The Cleft Palate–Craniofacial Journal 00(00) pp. 000–000 Month 0000 Ó Copyright 2015 American Cleft Palate–Craniofacial Association
ORIGINAL ARTICLE Evaluation of Delayed Puberty in Adolescents With Cleft Lip/Palate ˆ M.D., M.S., Ilza Lazarini Marques, M.D., PhD., Heloisa Bettiol, M.D., PhD. Maria Cristina Cres, Objective: To assess the frequency of delayed puberty in adolescents with cleft lip and/or cleft palate (CL/P). Design: This was a cross-sectional study of 203 patients with CL/P and no associated syndromes treated at the Hospital for Rehabilitation of Craniofacial Anomalies, University of Sa˜o Paulo, Bauru, Brazil. We evaluated boys aged 14–19 years and girls aged 13–18 years. The patients were classified according to Tanner stages of sexual development. The age of menarche was recorded. Patients were assigned to three groups according to cleft type: isolated cleft lip (CL), cleft lip and palate (CLP), and isolated cleft palate (CP).The results were expressed as frequencies and averages and compared with pubertal changes described for typically developing adolescents as reported in the literature. Results: Subjects were 115 boys and 88 girls. All boys in the CL group and the CP group had already started puberty, and two boys in the CLP group (2.3%) had delayed puberty. All girls had started puberty. The average age at menarche was 12.3 years in the CL group, 12.1 years in the CLP group, and 12.5 years in the CP group. Conclusions: The frequency of delayed puberty and the average age at menarche in adolescents with CL/P and no associated genetic syndromes or anomalies were within the expected range for typically developing adolescents (i.e., those without CL/P) in the same age group. KEY WORDS:
cleft lip/palate, development, delayed puberty, menarche
Delayed puberty is defined as the absence of testicular enlargement in boys or breast development in girls at an age that is 2 to 2.5 SDs later than the population mean (traditionally, the age of 14 years in boys and 13 years in girls) (Marshall and Tanner, 1969; Marshall and Tanner, 1970; Palmert and Dunkel, 2012). A possible association of CL/P with pituitary hormone deficiency (Laron et al., 1969; Roitman and Laron, 1978; Rudman et al., 1978; Tuohy and Franklin, 1984) has been suggested and is based on the shared embryonic origin of the pituitary and face structures that form the lip and palate. Although the embryogenesis of the palate and anterior pituitary is not directly dependent on one or the other structure, both have an ectodermal origin and have proximity in time and space (from 5 to 7 fetal weeks for the lip, from 5 to 12 fetal weeks for the palate, and from 3 to 8 fetal weeks for the anterior pituitary) (Moore and Persaud, 2008a; Moore and Persaud, 2008b; Muhamad, 2012). The action of a teratogenic factor during this embryonic period could simultaneously disturb the formation of these structures, leading to the development of CL/P and anatomic and/or functional pituitary changes (Rudman et al., 1978). Moreover, some studies have suggested that brain development is strongly related to face development and that craniofacial disorders may be associated with brain disorders (Kjaer, 1995; Nopoulos et al., 2001; Nopoulos et al., 2002; Calzolari et al., 2007; Mueller et al., 2007; Nopoulos et al., 2007).
Cleft lip and/or cleft palate (CL/P) is characterized by a morphologic disorder that alters the facial structures and affects the anatomy and function of facial muscles at varying degrees of severity. CL/P may affect the lip only (isolated cleft lip, CL), the lip and palate (cleft lip and palate, CLP), or the palate only (isolated cleft palate, CP). CL/P is one of the most frequent congenital disorders in humans, has a global average prevalence of 1:600 live births, and is recognized by the World Health Organization as an important public health problem (World Health Organization, 2002; Garib et al., 2010). Puberty development requires an intact hypothalamicpituitary-gonadal axis, which is responsible for the secretion of hormones that stimulate gonadal maturation and production of sex steroids (Nakamoto et al., 2010).
Dr. Maria Cristina Cres ˆ is Pediatrician Endocrinologist, Hospital Estadual Bauru, University of the State of Sa˜o Paulo, Bauru, Brazil. Dr. Ilza Lazarini Marques is Pediatrician and Director of Medical Service, Hospital for Rehabilitation of Craniofacial Anomalies, University of Sa˜o Paulo, Bauru, Brazil. Dr. Heloisa Bettiol is Associate Professor, University of Sa˜o Paulo, Department of Pediatrics, Hospital das Cl ´ınicas de Ribeira˜o Preto, Ribeira˜o Preto, Brazil. Submitted June 2014; Revised March 2015 and July 2015; Accepted September 2015. Address correspondence to: Maria Cristina Cres, ˆ Rua Gilberto Bresolin, n. 2-58, Bauru, Sa˜o Paulo, Brazil. E-mail: [email protected]. br. DOI: 10.1597/14-175 0
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TABLE 1
Tanner Staging Maturational
Breast Development: Female M1 ¼ Preadolescent: elevation of papilla only M2 ¼ Brest bud stage: elevation of breast and papilla as small mound. Enlargement of areolar diameter. M3 ¼ Further enlargement and elevation of breast and areola, with no separation of their contours. M4 ¼ Projection of aerola and papilla to form a secondary mound above the level of the breast. M5 ¼ Mature stage: projection of papilly only, due to recession of the areola to the general contour of the breast. Genital Development: Male G1 ¼ Preadolescent. Testes, scrotum, and penis are of about the same size and proportion as in early childhood. G2 ¼ Enlargement of scrotum and of testes. The skin of the scrotum reddens and changes in texture. Little or no enlargement of penis at this stage. G3 ¼ Enlargement of penis, which occurs at first mainly in length. Further growth of testes and scrotum. G4 ¼ Increased size of penis with growth in breadth and development of glands. Further enlargement of testes and scrotum; increased darkening of scrotal skin. G5 ¼ Genitalia adult in size and shape. Pubic Hair: Female and Male P1 ¼ Preadolescent. The vellus over the pubes is not further developed than that over the abdominal wall, that is, no pubic hair. P2 ¼ Sparse growth of long, slightly pigmented downy hair, straight or only slightly curled, appearing chiefly at the base the penis or along the labia. P3 ¼ Considerably darker, coarser, and curlier. The hair spreads sparsely over the junction of the pubes. P4 ¼ Hair now resembles adult in type, but the area covered by it is still considerably smaller than in an adult. No spread to the medial surface of the thighs. P5 ¼ Adult in quantity and type with distribution of the horizontal pattern. Spread to medial surface of thighs but not up linea alba or elsewhere above the base of the inverse triangle.
Schaefer (1995) reported that early puberty was rare in patients with CL/P but that delayed puberty was more frequent as a result of subtle central nervous system (CNS) midline disorders, and that an increased incidence of midline abnormalities was associated with CL/P. Additionally, changes in CNS development may occur without anatomic lesions in the CNS. In this study, we aimed to investigate the occurrence of delayed puberty in adolescents with CL/P and no associated syndromes, which may be the result of insufficient production of gonadotropin from anterior pituitary and suggests that changes in this gland and CL/ P may be associated. METHODS This was a cross-sectional study of 203 adolescents who were treated at the Hospital for Rehabilitation of Craniofacial Anomalies, University of Sa˜o Paulo (HRAC–USP), Bauru, Brazil. HRAC–USP is a reference center for the care of patients with CL/P in Brazil and sees patients from several Brazilian states. We selected patients with CL/P who had no other anomalies or known associated genetic syndromes. The age range was 14 to 19 years for boys and 13 to 18 years for girls. Adolescents with CL/P without associated genetic syndromes were not included in the study if they were born preterm or if they presented chronic or autoimmune diseases, because of the possible relationship of these conditions with delayed puberty (Palmert and Dunkel, 2012). Puberty was considered to be delayed when secondary sexual characteristics were absent in girls older than 13 years and in boys older than 14 years. The absence of menarche by the age of 16 was also considered to be late
puberty (Marshall and Tanner, 1969; Marshall and Tanner, 1970; Palmert and Dunkel, 2012). Data were collected once a week from May to December 2013. All patients who were part of the HRAC–USP treatment protocol and who met the study criteria were evaluated. All patients had undergone palatoplasty at an earlier age according to the HRAC–USP protocol (Bertier et al., 2007). Genital and pubic hair development in boys and breast and pubic hair development in girls were determined using the Tanner staging system (Marshall and Tanner, 1969; Marshall and Tanner, 1970), which considers breast bud (stage M2) and testis (4 cm3, stage G2) development to indicate the onset of puberty in girls and boys, respectively (Table 1). A Prader orchidometer was used to measure the size of testes, and the age of menarche was determined by asking girls when they had begun to menstruate. Data from boys and girls were analyzed separately, and patients were assigned to three groups according to cleft type: patients with isolated cleft lip (CL), patients with cleft lip and palate (CLP), and patients with isolated cleft palate (CP). Descriptive statistics (means and frequencies) were calculated for all variables. Fisher’s exact test was used to compare the three groups according to cleft type. The study was approved by the HRAC–USP Research Ethics Committee (CAAE number 10038513.2.0000.5441), and a parent or legal guardian gave written informed consent for the participation of each adolescent. RESULTS Of the 203 patients evaluated, 115 (56.7%) were boys and 88 (43.3%) were girls. Nineteen (16.5%) boys were in the CL group, 86 (74.8%) in the CLP group, and 10 (8.7%) in
ˆ et al., PUBERTY AND CLEFT LIP AND PALATE Cres
TABLE 2 Pubertal Staging and Cleft Type in Boys With Cleft Lip and/or Palate Cleft Type Pubertal Staging
CL
CLP
CP
Genitals G1 G2 G3 G4 G5
0 0 3 11 5
2 1 5 56 22
0 0 1 4 5
Pubic hair P1 P2 P3 P4 P5
0 0 5 11 3
1 3 14 51 17
0 0 1 5 4
* CL ¼ isolated cleft lip; CLP ¼ cleft lip and palate; CP ¼ isolated cleft palate; G1 to G5 ¼ Tanner staging for genital development; P1 to P5 ¼ Tanner staging for pubic hair development.
the CP group, whereas 23 (26.1%) girls were in the CL group, 55 (62.5%) in the CLP group and 10 (11.4%) in the CP group. All 19 boys in the CL group had already started puberty and had genitals and pubic hair between Tanner stages 3 and 5. In this group, 11 boys were 16 to 19 years old and had genitals in Tanner stages 4 or 5. Of the 86 boys in the CLP group, only two (2.3%) had delayed puberty (Tanner stage 1), whereas the other 84 had genitals and pubic hair between Tanner stages 2 and 5. In this group, 46 boys were 16 to 19 years old; 45 of them (97.8%) had genitals in stages 4 or 5 and one (2.2%) had genitals in stage 2 with late onset (constitutional delay) or slow progression of puberty (Table 2). All 10 boys in the CP group had already started puberty and had genitals and pubic hair between Tanner stages 3 and 5. In this group, 5 boys were 16 to 19 years old and had genitals in stages 4 or 5. The frequency of delayed puberty did not differ significantly between the three groups of boys according to cleft type (p ¼ 1.00). TABLE 3 Pubertal Staging and Cleft Type in Girls With Cleft Lip and/or Palate Cleft Type Pubertal Staging
CL
CLP
CP
Breast B1 B2 B3 B4 B5
0 0 1 2 20
0 0 3 4 48
0 0 0 2 8
Pubic hair P1 P2 P3 P4 P5
0 0 2 2 19
0 0 5 8 42
0 0 0 4 6
* CL ¼ isolated cleft lip; CLP ¼ cleft lip and palate; CP ¼ isolated cleft palate; B1 to B5 ¼ Tanner staging for breast development; P1 to P5 ¼ Tanner staging for pubic hair development.
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All girls in the CL, CLP, and CP groups had already started puberty and had genital development between Tanner stages 3 and 5 (Table 3). Twenty-two girls in the CL group (95.6%), 50 girls in the CLP group (90.9%), and 10 girls in the CP group (100%) had already started to menstruate. In addition, all girls aged 15 to 18 years had breast development in stages 4 or 5 and had already menstruated. The average age of menarche was 12.3 years (range: 8.8 to 14.1 years) in the CL group, 12.1 years in the CLP group (range: 10.0 to 15.2 years), and 12.5 years (range: 11.0 to 15.0 years) in the CP group. The six girls (one from the CL group and five from the CLP group) who had not yet had menarche were 13.2 to 13.8 years old and were in stages 3 or 4 of pubertal development. DISCUSSION In this study, we observed a higher frequency of boys than girls (1.3:1) and a higher frequency of lip and palate clefts than isolated lip clefts and isolated palate clefts in both sexes, findings that are consistent with the literature on CL/P (Rodrigues et al, 2009). In addition, of all adolescents evaluated, only two boys in the CLP group (2.3%) had not started puberty by age 14. The cases of delayed onset of puberty observed in our study may have been caused by gonadotropin deficiencies and may have been associated with the same etiologic origin of CL/P. Another patient in the CLP group had less developed genitals than expected for his chronological age, which may represent a constitutional delay or slow progression of puberty caused by gonadotropin deficiency. However, the frequency of cases of delayed puberty observed in this study was within the expected range for adolescents in the general population, estimated at around 2.5% (Marshall and Tanner, 1969; Marshall and Tanner, 1970). Some of these cases may represent a constitutional delay of puberty, by which adolescents spontaneously begin puberty at older ages (Palmert and Dunkel, 2012). In a study that evaluated a large number of cases of delayed puberty, approximately 65% of boys and 30% of girls had a constitutional delay of puberty (Sedlmeyer and Palmert, 2002). Thus, the precise diagnosis of these cases could only be determined after laboratory evaluation and patient follow-up, which was not possible in a cross-sectional study such as ours. Curiously, all patients with some degree of delayed puberty were from the CLP group, that is, patients with lip and palate clefts, indicating that some type of association between delayed development and presence of CLP may exist. The association between pituitary deficiencies and CLP without associated genetic syndromes was proposed in studies on children with CLP (Laron et al., 1969; Roitman and Laron, 1978; Tuohy and Franklin, 1984). The lip, palate, and anterior pituitary have the same embryonic origin. The ectodermal cells of the neural crest
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Cleft Palate–Craniofacial Journal, Month 0000, Vol. 00 No. 00
migrate to the future site of the head and neck, developing prominences to form the primitive oral cavity. The anterior pituitary is formed from the Rathke pouch, an evagination from the ectodermal roof of the primitive oral cavity (Moore and Persaud, 2008b). This close embryologic relationship and the cases of gonadotropin deficiencies in patients with CL/P reported previously (Laron et al., 1969; Rudman et al., 1978; Tuohy and Franklin, 1984) reinforce the suspicion that changes in the anterior pituitary and lip and palate may be associated. Moreover, brain changes and abnormal brain development have been reported in patients with CL/P (Nopoulos et al., 2001; Nopoulos et al., 2002; Mueller et al., 2007; Nopoulos et al., 2007). Conversely, no anatomic differences were found in a study that analyzed the volume of the pituitary gland in patients with CL/P and no associated syndromes aged 7 to 25 years (Van der Plas et al., 2012). However, subtle changes, which may lead to functional changes to the pituitary gland, may occur even in the absence of anatomic abnormalities detected by currently available imaging tests. Thus, hormonal deficiencies may in fact be involved in cases of delayed puberty in adolescents with CL/P. Girls did not show delayed pubertal development or menarche. In clinical practice, delayed puberty is more often observed in boys than in girls, and this pattern was also observed in the present study. The present study cannot confirm the association between CL/P and delayed puberty, but if this association exists, the frequency of delayed puberty was not greater in patients with CL/P than in patients without CL/P in this sample. Short stature has been reported in children and adolescents with CL/P (Montagnoli et al., 2005; Perssonet al., 2007; Zanateet al., 2010; Van der Plas et al., 2012) and delayed onset of puberty can enhance the height deficit during this period. However, if this height deficit is identified early and properly treated, the final height may still be within the genetic size expected for the patient. Adolescence is a time of anxiety about self-image. Delayed puberty can contribute to the fact that adolescents with CL/P feel even more different from their friends (Graciano et al., 2007). For patients with CL/P, appropriate actions on the part of health professionals, the development of a plan of treatment that includes the patients and their families, addressing the patients as a whole, can contribute to the process of social inclusion of these individuals (Graciano et al., 2007; Berger and Dalton, 2011). Several studies have assessed the growth of children with CL/P, mainly in children under 10 years of age (Bowers et al., 1987; Cunningham and Jerome, 1997; Montagnoli et al., 2005; Marques et al., 2009; Zanateet al., 2010; Marques, 2012), but few studies have evaluated growth during adolescence (Persson et al., 2007; Koltz et al., 2012) and no studies have assessed pubertal development in adolescents with CL/P. The delay in the onset of pubertal
development in patients with CL/P can be an important sign of pituitary hormonal deficiencies. This could guide health professionals in identifying patients who should be investigated for possible pituitary changes. On the other hand, the cross-sectional design was a limitation of the study, because we could not evaluate the onset and progress of pubertal development. Nevertheless, this experimental design enabled us to determine that the frequency of delayed puberty in adolescents with clefts did not differ from that expected for typical adolescents at the ages evaluated in this sample. Further studies in younger age groups may help to assess early puberty. Larger samples and longitudinal studies during the pubertal period may help to investigate possible changes in pubertal progress in these patients and provide a better assessment of the hypothalamic-pituitary-gonadal axis. CONCLUSIONS The frequency of delayed puberty and the average age of menarche in adolescents with CL/P and no associated genetic syndromes or anomalies were within the expected range for typical adolescents (i.e., those without CL/P) in the same age group. REFERENCES Berger ZE, Dalton LJ. Coping with a cleft II: factors associated with psychosocial adjustment of adolescents with a cleft lip and palate and their parents. Cleft Palate Craniofac J. 2011;48:82– 90. Bertier CE, Trindade IEK, Silva Filho OG. Cirurgias Prima´rias de La´bio e Palato. In: Trindade IEK, Silva Filho OG. Fissuras Labiopalatinas: Uma Abordagem Interdisciplinar. Sa˜o Paulo: Santos Editora; 2007:73–85. Bowers EJ, Mayro RF, Whitaker LA, Pasquariello PS, La Rossa D, Randall P. General body growth in children with clefts of the lip, palate, and craniofacial structure. Scand J Plast Reconstr Surg. 1987;21:7–14. Calzolari E, Pierini A, Astolfi G, Bianchi F, Neville AJ, Rivieri F, EUROCAT Working Group. Associated anomalies in multimalformed infants with cleft lip and palate: an epidemiologic study of nearly 6 million births in 23 EUROCAT registries. Am J Med Genet Part A. 2007;143(A):528–537. Cunningham ML, Jerome JT. Linear growth characteristics of children with cleft lip and palate. J Pediatr. 1997;131:707–711. Garib DG, Silva Filho OG, Janson G, Pinto JHN. Etiologia das ma´s oclusoes: perspectiva cl ´ınica (parte III): fissuras labiopa˜ ´ Ortodon Dent Press. 2010;9(4):30–36. latinas. Ver Clın Graciano MIG, Tavano LD, Bachega MI. Aspectos psicossociais da reabilitaca ¸ ˜ o. In: Trindade IEK, Silva Filho OG. Fissuras Labiopalatinas: Uma Abordagem Interdisciplinar. Sa˜o Paulo: Santos Editora; 2007:311–333. Kjaer I. Human prenatal craniofacial development related to brain development under normal and pathologic conditions. Acta Odontol Scand. 1995;53:135–143. Koltz PF, Wasicek P, Mays C, Bloom J, Girotto JA. Growth trajectory of children and adolescents with isolated cleft lip
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and/or palate through the first two decades of life. Int J Oral Maxillofac Surg. 2012;41:1244–1247. Laron Z, Taube E, Kaplan J. Pituitary growth hormone insufficiency associated with cleft lip and palate. Helv Paediatr Acta. 1969;24:576–581. Marques IL. Growth of children with cleft lip-palate from birth to 10 years of age. In: Preedy VR, ed. Handbook of Growth and Growth Monitoring in Health and Disease. London: Springer; 2012:1763–1778. Marques IL, Nackashi JA, Borgo HC, Martinelli APMC, Pegoraro-Krook MI, Williams WN, et al. Longitudinal study of growth of children with unilateral cleft-lip palate from birth to two years of age. Cleft Palate Craniofac J. 2009;46:603–609. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in girls. Arch Dis Child. 1969;44:291–303. Marshall WA Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child. 1970;45:13–24. Montagnoli LC, Barbieri MA, Bettiol H, Marques IL, Souza L. Preju ´ızo no crescimento de criancas ¸ com diferentes tipos de fissura la´bio-palatina nos 2 primeiros anos de idade. Um estudo transversal. J Pediatr. 2005;81(6):461–465. ´ Moore LK, Persaud TVN. Embriologia Clınica. Rio de Janeiro: Elsevier; 2008a:162–198. ´ Moore LK, Persaud TVN. Embriologia Clınica. Rio de Janeiro: Elsevier, 2008b:406–409. Muhamad AH. Cleft lip and palate: etiological factors, a review. Indian J Dent Adv. 2012;4:830–837. Mueller AA, Sader R, Honigmann K, Zeilhofer H-F, SchwenzerZimmerer K. Central nervous malformations in presence of clefts reflect developmental interplay. Int J Oral Maxillofac Surg. 2007;36:289–295. Nakamoto JM, Franklin SR, Geffner ME. Puberdade. In: Kappy MS, Allen DB, Geffner ME. Pra´tica pedia´trica: endocrinologia. Rio de Janeiro: Guanabara Koogan; 2010:246–283. Nopoulos P, Berg S, Canady J, Richman L, Van Demark D, Andreasen NC. Structural brain abnormalities in adult males with clefts of the lip and/or palate. Genet Med. 2002;4:1–9. Nopoulos P, Berg S, Vandemark D, Richman L, Canady JC. Increased incidence of a midline brain anomaly in patients with
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nonsyndromic clefts of the lip and/or palate. J Neuroimaging. 2001;11:418–424. Nopoulos P, Langbehn DR, Canady J, Magnotta V, Richman L. Abnormal brain structure in children with isolated clefts of the lip or palate. Arch Pediatr Adolesc Med. 2007;161:753–758. Palmert MR, Dunkel L. Delayed puberty. N Engl J Med. 2012;366:443–453. Persson M, Becker M; Svensson H. Physical characteristics of young men with cleft lip, with or without cleft palate, and cleft palate only. Scand F Plast Reconstr Surg Hand Surg. 2007;41:6– 9. Rodrigues K, Sena MF, Roncalli AG, Ferreira MAF. Prevalence of orofacial clefts and social factors in Brazil. Braz Oral Res. 2009;23(1):38–42. Roitman A, Laron Z. Hypothalamo-pituitary hormone insufficiency associated with cleft lip and palate. Arch Dis Child. 1978;53:952–955. Rudman D, Davis GT, Priest JH, Patterson JH, Kutner MH, Heymsfield SB, et al. Prevalence of growth hormone deficiency in children with cleft lip or palate. Pediatrics. 1978;93:378–382. Schaefer GB. Neuroendocrine and neurophysiologic changes of adolescence. Cleft Palate Craniofac J. 1995;32:95–98. Sedlmeyer IL, Palmert MR. Delayed puberty: analysis of a large case series from an academic center. J Clin Endocrinol Metab. 2002;87:1613–1620. Tuohy PG, Franklin RC. Cleft palate and gonadotropin deficiency. Arch Dis Child. 1984;59:580–582. Van der Plas E, Caspell CJ, Aerts AM, TsalikianE,.Richman LC, Dawson JD, Nopoulos P. Height, BMI, and pituitary volume in individuals with and without isolated cleft lip and/or palate. Pediatr Res. 2012;71:612–618. World Health Organization. Global strategies to reduce the health-care burden of craniofacial anomalies. Geneva. 2002. Available at http://www.nidcr.nih.gov/NR/rdonlyres/ 8BF00CA3-AA3D-468E-97A7-68674D58E673/0/ CraniofacialA. Accessed June 15, 2014. Zarate YA, Martin LJ, Hopkin RJ, Bender PL, Zhang X, Saal HM. Evaluation of growth in patients with isolated cleft lip and/or cleft palate. Pediatrics. 2010;125:e1–e7.
ORIGINAL ARTICLE Evaluation of Delayed Puberty in Adolescents With Cleft Lip/Palate ˆ M.D., M.S., Ilza Lazarini Marques, M.D., PhD., Heloisa Bettiol, M.D., PhD. Maria Cristina Cres, Objective: To assess the frequency of delayed puberty in adolescents with cleft lip and/or cleft palate (CL/P). Design: This was a cross-sectional study of 203 patients with CL/P and no associated syndromes treated at the Hospital for Rehabilitation of Craniofacial Anomalies, University of Sa˜o Paulo, Bauru, Brazil. We evaluated boys aged 14–19 years and girls aged 13–18 years. The patients were classified according to Tanner stages of sexual development. The age of menarche was recorded. Patients were assigned to three groups according to cleft type: isolated cleft lip (CL), cleft lip and palate (CLP), and isolated cleft palate (CP).The results were expressed as frequencies and averages and compared with pubertal changes described for typically developing adolescents as reported in the literature. Results: Subjects were 115 boys and 88 girls. All boys in the CL group and the CP group had already started puberty, and two boys in the CLP group (2.3%) had delayed puberty. All girls had started puberty. The average age at menarche was 12.3 years in the CL group, 12.1 years in the CLP group, and 12.5 years in the CP group. Conclusions: The frequency of delayed puberty and the average age at menarche in adolescents with CL/P and no associated genetic syndromes or anomalies were within the expected range for typically developing adolescents (i.e., those without CL/P) in the same age group. KEY WORDS:
cleft lip/palate, development, delayed puberty, menarche
Delayed puberty is defined as the absence of testicular enlargement in boys or breast development in girls at an age that is 2 to 2.5 SDs later than the population mean (traditionally, the age of 14 years in boys and 13 years in girls) (Marshall and Tanner, 1969; Marshall and Tanner, 1970; Palmert and Dunkel, 2012). A possible association of CL/P with pituitary hormone deficiency (Laron et al., 1969; Roitman and Laron, 1978; Rudman et al., 1978; Tuohy and Franklin, 1984) has been suggested and is based on the shared embryonic origin of the pituitary and face structures that form the lip and palate. Although the embryogenesis of the palate and anterior pituitary is not directly dependent on one or the other structure, both have an ectodermal origin and have proximity in time and space (from 5 to 7 fetal weeks for the lip, from 5 to 12 fetal weeks for the palate, and from 3 to 8 fetal weeks for the anterior pituitary) (Moore and Persaud, 2008a; Moore and Persaud, 2008b; Muhamad, 2012). The action of a teratogenic factor during this embryonic period could simultaneously disturb the formation of these structures, leading to the development of CL/P and anatomic and/or functional pituitary changes (Rudman et al., 1978). Moreover, some studies have suggested that brain development is strongly related to face development and that craniofacial disorders may be associated with brain disorders (Kjaer, 1995; Nopoulos et al., 2001; Nopoulos et al., 2002; Calzolari et al., 2007; Mueller et al., 2007; Nopoulos et al., 2007).
Cleft lip and/or cleft palate (CL/P) is characterized by a morphologic disorder that alters the facial structures and affects the anatomy and function of facial muscles at varying degrees of severity. CL/P may affect the lip only (isolated cleft lip, CL), the lip and palate (cleft lip and palate, CLP), or the palate only (isolated cleft palate, CP). CL/P is one of the most frequent congenital disorders in humans, has a global average prevalence of 1:600 live births, and is recognized by the World Health Organization as an important public health problem (World Health Organization, 2002; Garib et al., 2010). Puberty development requires an intact hypothalamicpituitary-gonadal axis, which is responsible for the secretion of hormones that stimulate gonadal maturation and production of sex steroids (Nakamoto et al., 2010).
Dr. Maria Cristina Cres ˆ is Pediatrician Endocrinologist, Hospital Estadual Bauru, University of the State of Sa˜o Paulo, Bauru, Brazil. Dr. Ilza Lazarini Marques is Pediatrician and Director of Medical Service, Hospital for Rehabilitation of Craniofacial Anomalies, University of Sa˜o Paulo, Bauru, Brazil. Dr. Heloisa Bettiol is Associate Professor, University of Sa˜o Paulo, Department of Pediatrics, Hospital das Cl ´ınicas de Ribeira˜o Preto, Ribeira˜o Preto, Brazil. Submitted June 2014; Revised March 2015 and July 2015; Accepted September 2015. Address correspondence to: Maria Cristina Cres, ˆ Rua Gilberto Bresolin, n. 2-58, Bauru, Sa˜o Paulo, Brazil. E-mail: [email protected]. br. DOI: 10.1597/14-175 0
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TABLE 1
Tanner Staging Maturational
Breast Development: Female M1 ¼ Preadolescent: elevation of papilla only M2 ¼ Brest bud stage: elevation of breast and papilla as small mound. Enlargement of areolar diameter. M3 ¼ Further enlargement and elevation of breast and areola, with no separation of their contours. M4 ¼ Projection of aerola and papilla to form a secondary mound above the level of the breast. M5 ¼ Mature stage: projection of papilly only, due to recession of the areola to the general contour of the breast. Genital Development: Male G1 ¼ Preadolescent. Testes, scrotum, and penis are of about the same size and proportion as in early childhood. G2 ¼ Enlargement of scrotum and of testes. The skin of the scrotum reddens and changes in texture. Little or no enlargement of penis at this stage. G3 ¼ Enlargement of penis, which occurs at first mainly in length. Further growth of testes and scrotum. G4 ¼ Increased size of penis with growth in breadth and development of glands. Further enlargement of testes and scrotum; increased darkening of scrotal skin. G5 ¼ Genitalia adult in size and shape. Pubic Hair: Female and Male P1 ¼ Preadolescent. The vellus over the pubes is not further developed than that over the abdominal wall, that is, no pubic hair. P2 ¼ Sparse growth of long, slightly pigmented downy hair, straight or only slightly curled, appearing chiefly at the base the penis or along the labia. P3 ¼ Considerably darker, coarser, and curlier. The hair spreads sparsely over the junction of the pubes. P4 ¼ Hair now resembles adult in type, but the area covered by it is still considerably smaller than in an adult. No spread to the medial surface of the thighs. P5 ¼ Adult in quantity and type with distribution of the horizontal pattern. Spread to medial surface of thighs but not up linea alba or elsewhere above the base of the inverse triangle.
Schaefer (1995) reported that early puberty was rare in patients with CL/P but that delayed puberty was more frequent as a result of subtle central nervous system (CNS) midline disorders, and that an increased incidence of midline abnormalities was associated with CL/P. Additionally, changes in CNS development may occur without anatomic lesions in the CNS. In this study, we aimed to investigate the occurrence of delayed puberty in adolescents with CL/P and no associated syndromes, which may be the result of insufficient production of gonadotropin from anterior pituitary and suggests that changes in this gland and CL/ P may be associated. METHODS This was a cross-sectional study of 203 adolescents who were treated at the Hospital for Rehabilitation of Craniofacial Anomalies, University of Sa˜o Paulo (HRAC–USP), Bauru, Brazil. HRAC–USP is a reference center for the care of patients with CL/P in Brazil and sees patients from several Brazilian states. We selected patients with CL/P who had no other anomalies or known associated genetic syndromes. The age range was 14 to 19 years for boys and 13 to 18 years for girls. Adolescents with CL/P without associated genetic syndromes were not included in the study if they were born preterm or if they presented chronic or autoimmune diseases, because of the possible relationship of these conditions with delayed puberty (Palmert and Dunkel, 2012). Puberty was considered to be delayed when secondary sexual characteristics were absent in girls older than 13 years and in boys older than 14 years. The absence of menarche by the age of 16 was also considered to be late
puberty (Marshall and Tanner, 1969; Marshall and Tanner, 1970; Palmert and Dunkel, 2012). Data were collected once a week from May to December 2013. All patients who were part of the HRAC–USP treatment protocol and who met the study criteria were evaluated. All patients had undergone palatoplasty at an earlier age according to the HRAC–USP protocol (Bertier et al., 2007). Genital and pubic hair development in boys and breast and pubic hair development in girls were determined using the Tanner staging system (Marshall and Tanner, 1969; Marshall and Tanner, 1970), which considers breast bud (stage M2) and testis (4 cm3, stage G2) development to indicate the onset of puberty in girls and boys, respectively (Table 1). A Prader orchidometer was used to measure the size of testes, and the age of menarche was determined by asking girls when they had begun to menstruate. Data from boys and girls were analyzed separately, and patients were assigned to three groups according to cleft type: patients with isolated cleft lip (CL), patients with cleft lip and palate (CLP), and patients with isolated cleft palate (CP). Descriptive statistics (means and frequencies) were calculated for all variables. Fisher’s exact test was used to compare the three groups according to cleft type. The study was approved by the HRAC–USP Research Ethics Committee (CAAE number 10038513.2.0000.5441), and a parent or legal guardian gave written informed consent for the participation of each adolescent. RESULTS Of the 203 patients evaluated, 115 (56.7%) were boys and 88 (43.3%) were girls. Nineteen (16.5%) boys were in the CL group, 86 (74.8%) in the CLP group, and 10 (8.7%) in
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TABLE 2 Pubertal Staging and Cleft Type in Boys With Cleft Lip and/or Palate Cleft Type Pubertal Staging
CL
CLP
CP
Genitals G1 G2 G3 G4 G5
0 0 3 11 5
2 1 5 56 22
0 0 1 4 5
Pubic hair P1 P2 P3 P4 P5
0 0 5 11 3
1 3 14 51 17
0 0 1 5 4
* CL ¼ isolated cleft lip; CLP ¼ cleft lip and palate; CP ¼ isolated cleft palate; G1 to G5 ¼ Tanner staging for genital development; P1 to P5 ¼ Tanner staging for pubic hair development.
the CP group, whereas 23 (26.1%) girls were in the CL group, 55 (62.5%) in the CLP group and 10 (11.4%) in the CP group. All 19 boys in the CL group had already started puberty and had genitals and pubic hair between Tanner stages 3 and 5. In this group, 11 boys were 16 to 19 years old and had genitals in Tanner stages 4 or 5. Of the 86 boys in the CLP group, only two (2.3%) had delayed puberty (Tanner stage 1), whereas the other 84 had genitals and pubic hair between Tanner stages 2 and 5. In this group, 46 boys were 16 to 19 years old; 45 of them (97.8%) had genitals in stages 4 or 5 and one (2.2%) had genitals in stage 2 with late onset (constitutional delay) or slow progression of puberty (Table 2). All 10 boys in the CP group had already started puberty and had genitals and pubic hair between Tanner stages 3 and 5. In this group, 5 boys were 16 to 19 years old and had genitals in stages 4 or 5. The frequency of delayed puberty did not differ significantly between the three groups of boys according to cleft type (p ¼ 1.00). TABLE 3 Pubertal Staging and Cleft Type in Girls With Cleft Lip and/or Palate Cleft Type Pubertal Staging
CL
CLP
CP
Breast B1 B2 B3 B4 B5
0 0 1 2 20
0 0 3 4 48
0 0 0 2 8
Pubic hair P1 P2 P3 P4 P5
0 0 2 2 19
0 0 5 8 42
0 0 0 4 6
* CL ¼ isolated cleft lip; CLP ¼ cleft lip and palate; CP ¼ isolated cleft palate; B1 to B5 ¼ Tanner staging for breast development; P1 to P5 ¼ Tanner staging for pubic hair development.
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All girls in the CL, CLP, and CP groups had already started puberty and had genital development between Tanner stages 3 and 5 (Table 3). Twenty-two girls in the CL group (95.6%), 50 girls in the CLP group (90.9%), and 10 girls in the CP group (100%) had already started to menstruate. In addition, all girls aged 15 to 18 years had breast development in stages 4 or 5 and had already menstruated. The average age of menarche was 12.3 years (range: 8.8 to 14.1 years) in the CL group, 12.1 years in the CLP group (range: 10.0 to 15.2 years), and 12.5 years (range: 11.0 to 15.0 years) in the CP group. The six girls (one from the CL group and five from the CLP group) who had not yet had menarche were 13.2 to 13.8 years old and were in stages 3 or 4 of pubertal development. DISCUSSION In this study, we observed a higher frequency of boys than girls (1.3:1) and a higher frequency of lip and palate clefts than isolated lip clefts and isolated palate clefts in both sexes, findings that are consistent with the literature on CL/P (Rodrigues et al, 2009). In addition, of all adolescents evaluated, only two boys in the CLP group (2.3%) had not started puberty by age 14. The cases of delayed onset of puberty observed in our study may have been caused by gonadotropin deficiencies and may have been associated with the same etiologic origin of CL/P. Another patient in the CLP group had less developed genitals than expected for his chronological age, which may represent a constitutional delay or slow progression of puberty caused by gonadotropin deficiency. However, the frequency of cases of delayed puberty observed in this study was within the expected range for adolescents in the general population, estimated at around 2.5% (Marshall and Tanner, 1969; Marshall and Tanner, 1970). Some of these cases may represent a constitutional delay of puberty, by which adolescents spontaneously begin puberty at older ages (Palmert and Dunkel, 2012). In a study that evaluated a large number of cases of delayed puberty, approximately 65% of boys and 30% of girls had a constitutional delay of puberty (Sedlmeyer and Palmert, 2002). Thus, the precise diagnosis of these cases could only be determined after laboratory evaluation and patient follow-up, which was not possible in a cross-sectional study such as ours. Curiously, all patients with some degree of delayed puberty were from the CLP group, that is, patients with lip and palate clefts, indicating that some type of association between delayed development and presence of CLP may exist. The association between pituitary deficiencies and CLP without associated genetic syndromes was proposed in studies on children with CLP (Laron et al., 1969; Roitman and Laron, 1978; Tuohy and Franklin, 1984). The lip, palate, and anterior pituitary have the same embryonic origin. The ectodermal cells of the neural crest
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Cleft Palate–Craniofacial Journal, Month 0000, Vol. 00 No. 00
migrate to the future site of the head and neck, developing prominences to form the primitive oral cavity. The anterior pituitary is formed from the Rathke pouch, an evagination from the ectodermal roof of the primitive oral cavity (Moore and Persaud, 2008b). This close embryologic relationship and the cases of gonadotropin deficiencies in patients with CL/P reported previously (Laron et al., 1969; Rudman et al., 1978; Tuohy and Franklin, 1984) reinforce the suspicion that changes in the anterior pituitary and lip and palate may be associated. Moreover, brain changes and abnormal brain development have been reported in patients with CL/P (Nopoulos et al., 2001; Nopoulos et al., 2002; Mueller et al., 2007; Nopoulos et al., 2007). Conversely, no anatomic differences were found in a study that analyzed the volume of the pituitary gland in patients with CL/P and no associated syndromes aged 7 to 25 years (Van der Plas et al., 2012). However, subtle changes, which may lead to functional changes to the pituitary gland, may occur even in the absence of anatomic abnormalities detected by currently available imaging tests. Thus, hormonal deficiencies may in fact be involved in cases of delayed puberty in adolescents with CL/P. Girls did not show delayed pubertal development or menarche. In clinical practice, delayed puberty is more often observed in boys than in girls, and this pattern was also observed in the present study. The present study cannot confirm the association between CL/P and delayed puberty, but if this association exists, the frequency of delayed puberty was not greater in patients with CL/P than in patients without CL/P in this sample. Short stature has been reported in children and adolescents with CL/P (Montagnoli et al., 2005; Perssonet al., 2007; Zanateet al., 2010; Van der Plas et al., 2012) and delayed onset of puberty can enhance the height deficit during this period. However, if this height deficit is identified early and properly treated, the final height may still be within the genetic size expected for the patient. Adolescence is a time of anxiety about self-image. Delayed puberty can contribute to the fact that adolescents with CL/P feel even more different from their friends (Graciano et al., 2007). For patients with CL/P, appropriate actions on the part of health professionals, the development of a plan of treatment that includes the patients and their families, addressing the patients as a whole, can contribute to the process of social inclusion of these individuals (Graciano et al., 2007; Berger and Dalton, 2011). Several studies have assessed the growth of children with CL/P, mainly in children under 10 years of age (Bowers et al., 1987; Cunningham and Jerome, 1997; Montagnoli et al., 2005; Marques et al., 2009; Zanateet al., 2010; Marques, 2012), but few studies have evaluated growth during adolescence (Persson et al., 2007; Koltz et al., 2012) and no studies have assessed pubertal development in adolescents with CL/P. The delay in the onset of pubertal
development in patients with CL/P can be an important sign of pituitary hormonal deficiencies. This could guide health professionals in identifying patients who should be investigated for possible pituitary changes. On the other hand, the cross-sectional design was a limitation of the study, because we could not evaluate the onset and progress of pubertal development. Nevertheless, this experimental design enabled us to determine that the frequency of delayed puberty in adolescents with clefts did not differ from that expected for typical adolescents at the ages evaluated in this sample. Further studies in younger age groups may help to assess early puberty. Larger samples and longitudinal studies during the pubertal period may help to investigate possible changes in pubertal progress in these patients and provide a better assessment of the hypothalamic-pituitary-gonadal axis. CONCLUSIONS The frequency of delayed puberty and the average age of menarche in adolescents with CL/P and no associated genetic syndromes or anomalies were within the expected range for typical adolescents (i.e., those without CL/P) in the same age group. REFERENCES Berger ZE, Dalton LJ. Coping with a cleft II: factors associated with psychosocial adjustment of adolescents with a cleft lip and palate and their parents. Cleft Palate Craniofac J. 2011;48:82– 90. Bertier CE, Trindade IEK, Silva Filho OG. Cirurgias Prima´rias de La´bio e Palato. In: Trindade IEK, Silva Filho OG. Fissuras Labiopalatinas: Uma Abordagem Interdisciplinar. Sa˜o Paulo: Santos Editora; 2007:73–85. Bowers EJ, Mayro RF, Whitaker LA, Pasquariello PS, La Rossa D, Randall P. General body growth in children with clefts of the lip, palate, and craniofacial structure. Scand J Plast Reconstr Surg. 1987;21:7–14. Calzolari E, Pierini A, Astolfi G, Bianchi F, Neville AJ, Rivieri F, EUROCAT Working Group. Associated anomalies in multimalformed infants with cleft lip and palate: an epidemiologic study of nearly 6 million births in 23 EUROCAT registries. Am J Med Genet Part A. 2007;143(A):528–537. Cunningham ML, Jerome JT. Linear growth characteristics of children with cleft lip and palate. J Pediatr. 1997;131:707–711. Garib DG, Silva Filho OG, Janson G, Pinto JHN. Etiologia das ma´s oclusoes: perspectiva cl ´ınica (parte III): fissuras labiopa˜ ´ Ortodon Dent Press. 2010;9(4):30–36. latinas. Ver Clın Graciano MIG, Tavano LD, Bachega MI. Aspectos psicossociais da reabilitaca ¸ ˜ o. In: Trindade IEK, Silva Filho OG. Fissuras Labiopalatinas: Uma Abordagem Interdisciplinar. Sa˜o Paulo: Santos Editora; 2007:311–333. Kjaer I. Human prenatal craniofacial development related to brain development under normal and pathologic conditions. Acta Odontol Scand. 1995;53:135–143. Koltz PF, Wasicek P, Mays C, Bloom J, Girotto JA. Growth trajectory of children and adolescents with isolated cleft lip
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