In the present study, we provided two important findings of a male child with CdLS. First, in our study, the child had non-classical and mild clinical features according to the international CdLS consensus [1]，but have additional renal involvement that it isn’t included in the CdLS criteria. Second，We identified a novel heterozygous variant (c.8325_8326delAA) in the NIPBL gene, which was predicted to be pathogenic. This finding expanded the spectrum of pathogenic mutations for CdLS and provided evidence as to whether the diagnosis of CdLS.
CdLS is a multisystem malformation syndrome recognized primarily based on the morphological characteristics [7]. The presentation of CdLS can vary widely, from mild to severe and with different degrees of facial and limb involvement. Classic CdLS is easily recognized by experienced pediatricians and clinical geneticists because of a distinctive craniofacial appearance, growth retardation and limb malformations, and classic clinical features may contribute to the prenatal diagnosis [3, 8]. But it may be difficult to diagnosis milder or non-classic phenotypes based on physical features. Considering of the great phenotypic variability of CdLS and the wide heterogeneity in diagnostics, a group of international experts, representing the Scientific Advisory Council of the World Federation of CdLS Support Groups, established an International CdLS Consensus Group to present recommendations for the diagnosis and management of CdLS in 2018 [1]. According to this consensus, our patient received a clinical score of 6, including two cardinal features (synophrys with arched and thick eyebrows, long philtrum) and two suggestive features (postnatal growth retardation, short digits of the thumbs and fifth digits). But our patient had additional features，that are horseshoe kidney and renal insufficiency.
Furthermore, trio WES was performed on the boy and his parents to clarify the diagnosis. We identified a novel heterozygous variant (c.8325_8326delAA) in the NIPBL gene. This frameshift mutation was predicted to cause the loss of function of NIPBL. The NIPBL gene consists of 47 exons and is currently considered the cohesin loader, which regulates the loading of the ring of the cohesin complex onto chromatin [9]. Up to 60%~70% of CdLS cases carry heterozygous mutations in NIPBL. Haploinsufficiency caused by loss-of-function variants in the NIPBL gene is thought to be the most common cause of CdLS [10, 11]. And additionally, gene mutations affecting RNA transcription and proteins, such as frameshift mutations, have been found in patients with severe phenotypes of CdLS. It has been known that genotype-phenotype correlation exists on NIPBL. One study of NIPBL mutational analysis in 120 individuals showed that CdLS patients who have no mutation may have a milder phenotypes than patients who have the gene mutation, and patients who have missense mutations have a milder phenotypes than patients who have truncating mutations, which suggests NIPBL as a dosage-sensitive gene [10]. Our patient was diagnosed as CdLS by identifying a novel mutation of NIPBL gene. This frameshift mutation generates a prematurely truncated protein, which could result in NIPBL haploinsufficiency, inducing severe phenotype. But inconsistent with expectation, our patient had non-classical and mild clinical features according to the international CdLS consensus [1]. In addition, our patient had renal malformation and renal insufficiency. These findings suggest that maybe genotype–phenotype correlation of NIPBL in CdLS is still unclear, or maybe renal involvement is one of the severe phenotypes of NIPBL.
Interestingly, it had been reported that NIPBL is strongly expressed in fetal and adult kidney, and NIPBL involves the developing kidney in human embryonic tissue sections [12]. But there are only few reports about renal involvement in CdLS patients. Furthermore，renal involvement wasn’t included in the clinical diagnostic criteria of the first international consensus statement for the diagnosis and management of CdLS [6]. In this case, it may result that the clinicians underestimate the value of renal malformation and renal impairment for the diagnosis and management of CdLS patients.
In 1982，Wick MR et al first reported an infant have renal malformation with CdLS [13]. But to date, there was only one cross sectional study to evaluate the congenital anomalies of the kidney and urinary tract in CdLS, which was published in 2005 [14]. In that study, Sixty-one Italian patients of CdLS from 61 different families underwent a careful renal and urological evaluation. Twenty-five patients (41%) were diagnosed as structural anomalies of the kidney and urinary tract by ultrasound or voiding cystourethrography, including absent or poor corticomedullary differentiation, pelvic dilation, vesicoureteral reflux, small kidney, isolated renal cyst and renal ectopia. Renal function was reduced in 9 patients with renal tract abnormalities. The anomalies of the kidney and urinary tract and renal functional impairment more frequently occurred in patients with the classic rather than the mild clinical phenotype. These results suggested that anomalies of the kidney and urinary tract are maybe common in CdLS patients. But it is to be regretted that since 2005, only Jaiprakash and his colleague reported a female child of CdLS additionally had multicystic dysplastic kidneys[15]. By investigating 26 Chinese cases of CdLS, no one got the kidney and urinary tract ultrasound[16]. Schrier et al retrospectively reviewed a total of 426 propositi with confirmed clinical diagnoses of CdLS in their database who died in a 41-year period between 1966 and 2007 [17]. They found that renal disease accounted for 1.7% of deaths[17]. According to available literature, our patient had additional clinical manifestations compared with previously described that have not been mentioned in previously reported cases. In the present study, there is no significant family history with respect to renal or renal tract abnormalities and kidney disease. So, it suggested that the horseshoe kidney and renal insufficiency are related to the novel mutation of NIPBL gene, and maybe the pivotal manifestations in the patients of CdLS. Additionally, impaired renal function in this child may indicate that renal disease might progress to end-stage renal disease. Based on these data, clinicians need to pay attention on the analysis of renal involvement in CdLS, then to confirm the value of renal involvement in the diagnosis and management of CdLS.
In conclusion, we described a novel NIPBL variant that causes Cornelia de Lange Syndrome with horseshoe kidney and renal insufficiency. The patient harbored a frameshift mutation but had non-classical and mild clinical features.
It suggests that anomalies of the kidney and urinary tract may also have major clinical implications for the diagnosis of CdLS and genotype–phenotype correlation of NIPBL need further investigation. Once the clinical diagnosis of CdLS has been confirmed, the patient needs to be evaluated for kidney and urinary tract anomalies by ultrasound that require management or surveillance. And renal function should be monitored in CdLS with structural renal malformations. It needs further studies to confirm whether the renal malformation is one of the cardinal features in CdLS.