Revisiting X-linked congenital ichthyosis
Baishun Zhou
Department of Pathology, School of Medicine, Hunan Normal University, Changsha, People's Republic of China
Search for more papers by this authorCancan Liang
Department of Pathology, School of Medicine, Hunan Normal University, Changsha, People's Republic of China
Search for more papers by this authorCorresponding Author
Peiyao Li
Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, China NHC Key Laboratory of Carcinogenesis, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
Correspondence
Heng Xiao
Department of Pathology
School of Medicine
Hunan Normal University
371 Tongzipo Road
Changsha
Hunan 410013
People's Republic of China
E-mail: [email protected]
Peiyao Li
Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
China NHC Key Laboratory of Carcinogenesis
Xiangya Hospital
Central South University
Changsha
Hunan 410008
People's Republic of China
E-mail: [email protected]
Search for more papers by this authorCorresponding Author
Heng Xiao
Department of Pathology, School of Medicine, Hunan Normal University, Changsha, People's Republic of China
Correspondence
Heng Xiao
Department of Pathology
School of Medicine
Hunan Normal University
371 Tongzipo Road
Changsha
Hunan 410013
People's Republic of China
E-mail: [email protected]
Peiyao Li
Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
China NHC Key Laboratory of Carcinogenesis
Xiangya Hospital
Central South University
Changsha
Hunan 410008
People's Republic of China
E-mail: [email protected]
Search for more papers by this authorBaishun Zhou
Department of Pathology, School of Medicine, Hunan Normal University, Changsha, People's Republic of China
Search for more papers by this authorCancan Liang
Department of Pathology, School of Medicine, Hunan Normal University, Changsha, People's Republic of China
Search for more papers by this authorCorresponding Author
Peiyao Li
Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, China NHC Key Laboratory of Carcinogenesis, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
Correspondence
Heng Xiao
Department of Pathology
School of Medicine
Hunan Normal University
371 Tongzipo Road
Changsha
Hunan 410013
People's Republic of China
E-mail: [email protected]
Peiyao Li
Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
China NHC Key Laboratory of Carcinogenesis
Xiangya Hospital
Central South University
Changsha
Hunan 410008
People's Republic of China
E-mail: [email protected]
Search for more papers by this authorCorresponding Author
Heng Xiao
Department of Pathology, School of Medicine, Hunan Normal University, Changsha, People's Republic of China
Correspondence
Heng Xiao
Department of Pathology
School of Medicine
Hunan Normal University
371 Tongzipo Road
Changsha
Hunan 410013
People's Republic of China
E-mail: [email protected]
Peiyao Li
Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education
China NHC Key Laboratory of Carcinogenesis
Xiangya Hospital
Central South University
Changsha
Hunan 410008
People's Republic of China
E-mail: [email protected]
Search for more papers by this authorConflict of interest: None.
Funding source: This work was supported by the National Natural Science Foundation of China (81903199, 81802871) and the Natural Science Foundation of Hunan Province (2021JJ40373, 2023JJ30901).
Abstract
X-linked recessive ichthyosis (XLI) is a hereditary skin disease characterized by generalized dryness and scaling of the skin, with frequent extracutaneous manifestations. It is the second most common type of ichthyosis, with a prevalence of 1/6,000 to 1/2,000 in males and without any racial or geographical differences. The causative gene for XLI is the steroid sulfatase gene (STS), located on Xp22.3. STS deficiency causes an abnormal cholesterol sulfate (CS) accumulation in the stratum corneum (SC). Excess CS induces epidermal permeability barrier dysfunction and scaling abnormalities. This review summarizes XLI's genetic, clinical, and pathological features, pathogenesis, diagnosis and differential diagnoses, and therapeutic perspectives. Further understanding the role of the STS gene pathogenic variants in XLI may contribute to a more accurate and efficient clinical diagnosis of XLI and provide novel strategies for its treatment and prenatal diagnosis.
Supporting Information
| Filename | Description |
|---|---|
| ijd17396-sup-0001-TableS1.docxWord 2007 document , 37.8 KB |
Table S1. Partial deletions of the STS gene in previous reports on XLI. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Hernández-Martín A, González-Sarmiento R, De Unamuno P. X-linked ichthyosis: an update. Br J Dermatol. 1999; 141(4): 617–627.
- 2Fernandes NF, Janniger CK, Schwartz RA. X-linked ichthyosis: an oculocutaneous genodermatosis. J Am Acad Dermatol. 2010; 62(3): 480–485.
- 3Afzal S, Ramzan K, Ullah S, Wakil SM, Jamal A, Basit S, et al. A novel nonsense mutation in the STS gene in a Pakistani family with X-linked recessive ichthyosis: including a very rare case of two homozygous female patients. BMC Med Genet. 2020; 21(1): 20.
- 4Ingordo V, D'Andria G, Gentile C, Decuzzi M, Mascia E, Naldi L. Frequency of X-linked ichthyosis in coastal southern Italy: a study on a representative sample of a young male population. Dermatology. 2003; 207(2): 148–150.
- 5Nagtzaam IF, Stegmann AP, Steijlen PM, Herbergs J, Van Lent-Albrechts JA, Van Geel M, et al. Clinically manifest X-linked recessive ichthyosis in a female due to a homozygous interstitial 1.6-Mb deletion of Xp22.31. Br J Dermatol. 2012; 166(4): 905–907.
- 6Ramesh R, Chen H, Kukula A, Wakeling EL, Rustin MH, McLean WH. Exacerbation of X-linked ichthyosis phenotype in a female by inheritance of filaggrin and steroid sulfatase mutations. J Dermatol Sci. 2011; 64(3): 159–162.
- 7Murtaza G, Siddiq S, Khan S, Hussain S, Naeem M. Molecular study of X-linked ichthyosis: report of a novel 2-bp insertion mutation in the STS and a very rare case of homozygous female patient. J Dermatol Sci. 2014; 74(2): 165–167.
- 8Diociaiuti A, Angioni A, Pisaneschi E, Margollicci M, Boldrini R, Alesi V, et al. Next generation sequencing uncovers a rare case of X-linked ichthyosis in an adopted girl homozygous for a novel nonsense mutation in the STS gene. Acta Derm Venereol. 2019; 99(9): 828–830.
- 9Thauvin-Robinet C, Lambert D, Vaillant G, Caillier P, Donzel A, Cusin V, et al. X-linked recessive ichthyosis in a girl: strategy for identifying the causal mechanism. Br J Dermatol. 2005; 152(1): 191–193.
- 10Chatterjee S, Humby T, Davies W. Behavioural and psychiatric phenotypes in men and boys with X-linked ichthyosis: evidence from a worldwide online survey. PLoS One. 2016; 11(10):e0164417.
- 11Maloney ME, Williams ML, Epstein EH Jr, Law MY, Fritsch PO, Elias PM. Lipids in the pathogenesis of ichthyosis: topical cholesterol sulfate-induced scaling in hairless mice. J Invest Dermatol. 1984; 83(4): 252–256.
- 12Zettersten E, Man MQ, Sato J, Denda M, Farrell A, Ghadially R, et al. Recessive X-linked ichthyosis: role of cholesterol-sulfate accumulation in the barrier abnormality. J Invest Dermatol. 1998; 111(5): 784–790.
- 13Høyer H, Lykkesfeldt G, Ibsen HH, Brandrup F. Ichthyosis of steroid sulphatase deficiency. Clinical study of 76 cases. Dermatologica. 1986; 172(4): 184–190.
- 14Shapiro LJ. X-linked ichthyosis. Int J Dermatol. 1981; 20(1): 26–31.
- 15Shwayder T. Disorders of keratinization: diagnosis and management. Am J Clin Dermatol. 2004; 5(1): 17–29.
- 16Hung C, Ayabe RI, Wang C, Frausto RF, Aldave AJ. Pre-Descemet corneal dystrophy and X-linked ichthyosis associated with deletion of Xp22.31 containing the STS gene. Cornea. 2013; 32(9): 1283–1287.
- 17Shi H, Qi XF, Liu TT, Hao Q, Li XH, Liang LL, et al. In vivo confocal microscopy of pre-Descemet corneal dystrophy associated with X-linked ichthyosis: a case report. BMC Ophthalmol. 2017; 17(1): 29.
- 18Okusa T, Yamamichi G, Taniguchi A, Kishimoto N, Tsutahara K, Tanigawa G, et al. A case of steroid sulfatase deficiency complicated by bilateral undescended testis. Hinyokika Kiyo. 2016; 62(11): 595–597.
- 19Mishra K, Batra VV, Basu S, Rath B, Saxena R. Steroid-resistant nephrotic syndrome associated with steroid sulfatase deficiency-x-linked recessive ichthyosis: a case report and review of literature. Eur J Pediatr. 2012; 171(5): 847–850.
- 20Ozawa H, Osawa M, Nagai T, Sakura N. Steroid sulfatase deficiency with bilateral periventricular nodular heterotopia. Pediatr Neurol. 2006; 34(3): 239–241.
- 21Hernández-Martín A, Cuadrado-Corrales N, Ciria-Abad S, Arias-Palomo D, Mascaró-Galy JM, Escámez MJ, et al. X-linked ichthyosis along with recessive dystrophic epidermolysis bullosa in the same patient. Dermatology. 2010; 221(2): 113–116.
- 22Vélez A, Moreno J. Poland's syndrome and recessive X-linked ichthyosis in two brothers. Clin Exp Dermatol. 2000; 25(4): 308–311.
- 23Bai J, Qu Y, Cao Y, Li Y, Zhang W, Jin Y, et al. X-linked ichthyosis and Crigler-Najjar syndrome I: coexistence in a male patient with two copy number variable regions of 2q37.1 and Xp22.3. Mol Med Rep. 2016; 13(2): 1135–1140.
- 24Matsudate Y, Niki M, Hida Y, Kubo Y. Coexistence of X-linked ichthyosis and Nagashima-type palmoplantar keratosis: a case report. J Dermatol. 2019; 46(2): e54–e55.
- 25Abdel-Hamid MS, Ismail MF, Darwish HA, Effat LK, Zaki MS, Abdel-Salam GM. Co-occurrence of primary microcephaly caused by a novel homozygous ASPM mutation along with X-linked ichthyosis in the same patient. Genet Couns. 2016; 27(1): 25–33.
- 26Goodwin G, Hawley PP, Miller DT. A case of HDR syndrome and ichthyosis: dual diagnosis by whole-genome sequencing of novel mutations in GATA3 and STS genes. J Clin Endocrinol Metab. 2016; 101(3): 837–840.
- 27Kent L, Emerton J, Bhadravathi V, Weisblatt E, Pasco G, Willatt LR, et al. X-linked ichthyosis (steroid sulfatase deficiency) is associated with increased risk of attention deficit hyperactivity disorder, autism and social communication deficits. J Med Genet. 2008; 45(8): 519–524.
- 28Malik A, Amer AB, Salama M, Haddad B, Alrifai MT, Balwi MA, et al. X-linked ichthyosis associated with psychosis and behavioral abnormalities: a case report. J Med Case Rep. 2017; 11(1): 267.
- 29Mesquita-Guimarães J. X-linked ichthyosis. Ultrastructural study of 4 cases. Dermatologica. 1981; 162(3): 157–166.
- 30Milstone LM. Epidermal desquamation. J Dermatol Sci. 2004; 36(3): 131–140.
- 31Reed MJ, Purohit A, Woo LW, Newman SP, Potter BV. Steroid sulfatase: molecular biology, regulation, and inhibition. Endocr Rev. 2005; 26(2): 171–202.
- 32Mueller JW, Gilligan LC, Idkowiak J, Arlt W, Foster PA. The regulation of steroid action by sulfation and desulfation. Endocr Rev. 2015; 36(5): 526–563.
- 33Anbar HS, Isa Z, Elounais JJ, Jameel MA, Zib JH, Samer AM, et al. Steroid sulfatase inhibitors: the current landscape. Expert Opin Ther Pat. 2021; 31(6): 453–472.
- 34Elias PM, Crumrine D, Rassner U, Hachem JP, Menon GK, Man W, et al. Basis for abnormal desquamation and permeability barrier dysfunction in RXLI. J Invest Dermatol. 2004; 122(2): 314–319.
- 35Feingold KR. Thematic review series: skin lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis. J Lipid Res. 2007; 48(12): 2531–2546.
- 36Strott CA, Higashi Y. Cholesterol sulfate in human physiology: what's it all about? J Lipid Res. 2003; 44(7): 1268–1278.
- 37Epstein EH, Williams ML, Elias PM. The epidermal cholesterol sulfate cycle. J Am Acad Dermatol. 1984; 10(5 Pt 1): 866–868.
- 38Feingold KR, Jiang YJ. The mechanisms by which lipids coordinately regulate the formation of the protein and lipid domains of the stratum corneum: role of fatty acids, oxysterols, cholesterol sulfate and ceramides as signaling molecules. Dermatoendocrinol. 2011; 3(2): 113–118.
- 39Hanyu O, Nakae H, Miida T, Higashi Y, Fuda H, Endo M, et al. Cholesterol sulfate induces expression of the skin barrier protein filaggrin in normal human epidermal keratinocytes through induction of RORα. Biochem Biophys Res Commun. 2012; 428(1): 99–104.
- 40Shang DD, Zhang X, Liu A, Du L, Jiang WY, Xiao SX. Xp22.3 microdeletions in three Chinese families with X-linked ichthyosis. J Dermatol Sci. 2009; 55(3): 193–195.
- 41Jimenez Vaca AL, Valdes-Flores Mdel R, Rivera-Vega MR, González-Huerta LM, Kofman-Alfaro SH, Cuevas-Covarrubias SA. Deletion pattern of the STS gene in X-linked ichthyosis in a Mexican population. Mol Med. 2001; 7(12): 845–849.
- 42Huang Y, Luo S, Zhao P, Tan L, Fu G, Zhou A, et al. A novel STS mutation and an Xp22.31 microdeletion in a Chinese family with X-linked ichthyosis. Clin Exp Dermatol. 2021; 46(3): 614–617.
- 43Borská R, Pinková B, Réblová K, Bučková H, Kopečková L, Němečková J, et al. Inherited ichthyoses: molecular causes of the disease in Czech patients. Orphanet J Rare Dis. 2019; 14(1): 92.
- 44Ohyama A, Nakano H, Imanishi Y, Seto T, Tsuruta D, Fukai K. A novel missense mutation of the STS gene in two siblings with X-linked ichthyosis, complicated by short stature, bone density reduction, epilepsy, and cryptorchidism. Clin Exp Dermatol. 2019; 44(1): 78–79.
- 45Diociaiuti A, Angioni A, Pisaneschi E, Alesi V, Zambruno G, Novelli A, et al. X-linked ichthyosis: clinical and molecular findings in 35 Italian patients. Exp Dermatol. 2019; 28(10): 1156–1163.
- 46Cuevas-Covarrubias SA, González-Huerta LM. Analysis of the VCX3A, VCX2 and VCX3B genes shows that VCX3A gene deletion is not sufficient to result in mental retardation in X-linked ichthyosis. Br J Dermatol. 2008; 158(3): 483–486.
- 47Lodén M. Role of topical emollients and moisturizers in the treatment of dry skin barrier disorders. Am J Clin Dermatol. 2003; 4(11): 771–788.
- 48Elias PM, Williams ML, Choi EH, Feingold KR. Role of cholesterol sulfate in epidermal structure and function: lessons from X-linked ichthyosis. Biochim Biophys Acta. 2014; 1841(3): 353–361.
- 49McGeoghan F, Camera E, Maiellaro M, Menon M, Huang M, Dewan P, et al. RNA sequencing and lipidomics uncovers novel pathomechanisms in recessive X-linked ichthyosis. Front Mol Biosci. 2023; 10:1176802.
- 50Hoppe T, Winge MC, Bradley M, Nordenskjöld M, Vahlquist A, Berne B, et al. X-linked recessive ichthyosis: an impaired barrier function evokes limited gene responses before and after moisturizing treatments. Br J Dermatol. 2012; 167(3): 514–522.
- 51Kwon TU, Kwon YJ, Baek HS, Park H, Lee H, Chun YJ. Unraveling the molecular mechanisms of cell migration impairment and apoptosis associated with steroid sulfatase deficiency: implications for X-linked ichthyosis. Biochim Biophys Acta Mol basis Dis. 2024; 1870(3):167004.
- 52McGovern JA, Meinert C, de Veer SJ, Hollier BG, Parker TJ, Upton Z. Attenuated kallikrein-related peptidase activity disrupts desquamation and leads to stratum corneum thickening in human skin equivalent models. Br J Dermatol. 2017; 176(1): 145–158.
- 53Japtok L, Bäumer W, Kleuser B. Sphingosine-1-phosphate as signaling molecule in the skin: relevance in atopic dermatitis. Allergo J Int. 2014; 23(2): 54–59.
- 54Nemes Z, Demény M, Marekov LN, Fésüs L, Steinert PM. Cholesterol 3-sulfate interferes with cornified envelope assembly by diverting transglutaminase 1 activity from the formation of cross-links and esters to the hydrolysis of glutamine. J Biol Chem. 2000; 275(4): 2636–2646.
- 55Bruno DL, Stark Z, Amor DJ, Burgess T, Butler K, Corrie S, et al. Extending the scope of diagnostic chromosome analysis: detection of single gene defects using high-resolution SNP microarrays. Hum Mutat. 2011; 32(12): 1500–1506.
- 56Idkowiak J, Taylor AE, Subtil S, O'Neil DM, Vijzelaar R, Dias RP, et al. Steroid sulfatase deficiency and androgen activation before and after puberty. J Clin Endocrinol Metab. 2016; 101(6): 2545–2553.
- 57Takeichi T, Akiyama M. Inherited ichthyosis: non-syndromic forms. J Dermatol. 2016; 43(3): 242–251.
- 58Cañueto J, Ciria S, Hernández-Martín A, Unamuno P, González-Sarmiento R. Analysis of the STS gene in 40 patients with recessive X-linked ichthyosis: a high frequency of partial deletions in a Spanish population. J Eur Acad Dermatol Venereol. 2010; 24(10): 1226–1229.
- 59Aviram-Goldring A, Goldman B, Netanelov-Shapira I, Chen-Shtoyerman R, Zvulunov A, Tal O, et al. Deletion patterns of the STS gene and flanking sequences in Israeli X-linked ichthyosis patients and carriers: analysis by polymerase chain reaction and fluorescence in situ hybridization techniques. Int J Dermatol. 2000; 39(3): 182–187.
- 60Dreyer FE, Abdulrahman GO, Waring G, Hinshaw K. Placental steroid sulphatase deficiency: an approach to antenatal care and delivery. Ann Saudi Med. 2018; 38(6): 445–449.
- 61Thyssen JP, Godoy-Gijon E, Elias PM. Ichthyosis vulgaris: the filaggrin mutation disease. Br J Dermatol. 2013; 168(6): 1155–1166.
- 62Jaffar H, Shakir Z, Kumar G, Ali IF. Ichthyosis vulgaris: an updated review. Skin Health Dis. 2023; 3(1):e187.
- 63Oji V, Tadini G, Akiyama M, Blanchet Bardon C, Bodemer C, Bourrat E, et al. Revised nomenclature and classification of inherited ichthyoses: results of the first ichthyosis consensus conference in Sorèze 2009. J Am Acad Dermatol. 2010; 63(4): 607–641.
- 64Vahlquist A, Gånemo A, Virtanen M. Congenital ichthyosis: an overview of current and emerging therapies. Acta Derm Venereol. 2008; 88(1): 4–14.
- 65Schmuth M, Martinz V, Janecke AR, Fauth C, Schossig A, Zschocke J, et al. Inherited ichthyoses/generalized Mendelian disorders of cornification. Eur J Hum Genet. 2013; 21(2): 123–133.
- 66Crane JS, Paller AS. X-linked ichthyosis. Treasure Island, FL: StatPearls; 2024.
- 67Hernández-Martin A, Aranegui B, Martin-Santiago A, Garcia-Doval I. A systematic review of clinical trials of treatments for the congenital ichthyoses, excluding ichthyosis vulgaris. J Am Acad Dermatol. 2013; 69(4): 544–549.e8.
- 68Limmer AL, Nwannunu CE, Patel RR, Mui UN, Tyring SK. Management of ichthyosis: a brief review. Skin Therapy Lett. 2020; 25(1): 5–7.
- 69Digiovanna JJ, Mauro T, Milstone LM, Schmuth M, Toro JR. Systemic retinoids in the management of ichthyoses and related skin types. Dermatol Ther. 2013; 26(1): 26–38.
- 70Ibsen HH, Brandrup F, Secher B. Topical cholesterol treatment of recessive X-linked ichthyosis. Lancet. 1984; 2(8403): 645.
- 71Cotellessa C, Cuevas-Covarrubias SA, Valeri P, Fargnoli MC, Peris K. Topical tazarotene 0.05% versus glycolic acid 70% treatment in X-linked ichthyosis due to extensive deletion of the STS gene. Acta Derm Venereol. 2005; 85(4): 346–348.
- 72Nguyen V, Cunningham BB, Eichenfield LF, Alió AB, Buka RL. Treatment of ichthyosiform diseases with topically applied tazarotene: risk of systemic absorption. J Am Acad Dermatol. 2007; 57(5 Suppl): S123–S125.
- 73Teng JMC, Bunick CG, Guenthner S, Murrell DF, Marathe K, Kempers S, et al. The control study: a randomized, double-blind vehicle-controlled phase 2b study of novel topical isotretinoin formulation demonstrates improvement in recessive X-linked and autosomal recessive lamellar congenital ichthyosis. J Am Acad Dermatol. 2022; 87(6): 1455–1458.
- 74Murrell DF, Teng JMC, Guenthner S, Marathe K, Kempers S, Eads K, et al. Phase IIb randomized control study demonstrates a novel topical isotretinoin formulation, TMB-001, is safe and effective in participants with either recessive X-linked or autosomal recessive lamellar congenital ichthyosis. Clin Exp Dermatol. 2023; 48(6): 623–630.
- 75Vahlquist A, Fischer J, Törmä H. Inherited nonsyndromic ichthyoses: an update on pathophysiology, diagnosis and treatment. Am J Clin Dermatol. 2018; 19(1): 51–66.
- 76Hasbani DJ, Hamie L, Eid E, Tamer C, Abbas O, Kurban M. Treatments for non-syndromic inherited ichthyosis, including emergent pathogenesis-related therapy. Am J Clin Dermatol. 2022; 23(6): 853–867.
- 77Orfanos CE, Zouboulis CC, Almond-Roesler B, Geilen CC. Current use and future potential role of retinoids in dermatology. Drugs. 1997; 53(3): 358–388.
- 78Chulpanova DS, Shaimardanova AA, Ponomarev AS, Elsheikh S, Rizvanov AA, Solovyeva VV. Current strategies for the gene therapy of autosomal recessive congenital ichthyosis and other types of inherited ichthyosis. Int J Mol Sci. 2022; 23(5):2506.
- 79Shinkuma S. Advances in gene therapy and their application to skin diseases: a review. J Dermatol Sci. 2021; 103(1): 2–9.
- 80Ain QU, Campos EVR, Huynh A, Witzigmann D, Hedtrich S. Gene delivery to the skin – how far have we come? Trends Biotechnol. 2021; 39(5): 474–487.
- 81Goswami R, Subramanian G, Silayeva L, Newkirk I, Doctor D, Chawla K, et al. Gene therapy leaves a vicious cycle. Front Oncol. 2019; 9: 297.
- 82Smatti MK, Al-Sadeq DW, Ali NH, Pintus G, Abou-Saleh H, Nasrallah GK. Epstein-Barr virus epidemiology, serology, and genetic variability of LMP-1 oncogene among healthy population: an update. Front Oncol. 2018; 8: 211.
- 83Akiyama M, Sawamura D, Shimizu H. The clinical spectrum of nonbullous congenital ichthyosiform erythroderma and lamellar ichthyosis. Clin Exp Dermatol. 2003; 28(3): 235–240.
Citing Literature
