Laboratory Studies
Molecular genetic diagnosis can be performed using sequencing and deletion/duplication analysis of NIPBL, SMC3, RAD21, SMC1A, and HDAC8.
This testing can confirm the diagnosis, especially in mild or atypical cases, and the results can help in identifying the family specific mutation for prenatal testing in future pregnancies. Updated laboratory information can be obtained at Gene Tests.
CBC analysis has led to a finding of thrombocytopenia.
Imaging Studies
See the list below:
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Radiography may reveal the following:
Delayed bone age (100%)
Spurs in the anterior angle of the mandible (42%) and a prominent symphysis (66%)
Digital abnormalities, which range from acheiria to oligodactyly
Long-bone abnormalities, including ulnar aplasia and/or hypoplasia, aplasia and/or hypoplasia of the radial head, or fusion of the elbow: When a single forearm bone is present, fusion at the elbow and oligodactyly often occur; this condition makes it difficult to determine if the radius or ulna is absent.
Hypoplastic first metacarpal (79%), hypoplastic fifth middle phalanx (93%), and clinodactyly (64%)
Short sternum with precocious fusion (54%)
Thirteen ribs (56%)
Thin rib cortices with undulating appearance (33%)
Hiatal hernia
Aspiration pneumonia (50%)
Gastroesophageal reflux (90%)
Intestinal obstruction, malrotation, volvulus (17%)
Pelvic abnormalities (33%)
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Ultrasonography at diagnosis to assess for kidney and urinary tract abnormalities (40%) may reveal the following:
Horseshoe kidney
Altered corticomedullary differentiation
Pelvic dilation
Small kidneys
Renal cysts
Renal ectopia
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Voiding cystourethrography is indicated for evaluation of recurrent urinary tract infections or hydronephrosis.
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Echocardiography is indicated for evaluation of congenital heart disease.
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Radiologic brain findings may include enlarged ventricles, including enlargement of basal cisterns; thinning or atrophy of white matter, particularly frontal lobes, with relative sparing of parietal lobes; brainstem hypoplasia; and cerebellar vermian hypoplasia or agenesis.
Other Tests
Hearing evaluation is recommended in Cornelia de Lange syndrome.
High-resolution chromosomal studies are indicated when the syndrome's diagnosis is uncertain.
A spectrum of endocrinopathies may be observed in this disorder in addition to growth-hormone deficiency. These conditions include problems relating to gonadotropin and prolactin secretion and panhypopituitarism. In a study of 24 patients with Cornelia de Lange syndrome, Ascaso et al found hyperprolactinemia to be the most common endocrine disorder. Mildly delayed puberty and genital abnormalities, such as cryptorchidism, were noted in the cohort, and the presence of subclinical hypothyroidism was reported in three individuals. In three prepubertal patients, lab results suggested insulin resistance, despite a lack of risk factors. The group demonstrated, on average, normal levels of insulin-like growth factor 1 and insulin-like growth factor–binding protein 3. [23]
Staging
Diagnosis requires (1) positive mutation finding on Cornelia de Lange syndrome gene testing; (2) confirmed facial findings and confirmed criteria from any 2 of the growth, developmental, or behavioral categories; or (3) confirmed facial findings and confirmed criteria for 3 other categories, including one from growth, developmental, or behavioral categories and 2 from the other categories. [24]
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Facial characteristics must include synophrys and at least 3 of the following:
Long eyelashes
Short nose, anteverted nares
Long, prominent philtrum
Broad or depressed nasal bridge
Small or square chin
Thin lips, down-turned corners
High palate
Widely spaced or absent teeth
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Growth characteristics must include at least 2 of the following:
Weight below the fifth percentile for age
Height or length below the fifth percentile for age
Occipitofrontal circumference below the second percentile for age
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Developmental characteristics must include at least 1 of the following:
Developmental delays or mental retardation
Learning disabilities
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Behavioral characteristics must include at least 2 of the following:
Constant roaming
Aggression
Self-injurious behavior
Extreme shyness or withdrawal
Autisticlike features
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Musculoskeletal characteristics include reduction defects with absent forearms alone, small hands or feet (below the third percentile for age) or oligodactyly and at least two of the following, or none of these features and at least three of the following:
Clinodactyly of the fifth finger
Abnormal palmar crease
Radial head dislocation, abnormal elbow extension
Short first metacarpal, proximally placed thumb
Bunion
Partial syndactyly toes
Scoliosis
Hip dislocation or dysplasia
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Neurosensory and skin characteristics must include at least 3 of the following:
Ptosis
Tear duct malformation or blepharitis
Myopia
Major eye malformation or peripapillary pigmentation
Deafness or hearing loss
Seizures
Cutis marmorata
Hirsutism, generalized
Small nipples and/or umbilicus
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Other major system characteristics must include at least 3 of following:
GI malformation/malrotation
Diaphragmatic hernia
Gastroesophageal reflux disease
Cleft palate or submucous cleft palate
Congenital heart defect
Hypospadias
Renal or urinary tract malformation
Table. Scoring System for Severity of Cornelia de Lange Syndrome [24] (Open Table in a new window)
Parameter |
1 point |
2 point |
3 point |
Birth weight |
Above 2,500 g |
2,000–2,500 g |
Below 2,000 g |
Sitting alone |
< 9 mo |
9–20 mo |
>20 mo |
Walking alone |
< 18 mo |
18–42 months |
>42 mo |
Saying first word |
< 24 mo |
24–48 mo |
>48 mo |
Upper limb malformation |
No defect |
Partial defect (>2 digits) |
Severe defect (< 2 digits) |
Number of other major malformations |
0-1 |
2-3 |
>3 |
Hearing loss |
Absent |
... |
... |
A score of less than 15 points indicates mild involvement, a score of 15-22 points indicates moderate involvement, and a score of more than 22 points indicates severe involvement. |
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Facial appearance of a patient with Cornelia de Lange syndrome. Courtesy of Ian Krantz, MD, Children's Hospital of Philadelphia.
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Facial profile of a patient with Cornelia de Lange syndrome. Courtesy of Ian Krantz, MD, Children's Hospital of Philadelphia.
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Severe upper-extremity malformations in a patient with Cornelia de Lange syndrome. Courtesy of Ian Krantz, MD, Children's Hospital of Philadelphia.