MA, et al. Cheng R, et al.
Year
2013 2015 2015 2016
Case1 (family 1) Case2 (family 1) Case3 (family 2) Case4 (family 3) Case5 (family 4) Case 6 (family 5) Case 7 (family 5)
Age/sex 7 years/female 3 years/female 9 months/female 17 years/female 6 years/male 13 years/female 7 years/male
Consanguinity + + + + +
Congenital erythroderma + + + + + + +
PPK + + + + + + +
Hair/nails Hypotrichosis Hypotrichosis Hypotrichosis Curly hair Hypotrichosis Curly hair N
Multiple allergies + + + + +
Metabolic wasting + + + +
Other Systemic involvement Hypernatremia, recurrent infections, eosinophilic esophagitis, GERD, malabsorption, microcephaly, VSD, PS Hypernatremia, recurrent infections, eosinophilic esophagitis, GERD, malabsorption, microcephaly, VSD, PS Recurrent infections, growth retardation Macrocephaly, developmental delay, nystagmus, keratitis Recurrent infections, growth retardation
Family history PPK in parents PPK in parents PPK in parents/2 siblings death Focal PPK in parents N PPK in parents/sibling death PPK in parents/sibling death
Ig E levels Raised Raised Raised Raised Raised Raised N
Gene/mutation HOM/DSG1/c. 49-1G>A HOM/DSG1/c. 49-1G >A HOM/DSG1/C.1861delG HOM/DSG1/c. 2659C>T HET/DSP/c. 6208G>A HOM/DSG1/c. 1892-1delG HOM/DSG1/c. 1892-1delG
Study Schlipf NA et al. Danescu S, et al. JYW Lee, et al. Shahar Taiber et al. Present case
Year
2016 2016 2017 2018 2019
Case 8 (family 6) Case 9 (family 6) Case 10 (family 7) Case 11 (family 8) Case 12 (family 9) Case 13 (family 10) Case 14 (family 10) Case 15 (family 11)
Age/sex 27 years/male 11years/male 2 years/female 19 years/female 2.5 years/male 2 months/female 17 years/female 4 years/male
Consanguinity + + + + +
Congenital erythroderma + + + + + + + +
PPK + + + + + + + +
Hair/nails N N Curly N Hypotrichosis N N Hypotrichosis
Multiple allergies + + + + +
Metabolic wasting +
Other Systemic involvement Recurrent respiratory infections, failure to thrive, metabolic wasting, short stature, developmental delay, growth hormone deficiency
Study Schlipf NA et al. Danescu S, et al. JYW Lee, et al. Shahar Taiber et al. Present case
Year
2016 2016 2017 2018 2019
Case 8 (family 6) Case 9 (family 6) Case 10 (family 7) Case 11 (family 8) Case 12 (family 9) Case 13 (family 10) Case 14 (family 10) Case 15 (family 11)
Family history Mother - PPK Mother- PPK Father- PPK N Plantar keratoderma in parents PPK in parents PPK in parents PPK in parents
Ig E levels Raised Raised Raised Raised N Raised Raised Raised
Gene/mutation HOM/DSG1/c. 2614delA HOM/DSG1/c. 2614delA Compound HET/DSG1/c. 811_812delAC HOM/DSG1/c. 1892-2A>C HOM/DSG1/c. 280C>T HOM/DSG1/c. 2659C>T HOM/DSG1/c. 2659C>T HOM/DSG1/c. 2601-2602delAG

+: Present, -: Absent, N: Normal, GERD: Gastroesophageal reflux disease, VSD: Ventricular septal defect, PS: Pulmonary stenosis, GH: Growth hormone deficiency, HOM: Homozygous, HET: Heterozygous, DSG: Desmoglein, DSP: Desmoplakin, PPK: Palmoplantar keratoderma

Table 2:: Differential diagnosis of severe dermatitis, multiple allergies and metabolic wasting syndrome
Disorder Gene Mode of inheritance Clinical features
Atopic dermatitis FLG AD Pruritus, eczematous reactions along with characteristic distribution, erythroderma in childhood, features of diagnostic criteria by Hanifin and Rajka. No systemic involvement
Hyperimmunoglobulinemia E syndrome STAT3/DOCK8 AD/AR Atopic dermatitis/erythroderma, cutaneous staphylococcal infections, severe viral infections, sinopulmonary abscess, recurrent bronchitis, pneumonia, emphysema, bronchiectasis, abscess, coarse facies, dental and skeletal abnormalities
Netherton syndrome SPINK 5 AR Generalized scaling, erythroderma, ichthyosis linearis circumflexa, failure to thrive, diarrhea, atopic features, trichorrhexis invaginata
Nonbullous ichthyosiform erythroderma TGM1/ABCA 12, ALOXE3, ALOX12B, CYP4F22 AR At birth as collodion membrane, generalized erythema, scaling, ectropion, alopecia, rarely intrauterine growth retardation and failure to thrive
Trichothiodystrophy ERCC2, ERCC3, GTF2H5, C7Orf11 AR Congenital ichthyosiform erythroderma, brittle hair, impaired intelligence, short stature, decreased fertility, photosensitivity, “tiger tail” hair shaft defect on polarized microscopy
Ichthyosis hypotrichosis syndrome ST14 AR Generalized ichthyosis with sparing of face, palms and soles, alopecia of scalp, eyebrows and eyelashes, follicular atrophoderma, photophobia, hypohidrosis, dental abnormalities
EGFR deficiency EGFR AR Generalized erythema with scaling, pustules, alopecia, failure to thrive, diarrhea, high IgE, hypernatremia, recurrent bronchiolitis
ADAM17 deficiency ADAM17 AR Erythroderma, failure to thrive, short stature, malabsorption, recurrent infections, cardiomyopathy
NISCH syndrome CLDN1 AR Generalized scaling, sparing of skin folds, palms and soles, curly hair, frontotemporal cicatricial alopecia, sclerosing cholangitis, hepatomegaly, oligodontia

AD: Autosomal dominant, AR: Autosomal recessive, FLG: Filaggrin, STAT3 gene: Signal transducer and activator of transcription 3, DOCK8: Dedicator of cytokinesis, SPINK5: Serine Peptidase Inhibitor Kazal Type 5, TGM1: Transglutaminase 1, ALOXE3: Archidonate Lipoxygenase 3, CYP4F22: Cytochrome P450 Family 4 Subfamily F Member 22, GTF2H5: General Transcription Factor IIH Subunit 5, ST14: Suppressor of Tumorigenicity 14 protein, EGFR: Epidermal growth factor receptor gene, NISCH: Neonatal ichthyosis-sclerosing cholangitis , CLDN1: Claudin 1

In conclusion, our described case of severe dermatitis, multiple allergies and metabolic wasting syndrome of Indian origin presented with characteristic clinical features with a novel homozygous frameshift mutation in the DSG1gene. Growth hormone deficiency with microphallus was unique in our case. This study expands the spectrum of the DSG1 mutation database and emphasizes the important role played by DSG1 in maintaining epidermal integrity, signal transduction pathways and keratinocyte differentiation. DSG1 mutation screening needs to be done in all suspected cases of severe dermatitis, multiple allergies and metabolic wasting syndrome.

Limitations of the study: Functional assays have not been done due to logistic reasons. Further studies need to be done to understand the exact pathogenesis of severe dermatitis, multiple allergies and metabolic wasting syndrome. Change in a phenotypic presentation in our case may be due to the different position of the mutation loci and epigenetic modifiers with multiple environmental factors.

Acknowledgment

We the authors would like to thank Medgenome Labs LTD for performing genetic analysis for our patients.

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. , , , , , , et al. Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting. Nat Genet. 2013;45:1244-8.
    [CrossRef] [PubMed] [Google Scholar]
  2. , , , , , , et al. Severe dermatitis, multiple allergies, and metabolic wasting syndrome caused by a novel mutation in the N terminal plakin domain of desmoplakin. J Allergy Clin Immunol. 2015;136:1268-76.
    [CrossRef] [PubMed] [Google Scholar]
  3. , , , , , , et al. Heterozygous truncating variants in POMP escape nonsense mediated decay and cause a unique immune dysregulatory syndrome. Am J Hum Genet. 2018;102:1126-42.
    [CrossRef] [PubMed] [Google Scholar]
  4. , , , , , . Loss of desmoglein 1 associated with palmoplantar keratoderma, dermatitis and multiple allergies. Br J Dermatol. 2015;172:257-61.
    [CrossRef] [PubMed] [Google Scholar]
  5. . Homozygous desmoglein1 gene mutations and severe dermatitis, multiple allergies and metabolic wasting (SAM syndrome) Ann Dermatol Venereol. 2015;142:798-9.
    [Google Scholar]
  6. , , , , , , et al. SAM syndrome is characterized by extensive phenotypic heterogeneity. Exp Dermatol. 2018;27:787-90.
    [CrossRef] [PubMed] [Google Scholar]
  7. , , , , , , et al. Homozygous acceptor splice site mutation in DSG1 disrupts plakoglobin localization and results in keratoderma and skin fragility. J Dermatol Sci. 2018;89:198-201.
    [CrossRef] [PubMed] [Google Scholar]

Fulltext Views
1059

PDF downloads
189
View/Download PDF
Download Citations
BibTeX
RIS
Show Sections