Am J Hum Genet 28:400-403, 1976
Congenital Cleft Lip and Fluctuating Dermatoglyphic Asymmetry CHARLES M. WOOLF1
AND
ANN D. GIANAS
It has been well established that relatives of propositi with cleft lip with or without cleft palate (CL[P]) have an increased frequency of CL(P) but not cleft palate (CP), while relatives of propositi with CP have an increased frequency of CP but not CL (P) [1-3]. Thus, when concordance is present in parent-child combinations, the type of cleft appearing in a parent (i.e., CL(P) or CP) is the type usually found in his child [4]. Although exceptions do occur, such as the van der Woude (lip pit) syndrome [5] and related syndromes [6], the genetic mechanisms responsible for CL(P) and CP appear to be different. Because of the higher incidence of CL(P), it has been studied more often. While most cases of CL(P) have a polygenic mode of inheritance [4], a certain proportion result from chromosomal aberrations [7], rare mutant genes [6], and unknown exogenous factors. The heritability of CL(P) has been estimated to be .76 [8-9]. Data are also compatible with the hypothesis that unilateral and bilateral CL(P) are part of a genetic continuum, with more genes required for the bilateral condition [9]. Adams and Niswander [10] observed that propositi with CL(P) who have a family history of this disorder demonstrate increased fluctuating asymmetry of their dermatoglyphics and molar teeth, but those who lack a family history do not. Fluctuating asymmetry is described as random deviation from symmetry in a bilateral organism. Based upon the models developed by others [11-13], Adams and Niswander [10] concluded that polygenic systems buffer the development of an organism against environmental influences; the substitution of genes in one of these systems lowers developmental stability and thereby increases the probability of the occurrence of CL(P) and, concomitantly, increased fluctuating asymmetry.
The results of Adams and Niswander [10] suggested the need for a study of relatives of propositi with CL(P). If their conclusions are correct, relatives of CL(P) propositi with a familial history of this congenital malformation may show a tendency for increased fluctuating asymmetry. The present study examines the palmar dermatoglyphics of the normal sibs and parents of CL(P) propositi with and without a family history of this congenital malformation. Received November 17, 1975; revised January 29, 1976. This work was supported by the U.S. Energy Research and Development Administration Contract E(11-1)-2013 to Arizona State University. 1 Both authors: Department of Zoology, Arizona State University, Tempe, Arizona. © 1976 by the American Society of Human Genetics. All rights reserved.
400
CLEFT LIP AND FLUCTUATING ASYMMETRY
401
MATERIAL AND METHODS
Because of the possible influence of early age on the results [10], only individuals at least 5 years of age were studied. Propositi were obtained from the Crippled Children's Hospital, Phoenix, Arizona and from a group of CL(P) propositi previously studied by Woolf [9]. The latter were used to increase the number of propositi with a family history of CL(P). Normal parents attending the meetings of the Arizona Cleft Lip/Palate Association were also included in this study even if their CL(P) children were not available for printing or were under 5 years of age. The controls included 83 children (5-17-yearsold) and 83 adults (18-50-years-old). These children were from church schools or summer recreational programs in Phoenix or Tempe, Arizona. The adult controls were students, faculty, and staff at Arizona State University. Permanent dermal prints were obtained from 721 individuals using the technique of Aase and Lyons [14]. All of the propositi and controls were Caucasian. The dermatoglyphic measurement used in this study was the atd angle which was found by drawing lines from the a and d triradii to the t triradius. The difference between the angle from the right and left hands was then determined. Absolute values were used in calculating the variance of these differences (intra-pair variance). An F value was obtained by dividing the intra-pair variance for the propositi, normal sibs, and normal parents by the intra-pair variance for the controls. A propositus was categorized as a familial case if CL(P) had occurred in a relative with a coefficient of relationship greater than r = 1/32. Individuals were excluded if a landmark such as an a triradius or a t triradius was missing or if they exhibited asymmetrical hypothenar patterns [10]. RESULTS AND DISCUSSION
This investigation (table 1) confirms the observations of Adams and Niswander [10] that familial but not sporadic cases of CL(P) have increased fluctuating asymmetry for the atd angle. This investigation also shows that the normal sibs and normal parents of the familial and sporadic cases are similar to the controls for this type of asymmetry. The similarity between relatives of the familial cases of CL(P) and the controls does not negate the hypothesis that the substitution of genes in a given polygenic system lowers developmental stability and thereby TABLE 1 ANALYSIS OF THE atd ANGLE IN RIGHT AND LEFT HANDS Individuals
Family history of CL(P): propositi ..................... normal sibs .................. normal parents ......... ...... No family history of CL(P): propositi ..................... normal sibs .................. normal parents ......... ...... Controls ....................... * Significant at the 0.01
level.
No.
Intra-Pair Variance
F value
47 81 86
12.9 6.7 4.2
2.39* 1.24 0.78
42 77 95 166
6.0 5.1 6.9 5.4
1.11 0.94 1.28 ...
402
WOOLF AND GIANAS
increases the probability of occurrence of CL(P) and increased fluctuating asymmetry. Most of the familial cases of CL(P) fell within the range of the controls for the difference measurement (table 2), signifying that the biological effect is TABLE 2 AsYMMETRY OF THE atd ANGLE DIFFERENCE BETWEEN atd ANGLES IN RIGHT AND LEFT HANDS
INDIVIDUALS
No.
0
1-5
6-9
-10
Controls ........................... First degree relatives of propositi* .... Propositi* ..........................
166 119 47
22.3 17.6
69.9 69.7 70.2
6.6 10.1 12.8
1.2 2.5 6.4
10.6
= percent. NOTE.-NOS. * With a family history of CL(P).
small. Because of this overlap and the fact that segregation would diminish the effect in relatives, it is perhaps predictable that relatives of familial cases could not be distinguished from the controls by comparing intra-pair variances based on small or even moderately large samples. It is interesting, however, that the array of differences for first degree relatives of familial cases tends to fit the model specified by the hypothesis (table 2). The percent of these relatives in the classes representing no or extreme asymmetry is intermediate to the controls and propositi. The intra-pair variances obtained by Adams and Niswander [10] are consistently larger than those obtained in the present study, which may reflect different methods of obtaining the dermal prints or measuring the atd angle. The two sets of intra-pair variances follow, with those obtained by Adams and Niswander [10] appearing first: familial cases, 16.5 vs. 12.9; sporadic cases, 9.6 vs. 6.0; and controls, 7.9 vs. 5.4. The observation that sporadic cases do not deviate significantly from the controls in either study emphasizes that it is not the developmental error per se leading to CL(P) that produces the asymmetry. Other types of congenital malformations purported to have a polygenic mode of inheritance should be investigated in this manner. It would be of biological interest if individuals born with other malformations, such as congenital dislocation of the hip and spina bifida cystica, showed increased fluctuating asymmetry when they had a family history of the malformation. SUMMARY
Fluctuating asymmetry for the palmar atd angle was studied in propositi born with CL(P) and their normal parents and sibs. The propositi with a family history of this congenital malformation were significantly different from the controls for this type of asymmetry. The propositi without a family history and the normal parents and sibs of both types of propositi were similar to the controls. The difference between the two types of propositi suggests that in some individuals a
CLEFT LIP AND FLUCTUATING ASYMMETRY
403
genetic mechanism may account for CL(P) and increased fluctuating asymmetry for this dermatoglyphic trait. REFERENCES 1. FOGH-ANDERSON P: Inheritance of Harelip and Cleft Palate. Copenhagen, A. Busck, 1942 2. CURTIS E, FRASER FC, WARBURTON D: Congenital cleft lip and palate. Am J Dis Child 102:853-857, 1961 3. WOOLF CM, WOOLF RM, BROADBENT TR: A genetic study of cleft lip and palate in Utah. Am J Hum Genet 15:209-215, 1963 4. WOOLF CM, WOOLF RM, BROADBENT TR: Cleft lip and palate in parent and child. Plast Reconstr Surg 44:436-440, 1969 5. VAN DER WOUDE A: Fistula labii inferioris congenita and its association with cleft lip and palate. Am J Hum Genet 6:244-256, 1954 6. GORLIN RJ, PINDBORG JJ: Syndromes of the Head and Neck. New York, McGrawHill, 1964 7. LUBS HA, KOENIG EU, BRANDT IK: Trisomy 13-15: a clinical syndrome. Lancet 2:1001-1002, 1961 8. CARTER CO: Genetics of common disorders. Br Med Bull 25:52-57, 1969 9. WOOLF CM: Congenital cleft lip: a genetic study of 496 propositi. J Med Genet 8:65-83, 1971
10. ADAMS MS, NISWANDER JD: Developmental "noise" and a congenital malformation. Genet Res 10:313-317, 1967 11. WADDINGTON CH: The Strategy of the Genes. New York, Macmillan, 1957 12. LERNER M: Genetic Homeostasis. New York, John Wiley, 1954 13. NEEL JV: A study of major congenital defects in Japanese infants. Am J Hum Genet 10:398-445, 1958 14. AASE JM, LYONS RB: Techniques for recording dermatoglyphics. Lancet 1:432433, 1971
Congenital Cleft Lip and Fluctuating Dermatoglyphic Asymmetry CHARLES M. WOOLF1
AND
ANN D. GIANAS
It has been well established that relatives of propositi with cleft lip with or without cleft palate (CL[P]) have an increased frequency of CL(P) but not cleft palate (CP), while relatives of propositi with CP have an increased frequency of CP but not CL (P) [1-3]. Thus, when concordance is present in parent-child combinations, the type of cleft appearing in a parent (i.e., CL(P) or CP) is the type usually found in his child [4]. Although exceptions do occur, such as the van der Woude (lip pit) syndrome [5] and related syndromes [6], the genetic mechanisms responsible for CL(P) and CP appear to be different. Because of the higher incidence of CL(P), it has been studied more often. While most cases of CL(P) have a polygenic mode of inheritance [4], a certain proportion result from chromosomal aberrations [7], rare mutant genes [6], and unknown exogenous factors. The heritability of CL(P) has been estimated to be .76 [8-9]. Data are also compatible with the hypothesis that unilateral and bilateral CL(P) are part of a genetic continuum, with more genes required for the bilateral condition [9]. Adams and Niswander [10] observed that propositi with CL(P) who have a family history of this disorder demonstrate increased fluctuating asymmetry of their dermatoglyphics and molar teeth, but those who lack a family history do not. Fluctuating asymmetry is described as random deviation from symmetry in a bilateral organism. Based upon the models developed by others [11-13], Adams and Niswander [10] concluded that polygenic systems buffer the development of an organism against environmental influences; the substitution of genes in one of these systems lowers developmental stability and thereby increases the probability of the occurrence of CL(P) and, concomitantly, increased fluctuating asymmetry.
The results of Adams and Niswander [10] suggested the need for a study of relatives of propositi with CL(P). If their conclusions are correct, relatives of CL(P) propositi with a familial history of this congenital malformation may show a tendency for increased fluctuating asymmetry. The present study examines the palmar dermatoglyphics of the normal sibs and parents of CL(P) propositi with and without a family history of this congenital malformation. Received November 17, 1975; revised January 29, 1976. This work was supported by the U.S. Energy Research and Development Administration Contract E(11-1)-2013 to Arizona State University. 1 Both authors: Department of Zoology, Arizona State University, Tempe, Arizona. © 1976 by the American Society of Human Genetics. All rights reserved.
400
CLEFT LIP AND FLUCTUATING ASYMMETRY
401
MATERIAL AND METHODS
Because of the possible influence of early age on the results [10], only individuals at least 5 years of age were studied. Propositi were obtained from the Crippled Children's Hospital, Phoenix, Arizona and from a group of CL(P) propositi previously studied by Woolf [9]. The latter were used to increase the number of propositi with a family history of CL(P). Normal parents attending the meetings of the Arizona Cleft Lip/Palate Association were also included in this study even if their CL(P) children were not available for printing or were under 5 years of age. The controls included 83 children (5-17-yearsold) and 83 adults (18-50-years-old). These children were from church schools or summer recreational programs in Phoenix or Tempe, Arizona. The adult controls were students, faculty, and staff at Arizona State University. Permanent dermal prints were obtained from 721 individuals using the technique of Aase and Lyons [14]. All of the propositi and controls were Caucasian. The dermatoglyphic measurement used in this study was the atd angle which was found by drawing lines from the a and d triradii to the t triradius. The difference between the angle from the right and left hands was then determined. Absolute values were used in calculating the variance of these differences (intra-pair variance). An F value was obtained by dividing the intra-pair variance for the propositi, normal sibs, and normal parents by the intra-pair variance for the controls. A propositus was categorized as a familial case if CL(P) had occurred in a relative with a coefficient of relationship greater than r = 1/32. Individuals were excluded if a landmark such as an a triradius or a t triradius was missing or if they exhibited asymmetrical hypothenar patterns [10]. RESULTS AND DISCUSSION
This investigation (table 1) confirms the observations of Adams and Niswander [10] that familial but not sporadic cases of CL(P) have increased fluctuating asymmetry for the atd angle. This investigation also shows that the normal sibs and normal parents of the familial and sporadic cases are similar to the controls for this type of asymmetry. The similarity between relatives of the familial cases of CL(P) and the controls does not negate the hypothesis that the substitution of genes in a given polygenic system lowers developmental stability and thereby TABLE 1 ANALYSIS OF THE atd ANGLE IN RIGHT AND LEFT HANDS Individuals
Family history of CL(P): propositi ..................... normal sibs .................. normal parents ......... ...... No family history of CL(P): propositi ..................... normal sibs .................. normal parents ......... ...... Controls ....................... * Significant at the 0.01
level.
No.
Intra-Pair Variance
F value
47 81 86
12.9 6.7 4.2
2.39* 1.24 0.78
42 77 95 166
6.0 5.1 6.9 5.4
1.11 0.94 1.28 ...
402
WOOLF AND GIANAS
increases the probability of occurrence of CL(P) and increased fluctuating asymmetry. Most of the familial cases of CL(P) fell within the range of the controls for the difference measurement (table 2), signifying that the biological effect is TABLE 2 AsYMMETRY OF THE atd ANGLE DIFFERENCE BETWEEN atd ANGLES IN RIGHT AND LEFT HANDS
INDIVIDUALS
No.
0
1-5
6-9
-10
Controls ........................... First degree relatives of propositi* .... Propositi* ..........................
166 119 47
22.3 17.6
69.9 69.7 70.2
6.6 10.1 12.8
1.2 2.5 6.4
10.6
= percent. NOTE.-NOS. * With a family history of CL(P).
small. Because of this overlap and the fact that segregation would diminish the effect in relatives, it is perhaps predictable that relatives of familial cases could not be distinguished from the controls by comparing intra-pair variances based on small or even moderately large samples. It is interesting, however, that the array of differences for first degree relatives of familial cases tends to fit the model specified by the hypothesis (table 2). The percent of these relatives in the classes representing no or extreme asymmetry is intermediate to the controls and propositi. The intra-pair variances obtained by Adams and Niswander [10] are consistently larger than those obtained in the present study, which may reflect different methods of obtaining the dermal prints or measuring the atd angle. The two sets of intra-pair variances follow, with those obtained by Adams and Niswander [10] appearing first: familial cases, 16.5 vs. 12.9; sporadic cases, 9.6 vs. 6.0; and controls, 7.9 vs. 5.4. The observation that sporadic cases do not deviate significantly from the controls in either study emphasizes that it is not the developmental error per se leading to CL(P) that produces the asymmetry. Other types of congenital malformations purported to have a polygenic mode of inheritance should be investigated in this manner. It would be of biological interest if individuals born with other malformations, such as congenital dislocation of the hip and spina bifida cystica, showed increased fluctuating asymmetry when they had a family history of the malformation. SUMMARY
Fluctuating asymmetry for the palmar atd angle was studied in propositi born with CL(P) and their normal parents and sibs. The propositi with a family history of this congenital malformation were significantly different from the controls for this type of asymmetry. The propositi without a family history and the normal parents and sibs of both types of propositi were similar to the controls. The difference between the two types of propositi suggests that in some individuals a
CLEFT LIP AND FLUCTUATING ASYMMETRY
403
genetic mechanism may account for CL(P) and increased fluctuating asymmetry for this dermatoglyphic trait. REFERENCES 1. FOGH-ANDERSON P: Inheritance of Harelip and Cleft Palate. Copenhagen, A. Busck, 1942 2. CURTIS E, FRASER FC, WARBURTON D: Congenital cleft lip and palate. Am J Dis Child 102:853-857, 1961 3. WOOLF CM, WOOLF RM, BROADBENT TR: A genetic study of cleft lip and palate in Utah. Am J Hum Genet 15:209-215, 1963 4. WOOLF CM, WOOLF RM, BROADBENT TR: Cleft lip and palate in parent and child. Plast Reconstr Surg 44:436-440, 1969 5. VAN DER WOUDE A: Fistula labii inferioris congenita and its association with cleft lip and palate. Am J Hum Genet 6:244-256, 1954 6. GORLIN RJ, PINDBORG JJ: Syndromes of the Head and Neck. New York, McGrawHill, 1964 7. LUBS HA, KOENIG EU, BRANDT IK: Trisomy 13-15: a clinical syndrome. Lancet 2:1001-1002, 1961 8. CARTER CO: Genetics of common disorders. Br Med Bull 25:52-57, 1969 9. WOOLF CM: Congenital cleft lip: a genetic study of 496 propositi. J Med Genet 8:65-83, 1971
10. ADAMS MS, NISWANDER JD: Developmental "noise" and a congenital malformation. Genet Res 10:313-317, 1967 11. WADDINGTON CH: The Strategy of the Genes. New York, Macmillan, 1957 12. LERNER M: Genetic Homeostasis. New York, John Wiley, 1954 13. NEEL JV: A study of major congenital defects in Japanese infants. Am J Hum Genet 10:398-445, 1958 14. AASE JM, LYONS RB: Techniques for recording dermatoglyphics. Lancet 1:432433, 1971
