Bruck Syndrome 2

A number sign (#) is used with this entry because Bruck syndrome-2 (BRKS2) is caused by homozygous mutation in the PLOD2 gene (601865), which encodes telopeptide lysyl hydroxylase, on chromosome 3q24.

For a phenotypic description and a discussion of genetic heterogeneity of Bruck syndrome, see Bruck syndrome-1 (259450).

Clinical Features

Ha-Vinh et al. (2004) described a child with Bruck syndrome who was the offspring of healthy nonconsanguineous Turkish parents. At birth, pterygia were present at the left elbow and at both knees, and extension of these joints was limited. Contractures were also present at the wrists, and there were bilateral clubfeet. Bilateral inguinal hernias were present. A fracture of the left arm was recognized immediately after birth, and the boy had 2 more fractures in the first 3 months of life. His urine contained high levels of hydroxyproline but low levels of collagen crosslinks degradation products.

Van der Slot et al. (2003) stated that they were unaware of any phenotypic differences between Bruck syndromes 1 and 2.

Biochemical Features

Bank et al. (1999) reported that the molecular defect underlying Bruck syndrome is a deficiency of bone-specific telopeptide lysyl hydroxylase, which results in aberrant crosslinking of bone collagen. Bank et al. (1999) found that lysine residues within the telopeptides of type I collagen (see 120150) in bone are underhydroxylated, leading to aberrant crosslinking, but that the lysine residues in the triple helix are normally modified. In contrast to bone, cartilage and ligament showed unaltered telopeptide hydroxylation in Bruck syndrome, as evidenced by normal patterns of crosslinking. The results provided evidence that collagen crosslinking is regulated primarily by tissue-specific enzymes that hydroxylate only telopeptide lysine residues and not those destined for the helical portion of the molecule. Bank et al. (1999) proposed that the form of lysyl hydroxylase that specifically hydroxylates lysyl residues in the alpha-helix should be termed helical lysyl hydroxylase. Because they mapped Bruck syndrome in 1 family to chromosome 17p12, they proposed this site for the gene encoding telopeptide-specific lysyl hydroxylase; however, the gene was later found to be PLOD2 on chromosome 3 in patients with Bruck syndrome-2 (van der Slot et al., 2003).

Molecular Genetics

In 2 families with Bruck syndrome in which linkage to chromosome 17p12 was excluded, van der Slot et al. (2003) identified homozygous missense mutations in exon 17 of the PLOD2 gene (601865.0001-601865.0002). Parents of both families were heterozygous for the respective mutations. Mutation analysis of a family showing linkage to chromosome 17p12 did not reveal any mutations in the exons, intron/exon boundaries, or promoter region of the PLOD2 gene.

In a child with Bruck syndrome, the offspring of healthy nonconsanguineous Turkish parents, Ha-Vinh et al. (2004) identified homozygosity for a novel mutation in exon 17 of the PLOD2 gene, resulting in an arg598-to-his substitution (601865.0003). The mutation was close to the mutations identified by van der Slot et al. (2003), suggesting a functionally important hotspot.

Puig-Hervas et al. (2012) screened for mutations in 6 consanguineous unrelated Egyptian families with Bruck syndrome and identified homozygous changes in the PLOD2 gene in 4 families and in the FKBP10 gene (610968) in 2 (see 607083). Two of the probands had an LH2(long) isoform-specific homozygous mutation consisting of a single-nucleotide duplication in the alternative exon 13a of the PLOD2 gene (1559dupC; 601865.0004), indicating that specific inactivation of the longer protein isoform is sufficient to cause Bruck syndrome 2.