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Advances in dermatology and venereology Acta Dermato-Venereologica
Desmoglein 4 Mutation Underlies Autosomal Recessive Keratosis Pilaris Atrophicans
Eran COHEN-BARAK 1 – 3 #, Nada DANIAL-FARRAN 2, 4 #, Helwa HAMMAD 1, Ola ALEME 4, Judith KRAUZ 5, Ester GAVISH 1, Morad KHAYAT 4, Michael ZIV 1 and Stavit SHALEV 2, 4 *
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Department of Dermatology, 4 The Genetic Institute and 5 Department of Pathology,“ Emek” Medical Center, Afula, 2 Bruce and Ruth Rappaport Faculty of Medicine, Technion, Haifa, Israel, and 3 Department of Dermatology and Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. E-mail: stavit _ sh @ clalit. org. il
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These authors contributed equally. Accepted May 22 2018; Epub ahead of print May 24, 2018
Keratosis pilaris atrophicans( KPA) is a group of hair follicle disorders that share features of follicular keratinization abnormality. KPA has long been suspected to have a strong underlying genetic background, but this has not been thoroughly elucidated. This study investigated the genetics of 2 patients who presented in early infancy with clinical manifestations reminiscent of keratosis pilaris atrophicans faciei / ulerythema ophryogenes. Following DNA extraction from leukocytes from these 2 patients and their family members, whole exome sequencing was performed, which identified a previously unreported homozygous variant in Desmoglein 4 c. 129DelAACA. This mutation is predicted to cause a frameshift and introduce a premature stop codon( p. Thr43fs40 *) in the 2 patients. This report helps explain the genetic background underlying KPA and opens the way for further investigation regarding the role of Desmoglein 4 in other hair diseases.
CASE REPORT
KPA is a group of hair follicle disorders that share features of follicular keratinization abnormality and atrophy, which includes keratosis pilaris atrophicans faciei( KPAF, ulerythema ophryogenes), atrophoderma vermiculatum, and keratosis follicularis spinulosa decalvans( KFSD)( 1). KPAF is characterized by early onset( in infancy) of keratotic follicular papules of the facial area, leading to follicular atrophy of the lateral eyebrows and keratosis pilaris over the trunk and extremities( 2). KFSD is more severe with more extensive distribution of follicular papules, scarring alopecia, and extrafollicular involvement( keratitis and keratoderma)( 3). Patients with atrophoderma vermiculatum present in childhood with pitted atrophic depression in a honeycomb pattern( 4). Individuals affected by this family of diseases may manifest overlapping features( 4).
Overall, the genetic background underlying KPA has not yet been fully elucidated. Although most cases are sporadic, several familial cases were reported consistent with autosomal dominant or X-linked inheritance. Mutations in the membrane-bound transcription factor protease site 2 gene( MBTPS2) were found to cause X- linked KFSD( 3). Recessive inheritance was recently reported in patients manifesting with KFSD-atrophoderma vermiculatum overlap( 4), which was suggested, after whole exome sequencing, to be caused by homozygous mutation in LRP-1, encoding LDL-related protein 1. KPAF is reportedly inherited in an autosomal dominant pattern. It is associated with RASopathies and with cases of 18p monosomy( 2); however, no underlying gene has been found. We report here, for the first time, a homozygous mutation in desmoglein 4( DSG4) underlying
AR KPAF. A 10-year-old Muslim-Arab girl( patient 1, Fig. 1a, individual III-2, family A) from the north of Israel presented in the early months of life with localized hypotrichosis over the eyebrows and eyelashes. No other abnormalities were present, including sweating, teeth, nails, palms or soles. Her family medical history disclosed a similar phenotype in her grandmother. Thorough examination of the skin revealed hypotrichosis of the eyebrows( more prominent on the lateral third) accompanied by follicular papules and focal atrophy, as well as hypotrichosis of the lower eyelids( Fig. 2a). Widespread keratotic follicular papules were observed over the face, scalp and extremities, accompanied by skin xerosis. Scalp hair appeared normal, with mild diminution in the frontal area( Fig. 2a). Her hair was neither fragile nor pluckable. Biopsy of a keratotic papule revealed hair follicles with widened infundibulum. Patient 2( Fig. 1a, individual I-2, family B) is a 2.5-year-old Muslim-Arab boy, born to second-degree family relatives, with a birth onset of partial hypotrichosis over the eyebrows, which deteriorated over the early years of life. Physical examination revealed localized hypotrichosis over the eyebrows and lower lids, accompanied by generalized follicular keratotic papules over the face, scalp, trunk and extremities. His scalp hair was dense( Fig. 2b). Microscopy of hair from both patients did not reveal any changes in the hair shaft. Following consent from the guardians, DNA was extracted from leukocytes of patients and family members( Fig. 1a). The DNA sample of patient 2 was analysed using whole exome sequencing. Following filtering for homozygous variants in genes expressed in hair follicles, considering the probable autosomal recessive( AR) inheritance, 4 variants were found, including a novel variant in DSG4 c. 126- 129DelAACA( Fig. 1b), which is predicted to cause a frameshift and premature termination in the pro-peptide domain of DSG4
Fig. 1. Genetic analysis of families A and B.( a) Pedigrees of families A and B. Filled symbols denote patients affected by keratosis pilaris atrophicans( KPA). * Individuals whose DNA was analysed.( b) Molecular analysis. Whole exome sequencing revealed a homozygous c. 126-129DelAACA mutation in the desmoglein 4( DSG4) gene in patient 2. The same mutation was found in patient 1. Individuals II-2, III-3 of family A and individual I-1 of family B were found to be heterozygous carriers of the mutation. DSG4 wildtype( WT) sequence is given for comparison( upper panel).
This is an open access article under the CC BY-NC license. www. medicaljournals. se / acta Journal Compilation © 2018 Acta Dermato-Venereologica. doi: 10.2340 / 00015555-2976 Acta Derm Venereol 2018; 98: 809 – 810