Prenatal detection of bilateral clubfoot should prompt a systematic evaluation for associated anomalies, particularly sacral defects and other lower-limb malformations. Arthrogryposis must also be considered in the differential diagnosis. Importantly, prenatal imaging should be complemented by postnatal assessments, which may, as in the present case, uncover a misdiagnosis with major implications for future pregnancies. This case report illustrated how detailed postnatal investigations led to the revision of an initial diagnosis of caudal regression syndrome to the final, exceptionally rare diagnosis of Wieacker-Wolff Syndrome. Such diagnostic correction carries substantial consequences for genetic counseling. Wieacker-Wolff syndrome, also referred to as intellectual disability, developmental delay, and contractures syndrome, is a severe neurodevelopmental disorder characterized by arthrogryposis and intellectual disability. It is inherited in an X-linked manner, either dominant or recessive, and is caused by pathogenic variants in the ZC4H2 gene.

Wieacker-Wolff syndrome (WRWF) is an X-linked genetic disorder characterized by neuromusculoskeletal abnormalities caused by loss-of-function variants of the ZC4H2 gene. Here, we report the case of a male infant with WRWF manifesting as multiple joint contractures and congenital anomalies at birth. He underwent gastrostomy to treat the gastroesophageal reflux disease, which caused mixed apnea and transient bradycardia. The patient subsequently developed hyperinsulinemic hypoglycemia (HH) and was diagnosed with dumping syndrome. Although he underwent multiple treatments, including alpha-glucosidase inhibitors (α-GI) administration, he continued to exhibit HH with seizures and loss of consciousness. Whole-exome sequencing revealed a novel missense variant of ZC4H2 [NM_018684.4: c.557T>G, p.(Met186Arg)] at Xq11.2 in both the patient and his mother. Based on these results and clinical symptoms, the patient was diagnosed with WRWF. Although WRWF is not considered a major cause of HH, we regarded it as a related complication based on previous reports. Diazoxide treatment was initiated, and the hypoglycemic attacks resolved almost entirely without any notable side effects after 18 mo. To the best of our knowledge, this is the first report of WRWF-associated HH treated with low-dose diazoxide and α-GI. Therefore, diazoxide is recommended for the treatment of WRWF-associated HH.

ZC4H2 (MIM# 300897) is a nuclear factor involved in various cellular processes including proliferation and differentiation of neural stem cells, ventral spinal patterning and osteogenic and myogenic processes. Pathogenic variants in ZC4H2 have been associated with Wieacker-Wolff syndrome (MIM# 314580), an X-linked neurodevelopmental disorder characterized by arthrogryposis, development delay, hypotonia, feeding difficulties, poor growth, skeletal abnormalities, and dysmorphic features. Zebrafish zc4h2 null mutants recapitulated the human phenotype, showed complete loss of vsx2 expression in brain, and exhibited abnormal swimming and balance problems. Here we report 7 new patients (four males and three females) with ZC4H2-related disorder from six unrelated families. Four of the 6 ZC4H2 variants are novel: three missense variants, designated as c.142T>A (p.Tyr48Asn), c.558G>A (p.Met186Ile) and c.602C>T (p.Pro201Leu), and a nonsense variant, c.618C>A (p.Cys206*). Two variants were previously reported : a nonsense variant c.199C>T (p.Arg67*) and a splice site variant (c.225+5G>A). Five patients were on the severe spectrum of clinical findings, two of whom had early death. The male patient harboring the p.Met186Ile variant and the female patient that carries the p.Pro201Leu variant have a relatively mild phenotype. Of note, 4/7 patients had a tethered cord that required a surgical repair. We also demonstrate and discuss previously under-recognized phenotypic features including sleep apnea, arrhythmia, hypoglycemia, and unexpected early death. To study the effect of the missense variants, we performed microinjection of human ZC4H2 wild-type or variant mRNAs into zc4h2 null mutant zebrafish embryos. The p.Met186Ile mRNA variant was able to partially rescue vsx2 expression while p.Tyr48Asn and p.Pro201Leu mRNA variants were not. However, swimming and balance problems could not be rescued by any of these variants. These results suggest that the p.Met186Ile is a hypomorphic allele. Our work expands the genotypes and phenotypes associated with ZC4H2-related disorder and demonstrates that the zebrafish system is a reliable method to determine the pathogenicity of ZC4H2 variants.