４p欠失症候群

Mucopolysaccharidosis Type I (MPS I) is a rare lysosomal storage disorder caused by α-l-iduronidase deficiency, leading to glycosaminoglycan accumulation and multisystem involvement. Wolf-Hirschhorn Syndrome (WHS) is a chromosomal disorder characterized by growth delay, dysmorphism, and developmental impairment. Because the IDUA gene is located within the 4p16.3 region, the coexistence of WHS and MPS I is biologically plausible but rarely documented. We describe a 2-year-old child of North African origin presenting with dysmorphic features, developmental delay, and thoracolumbar kyphosis. Chromosomal microarray analysis identified a 5.8 Mb deletion at 4p16.3-p16.2, confirming WHS at 17 months. However, additional clinical features remained unexplained. Incidentally, during a routine blood test, a blood smear revealed lymphocytes with metachromatic inclusions, raising suspicion of a lysosomal storage disorder. An enzymatic assay confirmed α-l-iduronidase deficiency, and molecular analysis identified biallelic pathogenic alterations in the IDUA gene located on chromosome 4p16.3, establishing the diagnosis of MPS I at 18 months. Enzyme replacement therapy was initiated at 19 months and was associated with stabilization of the somatic manifestations of MPS I, including improvement in respiratory symptoms. This observation highlights the risk of diagnostic overshadowing in rare diseases. A confirmed genetic diagnosis should not preclude further investigations when clinical features are discordant.

Haploinsufficiency of the histone methyltransferase NSD2 is a major cause of Wolf-Hirschhorn syndrome (WHS) and the related Rauch-Steindl syndrome (RAUST), both of which exhibit microcephaly and intellectual disability. However, the precise role of NSD2 in brain development remains unclear. Here, we identify NSD2 as a pivotal epigenetic regulator orchestrating the transition from neurogenesis to gliogenesis in the developing mouse neocortex. Conditional knockout of Nsd2 severely impairs astrocyte production in late embryogenesis, while its overexpression promotes astrocytic fate. Integrated epigenomic and transcriptomic analyses reveal that NSD2 deposits the activating histone mark H3K36me2 directly at the Egfr promoter, sustaining EGFR expression and downstream ERK signaling-a pathway essential for gliogenesis. Pharmacological activation of ERK phosphorylation rescues the astrogliogenesis defects both in vitro and in vivo. Notably, Nsd2-deficient mice exhibit significant deficits in learning and memory. Our findings define an NSD2-H3K36me2-EGFR-ERK axis that drives cortical gliogenesis and provide mechanistic insights into the potential contribution of NSD2 deficiency to neurodevelopmental abnormalities.

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.