http://www.stockton-press.co.uk/ejhg deletions was detected, which removed between 1 and 30 exons from the gene. Most microdeletions and insertions occurred at homopolymeric tracts or direct repeats within the coding sequence. These features have not been observed in the other FA gene which has been cloned to date (FAC) and may be indicative of a higher mutation rate in FAA. This would explain why FA group A is much more common than the other complementation groups. The heterogeneity of the mutation spectrum and the frequency of intragenic deletions present a considerable challenge for the molecular diagnosis of FA. A scan of the entire coding sequence of the FAA gene may be required to detect the causative mutations, and scanning protocols will have to include methods which will detect the deletions in compound heterozygotes.

No abstract

Gain-of-function mutations in LRP5 have been shown to cause high BMD disorders showing variable expression of some clinical symptoms, including torus palatinus and neurological complications. In an extended family, we were able to add craniosynostosis and developmental delay to the clinical spectrum associated with LRP5 mutations.We report on an extended four-generation family with 13 affected individuals (7 men and 6 women) in which an autosomal dominant type of osteosclerosis segregates. Osteosclerosis was most pronounced in the cranial base and calvarium, starting in early childhood with variable expression and a progressive character. Craniosynostosis at an early age was reported in four affected family members (two males and two females). The patients also presented with dysmorphic features (macrocephaly, brachycephaly, wide and high forehead, hypertelorism, prominent cheekbones, prominent jaw). They have normal height and proportions. Neurological complications like entrapment of cranial nerves resulting in optical nerve atrophy, hearing loss, and facial palsy were reported in two individuals. A mild developmental delay was reported in three affected individuals. None of the patients have torus palatinus, increased rate of fractures, osteomyelitis, hepatosplenomegaly, or pancytopenia. A missense mutation 640G→A (A214T) in the low-density lipoprotein receptorrelated protein 5 (LRP5) gene was found in all affected individuals analyzed, including cases in whom craniosynostosis, a mild developmental delay, and/or macrocephaly is observed. To our knowledge, this is the first report in the literature of patients presenting with autosomal dominant osteosclerosis in whom a variable expression of craniosynostosis, macrocephaly, and mild developmental delay is observed, which is most likely associated with a mutation in the LRP5 gene. These phenotypes can therefore be added to the clinical spectrum of LRP5-associated bone disorders.

No abstract

Mesomelic dysplasia Kantaputra type (MDK) is characterized by marked mesomelic shortening of the upper and lower limbs originally described in a Thai family. To identify the cause of MDK, we performed array CGH and identified two microduplications on chromosome 2 (2q31.1-q31.2) encompassing B481 and 507 kb, separated by a segment of normal copy number. The more centromeric duplication encompasses the entire HOXD cluster, as well as the neighboring genes EVX2 and MTX2. The breakpoints of the duplication localize to the same region as the previously identified inversion of the mouse mutant ulnaless (Ul), which has a similar phenotype as MDK. We propose that MDK is caused by duplications that modify the topography of the locus and as such result in deregulation of HOXD gene expression. The ulnae are very short, and the radii are bowed. The distal humerus has a dumbbell shape, the hands are relatively normal but show progressive flexion contractures of the proximal interphalangeal joints. Carpal and tarsal synostoses are observed in some individuals. In the lower limbs, feet are fixed in plantar flexion with sole facing backward, causing 'ballerina-like standing' . The prominent distal fibula on the ventral aspect is a consistent feature and considered as the 'signature' finding of the syndrome. Calcaneus is small or missing. Small fibula and talus, and fibulo-calcaneal synostosis are characteristic features. Tibial bony knot articulates with the proximal end of the fibula. Since the original description, several other cases have been described that show similar changes. 3,4 In an Italian family with a mesomelic dysplasia, a balanced translocation t(2;8)(q31;p21) had previously been observed. 5,6 On the basis of the phenotypic similarities with MDK, chromosomes 2 and 8 were tested as candidate regions and a region on chromosome 2 (2q24-q32) spanning about 22.7 cM was identified to harbor the MDK gene. 7 Interestingly, this interval contains the HOXD cluster. However, sequencing of individual genes of the HOXD cluster revealed no mutation associated with MDK. We here describe genomic rearrangements including the entire HOXD cluster identified in the Thai family originally described by Kantaputra et al 1,2 as the likely cause for MDK.