Cutaneous Manifestations of Cornelia de Lange Syndrome Workup

Updated: Jun 02, 2022
  • Author: Krystyna H Chrzanowska, MD, PhD; Chief Editor: William D James, MD  more...
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Laboratory Studies

When the diagnosis of Cornelia de Lange syndrome (CDLS) is considered, a standard karyotypic analysis is recommended, even though it is expected to be normal. The following genetic tests are recommended to verify a clinical diagnosis:

  • Molecular analysis of the NIPBL gene allows confirmation of a disease-causing mutation in a proportion of cases (approximately 50%), and it provides the basis for prenatal diagnosis in families with parental transmission or proven paternal gonadal mosaicism. [5, 6, 8, 9, 10, 11, 12, 13, 19] To find a genetics or prenatal diagnosis clinic, see the Laboratory Directory at GeneTests.

  • In NIPBL mutation–negative patients, sequence analysis of the SMC1A,SMC3, RAD21, and HDAC8 genes allows identification of the mutation in 5% of probands. [18, 20, 21, 23, 24, 43]

  • Large genomic rearrangements in NIPBL occur infrequently, but they can be detected by using multiplex ligation-dependent probe amplification (MLPA). [8, 16, 17]

  • If molecular test results are negative, a genome-wide array comparative genomic hybridization (array-CGH) is worthwhile to identify copy number alterations [90] ; high-resolution chromosomal analysis can delineate cases of chromosomal aberrations with phenotypic overlap with CDLS.

Endocrinologic studies are warranted in patients with severe growth retardation. [52, 53, 91]

Periodical evaluations, including routine blood cell counts, iron metabolism testing, liver and renal function tests, urinalysis, and a search for stool blood, are recommended, especially in first years of life. Anemia (normochromic or hypochromic) may occur as a consequence of GI problems such as malnutrition or recurrent episodes of pneumonia. Thrombocytopenia, most probably related to cavernous or capillary hemangiomas, has occasionally been reported.


Imaging Studies

In Cornelia de Lange syndrome (CDLS), skeletal radiography may help increase diagnostic precision. A high incidence of microcephaly, various distal limb defects, a dislocated and/or hypoplastic radial head, and delayed ossification are stressed. Chest anomalies often involve a short sternum with premature fusion and the occurrence of 13 pairs of ribs. Pattern profiles commonly show shortness of the first metacarpal and fifth distal phalanx. [92, 67]

Barium esophagography under fluoroscopic control may allow demonstration of hiatal hernia, gastroesophageal reflux (GER), and esophageal dysmotility. [73, 75, 77, 80, 92]

Gastric scintigraphy can also be used to document GER.

Temporal bone CT scanning could document combined structural abnormalities of the external, middle, and inner ear. Kim et al found good correlation of CT abnormalities with the audiometric results. [93]

Echocardiography can be used for imaging structural heart abnormalities.

Assessment of gallbladder and assessment of the genitourinary system may require abdominal ultrasonography or radiologic examination, such as urography or cystoureterography.


Other Tests

Ear examination and hearing assessment are strongly recommended for all children as soon as possible. Hearing deficits frequently occur in patients with Brachmann-de Lange syndrome (BDLS) and are related to the significant developmental and speech delays that are experienced in many of the children. Specific testing appropriate for individuals with mental retardation is required; such testing includes brain-evoked response audiometry (BERA). [36]

Ophthalmologic examination is important in early care of the child. Myopia is common, but glasses are often poorly tolerated.

EEG is recommended in patients with seizures.

Esophagoscopy with biopsy is a superior diagnostic technique for evaluation of GER, and it may reveal the presence of Barrett esophagitis. The severity and frequency of reflux can be documented by using continuous pH monitoring in the distal esophagus or by using apnea evaluations with the thermistor oxygenation pneumocardiography. [73]

Assessment of the growth rate with serial anthropometric measurements of height, weight, and occipitofrontal circumference is recommended. Specific growth charts for Cornelia de Lange syndrome (CDLS) individuals have been developed and are available on the CdLS-USA Foundation Web site.

Evaluation of symptoms of autistic disorder has been made mostly by means of the Child Autism Rating Scale (CARS), Autism Diagnostic Observation Schedule (ADOS), and Autism Diagnostic Interview-Revised (ADI-R) tools. [55]


Histologic Findings

Postmortem examination has revealed various congenital malformations of the internal organs, including cardiac defects, pulmonary hypoplasia, diaphragmatic hernias, GI anomalies, and genitourinary anomalies. [44, 87] Microscopy of the internal organs has shown no consistent abnormalities. Microcytic changes of the kidney have been observed in some individuals. [65] Histological examination of the brain has demonstrated neuronal heterotopias in the cerebellum and ectopic neurons in the cerebral white matter in one newborn. [65] A detailed neuropathologic analysis of a 35-year-old patient has revealed abnormal convolution patterns of the cerebral gyri and frontal lobe hypoplasia. [94]