Sifrim-Hitz-Weiss syndrome associated with a novel de novo variant in the CHD4 gene: a case report with neurodevelopmental delay and congenital malformations

Abstract

Case Presentation: A male patient, born to non-consanguineous parents, was referred to medical genetics due to congenital central hypotonia, motor developmental delay, and craniofacial dysmorphisms. Physical examination revealed a broad forehead, low nasal bridge and saddle nose, telecanthus, narrow palpebral fissures, external eyelid eversion, prominent and simplified ears, micrognathia, micropenis, bilateral post-axial polydactyly of the upper limbs, and a sacral dimple. Echocardiogram showed patent ductus arteriosus and atrial septal defect. Ophthalmologic evaluation showed myopia of -2.5 diopters and astigmatism of -3.5 diopters. Brain magnetic resonance revealed cystic/lacunar areas with FLAIR hyperintensity in the bilateral periventricular white matter associated with ventricular enlargement, compatible with gliosis and periventricular leukomalacia. Additionally, diffuse thinning of the corpus callosum was observed. Exome sequencing identified a heterozygous variant c.3661T>A(p.Phe1221Ile) in the CHD4 gene, previously unreported in the literatureParental testing confirmed the variant as de novo, leading to its reclassification as likely pathogenic and confirming the diagnosis of Sifrim-Hitz-Weiss syndrome. Discussion: Sifrim-Hitz-Weiss syndrome is a rare autosomal dominant condition caused by pathogenic variants in the CHD4 gene. It is characterized by neurodevelopmental delay and intellectual disability, with variable phenotypic manifestations including facial dysmorphisms, congenital heart defects, and neurological and ophthalmological abnormalities. After diagnosis, evaluation is recommended to investigate congenital/infantile stroke, intracranial hypertension (including hydrocephalus), Chiari type I malformation, syringomyelia, and spinal cord compression, with attention to cervical instability. Developmental delay is common, particularly affecting language, although most individuals develop functional verbal communication. Mild to moderate intellectual disability is predominant, present in 82% of cases. Independent walking usually occurs later than expected, on average at 30 months. Hypotonia during the first years of life is common and may be associated with feeding difficulties. Behavioral changes are less frequent but may include Autism Spectrum Disorder, attention deficit, impulsivity, or anxiety. At birth, weight and head circumference are usually adequate, with possible evolution to macrocephaly or microcephaly. Short stature occurs in some patients; growth hormone deficiency may be present, with a good response to therapy. Final Comments: This report highlights the importance of early genetic evaluation in patients presenting with global developmental delay associated with multiple malformations and dysmorphic features. Early identification of the syndrome enables targeted interventions, genetic counseling, and longitudinal care planning, with a positive impact on the prognosis and quality of life.