Genetic Basis of Congenital Upper Limb Anomalies: Analysis of 487 Cases of a Specialized Clinic

Abstract

The two etiologies differ in terms of patient's clinical features, morphology defect and axis involvement. This data may be helpful to the clinician during the patient's diagnostic workup by indicating the necessity for genetic testing and for determining the anomaly's recurrence risk.

Congenital limb deficiencies and major associated anomalies in Alberta for the years 1980–2012

“…There are large numbers of known single gene mutations listed either by name or number in MIM. Some detailed genetic studies of limb defects have been done by others; for example, Carli et al () in a retrospective review of 487 cases of congenital anomalies involving the upper limb, found a genetic etiology in 41% ( n = 199) and non‐genetic in the remainder ( n = 288); 13 with confirmed chromosome abnormalities and 186 ascribed to a single gene causation, but only 23 confirmed by testing. Their non‐Mendelian list included 26 cases of VACTERL and 15 with unilateral isolated thumb and all the radial aplasias were in the Mendelian group.…”

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

“…However, the exact incidence of non-syndromic thumb hypoplasia is difficult to determine, since the isolated malformation does not differ from syndromic cases that in older studies might have gone undetected. In a recent report from a multidisciplinary group on upper limb anomalies, isolated thumb hypoplasia was found in 24/487 cases (4,9%); moreover, in 9 of those the anomaly was bilateral (1,8% of the total and 37.5% of the thumb anomalies) [ 6 ]. In other studies, the bilateral involvement is reported in about 60% of the affected patients, but when unilateral, the right hand is more commonly affected [ 50 , 51 ].…”

“…Radial deficiencies (RDs) are defined as any degree of congenital hypo/aplasia of thumb, thenar muscles, first metacarpal bone, radial carpal bones (scaphoid and trapezium) and/or radius, occurring with a live birth incidence ranging from 1 out of 30,000 to 1 out 6,000 newborns [ 1 - 3 ] and representing about one third/one fourth of the total incidence of the congenital upper limb anomalies [ 4 - 6 ]. The RDs explain the vast majority of the malformations of the radial side of the arm, whereas the frequency of other defects, i.e.…”

“…The RDs explain the vast majority of the malformations of the radial side of the arm, whereas the frequency of other defects, i.e. thumb duplication or triphalangism, represent only about one tenth of the total [ 6 ]. In spite of the high clinical variability, ranging from a minimal hypoplasia of the thenar muscles to a severe shortening of the forearm with a complete radial absence, RDs can be all included into the embryological class of formation defects, for which the primary event is a localized developmental failure due to genetic or non genetic factors [ 5 ].…”

“…For all those factors, it is clear that establishing an etiological diagnosis is highlybeneficial to the parents not only for the assignment of the disease prognosis, which includes also the associated malformations, the resulting disability and the lifelong risks, but also for the obvious reflection on the attributable recurrence risks. Genetic testing gives now an important contribution to the diagnosis of the mendelian forms, which however represent only about half of the total cases of RDs [ 6 ], whereas for the other half, mostly sporadic, the diagnosis remains only clinical due to the absence of a known causative gene involved. Moreover, the common clinical criteria which are usually employed for the differential diagnosis between the mendelian and the apparently sporadic forms, like the bilaterality or the presence of associated features in other organs, do not strictly apply in RDs: for example, one of the most paradigmatic case, the association of Vertebral defects, Anal atresia, Tracheo-Esophageal fistula with esophageal atresia, Cardiac defects, Renal and Limb anomalies (VACTERL), affects by definition multiple organs, has a limb involvement which is bilateral in about one fourth of the cases [ 9 ], but it is mostly sporadic with no responsible gene or genomic region involved [ 10 ].…”