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CONFERENCE REPORT
Cornelia de Lange Syndrome: Extending thePhysical and Psychological PhenotypeChris Oliver,1* Maria Francesca Bedeschi,2 Natalie Blagowidow,3 Cheri S. Carrico,4 Anna Cereda,5
David R. FitzPatrick,6 Cristina Gervasini,7 Gemma M. Griffith,8 Antonie D. Kline,3
P. Marchisio,2 Joanna Moss,1,9 Feliciano J. Ramos,10 Angelo Selicorni,11 Penny Tunnicliffe,1
Jolanta Wierzba,11 and Raoul C.M. Hennekam12
1School of Psychology, University of Birmingham, Birmingham, UK2Department of Maternal and Pediatric Sciences, Milan, Italy3Harvey Institute of Human Genetics, Greater Baltimore Medical Center, Baltimore, Maryland4Speech-Language-Hearing Clinic, Elmhurst College, Elmhurst, Illinois5Department of Pediatrics, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy6MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK7Medical Genetics, San Paolo School of Medicine, Milan, Italy8School of Psychology, Bangor University, Bangor, UK9Institute of Psychiatry, Kings College, London, UK10Laboratorio de Gen�etica Cl�ınica y Gen�omica Funcional, Facultad de Medicina, Zaragoza, Spain11Department of General Nursery and Department of Pediatrics, Hematology, Oncology and Endocrinology, Medical University, Gdansk, Poland12Department of Pediatrics, Academic Medical Centre, UVA, The Netherlands
Received 11 January 2010; Accepted 24 January 2010
Key words: Cornelia de Lange syndrome; behavioral phenotype
INTRODUCTION
The third Cornelia de Lange Syndrome World Scientific Con-
ference was held in July 2009 in Brighton, United Kingdom. The
Scientific Conference preceded a conference for professionals from
health, education and other backgrounds who work with children
and adults with Cornelia de Lange syndrome (CdLS) and a 2-day
family conference. Delegates and families from over 20 countries
attended the conferences.
The goal of the conference was to provide a forum for the
exchange of research results, information on best clinical practice,
and perspectives on support relevant to the wellbeing of children
and adults with CdLS. The purpose of this proceeding is to provide a
summary of the scientific conference to those researchers and
clinicians who were unable to attend.
SUMMARY OF PRESENTATIONS
The scientific conference included presentations on molecular
genetics, genotype–phenotype correlations, sensory abnormalities,
physical health, aging, the social and behavioral phenotype of CdLS,
and family perspectives on care and management for persons with
CdLS. The diversity of research presentations is indicative of the
Grant sponsor: Ministerio de Sanidad y Pol�ıtica Social of Spain (Ref.
PI061343); Grant sponsor: Gobierno de Arag�on (Ref. B20).
Proceedings from the 3rd Cornelia de Lange World Conference 2009.
*Correspondence to:
Chris Oliver, Cerebra Centre for Neurodevelopmental Disorders, School of
Psychology, University of Birmingham, Birmingham B15 2TT, UK.
E-mail: [email protected]
Published online 13 April 2010 in Wiley InterScience
(www.interscience.wiley.com)
DOI 10.1002/ajmg.a.33363
How to Cite this Article:Oliver C, Bedeschi MF, Blagowidow N,
Carrico CS, Cereda A, FitzPatrick DR,
Gervasini C, Griffith GM, Kline AD,
Marchisio P, Moss J, Ramos FJ, Selicorni A,
Tunnicliffe P, Wierzba J, Hennekam RCM.
2010. Cornelia de Lange syndrome: Extending
the physical and psychological phenotype.
Am J Med Genet Part A 152A:1127–1135.
� 2010 Wiley-Liss, Inc. 1127
breadth of activity and perspectives in a growing research agenda.
CdLS is a complex developmental disorder with the cause identified
in approximately 55–60% of those clinically diagnosed as arising
from mutations of the NIPBL, SMC1A, and SMC3 genes [Krantz
et al., 2004; Tonkin et al., 2004; Bhuiyan et al., 2006; Musio et al.,
2006; Deardorff et al., 2007; Kline et al., 2007a]. There is evidence
that NIBL mutations are associated with a more severe phenotype
(Abstract 2) but there is variability in the phenotypes for each
gene mutation (Abstract 15). Mutations of the PDS5A and
CTCF genes have been investigated as possible causes of CdLS in
those who do not have NIPBL, SMC1A, and SMC3 genes, with
negative results (Abstracts 11 and 12).
Impaired growth, craniofacial and upper limb abnormalities are
common in CdLS and numerous physical health problems are
reported with a high prevalence of gastrointestinal disorders and
feeding disorders. In a clinical cohort of 100 patients with CdLS
postnatal growth was below the third centile for 84% of patients and
gastroesophageal reflux (GER) was present in 73% (Abstract 14).
Abdominal ultrasound has been found to be a useful adjunct to
clinical examination for the purpose of diagnosis of renal, urinary,
and uterine anomalies (Abstract 3). Kidney malformations are
evident in approximately 30% of patients and cardiac malforma-
tions (primarily pulmonary stenosis) occur in 35% (Abstracts 13
and 14). A broad array of feeding problems is reported (Abstracts 1
and 10), including a lack of sucking reflex in neonates (56%).
Audiological assessment reveals abnormal hearing in 82% of pa-
tients with conductive hearing loss being the most commonly
reported problem (Abstract 6). A second study revealed 45% of
patients to have either sensorineural or conductive hearing loss
(Abstract 7) and that these disorders were related to the size of the
NIPBL mutation. Additionally, this study reports myopia and
ptosis to be associated with truncating NIPBL mutations.
Profound to severe intellectual disability is normally evident in
CdLS [Oliver et al., 2008] with autism spectrum disorders reported
in approximately 50–67% of children and adults [Berney et al.,
1999; Bhuiyan et al., 2006; Basile et al., 2007; Moss et al., 2008]
alongside impaired expressive communication, compulsive
behaviors, and social anxiety [Hyman et al., 2002; Richards
et al., 2009; Moss et al., 2009; Wulffaert et al., 2009]. In comparison
with other genetic syndromes a lack of sociability combined with
autism spectrum-like characteristics are evident even when degree
of intellectual disability is controlled for (Abstract 8). Unusually
high levels of self-injurious behavior with comparatively low levels
of aggression are reported [Oliver et al., 2009] with increasing
evidence of a relationship between self-injury and GER (Abstracts 9
and 14).
Three issues are likely to feature prominently in future research.
First, genotype–phenotype correlations and the differentiation of a
mild from classic phenotype is important for prognosis and under-
standing the effects of the different gene mutations (Abstract 5).
Second, reports of significant age-related changes in the physical
phenotype allude to a potential role for abnormalities in DNA
repair pathways [Kline et al., 2007b] (Abstract 4). The changes
with age in the physical phenotype, behavior, and neuropsychologi-
cal functioning warrant examination in cross-sectional and
longitudinal studies. Third, the complexity of the task facing
families and professionals when trying to support children
and adults with CdLS is clearly evident given the diverse and
multi-system effects of the syndrome (Abstract 18). Coordination
of timely service delivery is an important but infrequently explored
issue.
SPEAKERS’ ABSTRACTS
Perinatal and Neonatal Data in 43 Polish PatientsJolanta Wierzba. We studied the perinatal and neonatal data in
43 live born classically affected CdLS patients recruited through the
CdLS Association, Poland. Fourteen newborns (32.6%) were born
prematurely, and 26 individuals (60.5%) were small for gestational
age; 7 of these were born prematurely. Frequent congenital mal-
formations were limb defects (n¼ 28; 65.1%) of whom 7 (16.3%)
had severe upper limb reduction defects; heart malformations
(n¼ 26; 60.5%); renal tract malformations (n¼ 9; 20.9%); and
cleft palate (n¼ 11; 25.6%). Cryptorchidism was observed in
all males but one. All individuals demonstrated abnormal
muscular tone. Trembling and convulsions were observed inciden-
tally. Feeding problems were frequent (n¼ 41; 95.3%). Twenty-
four neonates (55.8%) demonstrated initially a total lack of sucking
reflex. Surgical interventions in the neonate period were needed in
three newborns because of a congenital heart defect with esophageal
and duodenal atresia, inguinal hernia incarceration, and intestine
perforation.
The data from the Polish cohort are consistent with earlier
reports from both American and European studies. The multiple
organs that can be affected in CdLS newborns, and the wide
variability indicates the need for multidisciplinary diagnostics and
intervention in the neonatal period.
Correlation of the Neonatal Phenotypeand GenotypeA. Cereda, L. Colombo, A. Passarini, S. Russo, P. Castronovo, D.
Milani, A. De Paoli, F Mosca, L. Memo, and A. Selicorni. CdLS is
usually diagnosed at birth or during the first months of life. This
period can be particularly stressful for parents, both because of the
frequent medical problems and because families have to cope with
the diagnosis. We focused attention on neonatal features and
feeding problems of a large group of Italian CdLS patients. All the
patients were studied molecularly for NIPBL and SMC1 mutations.
As the number of SMC1-positive patients was small clinical data
were only compared between NIPBL-positive and -negative
patients.
We collected data on the neonatal period in 101 CdLS patients
(57 men). In 23%, clinical diagnosis was established at birth; 75% of
them had a NIPBL mutation. In 52% of patients the clinical
diagnosis was established later on but within the first years of life;
an NIPBL mutation was present in 63%. In patients diagnosed after
the first year (25%) a NIPBL mutation was found in 29%. Prenatal
growth retardation was evident in 58% (62% with a NIPBL
mutation) and absent in 42% (25% with a NIPBL mutation). Mean
gestational duration was 38 weeks, mean birth weight was 2,440 g in
men and 2,310 g in women, and mean length at birth was 45.5 cm in
men and 44.0 cm in women. Mean head circumference at birth was
1128 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
31.0 cm in men and 30.2 cm in women. Data for NIPBL-positive
and -negative patients were for birth weight 2,180 and 2,570 g, for
length 44 and 46 cm, and for head circumference 30 and 31 cm,
respectively. Some form of neonatal resuscitation was needed in
19.5% of patients (53% NIPBL-positive; if no resuscitation needed
39% was NIPBL-positive). Feeding problems were present in 71%
of patients and 43% needed additional nutritional support (56%
NIPBL-positive; without feeding problems 36% was NIPBL-
positive).
These data confirmed that CdLS newborns with an NIPBL
mutation show a more severe phenotype: prenatal growth is more
reduced, birth weight and length are lower, neonatal resuscitation
was more frequently needed, and feeding problems and assisted
nutrition were more common. In accordance with this, the more
severe neonatal phenotype in NIPBL-positive cases led to an earlier
diagnosis, usually before 1 year of age.
2D and 3D Abdominal Ultrasound inAdolescents and AdultsNatalie Blagowidow, J. Camak, and K. Teagarden. Individuals with
CdLS are at increased risk for a variety of medical conditions,
including renal anomalies, urinary reflux, and uterine anomalies. In
addition, we have observed cholelithiasis and prostate enlargement
in adult patients with CdLS. Communication of symptoms is
difficult for those with more significant developmental delay.
Clinical examination can also be challenging. In particular, female
patients may not cooperate with a gynecologic examination, re-
sulting in few or no examinations. We elected to evaluate the utility
of abdominal ultrasound in adolescent and adult CdLS patients.
We performed abdominal ultrasound in 18 consecutive
individuals attending the multidisciplinary aging CdLS clinic. The
physician interpreting the studies was present for all examinations.
In 14 patients both 2D and 3D imaging was performed. Ten patients
were studied in only the supine position, one only seated, and seven
both seated and supine. Significant findings were small kidneys
(n¼ 4), and a renal cyst, a bicornuate uterus, a fatty liver, and a
calcification within the prostate (one each). Satisfactory imaging
was achieved for the liver in 94%, gallbladder in 71%, spleen in 61%,
kidneys in 56%, uterus in 100%, ovaries in 57%, and prostate in
50%. Images were suboptimal owing to patient inability to coop-
erate, and because of obesity. The 3D modality provided similar
imaging as the 2D, with helpful imaging of abnormal findings. The
seated position was effective for upper abdominal imaging, but the
supine position provided more satisfactory images in three patients.
We concluded that eight significant abnormalities were identified
in 18 patients. We were able to examine several women in whom
a gynecologic examination had not been tolerated. Abdominal
ultrasound is a useful diagnostic tool, and can serve as an adjunct
to clinical examination.
Premature AgingAntonie D. Kline. CdLS is a variable syndrome that can present with
a broad spectrum of involvement. Significant progress has been
made in recent years with the clinical and molecular delineation of
CdLS, contributing to new insights with respect to clinical findings,
and allowing observations about natural history. Some evidence for
premature aging has been found, and mechanistically this is likely to
be linked to the abnormal function of cohesin owing to the gene
mutations causing CdLS.
We evaluated 71 adolescent and adult patients in a multi-
disciplinary aging clinic for CdLS, with patients recruited through
the CdLS Foundation. Medical histories and physical examinations
were performed on each patient, with specialized evaluations given
by the subspecialists.
The age range was 13–50 years with an equal sex ratio. There was
a specific pattern of aging to the facies, with lengthening of the face,
slight coarsening of features, and squaring of the chin. Facial
asymmetry was also noted. Many individuals had a physical
appearance older than their chronologic years. In the cohort,
5% developed Type II diabetes, 4% developed hypertension, and
there was no evidence for myocardial infarctions. Clinically
insignificant small pericardial effusion was seen echographically
in 5 of 7 investigated patients. GER was noted in over 90% of
patients, and 14% developed a Barrett esophagus, some as early
as 17 years. Two percent of the patients have had cholecystitis
requiring cholecystectomy. Ninety percent of a cohort of 20 am-
bulatory patients was found to have some degree of decreased bone
density with age and 75% to have low vitamin D. Three patients had
an enlarged prostate, one of which was removed by 41 years of age.
No patient developed any form of cancer. Behavioral issues were
prevalent, including self-injury, aggression, and anxiety, and could
be debilitating. Sleep disturbance occurred in 80%.
One biologic pathway that has been linked to premature aging is
that of DNA repair. Cohesin is recruited to sites of DNA damage,
and is known to help with double-stranded repair. Cells of patients
with mutations in one of the three cohesin genes have been found to
have poor ability to tolerate DNA-damaging agents. Faulty DNA
repair regionally could explain the presence of early aging in some
body systems, such as the skin, gastrointestinal tract, genitourinary
tract, and musculoskeletal system. Long-term effects of disruption
of DNA repair could explain many of these clinical finding.
The Mild CdLS PhenotypeA. Cereda, F.J. Ramos, J. Wierzba, G. Gillessen-Kaesbach, S. Maitz,
M.P. Ribate, M. Ratajska, J. Limon, J. Pie, Silvia Russo, Lidia Larizza,
and A. Selicorni. Classic CdLS needs to be distinguished from the
mild CdLS phenotype. As no clear data were available regarding the
natural history of this subgroup, we collected clinical and
molecular data on a group of patients with a mild CdLS phenotype.
We analyzed growth parameters, age of achievement of the
main developmental milestones, presence of major congenital
malformations, and results of molecular analysis.
We gathered data on 66 mild CdLS patients (30 men; mean age 11
years; range 1–36 years) from Italy, Poland, Germany, and Spain.
The mean age of clinical diagnosis was 3 years (range: birth to
25 years). Mean birth weight was 2,514 g (mean gestational age was
38.5 weeks), and a low birth weight (<2,500 g) was found in 39%.
Postnatal growth regarding height and weight followed centiles
above the 50th centile of dedicated CdLS growth charts in 93.5%
and 95% of cases, respectively. No major malformations were
present in 36% of patients, and 64% had one or more congenital
OLIVER ET AL. 1129
anomalies (one malformation: 35%; two malformations in 18%;
three malformations in 6%; four malformations in 5%). One
patient had a limb reduction defect, and two others had ectro-
dactyly. The major malformations were scored as mild (no treat-
ment needed) in 44% of patients, moderate (nonsurgical
treatments) in 18%, and severe (surgical treatments) in 38%.
Mean age of achievement of major developmental milestones
were: sitting, 10 months (53%,<9 months; 45%, 9–18 months; 2%,
>18 months); walking, 19 months (65%,<18 months; 25%, 18–24
months; 10%, >24 months); first words, 29 months (28%,
<18 months; 57%, 18–36 months; 17%, >36 months). Cognitive
development was determined to be normal in 9% of patients,
borderline in 20%, and mildly delayed in 71%. Molecular analysis
showed an NIPBL mutation in 38.5% of patients and an SMC1
mutation in 8%.
These data demonstrated that the mild CdLS phenotype may be
less uncommon than previously anticipated. By definition, a nor-
mal birth weight, absence of severe major malformations, postnatal
growth within normal limits, and a (near) normal or only slightly
delayed psychomotor development are the features. Molecular
analysis showed the prevalence of NIPBL mutations to be lower
compared with the prevalence in series with classical CdLS.
Possibly, SMC1A mutations are more common but the series
described here are small and ascertainment bias may play a role.
Correlation of Audiological Findings With ClinicalSeverity and GenotypeP. Marchisio, A. Selicorni, A. Cereda, M. Ceruti, E. Baggi, E. Nazzari,
J. Azzollini, C. Gervasini, L. Pignataro, and N. Principi. Hearing
impairment is almost universal in CdLS: 20% of CdLS individuals
show sensorineural hearing loss (SNHL) and 80% have conductive
HL as result of persistent otitis media with effusion (OME). We
studied whether there could be a correlation between audiological
findings, genotype, and clinical severity as scored by combining
auxological, neurodevelopmental, and malformative data.
The study cohort consisted of 44 CdLS children (1–81 years;
22 men). All children received a full otolaryngologic and audio-
logical examination (tympanogram, audiogram, and/or an ABR
recording). The diagnosis of OME was based on impaired mobility,
opacification, fullness or retraction of the eardrum, associated with
a flat tympanogram, and the absence of signs and symptoms of
acute infection. Ten children (23%) had SNHL, 26 had conductive
HL (59%), and 8 normal hearing (18%). NIPBL mutations were
detected in 22 patients (50%): 4 missense mutations, 3 frameshift
mutations, 5 splicing site mutations, 8 truncating mutations, and
2 in-frame mutations. No SMC1 mutation was observed.
NIPBL mutations were detected in 7/10 children (70%) with SNHL
and in 15/34 without SNHL (44%; OR: 2.96). Conductive HL was
borderline in 11/26 (42.3%), mild in 10/26 (38.5%), and moderate
in 5/26 (19.3%) of the children. The presence of NIPBL mutations
did not correlate with the severity of conductive HL. A more
severe clinical severity was associated with more marked
(�30 dB) conductive HL (7/8 versus 10/21 with a less marked
clinical severity; P¼ 0.06).
These data showed a correlation between sensorineural HL and
NIPBL mutations, possibly explainable by the NIPBL expression in
the embryonic inner ear. The association between the severity of
conductive HL owing to OME and clinical severity stresses the need
for aggressive treatment of OME in CdLS children.
Sensory Input Related to GenotypeAntonie D. Kline, A. Kimball, C. Schoedel, and S. Ishman. CdLS
typically presents with a number of malformations and limitations
with respect to development. We were interested in assessing
sensory deficits in CdLS as these could have a direct effect on
learning and on the activities of daily living. We would anticipate
that input from the five senses would be diminished and that there
would be a genotype–phenotype correlation regarding severity. It
has been documented that visual deficits occur, particularly
myopia, reported in two-thirds of patients with CdLS, and ptosis,
seen in about 40%. In addition, up to 20% have limb truncation
defects, and sensory input from a single digit or abnormal limb
would be different and difficult physically. Hearing loss in CdLS has
been reported in the majority of patients, both conductive and
seonsorineural. We reasoned that also anosmia might be present
but remain undetected. Anosmia has been associated with other
syndromes, such as Down syndrome, Bardet–Biedl syndrome, and
other ciliopathies.
We studied 71 adolescent and adult CdLS patients from a
multidisciplinary aging clinic, and 12 additional patients evaluated
through meetings of the CdLS Foundation. An ophthalmologic
evaluation was carried out on each individual. Standard audiology
testing was performed on seven patients and records collected on
the others. To assess the sensation of smell, the Brief Smell Identi-
fication Test� [Sensonics, Inc., Haddon Heights, NJ] (B-SIT) was
performed on those CdLS individuals, able to communicate the
answers to us in some way. The Alcohol Sniff Test (AST) was
performed on four individuals.
The age range of the participants was 13–50 years with an equal
sex ratio. In the aging cohort, 33% were found to have myopia, 20%
had high myopia with one secondary retinal detachment, and
42% had ptosis. Both myopia and ptosis were more severe in the
individuals with otherwise a more severe phenotype and more
frequent in truncating NIPBL mutations. Forty-five percent were
found to have some degree of deafness, both sensorineural and
conductive. Increased severity of the mutation indicated a worse
hearing loss. All 11 patients tested by the B-SIT were able to smell,
but the test was only possible in less severely affected individuals. In
four more severely affected individuals the AST was performed, and
one was unable to smell.
It can be concluded that sensory input is decreased in CdLS,
particularly with truncating mutations. Routine audiologic and
ophthalmologic evaluations are mandatory in all CdLS patients.
Olfactory function seems normal in at least individuals with a less
severe phenotype.
Understanding Social FunctioningJoanna Moss, Pat Howlin, Penny Tunnicliffe, Jane Petty, Gemma
Griffith, Richard Hastings, Sarah Beaumont, Rachel Yates, and Chris
Oliver. Several studies have reported an increased prevalence of
autism spectrum characteristics in CdLS. This association cannot
1130 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
be fully accounted for by degree of intellectual disability. The profile
of autism spectrum characteristics in CdLS appeared somewhat
different from that of idiopathic autism and a presentation of social
anxiety has been suggested to be characteristic. We studied the
specific nature of social impairments in CdLS, focusing on
sociability, motivation for social interaction and stranger discrimi-
nation, and compared these with patients with two other syn-
dromes: Cri du Chat syndrome (CdCS) and Angelman syndrome
(AS).
Participants were 60 individuals (aged 2–19 years), of whom 20
had CdLS (mean chronological age [CA]¼ 12.1; SD¼ 3.4), 20 had
CdCS (mean CA¼ 9.0; SD¼ 4.8), and 20 AS (mean CA¼ 10.4;
SD¼ 4.7). The CdCS group scored significantly higher on the
Adaptive Behavior Composite score of the VABS-II compared with
the AS and CdLS groups (P< 001). The Social Communication
Questionnaire (SCQ) and the Sociability Questionnaire for people
with Intellectual Disability (SQID) were employed to assess the
presence of autistic characteristics and levels of sociability. An
observational assessment of sociability, social interaction skills,
and stranger discrimination was also conducted. The CdLS group
scored significantly higher than the CdCS group on the social
interaction subscale and total score of the SCQ (P� 0.01). Signifi-
cantly more individuals with AS (93.8%) and CdLS (100%) scored
above the cut-off for autism spectrum disorder compared with
individuals with CdCS (P¼ 0.001). The difference between the
proportion of individuals scoring above the cut-off for autism
(CdLS 52.9%; CdCS 13.3%; AS 43.8%) approached significance
(P¼ 0.058). Individuals with CdLS scored significantly lower than
those with AS and CdCS on the total familiar score of the SQID
(P< 0.02), and significantly lower than individuals with AS on the
total unfamiliar score of the SQID (P< 0.02). Analysis of the
observational assessments is ongoing but preliminary analyses
suggest that our observations are consistent with the profile of
scores on the SCQ and SQID.
The findings confirm previous reports of lower levels of overall
sociability with both familiar and unfamiliar adults and increased
levels of autistic-like characteristics in CdLS compared with indi-
viduals with CdCS and AS. These impairments do not appear to be
accounted for by degree of intellectual disability and may be
considered to be syndrome-specific impairments.
Environmental Determinants ofSelf-Injurious BehaviorPenny Tunnicliffe, Chris Oliver, Joanna Moss, Jane Petty, Gemma
Griffith, Richard Hastings, and Pat Howlin. The prevalence of self-
injurious behavior in CdLS is estimated to be approximately 60%.
Previous research has identified pain and operant learning as
possible causal mechanisms but there have been not been any large
-scale studies comparing potential causes across syndrome groups.
Additionally, contemporary methods of functional analysis to
identify operant learning processes are rarely employed with this
group.
We compared the self-injury and aggressive behavior of children
aged 2–19 years with CDLS (n¼ 20; mean CA¼ 12.1; SD¼ 3.4),
CdCS (n¼ 20; mean CA¼ 9.0; SD¼ 4.8), and AS on an established
questionnaire measure (Questionnaire About Behavioral Function;
QABF) of the causes of challenging behavior. We also used experi-
mental functional analysis and structured descriptive analyses in
which we systematically manipulated environmental conditions in
single-case experimental designs.
Analysis of the results of the QABF showed that the CdLS group
scored significantly higher than the CdCS and AS groups on the
pain subscale (P< 0.02 and P< 0.04, respectively) indicating that
pain was related to challenging behavior in this group. Using an
arbitrary cut-off of Cliff’s d-statistic of .3, within the CDLS
group, experimental functional analysis of self-injury revealed an
attention-maintained function for four (20%) participants and a
demand escape function for six (30%) participants.
The results confirmed previous findings by demonstrating a
significant association between pain and challenging behavior in
CdLS and the possibility that the behavior is influenced by operant
learning for some CdLS children. The comparison with other
syndrome groups identified pain as a more prominent cause in
CdLS with implications for prioritizing clinical investigation of self-
injury in this group.
Issues Related to FeedingCheri S. Carrico. Individuals with CdLS exhibit medical, physical,
and behavioral challenges that place them at risk for difficulties
related to oral feeding. These challenges primarily are associated
with a history of gastroesophageal reflux disease (GERD), tube
feeding, low muscle tone in the oral area, micrognathia, and
cleft palate. A history of autistic tendencies also may be related
to feeding difficulties. Additional factors, such as delayed
physical growth and possible failure to thrive, may be the result
of feeding issues in this population. We studied various aspects of
feeding difficulties in 47 CdLS individuals, based on personal
observations of feeding behaviors and information reported by
caregivers.
Participants included 24 men and 23 women, aged 3 months
through 36 years, from countries all over the world. Reported
concerns associated with feeding included difficulties in sucking,
swallowing, chewing, and biting; consumption of only small bites
of food; lack of transition to solid foods; lack of transition to
cup drinking; selective eating habits; messy feeding habits;
choking, coughing, gagging, vomiting, and spitting food out at
meal times; oral defensiveness; crying during meals; making un-
pleasant faces; ‘‘stuffing food;’’ food aversions, particularly based
on texture or taste; and refusal to feed orally. In addition, many
individuals required pureed foods and thickened liquids to feed
orally, as well as modifications, such as a cup with a spout, for
drinking. Most individuals also were reported to be slow eaters. In
addition, a history of tube feeding, GERD, and esophagitis were
common findings that may be related to the identified feeding
challenges.
Primary feeding concerns reported by caregivers included
transitioning to oral feeding, promoting eating of solid foods,
promoting eating of foods of various textures, encouraging better
overall eating habits, and developing appropriate feeding tech-
niques. In addition, although half of the individuals reported good
general health, a history of colds, ear infections, sinusitis, fevers,
allergies, hoarse voice, asthma, and celiac disease were prevalent.
OLIVER ET AL. 1131
Individuals with CdLS were found to exhibit a variety of
characteristics that lead to challenges in oral feeding: medical
conditions, and especially GERD, may make feeding unpleasant;
low muscle tone, micrognathia; and cleft palate can make oral
feeding difficult; and tube feeding may render oral feeding unnec-
essary. Individuals who have unpleasant experiences associated
with oral feeding or who lack a history of oral feeding frequently
develop feeding aversions. Once feeding aversions develop, it is very
difficult to encourage oral feeding.
Techniques to facilitate and improve oral feeding vary and
depend on the needs of the individual. Oral stimulation should
be provided as early as possible, particularly in individuals who are
tube fed, to avoid later feeding aversions. Among individuals who
cannot tolerate oral presentation of food, non-nutritive tactile
stimulation should be provided in the mouth. Taste stimulation,
including varying textures and temperatures, should be provided as
early as possible. The majority of individuals in this study did not
receive feeding therapy. Perhaps with early intervention related to
oral feeding, some of the feeding difficulties reported can be
minimized.
Molecular Studies of NIPBL, SMC1A, and PDS5ACristina Gervasini, Maura Masciadri, Paola Castronovo, Jacopo
Azzollini, Donatella Milani, Anna Cereda, Giuseppe Zampino,
Angelo Selicorni, Silvia Russo, and Lidia Larizza. The three genes
known to be involved in the pathogenesis of CdLS encode for
proteins of the cohesin pathway: SMC1A and SMC3 are structural
cohesin complex subunits, and NIPBL is a regulatory element.
PDS5A is also a gene encoding a regulatory element of the cohesion
complex. The essential role for the cohesin complex is to control
sister chromatid segregation during mitosis and meiosis and facili-
tate the repair of damaged DNA. Recent evidence has shown that
cohesin binds to the same sites in mammalian genomes as the zing
finger transcription factor CTCF suggesting that the developmental
deficits of CdLS likely result from dysregulation of gene expression,
owing to alterations in the cohesin genes.
We investigated molecularly a sample of 137 Italian CdLS
patients. All patients entered a molecular flowchart which implied
in sequence the search for mutations of: (i) NIPBL, (ii) SMC1A (for
patients negative for NIPBL mutations), and (iii) PDS5A (for
patients negative for NIPBL and SMC1A mutations). Mutational
screenings for NIPBL, SMC1A, and PDS5A were carried out using
DHPLC and direct sequencing. In addition, the NIPBL scan in-
cluded an MLPA kit to test for large NIPBL exon deletions or
duplications. Transcription analysis was performed on carriers of
missense, in-frame deletions, and splicing mutations. We identified
42 point mutations (6 missense; 1 in frame deletion; 13 splice-site
mutations; 8 nonsense mutations; 13 frameshift mutations; and
1 promoter site mutation). MLPA of NIPBL disclosed five large
deletions and one duplication encompassing one or several exons.
One patient carrying a deletion affecting NIPBL exons 1–10 was
further characterized by FISH analysis and had a 2-Mb deletion
which included 14 genes next to NIPBL and indicating a contiguous
gene syndrome.
Sixty-seven of the 89 NIPBL-negative patients were tested
for SMC1A mutations, which were present in 5: all had point
mutations, either in frame deletions or missense mutations. Twenty
of the 62 patients negative for NIPBL and SMC1A testing were tested
for PDS5A mutations and no mutations were found.
The stepwise molecular analysis enabled us to find the molecular
defect in 53 of the 137 patients. The study confirmed the major role
of NIPBL in the etiology of CdLS, and the minor role of SMC1A,
while thus far no mutation was found in the candidate gene PDS5A.
Molecular characterization of CdLS patients is mandatory for an
adequate genotype–phenotype correlation study, and our stepwise
approach may help in classifying CdLS patients for this purpose.
Exclusion of CTCF Mutations as a Common CauseDavid R. FitzPatrick, Cheng Yee Chen, Kathy Williamson, and Stuart
McKay. Heterozygous loss-of-function mutations in NIPBL are the
most commonly identified molecular lesions in CdLS, accounting
for about 40% of cases. Missense mutations in the same gene are
generally, but not always, associated with less severe disease.
Mutations in SMC1A account for 5% of cases, whereas sequence
alterations in SMC3 appear are very rare. The products of these
three genes function as structural or loading components of the
cohesin complex. The cohesinopathy associated with CdLS is likely
to primarily impair gene regulation rather than by impairing
chromosome separation at metaphase. A significant proportion
of cases with classical CdLS remain unexplained from a genetic
point of view. CTCF is a protein that functions as a chromatin
‘‘insulator’’ and it has recently been shown to associate with the
cohesin complex in interphase chromosomes. We screened 50 cases
of CdLS for mutations in CTCF, located at 16q22.1, but identified
no sequence variants, suggesting that mutations in this gene are not
a common cause of CdLS. In the course of this study, we also
identified four novel nonsense and two novel missense mutations in
NIPBL in UK cases. The NIPBL mutations identified in our study
together with all published mutations have been submitted to a
LOVD mutation database: https://lsdb.hgu.mrc.ac.uk/home.php?
select_db¼NIPBL
Correlation of Major Malformations Withthe GenotypeA. Cereda, A. Passarini, C. Gervasini, P. Castronovo, M. Masciadri, A.
De Paoli, F. Menni, A. Colli, M.A.Galli, M.A. Pavesi, I. Borzani, and
A. Selicorni. Next to limb defects CdLS is characterized by various
major malformations although none of them is critical for the
clinical diagnosis. We studied the incidence of major malforma-
tions in relation to genotype in an Italian CdLS cohort. Only five
SMC1A mutations were found which precluded meaningful statis-
tical analysis with SMC1A.
Detailed information on the type and severity of major malfor-
mations was gathered in 103 CdLS patients (mean age 14 years;
range 1–42 years; 59 males). Ultrasound, radiology, and/or mag-
netic resonance imaging (MRI) were performed to assess a struc-
tural visceral anomaly. Functional renal tests were also performed
in all patients.
Kidney malformations were evident in 30% of patients. Creati-
nine clearance was abnormal in 24% of patients with a structural
renal anomaly. NIPBL mutations were detected in 43% of patients
1132 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
with structural renal anomalies, in 22% without a renal malforma-
tion, in 57% with an impaired renal function, and in 43% with a
normal renal function. Cardiac malformations were demonstrated
in 35% of patients, of whom 53% had an NIPBL mutation. In 36%
of patients with cardiac defect an NIPBL mutation was found. Heart
defects were pulmonary stenosis (28%), atrial septum defects
(17%) and ventricular septum defects (19%), and prevalence of
NIPBL mutations in these defects were 70% (pulmonary stenosis),
50% (atrial septum defects), and 29% (ventricular septum defects),
respectively. Limb reduction defects were evident in 17% of the
cohort, of whom 78% had an NIPBL mutation. A CNS anomaly was
observed in 32% of those who underwent an NMR: 33% of them
had an NIPBL mutation. Genital anomalies were present in 31%,
52% having an NIPBL mutation, and 41% of the patients without
genital anomalies had a mutation. Palate anomalies were observed
in 13% of patients with 54% having an NIPBL mutation. Major eye
anomalies were observed in 4% of the cohort and 50% of them had
an NIPBL mutation.
This study confirmed the relatively high frequency of heart and
kidney anomalies in CdLS individuals. Decreased renal function
was not uncommon and should be evaluated in patients with
structural renal anomalies. Analysis of the correlation with the
genotype showed a higher prevalence of NIPBL mutations in
patients with limb reduction defects, as demonstrated in other
studies, and in patients with heart anomalies, especially pulmonary
stenosis. For other malformation differences were small and further
studies in larger cohorts are needed.
Correlation of Growth and Medical ComplicationsWith the GenotypeA. Cereda, A. Passarini, M. Masciadri, C. Gervasini, M. Cerutti, S.
Luzzani, F. Macchini, A. Valad�e, E. Vismara, and A. Selicorni.
Postnatal growth retardation and various medical complications
are frequent manifestations of CdLS. We collected detailed infor-
mation regarding evolution of growth parameters and prevalence of
the various medical complications in a cohort of 100 CdLS patients
(mean age 14 years; 55 men), whom we also studied molecularly.
Postnatal failure to thrive was present in 75% of patients (54% with
a NIPBL mutation; in those with normal weight gain, 25% had a
mutation). Postnatal growth in height was below the 3rd centile in
84% (54% had an NIPBL mutation; with normal height 30% had a
mutation). Microcephaly was present in 77% (44% had an NIPBL
mutation; with normal head circumference 22% had a mutation).
The most common medical complication in the CdLS cohort was
GER present in 73%. An NIPBL mutation was present equally in
cases with or without GER (48% vs. 52%). Behavioral problems
were found to be associated with GER: GER was evident in 93% of
patients with sleep problems, in 82% of the aggressive patients, but
in 30% of hyperactive patients. Seizures were observed in the 26% of
the cohort (15% related to fever), of whom 30% had an NIPBL
mutation. Blepharitis was evident in 12%, ptosis in 17%, squint in
7%, and refractive errors in 56% (of whom 70% had myopia).
NIPBL mutations were present in 43% of those with refractive
errors and in 57% of those without.
The prevalence of growth impairments and medical complica-
tions in this CdLS cohort was similar to that found in other studies.
A NIPBL mutation was more frequent in the patients with markedly
decreased growth in height and skull circumference, as found in
other studies as well. Data regarding SMC1-mutated patients are
limited. Only a tendency for a higher prevalence of seizures in CdLS
cases with an SMC1 mutation was clear.
An SMC1A Mutation With Severe ClinicalManifestationsFeliciano J. Ramos, Mar�ıa Pilar Ribate, Milagros Ciero, Juan Carlos de
Karam, Mar�ıa Concepci�on Gil-Rodr�ıguez, Mar�ıa Arnedo, Aliesky
Luis D�ıaz, Beatriz Puisac, and Juan Pi�e. In about 60% of CdLS
patients, mutations in two major genes (NIPBL and SMC1A) of
the cohesin complex and its regulators can be found. To date,
11 different mutations in 14 unrelated individuals have been
reported in the X-linked SMC1A gene. We investigated a 3-year-
old boy with a facial appearance that resembled CdLS only in a
limited way, microcephaly, postnatal growth retardation, and
moderate psychomotor retardation with complete absence of
speech. He had bilateral brachyclinodactyly of the fifth finger and
cutaneous syndactyly of the second and third toes. Furthermore, he
had congenital heart defects (atrial septum defect and persistent
ductus arteriosus) and severe GER causing Sandifer complex with
cyanotic, ‘‘seizure-like’’ episodes. He was found to have a novel de
novo mutation in the SMC1A gene (p.R711Q) that altered a highly
conserved residue and was not detected in his parents or in
50 control individuals. The mutation was located at the SMC
coiled-coil domain and may affect the folding of the protein. The
patient underscores that, although most reported mutations in
SMC1A have caused a mild phenotype, some mutations may result
in severe physical and cognitive impairments.
Investigating Large NIPBL RearrangementsJolanta Wierzba, Magdalena Ratajska, Jiong Yan, Feng Zhang, James
R. Lupski, and Janusz Limon. Most CdLS cases are dominant and
sporadic. Approximately half of CdLS individuals carry loss-
of-function mutations in NIPBL, about 5% carry an SMC1A
mutation, and rarely an SMC3 mutation is found. It has been
suggested that patients without mutation in these genes, may carry
mutations in other structural components of the cohesin complex
(Rad21, Stag2) or mutations could be localized in regulatory
sequence for NIPBL.
We studied 11 CdLS patients (9 boys; 4–28 years) who were
negative by conventional NIPBL/SMC1A screening (DHPLC and
direct sequencing techniques), using multiplex ligation-dependent
PCR amplification (MLPA). To confirm different peak patterns,
suggesting the presence of large deletion/duplication within these
genes, a second MLPA reaction was performed. We found one
patient to carry a large deletion within NIPBL. Abnormal RPA
ratio was detected for exons 35–47, average RPA reduction was
47%, indicative of a large deletion. The result was confirmed
with a second MLPA reaction followed by array-CGH analysis.
Array-CGH showed the presence of�58-Kb deletion, including the
NIPBL and the next FLJ13231 gene. Clinically this patient presented
with psychomotor retardation, growth retardation, distinctive
facial appearance, and severe gastrointestinal problems.
OLIVER ET AL. 1133
To our knowledge, this was the second CdLS patient carrying a
large NIPBL deletion and the first with a rearrangement extending
not only NIPBL but also the neighboring FLJ13231 gene. Large
rearrangements in NIPBL are likely rare but may be missed using
conventional PCR-based methods. We suggest performing
extended mutational analysis in CdLS patients negative for
NIPBL/SMC1L1 point mutations.
A Reproductive Risk QuestionnaireMaria Francesca Bedeschi, Vera Bianchi, Faustina Lalatta, Donatella
Milani, Anna Cereda, Silvia Maitz, Marta Cerutti, and Angelo Selicorni.
CdLS is a genetically heterogeneous disorder, being caused by
mutations or deletions in two autosomal genes and one X-linked
gene, and sometimes CdLS is the result of an unbalanced translo-
cation which may or may not be familial. Families should be
adequately informed about this genetic heterogeneity and the
various reproductive risks. We created a questionnaire, to be used
as a tool to collect data about the specific needs of CdLS families.
The questionnaire consisted of 24 items subdivided in five sections:
in Section 1, data were collected about the pedigree and family
history; in Section 2, questions about the diagnosis and parents’
perception of the disorder were posed; in Section 3, questions were
posed about reproductive risks, prenatal diagnosis options, preg-
nancy surveillance, and parental anxieties; in Section 4, reproduc-
tive risk questions for offspring were posed; in Section 5, questions
were asked about the parental opinion on genetic testing in
general, and also for reproductive counseling and determining
the prognosis of their CdLS child and possibly usable in future
management. Finally an open question was included, in which
parents were asked to provide advice and suggestions for other
parents with a CdLS child.
We gathered data from 35 families with 20 male and 15 female
CdLS probands (mean age 9.5 years; range 0.9–35 years). Mean age at
diagnosis was 1 year (range 0–12 years). In most probands, a
moderate to severe developmental delay was reported by the parents.
Genetic counseling was offered to 27 of the 35 families. Parents of 19
families considered their reproductive risk regarding CdLS as the
same as the risk in the general population. At the time of a subsequent
pregnancy 18 of the families asked for a second genetic counseling
session. Parents selected as options for prenatal diagnosis amniocen-
tesis and ultrasound scans. The parental opinion about efficacy of
prenatal diagnosis was influenced by personal belief and educational
status. Usually parents had very limited knowledge and understand-
ing on the limitations of amniocentesis and fetal ultrasounds. Parents
showed confidence in genetic testing, to try to define the prognosis of
their child, and to apply in future therapies.
Our results showed limited knowledge of the parents about the
genetic heterogeneity of CdLS. There is a need for follow-up, to re-
evaluate inheritance patterns and risk estimates with the families,
and to apply novel knowledge about CdLS in the management.
‘‘You Have to Sit and Explain it All,and Explain Yourself’’Gemma M. Griffith, Richard P. Hastings, Susie Nash, Michael
Petalas, Patricia Howlin, Joanna Moss, Chris Oliver, Jane Petty, and
Penelope Tunnicliffe. In the United Kingdom, it is estimated that
around 50–60% of adults with intellectual disabilities continue to
live in the family home well into their middle age. Little research
has been conducted about caregivers of adults with intellectual
disabilities, and their perceptions of formal support. Some
literature suggests that dealings with formal support services may
generate further work and effort on the parent’s part. However,
there is a lack of qualitative family research on adults with rare
syndromes, and the purpose of this study was to gather data on the
experiences of such families in the United Kingdom.
We used semi-structured interviews to investigate mothers’
experiences of formal support. Eight mothers of young adults with
either CdLS, AS, or CdCS were interviewed. The interview tran-
scripts were analyzed using Interpretative Phenomenological Anal-
ysis. The themes which emerged were: (i) social inclusion and
stigma, (ii) uneven medical and social care service provision, (iii)
the inertia of social care services, and (iv) mothers as advocates.
Parental experiences differed widely across these themes. With day-
to-day services, mothers described the benefits of having care staff
who were settled in their jobs, whereas others reported multiple
problems owing to a high turnover of care staff. In terms of
communication, mothers found that formal support services were
often indifferent and slow to respond to their enquiries. Generally,
mothers reported a lack of awareness of their young adult’s syn-
drome within formal support services, but this did not seem to
disadvantage families in terms of their access to formal support.
However, it did make a difference to accessing health care, as the
rareness of these syndromes are such that medical professionals may
be reliant on information parents provide about the syndrome, and
as a result may not be able to offer sufficient medical advice to
parents.
These findings suggested that accessing appropriate formal
support and health services for adults with intellectual disabilities
was a lengthy and complex process for parents of adults with rare
genetic syndromes. These data may help inform service providers
about how best to support young adults with rare genetic syn-
dromes and their carers.
ACKNOWLEDGMENTS
The authors thank all the participants who attended the 3rd
Cornelia de Lange World Conference for making the event such
a success. The Scientific Conference was supported by the Dyna and
Fala Weinstock Charitable Trust. They thank all participating
Cornelia de Lange Support groups for their continuous support.
The work of Dr. Ramos was in part supported by a grant from the
Ministerio de Sanidad y Pol�ıtica Social of Spain (Ref. PI061343) and
from the Gobierno de Arag�on (Ref. B20).
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