Cornelia de Lange syndrome: Clinical review, diagnostic and scoring systems, and anticipatory guidance

Abstract

Cornelia de Lange syndrome (CdLS), also known as Brachmann-de Lange syndrome, is a well-described multiple malformation syndrome typically involving proportionate small stature, developmental delay, specific facial features, major malformations (particularly the cardiac, gastrointestinal and musculoskeletal systems), and behavioral abnormalities. There is a broad spectrum of clinical involvement, with increasing recognition of a much milder phenotype than previously recognized. Significant progress has been made in recent years in the clinical and molecular delineation of CdLS, necessitating a revision of the diagnostic criteria, more inclusive of the milder cases. In addition, a scoring system of severity has been found to correlate with specific brain changes. Thus, a clinical overview and recommendations for anticipatory guidance are timely in aiding caretakers and professionals to individualize care decisions and maximize developmental potential for individuals with CdLS. These guidelines are derived from consensus based on collective experience of over 500 patients with CdLS, observations of the natural history in children, adolescents, and adults, a review of the literature, and contacts with national support organizations in North America and Europe.

Cornelia de Lange syndrome (CdLS): prenatal and autopsy findings

“…A variety of congenital heart defects is seen in CdLS and reported in 25% of patients (Kline et al, 2007a); our cases were consistent with this variability. Finally, examination of the placentas in our cases showed intervillous thrombi consistent with signs of placental insufficiency and IUGR.…”

“…Perhaps these gynecological findings on autopsy are the pathological explanation for some of these later endocrine events. Ambiguous genitalia has been described in CdLS as well as other genitourinary malformations (Kline et al, 2007a), and was noted prenatally in our Case 3.…”

“…The HEAT repeats are conserved across species and are protein-protein interacting motifs that are found in complexes with chromosome-related functions (Strachan, 2005;Yan et al, 2006). The mutation in Case 2 is predicted to produce the shortest protein with a mutation in the caldesmon domain, a highly conserved region among species that bind calmodulin causing inhibition of smooth muscle contraction (Yan et al, 2006;Kline et al, 2007a). Potentially, this function may explain the gastrointestinal hyperactivity in some CdLS patients and possibly the presence of the abdominal cyst in our case.…”

“…Upper extremity malformations are typically present in one-third of patients with CdLS ranging from oligodactyly to ulnar deficiency to absent forearm with digits present just distal to the elbow (Kline et al, 2007a). Atypical ultrasound findings in CdLS including DandyWalker variant and cerebellar vermis hypoplasia have been previously reported but are not common (Ranzini et al, 1997;Urban and Hartung, 2001).…”

“…However, these cases are mild, in comparison to the autosomal dominant cases, and do not present with limb abnormalities. Yan et al, 2006) Forty to 56% of individuals with CdLS who had DNA analysis for the NIPBL gene were found to have mutations in the NIPBL gene located at 5p13 (Gillis et al, 2004;Yan et al, 2006) and encoding the protein delangin (Krantz et al, 2004;Yan et al, 2006;Kline et al, 2007a). Genotype phenotype correlation has not been very informative in CdLS; however, it seems that truncating lesions result in more severe phenotype (Selicorni et al, 2007).…”