J Plast Surg Hand Surg, 2015; Early Online: 1–6 ISSN: 2000-656X print / 2000-6764 online DOI: 10.3109/2000656X.2015.1042387
ORIGINAL ARTICLE
Evaluating fluctuating asymmetry in a Brazilian population with non-syndromic cleft lip and/or palate
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Bárbara Daniane G. L. Leite1, Izabella Nobre Queiroz1, Sibele Nascimento de Aquino2, Renato Assis Machado3, Lívia Maris R. Paranaíba1, Daniella Reis B. Martelli1, Mário Sérgio O. Swerts4 & Hercílio Martelli-Júnior1,4 1 Stomatology Clinic, Dental School, State University of Montes Claros, Montes Claros, Minas Gerais, Brazil, 2School of Dentistry, Federal University of Juiz de Fora, Governador Valadares, Minas Gerais, Brazil, 3Department of Oral Diagnosis, School of Dentistry, State University of Campinas, Piracicaba, São Paulo, Brazil and 4Center for Rehabilitation of Craniofacial Anomalies, Dental School, University of José Rosário Vellano, Alfenas, Minas Gerais, Brazil
Abstract Objective: The objective of this work was to analyse the levels of dermatoglyphic asymmetry between both parents and individuals with nonsyndromic cleft lip and/or palate (NSCL/P) and unaffected control trios. Methods: A case-control analysis was carried out of 51 affected trios (unaffected parents and NSCL/P subjects), and 50 unaffected control trios. Finger and palm prints were taken from each participant, and dermatoglyphic patterns, the number of lines on the digits, and the palmar angles were recorded. To determine the level of fluctuating asymmetry the case group was compared with the control group, significance accepted at p £ 0.05. Results: There was a statistically significant difference between the atd angles (angle between the lines triradii a and t and triradii t and d) of fathers of those affected by NSCL/P, and the dermatoglyphic patterns of the affected mothers, with significantly more arches in the control group. However, in this study, multiple comparisons were used, and the results must be evaluated as initial findings and evaluated carefully since the significance disappears after correction for multiple comparisons. Other parameters did not differ between groups. There was no difference in parameters among patients affected by NSCL/P. Conclusions: Based on these results it is speculated that the mechanisms responsible for the formation of NSCL/P may be associated with those responsible for deviations in the asymmetry of the atd angles in the fathers and dermatoglyphic patterns of the mothers of affected patients. Besides, further studies are required to determine the real relationship between these conditions. Key Words: Dermatoglyphics, fluctuating asymmetry, non-syndromic cleft lip and/or palate
Introduction Non-syndromic cleft lip and/or palate (NSCL/P, OMIM #119530) is the most common craniofacial anomaly, affecting one in every 700 newborns, with geographic, ethnic, and socioeconomic influences [1]. Studies show an incidence ranging between 0.19–1.54 per 1000 live births [2-4]. The aetiology of NSCL/P is complex, with both environmental and genetic factors playing important roles, and, although much effort has been made to determine the major risk factors, they remain unknown [1]. Although NSCL/P is not a major cause of mortality, it is responsible for a considerable number of morbidities associated with nutrition, speaking and hearing, risk of cancer and numerous other chromosomal and genetic diseases, and psychological and social problems, and imposes a substantial financial burden on families with a concomitant societal burden [1,5-8]. Such problems have stimulated research into the phenotypic markers of this condition, arising from the instability of embryonic development [9-11]. One of these markers is called fluctuating asymmetry (FA) [11,12]. Fluctuating asymmetry is characterised by deviations between structures on the right and left sides of the body, which are usually bilaterally symmetrical. These bilateral structures are programmed by the same genes and, thus, deviations from
bilateral symmetry may represent a phenotypic record of instability present during development [13,14]. The magnitude of this asymmetry is calculated as the difference between the right and left sides of the body [13,15]. Several structures of the human body can be analysed in studies of FA: the sizes and shapes of skeletal elements such as the ears, shoulders, chest, arms, hands, fingers, legs, and feet [12,16,17]; craniofacial form [13,14]; and dental morphology, including the size, position, rotation, and angulation of the teeth [16,18-22]. Studies have also investigated FA based on dermatoglyphics, which is the science of skin relief and drawings from the fingertips, the palms and the soles of feet, revealing qualitative and quantitative characteristics that are not adaptable [11,12,15,23-25]. With the aim of seeking such an association, this study investigated whether the FA of parents and individuals with NSCL/P is significantly higher than that of their unaffected peers. Materials and methods We conducted a case-control study, in which the sample consisted of 303 individuals. The case group (n = 153) included 51 trios formed by individuals with NSCL/P and their parents. The control group (n = 150) also included 50 trios formed by
Correspondence: Sibele Nascimento de Aquino, Department of Oral Diagnosis, School of Dentistry, State University of Campinas, CEP 13414-018, Piracicaba, São Paulo, Brazil. E-mail: [email protected] (Received 9 July 2014; accepted 16 March 2015) 2015 Informa Healthcare.
2 B. D. G. L. Leite et al. A
B
C
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Figure 1. A) arch; B) loop; C) whorl.
parents and individuals who did not have a cleft lip and/or palate, syndrome, or any severe malformation or family history of these conditions. Consanguinity of the parents was recorded by interview, analysing four generations of each family. Finger and palm prints were obtained using the method of Durham and Plato [26]. The phalanges were covered with ink from side to side (radial and ulnar) up to the nails, then immediately supported on paper, rolling on its longitudinal axis from the ulnar side to the radial side. This process was repeated with each finger, starting with the little finger (Finger V) and ending with the thumb (Finger I). For palm prints, the inked hand was supported and gently pressed onto a piece of paper placed on a cylindrical surface so that the whole palm was clearly printed [27], with the aid of the evaluators (I.N.Q and S.N.A). Upon completion of printing, the prints were dermatoglyphically classified. Patterns on the fingers varied according to the number of triradii (deltas) and the presence of a core. The triradii are shaped like a triangle, the sides of which are formed by the meeting of the ridges of the basal region, the marginal region, and nuclear region [28]. Three basic dermatoglyphic patterns can be observed in fingerprints: arch, loop, and whorl (Figure 1). The arch is the simplest pattern, with no cores or triradii and papillary lines that are arranged almost in parallel. The loop has one triradius and one core and the lines are directed to the right or left. The whorl is characterised by the presence of two deltas and one or two cores, with an appearance similar to a “swirl” [24,28]. Ridge counts (RC) were recorded in addition to dermatoglyphic patterns, corresponding to the number of papillary ridges touched by Galton’s line. Galton’s line is an imaginary line between the triradii and the core of the digit. Thus, the RC in an arch is equal to zero because there are no triradii, but there are two counts in a whorl [24] (Evaluator B.D. G.L.L). There is usually a triradius at the base of fingers II–V; these are called a, b, c, and d, respectively. There is also a triradius located more proximal to the wrist and central axis of the hand; this is called triradius t. This triradius, located at the base of the palm, is sometimes found higher up, but below the midline of the palm, in which case it is named t’. When the triradius is located exactly on the midline of the palm, it is called t’’ and, if it is located above the midline, it is called t’’’ [24]. In the current study, palmar angles were calculated according to a straight line drawn between the triradii a and t, between triradii t and d, finally, between triradii a and d, forming a triangle, the angles of which were called atd, tda, and dat (Figure 2). To determine the asymmetry between the right and left hands, differences in standards between the digits, arches, loops, and whorls were recorded, with “0” being assigned for similar patterns and “1” being assigned when patterns differed. The
Figure 2. Trirradiis and palmar angles.
scores for all five pairs of digits were combined, and, thus, in each individual, the score ranged from 0 (when all five pairs showed identical patterns) to 5 (when all five pairs showed different patterns). The dermatoglyphic patterns prevalent among fathers, mothers, and children, cases and controls were assessed. Differences in the RC were also recorded, by subtracting the number of lines on each finger of the right hand from those on the left hand, and summing the total. For palmar angles (atd, tda, dat), the asymmetry was calculated as the difference between each angle obtained on the right hand and its respective angle on the left hand. Data were analysed using the Statistical Package for the Social Sciences version 18.0. Differences between the dermatoglyphic patterns were tested using the Chi-square test. The Mann-Whitney test was used to test for asymmetry between the RC and palmar angles. In all tests, p £ 0.05 was used as the Table I. Age, family history of cleft, and consanguinity in case and control groups.
Age, Mean (SD) Father Mother Son Family history of cleft, n (%) Father Mother Son Consanguinity, n (%) Father Mother
Case
Control
40.7 (9.2) 36.6 (7.4) 9.5 (6.3)
50 (10.8) 46.6 (10.3) 18.4 (7.6)
11 (21.6) 13 (25.5) 22 (43.1)
0 (0.0) 0 (0.0) 0 (0.0)
1 (2.0) 1 (2.0)
0 (0.0) 0 (0.0)
* Statistically significant difference based on the Chi-square test. ** Statistically significant difference based on the T-test.
Fluctuating asymmetry in cleft lip and/or palate
3
Table II. Mean (standard deviation) for ridge counts in each group and category. Father (n = 101) Case Control Digit I Digit II Digit III Digit IV
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Digit V Total
R L R L R L R L R L R L
27.9 21.1 17.4 16.5 14.3 14.5 24.3 23.1 15.4 15.3 99.4 93.0
(14.8) (14.8) (11.8) (11.5) (8.3) (7.8) (12.6) (12.9) (8.3) (7.7) (45.4) (42.1)
28.6 24.1 17.6 17.5 15.4 16.7 21.5 20.6 16.5 16.1 99.8 95.0
Mother (n = 101) Case Control
(12.8) (12.2) (10.7) (12.1) (9.8) (10.6) (11.3) (10.5) (6.9) (7.4) (40.2) (40.2)
25.6 22.5 17.8 15.7 16.0 15.1 22.4 22.7 15.5 16.2 97.3 92.2
level of statistical significance. This study was approved by the institutional Research Ethics Committee of the research. Results The general characteristics of the participating groups are shown in Table I, including age, CL/P in the family history of the children and their parents, and consanguinity in the parents. Table II presents the means and standard deviations (SD) of RC per digit and the total for the right and left hands, the parents (n = 151), mothers (n = 151), and children (n = 151). There was no significant difference in this variable between the different groups. The FA in the RC per digit and total RC did not differ significantly between cases and controls, as shown in Table III. Likewise, there was no difference between the cases and
Table III. Asymmetry in the ridge counts on the five digits in each group and category.
Father Digit I Digit II Digit III Digit IV Digit V Total Mother Digit I Digit II Digit III Digit IV Digit V Total Son Digit I Digit II Digit III Digit IV Digit V Total
Case, Mean (SD)
Control, Mean (SD)
n = 51 4.8 (7.5) 1.0 (8.8) 0.2 (6.3) 1.1 (7.8) 0.2 (4.1) 7.2 (17.4) n = 51 3.1 (7.4) 2.1 (8.0) 1.0 (4.6) 0.2 (8.2) 0.8 (5.6) 5.2 (17.0) n = 51 4.5 (7.2) 0.5 (8.5) 2.5 (7.4) 1.0 (9.6) 1.1 (5.6) 2.6 (20.9)
n = 50 4.5 (10.4) 0.2 (9.0) 1.3 (8.4) 1.0 (7.2) 0.5 (3.7) 4.9 (19.9) n = 50 3.1 (9.4) 1.3 (9.5) 1.2 (7.3) 0.4 (8.1) 0.5 (4.4) 2.3 (18.6) n = 50 1.1 (8.8) 1.6 (8.1) 1.1 (7.6) 0.1 (7.4) 0.04 (4.5) 1.4 (19.7)
p-value 0.39 0.76 0.50 0.88 0.91 0.59 0.93 0.96 0.23 0.80 0.82 0.65 0.13 0.92 0.33 0.57 0.93 0.75
(14.4) (14.2) (13.7) (12.8) (11.5) (11.9) (13.9) (13.7) (8.1) (9.5) (52.3) (51.9)
26.7 23.6 17.7 16.4 15.2 16.4 21.4 21.8 14.8 15.3 95.9 93.6
(13.5) (13.9) (13.3) (13.0) (10.2) (11.9) (10.6) (12.4) (6.5) (7.4) (43.6) (46.2)
Case 25.8 20.9 15.7 15.2 13.1 15.6 20.9 21.9 15.5 14.4 90.5 87.9
Son (n = 101) Control
(13.5) (13.2) (12.0) (12.7) (8.7) (11.5) (11.1) (13.8) (8.1) (6.7) (41.9) (47.6)
25.8 24.8 16.9 15.4 13.6 14.7 20.1 20.1 15.2 15.3 91.6 90.2
(11.8) (12.1) (12.6) (11.2) (7.4) (10.7) (11.2) (12.8) (7.4) (7.7) (38.5) (43.9)
controls in terms of the asymmetries in digital dermatoglyphic patterns (arches, loops, and whorls) measured by the difference in score between the left and right sides (Table IV). With regards to the prevalence of dermatoglyphic finger patterns, Table V reveals that only the mothers showed significant differences when comparing cases and controls (p = 0.01), with a significantly higher number of arches in the digits of the case group (n = 49) compared to controls (n = 26). Table VI presents the means and SD of the palmar atd, tda. and dat angles of fathers, mothers. and children, with no significant differences between groups. However, analysis of the FA between the angles (Table VII) revealed a significant difference between the fathers in terms of the atd angle fissures (p = 0.04), with greater asymmetry between the cases than the controls. Mothers (p = 0.29) and children (p = 0.44) showed no differences in the FA of this angle. Discussion Fluctuating asymmetry measured by dermatoglyphics can be considered one of these markers, as the presence of excessive asymmetry of dermatoglyphic patterns between the right and left hands may reflect unstable genetic control during embryogenesis that may contribute to the development of congenital malformations such as NSCL/P [12,29,30]. The presence of CL/P is directly related to the development of the primary palate and lips, which is completed in the 7th week of intrauterine life, and the secondary palate, which is completed in the 12th week. This period of craniofacial formation coincides with the formation of papillary lines, which develop from the volar pads from the 6th to the 12th or 13th week. This means that genetic messages contained in the genome that are deciphered during this period are also reflected by dermatoglyphics [23], which in this study was assessed
Table IV. Mean (standard deviation) of the difference in dermatoglyphic pattern scores by group and category.
Father Mother Son
Case
Control
0.90 (0.88) 1.04 (0.94) 1.25 (1.17)
0.94 (0.91) 1.18 (1.06) 1.06 (0.91)
p-value 0.87 0.60 0.54
4 B. D. G. L. Leite et al. Table V. Number and percentage of dermatoglyphic patterns by category.
Father Mother Son
Arch, n (%)
Case Loop, n (%)
Whorl, n (%)
Arch, n (%)
Control Loop, n (%)
Whorl, n (%)
p-value
22 (4.3) 49 (9.6) 38 (7.5)
336 (66.1) 302 (59.2) 333 (65.3)
150 (29.5) 159 (31.2) 139 (27.3)
17 (3.4) 26 (5.2) 25 (5.0)
335 (67.0) 333 (66.6) 346 (69.2)
148 (29.6) 141 (28.2) 129 (25.8)
0.75 0.01* 0.20
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* Statistically significant difference based on the Chi-square test.
according to the dermatoglyphic pattern, ridge counts, and palmar angles. This study showed no statistically significant difference between the average RC on the left and right sides of the individuals in the case and control groups, and no significant difference in the asymmetry of the RC, as in the study of Neiswanger et al. [11]. In a similar study, Jahanbin et al. [24] found no difference in the RC of the fathers, but observed a difference on digit I of the mothers. While there were no statistically significant differences, both RC and CLP/NS are highly heritable, and estimates using traditional methods based on correlation or structural equation models in twins or families have shown that genetic effects account for ~90% of all variation. This genetic effect can be observed both in the total ridge count (TRC) and the ridge counts per finger [31]. There was no significant difference in the asymmetry of dermatoglyphic patterns, arches, loops, or whorls based on the assignment of scores. As in our study, Jahanbin et al. [24] found no significant asymmetry in the dermatoglyphic patterns of parents of children with NSCL/P. Analysing themselves affected by NSCL/P, Woolf and Gianas [29] found more statistically significant differences in asymmetry between those who had cases of CL/P in the family than in sporadic cases. Using a similar methodology, Scott et al. [32] also found a statistically significant difference in this variable in individuals with CL/P, and this difference was more pronounced in women, indicating some kind of gender-linked inheritance. Scott et al. [32] also highlighted the fact that these scores are typically used as measures of asymmetry and are, thus, in turn, markers of instability. Analysis of the palmar dermatoglyphics performed by Neiswanger et al. [11], who measured the atd angles of those affected by cleft and their parents, showed no significant differences between cases and controls. Jahanbin et al. [24] found significant differences in asymmetry in both fathers and mothers of cleft individuals, compared with the control group. In a comparison of those affected by cleft who had a family history of CL/P with individuals with no family history of cleft, Woolf and Gianas [29] also found significant differences in the
asymmetry of atd angles, such that those affected with a family history were more asymmetrical, reinforcing the genetic character of the FA. The frequencies of the patterns were also evaluated, with similarities in frequencies being observed between case and control groups. An exception was observed in the mothers, in whom there were more arches in mothers of affected children than in those in the control group (p = 0.01). These results are similar to the results of Jahanbin et al. [24], who, besides an increase in the number of arches, also showed a reduced number of whorls in the mothers of the case group compared to those in the control group. Mathew et al. [23] found that CL/P patients had more arches on their digits than non-cleft individuals. Scott et al. [32] also found that the case group had more arches than the control group, at 3.6% and 0.9%, respectively, with data similar to that reported here, although the differences were not statistically significant in the present study. According to Kücken and Newell [33], of the three dermatoglyphic patterns, arches are the last to develop. The primary ridges that give rise to the arches arise when the volar pads are almost absorbed, and this timing is genetically guided. Thus, it is possible to speculate that delayed development of the papillae, which generates a greater number of arches, coincides with craniofacial malformation. In our study, only fathers of individuals affected by cleft showed a significant difference between the right and left side in terms of atd angle (p = 0.04); mothers and their affected children showed no significant difference in this respect. There was no difference in the asymmetry of the other angles analysed. According to Sánchez-Cascos [34], the magnitude of the atd angle is determined by more than one pair of genes, although it may be influenced by environmental factors during the initial development of the foetus, as well as by NSCL/P. However, in the present study the statistically significant result was obtained from multiple comparisons, and a statistical correction could override this association. Thus, these results should be evaluated as initial and suggestive findings in the Brazilian population. An hereditary character is present in NSCL/P, in which an affected parent has a 5% chance of generating an affected child [35]. Thus, unaffected family members could carry a variable
Table VI. Mean (standard deviation) of the palmar angle by group and category. Case ATD TDA DAT
R L R L R L
44.3 42.4 79.2 80.6 56.5 57.0
Father, n = 101 Control
(6.2) (4.8) (4.1) (4.4) (5.8) (5.2)
45.2 45.3 77.0 77.5 57.8 57.2
(6.1) (6.5) (4.8) (5.7) (5.1) (5.6)
Mother, n = 101 Case Control 45.3 45.0 79.0 79.8 55.8 55.3
(8.6) (6.9) (5.0) (6.2) (7.1) (7.3)
46.8 46.1 76.9 77.0 56.4 57.0
(5.1) (5.3) (5.0) (6.6) (5.7) (4.8)
Case 43.8 43.7 79.1 79.1 57.1 57.2
Son, n = 101 Control
(8.1) (7.5) (5.8) (6.7) (8.1) (7.3)
46.2 45.2 79.1 77.1 57.5 57.7
(7.6) (8.2) (5.7) (6.7) (7.2) (7.4)
Fluctuating asymmetry in cleft lip and/or palate
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Table VII. Asymmetry of the palmar angle by group and category.
Father ATD TDA DAT Mother ATD TDA DAT Son ATD TDA DAT
Case, Mean (SD)
Control, Mean (SD)
n = 51 2.0 (4.1) 1.4 (4.3) 0.6 (5.6) n = 51 0.3 (6.1) 0.8 (5.1) 0.5 (5.9) n = 51 0.1 (4.5) 0.04 (4.7) 0.1 (5.6)
n = 50 0.2 (6.2) 0.3 (4.3) 0.5 (5.1) n = 50 0.9 (4.2) 0.2 (4.6) 0.6 (4.7) n = 50 1.0 (5.4) 0.8 (5.0) 0.2 (3.5)
p-value 0.04* 0.22 0.26 0.29 0.63 0.21 0.44 0.56 0.97
* Statistically significant difference based on the Mann-Whitney test.
number of cleft susceptibility alleles, which are not sufficient to raise them over the threshold leading to an overt cleft, but which may result in subtle, subclinical differences between them and unrelated controls with no family history of clefting [36]. In this way, unaffected individuals in families with clefting have been observed to have increased frequencies of several subclinical traits, including differences in fluctuating asymmetry in dermatoglyphics [11,24,29], other asymmetries such as middle finger length, palm length, palpebral fissure width, and ear length [12], hypodontia [37], and subcutaneous defects in the orbicularis oris (OO) muscle [38,39]. The identification of sub-phenotypes associated with the parents and relatives of affected individuals will be important, so that, in future, in association with epidemiological, genetic, and molecular studies, a strong predictor phenotype can be identified in order to improve treatment and prevent NSCL/P. Conclusion This study found a slight difference in the symmetry of the palmar atd angle of the fathers and the dermatoglyphic patterns of the mothers in association with NSCL/P. This association can be evaluated as suggestive since a statistical correction for multiple comparisons would be able to override these associations. According to the literature and our results, mechanisms responsible for deviations in asymmetric dermatoglyphics in parents may be associated with the factors responsible for the formation of CL/P in children, and further studies are needed to identify the real relationship between these conditions. Research on the molecular biology and cellular genetics of this condition should be conducted to further elucidate this possible association. Acknowledgements The authors would like to thank the members of the Center for Rehabilitation of Craniofacial Anomalies, Minas Gerais State, Brazil. We appreciate the suggestions made by Dr Marise Fagundes Silveira. We would also like to thank the National Council for Scientific and Technological Development (CNPq), Research Support Foundation of the State of Minas Gerais (Fapemig) and Casadinho/Procad - Coordination of
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Improvement of Higher Education Personnel (CAPES) and CNPq, Brazil (HMJ). Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References [1] Dixon MJ, Marazita ML, Beaty TH, Murray JC. Cleft lip and palate: understanding genetic and environmental influences. Nature 2011;12:167–78. [2] Martelli-Júnior H, Orsi Júnior J, Chaves MR, et al. Estudo epidemiológico das fissuras labiais e palatais em Alfenas Minas Gerais - de 1986 a 1998. RPG 2006;13:31–5. [3] Martelli-Júnior H, Porto LV, Martelli DRB, et al. Prevalence of non-syndromic in the state of Minas Gerais, Brazil, between 2000-2005. Braz Oral Res 2007;21:314–17. [4] Paranaíba LMR, Miranda RT, Martelli DRB, et al. Cleft lip and palate: series of unusual clinical cases. Braz J Otorhinolaryngol 2010;76:649–53. [5] Zhu JL, Basso O, Hasle H, et al. Do parents of children with congenital malformations have a higher cancer risk? A national study in Denmark. Br J Cancer 2002;87:524–8. [6] Christensen K, Juel K, Herskind AM, Murray JC. Long-term follow-up study of survival associated with cleft lip and palate at birth. Braz J Microbiol 2004;328:1405–6. [7] Cobourne MT. The complex genetics of cleft lip and palate. Eur J Orthod 2004;29:7–16. [8] Wehby GL, Cassell CH. The impact of orofacial clefts on quality of life and healthcare use and costs. Oral Dis 2010; 16:3–10. [9] Reed T. Dermatoglyphics in medicine: problems and use in suspected chromosome abnormalities. Am J Med Genet 1981;8: 411–29. [10] Jalali F, Hajian-Tilaki KO. A comparative study of dermatoglyphic patterns in patients with myocardial infarction and control group. Acta Med Iranica 2002;40:187–91. [11] Neiswanger K, Cooper ME, Weinberg SM, et al. Cleft lip with or without cleft palate and dermatoglyphic asymmetry: evaluation of a Chinese population. Orthod Craniofac Res 2002;5: 140–6. [12] Neiswanger K, Cooper ME, Liu YE, et al. Bilateral asymmetry in Chinese families cleft lip with or without cleft palate. Cleft Palate Craniofac J 2005;42:192–6. [13] Weinberg SM, Neiswanger K, Martin RA, et al. The Pittsburgh Oral-Facial Cleft study: expanding cleft phenotype. Background and justification. Cleft Palate Craniofac J 2006;43:7–20. [14] De Leon VB, Richtsmeier JT. Fluctuating asymmetry and developmental instability in sagittal craniosynostosis. Cleft Palate Craniofac J 2009;46:187–96. [15] Saha S, Loesch D, Chant D, et al. Directional and fluctuating asymmetry in finger and a-b ridge counts in psychosis: a casecontrol study. BMC Psychiatry 2003;3:1–9. [16] Palmer AR, Strobeck C. Fluctuating asymmetry: measurement, analysis, patterns. Ann Rev Ecol Syst 1986;17:391–421. [17] Brown WM, Price ME, Kang J, et al. Fluctuating asymmetry and preferences for sex-typical bodily characteristics. PNAS 2008; 105:12.938–43. [18] Townsend GC. Fluctuating asymmetry in the deciduous dentition of Australian Aboriginals. J Dent Res 1981;60: 1849–57. [19] Kieser JA, Groeneveld HT. Fluctuating odontometric asymmetry in an urban South African black population. J Dent Res 1988; 67:1200–5. [20] Khalaf K, Elcock C, Smith RN, Brook AH. Fluctuating dental asymmetry of multiple crown variables measured by an image analysis system. Arch Oral Biol 2005;50:249–53. [21] Sprowls MW, Ward RE, Jamison PL, Hartsfield JK. Dental arch asymmetry, fluctuating dental asymmetry, and dental crowding:
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[22] [23] [24] [25]
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a comparison of tooth position and tooth size between antimeres. Semin Orthod 2008;14:157–65. Angelopoulous MV, Vlachou V, Halazonetis DJ. Fluctuating molar asymmetry in relation to environmental radioactivity. Arch Oral Biol 2009;54:666–70. Mathew L, Hegde AM, Rai K. Dermatoglyphic peculiarities in children with oral clefts. J Indian Soc Pedod Prev Dent 2005;12: 179–82. Jahanbin A, Mahdavishahri N, Naseri MM, et al. Dermatoglyphic analysis in parents with nonfamilial bilateral cleft lip and palate children. Cleft Palate Craniofac J 2010;47:9–14. Ghosh JR, Chatterjee M, Raja W, Bandyopadhyay AR. Study on finger and palmar dermatoglyphics among the Sunni Muslims of West Bengal. Anthropologist 2011;13:107–9. Durham NM, Plato CC. Trends in dermatoglyphic research. Netherlands: Kluwer Academic Publishers; 1990. Cummins H. Dermatoglyphics: significant patterning of the body surface. Yale J Biol Med 1946;1:551–67. Reed T, Meier R. Taking Dermatoglyphic Prints: A SelfInstruction Manual, American Dermatoglyphic Association, Bloomington, Ind, USA. 1990. Woolf CM, Gianas AD. A study of fluctuating dermatoglyphic asymmetry in the sibs and parents of cleft lip propositi. Am J Hum Genet 1977;29:503–7. Naugler CT, Ludman MD. Fluctuating asymmetry and disorders of developmental origin. Am J Med Genet 1996;66:15–20.
[31] Medland SE, Loesch DZ, Mdzewski B, et al. Linkage analysis of a model quantitative trait in humans: finger ridge count shows significant multivariate linkage to 5q14.1. Plos Genet 2007;3: 1836–744. [32] Scott NM, Weinberg SM, Neiswanger K, et al. Dermatoglyphic pattern types in subjects with nonsyndromic cleft lip with or without cleft palate (CL/P) and their unaffected relatives in the Philippines. Cleft Palate Craniofac J 2005;42:362–6. [33] Kücken M, Newell AC. Fingerprint formation. J Theoretical Biol 2005;235:71–83. [34] Sánchez-Cascos A. Palm-print patterns in congenital heart disease. Brit Heart J 1965;27:599–630. [35] Bender PL. Genetics of cleft lip and palate. J Pediatr Nurs 2000; 15:242–9. [36] Neiswanger K, Deleyiannis FWB, Avila JR, et al. Candidate genes for oral-facial clefts in Guatemalan families. Ann Plast Surg 2006;56:518–21. [37] Eerens K, Vlietinck R, Heidbuchel K. Hypodontia and tooth formation in groups of children with cleft, siblings without cleft, and nonrelated controls. Cleft Palate Craniofac J 2001;38:374–8. [38] Martin RA, Hunter V, Neufeld-Kaiser W, et al. Ultrasonographic detection of orbicularis oris defects in first degree relatives of isolated cleft lip patients. Am J Med Genet 2000;90:155–61. [39] Yoon YJ, Perkiomaki MR, Tallents RH, et al. Associations of nasomaxillary asymmetry in children with unilateral cleft lip and palate and their parents. Cleft Palate Craniofac J 2003;40:493–7.
ORIGINAL ARTICLE
Evaluating fluctuating asymmetry in a Brazilian population with non-syndromic cleft lip and/or palate
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Bárbara Daniane G. L. Leite1, Izabella Nobre Queiroz1, Sibele Nascimento de Aquino2, Renato Assis Machado3, Lívia Maris R. Paranaíba1, Daniella Reis B. Martelli1, Mário Sérgio O. Swerts4 & Hercílio Martelli-Júnior1,4 1 Stomatology Clinic, Dental School, State University of Montes Claros, Montes Claros, Minas Gerais, Brazil, 2School of Dentistry, Federal University of Juiz de Fora, Governador Valadares, Minas Gerais, Brazil, 3Department of Oral Diagnosis, School of Dentistry, State University of Campinas, Piracicaba, São Paulo, Brazil and 4Center for Rehabilitation of Craniofacial Anomalies, Dental School, University of José Rosário Vellano, Alfenas, Minas Gerais, Brazil
Abstract Objective: The objective of this work was to analyse the levels of dermatoglyphic asymmetry between both parents and individuals with nonsyndromic cleft lip and/or palate (NSCL/P) and unaffected control trios. Methods: A case-control analysis was carried out of 51 affected trios (unaffected parents and NSCL/P subjects), and 50 unaffected control trios. Finger and palm prints were taken from each participant, and dermatoglyphic patterns, the number of lines on the digits, and the palmar angles were recorded. To determine the level of fluctuating asymmetry the case group was compared with the control group, significance accepted at p £ 0.05. Results: There was a statistically significant difference between the atd angles (angle between the lines triradii a and t and triradii t and d) of fathers of those affected by NSCL/P, and the dermatoglyphic patterns of the affected mothers, with significantly more arches in the control group. However, in this study, multiple comparisons were used, and the results must be evaluated as initial findings and evaluated carefully since the significance disappears after correction for multiple comparisons. Other parameters did not differ between groups. There was no difference in parameters among patients affected by NSCL/P. Conclusions: Based on these results it is speculated that the mechanisms responsible for the formation of NSCL/P may be associated with those responsible for deviations in the asymmetry of the atd angles in the fathers and dermatoglyphic patterns of the mothers of affected patients. Besides, further studies are required to determine the real relationship between these conditions. Key Words: Dermatoglyphics, fluctuating asymmetry, non-syndromic cleft lip and/or palate
Introduction Non-syndromic cleft lip and/or palate (NSCL/P, OMIM #119530) is the most common craniofacial anomaly, affecting one in every 700 newborns, with geographic, ethnic, and socioeconomic influences [1]. Studies show an incidence ranging between 0.19–1.54 per 1000 live births [2-4]. The aetiology of NSCL/P is complex, with both environmental and genetic factors playing important roles, and, although much effort has been made to determine the major risk factors, they remain unknown [1]. Although NSCL/P is not a major cause of mortality, it is responsible for a considerable number of morbidities associated with nutrition, speaking and hearing, risk of cancer and numerous other chromosomal and genetic diseases, and psychological and social problems, and imposes a substantial financial burden on families with a concomitant societal burden [1,5-8]. Such problems have stimulated research into the phenotypic markers of this condition, arising from the instability of embryonic development [9-11]. One of these markers is called fluctuating asymmetry (FA) [11,12]. Fluctuating asymmetry is characterised by deviations between structures on the right and left sides of the body, which are usually bilaterally symmetrical. These bilateral structures are programmed by the same genes and, thus, deviations from
bilateral symmetry may represent a phenotypic record of instability present during development [13,14]. The magnitude of this asymmetry is calculated as the difference between the right and left sides of the body [13,15]. Several structures of the human body can be analysed in studies of FA: the sizes and shapes of skeletal elements such as the ears, shoulders, chest, arms, hands, fingers, legs, and feet [12,16,17]; craniofacial form [13,14]; and dental morphology, including the size, position, rotation, and angulation of the teeth [16,18-22]. Studies have also investigated FA based on dermatoglyphics, which is the science of skin relief and drawings from the fingertips, the palms and the soles of feet, revealing qualitative and quantitative characteristics that are not adaptable [11,12,15,23-25]. With the aim of seeking such an association, this study investigated whether the FA of parents and individuals with NSCL/P is significantly higher than that of their unaffected peers. Materials and methods We conducted a case-control study, in which the sample consisted of 303 individuals. The case group (n = 153) included 51 trios formed by individuals with NSCL/P and their parents. The control group (n = 150) also included 50 trios formed by
Correspondence: Sibele Nascimento de Aquino, Department of Oral Diagnosis, School of Dentistry, State University of Campinas, CEP 13414-018, Piracicaba, São Paulo, Brazil. E-mail: [email protected] (Received 9 July 2014; accepted 16 March 2015) 2015 Informa Healthcare.
2 B. D. G. L. Leite et al. A
B
C
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Figure 1. A) arch; B) loop; C) whorl.
parents and individuals who did not have a cleft lip and/or palate, syndrome, or any severe malformation or family history of these conditions. Consanguinity of the parents was recorded by interview, analysing four generations of each family. Finger and palm prints were obtained using the method of Durham and Plato [26]. The phalanges were covered with ink from side to side (radial and ulnar) up to the nails, then immediately supported on paper, rolling on its longitudinal axis from the ulnar side to the radial side. This process was repeated with each finger, starting with the little finger (Finger V) and ending with the thumb (Finger I). For palm prints, the inked hand was supported and gently pressed onto a piece of paper placed on a cylindrical surface so that the whole palm was clearly printed [27], with the aid of the evaluators (I.N.Q and S.N.A). Upon completion of printing, the prints were dermatoglyphically classified. Patterns on the fingers varied according to the number of triradii (deltas) and the presence of a core. The triradii are shaped like a triangle, the sides of which are formed by the meeting of the ridges of the basal region, the marginal region, and nuclear region [28]. Three basic dermatoglyphic patterns can be observed in fingerprints: arch, loop, and whorl (Figure 1). The arch is the simplest pattern, with no cores or triradii and papillary lines that are arranged almost in parallel. The loop has one triradius and one core and the lines are directed to the right or left. The whorl is characterised by the presence of two deltas and one or two cores, with an appearance similar to a “swirl” [24,28]. Ridge counts (RC) were recorded in addition to dermatoglyphic patterns, corresponding to the number of papillary ridges touched by Galton’s line. Galton’s line is an imaginary line between the triradii and the core of the digit. Thus, the RC in an arch is equal to zero because there are no triradii, but there are two counts in a whorl [24] (Evaluator B.D. G.L.L). There is usually a triradius at the base of fingers II–V; these are called a, b, c, and d, respectively. There is also a triradius located more proximal to the wrist and central axis of the hand; this is called triradius t. This triradius, located at the base of the palm, is sometimes found higher up, but below the midline of the palm, in which case it is named t’. When the triradius is located exactly on the midline of the palm, it is called t’’ and, if it is located above the midline, it is called t’’’ [24]. In the current study, palmar angles were calculated according to a straight line drawn between the triradii a and t, between triradii t and d, finally, between triradii a and d, forming a triangle, the angles of which were called atd, tda, and dat (Figure 2). To determine the asymmetry between the right and left hands, differences in standards between the digits, arches, loops, and whorls were recorded, with “0” being assigned for similar patterns and “1” being assigned when patterns differed. The
Figure 2. Trirradiis and palmar angles.
scores for all five pairs of digits were combined, and, thus, in each individual, the score ranged from 0 (when all five pairs showed identical patterns) to 5 (when all five pairs showed different patterns). The dermatoglyphic patterns prevalent among fathers, mothers, and children, cases and controls were assessed. Differences in the RC were also recorded, by subtracting the number of lines on each finger of the right hand from those on the left hand, and summing the total. For palmar angles (atd, tda, dat), the asymmetry was calculated as the difference between each angle obtained on the right hand and its respective angle on the left hand. Data were analysed using the Statistical Package for the Social Sciences version 18.0. Differences between the dermatoglyphic patterns were tested using the Chi-square test. The Mann-Whitney test was used to test for asymmetry between the RC and palmar angles. In all tests, p £ 0.05 was used as the Table I. Age, family history of cleft, and consanguinity in case and control groups.
Age, Mean (SD) Father Mother Son Family history of cleft, n (%) Father Mother Son Consanguinity, n (%) Father Mother
Case
Control
40.7 (9.2) 36.6 (7.4) 9.5 (6.3)
50 (10.8) 46.6 (10.3) 18.4 (7.6)
11 (21.6) 13 (25.5) 22 (43.1)
0 (0.0) 0 (0.0) 0 (0.0)
1 (2.0) 1 (2.0)
0 (0.0) 0 (0.0)
* Statistically significant difference based on the Chi-square test. ** Statistically significant difference based on the T-test.
Fluctuating asymmetry in cleft lip and/or palate
3
Table II. Mean (standard deviation) for ridge counts in each group and category. Father (n = 101) Case Control Digit I Digit II Digit III Digit IV
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Digit V Total
R L R L R L R L R L R L
27.9 21.1 17.4 16.5 14.3 14.5 24.3 23.1 15.4 15.3 99.4 93.0
(14.8) (14.8) (11.8) (11.5) (8.3) (7.8) (12.6) (12.9) (8.3) (7.7) (45.4) (42.1)
28.6 24.1 17.6 17.5 15.4 16.7 21.5 20.6 16.5 16.1 99.8 95.0
Mother (n = 101) Case Control
(12.8) (12.2) (10.7) (12.1) (9.8) (10.6) (11.3) (10.5) (6.9) (7.4) (40.2) (40.2)
25.6 22.5 17.8 15.7 16.0 15.1 22.4 22.7 15.5 16.2 97.3 92.2
level of statistical significance. This study was approved by the institutional Research Ethics Committee of the research. Results The general characteristics of the participating groups are shown in Table I, including age, CL/P in the family history of the children and their parents, and consanguinity in the parents. Table II presents the means and standard deviations (SD) of RC per digit and the total for the right and left hands, the parents (n = 151), mothers (n = 151), and children (n = 151). There was no significant difference in this variable between the different groups. The FA in the RC per digit and total RC did not differ significantly between cases and controls, as shown in Table III. Likewise, there was no difference between the cases and
Table III. Asymmetry in the ridge counts on the five digits in each group and category.
Father Digit I Digit II Digit III Digit IV Digit V Total Mother Digit I Digit II Digit III Digit IV Digit V Total Son Digit I Digit II Digit III Digit IV Digit V Total
Case, Mean (SD)
Control, Mean (SD)
n = 51 4.8 (7.5) 1.0 (8.8) 0.2 (6.3) 1.1 (7.8) 0.2 (4.1) 7.2 (17.4) n = 51 3.1 (7.4) 2.1 (8.0) 1.0 (4.6) 0.2 (8.2) 0.8 (5.6) 5.2 (17.0) n = 51 4.5 (7.2) 0.5 (8.5) 2.5 (7.4) 1.0 (9.6) 1.1 (5.6) 2.6 (20.9)
n = 50 4.5 (10.4) 0.2 (9.0) 1.3 (8.4) 1.0 (7.2) 0.5 (3.7) 4.9 (19.9) n = 50 3.1 (9.4) 1.3 (9.5) 1.2 (7.3) 0.4 (8.1) 0.5 (4.4) 2.3 (18.6) n = 50 1.1 (8.8) 1.6 (8.1) 1.1 (7.6) 0.1 (7.4) 0.04 (4.5) 1.4 (19.7)
p-value 0.39 0.76 0.50 0.88 0.91 0.59 0.93 0.96 0.23 0.80 0.82 0.65 0.13 0.92 0.33 0.57 0.93 0.75
(14.4) (14.2) (13.7) (12.8) (11.5) (11.9) (13.9) (13.7) (8.1) (9.5) (52.3) (51.9)
26.7 23.6 17.7 16.4 15.2 16.4 21.4 21.8 14.8 15.3 95.9 93.6
(13.5) (13.9) (13.3) (13.0) (10.2) (11.9) (10.6) (12.4) (6.5) (7.4) (43.6) (46.2)
Case 25.8 20.9 15.7 15.2 13.1 15.6 20.9 21.9 15.5 14.4 90.5 87.9
Son (n = 101) Control
(13.5) (13.2) (12.0) (12.7) (8.7) (11.5) (11.1) (13.8) (8.1) (6.7) (41.9) (47.6)
25.8 24.8 16.9 15.4 13.6 14.7 20.1 20.1 15.2 15.3 91.6 90.2
(11.8) (12.1) (12.6) (11.2) (7.4) (10.7) (11.2) (12.8) (7.4) (7.7) (38.5) (43.9)
controls in terms of the asymmetries in digital dermatoglyphic patterns (arches, loops, and whorls) measured by the difference in score between the left and right sides (Table IV). With regards to the prevalence of dermatoglyphic finger patterns, Table V reveals that only the mothers showed significant differences when comparing cases and controls (p = 0.01), with a significantly higher number of arches in the digits of the case group (n = 49) compared to controls (n = 26). Table VI presents the means and SD of the palmar atd, tda. and dat angles of fathers, mothers. and children, with no significant differences between groups. However, analysis of the FA between the angles (Table VII) revealed a significant difference between the fathers in terms of the atd angle fissures (p = 0.04), with greater asymmetry between the cases than the controls. Mothers (p = 0.29) and children (p = 0.44) showed no differences in the FA of this angle. Discussion Fluctuating asymmetry measured by dermatoglyphics can be considered one of these markers, as the presence of excessive asymmetry of dermatoglyphic patterns between the right and left hands may reflect unstable genetic control during embryogenesis that may contribute to the development of congenital malformations such as NSCL/P [12,29,30]. The presence of CL/P is directly related to the development of the primary palate and lips, which is completed in the 7th week of intrauterine life, and the secondary palate, which is completed in the 12th week. This period of craniofacial formation coincides with the formation of papillary lines, which develop from the volar pads from the 6th to the 12th or 13th week. This means that genetic messages contained in the genome that are deciphered during this period are also reflected by dermatoglyphics [23], which in this study was assessed
Table IV. Mean (standard deviation) of the difference in dermatoglyphic pattern scores by group and category.
Father Mother Son
Case
Control
0.90 (0.88) 1.04 (0.94) 1.25 (1.17)
0.94 (0.91) 1.18 (1.06) 1.06 (0.91)
p-value 0.87 0.60 0.54
4 B. D. G. L. Leite et al. Table V. Number and percentage of dermatoglyphic patterns by category.
Father Mother Son
Arch, n (%)
Case Loop, n (%)
Whorl, n (%)
Arch, n (%)
Control Loop, n (%)
Whorl, n (%)
p-value
22 (4.3) 49 (9.6) 38 (7.5)
336 (66.1) 302 (59.2) 333 (65.3)
150 (29.5) 159 (31.2) 139 (27.3)
17 (3.4) 26 (5.2) 25 (5.0)
335 (67.0) 333 (66.6) 346 (69.2)
148 (29.6) 141 (28.2) 129 (25.8)
0.75 0.01* 0.20
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* Statistically significant difference based on the Chi-square test.
according to the dermatoglyphic pattern, ridge counts, and palmar angles. This study showed no statistically significant difference between the average RC on the left and right sides of the individuals in the case and control groups, and no significant difference in the asymmetry of the RC, as in the study of Neiswanger et al. [11]. In a similar study, Jahanbin et al. [24] found no difference in the RC of the fathers, but observed a difference on digit I of the mothers. While there were no statistically significant differences, both RC and CLP/NS are highly heritable, and estimates using traditional methods based on correlation or structural equation models in twins or families have shown that genetic effects account for ~90% of all variation. This genetic effect can be observed both in the total ridge count (TRC) and the ridge counts per finger [31]. There was no significant difference in the asymmetry of dermatoglyphic patterns, arches, loops, or whorls based on the assignment of scores. As in our study, Jahanbin et al. [24] found no significant asymmetry in the dermatoglyphic patterns of parents of children with NSCL/P. Analysing themselves affected by NSCL/P, Woolf and Gianas [29] found more statistically significant differences in asymmetry between those who had cases of CL/P in the family than in sporadic cases. Using a similar methodology, Scott et al. [32] also found a statistically significant difference in this variable in individuals with CL/P, and this difference was more pronounced in women, indicating some kind of gender-linked inheritance. Scott et al. [32] also highlighted the fact that these scores are typically used as measures of asymmetry and are, thus, in turn, markers of instability. Analysis of the palmar dermatoglyphics performed by Neiswanger et al. [11], who measured the atd angles of those affected by cleft and their parents, showed no significant differences between cases and controls. Jahanbin et al. [24] found significant differences in asymmetry in both fathers and mothers of cleft individuals, compared with the control group. In a comparison of those affected by cleft who had a family history of CL/P with individuals with no family history of cleft, Woolf and Gianas [29] also found significant differences in the
asymmetry of atd angles, such that those affected with a family history were more asymmetrical, reinforcing the genetic character of the FA. The frequencies of the patterns were also evaluated, with similarities in frequencies being observed between case and control groups. An exception was observed in the mothers, in whom there were more arches in mothers of affected children than in those in the control group (p = 0.01). These results are similar to the results of Jahanbin et al. [24], who, besides an increase in the number of arches, also showed a reduced number of whorls in the mothers of the case group compared to those in the control group. Mathew et al. [23] found that CL/P patients had more arches on their digits than non-cleft individuals. Scott et al. [32] also found that the case group had more arches than the control group, at 3.6% and 0.9%, respectively, with data similar to that reported here, although the differences were not statistically significant in the present study. According to Kücken and Newell [33], of the three dermatoglyphic patterns, arches are the last to develop. The primary ridges that give rise to the arches arise when the volar pads are almost absorbed, and this timing is genetically guided. Thus, it is possible to speculate that delayed development of the papillae, which generates a greater number of arches, coincides with craniofacial malformation. In our study, only fathers of individuals affected by cleft showed a significant difference between the right and left side in terms of atd angle (p = 0.04); mothers and their affected children showed no significant difference in this respect. There was no difference in the asymmetry of the other angles analysed. According to Sánchez-Cascos [34], the magnitude of the atd angle is determined by more than one pair of genes, although it may be influenced by environmental factors during the initial development of the foetus, as well as by NSCL/P. However, in the present study the statistically significant result was obtained from multiple comparisons, and a statistical correction could override this association. Thus, these results should be evaluated as initial and suggestive findings in the Brazilian population. An hereditary character is present in NSCL/P, in which an affected parent has a 5% chance of generating an affected child [35]. Thus, unaffected family members could carry a variable
Table VI. Mean (standard deviation) of the palmar angle by group and category. Case ATD TDA DAT
R L R L R L
44.3 42.4 79.2 80.6 56.5 57.0
Father, n = 101 Control
(6.2) (4.8) (4.1) (4.4) (5.8) (5.2)
45.2 45.3 77.0 77.5 57.8 57.2
(6.1) (6.5) (4.8) (5.7) (5.1) (5.6)
Mother, n = 101 Case Control 45.3 45.0 79.0 79.8 55.8 55.3
(8.6) (6.9) (5.0) (6.2) (7.1) (7.3)
46.8 46.1 76.9 77.0 56.4 57.0
(5.1) (5.3) (5.0) (6.6) (5.7) (4.8)
Case 43.8 43.7 79.1 79.1 57.1 57.2
Son, n = 101 Control
(8.1) (7.5) (5.8) (6.7) (8.1) (7.3)
46.2 45.2 79.1 77.1 57.5 57.7
(7.6) (8.2) (5.7) (6.7) (7.2) (7.4)
Fluctuating asymmetry in cleft lip and/or palate
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Table VII. Asymmetry of the palmar angle by group and category.
Father ATD TDA DAT Mother ATD TDA DAT Son ATD TDA DAT
Case, Mean (SD)
Control, Mean (SD)
n = 51 2.0 (4.1) 1.4 (4.3) 0.6 (5.6) n = 51 0.3 (6.1) 0.8 (5.1) 0.5 (5.9) n = 51 0.1 (4.5) 0.04 (4.7) 0.1 (5.6)
n = 50 0.2 (6.2) 0.3 (4.3) 0.5 (5.1) n = 50 0.9 (4.2) 0.2 (4.6) 0.6 (4.7) n = 50 1.0 (5.4) 0.8 (5.0) 0.2 (3.5)
p-value 0.04* 0.22 0.26 0.29 0.63 0.21 0.44 0.56 0.97
* Statistically significant difference based on the Mann-Whitney test.
number of cleft susceptibility alleles, which are not sufficient to raise them over the threshold leading to an overt cleft, but which may result in subtle, subclinical differences between them and unrelated controls with no family history of clefting [36]. In this way, unaffected individuals in families with clefting have been observed to have increased frequencies of several subclinical traits, including differences in fluctuating asymmetry in dermatoglyphics [11,24,29], other asymmetries such as middle finger length, palm length, palpebral fissure width, and ear length [12], hypodontia [37], and subcutaneous defects in the orbicularis oris (OO) muscle [38,39]. The identification of sub-phenotypes associated with the parents and relatives of affected individuals will be important, so that, in future, in association with epidemiological, genetic, and molecular studies, a strong predictor phenotype can be identified in order to improve treatment and prevent NSCL/P. Conclusion This study found a slight difference in the symmetry of the palmar atd angle of the fathers and the dermatoglyphic patterns of the mothers in association with NSCL/P. This association can be evaluated as suggestive since a statistical correction for multiple comparisons would be able to override these associations. According to the literature and our results, mechanisms responsible for deviations in asymmetric dermatoglyphics in parents may be associated with the factors responsible for the formation of CL/P in children, and further studies are needed to identify the real relationship between these conditions. Research on the molecular biology and cellular genetics of this condition should be conducted to further elucidate this possible association. Acknowledgements The authors would like to thank the members of the Center for Rehabilitation of Craniofacial Anomalies, Minas Gerais State, Brazil. We appreciate the suggestions made by Dr Marise Fagundes Silveira. We would also like to thank the National Council for Scientific and Technological Development (CNPq), Research Support Foundation of the State of Minas Gerais (Fapemig) and Casadinho/Procad - Coordination of
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Improvement of Higher Education Personnel (CAPES) and CNPq, Brazil (HMJ). Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References [1] Dixon MJ, Marazita ML, Beaty TH, Murray JC. Cleft lip and palate: understanding genetic and environmental influences. Nature 2011;12:167–78. [2] Martelli-Júnior H, Orsi Júnior J, Chaves MR, et al. Estudo epidemiológico das fissuras labiais e palatais em Alfenas Minas Gerais - de 1986 a 1998. RPG 2006;13:31–5. [3] Martelli-Júnior H, Porto LV, Martelli DRB, et al. Prevalence of non-syndromic in the state of Minas Gerais, Brazil, between 2000-2005. Braz Oral Res 2007;21:314–17. [4] Paranaíba LMR, Miranda RT, Martelli DRB, et al. Cleft lip and palate: series of unusual clinical cases. Braz J Otorhinolaryngol 2010;76:649–53. [5] Zhu JL, Basso O, Hasle H, et al. Do parents of children with congenital malformations have a higher cancer risk? A national study in Denmark. Br J Cancer 2002;87:524–8. [6] Christensen K, Juel K, Herskind AM, Murray JC. Long-term follow-up study of survival associated with cleft lip and palate at birth. Braz J Microbiol 2004;328:1405–6. [7] Cobourne MT. The complex genetics of cleft lip and palate. Eur J Orthod 2004;29:7–16. [8] Wehby GL, Cassell CH. The impact of orofacial clefts on quality of life and healthcare use and costs. Oral Dis 2010; 16:3–10. [9] Reed T. Dermatoglyphics in medicine: problems and use in suspected chromosome abnormalities. Am J Med Genet 1981;8: 411–29. [10] Jalali F, Hajian-Tilaki KO. A comparative study of dermatoglyphic patterns in patients with myocardial infarction and control group. Acta Med Iranica 2002;40:187–91. [11] Neiswanger K, Cooper ME, Weinberg SM, et al. Cleft lip with or without cleft palate and dermatoglyphic asymmetry: evaluation of a Chinese population. Orthod Craniofac Res 2002;5: 140–6. [12] Neiswanger K, Cooper ME, Liu YE, et al. Bilateral asymmetry in Chinese families cleft lip with or without cleft palate. Cleft Palate Craniofac J 2005;42:192–6. [13] Weinberg SM, Neiswanger K, Martin RA, et al. The Pittsburgh Oral-Facial Cleft study: expanding cleft phenotype. Background and justification. Cleft Palate Craniofac J 2006;43:7–20. [14] De Leon VB, Richtsmeier JT. Fluctuating asymmetry and developmental instability in sagittal craniosynostosis. Cleft Palate Craniofac J 2009;46:187–96. [15] Saha S, Loesch D, Chant D, et al. Directional and fluctuating asymmetry in finger and a-b ridge counts in psychosis: a casecontrol study. BMC Psychiatry 2003;3:1–9. [16] Palmer AR, Strobeck C. Fluctuating asymmetry: measurement, analysis, patterns. Ann Rev Ecol Syst 1986;17:391–421. [17] Brown WM, Price ME, Kang J, et al. Fluctuating asymmetry and preferences for sex-typical bodily characteristics. PNAS 2008; 105:12.938–43. [18] Townsend GC. Fluctuating asymmetry in the deciduous dentition of Australian Aboriginals. J Dent Res 1981;60: 1849–57. [19] Kieser JA, Groeneveld HT. Fluctuating odontometric asymmetry in an urban South African black population. J Dent Res 1988; 67:1200–5. [20] Khalaf K, Elcock C, Smith RN, Brook AH. Fluctuating dental asymmetry of multiple crown variables measured by an image analysis system. Arch Oral Biol 2005;50:249–53. [21] Sprowls MW, Ward RE, Jamison PL, Hartsfield JK. Dental arch asymmetry, fluctuating dental asymmetry, and dental crowding:
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