Cornelia de Lange syndrome (CdLS, OMIM #122470, 300590, 300882, 610759, 614701) is a multisystem disorder that causes diverse physical and neurocognitive problems . The prevalence is estimated to be approximately 1 in 10,000-30,000 live births worldwide, irrespective of the ethnic group [1,2]. CdLS is inherited in either an autosomal dominant or X-linked manner depending on the affected genes, and the majority of the cases are sporadic . Common clinical features of CdLS include a distinctive craniofacial appearance, growth failure, developmental delay/intellectual disability, upper limb abnormalities, and hypertrichosis . Although pediatricians can easily recognize patients with a typical CdLS phenotype, arriving at the diagnosis is often complicated because of the clinical overlap with other disorders showing CdLS-like phenotypes, such as CHOPS syndrome, KBG syndrome, or Rubinstein-Taybi syndrome [1,2].
Pathogenic variations of the genes belonging to the cohesion pathway cause CdLS and are considered to be a group of ‘cohesinopathy’ . Cohesin plays an important role in chromatid cohesion, gene expression, and DNA repair . There are five CdLS-causative genes that are involved with the cohesin complex: three core cohesion subunits (
Genotype-phenotype correlation has been reported in patients with CdLS. Patients with
Fifteen unrelated patients who had shown suspicious features of CdLS with a clinical score (CS) of 4 or more at the Seoul National University Hospital between November 2010 and June 2021 were enrolled in this study. The medical records of these patients were retrospectively reviewed. Standard deviation scores (SDS) for growth parameters, including height, weight, and head circumference, were assigned in each case both at birth based on the Fenton growth charts and postnatally based on the 2017 Korean National Growth Charts [13,14]. Prenatal and postnatal growth retardation were defined as a birthweight and height –2 SDS below the scores of the respective age- and sex-matched controls [15,16]. Microcephaly was defined as a head circumference –2 SDS below the scores of the corresponding age- and sex-matched population group . Developmental milestones were evaluated by pediatric neurologists, and analysis of the brain magnetic resonance imaging (MRI) was performed by neuroradiologists. The full-scale intelligence quotient (FSIQ) was assessed in three patients using the Korean-Wechsler Preschool and Primary Scale of Intelligence-Fourth edition or Korean-Leiter International Performance Scale-Revised. Eye and ear-nose-throat abnormalities were ascertained by evaluating the ophthalmology and otorhinolaryngology records, respectively. The combined cardiac and renal malformations were assessed by performing echocardiography and renal sonography.
The CS was calculated for each patient according to the consensus statement of CdLS : 2 points were allotted for each of the six cardinal features (synophrys and/or thick eyebrows, short nose, concave nasal ridge and/or upturned nasal tip, long and/or smooth philtrum, thin upper lip vermilion and/or downturned corners of mouth, hand oligodactyly and/or adactyly, and congenital diaphragmatic hernia), and 1 point was allotted for each of the seven suggestive features (global developmental delay and/or intellectual disability, prenatal growth retardation, postnatal growth retardation, microcephaly, small hands and/or feet, short fifth finger, and hirsutism). Patients with a CS ≥11 (with at least three cardinal features) were classified as having classic CdLS. Patients with CS of 9-10 points (with at least two cardinal features) were considered to have non-classic CdLS, whereas those with CS of 4-8 points (with at least 1 cardinal feature) were defined as other phenotypes sharing limited signs of CdLS . This study was approved by the Institutional Review Board of the Seoul National University Hospital (IRB no. 2106-068-1225) and exempt from written informed consent.
Genomic DNA had been extracted from the leukocytes in the peripheral blood using a DNA isolation kit (QIAGEN, Hilden, Germany). Sanger sequencing had been performed to identify the
Continuous variables with a normal distribution are expressed as mean values with standard deviation, whereas those without a normal distribution are expressed as median values with range. All categorical variables are presented as numbers and percentages of the participants. The comparison between
Table 1 shows the baseline clinical characteristics of the 15 Korean patients with CdLS (3 males and 12 females). The median age at the time of diagnosis was 1.7 (range, 0.0-11.8) years, and median follow-up duration was 3.8 (range, 0.4-11.7) years. The mean birthweight SDS was –1.8±0.9, and the mean SDS of height, weight, and head circumference at the first visit (at a mean age of 1.3±1.5 years) were –2.4±2.3, –2.1±1.6, and –2.8±1.3, respectively. Eight (53.3%) patients were classified as having classic CdLS, two (13.3%) as having non-classic CdLS, and five (33.3%) as having other phenotypes sharing limited signs of CdLS. Regarding cardinal features, synophrys and/or thick eyebrows were most frequently noted in 13 (86.7%) patients, followed by a thin upper lip vermilion and/or downturned corners of the mouth in 12 (80.0%), short nose in 11 (73.3%), long and/or smooth philtrum in 10 (66.7%), and congenital diaphragmatic hernia in one (6.7%) patient. Regarding suggestive features, global developmental delay and/or intellectual disability was noted in 14 (93.3%) patients (except case 9, due to being lost to follow-up at 6 months of age), followed by microcephaly in 12 (80.0%), postnatal growth retardation in 11 (73.3%), hirsutism in 10 (66.7%), small hands and/or feet in 8 (53.3%), prenatal growth retardation in 6 (40.0%), and a short fifth finger in 3 (20.0%) patients (Fig. 1). Regarding other clinical features, ophthalmologic abnormalities including ptosis, myopia, hypermetropia, amblyopia, and/or strabismus were observed in ten (66.7%) patients, followed by hearing impairments in seven (46.7%), gastrointestinal abnormalities including gastroesophageal reflux disease in six (40.0%), cardiac anomalies in four (26.7%), and genitourinary abnormalities including small kidney, vesicoureteral reflux, and/or undescended testis in four (26.7%) patients.
The mean SDS of height, weight, and head circumference at last visit (at a mean age of 4.8±3.0 years) were –3.0±2.3, –2.8±2.1, and –3.4±1.9, respectively. The responses to growth hormone (GH) in two GH-treated patients were insufficient; the first-year changes in height SDS were –1.4 in case 4 (small for the gestational age without catch-up growth), and +0.2 in case 14 (GH-deficient). Four (26.7%) patients (case 6, 7, 8, and 10) developed seizures at the median age of 1.8 (range, 0.1-4.3) years. Among the 10 patients who underwent brain MRI, six showed abnormal findings: simplified gyral patterns (cases 2, 6, and 8), retrocerebellar cyst (case 7), diffuse brain atrophy (case 15), and pituitary gland hypoplasia (case 14 with GH deficiency). The FSIQ scores were below 40, 40, and 47 in cases 2, 3, and 4, respectively.
Fifteen causative variants (including 12 novel variants) were identified:
All five individuals with
In the present study, we described the clinical and molecular characteristics of 15 Korean patients with CdLS. These patients presented a wide clinical spectrum for CdLS with varying degrees of clinical severity. We identified 15 causative variants (including 12 novel variants) in four genes (
The common characteristics presented were consistent with those previously reported: typical facial features, developmental delay and/or intellectual disability, microcephaly, and prenatal and postnatal growth retardation [1,19-21]. Distinctive facial appearance (such as synophrys, thick eyebrows, thin upper vermilion border of the lip, downturned corners of the mouth, short nose, and long and smooth philtrum), as reported in previous studies, were the most recognizable clinical findings in these patients, especially in those with the classic CdLS phenotype [19,22]. Prenatal and postnatal growth retardation is a hallmark of CdLS, and the mean adult height was 155.8 cm in men and 131.1 cm in women among clinically diagnosed CdLS individuals . GH secretion is generally normal in most children diagnosed with CdLS [24-27]. However, the GH response in our two GH-treated patients (including one with GH-deficient) was not sufficient, although an appropriate response has been reported in a mildly affected case without GH deficiency . Regarding neurological findings other than developmental delay, seizures developed in 26.7% of our patients. Focal seizures were observed in three out of four patients and 1 to 5 kinds of antiepileptic drugs were necessary to control seizures, which were in accord with previous reports [3,29]. Abnormal neuroimaging findings included microcephaly, gyral simplification, and diffuse brain atrophy, which have also been reported as common features in patients with CdLS . The degree of limb involvement in our CdLS cohort was mild (small hands and feet only) in contrast to 25-46% patients having major limb anomalies (such as oligodactyly and adactyly) in previous reports [3,21,31]. Compared to the reports showing the clinical features of CdLS patients from China and Asia, Korean patients showed a similar distribution of typical characteristics except for higher rate of hearing loss (46.7% in Korean vs. 6.7% in Chinese or 22.2% in Asian) [19,20]. Clinodactyly was not significant in Korean patients compared to Chinese and Asian patients (0% in Korean vs. 66.7% in Chinese or 55.6% in Asian) [19,20].
We identified 15 genetic causative variants of
Among the CdLS causative variants identified in our study, c.6893G>A of
Our study had several limitations. First, there was a possibility of selection bias, as our study was performed in a single tertiary center. Second, statistical significance could not be estimated for some parameters related to genotype-phenotype correlation due to the small sample size. Third, due to the retrospective study design and short follow-up period, we could not evaluate the long-term growth and developmental outcomes. In addition, the objective degree of intellectual disability (such as the FSIQ) was measured in only a limited number of patients. However, our study was strengthened by detailed phenotyping of a Korean CdLS cohort with molecular confirmation. In addition, we identified 15 causal variants, of which 12 were novel, in genes involved in molecular pathways underlying cohesinopathies and some genotype-phenotype correlations.
In conclusion, we identified the clinical and genetic heterogeneity in Korean patients with CdLS. The clinical severity was higher in patients with
The authors declare that they do not have any conflicts of interest.
Conception and design: JMK. Acquisition of data: DK, HYK, JHC. Analysis and interpretation of data: DK, HYK, JHC. Drafting the article: DK. Critical revision of the article: HYK, JMK. Final approval of the version to be published: JMK.
Baseline characteristics of patients
|No.||Sex||Phenotype||Gene||GA (week)||Birth weight (SDS)||Age_i (year)||Ht_i (SDS)||Wt_i (SDS)||Clinical characteristics||Clinical score|
|Cardinal features||Suggestive features||Other features|
|1||F||Classic||37||–2.3||0.0||–8.1||–2.3||S, N, P, V||D, preGR, postGR, M, HF, F, H||ASD, VSD, PDA, SK, MEE, SNHL, G, L||15|
|2||F||Classic||37||–3.1||0.9||–4.8||–5.0||S, N, P, V, C||D, preGR, postGR, M, HF, H||SNHL, PT, O, G, L||16|
|3||M||Classic||38||–2.1||0.6||–3.1||–2.1||S, N, P, V||D, preGR, postGR, M, HF, H||B, L||14|
|4||M||Classic||36||–1.9||1.2||–2.4||–2.6||S, N, P, V||D, postGR, M, F, H||U, PT, O, A, L||13|
|5||M||Classic||39||–2.5||0.3||–1.8||–1.4||S, N, P, V||D, preGR, postGR, M, H||-||13|
|6||F||Classic||37||–1.5||1.2||–0.6||0.6||S, N, P, V||D, postGR, M, HF, H||Sz, TOF, E, SNHL, B, G, LM||13|
|8||F||Non-classic||38||–0.9||0.0||–1.2||–0.9||S, N, V||D, postGR, M, HF||MG, Sz, SK, MO, CHL, PT, HPS, G||10|
|9||F||Othera||40||–0.8||0.1||1.4||0.4||S, P, V||-||-||6|
|10||F||Othera||39||–1.3||1.3||–2.5||–3.7||S||D, postGR, M, H||Sz, MEE, HM, G||6|
|11||F||Classic||39||–3.7||2.3||–0.4||–0.9||S, N, P, V||D, preGR, M, H||B||12|
|12||F||Othera||39||–1.7||0.5||–1.7||–1.2||S, V||D, M, HF||SNHL||7|
|13||F||Classic||35||–0.6||0.7||–2.1||–2.4||N, P, V||D, postGR, M, HF, F, H||ASD, CHL, MEE, O||12|
|14||F||Non-classic||39||–1.6||5.3||–4.1||–2.8||S, P, V||D, postGR, H||GHD, VUR, MEE, O, DP||9|
|15||F||Othera||39||–2.6||0.9||–4.4||–4.5||N||D, preGR, postGR, M, HF||TOF, CHL, MEE, O, A||7|
aOther phenotypes sharing limited signs of CdLS.
GA, gestational age; SDS, standard deviation score; i, at initial visit; Ht, height; Wt, weight; F, female; M, male; S, synophrys; N, short nose; P, long philtrum; V, thin upper lip vermilion; C, congenital diaphragmatic hernia; D, developemental delay; preGR, prenatal growth retardation; postGR, postnatal growth retardation; M, microcephaly; HF, small hands and/or feet; F, short fifth finger; H, hirsutism; ASD, atrial septal defect; VSD, ventricular septal defect; PDA, patent ductus arteriosus; SK, small kidney; MEE, middle ear effusion; SNHL, sensorineural hearing loss; G, gastroesophageal reflux disease; L, limitation of motion of joints; PT, ptosis; O, myopia; B, strabismus; U, undescended testis; A, amblyopia; Sz, seizure; TOF, Tetralogy of Fallot; E, ear aplasia; LM, laryngomalacia; MG, micrognathia; MO, microotia; CHL, conductive hearing loss; HPS, hypertrophic pyloric stenosis; HM, hypermetropia; GHD, growth hormone deficiency; VUR, vesicoureteral reflux; DP, double pylorus.
Molecular findings of patients
|No||Sex||Phenotype||Gene||cDNA change||Protein change||Type||Inherited||Zygosity||Novelity||Location||ACMG classification|
|1||F||Classic||c.5428-1G>T||Exon 29 skipping||Mis-splicing||D||Hetero||Novel||Intron 28||P|
|6||F||Classic||c.3285+1G>C||exon 21 skipping||Mis-splicing||D||Hetero||Reported||Intron 21||P|
|10||F||Othera||c.3476-2A>G||exon 28 skipping||Mis-splicing||D||Hetero||Novel||Intron 27||P|
|11||F||Classic||c.2523_2525delCCA||p.Asp841_Gln842delinsGlu||Small deletion||D||Hetero||Novel||Exon 22||LP|
|12||F||Othera||Xq13.1q13.2 deletion (including
||-||Whole gene deletion||D||Hetero||Novel||Whole gene||P|
|14||F||Non-classic||c.437+1G>C||Exon 4 skipping||Mis-splicing||NA||Hetero||Novel||Intron 4||LP|
aOther phenotypes sharing limited signs of CdLS. bA 458Kb deletion at chromosome Xq13.1q13.2 (Hg19, chromosome X: 71502595-71960802).
cDNA, coding DNA; ACMG, American College of Medical Genetics and Genomics; F, female; M, male; D,
|Clinical characteristics||Total (n=15)||Non-
|Sex (female)||12 (80.0)||2 (40.0)||10 (100.0)||0.022|
|Birth weight (SDS)||–1.8±0.9||–2.4±0.5||–1.5±1.0||0.086|
|Synophrys and/or thick eyebrows||13 (86.7)||5 (100.0)||8 (80.0)||0.524|
|Short nose, concave nasal ridge and/or upturned nasal tip||11 (73.3)||5 (100.0)||6 (60.0)||0.231|
|Long and/or smooth philtrum||10 (66.7)||5 (100.0)||5 (50.0)||0.101|
|Thin upper lip vermilion and/or downturned corners of mouth||12 (80.0)||5 (100.0)||7 (70.0)||0.505|
|Congenital diaphragmatic hernia||1 (6.7)||1 (20.0)||0 (0.0)||0.333|
|Global developmental delay and/or intellectual disability||14 (93.3)||5 (100.0)||9 (90.0)||1.000|
|Prenatal growth retardation||6 (40.0)||4 (80.0)||2 (20.0)||0.089|
|Postnatal growth retardation||11 (73.3)||5 (100.0)||6 (60.0)||0.231|
|Microcephaly||12 (80.0)||5 (100.0)||7 (70.0)||0.505|
|Small hands and/or feet||8 (53.3)||3 (60.0)||5 (50.0)||1.000|
|Short fifth finger||3 (20.0)||2 (40.0)||1 (10.0)||0.242|
|Hirsutism||10 (66.7)||5 (100.0)||5 (50.0)||0.101|
|Seizure||4 (26.7)||0 (0.0)||4 (40.0)||0.231|
|Abnormal brain MRI findings||6 (40.0)||1 (20.0)||5 (50.0)||0.580|
|Congenital heart defects||4 (26.7)||1 (20.0)||3 (30.0)||1.000|
|Genitourinary anomaly||4 (26.7)||2 (40.0)||2 (20.0)||0.560|
|Hearing impairments||7 (46.7)||2 (40.0)||5 (50.0)||1.000|
|Ear anomaly||2 (13.3)||0 (0.0)||2 (20.0)||0.524|
|Ophthalmologic anomaly||10 (66.7)||3 (60.0)||7 (70.0)||1.000|
|Gastrointestinal anomaly||6 (40.0)||2 (40.0)||4 (40.0)||1.000|
|Respiratory tract anomaly||2 (13.3)||0 (0.0)||2 (20.0)||0.524|
Values are presented as number (%) or mean±standard deviation.
SDS, standard deviation score; Age_i, age at initial visit; Ht_i, height at initial visit; Wt_i, weight at initial visit; Age_l, age at last visit; Ht_l, height at last visit; Wt_l, weight at last visit; MRI, magnetic resonance imaging.