Alternative titles; symbols
SNOMEDCT: 389214003; ORPHA: 1802; DO: 0112251;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q34 | Ghosal hematodiaphyseal syndrome | 231095 | Autosomal recessive | 3 | TBXAS1 | 274180 |
A number sign (#) is used with this entry because of evidence that Ghosal hematodiaphyseal dysplasia (GHDD) can be caused by homozygous mutation in the TBXAS1 gene (274180), which encodes thromboxane synthase (TXAS), on chromosome 7q34.
Ghosal hematodiaphyseal dysplasia (GHDD) is an autosomal recessive disorder characterized by increased bone density with predominant diaphyseal involvement and aregenerative corticosteroid-sensitive anemia (summary by Genevieve et al., 2008).
Ghosal et al. (1988) presented 5 patients with a particular form of diaphyseal dysplasia and refractory anemia. In spite of certain similarities to Camurati-Engelmann disease (131300), major differences were noted. Most notably, in Camurati-Engelmann disease, only the diaphyses are involved, whereas in the disorder described by Ghosal et al. (1988), both diaphyses and metaphyses were affected.
Gumruk et al. (1993) described an affected brother and sister, aged 8 and 4 years, respectively, with diaphyseal dysplasia, severe anemia, leukopenia, and thrombocytopenia. The children were the products of a first-cousin marriage. Radiologically, both had wide medullary cavities in the long bones with discrete cortical hyperostosis. Bone marrow was hypocellular. The smooth surface of the long bones showed that there was no periosteal and only endosteal hyperostosis. The presence of anemia and other hematologic abnormalities, and the absence of gait disturbances, muscular involvement, and pain in the limbs also separated the disorder from Camurati-Engelmann disease. Parental consanguinity was present also in the case reported by Ozsoylu (1989). The apparent mode of inheritance as a recessive also distinguishes Ghosal disease from Camurati-Engelmann disease which is a dominant. Elevated levels of IgG and IgA were observed in the cases of Gumruk et al. (1993) and Ozsoylu (1989).
The transmission pattern of GHDD in the families studied by Genevieve et al. (2008) was consistent with autosomal recessive inheritance.
Isidor et al. (2007) performed a genomewide screen in 2 consanguineous families with Ghosal hematodiaphyseal dysplasia from Algeria and Tunisia, respectively, and found that the 5 affected individuals were homozygous at D7S684 and contiguous markers. Two-point linkage analysis between D7S2513 and the disease locus yielded a maximum lod score of 4.21 (theta = 0.0). Haplotype heterozygosity in the Tunisian family narrowed the locus to a 3.84-Mb interval between D7S2560 and AC091742 on chromosome 7q33-q34, a region that encompasses 37 genes.
In the Algerian and Tunisian families with GHDD studied by Isidor et al. (2007) and in 2 more families of Tunisian and Pakistani origin, Genevieve et al. (2008) identified mutations in the TBXAS1 gene (274180), which encodes thromboxane synthase (TXAS). TXAS, an enzyme of the arachidonic acid cascade, produces thromboxane A2 (TXA2). Platelets from subjects with GHDD showed a specific deficit in arachidonic acid-produced aggregation. They also found that TXAS and TXA2 modulated expression of TNFSF11 (602642) and TNFRSF11B (602643), which encode RANKL and osteoprotegerin (OPG), respectively, in primary cultured osteoblasts.
Genevieve, D., Proulle, V., Isidor, B., Bellais, S., Serre, V., Djouadi, F., Picard, C., Vignon-Savoye, C., Bader-Meunier, B., Blanche, S., de Vernejoul, M.-C., Legeai-Mallet, L., Fischer, A.-M., Le Merrer, M., Dreyfus, M., Gaussem, P., Munnich, A., Cormier-Daire, V. Thromboxane synthase mutations in an increased bone density disorder (Ghosal syndrome). Nature Genet. 40: 284-286, 2008. [PubMed: 18264100] [Full Text: https://doi.org/10.1038/ng.2007.66]
Ghosal, S. P., Mukherjee, A. K., Mukherjee, D., Ghosh, A. K. Diaphyseal dysplasia associated with anemia. J. Pediat. 113: 49-57, 1988. Note: Erratum: J. Pediat. 113: 410 only, 1988. [PubMed: 3385529] [Full Text: https://doi.org/10.1016/s0022-3476(88)80527-4]
Gumruk, F., Besim, A., Altay, C. Ghosal haemato-diaphyseal dysplasia: a new disorder. Europ. J. Pediat. 152: 218-221, 1993. [PubMed: 8444247] [Full Text: https://doi.org/10.1007/BF01956148]
Isidor, B., Dagoneau, N., Huber, C., Genevieve, D., Bader-Meunier, B., Blanche, S., Picard, C., De Vernejoul, M. C., Munnich, A., Le Merrer, M., Cormier-Daire, V. A gene responsible for Ghosal hemato-diaphyseal dysplasia maps to chromosome 7q33-34. Hum. Genet. 121: 269-273, 2007. [PubMed: 17203301] [Full Text: https://doi.org/10.1007/s00439-006-0311-1]
Ozsoylu, S. High-dose intravenous methylprednisolone therapy for anemia associated with diaphyseal dysplasia. (Letter) J. Pediat. 114: 904 only, 1989. [PubMed: 2715908] [Full Text: https://doi.org/10.1016/s0022-3476(89)80170-2]