Atypical Wolf–Hirschhorn Syndrome in a Boy with a Novel NSD2 Loss-of-Function Variant

We present the case of a 6-year and 7-month-old male patient, who presented prenatally with intrauterine growth restriction and later developed global developmental delay. Prenatal ultrasound demonstrated symmetric growth restriction, and birth was complicated by a double nuchal cord. Early concerns arose at the age of 4 months due to lack of grasping. Other motor developmental milestones were later delayed as well with independent sitting achieved at 13 months and walking at 21 months. He spoke his first syllables at 18 months. Metabolic screening from peripheral blood revealed elevated pyruvate and lactate. Brain MRI at 2 years demonstrated mild leukopathy. He was referred to our diagnostic center for genetic diagnostic at the age of 2 years and 5 months. At that time his growth parameters were below average (length 84.5 cm, 3rd percentile; weight 10 kg, <3rd percentile; head circumference 47 cm, 3rd–15th percentile) and dysmorphic features including triangular face and narrow palpebral fissures. In the patient we performed exome sequencing and identified a novel heterozygous duplication of 23 nucleotides in NSD2 (NM_001042424.3:c.2072_2094dup), predicted to cause frameshift and the insertion of a premature stop codon (p.(Arg699ThrfsTer42)) leading to the loss of function of the protein product. Pathogenic NSD2 variants have been reported as the cause of an atypical form of Wolf–Hirschhorn syndrome (OMIM 194190) characterized by intrauterine growth restriction, hypotonia, short stature, developmental delay, and mild intellectual disability, with variable dysmorphic features and rarely epilepsy. All previously reported loss-of-function variants have been de novo, except for one case with paternal inheritance and mild phenotype. The identified variant is absent from gnomAD, affects a loss-of-function intolerant gene (pLI=1), and matches the patient’s phenotype, supporting classification as likely pathogenic (ACMG criteria PVS1, PM2).