４p欠失症候群

OBJECTIVE: To analyze the results of genetic testing, indication for prenatal diagnosis, and intrauterine ultrasound phenotypes of ten fetuses with Wolf-Hirschhorn syndrome (WHS). METHODS: A retrospective analysis was conducted on the data of the fetuses diagnosed at the Obstetrics and Gynecology Medical Center of Nanjing University Medical School Affiliated Drum Tower Hospital between July 2020 and January 2026, including their medical history, indication for genetic testing, prenatal ultrasound findings, genetic testing methods and results, parental genetic information, pregnancy outcomes, and follow-up of prenatal genetic diagnosis results in some cases during subsequent pregnancies. Descriptive statistical analysis was performed on the data. This study was approved by the Ethics Committee of the hospital (Ethics No.: 2022-451-01). RESULTS: Among the ten WHS fetuses, one had prenatal ultrasound suggesting multiple malformations and intrauterine growth retardation, five had prenatal ultrasound suggesting intrauterine growth restriction, one had ultrasound suggesting increased NT thickness in the first trimester, one was signaled by NIPT with a deletion at 4p15.31p16.3, and the remaining two had indications of advanced maternal age and high risk for trisomy 21 by maternal serum screening, respectively. The deletions detected in fetuses had encompassed the critical region for WHS at 4p16.3. CONCLUSION: Intrauterine growth restriction is the most common prenatal intrauterine ultrasound phenotype of WHS fetuses, and is an important indication for prenatal diagnosis. The widespread application of NIPT technology has increased the detection rate for WHS during pregnancy.

We report 3 pediatric patients with Wolf-Hirschhorn syndrome who presented with congenital nasolacrimal duct obstruction and underwent endoluminal lacrimal duct recanalization under dacryoendoscopic guidance. All patients achieved complete resolution of epiphora without recurrence.

Rauch-Steindl syndrome (RAUST) is a very rare genetic syndrome caused by pathogenic variants in the NSD2 gene on chromosome 4p16.3. Its clinical phenotype resembles that of Wolf-Hirschhorn syndrome (WHS) but is generally milder. Using whole-exome sequencing (WES), we identified a novel de novo deletion spanning exons 6-22 of the NSD2 gene in a 6-year-old Chinese boy diagnosed with RAUST. The patient presented with facial dysmorphisms, language retardation, global developmental delay, autism, and hypotonia. These findings further support the notion that haploinsufficiency of NSD2 is a key mechanism in WHS and that molecular genetic testing provides a more accurate diagnosis for such patients. The novel variant reported here expands the known mutational spectrum of NSD2.

BACKGROUND: Rauch-Steindl syndrome (RAUST) is a rare neurodevelopmental disorder caused by pathogenic variants in NSD2, a histone methyltransferase gene at 4p16.3. Due to phenotypic overlap with Wolf-Hirschhorn syndrome (WHS), RAUST is often misdiagnosed. Missense variants in NSD2 are particularly challenging to interpret without functional validation. METHODS: Genomic DNA from the proband and her parents was extracted from peripheral blood. Trio-whole-exome sequencing (WES) was performed to identify candidate variants based on the clinical phenotype, followed by Sanger sequencing validation. RNA splicing impact was assessed via reverse transcription PCR and TA-cloning from peripheral blood mononuclear cells. RESULTS: A 7-year-8-month-old girl mainly presented with intrauterine and postnatal growth restriction, global developmental delay, intellectual disability, epilepsy, short stature, and facial dysmorphism was documented. Trio-WES identified a novel de novo missense variant in NSD2 (NM_001042424.3: c.2137G>C, p.Gly713Arg), which is located at the last base of exon 11 and was predicted to be highly likely to cause aberrant splicing. Functional analysis revealed this variant causes exon 11 skipping in 53% of transcripts, resulting in a frameshift (p.Leu672Glyfs*20) and premature truncation. CONCLUSION: This is the first report of an NSD2 missense variant that functionally acts as a splicing mutation leading to protein truncation. Our findings highlight the necessity of RNA-level functional assays for accurate variant interpretation and reinforce genotype-phenotype distinctions between RAUST and WHS.