Variants in the Gene Encoding Filaggrin Cause Autosomal-Dominant Symmetrical Acral Keratoderma

Symmetrical acral keratoderma (SAK) is a rare skin disorder characterized by brownish-black hyperkeratotic patches symmetrically distributed on the acral regions ( Fan et al., 2010 Fan Y.M. Li S.F. Yang Y.P. Chen Q.X. Li W. Is acquired symmetrical acrokeratoderma a new dermatosis? Two case reports and Chinese literature review. Int J Dermatol. 2010; 49: 647-652 Crossref PubMed Scopus (11) Google Scholar ; Vinay et al., 2016 Vinay K. Sawatkar G.U. Saikia U.N. Dogra S. Symmetrical acrokeratoderma: a case series in Indian patients. Orphanet J Rare Dis. 2016; 11: 156 Crossref PubMed Scopus (11) Google Scholar ). Our previous study found that many patients have a family history with an autosomal-dominant inheritance pattern ( Li et al., 2014a Li C.X. Han C.L. Zeng K. Zhang X.B. Ma Z.L. Clinical, demographic and histopathological features of symmetrical acral keratoderma. Br J Dermatol. 2014; 170: 948-951 Crossref PubMed Scopus (14) Google Scholar ) and that congenital genetic factors are likely to play a pivotal role in the pathogenesis of SAK. In this study, we clarify the underlying genes and genotype-phenotype correlations of SAK. This study was approved by the Medical Ethics Committee of Nanfang Hospital of Southern Medical University (NFEC-2022-483). With written informed consent, we recruited 2 families (family 1 and family 2; Figure 1a) and 29 unrelated cases (individuals 1–29) with SAK for whole-exome sequencing; demographic features and clinical manifestations are summarized in Table 1. Affected individuals reported distinct brownish-black hyperkeratotic patches symmetrically distributed on the wrists, elbows, and dorsal areas of the hands, feet, knees, and ankles (Figure 1b and c and Supplementary Figure S1a–h). The lesions became white and macerated soon after water exposure. Typically, the condition was aggravated in the summer and alleviated or even resolved spontaneously in the winter. A biopsy specimen was taken from brown hyperkeratotic patches on the wrists of family 1: III-3. Histopathological features were basket-weave hyperkeratosis, acanthosis, papillomatous hyperplasia, and mild superficial perivascular lymphocyte infiltration (Figure 1d). Electron microscopy revealed that the epidermis was remarkably thickened with a compact stratum corneum and acanthosis in SAK lesions, and keratin filaments were significantly clumped or aggregated and irregularly distributed in the horny, spinous, granular, and basal cell layers ( Li et al., 2014b Li C.X. Wen J. Zeng K. Tian X. Li X.M. Zhang X.B. Ultrastructural study of symmetrical acral keratoderma. Ultrastruct Pathol. 2014; 38: 420-424 Crossref PubMed Scopus (7) Google Scholar ) (Figure 1e). Table 1Clinical Features and FLG Variants in the SAK-Affected Individuals Individual Gender Age (Y) InvolvedAreas Accompanying Symptoms Fam History Variant Site (GenBank: NM_002016.2) Status and Phenotype PMID Allele Frequency (gnomAD) Base Change Amino Acid Change East Asian European (Non-Finnish) Fam1:I-1 M 68 Wrists, dorsal areas of hands None Fa c.5757_5760del p.Ser1919Argfs∗175 ReportedIV 28407221 0.0001631 0 Fam1:II-1 M 41 Wrists, dorsal areas of hands, ankles, knees None Fa c.5757_5760del p.Ser1919Argfs∗175 ReportedIV 28407221 0.0001631 0 Fam1:III-3 F 5 Wrists, dorsal areas of hands, ankles, knees, elbows, None Fa c.5757_5760del p.Ser1919Argfs∗175 ReportedIV 28407221 0.0001631 0 Fam1:III-5 M 2 Wrists None Fa c.5757_5760del p.Ser1919Argfs∗175 ReportedIV 28407221 0.0001631 0 Fam2:II-3 M 32 Wrists, dorsal areas of hands, ankles, knees IV Fa c.7945del p.Ser2649Valfs∗94 ReportedIV 28407221, 23301728 0.002054 0 Fam2:III-1 F 5 Wrists, dorsal areas of hands, ankles, knees, elbows IV Fa c.7945del p.Ser2649Valfs∗94 ReportedIV 28407221, 23301728 0.002054 0 Fam2:III-2 M 2 Wrists, dorsal areas of hands, ankles IV Fa c.7945del p.Ser2649Valfs∗94 ReportedIV 28407221, 23301728 0.002054 0 Individual 1 M 50 Wrists, dorsal areas of hands, ankles IV, PH Fa c.441_442del p.Gly149Glufs∗4 ReportedIV 23290076 0.0001003 0.00001554 Individual 2 M 34 Wrists, dorsal areas of hands IV S c.10969C>T p.Arg3657∗ ReportedIV 28407221 0.001557 0 Individual 3 M 41 Wrists, dorsal areas of hands, ankles None S c.2834del p.Ser945Metfs∗177 Unreported NA NA NA Individual 4 F 27 Wrists, dorsal areas of hands, elbows, ankles, knees IV S c.6950_6957del p.Ser2317∗ ReportedIV, AD 23301728, 21428977 0.002964 0 Individual 5 M 36 Wrists, dorsal areas of hands IV S c.3672_3675del p.Lys1224Asnfs∗221 ReportedXLI 21945601 0 0.00001758 Individual 6 M 16 Wrists, dorsal areas of hands, elbows, ankles, knees IV, PH Fa c.514G>T p.Glu172∗ Unreported NA 0 0.00000884 Individual 7 F 16 Wrists, dorsal areas of hands, ankles None S c.7249C>T p.Gln2417∗ ReportedIV 18239616, 23301728 0.001755 0 Individual 8 M 18 Wrists, dorsal areas of hands, ankles None S c.3321del p.Gly1109Glufs∗13 ReportedIV, AD 23301728, 19416262, 21428977, 17291859 0.01003 0.00003097 Individual 9 M 50 Wrists, dorsal areas of hands None S c.3321del p.Gly1109Glufs∗13 ReportedIV, AD 23301728, 19416262, 21428977, 17291859 0.01003 0.00003097 Individual 10 F 40 Wrists IV S c.7945del p.Ser2649Valfs∗94 ReportedIV 28407221, 23301728 0.002054 0 Individual 11 F 51 Wrists, dorsal areas of hands IV S c.7945del p.Ser2649Valfs∗94 ReportedIV 28407221, 23301728 0.002054 0 Individual 12 M 47 Wrists, dorsal areas of hands, ankles None S c.1217C>G p.Ser406∗ ReportedAD, IV 21428977, 28407221, 23301728 0.001002 0 Individual 13 M 34 Wrists, dorsal areas of hands, ankles None S c.3321del p.Gly1109Glufs∗13 ReportedIV, AD 23301728, 19416262, 21428977, 17291859 0.01003 0.00003097 Individual 14 M 28 Wrists, dorsal areas of hands, ankles IV, PH Fa c.1217C>G p.Ser406∗ ReportedAD, IV 21428977, 28407221, 23301728 0.001002 0 Individual 15 M 8 Wrists, dorsal areas of hands, knees AD S c.6950_6957del p.Ser2317∗ ReportedIV, AD 23301728, 21428977 0.002964 0 Individual 16 M 31 Wrists IV S c.6950_6957del p.Ser2317∗ ReportedIV, AD 23301728, 21428977 0.002964 0 Individual 17 M 26 Wrists, dorsal areas of hands, ankles IV S c.6950_6957del p.Ser2317∗ ReportedIV, AD 23301728, 21428977 0.002964 0 Individual 18 M 33 Wrists, dorsal areas of hands IV S c.4895del p.Asn1632Thrfs∗74 Unreported NA 0.0001087 0 Individual 19 M 32 Wrists, ankles IV Fa c.3321del p.Gly1109Glufs∗13 ReportedIV, AD 23301728, 19416262, 21428977, 17291859 0.01003 0.00003097 Individual 20 M 21 Wrists, dorsal areas of hands, ankles IV Fa c.6950_6957del p.Ser2317∗ ReportedIV 23301728, 21428977 0.002964 0 Individual 21 M 17 Wrists, dorsal areas of hands, ankles IV Fa c.2219del p.Arg740Glnfs∗58 Unreported NA NA NA Individual 22 M 33 Wrists, dorsal areas of hands None S c.7945del p.Ser2649Valfs∗94 ReportedIV 28407221, 23301728 0.002054 0 Individual 23 M 47 Wrists, dorsal areas of hands None S c.9722del p.Gly3241Aspfs∗150 Unreported NA NA NA Individual 24 M 42 Wrists, dorsal areas of hands, ankles, knees IV Fa c.7487del p.Thr2496Asnfs∗104 ReportedAD 32066784 0.0003262 0 Individual 25 M 26 Wrists, dorsal areas of hands, ankles IV S c.3321del p.Gly1109Glufs∗13 ReportedIV, AD 23301728, 19416262, 21428977, 17291859 0.01003 0.00003097 Individual 26 M 28 Wrists, dorsal areas of hands, ankles PH S c.7249C>T p.Gln2417∗ ReportedIV 30549102, 18239616 0.001755 0 Individual 27 M 18 Wrists, elbows None S NA NA NA NA NA NA Individual 28 M 39 Wrists, dorsal areas of hands IV S NA NA NA NA NA NA Individual 29 M 28 Wrists, dorsal areas of hands, elbows None S NA NA NA NA NA NA Abbreviations: AD, atopic dermatitis; F, Female; Fa, familial; Fam, family; IV, ichthyosis vulgaris; M, male; NA, not available; PH, palmoplantar hyperhidrosis; PMID, PubMed identifier; S, simplex; XLI, X-linked ichthyosis. Open table in a new tab Abbreviations: AD, atopic dermatitis; F, Female; Fa, familial; Fam, family; IV, ichthyosis vulgaris; M, male; NA, not available; PH, palmoplantar hyperhidrosis; PMID, PubMed identifier; S, simplex; XLI, X-linked ichthyosis.