Liebenberg Syndrome

A number sign (#) is used with this entry because of evidence that Liebenberg syndrome (LBNBG), or carpal synostosis with dysplastic elbow joints and brachydactyly, is caused by genomic rearrangement resulting in misexpression of the PITX1 gene (602149) on chromosome 5q31.

Description

Liebenberg syndrome is an upper limb malformation characterized by the combination of dysplastic elbow joints and the fusion of wrist bones with consequent radial deviation (summary by Spielmann et al., 2012).

Clinical Features

Liebenberg (1973) described 4 males and 6 females in 5 generations of a white South African family with upper limb deformities affecting the fingers, wrists, and elbows. Affected members had dysplasia of all bony components of the elbow causing flexion deformity and an appearance resembling anterior dislocation. At the wrist, anomalies were triquetro-pisiform fusion, small capitate, trapezium and trapezoid, enlarged triquetrum and hamate, and slight flexion and radial deviation. The fingers had short, club-shaped distal phalanges and small, grooved nails. One affected member had bilateral fifth finger camptodactyly (streblomicrodactyly). There were no other bony fusions, tarsal coalition or clubfeet, thus differentiating this disorder from others characterized by carpal synostosis with more extensive bony fusions (see 186400 and 186500). The disorder is also distinct from Banki syndrome (109300) which is characterized by lunatotriquetral fusion, brachymetacarpy, and leptometacarpy with normal elbows. Liebenberg (1973) examined 5 of the 6 living affected members of this kindred. Beighton (1985) reexamined the family with identification of additional affected persons and corroboration of the distinctive phenotype.

Tiberio et al. (2000) described a mother and 2 sons with clinical and radiologic features closely resembling those described by Liebenberg (1973). The bony components of the elbow joints were enlarged and poorly modeled. All 3 patients had a large triquetrum and camptodactyly of the fifth fingers. None of the patients in this family, however, had the triquetopisiform fusion described by Liebenberg (1973), although the children described were too young to have developed the ossification center of the pisiform. Triquetopisiform fusion was not seen in the mother; the fusion was between the scaphoid and lunate. All 3 affected individuals had 10% flexion at the elbows in the anatomic position, with radial deviation of wrist joints. Pronosupination was limited. In addition to camptodactyly, there was brachydactyly of all fingers. The 2 affected children and their mother were of normal intelligence, with normal growth parameters and good general health. Tiberio et al. (2000) suggested that Liebenberg syndrome might be due to mutations in the NOG gene (602991).

By in-depth imaging of skeletal and soft tissue abnormalities of affected members from 3 unrelated families with Liebenberg syndrome, Spielmann et al. (2012) demonstrated that the disorder involves a homeotic limb transformation in which the arms acquire morphologic characteristics of the legs. In affected individuals, the olecranon was hypoplastic or missing, and the distal humerus and the proximal head of the ulna were broadened such that they resembled the distal head of the femur and the proximal head of the tibia, respectively. Three-dimensional CT scans of the humerus showed a medial and lateral condyle separated by an intercondylar fossa resembling the femoral epicondyles of the knee and a patella-like structure fused to the distal head of the humerus. The joint surface of the radius and ulna was flat and resembled that of the tibia and fibula. In addition, the bones of the hand and wrist were highly abnormal, with long metacarpals resembling the metatarsals of the feet, and fusion of the triquetrum and pisiform led to a structure similar in shape to the calcaneus of the ankle. In addition, the scaphoid and lunate bones were fused and formed an element that was similar to the shape of the talus in the ankle, and the extensor minimi digiti and extensor carpi radialis muscles and tendons were absent from the hands.

Inheritance

Male-to-male transmission in the family with upper limb deformities reported by Liebenberg (1973) suggested autosomal dominant inheritance.

Mapping

In a large 7-generation family segregating autosomal dominant Liebenberg syndrome, Spielmann et al. (2012) performed genomewide SNP genotyping and identified a 9.8-Mb candidate region on chromosome 5q23-q31 between markers rs1366100 and rs2107331.

Cytogenetics

In twin sisters with Liebenberg syndrome, in whom there was no evidence of copy-number variation by array CGH analysis, Spielmann et al. (2012) performed paired-end whole-genome sequencing, which revealed a translocation between chromosomes 5 and 18; the predicted t(5;18)(q31.1;q12.3) translocation was confirmed by Sanger sequencing and fluorescence in situ hybridization. The translocation was associated with a 303-bp deletion on chromosome 5 (chr5:134,587,335-134,587,637, GRCh37) and a 350-bp deletion on chromosome 18 (chr18:43,049,294-43,049,643, GRCh37).

Molecular Genetics

In a large 7-generation family with Liebenberg syndrome mapping to chromosome 5q23-q31, Spielmann et al. (2012) performed exome enrichment of the critical region followed by high-throughput sequencing but did not identify a disease-causing mutation. Custom high-resolution array CGH analysis, however, revealed a heterozygous 134-kb deletion (chr5:134,624,602-134,759,492, GRCh37) encompassing the H2AFY gene (610054) and located 269 kb 5-prime of the PITX1 gene (602149). Array CGH analysis in another affected family showed an overlapping heterozygous 107-kb deletion (chr5:134,638,524-134,746,407, GRCh37), also encompassing the H2AFY gene. Because homozygous inactivation of H2AFY in mice leads to hepatic accumulation of lipids but does not result in a bone or limb phenotype, Spielmann et al. (2012) concluded that its deletion was unlikely to be causative. However, the deletions in both families relocated a highly conserved noncoding enhancer element, hs1473, into the gene desert 5-prime of PITX1, potentially affecting PITX1 expression. In a third family in which affected twin sisters had a t(5;18)(q31.1;q12.3) translocation, 2 highly conserved noncoding elements on chromosome 18, hs1464 and hs1440, were translocated upstream of PITX1 on the derivative chromosome 5. The authors demonstrated that all 3 enhancer elements had forelimb-specific activity in mouse embryos, and transgenic hs1473-Pitx1 mice showed features characteristic of Pitx1 misexpression at embryonic day 15.5, with forelimb-to-hindlimb transformation (see ANIMAL MODEL). Spielmann et al. (2012) hypothesized that the arm-to-leg transformation observed in affected members of the 3 families segregating Liebenberg syndrome was due to misexpression of PITX1 in the upper extremities.

In an Italian woman and her 2 sons with mild Liebenberg syndrome, originally reported by Tiberio et al. (2000), Kragesteen et al. (2019) performed whole-genome sequencing and identified an 8.5-kb deletion (chr5:134,729,406-134,737,909; GRCh37) spanning the noncoding first exon of the H2AFY gene that segregated with disease in the family. Using CRISPR-Cas9 engineering in mice, the authors demonstrated that the promoter of the H2afy gene insulates the Pitx1 enhancer Pen from Pitx1 in forelimbs, whereas loss of the H2afy promoter results in misexpression of Pitx1 by pan-limb activity of the Pen enhancer. The level of Pitx1 mRNA determines the severity of the phenotype in mice, and the authors suggested that this may occur in the human Liebenberg phenotype, whereby the closer Pen is placed in a linear relation to PITX1, the more complete the transformation of arms into legs.

Animal Model

Spielmann et al. (2012) generated single-copy hs1473-Pitx1 transgenic mice and observed that at embryonic day 15.5, the mutant mice showed characteristic features of Pitx1 misexpression resulting in a forelimb-to-hindlimb transformation. The mice showed loss of the olecranon, thus recapitulating the Liebenberg phenotype. Only 1 zeugopod bone was present. The distal head of the humerus was more similar to the distal femur, and the shape of the proximal head of the single zeugopodal element resembled the shape of the proximal tibia. Two digits were missing, and the remaining digit I had 2 phalanges and was fused to the metacarpal of digit II. Fusions of the carpals formed a structure similar in shape to the calcaneus of the hindlimb. The fusion of the carpals and radial deviation of the hands caused a foot-like appearance of the forelimb.