- Email: [email protected]
Teratogenic relationship between polydactyly, syndactyly and cleft hand
TERATOGENIC
RELATIONSHIP BETWEEN POLYDACTYLY, SYNDACTYLY AND CLEFT HAND T. OGINO
From the Department of Orthopaedic Surgery, School of Medicine, Hokkaido University, Japan
Several investigators have suggested that polydactyly, syndactyly and cleft hand might have arisen from a common teratogenic mechanism. To confirm this hypothesis, 75 hands with these anomalies were analysed. Advanced cases with central polydactyly or osseous syndactyly in which the fusion area extends as far as the proximal phalanx and metacarpus are identical to typical cleft hand. The author has induced the same deformities using myleran in rat foetuses. The clinical features of these anomalies in rats were the same as those in clinical cases and the critical periods of these anomalies were also the same. The findings suggest that these hand anomalies may appear in human beings when the same teratogenic factor acts on the embryo at the same developmental period and that they should belong to the same teratogenic entity. Journal of Hand Surgery (British Volume, 1990) 15B: 201-209
The external appearances of central polydactyly, osseous, syndactyly of the middle and ring fingers and cleft hand are quite different from each other, so each of these anomalies has been placed in a separate category in every classification. We have pointed out that there are some cases which are difficult or impossible to classify clearly into polydactyly, syndactyly or cleft hand, and we also often encounter cases in which polydactyly, syndactyly and cleft hand are associated in various combinations (Ogino et al. 1986). From these facts, several investigators have suggested that the failure of induction of finger rays in the process of formation of the fingers induced polydactyly, osseous syndactyly and also cleft hand (Miura, 1976; Ogino et al., 1977; Watari and Tsuge, 1979). This theory had no experimental support. To evaluate this theory, clinical cases of central polydactyly, osseous syndactyly and cleft hand were analysed. The same deformities were induced in rat foetuses and the teratogenic mechanism studied.
and metacarpus and it is impossible to distinguish these from typical cleft hand. In P-3 and P-4 type polydactyly, once bifid fingers make osseous union to adjacent ones in the proximal phalanx or metacarpal, such cases as P-3, S-3, P-4, S-3 and P-4, S-4 become identical to typical cleft hand. To support this scheme is to support the hypothesis that central polydactyly, osseous syndactyly and cleft hand may be caused by the same teratogenic mechanism. Grade of OsseO”S syndactyl Grade of
VOL. 15B No. 2 MAY
1990
s-o
S-l
s-2
s-3
s-4
\polydactyly
P-O
P-l
Materials and methods On the basis of the hypothesis that central polydactyly, osseous syndactyly and cleft hand are caused by the same teratogenic mechanism, a scheme of the relationship of the formation of these anomalies was made (Fig. l), modified from that of Watari and Tsuge (1979). When failure of induction of finger rays occurs in the digital formation process, polydactyly and/or osseous syndactyly are induced. Osseous syndactyly can be arranged in order of severity of the deformities from S-l to S-4. In addition, polydactyly of the middle finger varies from P-l to P-4. If the process of formation of polydactyly of the middle finger and that of osseous syndactyly of the middle and ring fingers occur simultaneously, many types of polysyndacrylies are induced. The skeletal changes of P-O, S-O are normal. In P-O type, which is osseous syndactyly without polydactyly, there are advanced cases in which the fusion area extends as far as the proximal phalanx
I
P-Z
P-3
P-4
Fig.
1
Cleft hand formation progressing from central polydactyly and/or osseous syndactyly. (From Ogino, T. A clinical and experimental study on teratogenic mechanism of cleft hand, polydactyly and syndactyly. Journal of the Japanese Orthopaedic Association, 1978). 201
T. OGINO
To evaluate this hypothesis, the following studies were carried out. Clinical analysis of central polydactyly, osseous syndactyly and cleft hand
We analysed our own 53 cases with polydactyly of the middle finger, osseous syndactyly of the middle and ring fingers and/or cleft hand. Following Barsky (1964), we defined cleft hand as absence of central fingers with a cone-shaped deep interdigital space (cleft in the palm). We analysed the clinical cases as follows : 1) Roentgenograms of all cases were classified according to the scheme. 2) The incidence of cleft in the palm in each type of anomaly in the schema was analysed. 3) In the cases with bilateral affection, the combinations of the anomalies in both hands were analysed. Experimental study
Wistar/Gun rats were used for this study. The animals were mated overnight. The day when spermatozoa in vaginal smears were observed was called the day zero of pregnancy. Pregnant females were treated by a single oral administration of myleran with 0.1% carboxy methyl celluloseondays8,8.5,9,9.5, 10, 10.5, 11, 11.5, 12, 12.5 and 13 of pregnancy (Kameyama et al., 1966). The doses of myleran were 30, 35 or 40 mg./Kg. of body weight. The foetuses were removed from the uterus on day 20 of pregnancy and examined externally. The cartilage and bone were stained with alizalin red S and alcian blue by Inoue’s method (1976) and examined. 162 pregnant rats were given myleran. 198 limbs with polydactyly of the ring finger, osseous syndactyly between the middle and ring fingers and cleft hand were induced. In these specimens, we observed the incidence of forelimb anomalies and of polydactyly of the ring finger, osseous syndactyly between the middle and ring fingers and cleft hand on each day of pregnancy. The incidence of anomalies was expressed as the ratio of the number of forelimbs with abnormalities to the total number of forelimbs examined. The animal specimens were analysed in the same way as the clinical cases. Results Clinical analysis
The 53 cases examined had 80 hands with anomalies, 65 of which could be classified by the scheme. The breakdown of anomalies of the other 15 hands was cutaneous syndactyly of the middle and ring fingers in four cases, palmar cleft without absence of a finger in one case and cleft hand with multiple finger defect in ten cases (Ogino and Kato, 1988). The incidence of each type of anomaly in the scheme is shown in Table 1. The 202
Table l-Incidence of each typeof central polydactyly, osseous syndactyly, and cleft hand in clinical cases
Typeof
polydactyly P-O P-l P-2 P-3 P-4
Type of osseous syndactyly s-o
S-l
s-2
s-3
s-4
normal 1 0 3 0
4 3 2 1 0
1
15
4
Note: *means intermediate t means intermediate
6 0
9(6*) 4
12(4U
type of P-O/S-3 and P-3/S-3 types. type of P-O/S-4 and P-4/S-4 types
skeletal changes of P-O type anomalies seemed to show the cleft hand formation processing from osseous syndactyly (Fig. 2). The skeletal changes of P-3 and P-4 types also seem to show that cleft hand formation progresses from central polydactylies (Fig. 3). As for the external appearance, a cleft in the palm is the essential feature for diagnosis of cleft hand. Here, the incidence of cleft in the palm in each type of deformity in the schema was analysed (Table 2). The formation of a cleft in the palm seemed to depend on the severity of the osseous syndactyly and central polydactyly. Of 53 patients, 27 had both hands affected. In 10 of these, the same type of anomalies appeared in both hands. In the other 17, different types of abnormality were present in the two hands (Fig. 4). These findings support the hypothesis of the common teratogenic mechanism causing cleft hand, central polydactyly and syndactyly. Experimental study
There were 198 forelimbs with cleft hand, polydactyly of the ring finger and syndactyly of the middle and ring fingers which were similar to clinical cases. These anomalies were induced only when myleran was given on the lOth, 10.5th, 11th and 11.5th days of pregnancy. The incidence of the different anomalies when treated by myleran on each day of pregnancy is shown in Figure 5. Next. these 198 forelimb anomalies were classified Table 2-Incidence of cleft in the palm in each type of cleft hand, central polydactyly and osseous syndactyly in clinical cases Type of polydactyly P-O P-l P-2 P-3 P-4
Type of osseous syndactyly s-o
S-I
s-2
s-3
s-4
normal O/l
O/4 O/3 O/2 O/l 0
O/l
4115
414
O/6 0
719 414
12112
073 0
Note: The numerator shows the number of hands with clefts in the palm. The denominator shows the total number of each type of anomaly.
THE
JOURNAL
OF HAND
SURGERY
TERATOGENIC
Fig. 2
RELATIONSHIP
BETWEEN
POLYDACTYLY,
SYNDACTYLY
AND
CLEFT HAND
The skeletal changes in P-O type anomalies. (a) P-O, S-l, (b) P-O, S-2, (c) P-O, S-3, (d) P-O, S-3, (e) P-O, S-4. These anomalies that cleft hand formation pro&esses from osseous syndactyly.
according to the schema (Table 3). The various kinds of combinations of S-l-S-4 and P-O-P-4 could be induced in rat foetuses. We could arrange the deformity of P-O and P-3 types in order of severity of the osseous fusion. In this way, the cleft hand progresses through S-O type and P-3 type in the same way as in clinical cases (Figs 6 and 7). The incidence of cleft in the palm was also analysed in the rat foetuses (Table 4). This seemed to depend on the VOL. 158 No. 2 MAY
1990
seem to show
severity of osseous syndactyly and central polydactyly, as in clinical cases. The combination of anomalies in both forelimbs of the rats was analysed (Fig. 8). 32 limbs were bilaterally affected. In 17 of these, the same type of anomalies appeared in both forelimbs of the rats and in the other 15 they were different. As for the combination of types of anomalies in each forelimb of the rats, the same tendency was observed as in clinical cases. 203
T. OGINO
Fig. 3
204
The skeletal changes in P-3 and P-4 types of anomalies. 4, (h) P-4, S-4. These anomalies also show a progression
(a) P-3, S-O, (b) P-3, S-l, (c) P-3, S-2, (d) P-3, S-3, (e) P-3, S-3, (f) P-4, S-3, (g) P-4, Sto cleft hand from central polydactyly.
THE JOURNAL
OF HAND SURGERY
TERATOGENIC
VOL. 15B No. 2 MAY
1990
RELATIONSHIP
BETWEEN
POLYDACTYLY,
SYNDACTYLY
AND
CLEFT HAND
205
T. OGINO
The right hand
The left hand
p - 0
p - 0
---(4)---
p - 1 ---co)---
P - 1
p - 2 ---co)---
P- 2
P-3
___(2)---
p _ 3
p - 4
---(l)---
P - 4
M
----(3)____
M
Table 34ncidence of each type of cleft hand, central polydactyly, syndactyly induced by myleran admiistration in rat
Typeof
polydactyly
P-3 P-4 M
Fig. 4
The left hand
The right hand
0
P-O P-l P-2 P-3 P.4
63 P-3
Type of osseous syndactyly s-o normal 41 43 25 0
S-l
s-2
s-3
s-4
2 1 1 11 0
5
7
0
32 0
17 0
3(3*)
3
-
P-4
Note: *means intermediate type of P-O/S-4 types.
2
M
Combinations of osseous syndactyly, central polydactyly and cleft hand in each hand of 17 bilaterally-affected cases. (Cut. Syn. means cutaneous syndactyly between the middle and ring fingers. Cleft means cleft formation in the palm without absence of the finger. M means cleft hand with multiple finger defect. Numbers in brackets are the number of patients with each combination of anomalies.)
Discussion The causes of congenital anomalies of the hand are various. Abnormal mesenchymal cell death at an early developmental stage might result in the formation of longitudinal ray deficiencies (Ogino and Kato, 1988). Abnormality of the apical ectodermal ridge is considered to cause many kinds of hand anomalies (Kameyama, 1969; Yasuda, 1975). An abnormal position of the apical ectodermal ridge and abnormal thickening of the apical ectodermal ridge was observed in the process of formation of polydactyly or syndactyly. Kameyama (1969) reported that hypoplasia of the apical ectodermal ridge was related to the cause of formation of cleft hand. On the basis of clinical analysis, several investigators have suggested that cleft hand, polydactyly of the middle finger and syndactyly of the middle and ring fingers are induced by a common teratogenic mechanism. We supposed that cleft hand formation progresses from polydactyly and syndactyly. In clinical analysis, we confirmed the true existence of many types of syndactylies
and polysyndactylies which fit this theory. In bilaterally affected cases, cleft hand, polydactyly of the middle finger and syndactyly of the middle and ring fingers appeared in both hands in various combinations, These results suggest that cleft hand, polydactyly of the middle finger and syndactyly of the middle and ring fingers might be induced by a common teratogenic mechanism: that is, failure of induction of finger rays. In the experimental study, cleft hand, polydactyly of the ring finger and syndactyly of the middle and ring fingers, which were similar to the clinical cases, could be induced in rats, They were induced only when the drug was given on day 10 to 11.5 of gestation. This shows that the critical periods for cleft hand, polydactyly of the ring finger and syndactyly of the middle and ring fingers are the same and these anomalies appeared in rats when the same teratogenic factors acted on the embryos at the same developmental stage. The experimentally-induced abnormalities in rats showed the same characteristics as clinical cases. The teratogenic mechanism of these anomalies in rats is considered fundamentally the same as that in human beings. In congenital constriction band syndrome, there are different phenotypes such as ring constriction, acrosyndactyly and amputation. The external appearance and skeletal changes of ring constriction, acrosyndactyly and amputation are quite different, However, these phenotypes can be induced by the same treatment at the same developmental stage in experimental animals and are considered to belong to the same teratogenic entity (Kino, Table Q-Incidence of cleft formation in the palm in cleft hand, central polydactyly and osseous syndactyly induced by myleran administration in rat Type of polydactyly P-O P-l P-2 P-3 P-4
Fig. 5
Incidence anomalies myleran.
of forelimb anomalies and that of P-O through in rat foetuses following maternal administration
P-4 of
Type of osseous syndactyly s-o
S-I
s-2
s-3
s-4
normal o/47 o/43 O/25 0
O/2
115
617
0
O/l O/l o/11 0
4132 0
16/17 0
313
Note: The numerator shows the number of the forelimbs with a cleft in the palm. The denominator shows the total number of each type of anomaly.
THE
JOURNAL
OF HAND
SURGERY
TERATOGENIC
RELATIONSHIP
BETWEEN
POLYDACTYLY,
SYNDACTYL‘Y
AND
CLEFT
HAND
Fig. 6 Skeletal changes in P-O type anomalies in rats. (a) P-O, S-l, (b) P-O, S-2, (c) PO, S-3, (d) P-O, S-3, (e) P-O, S-4. These anomalies seem to show that cleft hand formation progresses from osseous syndactyly, as in clinical cases.
VOL.
15B No. 2 MAY
1990
207
T. OGINO
Fig. 7
1975). When we classify congenital anomalies of the hand according to embryological failure, ring constriction, acrosyndactyly and amputation are classified into the same teratological entity: congenital constriction band syndrome. The situation is the same in cleft hand, 208
Skeletal changes of P-3 type anomalies in rats. (a) P-3, S-O, (b) P-3, S-l, (c) P-3, S-2, (d) P3, S-3, (e) P-3, S-3. These anomalies also suggest that cleft hand formation progresses from central polydactylies, as in clinical cases.
central polydactyly and syndactyly. Because they have similar reasons of causation, cleft hand, central polydactyly and syndactyly should be classified into the same entity: failure of induction of finger rays. As concerns sub-classification of failure of induction THE JOURNAL OF HAND SURGERY
TERATOGENIC
The right forelimb
The left forelimb
P - 0 --CO)--
P - 0
P - 1, --(4)--
P -
1
P - 2 --(2)--
P -
2
P - 3--(11)--P P - 4 --to)--
RELATIONSHIP
The right forelimb
BETWEEN POLYDACTYLY,
The left forelimb
- 3 p - 4
P-4
P-4
Fig. i3 Combination of osseous syndactyly, central polydactyly cleft hand in each forelimb of bilaterally-affected (Numbers in brackets are the number of rats with combination of anomalies.)
and rats. each
of finger rays, a cleft in the palm, cutaneous syndactyly, osseous syndactyly, absence of the central digits and central polydactyly occur alone or in various combinations. The cleft in the palm and cutaneous syndactyly are phenotypes of skin in failure of induction of finger rays. Osseous syndactyly, absence of the central digits and central polydactyly are phenotypes of bone in failure of induction of finger rays. Almost all types of hand deformities with failure of induction of finger rays can be expressed by a combination of these phenotypes. Acknowledgment The author expresses his sincere thanks to Professor Kiyoshi Kaneda, Department of Orthopedic Surgery, Hokkaido University, School of Medicine, Sapporo, Japan, for suggestion and advice throughout this investigation.
VOL. 15B No. 2 MAY 1990
SYNDACTYLY
AND CLEFT HAND
References BARSKY, A. J. (1964). Cleft hand: classification, incidence, and treatment. Journalof Bone and Joint Surgery, 46A: 1707-1720. INOUE, M. (1976). Differential staining of cartilage and bone in fetal mouse skeleton by alcian blue and alizarin S. Congenital Anomaly, 16: 171-173. KAMEYAMA, Y., SUGAWARA, T., OGAWA, T., HOSINO, K. and MURAKAMI, U. (1966). Effect of myleran on the development of the skeletal system in the rat and mouse embryos. Annals of the Research Institute of Environmental Medicine, Nagoya University, 14: 61-78. KAMEYAMA, Y. (1969). Morphogenesis of poly- and oligodactylisms in the rat fetus due to myleran. Teratology, 19: 262-263. KINO, Y. (1975). Clinical and experimental studies of the congenital constriction band syndrome, with an emphasis on its etiology. Journal of Bone and Joint Surgery, 57A: 636643. MIURA, T. (1976). Syndactylyand split hand. The Hand, 8: 2: 1255130. OGINO, T., ISHII, S., MINAMI, M., USUI, M., MURAMATSU, I. and MIYAKE, A. (1977). Roentgenological and clinical analyses of cleft hand and polydactyly of the middle finger. Seikeigeka, 28 : 1508-15 Il. OGINO, T. (1978). Clinical and experimental studies on the teratogenic mechanisms of the cleft hand, polydactyly and syndactyly. Journal of the Japanese Orthopedic Association, 52: 1753-1760. OGINO, T., MINAMI, A.: FUKUDA, K. and KATO, H. (1986). Congenital Anomalies of the Upper Limb Among the Japanese in Sapporo. Journal of Hand Surgery, 11B: 3: 364-375. OGINO, T. and KATO, H. (1988). Cleft hand without absence of a finger. Handchirurgie, 20: 184-188. OGINO, T. and KATO, H. (1988). Histological analysis of myleran induced oligodactyly of longitudinal deficiency in rats. Handchirurgie, 20: 271-274. WATARI, S. and TSUGE, K. (1979). A classification of cleft hands, based on clinical findings. Plastic and Reconstructive Surgery, 64: 381-389. YASUDA, M. (1975). Pathogenesis of preaxial polydactyly of the hand in human embryos. Journal of Embryology and Experimental Morphology, 33: 745756.
Accepted: 13 March 1990 T. Ogino, M.D., Dept. of Orthopaedic Surgery, School Kita-15, Nishi-7, KitakuSapporo, Japan. 0
1990 The British Society
for Surgery
of Medicine,
Hokkaido
University,
of the Hand
0266-7681/90/00154201/$10.00
209
RELATIONSHIP BETWEEN POLYDACTYLY, SYNDACTYLY AND CLEFT HAND T. OGINO
From the Department of Orthopaedic Surgery, School of Medicine, Hokkaido University, Japan
Several investigators have suggested that polydactyly, syndactyly and cleft hand might have arisen from a common teratogenic mechanism. To confirm this hypothesis, 75 hands with these anomalies were analysed. Advanced cases with central polydactyly or osseous syndactyly in which the fusion area extends as far as the proximal phalanx and metacarpus are identical to typical cleft hand. The author has induced the same deformities using myleran in rat foetuses. The clinical features of these anomalies in rats were the same as those in clinical cases and the critical periods of these anomalies were also the same. The findings suggest that these hand anomalies may appear in human beings when the same teratogenic factor acts on the embryo at the same developmental period and that they should belong to the same teratogenic entity. Journal of Hand Surgery (British Volume, 1990) 15B: 201-209
The external appearances of central polydactyly, osseous, syndactyly of the middle and ring fingers and cleft hand are quite different from each other, so each of these anomalies has been placed in a separate category in every classification. We have pointed out that there are some cases which are difficult or impossible to classify clearly into polydactyly, syndactyly or cleft hand, and we also often encounter cases in which polydactyly, syndactyly and cleft hand are associated in various combinations (Ogino et al. 1986). From these facts, several investigators have suggested that the failure of induction of finger rays in the process of formation of the fingers induced polydactyly, osseous syndactyly and also cleft hand (Miura, 1976; Ogino et al., 1977; Watari and Tsuge, 1979). This theory had no experimental support. To evaluate this theory, clinical cases of central polydactyly, osseous syndactyly and cleft hand were analysed. The same deformities were induced in rat foetuses and the teratogenic mechanism studied.
and metacarpus and it is impossible to distinguish these from typical cleft hand. In P-3 and P-4 type polydactyly, once bifid fingers make osseous union to adjacent ones in the proximal phalanx or metacarpal, such cases as P-3, S-3, P-4, S-3 and P-4, S-4 become identical to typical cleft hand. To support this scheme is to support the hypothesis that central polydactyly, osseous syndactyly and cleft hand may be caused by the same teratogenic mechanism. Grade of OsseO”S syndactyl Grade of
VOL. 15B No. 2 MAY
1990
s-o
S-l
s-2
s-3
s-4
\polydactyly
P-O
P-l
Materials and methods On the basis of the hypothesis that central polydactyly, osseous syndactyly and cleft hand are caused by the same teratogenic mechanism, a scheme of the relationship of the formation of these anomalies was made (Fig. l), modified from that of Watari and Tsuge (1979). When failure of induction of finger rays occurs in the digital formation process, polydactyly and/or osseous syndactyly are induced. Osseous syndactyly can be arranged in order of severity of the deformities from S-l to S-4. In addition, polydactyly of the middle finger varies from P-l to P-4. If the process of formation of polydactyly of the middle finger and that of osseous syndactyly of the middle and ring fingers occur simultaneously, many types of polysyndacrylies are induced. The skeletal changes of P-O, S-O are normal. In P-O type, which is osseous syndactyly without polydactyly, there are advanced cases in which the fusion area extends as far as the proximal phalanx
I
P-Z
P-3
P-4
Fig.
1
Cleft hand formation progressing from central polydactyly and/or osseous syndactyly. (From Ogino, T. A clinical and experimental study on teratogenic mechanism of cleft hand, polydactyly and syndactyly. Journal of the Japanese Orthopaedic Association, 1978). 201
T. OGINO
To evaluate this hypothesis, the following studies were carried out. Clinical analysis of central polydactyly, osseous syndactyly and cleft hand
We analysed our own 53 cases with polydactyly of the middle finger, osseous syndactyly of the middle and ring fingers and/or cleft hand. Following Barsky (1964), we defined cleft hand as absence of central fingers with a cone-shaped deep interdigital space (cleft in the palm). We analysed the clinical cases as follows : 1) Roentgenograms of all cases were classified according to the scheme. 2) The incidence of cleft in the palm in each type of anomaly in the schema was analysed. 3) In the cases with bilateral affection, the combinations of the anomalies in both hands were analysed. Experimental study
Wistar/Gun rats were used for this study. The animals were mated overnight. The day when spermatozoa in vaginal smears were observed was called the day zero of pregnancy. Pregnant females were treated by a single oral administration of myleran with 0.1% carboxy methyl celluloseondays8,8.5,9,9.5, 10, 10.5, 11, 11.5, 12, 12.5 and 13 of pregnancy (Kameyama et al., 1966). The doses of myleran were 30, 35 or 40 mg./Kg. of body weight. The foetuses were removed from the uterus on day 20 of pregnancy and examined externally. The cartilage and bone were stained with alizalin red S and alcian blue by Inoue’s method (1976) and examined. 162 pregnant rats were given myleran. 198 limbs with polydactyly of the ring finger, osseous syndactyly between the middle and ring fingers and cleft hand were induced. In these specimens, we observed the incidence of forelimb anomalies and of polydactyly of the ring finger, osseous syndactyly between the middle and ring fingers and cleft hand on each day of pregnancy. The incidence of anomalies was expressed as the ratio of the number of forelimbs with abnormalities to the total number of forelimbs examined. The animal specimens were analysed in the same way as the clinical cases. Results Clinical analysis
The 53 cases examined had 80 hands with anomalies, 65 of which could be classified by the scheme. The breakdown of anomalies of the other 15 hands was cutaneous syndactyly of the middle and ring fingers in four cases, palmar cleft without absence of a finger in one case and cleft hand with multiple finger defect in ten cases (Ogino and Kato, 1988). The incidence of each type of anomaly in the scheme is shown in Table 1. The 202
Table l-Incidence of each typeof central polydactyly, osseous syndactyly, and cleft hand in clinical cases
Typeof
polydactyly P-O P-l P-2 P-3 P-4
Type of osseous syndactyly s-o
S-l
s-2
s-3
s-4
normal 1 0 3 0
4 3 2 1 0
1
15
4
Note: *means intermediate t means intermediate
6 0
9(6*) 4
12(4U
type of P-O/S-3 and P-3/S-3 types. type of P-O/S-4 and P-4/S-4 types
skeletal changes of P-O type anomalies seemed to show the cleft hand formation processing from osseous syndactyly (Fig. 2). The skeletal changes of P-3 and P-4 types also seem to show that cleft hand formation progresses from central polydactylies (Fig. 3). As for the external appearance, a cleft in the palm is the essential feature for diagnosis of cleft hand. Here, the incidence of cleft in the palm in each type of deformity in the schema was analysed (Table 2). The formation of a cleft in the palm seemed to depend on the severity of the osseous syndactyly and central polydactyly. Of 53 patients, 27 had both hands affected. In 10 of these, the same type of anomalies appeared in both hands. In the other 17, different types of abnormality were present in the two hands (Fig. 4). These findings support the hypothesis of the common teratogenic mechanism causing cleft hand, central polydactyly and syndactyly. Experimental study
There were 198 forelimbs with cleft hand, polydactyly of the ring finger and syndactyly of the middle and ring fingers which were similar to clinical cases. These anomalies were induced only when myleran was given on the lOth, 10.5th, 11th and 11.5th days of pregnancy. The incidence of the different anomalies when treated by myleran on each day of pregnancy is shown in Figure 5. Next. these 198 forelimb anomalies were classified Table 2-Incidence of cleft in the palm in each type of cleft hand, central polydactyly and osseous syndactyly in clinical cases Type of polydactyly P-O P-l P-2 P-3 P-4
Type of osseous syndactyly s-o
S-I
s-2
s-3
s-4
normal O/l
O/4 O/3 O/2 O/l 0
O/l
4115
414
O/6 0
719 414
12112
073 0
Note: The numerator shows the number of hands with clefts in the palm. The denominator shows the total number of each type of anomaly.
THE
JOURNAL
OF HAND
SURGERY
TERATOGENIC
Fig. 2
RELATIONSHIP
BETWEEN
POLYDACTYLY,
SYNDACTYLY
AND
CLEFT HAND
The skeletal changes in P-O type anomalies. (a) P-O, S-l, (b) P-O, S-2, (c) P-O, S-3, (d) P-O, S-3, (e) P-O, S-4. These anomalies that cleft hand formation pro&esses from osseous syndactyly.
according to the schema (Table 3). The various kinds of combinations of S-l-S-4 and P-O-P-4 could be induced in rat foetuses. We could arrange the deformity of P-O and P-3 types in order of severity of the osseous fusion. In this way, the cleft hand progresses through S-O type and P-3 type in the same way as in clinical cases (Figs 6 and 7). The incidence of cleft in the palm was also analysed in the rat foetuses (Table 4). This seemed to depend on the VOL. 158 No. 2 MAY
1990
seem to show
severity of osseous syndactyly and central polydactyly, as in clinical cases. The combination of anomalies in both forelimbs of the rats was analysed (Fig. 8). 32 limbs were bilaterally affected. In 17 of these, the same type of anomalies appeared in both forelimbs of the rats and in the other 15 they were different. As for the combination of types of anomalies in each forelimb of the rats, the same tendency was observed as in clinical cases. 203
T. OGINO
Fig. 3
204
The skeletal changes in P-3 and P-4 types of anomalies. 4, (h) P-4, S-4. These anomalies also show a progression
(a) P-3, S-O, (b) P-3, S-l, (c) P-3, S-2, (d) P-3, S-3, (e) P-3, S-3, (f) P-4, S-3, (g) P-4, Sto cleft hand from central polydactyly.
THE JOURNAL
OF HAND SURGERY
TERATOGENIC
VOL. 15B No. 2 MAY
1990
RELATIONSHIP
BETWEEN
POLYDACTYLY,
SYNDACTYLY
AND
CLEFT HAND
205
T. OGINO
The right hand
The left hand
p - 0
p - 0
---(4)---
p - 1 ---co)---
P - 1
p - 2 ---co)---
P- 2
P-3
___(2)---
p _ 3
p - 4
---(l)---
P - 4
M
----(3)____
M
Table 34ncidence of each type of cleft hand, central polydactyly, syndactyly induced by myleran admiistration in rat
Typeof
polydactyly
P-3 P-4 M
Fig. 4
The left hand
The right hand
0
P-O P-l P-2 P-3 P.4
63 P-3
Type of osseous syndactyly s-o normal 41 43 25 0
S-l
s-2
s-3
s-4
2 1 1 11 0
5
7
0
32 0
17 0
3(3*)
3
-
P-4
Note: *means intermediate type of P-O/S-4 types.
2
M
Combinations of osseous syndactyly, central polydactyly and cleft hand in each hand of 17 bilaterally-affected cases. (Cut. Syn. means cutaneous syndactyly between the middle and ring fingers. Cleft means cleft formation in the palm without absence of the finger. M means cleft hand with multiple finger defect. Numbers in brackets are the number of patients with each combination of anomalies.)
Discussion The causes of congenital anomalies of the hand are various. Abnormal mesenchymal cell death at an early developmental stage might result in the formation of longitudinal ray deficiencies (Ogino and Kato, 1988). Abnormality of the apical ectodermal ridge is considered to cause many kinds of hand anomalies (Kameyama, 1969; Yasuda, 1975). An abnormal position of the apical ectodermal ridge and abnormal thickening of the apical ectodermal ridge was observed in the process of formation of polydactyly or syndactyly. Kameyama (1969) reported that hypoplasia of the apical ectodermal ridge was related to the cause of formation of cleft hand. On the basis of clinical analysis, several investigators have suggested that cleft hand, polydactyly of the middle finger and syndactyly of the middle and ring fingers are induced by a common teratogenic mechanism. We supposed that cleft hand formation progresses from polydactyly and syndactyly. In clinical analysis, we confirmed the true existence of many types of syndactylies
and polysyndactylies which fit this theory. In bilaterally affected cases, cleft hand, polydactyly of the middle finger and syndactyly of the middle and ring fingers appeared in both hands in various combinations, These results suggest that cleft hand, polydactyly of the middle finger and syndactyly of the middle and ring fingers might be induced by a common teratogenic mechanism: that is, failure of induction of finger rays. In the experimental study, cleft hand, polydactyly of the ring finger and syndactyly of the middle and ring fingers, which were similar to the clinical cases, could be induced in rats, They were induced only when the drug was given on day 10 to 11.5 of gestation. This shows that the critical periods for cleft hand, polydactyly of the ring finger and syndactyly of the middle and ring fingers are the same and these anomalies appeared in rats when the same teratogenic factors acted on the embryos at the same developmental stage. The experimentally-induced abnormalities in rats showed the same characteristics as clinical cases. The teratogenic mechanism of these anomalies in rats is considered fundamentally the same as that in human beings. In congenital constriction band syndrome, there are different phenotypes such as ring constriction, acrosyndactyly and amputation. The external appearance and skeletal changes of ring constriction, acrosyndactyly and amputation are quite different, However, these phenotypes can be induced by the same treatment at the same developmental stage in experimental animals and are considered to belong to the same teratogenic entity (Kino, Table Q-Incidence of cleft formation in the palm in cleft hand, central polydactyly and osseous syndactyly induced by myleran administration in rat Type of polydactyly P-O P-l P-2 P-3 P-4
Fig. 5
Incidence anomalies myleran.
of forelimb anomalies and that of P-O through in rat foetuses following maternal administration
P-4 of
Type of osseous syndactyly s-o
S-I
s-2
s-3
s-4
normal o/47 o/43 O/25 0
O/2
115
617
0
O/l O/l o/11 0
4132 0
16/17 0
313
Note: The numerator shows the number of the forelimbs with a cleft in the palm. The denominator shows the total number of each type of anomaly.
THE
JOURNAL
OF HAND
SURGERY
TERATOGENIC
RELATIONSHIP
BETWEEN
POLYDACTYLY,
SYNDACTYL‘Y
AND
CLEFT
HAND
Fig. 6 Skeletal changes in P-O type anomalies in rats. (a) P-O, S-l, (b) P-O, S-2, (c) PO, S-3, (d) P-O, S-3, (e) P-O, S-4. These anomalies seem to show that cleft hand formation progresses from osseous syndactyly, as in clinical cases.
VOL.
15B No. 2 MAY
1990
207
T. OGINO
Fig. 7
1975). When we classify congenital anomalies of the hand according to embryological failure, ring constriction, acrosyndactyly and amputation are classified into the same teratological entity: congenital constriction band syndrome. The situation is the same in cleft hand, 208
Skeletal changes of P-3 type anomalies in rats. (a) P-3, S-O, (b) P-3, S-l, (c) P-3, S-2, (d) P3, S-3, (e) P-3, S-3. These anomalies also suggest that cleft hand formation progresses from central polydactylies, as in clinical cases.
central polydactyly and syndactyly. Because they have similar reasons of causation, cleft hand, central polydactyly and syndactyly should be classified into the same entity: failure of induction of finger rays. As concerns sub-classification of failure of induction THE JOURNAL OF HAND SURGERY
TERATOGENIC
The right forelimb
The left forelimb
P - 0 --CO)--
P - 0
P - 1, --(4)--
P -
1
P - 2 --(2)--
P -
2
P - 3--(11)--P P - 4 --to)--
RELATIONSHIP
The right forelimb
BETWEEN POLYDACTYLY,
The left forelimb
- 3 p - 4
P-4
P-4
Fig. i3 Combination of osseous syndactyly, central polydactyly cleft hand in each forelimb of bilaterally-affected (Numbers in brackets are the number of rats with combination of anomalies.)
and rats. each
of finger rays, a cleft in the palm, cutaneous syndactyly, osseous syndactyly, absence of the central digits and central polydactyly occur alone or in various combinations. The cleft in the palm and cutaneous syndactyly are phenotypes of skin in failure of induction of finger rays. Osseous syndactyly, absence of the central digits and central polydactyly are phenotypes of bone in failure of induction of finger rays. Almost all types of hand deformities with failure of induction of finger rays can be expressed by a combination of these phenotypes. Acknowledgment The author expresses his sincere thanks to Professor Kiyoshi Kaneda, Department of Orthopedic Surgery, Hokkaido University, School of Medicine, Sapporo, Japan, for suggestion and advice throughout this investigation.
VOL. 15B No. 2 MAY 1990
SYNDACTYLY
AND CLEFT HAND
References BARSKY, A. J. (1964). Cleft hand: classification, incidence, and treatment. Journalof Bone and Joint Surgery, 46A: 1707-1720. INOUE, M. (1976). Differential staining of cartilage and bone in fetal mouse skeleton by alcian blue and alizarin S. Congenital Anomaly, 16: 171-173. KAMEYAMA, Y., SUGAWARA, T., OGAWA, T., HOSINO, K. and MURAKAMI, U. (1966). Effect of myleran on the development of the skeletal system in the rat and mouse embryos. Annals of the Research Institute of Environmental Medicine, Nagoya University, 14: 61-78. KAMEYAMA, Y. (1969). Morphogenesis of poly- and oligodactylisms in the rat fetus due to myleran. Teratology, 19: 262-263. KINO, Y. (1975). Clinical and experimental studies of the congenital constriction band syndrome, with an emphasis on its etiology. Journal of Bone and Joint Surgery, 57A: 636643. MIURA, T. (1976). Syndactylyand split hand. The Hand, 8: 2: 1255130. OGINO, T., ISHII, S., MINAMI, M., USUI, M., MURAMATSU, I. and MIYAKE, A. (1977). Roentgenological and clinical analyses of cleft hand and polydactyly of the middle finger. Seikeigeka, 28 : 1508-15 Il. OGINO, T. (1978). Clinical and experimental studies on the teratogenic mechanisms of the cleft hand, polydactyly and syndactyly. Journal of the Japanese Orthopedic Association, 52: 1753-1760. OGINO, T., MINAMI, A.: FUKUDA, K. and KATO, H. (1986). Congenital Anomalies of the Upper Limb Among the Japanese in Sapporo. Journal of Hand Surgery, 11B: 3: 364-375. OGINO, T. and KATO, H. (1988). Cleft hand without absence of a finger. Handchirurgie, 20: 184-188. OGINO, T. and KATO, H. (1988). Histological analysis of myleran induced oligodactyly of longitudinal deficiency in rats. Handchirurgie, 20: 271-274. WATARI, S. and TSUGE, K. (1979). A classification of cleft hands, based on clinical findings. Plastic and Reconstructive Surgery, 64: 381-389. YASUDA, M. (1975). Pathogenesis of preaxial polydactyly of the hand in human embryos. Journal of Embryology and Experimental Morphology, 33: 745756.
Accepted: 13 March 1990 T. Ogino, M.D., Dept. of Orthopaedic Surgery, School Kita-15, Nishi-7, KitakuSapporo, Japan. 0
1990 The British Society
for Surgery
of Medicine,
Hokkaido
University,
of the Hand
0266-7681/90/00154201/$10.00
209