A Novel Homozygous HERC2 c.4660C>T (p. Arg1554Ter) Variant in an Infant with Severe Neurodevelopmental Disorder and Diffuse Osteopenia: A Case Report

Abstract

Background: HERC2-related intellectual developmental disorder is a rare autosomal recessive neurodevelopmental condition, and its full phenotypic spectrum remains incompletely defined. Case Presentation: We report a 7-month-old female infant born to second-degree consanguineous parents who presented with profound global developmental delay, generalised hypotonia, feeding difficulties, failure to thrive, microcephaly, and facial dysmorphism. She was born at 37 weeks of gestation with a birth weight of 2,700 g and required neonatal intensive care for respiratory distress for seven days. At 5 months, she was hospitalised for Bordetella pertussis infection. At 7 months, her weight was 3.6 kg, length 56 cm, and head circumference 40 cm, all below −3 standard deviations for age and sex. She had not achieved head control, could not sit with support, had no voluntary grasping, and showed no social smile or visual tracking. Routine laboratory and metabolic investigations were largely unremarkable except for mild hyperlactataemia. Brain MRI and EEG were normal. Skeletal radiographs showed diffuse osteopenia, and bone age was approximately 3 months. Whole-exome sequencing identified a homozygous HERC2 nonsense variant, NM_004667.6:c.4660C>T (p.Arg1554Ter), classified as likely pathogenic. Conclusion: This case expands the documented clinical spectrum of HERC2-related disorder by highlighting diffuse osteopenia and delayed bone age alongside severe neurodevelopmental impairment, and it supports genomic evaluation in infants with unexplained developmental delay, particularly in consanguineous families.