We present a patient with acromesomelic chondrodysplasia and genital anomalies caused by a novel homozygous mutation in BMPR1B, the gene coding for bone morphogenetic protein receptor 1B. The 16 year old girl, the offspring of a multiconsanguinous family, showed a severe form of limb malformation consisting of aplasia of the fibula, severe brachydactyly, ulnar deviation of the hands, and fusion of carpal/tarsal bones. In addition, she presented with hypoplasia of the uterus and ovarian dysfunction resulting in hypergonadotrophic hypogonadism. Mutation analysis of BMPR1B revealed a homozygous 8 bp deletion (del359-366). This mutation is expected to result in a loss of function and is thus different from the heterozygous missense mutations in BMPR1B recently shown to cause brachydactyly type A2 through a dominant negative effect. The patient's skeletal phenotype shows an overlap with the clinical spectrum of the acromesomelic chondrodysplasias of the Grebe, HunterThompson, and DuPan types caused by homozygous mutations in the gene coding for growth differentiation factor 5 (GDF5) which is a high-affinity ligand to BMPR1B. However, the phenotype described here differs from GDF5 associated chondrodysplasias because of the additional presence of genital anomalies and the distinct limb phenotype. O steochondrodysplasias are a clinically and genetically heterogeneous group of disorders.1 Acromesomelic chondrodysplasias are a rare subgroup of these hereditary skeletal disorders characterised by short stature, very short limbs, and hand/foot malformations. The severity of limb abnormalities increases from proximal to distal with profoundly affected hands and feet showing brachydactyly and/or rudimentary fingers (knob-like fingers). The most severe type of the acromesomelic chondrodysplasias is known as Grebe syndrome, followed by the milder phenotypes of Hunter-Thompson and DuPan syndromes. These three related disorders share an autosomal recessive inheritance pattern and are caused by homozygous mutations in growth differentiation factor 5 (GDF5). Heterozygous carriers of GDF5 mutations are usually affected by brachydactyly type C (BDC), 2-4 a condition characterised by brachymesophalangy of index, middle, and little fingers and shortening of the first metacarpal. Ring fingers are only mildly affected and hyperphalangy of the index and middle fingers occurs. However, as shown recently, BDC can also be caused by a homozygous mutation in GDF5. 5GDF5 belongs to the bone morphogenetic proteins (BMPs) of the transforming growth factor-b (TGF-b) superfamily. GDF5 plays an essential role in chondrocyte condensation and differentiation as well as in joint formation as demonstrated by the brachypodism (bp) mouse which carries a loss of function mutation in Gdf5.6-8 The limb phenotype of the bp mutant consists of aplasia/hypoplasia of the middle and proximal phalanges and the metacarpals/metatarsals. The murine phenotype thus resembles the human homozygous GDF5 mutations. GDF5 signalling requires binding to the serine/threonine k...

The objective of this study was to evaluate the relationship between humoral and cell-mediated immune response parameters and impairment of immune functions in children with Down syndrome (DS). The patient group was consisted of cytogenetically documented 32 children with DS. Lymphocyte subsets and natural killer cells were counted by flow-cytometry system. Levels of interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10 and tumour necrosis factor-alpha (TNF-alpha) were detected by enzyme-linked immunosorbent assay method. Serum IgG, IgM, IgA levels were measured by turbidimetric methods. The percentage of CD8+ lymphocytes and CD56+ cells of patients with DS were significantly higher, whereas CD20+ lymphocytes were lower than that of controls (P < 0.05). The percentage of CD2 and CD4 levels and CD4/CD8 ratio of patients with DS and normal controls were similar (P > 0.05). Levels of IL-4 and IL-10 were significantly increased, but IL-6 and TNF-alpha levels were decreased in children with DS (P < 0.05). Levels of other studied cytokines between patients with DS and controls were not statistically different (P > 0.05, for all). Serum IgG, IgM and IgA levels were found to be similar between the groups (P > 0.05). It has been known that IL-4 and IL-10 are anti-inflammatory molecules which inhibit the synthesis of proinflammatory cytokines such as IL-6 and TNF-alpha. In this study, levels of IL-4 and IL-10 were significantly increased, but IL-6 and TNF-alpha levels were decreased in children with DS. These results may suggest that continuing anti-inflammatory state in DS and this process may explain the cause of recurrent infection of the disease. On the other hand, in contrast to the low percentage of CD20+ cells, high percentage of CD8+ and CD56+ cells were found. Our findings may demonstrate that the cell-mediated and humoral immune system parameters in children with DS were altered according to healthy children.

The cerebellum is the primary motor coordination centre of the central nervous system. Lesions or congenital defects of the cerebellum cause incoordination of the muscles resulting in irregular gait and falling. Recently, we reported a large family with cerebellum hypoplasia and quadrupedal locomotion as a recessive trait, which we mapped to chromosome 17p13. We identified one additional family with the same condition and mapped the underlying gene to a 14-cM interval on chromosome 9ptel using a genome-wide linkage approach. Sequencing of candidate genes identified a homozygous frameshift mutation in the very low-density lipoprotein receptor (VLDLR) gene in all affected individuals. The association of cerebellar hypoplasia with mutations in VLDLR has been reported previously in the Hutterite population and in a family from Iran. However, quadrupedal locomotion was never observed indicating that environmental factors play a major role in the pathogenesis of this form of locomotion.

In this retrospective study, karyotype results of 1510 couples with a history of recurrent spontaneous abortion were evaluated. The study was conducted at Balcalı Hospital in Adana region of Turkey. For all cases, peripheral blood lymphocytes were cultured for chromosome study using the standard method. Chromosome aberrations were detected in 62 couples (4.1% of all couples). At an individual level, chromosome aberrations were found in a total of 65 cases (41 females and 24 male cases), with structural chromosomal aberrations in 58 cases including balanced translocations in 30 cases, Robertsonian translocations in 12 cases, deletions in seven cases, inversions in nine cases and numerical chromosome aberrations in seven cases. The results of the study indicated that structural aberrations, particularly translocations, were the most common type of aberration observed among couples who had experienced recurrent spontaneous abortions and that these couples might benefit from cytogenetic analyses.

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