Wieacker–Wolff syndrome with associated cleft palate in a female case

Abstract

Wieacker-Wolff syndrome is a rare congenital syndrome with few reported cases in the current literature. It is traditionally described in males as an X-linked recessive disorder associated with congenital contractures of the feet, progressive neurologic muscular atrophy, and intellectual delay caused by ZC4H2 mutations. The purpose of this paper is to present a female individual with a classic phenotype and cleft palate, a previously undescribed finding in this syndrome. Recent reports have demonstrated that females are rarely severely affected and phenotypic expression is difficult to predict [Zanzottera et al. (); American Journal of Medical Genetics Part A 173A: 1358-1363]. This case supports the unpredictability of Wieacker-Wolff syndrome severity and prompts future questions regarding female mutations and phenotypic expression.

Deleterious de novo variants of X‐linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita

“…Detailed clinical descriptions are presented in Supporting Information Results. In the clinical evaluation, we also included publicly accessible information of three females reported to DECIPHER and all families and simplex cases published to date (Godfrey et al, ; Hirata et al, ; Kondo et al, ; May et al, ; Okubo et al, ; Zanzottera et al, ). A compilation of the main ( ≥ 30%) clinical features of affected males and females from these 42 families is given in Table and of the additional less common clinical features (< 30%) in Table S2.…”

“…In 2015, May et al identified ZC4H2 variants in four additional families, including a large family with syndromic X‐linked ID (XLID; MRXS4), previously described as having Miles‐Carpenter syndrome (MCS; Miles & Carpenter, ) and characterized by XLID, exotropia, distal muscle wasting, microcephaly, congenital contractures, and low digital arches (May et al, ). Most recently, three simplex females with heterozygous de novo deleterious ZC4H2 were reported, including an early truncating nonsense variant and two microdeletions (Godfrey, Dowlatshahi, Martin, & Rothkopf, ; Okubo et al, ; Zanzottera et al, ). As a result of these findings, these various allelic syndromes are now referred to as ZC4H2‐associated rare disorders (ZARD).…”

Neuromuscular and Neuroendocrinological Features Associated With ZC4H2-Related Arthrogryposis Multiplex Congenita in a Sicilian Family: A Case Report

“…Importantly, despite the fact that WWS is an X-linked recessive disorder, females carrying heterozygous ZC4H2 mutations may display a mild intellectual disability phenotype as well as subtle distal contractures and sometimes clubfoot ( 21 , 25 ). A recent study by Wang et al ( 22 ) demonstrated that mechanisms underlying X-chromosome inactivation (XCI) in females are not necessarily implicated in the disease phenotype.…”

A novel de novo nonsense mutation in ZC4H2 causes Wieacker‐Wolff Syndrome

“…However, female patients show various symptoms especially in deletion and nonsense mutation cases, and some of them are considered to be associated with nonrandom X-chromosome inactivation (XCI) (Hirata et al, 2013). So far, 7 missense mutations, 1 nonsense mutation, 1 frameshift mutation, 1 chromosomal breakpoint in Xq11.2, and 4 deletions in ZC4H2 gene have been reported ( Figure 1) (Godfrey, Dowlatshahi, Martin, & Rothkopf, 2018;Hennekam, Barth, Van Lookeren Campagne, De Visser, & Dingemans, 1991;Hirata et al, 2013;Kondo et al, 2018;May et al, 2015;Okubo et al, 2018;Zanzottera et al, 2017). The clinical presentation and genetic changes in female patients have been summarized in Table 1.…”