Hypotrichosis‐lymphedema‐telangiectasia syndrome: Report of ileal atresia associated with a <scp><i>SOX18</i></scp> de novo pathogenic variant and review of the phenotypic spectrum

Coulie, Richard; Niyazov, Dmitriy; Gambello, Michael J.; Fastré, Elodie; Brouillard, Pascal; Vikkula, Miikka

doi:10.1002/ajmg.a.62205

Cited by 8 publications

(3 citation statements)

References 15 publications

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“…Notably, variations in the SOX18 gene have previously been involved in hypotrichosis–lymphedema–telangiectasia syndrome as well as aortic dilation, pulmonary hypertension, dysmorphic face, renal failure, hydrocele, chylothorax, dysplastic nails, and cutis marmorata in humans [ 99 ]. In the present study, in addition to CHD, all the affected family members also manifested telangiectasia and hypotrichosis.…”

Section: Discussionmentioning

confidence: 99%

Identification of SOX18 as a New Gene Predisposing to Congenital Heart Disease

et al. 2022

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Congenital heart disease (CHD) is the most frequent kind of birth deformity in human beings and the leading cause of neonatal mortality worldwide. Although genetic etiologies encompassing aneuploidy, copy number variations, and mutations in over 100 genes have been uncovered to be involved in the pathogenesis of CHD, the genetic components predisposing to CHD in most cases remain unclear. We recruited a family with CHD from the Chinese Han population in the present investigation. Through whole-exome sequencing analysis of selected family members, a new SOX18 variation, namely NM_018419.3:c.349A>T; p.(Lys117*), was identified and confirmed to co-segregate with the CHD phenotype in the entire family by Sanger sequencing analysis. The heterozygous variant was absent from the 384 healthy volunteers enlisted as control individuals. Functional exploration via luciferase reporter analysis in cultivated HeLa cells revealed that Lys117*-mutant SOX18 lost transactivation on its target genes NR2F2 and GATA4, two genes responsible for CHD. Moreover, the genetic variation terminated the synergistic activation between SOX18 and NKX2.5, another gene accountable for CHD. The findings strongly indicate SOX18 as a novel gene contributing to CHD, which helps address challenges in the clinical genetic diagnosis and prenatal prophylaxis of CHD.

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Section: Discussionmentioning

confidence: 99%

Identification of SOX18 as a New Gene Predisposing to Congenital Heart Disease

et al. 2022

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“…Clinical Observation и синдромальный гипотрихоз (сочетанный с другими кожными дерматозами) [5]. К синдромальным формам относят сочетание гипотрихоза с ювенильной макулярной дистрофией или множественной семейной трихоэпителиомой, связанными с геном CDH3 (кодирует кадгерины -мембранные гликопротеины, ответственные за кальций-зависимую межклеточную адгезию) [6][7][8], и синдром гипотрихоз-лимфедема-телеангиэктазии, возникающий при изменениях в гене SOX18 (кодирует транскрипционные факторы, участвующие в развитии волос, а также кровеносных и лимфатических сосудов в эмбриональном периоде) [9,10]. Кроме того, выделяют доминантные и рецессивные формы наследственной алопеции.…”

Section: клиническое наблюдениеunclassified

<i>DSG4</i> Gene Variants as a Cause of Hypotrichosis in the Child with Severe Atopic Dermatitis: Clinical Case

Murashkin,

Epishev,

Dubenko

et al. 2023

Vopr. sovr. pediatr.

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Background. Hypotrichosis is a heritable form of alopecia that causes almost complete scalp hair loss in childhood. The diagnosis is typically established according to medical history and clinical picture. Genetic testing is an additional diagnostic method that allows to establish “hypotrichosis” in cases of ambiguous or subtle clinical signs of the disease, as well as to perform differential diagnosis of this condition with others commonly associated with atopic dermatitis (focal and diffuse alopecia). Clinical diagnosis of hypotrichosis in patients with severe dermatosis is challenging.Clinical case description. The girl, aged 2 years 4 months, was hospitalized with complaints on extended rash on the body with severe itching, and changes in hair thickness, quality of hair shaft, and hair loss. Severe atopic dermatitis and hypotrichosis were diagnosed. The diagnosis of atopic dermatitis was established clinically (SCORAD — 65), the diagnosis of hypotrichosis (type 6, monilethrix-like hypotrichosis) was confirmed via molecular genetic testing (nucleotide variant c.699C>T in exone 13 of the DSG4 gene (OMIM # 607892)). Patient's mother, brother, and two sisters were diagnosed with the nucleotide variant chr18:31409487C>T in heterozygous state in the DSG4 gene. Mother and brother had no clinical manifestations, while both sisters had mild scalp hair damage, as well as eyebrows and eyelashes, since birth. There were no clinical manifestations of atopic dermatitis in parents and other children in the family.Conclusion. Hypotrichosis clinical signs can be subtled, smoothed, or imitate the symptoms of other comorbid conditions, especially in patients with comorbidities or severe dermatosis. Also worth noting is that changes in certain genes can aggravate the course of atopic dermatitis. In this clinical case, mutation in the DSG4 gene leads to epidermal barrier failure by disrupting the synthesis of desmosomes transmembrane components. Thus, geneticist consultation and genetic testing (search for changes in certain genes) are crucial in such cases.

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“…The reported SOX18 pathogenic variants are very few, in a dozen of families, and yet the phenotypic spectrum is quite varied in the reported patients. Of note, two patients did not present with lymphatic dysfunction [ 5 , 6 ], whereas others already presented with lymphedema at birth and one died in utero with non-immune hydrops fetalis ([ 3 , 7 ] and references therein).…”

Section: Introductionmentioning

confidence: 99%

Lymphatic Defects in Zebrafish sox18 Mutants Are Exacerbated by Perturbed VEGFC Signaling, While Masked by Elevated sox7 Expression

Moleri,

Mercurio,

Pezzotta

et al. 2023

Cells

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Mutations in the transcription factor-coding gene SOX18, the growth factor-coding gene VEGFC and its receptor-coding gene VEGFR3/FLT4 cause primary lymphedema in humans. In mammals, SOX18, together with COUP-TFII/NR2F2, activates the expression of Prox1, a master regulator in lymphatic identity and development. Knockdown studies have also suggested an involvement of Sox18, Coup-tfII/Nr2f2, and Prox1 in zebrafish lymphatic development. Mutants in the corresponding genes initially failed to recapitulate the lymphatic defects observed in morphants. In this paper, we describe a novel zebrafish sox18 mutant allele, sa12315, which behaves as a null. The formation of the lymphatic thoracic duct is affected in sox18 homozygous mutants, but defects are milder in both zygotic and maternal-zygotic sox18 mutants than in sox18 morphants. Remarkably, in sox18 mutants, the expression of the closely related sox7 gene is elevated where lymphatic precursors arise. Sox7 could thus mask the absence of a functional Sox18 protein and account for the mild lymphatic phenotype in sox18 mutants, as shown in mice. Partial knockdown of vegfc exacerbates lymphatic defects in sox18 mutants, making them visible in heterozygotes. Our data thus reinforce the genetic interaction between Sox18 and Vegfc in lymphatic development, previously suggested by knockdown studies, and highlight the ability of Sox7 to compensate for Sox18 lymphatic dysfunction.

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Hypotrichosis‐lymphedema‐telangiectasia syndrome: Report of ileal atresia associated with a SOX18 de novo pathogenic variant and review of the phenotypic spectrum

Cited by 8 publications

References 15 publications

Identification of SOX18 as a New Gene Predisposing to Congenital Heart Disease

Identification of SOX18 as a New Gene Predisposing to Congenital Heart Disease

<i>DSG4</i> Gene Variants as a Cause of Hypotrichosis in the Child with Severe Atopic Dermatitis: Clinical Case

Lymphatic Defects in Zebrafish sox18 Mutants Are Exacerbated by Perturbed VEGFC Signaling, While Masked by Elevated sox7 Expression

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