Cornelia de Lange Syndrome

Excerpt

Clinical characteristics: Cornelia de Lange syndrome (CdLS) encompasses a spectrum of findings from mild to severe. Severe (classic) CdLS is characterized by distinctive facial features, growth restriction (prenatal onset; <5th centile throughout life), hypertrichosis, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nasal bridge with anteverted nares, small widely spaced teeth, and microcephaly. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS. Across the CdLS spectrum IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Other frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia.

Diagnosis/testing: The diagnosis of CdLS is established in a proband with suggestive clinical features and/or by identification of a heterozygous pathogenic variant in NIPBL, RAD21, SMC3, or BRD4, or a hemizyous pathogenic variant in HDAC8 or SMC1A by molecular genetic testing.

Management: Treatment of manifestations: Aggressive management of gastroesophageal reflux with assessment of potential gastrointestinal malrotation; consideration of fundoplication if reflux is severe. Supplementary formulas and/or gastrostomy tube placement to meet nutritional needs as necessary. Physical, occupational, and speech therapy to optimize psychomotor development and communication skills. Standard treatment for epilepsy, vision issues, nasolacrimal duct obstruction, hearing loss, cleft palate, anomalies of tooth formation and/or position, cardiac defects, cryptorchidism/hypospadias, bicornuate uterus, vesicoureteral reflux, anemia and/or thrombocytopenia, and immunodeficiency. If surgery is being considered, malignant hyperthermia precautions and preoperative evaluation for thrombocytopenia and cardiac disease with careful monitoring of the airway during anesthesia are recommended.

Surveillance: At each visit: measurement of growth parameters and evaluation of nutritional status and safety of oral intake; monitor for signs and symptoms of GERD and for evidence of aspiration with respiratory insufficiency; assessment for new manifestations such as seizures or signs of autonomic dysfunction; monitor developmental progress and educational needs; behavioral assessment for anxiety, attention, and aggressive or self-injurious behavior; assessment of mobility and self-help skills. At least annually: ophthalmology evaluation; dental evaluation with cleaning; audiology evaluation in childhood and adolescence.

Genetic counseling: NIPBL-CdLS, RAD21-CdLS, SMC3-CdLS and BRD4-CdLS are inherited in an autosomal dominant manner; HDAC8-CdLS and SMC1A-CdLS are inherited in an X-linked manner. The majority of affected individuals have a de novo heterozygous pathogenic variant in NIPBL. Fewer than 1% of individuals with autosomal dominant CdLS have an affected parent. When the parents are clinically unaffected, the risk to the sibs of a proband with CdLS is estimated to be 1.5% because of the possibility of germline mosaicism. The risk to sibs of a male proband with X-linked CdLS depends on the status of the proband's mother; the risk to sibs of a female proband with X-linked CdLS depends on the status of the proband's mother and father. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible for families in which the pathogenic variant has been identified.