Cornelia de Lange syndrome (CdLS) is a rare genetic disorder with symptoms, including facial anomalies (such as fused eyebrows, short nose, upturned nose tip, and downturned mouth corners), growth retardation, small head (microcephaly), developmental delays, cognitive impairments, excess hair growth, and limb anomalies. Currently, mutations in seven genes (NIBPL, SMC1A, SMC3, RAD21, BRD4, HDAC8, and ANKRD11) are known to be associated with CdLS. CdLS is diagnosed based on both genetic testing and clinical examination. However, the clinical and genetic characteristics of CdLS in the Chinese population have not been determined.
To address this research gap, a team led by Professor Chunxiu Gong from the National Center for Health, Beijing, China, examined Chinese pediatric patients with CdLS to determine the clinical presentation of the disease and the genetic alterations. The study was published online in Pediatric Investigation on 02 July 2025. Prof. Gong states that "Estimating the prevalence of CdLS has been challenging due to underdiagnosis or lack of recognition of milder phenotypes. Thus, elucidating the clinical and genetic characteristics of CdLS in the Chinese population will guide pediatricians to better diagnose and manage the disease in China."
After recording the clinical presentation of patients and the disease severity, the researchers extracted DNA from the blood of 19 children with CdLS and performed whole-exome sequencing, a technique for determining the sequence of protein-coding regions (exomes).
Based on a standard scoring system, 12 patients presented with classic CdLS. Global developmental delays were observed in 16 children, while prenatal growth retardation and short stature were observed in 14 children. The most frequent clinical presentations were craniofacial anomalies, especially a short nose and upturned nose tip, and small hands and/or feet. Skin aberrations and hearing loss were less common.
Whole-exome sequencing revealed 19 mutations in three genes. Most of these mutations (15 mutations) were detected in the gene NIPBL, which encodes a development-related protein delangin. Specifically, NIPBL harbored mutations that result in amino acid substitution (missense mutation), protein truncation (nonsense mutation), protein sequence alteration (frameshift mutation), and altered mRNA processing (splicing variant). Two new variants (one missense mutation and one splicing variant) were detected in SMC1A (a chromosome structure-regulating gene). Similarly, two new variants (one frameshift mutation and one deletion) were detected in RAD21 (a cell division-related gene).
The study also examined whether genetic changes are correlated with clinical presentation. The major correlation was detected with NIPBL null variants, which are a type of mutation that results in the complete loss of gene function. Patients with NIPBL null variants (nonsense, frameshift, and large deletion mutations) exhibited impaired growth and microcephaly.
To examine the potential therapeutic strategies for CdLS, the study focused on three patients whose parents requested recombinant human growth hormone (rh-GH) therapy. One female patient diagnosed with CdLS at the age of 3 years underwent rh-GH therapy at the age of 5 years. Although the patient's height increased by 8 cm, the treatment was discontinued as the parents deemed the response to be inadequate. One male patient diagnosed with CdLS at the age of 10 years continues to undergo rh-GH therapy and has increased his height by 12 cm. Another female patient aged 11 years underwent rh-GH therapy at the age of 7 years. Although the patient's height increased by 10 cm within 1 year, the treatment was discontinued owing to hand and foot enlargement. The lead author, Xiaoqiao Li, remarks that "While rh-GH therapy was effective in two cases, it was associated with undesirable outcomes in one patient. Hence, individualized treatment plan and dosage monitoring are critical to enhance treatment effectiveness and minimize adverse effects."
By identifying the characteristics of CdLS, this study provided directions for clinicians to diagnose CdLS and develop management strategies specifically for Chinese patients. These findings also provide a foundation for epidemiological studies on CdLS in China in the future.
