Role of Genetic Factors in the Pathogenesis of Radial Deficiencies in Humans

Abstract

Radial deficiencies (RDs), defined as under/abnormal development or absence of any of the structures of the forearm, radial carpal bones and thumb, occur with a live birth incidence ranging from 1 out of 30,000 to 1 out 6,000 newborns and represent about one third/one fourth of all the congenital upper limb anomalies. About half of radial disorders have a mendelian cause and pattern of inheritance, whereas the remaining half appears sporadic with no known gene involved. In sporadic forms certain anomalies, such as thumb or radial hypoplasia, may occur either alone or in association with systemic conditions, like vertebral abnormalities or renal defects. All the cases with a mendelian inheritance are syndromic forms, which include cardiac defects (in Holt-Oram syndrome), bone marrow failure (in Fanconi anemia), platelet deficiency (in thrombocytopenia-absent-radius syndrome), ocular motility impairment (in Okihiro syndrome). The genetics of radial deficiencies is complex, characterized by genetic heterogeneity and high inter- and intra-familial clinical variability: this review will analyze the etiopathogenesis and the genotype/phenotype correlations of the main radial deficiency disorders in humans.

The presentation and management of platelet disorders in pregnancy

“…Congenital heart disease, anomalies of genitourinary (GU) system and other abnormalities of the skeleton may also be present. 24 TAR syndrome is caused by a 200-kb microdeletion on chromosome 1q21.1, which causes a deficiency in the RNA binding motif protein 8A (RBM8A) gene. 25 The diagnosis of TAR syndrome is mainly a clinical one, but genotyping may be performed to confirm the diagnosis.…”

“…Thrombocytopenia‐absent radius (TAR) syndrome is a congenital disorder that is characterised by severe thrombocytopenia and bilateral absence of the radii, although the thumbs are always present. Congenital heart disease, anomalies of genitourinary (GU) system and other abnormalities of the skeleton may also be present …”

“…Thrombocytopenia-absent radius syndrome Very uncommon Bilateral absence of radii and thrombocytopenia. 24 Clinical findings confirm diagnosis, genotyping can be performed. 26 Platelet transfusion when platelet count <10 000 per microlitre or symptomatic.…”

Impact of genetic variants on haematopoiesis in patients with thrombocytopenia absent radii (TAR) syndrome

“…However, some patients remain incorrectly diagnosed into adulthood, calling for differential diagnoses to be considered in order to reduce these cases. Even though TAR syndrome is a rare disorder, it can be misinterpreted as Fanconi Anaemia (FA) (Alter, ; Elmakky et al , ). Although complete absence of radius bones is very rare in FA, it might occur together with low platelet counts, directing toward a wrong diagnosis.…”

“…Nonetheless, FA should be excluded by standard tests (cell cycle analysis and molecular testing of the FANC gene family, or chromosomal breakage analysis). Other disorders with similar skeletal malformations (including Robert syndrome or Holt‐Oram sydrome) are not primarily associated with haematological alterations (Elmakky et al , ).…”