Cornelia de Lange Syndrome (CDLS) is a rare congenital developmental disorder characterized by craniofacial malformations, growth and developmental abnormalities, limb malformations, cognitive impairment, and gastroesophageal reflux, among other symptoms (Li et al., 2021). Genetic variations associated with CDLS have been identified in several genes, including SMC1A, SMC3, RAD21, NIPBL, HDAC8, BRD4, and ANKRD11 (Cochran et al., 2019), with mutations in the NIPBL gene being the most prevalent (Kline et al., 2018). Instances of Cornelia de Lange type 3 (CDLS3) attributed to variations in the SMC3 gene are extremely rare. This study presents two cases of rare genetic variations: one involving SMC3 and MECP2 gene mutations, and the other involving SMC3 and PMP22 gene mutations, to enhance the understanding of these related rare diseases.

The incidence of Cornelia de Lange Syndrome (CdLS) in neonates is approximately 1 in 10,000 to 30,000 (Bottai et al., 2019), with inheritance patterns predominantly autosomal dominant or X-linked. The clinical spectrum of CdLS varies from mild to severe manifestations. The classical presentation of CdLS is characterized by distinctive facial features, growth retardation, hirsutism, and anomalies of the upper limbs and hands. Individuals exhibiting milder phenotypes demonstrate less pronounced growth, cognitive, and limb involvement. Additional common clinical manifestations include cardiac defects, gastrointestinal dysfunction, hearing impairment, myopia, cryptorchidism, and genital hypoplasia, among others (Deschamps, 2022). Advances in genetic technology have facilitated the identification of novel genetic variants associated with CdLS, beyond the previously recognized genes such as SMC1A, SMC3, RAD21, NIPBL, HDAC8, BRD4, and ANKRD11. Newly identified genes include MAU2 (Ascaso et al., 2024), KMT2D, KDM6A, and UBE2A, among others (Shangguan and Chen, 2022). A comprehensive literature review utilizing databases such as Wanfang, CNKI, VIP, the Chinese Medical Association's databases, PubMed, and Web of Science revealed a total of 62 reported cases of CdLS attributable to SMC3 mutations globally, with 27 cases providing detailed clinical histories. de novo pathogenic variants in SMC3 account for approximately 1–2% of Cornelia de Lange syndrome (CdLS) cases. The associated phenotype is characterized by postnatal-onset microcephaly, subtle craniofacial dysmorphism, and relatively mild prenatal growth retardation that progresses to more significant postnatal growth failure. Notably, these individuals exhibit infrequent occurrence of congenital structural cardiac anomalies and an absence of limb defects (Kaur et al., 2023). In this study, both children exhibited microcephaly, with no evidence of growth retardation detected during prenatal examinations, aligning with previous reports. The facial characteristics of the two children were relatively typical. Patient 1 presented with a low hairline, high-arched and thick eyebrows, a short nasal bridge, and a high palatal arch, whereas Patient 2 exhibited high-arched eyebrows, long eyelashes, prominent ears, and low ear positioning, which deviated from the aforementioned reports. Cardiac ultrasound results for Patient 1 were normal, while Patient 2 displayed a patent ductus arteriosus. Additionally, Patient 2 had a single transverse palmar crease and a clinodactyly of the fifth finger, whereas Patient 1 showed no limb development abnormalities. These observations underscore the fact that identical genetic variations can result in diverse clinical phenotypes, highlighting the heterogeneity of clinical presentations. A domestic report previously described a case of fetal hand deformity associated with the c.3298G>A missense variation in the SMC3 gene (Huang et al., 2024). In contrast, our two subjects exhibited no significant limb-related deformities during prenatal examinations.

In this study, Patient 1 exhibited dual-positive variations in the SMC3 and MECP2 genes. The MECP2 gene is predominantly associated with Rett syndrome, which is categorized into two forms: typical and atypical. Notably, this patient did not exhibit hallmark symptoms of Rett syndrome, such as stereotypical hand movements, loss of language function, abnormal gait, epileptic seizures, developmental regression, or respiratory and sleep abnormalities. According to the expert consensus on the international diagnostic criteria for Rett syndrome established in 2010, this patient did not fulfill the criteria for either typical or atypical Rett syndrome (Neul et al., 2010). Literature indicates that MECP2 gene variations have been identified in individuals without Rett syndrome, including a female asymptomatic carrier within a Rett syndrome family, a phenomenon attributed to extreme skewing of X chromosome inactivation (Wan et al., 1999). Individuals with MECP2 variations may present with other neurodevelopmental disorders, including autism, Angelman syndrome-like manifestations, and nonspecific intellectual disabilities (Carney et al., 2003; Watson et al., 2001). The splicing variant c.2535 + 1G > A in the SMC3 gene results in a spectrum of severe clinical phenotypes (Lei et al., 2024). In contrast, missense variants in the NIPBL and SMC3 genes are typically associated with milder clinical manifestations (Zhu and Wang, 2018). Among the six reported cases of amino acid frameshift variations caused by nucleotide deletions in the SMC3 gene with detailed clinical data, five exhibited mild to moderate clinical phenotypes. Most variations in the SMC3 gene are associated with mild to moderate cognitive developmental impairments (Li et al., 2021). However, the subject of this study presents with severe intellectual disability. Currently 14 years old, the subject exhibits language developmental disorders, can articulate only short sentences of six to seven words, experiences drooling, displays hyperactivity, has poor concentration, and can comprehend and follow only simple instructions. It is hypothesized that these severe manifestations may be attributed to the combined effects of variations in the SMC3 and MECP2 genes. Charcot–Marie–Tooth disease (CMT) represents the most prevalent monogenic hereditary disorder affecting the peripheral nerves, with an estimated prevalence of approximately 40 per 100,000 individuals. The onset of CMT typically occurs during childhood or adolescence, and its clinical manifestations include chronic progressive symmetrical muscle weakness and atrophy, distal sensory impairment, diminished or absent tendon reflexes, pes cavus, and other skeletal deformities (Pareyson and Marchesi, 2009). The demyelinating form of CMT is characterized by a marked reduction in nerve conduction velocity (NCV), with the motor NCV in the upper limbs generally measuring less than 38 m/s. Pathological examination of nerve biopsies often reveals significant abnormalities in peripheral nerve myelin (Yao and He, 2024). CMT1, an autosomal dominant demyelinating form of CMT, is the most prevalent type. Within this category, CMT1A is the most common subtype, accounting for 40 to 50% of all CMT cases. The majority of CMT1A cases are associated with a duplication of a 1.4 Mb segment on chromosome 17p11.2-12, which includes the peripheral myelin protein 22 (PMP22) gene (Lupski et al., 1992). The CNV analysis for Patient 2 revealed a pathogenic haploid duplication of approximately 1.38 Mb at the chromosomal location chr17:14095305–15472344. The mother was identified as wild-type, while the duplicated segment included the PMP22 gene. Verification through quantitative polymerase chain reaction (q-PCR) demonstrated that the cousin, aunt, father, and grandfather of the affected family members also possessed the PMP22 gene duplication. These individuals exhibited phenotypic characteristics such as high foot arches and abnormal gait. Notably, the grandfather, father, and aunt displayed the ability to stand on one leg, reminiscent of a crane posture, in the lower limbs, consistent with familial genetic co-segregation. Electromyography of the proband indicated a nerve conduction velocity (NCV) of the limbs at less than 38 m/s. Considering the clinical manifestations in the child, including hand and foot tremors, external foot rotation, a staggering gait, inability to squat, and distal limb muscle strength rated at 5-, alongside the electromyography and genetic findings, a diagnosis of Charcot–Marie–Tooth disease (CMT) was established, specifically aligning with the CMT1A subtype. Additionally, Patient 2 exhibited a de novo mutation in the SMC3 gene and was diagnosed with Cornelia de Lange Syndrome type 3 (CdLS3) based on the clinical phenotype. This child presented with two rare genetic conditions. Iran reports a case with concomitant variants: a novel homozygous HERC1 gene variant and a novel heterozygous PMP22 duplication (Reshadmanesh et al., 2024). CAPRA (a probabilistic risk assessment platform) and adverse pathology (AP) report three unrelated cases of dual diagnosis (Capra et al., 2023). Consequently, when the clinical phenotype of a child cannot be attributed to a single gene, it becomes imperative to consider the possibility of additional genetic abnormalities.

In conclusion, our study identified two pediatric cases exhibiting rare diseases attributable to dual-positive genetic variations. In the first case, the patient presented with Cornelia de Lange syndrome type 3, accompanied by severe cognitive impairment, resulting from variations in the SMC3 and MECP2 genes. It is posited that the non-Rett syndrome phenotype, associated with the MECP2 gene variation, may exacerbate the cognitive impairment observed in this patient. The second case involved a patient with Cornelia de Lange syndrome type 3, co-occurring with Charcot–Marie–Tooth disease type 1A, due to an SMC3 gene variation and PMP22 gene duplication. These findings underscore the necessity of considering additional genetic variations when a single gene cannot be fully explain a clinical phenotype. This approach can enhance the foundation for genetic counseling for affected families and inform strategies for eugenics, as well as optimal prenatal and postnatal care. Due to the small number of cases, this article has certain limitations and requires more case studies to fully describe the clinical characteristics of this gene mutation.