Cornelia de Lange syndrome with NIPBL mutation and mosaic Turner syndrome in the same individual

Abstract

Background: Cornelia de Lange syndrome (CdLS) is a dominantly inherited disorder characterized by facial dysmorphism, growth and cognitive impairment, limb malformations and multiple organ involvement. Mutations in NIPBL gene account for about 60% of patients with CdLS. This gene encodes a key regulator of the Cohesin complex, which controls sister chromatid segregation during both mitosis and meiosis. Turner syndrome (TS) results from the partial or complete absence of one of the X chromosomes, usually associated with congenital lymphedema, short stature, and gonadal dysgenesis.

Case presentation: Here we report a four-year-old female with CdLS due to a frameshift mutation in the NIPBL gene (c.1445_1448delGAGA), who also had a tissue-specific mosaic 45,X/46,XX karyotype. The patient showed a severe form of CdLS with craniofacial dysmorphism, pre- and post-natal growth delay, cardiovascular abnormalities, hirsutism and severe psychomotor retardation with behavioural problems. She also presented with minor clinical features consistent with TS, including peripheral lymphedema and webbed neck. The NIPBL mutation was present in the two tissues analysed from different embryonic origins (peripheral blood lymphocytes and oral mucosa epithelial cells). However, the percentage of cells with monosomy X was low and variable in tissues. These findings indicate that, ontogenically, the NIPBL mutation may have appeared before the mosaic monosomy X.

Conclusions: The coexistence in several patients of these two rare disorders raises the issue of whether there is indeed a cause-effect association. The detailed clinical descriptions indicate predominant CdLS phenotype, although additional TS manifestations may appear in adolescence.

Figure 1

Phenotype of the patient. ( A) Frontal view of the patient in the first week of life. ( B) Frontal view and right hand of the patient at the age of 2 years and 10 months; and ( C) at 3 years. ( D) Roentgenogram of the left hand at the age of 3 years and 6 months and ( E) left foot of the patient at the age of 3 years. Note typical CdLS facial features seen in our patient included synophrys, arched eyebrows, long eyelashes, depressed nasal bridge and anteverted nares, long and flat philtrum, thin upper lip, downslanting corners of the mouth, low set and posteriorly rotated ears and microbrachycephaly ( A- C). Several mild musculoskeletal anomalies were noted including small hands and feet ( D and E), clinodactyly of the fifth finger and proximally placed thumb ( D).

Figure 2

(A) Pedigree of the affected family and partial electropherograms of exon 9 of the NIPBL gene. White symbols indicate unaffected individuals, whereas black symbol indicate the affected individual. The sequencing analysis performed on genomic DNA from the patient peripheral blood lymphocytes (v) and oral mucosa epithelial cells (vi) shows similar heights of the peaks of the allele carrying the c.1445_1448delGAGA mutation in both tissues. Wild-type electropherograms identified in the normal parents are also indicated (i-iv). (B) Schematic model of the NIPBL gene. Sequence features of human NIPBL protein previously reported are indicated [23,30] . The open reading frame of NIPBL gene is marked in light grey. The exon 9 of the NIPBL gene is highlighted in red.

Figure 3

GTG-banded and FISH images from lymphocytes and buccal epithelial cells. Panels ( A- B) show karyotypes of peripheral blood lymphocytes demonstrating the 45,X/46,XX mosaicism. Panels ( C- E) show FISH analysis using CEP X Spectrum Orange/Y Spectrum Green Direct Labelled Fluorescent DNA probes from Abbott Molecular within of interphase nuclei of lymphocytes ( C- D) and buccal epithelial cells ( E). ( C) and ( E) show FISH interphase cells with one copy of the X chromosome (arrow). ( D) and ( E) show the presence of two copies of the X chromosomes (double arrows). Only representative cells with different karyotypes are shown here.