OTUD5-related rare X-linked multiple congenital anomalies and neurodevelopmental syndrome: Clinical findings and review of the literature

Abstract

The OTUD5 gene (OMIM #300713), located on Xp11.23, encodes the ovarian tumor deubiquitinase 5, a deubiquitinase enzyme with critical functions in chromatin remodeling, transcriptional regulation, neuroectodermal differentiation, and innate immune signaling. Hemizygous pathogenic variants in OTUD5 are associated with X-linked multiple congenital anomalies–neurodevelopmental syndrome (MCAND, OMIM #301056), a rare multisystem disorder characterized by developmental delay, intellectual disability, craniofacial dysmorphism, and variable involvement of the cardiac, skeletal, and genitourinary systems. Although fewer than 30 cases have been reported worldwide, the clinical spectrum appears to be highly heterogeneous, ranging from early infantile lethality to survival into adulthood.We report a male patient, born prematurely at 32 weeks, who presented with global developmental delay, neonatal seizures, truncal hypotonia, and multiple dysmorphic features. Facial dysmorphism, microcephaly, overlapping fingers, hypospadias, bilateral cryptorchidism, congenital heart defects, bilateral sensorineural hearing loss, and structural brain abnormalities were observed. Despite supportive management, the patient died at 1.5 years of age due to pneumonia complicated by sepsis.Genetic testing through whole-exome sequencing identified a hemizygous missense variant in OTUD5, NM_001136157.2:c.1195 C > T (NP_001129629.1:p.Arg399Trp). Segregation analysis confirmed maternal carrier status and heterozygosity in one female sibling. Our findings indicate that bilateral sensorineural hearing loss and cranial anomalies may constitute variable or previously underrecognized features of MCAND; however, validation in additional, systematically evaluated cases is necessary before these manifestations can be regarded as part of the established phenotypic spectrum. Furthermore, the patient’s fatal course due to infectious complications underscores the role of OTUD5 in innate immunity and suggests a possible predisposition to immune deficiency. This case emphasizes the importance of early genetic testing in patients with complex congenital anomalies and supports close monitoring for infections as part of comprehensive clinical management.