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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