Thumb deficiency was classified according to a modification of the scheme described by Blauth and Schneider-Sickert10,11. Classification with this system requires detailed clinical examination and adequate radiographs (Table I and Figs. 1-A, 1-B, 1-C, 1-D, 1-E, 1-F, 1-G). Important structures for classification include the size of the first web space, the presence and function of the intrinsic and extrinsic muscles of the thumb, the presence and function of the collateral ligaments of the metacarpophalangeal joint, and the presence and size of the bones of the first ray. Types 1, 2, and 3A thumbs can be reconstructed surgically (although type 1 does not usually require reconstruction). Types 3B, 4, and 5 are treated with ablation of the thumb, if present, and pollicization of the index finger. For six patients, sufficient information was available to determine that they had either a type-2 or type-3A thumb, but there was not enough information to determine between these two types. Thus, for the purposes of statistical analysis, types 2 and 3A were combined (Table V).
Radial longitudinal deficiency was classified according to our modification of the Bayne and Klug criteria6,12. This system is based on radiographic evaluation of both the radius and the carpus (Table II and Figs. 2-A, 2-B, 2-C, 2-D). Several carpal anomalies are seen in association with radial and thumb deficiency, including hypoplasia and absence of the scaphoid, trapezium, and lunate as well as carpal coalitions. Normal radiographic ossification of the scaphoid begins by the age of eight years13,14, and therefore only children eight years of age and older at the time of the most recent radiographic examination were classified as having an absent scaphoid (type 0). Children who were seven years of age or younger were classified as having a type-N or 0 deficiency. Since the classification of type-N radii in children who are less than eight years old may change as the children grow older, types N and 0 were combined into one category for the statistical analysis (Table V).
The correlation between thumb deficiency and radial deficiency was analyzed with use of Spearman rho and Kendall tau with significance determined by p < 0.01.
Radial deficiency was highly correlated with thumb deficiency; all extremities with radial or carpal deficiency had thumb deficiency (Table V). Ninety-five (50%) of the 191 extremities had thumb deficiency with no radial deficiency (type N) or thumb and carpal deficiency with no radial deficiency (type 0). Forty-eight (94%) of the fifty-one limbs with complete absence of the radius (type-4 radial deficiency) had a non-reconstructible thumb (type-4 or 5 thumb deficiency), whereas sixty-three (66%) of the ninety-five limbs with a normal radius had a reconstructible thumb (type-1, 2, or 3A thumb deficiency).
In addition, seventy-one (91%) of the seventy-eight extremities with a reconstructible thumb (type 1, 2, or 3A) had a radius that was either of normal length or did not require surgical reconstruction (type N, 0, or 1). Of the 113 extremities with a non-reconstructible thumb (type 3B, 4, or 5), fifty-eight (51%) had a type-2, 3, or 4 radius.
Spearman rho and Kendall tau calculations both showed a highly significant and positive association between the severity of radial deficiency and the severity of thumb deficiency as classified with the modified Blauth and Schneider-Sickert and Bayne and Klug systems, with a p value of <0.0001 for both. The Spearman correlation was 0.6007, and the Kendall correlation was 0.5260.
The underlying cause of thumb and radial deficiencies and their true relationship with each other remain unknown. In this clinical series of patients with thumb and radial deficiencies, proximal deficiency (i.e., of the radius) was always associated with distal deficiency, but distal deficiency often occurred in isolation. Several authors have reported the association of thumb deficiency with radial deficiency1-6,15-17. Previous descriptions have focused on the association between thumb deficiency and carpal anomalies18-20 as well as the association between radial deficiency and carpal anomalies5,16. Published case reports of carpal deficiency have usually described either thumb and/or radial deficiency coexisting with carpal abnormality16,19,21-26; isolated carpal absence is extremely rare26-29 and did not occur in our series. Patients with TAR syndrome were excluded from our series because the thumb deficiency could not be classified with use of the modified Blauth and Schneider-Sickert classification. These patients all have type-4 radial deficiency and do not appear to have distal progression of severity.
Although the etiology of radial deficiency is unknown, it is certainly multifactorial. Specific genes are known to be associated with limb development30, and some cases of radial deficiency are clearly genetic. Associations with multiple congenital anomaly syndromes suggest that radial deficiency may occur with the deletion of chromosome 22q1131. Holt-Oram syndrome appears to be heterogeneous, with linkage to gene map locus 12q24.1 in some cohorts and TBX5 gene mutations in others32-34. Fanconi anemia has been mapped to gene locus 16q24.335, and diagnosis with chromosomal breakage analysis has made it possible to treat this previously fatal aplastic anemia with bone marrow transplantation36-38. TAR syndrome has not yet been mapped39.
Thus, thumb deficiency is associated with many syndromes mapped to numerous loci throughout the genome. Other heritable thumb malformations, such as triphalangeal thumb and thumb polydactyly, have been mapped to chromosome 7q3640.
Fetal exposure to toxins such as thalidomide can cause radial deficiency. It is possible that some cases of radial deficiency are caused by unknown environmental toxins that interrupt longitudinal development of the upper limb when the fetus is exposed to them at a critical phase of development. Unique features of individual digits are known to develop in utero in response to the zone of polarizing activity, a specialized area of the posterior apical epidermal ridge41. In the vertebrate limb bud, signals from the zone of polarizing activity are known to control the pattern of cellular differentiation in a radioulnar direction41-43. The zone of polarizing activity, through mechanisms currently under investigation, has some regulatory power over the apical epidermal ridge41. Digit formation is also under the control of the zone of polarizing activity, which seems to be responsible for ordering digit type and number44 and is therefore potentially responsible for forming the unique features of the thumb. As early as 1977, Lamb suggested a localized absence of the apical epidermal ridge as a cause for radial deficiencies4. More recently, sonic hedgehog protein (Shh) has been shown to mediate the activity of the zone of polarizing activity45, and, in mice, disruption of the Shh pathway has been associated with a spectrum of developmental anomalies very similar to VACTERL46.
The interaction of the apical epidermal ridge with the underlying undifferentiated mesoderm is responsible for limb outgrowth in a proximal-to-distal direction, with proximal structures being formed first44. The known precedence of proximal development supports our clinical finding that radial deficiency is always associated with thumb deficiency, but thumb deficiency can occur in isolation. However, proximal-to-distal development is extremely complex and not yet completely understood; it would be an oversimplification to conclude that the development of distal structures depends solely on the antecedent development of proximal structures. TAR syndrome, in which a type-4 radius is consistently associated with a relatively well-developed thumb, refutes this conclusion.
The impetus for this study was an observation in previous investigations that the majority of patients with radial deficiency had thumb deficiency12. The specific aim was to determine if radial deficiency correlated with thumb hypoplasia and to thereby determine if the degree of radial deficiency was associated with the reconstructibility of the thumb. We found that radial deficiency always occurred in the presence of thumb deficiency and, when classified according to well-established systems that can be used to predict prognosis and guide treatment, the severity of thumb deficiency was proportional to the severity of radial deficiency (p < 0.0001). Furthermore, extremities with type-4 radial deficiency nearly always had a non-reconstructible thumb.
This study adds to a growing body of evidence that thumb hypoplasia and radial longitudinal deficiency are part of a spectrum of abnormal upper-extremity development rather than independent processes. The severity of these malformations progresses distally and thus the presence of a severe radial deficiency signals the presence of a severely deficient or absent thumb.
NOTE: The authors acknowledge Kent Yinger, MD, for his assistance with the chart and radiographic review.
The authors did not receive grants or outside funding in support of their research or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.
Investigation performed at Shriners Hospitals for Children, Northern California, Sacramento, California
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