Full List of Recommendations

Physical characteristic recommendations:

R1: The CdLS spectrum encompasses a range of phenotypes consisting of classic (or typical) CdLS and non-classic CdLS, which are characterised by a combination of features (see Box 1).

R2: The International CdLS Consensus Group propose consensus criteria based on the presence of a combination of signs and features (see Box 1). A diagnosis of classic CdLS can be confirmed if a score of 11 is reached, irrespective of the presence of a variant in a gene known to result in CdLS.

R3: Presently available severity scoring schemes should be used cautiously as these do not adequately reflect the severity as experienced by the individuals with CdLS and their families.

Causes of Cornelia de Lange Syndrome recommendations:

R4: Classic CdLS is usually caused by variants in NIPBL; however, variants in one of six other genes – SMC1A, SMC3, RAD21, BRD4, HDAC8 or ANKRD11/ – should also be considered, as they may lead to a similar phenotype.

R5: Mosaicism should be considered in individuals with CdLS in whom a variant in a gene known to cause CdLS cannot be detected in blood cells, in which case other tissues such as fibroblasts (skin), buccal (cheek) cells or bladder epithelial cells from urine should be studied.

R6: Genetic counselling should be offered to all families with a family member with CdLS. Families should be counselled that the recurrence risk of CdLS differs depending on the gene involved. In the non-X-linked forms, the recurrence risk is 0.89% due to germline mosaicism. Autosomal dominant inheritance of CdLS does occur, meaning if one copy of the mutation is present, the individual will show clinical effects. In clinically diagnosed individuals with CdLS, the recurrence risk is 1.5%.

Diagnosis recommendations:

R7: If a prenatal ultrasound scan (sonography) detects features consistent with CdLS, possibilities for prenatal genetic testing should be discussed with the parents.

R8: If a causative gene change has been detected in an earlier child or pregnancy, reliable prenatal diagnostic testing should be discussed with the family. Targeted variant testing can be performed using DNA derived from the placenta or amniotic fluid.

R9: If available, first-line genetic testing should be performed using panel sequencing to screen all genes known to cause CdLS spectrum (NIPBL, SMC1A, SMC3, RAD21, BRD4, HDAC8 and ANKRD11). Medico-legal, technical, and insurance-related national practices may require other tests, such as Sanger sequencing of individual genes.

Paediatric Medical Care:

R10: Every infant and young child with CdLS should be assessed for cardiac (heart) and renal (kidney) malformations subsequent to diagnosis.

R11: The growth of every child with CdLS should be monitored by using CdLS-specific growth charts.

R12: In every CdLS individual with prolonged and marked feeding difficulties, the multidisciplinary assessment (from healthcare workers across many disciplines) should consider (temporary) placement of a gastrostomy (surgical opening through the abdomen into the stomach) as a supplement to oral feeding.

R13: In individuals with CdLS who have recurrent respiratory infections, reflux and/or aspiration (breathing foreign objects into airways) should be ruled out.

R14: The palate should be closely examined at diagnosis. In case of symptoms of a (submucous) cleft palate, referral for specialist assessment is indicated.

R15: Dental assessment and cleaning should take place regularly; a more thorough dental examination or treatment under anaesthesia may be necessary.

R16: Developmental milestones should be closely monitored.

R17: Vaccinations should be given to every child with CdLS according to national guidelines.

R18: As pain can easily remain unrecognised in a child with CdLS, all care providers should be aware of the different manifestations and the possible sources of pain. Specific tools to assess pain are recommended.

R19: Regular follow-up of every child with CdLS is needed, preferably by a paediatrician or clinical geneticist experienced in treating individuals with CdLS; schedules depend on local practices and possibilities.

Medical Care in Adulthood:

R20: Sexual education appropriate to the level of understanding should be offered, and contraception management should follow local standard for the general population.

R21: Hysterectomy is indicated if abnormally heavy bleeding at menstruation is present and does not respond to medical treatment.

R22: Specific attention to diet and stimulation of activities are recommended as obesity can occur.

R23: Renal (kidney) function should be regularly monitored in children and adults with CdLS who have structural renal malformations.

R24: Prostate enlargement in men with CdLS should be treated according to national guidelines for the general population.

R25: Women with CdLS should be offered breast cancer screening according to national guidelines for the general population.

R26: Routine gynaecologic care including cervical screening should be performed in women with CdLS, according to national guidelines for the general population.

R27: The use of emergency cards should be considered for every person with CdLS.

What health difficulties might a child with CdLS face?

R28: Every new born suspected or proven to have CdLS should be carefully evaluated for signs and symptoms consistent with gastrointestinal malformations.

R29: Presentation of any abdominal symptoms in an individual with CdLS, irrespective of age, should prompt consideration of intestinal malrotation.

R30: Evaluation for the presence of intestinal malrotation needs to be discussed and decided together with the family, balancing the potential gain in health and burden for the individual with CdLS.

R31: Constipation is present in almost half of all individuals with CdLS and should be treated as in the general population.

R32: Consider always gastro-oesophageal reflux disease (GORD) in any individual with CdLS owing to its frequency and wide variability in presentation, which includes challenging behaviour.

R33: Modification of nutrition and proton pump inhibitors (PPI) are the first-line treatments of GORD. Anti-reflux medications need to be used to their maximum dosage. Surgical interventions for GORD should be limited to those individuals with CdLS in whom nutritional and medical treatments have been unsuccessful or airway safety is at risk.

R34: If GORD symptoms persist, endoscopy should be strongly considered whilst an individual with CdLS is still in paediatric care.

R35: Surveillance for Barrett’s Oesophagus needs to be discussed with and decided together with the family, balancing the potential gain in health and burden for the individual with CdLS.

R36: Surgical correction of ptosis should be considered if vision is significantly affected or if the individual is lifting their chin in attempt to see more clearly and it is affecting the individual’s ability to move around.

R37: Blepharitis in individuals with CdLS should be treated conservatively with lid hygiene. Nasolacrimal duct obstruction (blocked tear ducts) should be suspected if symptoms are not improved with lid hygiene.

R38: Vision should be regularly evaluated in all individuals with CdLS, especially in infancy and childhood. Problems with vision should be corrected early to prevent amblyopia (lazy eye), although children may have difficulty tolerating glasses or contact lenses.

R39: Hearing should be assessed in individuals with CdLS at an early age and should be followed up over time. Those with severe sensorineural hearing loss should be assessed for auditory neuropathy.

R40: Regular eye (ophthalmologic) and ear, nose and throat (otolaryngologic) evaluations are recommended in adults with CdLS.

R41: Otitis media (middle ear infections) with fluid build up and sinusitis in individuals with CdLS should be considered and treated according to the national guidelines for the general population.

R42: The anaesthesiologist should be aware of the potential difficulty with intubation in individuals with CdLS.

R43: As function is often remarkably good in major limb anomalies, caution is recommended regarding surgical procedures in individuals with CdLS.

R44: Prosthetic devices targeting a single function should be considered depending on the needs and tolerance in individuals with CdLS.

R45: Prognosis regarding development and mobility should be taken into account when considering treatment of musculoskeletal problems in individuals with CdLS.

R46: Scoliosis and leg length differences need specific attention in adults with CdLS at regular medical check-ups.

R47: Seizures in individuals with CdLS should be treated using the general management schemes.

R48: An MRI of the brain should be considered only if the individual with CdLS shows neurological signs other than microcephaly (smaller than normal head).

R49: Sleep problems in individuals with CdLS can have serious consequences, and behavioural sleep management should be considered.

What are the Cognitive and Behavioural Characteristics of Cornelia de Lange Syndrome?:

R50: Bei Personen mit CdLS müssen Hyper- und Hyposensitivität (sensorische Über- und Unterempfindlichkeit) und andere Schwierigkeiten in der sensorischen Verarbeitung untersucht und lebenslange Strategien zur Unterstützung umgesetzt werden.

R51: Die Stärkung der adaptiven Fähigkeiten mit dem Ziel einer größeren Selbstständigkeit sollte lebenslang im Vordergrund stehen und auf die Person abgestimmte spezifische Zielsetzungen und Lehrstrategien umfassen.

R52: Menschen mit CdLS müssen zusätzliche Unterstützung in ihrer Entwicklung und Schulbildung erhalten, um im Rahmen ihrer individuellen kognitiven Beeinträchtigung ihr maximales kognitives und Lernpotenzial zu erreichen.

R53: Die kognitiven Stärken und Schwächen von Menschen mit CdLS müssen eingestuft werden, um Strategien für ihren Bildungsweg und mögliche Interventionsstrategien zu erarbeiten.

R54: Um die Ursache für selbstverletzendes Verhalten bei Menschen mit CdLS zu ermitteln, sind medizinische Untersuchungen mit Fokus auf möglichen Schmerzquellen notwendig, gefolgt von einer Verhaltenseinstufung zum Aspekt der Selbstbeherrschung und einer anschließenden funktionalen Analyse.

R55: Die Behandlung von selbstverletzendem Verhalten muss sowohl medizinische als auch verhaltensbezogene Strategien umfassen.

R56: Für Personen mit CdLS in jeder Altersstufe ist die Diagnose einer Autismus-Spektrum-Störung (ASS) zu erwägen, wobei atypische Erscheinungsbilder berücksichtigt werden müssen.

R57: Zusätzlich zu den standardisierten ASS-Diagnosewerkzeugen sind auch genaueste Beobachtungen sinnvoll, um das individuelle Profil der sozialen Funktion exakt zu ermitteln.

R58: Bei allen Personen mit CdLS sind ASS-spezifische Interventionen zu erwägen, kombiniert mit Ansätzen, die auch das breitere Profil der sozialen Funktion bei diesem Syndrom berücksichtigen.

R59: Bei Interventionen, die auf problematisches repetitives Verhalten bei Menschen mit CdLS zielen, müssen Aspekte wie Angst, sensorische Probleme und soziale Anforderungen sowie auch Faktoren des Umfelds berücksichtigt werden.

R60: Bei Auftreten von Verhaltensveränderungen sind auch atypische Ausprägungen von Angst- und Stimmungsstörungen zu berücksichtigen.

R61: Da Angst während Veränderungs- oder Übergangsphasen des Umfelds ein häufiges Phänomen bei Menschen mit CdLS ist, sollten potenziell beängstigende Situationen nach einem vorgeplanten Programm abgewickelt werden.

R62: Zur Behandlung von Angst- und Stimmungsstörungen bei Personen mit CdLS sind psychosoziale Interventionen (Therapien) sowie Pharmakotherapie, also die Gabe von Medikamenten, zu erwägen.

R63: Bei der Einstufung der Kommunikationsfähigkeit sind Seh- und Hörprobleme, Sprachbehinderungen, geistige Einschränkung, Schwierigkeiten in der sozialen Interaktion sowie soziale Angst zu berücksichtigen. Hier können Videoaufnahmen sehr hilfreich sein.

R64: Mit an die Entwicklung angepassten Kommunikationsstrategien (wie Sprachtherapie, gestützte Kommunikation) sollte innerhalb der ersten 18 Lebensmonate begonnen werden.

Do Cognitive and Behavioural Characteristics Change with Age in CdLS?:

R65: Individuals with CdLS should receive extra support during adolescence and early adulthood, using a person-centred approach to reduce mental health issues and challenging behaviour.

Care Planning in CdLS:

R66: Individuals with CdLS and their families need life-long care provided by healthcare providers and social services, who should educate themselves about CdLS.

R67: Syndrome-specific and personalised care plans through shared decision-making should be offered to every individual with CdLS and their caregivers.

R68: Transition of care should be initiated at an early phase, with proper transfer of medical history and knowledge about the personal characteristics of the individual with CdLS. It is recommended that current and future health care providers jointly evaluate individuals with CdLS in order to smooth the transition.