Characterization of limb differences in children with Cornelia de Lange Syndrome

Abstract

Cornelia de Lange syndrome (CdLS) is a well-described multisystem developmental disorder characterized by dysmorphic facial features, growth and behavioral deficits, and cardiac, gastrointestinal, and limb anomalies. The limb defects seen in CdLS can be mild, with small feet or hands only, or can be severe, with variable deficiency defects involving primarily the ulnar structures and ranging from mild hypoplasia of the fifth digit to complete absence of the forearm. Interestingly, the upper limbs are typically much more involved than the lower extremities that generally manifest with small feet and 2-3 syndactyly of the toes and shortened fourth metatarsal. The upper limbs often manifest asymmetric involvement. The limb findings in our cohort of 378 individuals with CdLS demonstrate a consistent pattern of laterality and symmetry involvement (with increased severity of right-sided limb in individuals with asymmetric limb defects) and a correlation of more significant limb defects with an increased risk of other structural anomalies, and more severe behavioral outcomes. Additionally, we found that individuals with mutations in NIPBL were most likely to have limb defects compared to mutations in other genes with nonsense, exonic deletion, and frameshift mutations being most prevalent in those with limb defects. Characterization of the limb differences in children with CdLS may provide a tool to assist in genetic counseling and determining prognosis. This paper will review the limb involvement in a large cohort of individuals with CdLS assessing the correlation with molecular etiologies, symmetry, additional structural birth defects, and cognitive outcomes. © 2016 Wiley Periodicals, Inc.

A report of 2 cases of Cornelia de Lange syndrome (CdLS) and an analysis of clinical and genetic characteristics in a Chinese CdLS cohort

“…Among the 26 Chinese individuals diagnosed with CdLS, 25 patients of them had some extremity malformations including minor differences in morphologies involving the limbs (e.g., proximally placed thumb, small hand, clinodactyly, syndactyly) (Table 2). This result was consistent with previously described results in the literature, in which 86% of the 310 CdLS individuals observed by Jackson, Kline, Barr, and Koch (1993) and 100% of the 378 CdLS subjects in the large cohort studied by Mehta et al (2016) CdLS patients are more common than those of the lower extremities (Mehta et al, 2016). And this is also true for the 26 Chinese CdLS cases: 8 cases had both upper and lower extremities anomalies, 16 cases had only upper extremities anomalies and no cases had only lower extremities manifestations (Table 2).…”

Genetic enhancement of limb defects in a mouse model of Cornelia de Lange syndrome

“…Overall, 77% of unilateral forelimb polydactyly involved the right forelimb and 89% of unilateral hindlimb polydactyly involved the right hindlimb. A similar right‐sided prevalence has been noted for the limb abnormalities that occur in CdLS, including the severe reduction defects [Mehta and Krantz, ].…”

“…Several aspects of the polydactyly that was enhanced by Bmp4 and Hox mutant backgrounds bear strong resemblance to what is seen in CdLS: These include predominantly post‐axial positioning, and a much greater prevalence on fore‐ versus hind‐limbs. In addition, polydactyly was strongly right‐side biased, just as is observed with more severe reduction defects in CdLS [Mehta and Krantz, , this issue].…”

Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement

“…Musculoskeletal problems are common, irrespective of the gene involved. In individuals with NIPBL variants, major upper limb anomalies are the most frequent (25%), whereas in those with variants in other genes, such malformations are infrequent (SMC3, HDAC8 and RAD21) or absent (SMC1A) 3,115 . Individuals with truncating NIPBL variants have been reported to particularly have major limb defects 11,25,26,115 .…”

“…Major limb anomalies are almost exclusively found in the upper limbs, more frequently in male individuals 11 , and are asymmetric in 65% (in 75% of these individuals, the right side is the more affected side) 115,116 . Malformations include an absent forearm, abnormal fusion of the radius and ulna (radioulnar synostosis), absent radius or ulna, and oligodactyly.…”