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Orthodontic treatment with growth hormone therapy in a girl of short stature
CASE REPORT
Orthodontic treatment with growth hormone therapy in a girl of short stature Chung-Ju Hwang, DDS, PhD,a and Jung-Yul Cha, DDS, MSb Seoul, South Korea The purpose of this article is to review the characteristics of craniofacial morphology in children of short stature and the effects of human growth hormone (HGH) therapy on the craniofacial complex. Changes in body height, facial growth, and dental maturity of a 9-year-old girl who received HGH therapy during orthodontic treatment were observed. Orthodontists need to understand the skeletal characteristics of the craniofacial complex of short-stature patients before beginning orthodontic treatment and consider how the differences between chronologic and skeletal ages affect the timing and method of orthodontic treatment. If short-stature children are undergoing HGH therapy, its cranioskeletal effect should be considered; if possible, it is better to delay orthodontic treatment until HGH is finished. However, if orthodontic treatment is performed, the following should be considered: (1) HGH therapy affects the growth of the mandible more than the growth of the maxilla, (2) the amount and pattern of growth during HGH administration are unpredictable, and (3) HGH therapy rarely affects dental maturity. (Am J Orthod Dentofacial Orthop 2004;126: 118-26)
T
he definition of short stature has varied with time and place. On some growth charts, short stature is defined as height below the fifth percentile for age; others have defined it as the lower limit of normal for height at the third or even the fourth percentile for age.1,2 A short-stature patient grows less than 4 cm annually after 3 years of age, and the skeletal age is usually delayed 2 years compared with the chronologic age. Along with these characteristics, idiopathic short-stature patients have a normal thyroid with no chronic disease, and no growth hormone deficiency according to the classic criteria. Familial short stature is a typical example. Children of short stature without growth hormone deficiency have been treated with biosynthetic human growth hormones (HGH). But there has been much controversy regarding the effects of systemic HGH administration in patients with familial short stature who do not have growth hormone deficiencies. Various reports suggest that giving HGH to children with idiopathic short stature results in increases in growth rate and standard-deviation scores for height.3-5 HowFrom the Department of Orthodontics, College of Dentistry, Yonsei University, Seoul, South Korea. a Professor. b Research fellow. Reprint requests to: Chung-Ju Hwang, Department of Orthodontics, College of Dentistry, Yonsei University, Seoul, South Korea; e-mail, hwang@yumc. yonsei.ac.kr. Submitted, March 2003; revised and accepted, July 2003. 0889-5406/$30.00 Copyright © 2004 by the American Association of Orthodontists. doi:10.1016/j.ajodo.2003.07.013
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ever, some doubt that final adult height is significantly affected. The effects of HGH therapy are still being studied.6 There have been many studies of the craniofacial characteristics of children with short stature. Special attention has been given to the morphologic characteristic of the cranial base and the mandible and the relationship between tooth eruption and maturation. In most studies, the mandible was found to be retropositioned, the gonial angle widened, and lower facial height relatively increased.7-10 There has also been much research on the changes in craniofacial morphology, dental occlusion, and tooth eruption among children of short stature who have received HGH therapy. In these studies, accelerated growth in posterior total facial height, overall mandibular length, and posterior cranial base length (S-Ar) were observed after HGH therapy.7,11-14 There have been many attempts to treat skeletal discrepancies with HGH therapy in conjunction with orthodontic treatment.15 Some authors have presented case reports of patients with Turner syndrome who were treated with orthodontic therapy and orthognathic surgery.16 They intended to use the desirable growth of the mandible caused by HGH therapy. Although the effect of HGH on craniofacial bony components is poorly understood, it is believed that growth hormone therapy primarily affects craniofacial regions where cartilage-mediated growth happens and regions that adapt to cartilage growth—particularly the mandibular ramus.17,18 Therefore, the orthodontist must understand
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Fig 1. Pretreatment facial photographs.
Fig 2. Pretreatment intraoral photographs.
the characteristics of short stature and the effects of HGH therapy on these patients before beginning orthodontic treatment and modify the treatment plan accordingly. DIAGNOSIS AND ETIOLOGY
A girl, age 9 years 3 months, came to our hospital with an anterior crossbite as the chief complaint. Her height was 120.9 cm, which was in the third percentile of the Korean children’s height chart. Her father’s height was 174 cm, and her mother was 150 cm tall. The patient was found to secrete growth hormone above 20 /L and was
not defined as deficient in growth hormones according to the cutoff level in the arginin insulin-tolerance test, but she showed a slow postnatal growth rate and a body height standard-deviation score less than ⫺2. In addition, screening laboratory studies were performed to exclude nonendocrine causes of short stature (determination of sedimentation rate; blood cell count; liver and kidney function tests; determination of serum electrolyte, calcium, and phosphorus values; and urinalysis). The patient had a normal birth weight for gestational age and no clinical or laboratory evidence of systemic disease of dysmorphic features.
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Fig 3. Pretreatment dental casts.
Fig 5. Pretreatment panoramic radiograph.
Fig 4. Pretreatment cephalometric tracing.
One week after the initial examination, she began a regimen of therapy—HGH (Eutropin, LGLS, Taejon, Korea) 2 IU/m2 subcutaneously, 6 times each week. As her body weight increased, the HGH dose was increased to 3 IU/m2 and then to 5 IU/m2 at the fourth year. Her skeletal age was 7.5 years, which was about 1.8 years behind her chronologic age. Thyroid hormone and testosterone were monitored every 3 months. The patient had a high mandibular angle and a Class
III dental malocclusion. Skeletally, however, she had an underdeveloped chin due to the retrograthic mandible (Figs 1-5). Cephalometric measurements are listed in the Table. The malocclusion consisted of anterior crossbite (⫺2 mm overjet), openbite, constricted maxillary arch resulting in buccal edge bite, incompetent lips, mild anterior crowding in both arches, and midline deviation. She had no signs or symptoms of temporomandibular dysfunction. TREATMENT OBJECTIVES AND ALTERNATIVES
The treatment objectives included correcting the anterior crossbite, correcting the buccal edge bite through maxillary arch-width control, growth control of
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Table.
Cephalometric measurements Age (in years)
SNA (°) SNB (°) ANB (°) S-N (mm) S-Ba (mm) Ar-Pg (mm) Gonial (°) SN-MP (°) Y-axis (°) UFH (mm) LFH (mm) Post/ant (%) 1 to SN (°) IMPA (°)
9
10
11
12
13
14
15
16
86.1 79.1 7.0 65.3 41.8 95.9 133.1 48.9 73.1 49.6 66.8 53.7 92.0 83.4
85.5 78.4 7.1 66.4 44.3 101.8 134.9 51.2 75.3 52.5 71.4 52.4 102.7 84.2
86.0 80.5 5.5 66.9 45.5 103.9 134.6 49.1 74.0 54.3 72.1 54.7 98.0 83.7
85.0 80.6 4.4 68.3 47.1 108.6 134.8 49.7 73.7 56.4 76.6 54.1 105.8 88.0
84.7 79.7 5.0 68.5 47.5 111.4 134.5 51.7 76.0 58.7 78.8 53.8 100.7 72.9
83.3 77.4 5.8 68.5 47.8 111.3 132.7 53.9 78.1 58.3 81.7 52.0 99.2 78.6
83.0 76.8 6.2 68.6 47.8 111.8 136.8 55.2 78.9 58.6 81.8 52.6 97.3 73.9
83.0 76.5 6.5 68.7 47.8 112.3 136.8 55.3 79.0 58.9 82.0 52.6 96.2 75.9
the mandible, relief of mild crowding, and correcting the Class III malocclusion to Class I, with coincident midlines. Various methods could have been used to correct the crossbite for this patient, but, considering that the HGH would have a greater effect on the mandible than on the maxilla, a more active treatment was planned. Periodic radiographs were evaluated because mandibular growth is unpredictable, and the patient showed delayed and reduced growth. For the active treatment of the anterior crossbite, rapid palatal expansion (RPE) and facemask therapy were used. After correcting the crossbite, a vertical chincup was used to control the vertical discrepancy. Because of possible excessive mandibular growth, the possibility of future orthognathic surgery was explained to the parents. TREATMENT PROGRESS
After maxillary expansion with RPE, the facemask was worn for 8 months. However, due to lack of patient cooperation, good treatment effects were difficult to obtain. An upper plate with an anteroposterior screw was used for 3 months. At the 15th month of treatment, a spring-loaded posterior occlusal bite block appliance was used on the mandibular dentition, with a chincap to control the vertical discrepancy. At the 28th month, the molar relationship was still Class III with an anterior edge-to-edge bite. The patient’s height showed an annual increase of 10 cm during the 24-month treatment period, followed by 7.3 cm in the thirrd year and 5.2 cm in the fourth year. When 3 years 7 months had passed since the start of treatment, brackets (Tomy, Tokyo, Japan) and bands were fixed on the maxillary and mandibular teeth to correct the anterior
crossbite and close the space in the mandibular arch. The patient was instructed to keep wearing the chincup, but, because of poor cooperation, Class III elastics were used to correct the edge-to-edge bite. Vertical elastics were used on the anterior teeth to improve the overbite. At the fifth year of treatment, because of the vertical overgrowth in facial pattern, she was instructed to wear the elastics only during sleep. Continuous chincup use was recommended, but the patient was still uncooperative. TREATMENT RESULTS
The patient was initially in the third percentile of height for Korean children; during the HGH therapy, she moved up into the 25th percentile but then fell below the 25th percentile when HGH therapy ended at 13 years 10 months (Fig 6). The patient’s weight, initially 24 kg, increased to 47 kg, which is within the 18th percentile. The intermaxillary elastics caused the mandibular plane angle to increase, and the mandible rotated clockwise with extrusion of the maxillary molars (Fig 7). The length of the mandible increased significantly after starting HGH therapy, but when it ceased, the rate of increase gradually diminished (Fig 8). Annualized growth increments for height, sella-nasion, sella-basion, and articulare-pogonion are shown in Fig 9. Molar width improved, and anterior crowding was relieved. Improved overjet and overbite were obtained by correcting the anterior crossbite, but the facial profile showed little improvement (Figs 10-14). DISCUSSION
The mechanism controlling craniofacial growth is a complex interaction between genes, hormones, and nutrition, and these affect the final shape of the cranio-
122 Hwang and Cha
Fig 6. Height growth curve for patient.
Fig 7. Superimposition of lateral cephalograms on cranial base.
facial bones. If a disorder occurs in this mechanism, it can lead to an imbalance in the growth pattern.19 Short stature also results from this imbalance of growth pattern, which might affect craniofacial growth. Comparisons of facial morphology between children with idiopathic short stature and growth hormone deficiency show rather similar characteristics in the 2 groups.8,11 Nearly all linear measurements of the facial structures are significantly smaller than Korean standards. Disproportionate growth in the cranial base structures and the jaws resulted in facial retrognathia, a proportionately smaller posterior than anterior facial height, and a steep vertical inclination of the mandible.11 Additionally, the incidence of orthodontic treat-
American Journal of Orthodontics and Dentofacial Orthopedics July 2004
Fig 8. Change in mandibular length (Ar-Pg).
Fig 9. Annualized growth increments for selected dimensions.
ment was shown to be high because of the high incidence of crowding among children with short stature. This study is important because it compares facial growth of healthy short-stature children without symptoms and children with hormonal deficiencies. Although there are many opinions regarding whether growth retardation affects all facial structures, in general, the maxilla is less likely to be affected than the mandible. The increased cranial base angle (NSB) and mandibular inclination (SN-MP) are shown, and the mandible was more retropositioned than the Korean standard. But the lengths of the anterior and posterior cranial bases and the angulations between the bases show differences among studies.7,8,11,13,20,21
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Fig 10. Posttreatment facial photographs.
Fig 11. Posttreatment intraoral photographs.
In this patient, the cephalometric variables were all small. The posterior facial height was smaller than the anterior facial height, and the mandibular plane angle was very steep, producing a rather retruded mandible. The gonial angle was fairly large (133.1°), and the cranial base measurements were also small. The mandibular plane angle was large— 48.5°—in this patient. During the initial treatment phase with RPE and facemask therapy, the mandible was rotated backward and downward; this made the mandibular plane angle increase. Even though a vertical chincup was used to prevent this side effect, it was difficult to inhibit
mandibular rotation because of lack of patient cooperation. In addition, because the length of the mandible increased continuously during the HGH therapy, the correction of the anterior crossbite had its limitations. The target tissue of the HGH was reported to be the chondrocytes of the epiphyseal growth cartilage; therefore, the HGH might have had a greater effect on mandibular growth than on periosteal growth.22-25 In a study related to molar relationships of shortstature children, 22%-25% of the patients had Class II malocclusions with large overjets, but Class I malocclusion made up the greatest proportion.11 However,
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American Journal of Orthodontics and Dentofacial Orthopedics July 2004
Fig 12. Posttreatment dental casts.
Fig 14. Posttreatment panoramic radiograph.
Fig 13. Posttreatment cephalometric tracing.
this patient had a Class III malocclusion with anterior crossbite; this is a specific example of Asian skeletal characteristics. Therefore, further research is necessary on the craniofacial characteristics of Asians with short stature. In previous studies, HGH was known to affect the condyle and induce vertical growth of the ramus, leading to change in mandibular growth direction from posterior to anterior. However, a vertical growth pat-
tern, with increase in the y-axis, was observed in this patient. Although this can be considered an outcome of molar extrusion with intermaxillary elastics, the degree of extrusion was much more than we expected. Therefore, during HGH therapy, it is difficult to predict the direction of mandibular growth; this can create problems during orthodontic treatment in children with large mandibular plane angles and relatively normal sizes. It can be advised that the treatment of children with short stature and anterior crossbite should be delayed until HGH therapy is finished. Impetuous treatment should be avoided because of the unpredictability of mandibular growth. Even though we improved this patient’s anterior crossbite, her facial profile actually got worse.
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Many studies have compared HGH therapy between patients with growth-hormone disorders and patients who were not HGH-deficient. Long-term results suggest that the predicted adult height in both groups showed catch-up growth and improvement. Greater increases were seen in the patients with growthhormone disorders, but, because there was no control group without HGH therapy, these results should be interpreted with caution. Another important aspect is that adult height can be maximized by starting treatment earlier.4 At present, however, the only group of short children with growth-hormone disorders for whom improved height has been documented is girls with Turner syndrome.13 There could be some doubt about the amount of height increase achieved with HGH therapy, because the patient’s current height, 156.0 cm, is near the target height (155.5 cm) calculated by her parent’s height (Fig 6). Although there is probably some growth remaining for this patient, it seems unlikely that she will exceed her target height significantly because her growth rate decreased drastically after the HGH therapy ended. Therefore, it is unknown whether her final height increase is attributable to the HGH therapy or her parents’ genetics. Orthodontic treatment of patients with short stature has been reported in articles dealing with Turner syndrome.15,16 The skeletal characteristics of Turner syndrome are decreased maxillary growth with midface hypoplasia and a wide, micrognathic mandible. In the patients of Davies15 and Russell,16 HGH therapy showed good effects with stable skeletal results; they also reported that patients with short stature and retrognathic mandibles obtained good results with functional appliances. Their patients were the first to be reported in the literature to undergo growth modification with HGH therapy and functional appliances. They advised that, because HGH therapy can cause unpredictable mandibular growth, it would be better to delay orthodontic treatment until HGH therapy has been completed.15,16 CONCLUSIONS
It was difficult to correct the anterior crossbite of this patient during HGH therapy. Although the growth pattern might have been the primary factor in the failure, accelerated mandibular and height growth caused by the HGH therapy might have also affected the orthodontic treatment. Therefore, to obtain the proper treatment plan for orthodontic patients, the effects of HGH on the craniofaical complex must be considered when evaluating dental age, chronologic age, and delayed skeletal age. In addition, as the
number of short-stature patients receiving HGH therapy increases, so too will the number of those patients seeking orthodontic treatment. Therefore, further research is necessary on the effect of HGH therapy, not only on facial growth, but also on tooth movement during orthodontic treatment. REFERENCES 1. Centers for Disease Control and Prevention, National Center for Health Statistics. National Health and Nutrition Examination Survey. Clinical growth charts. Available from: URL:http://www.cdc. gov/nccdphp/dnpa/growthcharts/training/modules/module2/text/ page6b.htm. Accessed January 17, 2002. 2. Freeman JV, Cole TJ, Chinn S, Jones PR, White EM, Preece MA. Cross sectional stature and weight reference curves for the UK, 1990. Arch Dis Child 1995;73:17-20. 3. Guidelines for the use of growth hormone in children with short staturea report by the drug and therapeutics committee of the Lawson Wilkins pediatric endocrine societyJ Pediatr1995123: 857– 67. 4. Zadik Z, Chalew S, Zung A, Landau H, Leiberman E, Koren R, et al. Effect of long-term growth hormone therapy on bone age and pubertal maturation in boys with and without classic growth hormone deficiency. J Pediatr 1994;125:189-95. 5. Kaplowitz PB. Effect of growth hormone therapy on final versus predicted height in short twelve- to sixteen-year-old boys without growth hormone deficiency. J Pediatr 1995;126:478-80. 6. Hintz RL, Attie KM, Baptista J, Roche A. Effect of growth hormone treatment on adult height of children with idiopathic short stature. N Engl J Med 1999;340:502-7. 7. Van Erum R, Mulier M, Carels C, Verbeke G, De Zegher F. Craniofacial growth in short children born small for gestational age: effect of growth hormone treatment. J Dent Res 1997;76: 1579-86. 8. Spiegel RN, Sather AH, Hayles AB. Cephalometric study of children with various endocrine diseases. Am J Orthod 1971;59: 362-75. 9. Cantu G, Buschang PH, Gonzalez JL. Differential growth and maturation in idiopathic growth-hormone-deficient children. Eur J Orthod 1997;19:131-9. 10. Pirinen S, Majurin A, Lenko HL, Koski K. Craniofacial features in patients with deficient and excessive growth hormone. J Craniofac Genet Dev Biol 1994;14:144-52. 11. Kjelberg H, Beiring M, Wikland KA. Craniofacial morphology, dental occlusion, tooth eruption, and dental maturity in boys of short stature with or without growth hormone deficiency. Eur J Oral Sci 2000;108:359-67. 12. Van Erum R, Carels C, Verbeke G, De Zegher F. Craniofacial growth in short children born small for gestational age: two years follow-up after high-dose growth hormone treatment. J Cranifac Genet Dev Biol 1997;17:184-9. 13. Van Erum R, Mulier M, Carels C, De Zegher F. Short stature of prenatal origin: craniofacial growth and dental maturation. Eur J Orthod 1998;20:417-25. 14. Van Erum R, Mulier G, Carels C, De Zegher F. Craniofacial growth and dental maturation in short children born small for gestational age: effect of growth hormone treatment. Horm Res 1998;50:141-6. 15. Davies TI, Rayner PHW. Functional appliance therapy in conjunction with growth hormone treatment: a case report. Br J Orthod 1995;22:361-5.
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16. Russell KA. Orthodontic treatment for patients with Turner syndrome. Am J Orthod Dentofacial Orthop 2001;120:314-22. 17. Pirinen S. Endocrine regulation of craniofacial growth. Acta Odontol Scand 1995;53:179-85. 18. Simmons KE. Growth hormone and craniofacial changes: preliminary data from studies in Turner’s syndrome. Pediatrics 1999;104:1021-4. 19. Thilander B. Basic mechanism in craniofacial growth. Acta Odontol Scand 1995;53:144-51. 20. Edler RJ. Cephalometric parameters in hypopituitary patients. Br J Orthod 1979;6:19-22. 21. Cantu G, Buschang PH, Gonzalez JL. Differential growth and maturation in idiopathic growth-hormone-deficient children. Eur J Orthod 1997;19:131-9.
American Journal of Orthodontics and Dentofacial Orthopedics July 2004
22. Lewinson D, Bialik GM, Hochberg Z. Differential effects of hypothyroidism on the cartilage and the osteogenic process in the mandibular condyle: recovery by growth hormone and thyroxine. Endocrinology 1994;135:1504-10. 23. Yamaguchi T, Maki K, Shibasaki Y. Growth hormone receptor gene variant and mandibular height in the normal Japanese polulation. Am J Orthod Dentofacial Orthop 2001;119:650-3. 24. Livne E, Laufer D, Blumenfeld I. Comparison of in vitro response to growth hormone by chondrocytes from mandibular condyle cartilage of young and old mice. Calcif Tissue Int 1997;61:62-7. 25. Visnapuu V, Peltomaki T, Ronning O, Vahlberg T, Helenius H. Growth hormone and insulin-like growth factor I receptors in the temporomandibular joint of the rat. J Dent Res 2001;80:1903-7.
Orthodontic treatment with growth hormone therapy in a girl of short stature Chung-Ju Hwang, DDS, PhD,a and Jung-Yul Cha, DDS, MSb Seoul, South Korea The purpose of this article is to review the characteristics of craniofacial morphology in children of short stature and the effects of human growth hormone (HGH) therapy on the craniofacial complex. Changes in body height, facial growth, and dental maturity of a 9-year-old girl who received HGH therapy during orthodontic treatment were observed. Orthodontists need to understand the skeletal characteristics of the craniofacial complex of short-stature patients before beginning orthodontic treatment and consider how the differences between chronologic and skeletal ages affect the timing and method of orthodontic treatment. If short-stature children are undergoing HGH therapy, its cranioskeletal effect should be considered; if possible, it is better to delay orthodontic treatment until HGH is finished. However, if orthodontic treatment is performed, the following should be considered: (1) HGH therapy affects the growth of the mandible more than the growth of the maxilla, (2) the amount and pattern of growth during HGH administration are unpredictable, and (3) HGH therapy rarely affects dental maturity. (Am J Orthod Dentofacial Orthop 2004;126: 118-26)
T
he definition of short stature has varied with time and place. On some growth charts, short stature is defined as height below the fifth percentile for age; others have defined it as the lower limit of normal for height at the third or even the fourth percentile for age.1,2 A short-stature patient grows less than 4 cm annually after 3 years of age, and the skeletal age is usually delayed 2 years compared with the chronologic age. Along with these characteristics, idiopathic short-stature patients have a normal thyroid with no chronic disease, and no growth hormone deficiency according to the classic criteria. Familial short stature is a typical example. Children of short stature without growth hormone deficiency have been treated with biosynthetic human growth hormones (HGH). But there has been much controversy regarding the effects of systemic HGH administration in patients with familial short stature who do not have growth hormone deficiencies. Various reports suggest that giving HGH to children with idiopathic short stature results in increases in growth rate and standard-deviation scores for height.3-5 HowFrom the Department of Orthodontics, College of Dentistry, Yonsei University, Seoul, South Korea. a Professor. b Research fellow. Reprint requests to: Chung-Ju Hwang, Department of Orthodontics, College of Dentistry, Yonsei University, Seoul, South Korea; e-mail, hwang@yumc. yonsei.ac.kr. Submitted, March 2003; revised and accepted, July 2003. 0889-5406/$30.00 Copyright © 2004 by the American Association of Orthodontists. doi:10.1016/j.ajodo.2003.07.013
118
ever, some doubt that final adult height is significantly affected. The effects of HGH therapy are still being studied.6 There have been many studies of the craniofacial characteristics of children with short stature. Special attention has been given to the morphologic characteristic of the cranial base and the mandible and the relationship between tooth eruption and maturation. In most studies, the mandible was found to be retropositioned, the gonial angle widened, and lower facial height relatively increased.7-10 There has also been much research on the changes in craniofacial morphology, dental occlusion, and tooth eruption among children of short stature who have received HGH therapy. In these studies, accelerated growth in posterior total facial height, overall mandibular length, and posterior cranial base length (S-Ar) were observed after HGH therapy.7,11-14 There have been many attempts to treat skeletal discrepancies with HGH therapy in conjunction with orthodontic treatment.15 Some authors have presented case reports of patients with Turner syndrome who were treated with orthodontic therapy and orthognathic surgery.16 They intended to use the desirable growth of the mandible caused by HGH therapy. Although the effect of HGH on craniofacial bony components is poorly understood, it is believed that growth hormone therapy primarily affects craniofacial regions where cartilage-mediated growth happens and regions that adapt to cartilage growth—particularly the mandibular ramus.17,18 Therefore, the orthodontist must understand
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American Journal of Orthodontics and Dentofacial Orthopedics Volume 126, Number 1
Fig 1. Pretreatment facial photographs.
Fig 2. Pretreatment intraoral photographs.
the characteristics of short stature and the effects of HGH therapy on these patients before beginning orthodontic treatment and modify the treatment plan accordingly. DIAGNOSIS AND ETIOLOGY
A girl, age 9 years 3 months, came to our hospital with an anterior crossbite as the chief complaint. Her height was 120.9 cm, which was in the third percentile of the Korean children’s height chart. Her father’s height was 174 cm, and her mother was 150 cm tall. The patient was found to secrete growth hormone above 20 /L and was
not defined as deficient in growth hormones according to the cutoff level in the arginin insulin-tolerance test, but she showed a slow postnatal growth rate and a body height standard-deviation score less than ⫺2. In addition, screening laboratory studies were performed to exclude nonendocrine causes of short stature (determination of sedimentation rate; blood cell count; liver and kidney function tests; determination of serum electrolyte, calcium, and phosphorus values; and urinalysis). The patient had a normal birth weight for gestational age and no clinical or laboratory evidence of systemic disease of dysmorphic features.
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Fig 3. Pretreatment dental casts.
Fig 5. Pretreatment panoramic radiograph.
Fig 4. Pretreatment cephalometric tracing.
One week after the initial examination, she began a regimen of therapy—HGH (Eutropin, LGLS, Taejon, Korea) 2 IU/m2 subcutaneously, 6 times each week. As her body weight increased, the HGH dose was increased to 3 IU/m2 and then to 5 IU/m2 at the fourth year. Her skeletal age was 7.5 years, which was about 1.8 years behind her chronologic age. Thyroid hormone and testosterone were monitored every 3 months. The patient had a high mandibular angle and a Class
III dental malocclusion. Skeletally, however, she had an underdeveloped chin due to the retrograthic mandible (Figs 1-5). Cephalometric measurements are listed in the Table. The malocclusion consisted of anterior crossbite (⫺2 mm overjet), openbite, constricted maxillary arch resulting in buccal edge bite, incompetent lips, mild anterior crowding in both arches, and midline deviation. She had no signs or symptoms of temporomandibular dysfunction. TREATMENT OBJECTIVES AND ALTERNATIVES
The treatment objectives included correcting the anterior crossbite, correcting the buccal edge bite through maxillary arch-width control, growth control of
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Table.
Cephalometric measurements Age (in years)
SNA (°) SNB (°) ANB (°) S-N (mm) S-Ba (mm) Ar-Pg (mm) Gonial (°) SN-MP (°) Y-axis (°) UFH (mm) LFH (mm) Post/ant (%) 1 to SN (°) IMPA (°)
9
10
11
12
13
14
15
16
86.1 79.1 7.0 65.3 41.8 95.9 133.1 48.9 73.1 49.6 66.8 53.7 92.0 83.4
85.5 78.4 7.1 66.4 44.3 101.8 134.9 51.2 75.3 52.5 71.4 52.4 102.7 84.2
86.0 80.5 5.5 66.9 45.5 103.9 134.6 49.1 74.0 54.3 72.1 54.7 98.0 83.7
85.0 80.6 4.4 68.3 47.1 108.6 134.8 49.7 73.7 56.4 76.6 54.1 105.8 88.0
84.7 79.7 5.0 68.5 47.5 111.4 134.5 51.7 76.0 58.7 78.8 53.8 100.7 72.9
83.3 77.4 5.8 68.5 47.8 111.3 132.7 53.9 78.1 58.3 81.7 52.0 99.2 78.6
83.0 76.8 6.2 68.6 47.8 111.8 136.8 55.2 78.9 58.6 81.8 52.6 97.3 73.9
83.0 76.5 6.5 68.7 47.8 112.3 136.8 55.3 79.0 58.9 82.0 52.6 96.2 75.9
the mandible, relief of mild crowding, and correcting the Class III malocclusion to Class I, with coincident midlines. Various methods could have been used to correct the crossbite for this patient, but, considering that the HGH would have a greater effect on the mandible than on the maxilla, a more active treatment was planned. Periodic radiographs were evaluated because mandibular growth is unpredictable, and the patient showed delayed and reduced growth. For the active treatment of the anterior crossbite, rapid palatal expansion (RPE) and facemask therapy were used. After correcting the crossbite, a vertical chincup was used to control the vertical discrepancy. Because of possible excessive mandibular growth, the possibility of future orthognathic surgery was explained to the parents. TREATMENT PROGRESS
After maxillary expansion with RPE, the facemask was worn for 8 months. However, due to lack of patient cooperation, good treatment effects were difficult to obtain. An upper plate with an anteroposterior screw was used for 3 months. At the 15th month of treatment, a spring-loaded posterior occlusal bite block appliance was used on the mandibular dentition, with a chincap to control the vertical discrepancy. At the 28th month, the molar relationship was still Class III with an anterior edge-to-edge bite. The patient’s height showed an annual increase of 10 cm during the 24-month treatment period, followed by 7.3 cm in the thirrd year and 5.2 cm in the fourth year. When 3 years 7 months had passed since the start of treatment, brackets (Tomy, Tokyo, Japan) and bands were fixed on the maxillary and mandibular teeth to correct the anterior
crossbite and close the space in the mandibular arch. The patient was instructed to keep wearing the chincup, but, because of poor cooperation, Class III elastics were used to correct the edge-to-edge bite. Vertical elastics were used on the anterior teeth to improve the overbite. At the fifth year of treatment, because of the vertical overgrowth in facial pattern, she was instructed to wear the elastics only during sleep. Continuous chincup use was recommended, but the patient was still uncooperative. TREATMENT RESULTS
The patient was initially in the third percentile of height for Korean children; during the HGH therapy, she moved up into the 25th percentile but then fell below the 25th percentile when HGH therapy ended at 13 years 10 months (Fig 6). The patient’s weight, initially 24 kg, increased to 47 kg, which is within the 18th percentile. The intermaxillary elastics caused the mandibular plane angle to increase, and the mandible rotated clockwise with extrusion of the maxillary molars (Fig 7). The length of the mandible increased significantly after starting HGH therapy, but when it ceased, the rate of increase gradually diminished (Fig 8). Annualized growth increments for height, sella-nasion, sella-basion, and articulare-pogonion are shown in Fig 9. Molar width improved, and anterior crowding was relieved. Improved overjet and overbite were obtained by correcting the anterior crossbite, but the facial profile showed little improvement (Figs 10-14). DISCUSSION
The mechanism controlling craniofacial growth is a complex interaction between genes, hormones, and nutrition, and these affect the final shape of the cranio-
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Fig 6. Height growth curve for patient.
Fig 7. Superimposition of lateral cephalograms on cranial base.
facial bones. If a disorder occurs in this mechanism, it can lead to an imbalance in the growth pattern.19 Short stature also results from this imbalance of growth pattern, which might affect craniofacial growth. Comparisons of facial morphology between children with idiopathic short stature and growth hormone deficiency show rather similar characteristics in the 2 groups.8,11 Nearly all linear measurements of the facial structures are significantly smaller than Korean standards. Disproportionate growth in the cranial base structures and the jaws resulted in facial retrognathia, a proportionately smaller posterior than anterior facial height, and a steep vertical inclination of the mandible.11 Additionally, the incidence of orthodontic treat-
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Fig 8. Change in mandibular length (Ar-Pg).
Fig 9. Annualized growth increments for selected dimensions.
ment was shown to be high because of the high incidence of crowding among children with short stature. This study is important because it compares facial growth of healthy short-stature children without symptoms and children with hormonal deficiencies. Although there are many opinions regarding whether growth retardation affects all facial structures, in general, the maxilla is less likely to be affected than the mandible. The increased cranial base angle (NSB) and mandibular inclination (SN-MP) are shown, and the mandible was more retropositioned than the Korean standard. But the lengths of the anterior and posterior cranial bases and the angulations between the bases show differences among studies.7,8,11,13,20,21
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Fig 10. Posttreatment facial photographs.
Fig 11. Posttreatment intraoral photographs.
In this patient, the cephalometric variables were all small. The posterior facial height was smaller than the anterior facial height, and the mandibular plane angle was very steep, producing a rather retruded mandible. The gonial angle was fairly large (133.1°), and the cranial base measurements were also small. The mandibular plane angle was large— 48.5°—in this patient. During the initial treatment phase with RPE and facemask therapy, the mandible was rotated backward and downward; this made the mandibular plane angle increase. Even though a vertical chincup was used to prevent this side effect, it was difficult to inhibit
mandibular rotation because of lack of patient cooperation. In addition, because the length of the mandible increased continuously during the HGH therapy, the correction of the anterior crossbite had its limitations. The target tissue of the HGH was reported to be the chondrocytes of the epiphyseal growth cartilage; therefore, the HGH might have had a greater effect on mandibular growth than on periosteal growth.22-25 In a study related to molar relationships of shortstature children, 22%-25% of the patients had Class II malocclusions with large overjets, but Class I malocclusion made up the greatest proportion.11 However,
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Fig 12. Posttreatment dental casts.
Fig 14. Posttreatment panoramic radiograph.
Fig 13. Posttreatment cephalometric tracing.
this patient had a Class III malocclusion with anterior crossbite; this is a specific example of Asian skeletal characteristics. Therefore, further research is necessary on the craniofacial characteristics of Asians with short stature. In previous studies, HGH was known to affect the condyle and induce vertical growth of the ramus, leading to change in mandibular growth direction from posterior to anterior. However, a vertical growth pat-
tern, with increase in the y-axis, was observed in this patient. Although this can be considered an outcome of molar extrusion with intermaxillary elastics, the degree of extrusion was much more than we expected. Therefore, during HGH therapy, it is difficult to predict the direction of mandibular growth; this can create problems during orthodontic treatment in children with large mandibular plane angles and relatively normal sizes. It can be advised that the treatment of children with short stature and anterior crossbite should be delayed until HGH therapy is finished. Impetuous treatment should be avoided because of the unpredictability of mandibular growth. Even though we improved this patient’s anterior crossbite, her facial profile actually got worse.
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Many studies have compared HGH therapy between patients with growth-hormone disorders and patients who were not HGH-deficient. Long-term results suggest that the predicted adult height in both groups showed catch-up growth and improvement. Greater increases were seen in the patients with growthhormone disorders, but, because there was no control group without HGH therapy, these results should be interpreted with caution. Another important aspect is that adult height can be maximized by starting treatment earlier.4 At present, however, the only group of short children with growth-hormone disorders for whom improved height has been documented is girls with Turner syndrome.13 There could be some doubt about the amount of height increase achieved with HGH therapy, because the patient’s current height, 156.0 cm, is near the target height (155.5 cm) calculated by her parent’s height (Fig 6). Although there is probably some growth remaining for this patient, it seems unlikely that she will exceed her target height significantly because her growth rate decreased drastically after the HGH therapy ended. Therefore, it is unknown whether her final height increase is attributable to the HGH therapy or her parents’ genetics. Orthodontic treatment of patients with short stature has been reported in articles dealing with Turner syndrome.15,16 The skeletal characteristics of Turner syndrome are decreased maxillary growth with midface hypoplasia and a wide, micrognathic mandible. In the patients of Davies15 and Russell,16 HGH therapy showed good effects with stable skeletal results; they also reported that patients with short stature and retrognathic mandibles obtained good results with functional appliances. Their patients were the first to be reported in the literature to undergo growth modification with HGH therapy and functional appliances. They advised that, because HGH therapy can cause unpredictable mandibular growth, it would be better to delay orthodontic treatment until HGH therapy has been completed.15,16 CONCLUSIONS
It was difficult to correct the anterior crossbite of this patient during HGH therapy. Although the growth pattern might have been the primary factor in the failure, accelerated mandibular and height growth caused by the HGH therapy might have also affected the orthodontic treatment. Therefore, to obtain the proper treatment plan for orthodontic patients, the effects of HGH on the craniofaical complex must be considered when evaluating dental age, chronologic age, and delayed skeletal age. In addition, as the
number of short-stature patients receiving HGH therapy increases, so too will the number of those patients seeking orthodontic treatment. Therefore, further research is necessary on the effect of HGH therapy, not only on facial growth, but also on tooth movement during orthodontic treatment. REFERENCES 1. Centers for Disease Control and Prevention, National Center for Health Statistics. National Health and Nutrition Examination Survey. Clinical growth charts. Available from: URL:http://www.cdc. gov/nccdphp/dnpa/growthcharts/training/modules/module2/text/ page6b.htm. Accessed January 17, 2002. 2. Freeman JV, Cole TJ, Chinn S, Jones PR, White EM, Preece MA. Cross sectional stature and weight reference curves for the UK, 1990. Arch Dis Child 1995;73:17-20. 3. Guidelines for the use of growth hormone in children with short staturea report by the drug and therapeutics committee of the Lawson Wilkins pediatric endocrine societyJ Pediatr1995123: 857– 67. 4. Zadik Z, Chalew S, Zung A, Landau H, Leiberman E, Koren R, et al. Effect of long-term growth hormone therapy on bone age and pubertal maturation in boys with and without classic growth hormone deficiency. J Pediatr 1994;125:189-95. 5. Kaplowitz PB. Effect of growth hormone therapy on final versus predicted height in short twelve- to sixteen-year-old boys without growth hormone deficiency. J Pediatr 1995;126:478-80. 6. Hintz RL, Attie KM, Baptista J, Roche A. Effect of growth hormone treatment on adult height of children with idiopathic short stature. N Engl J Med 1999;340:502-7. 7. Van Erum R, Mulier M, Carels C, Verbeke G, De Zegher F. Craniofacial growth in short children born small for gestational age: effect of growth hormone treatment. J Dent Res 1997;76: 1579-86. 8. Spiegel RN, Sather AH, Hayles AB. Cephalometric study of children with various endocrine diseases. Am J Orthod 1971;59: 362-75. 9. Cantu G, Buschang PH, Gonzalez JL. Differential growth and maturation in idiopathic growth-hormone-deficient children. Eur J Orthod 1997;19:131-9. 10. Pirinen S, Majurin A, Lenko HL, Koski K. Craniofacial features in patients with deficient and excessive growth hormone. J Craniofac Genet Dev Biol 1994;14:144-52. 11. Kjelberg H, Beiring M, Wikland KA. Craniofacial morphology, dental occlusion, tooth eruption, and dental maturity in boys of short stature with or without growth hormone deficiency. Eur J Oral Sci 2000;108:359-67. 12. Van Erum R, Carels C, Verbeke G, De Zegher F. Craniofacial growth in short children born small for gestational age: two years follow-up after high-dose growth hormone treatment. J Cranifac Genet Dev Biol 1997;17:184-9. 13. Van Erum R, Mulier M, Carels C, De Zegher F. Short stature of prenatal origin: craniofacial growth and dental maturation. Eur J Orthod 1998;20:417-25. 14. Van Erum R, Mulier G, Carels C, De Zegher F. Craniofacial growth and dental maturation in short children born small for gestational age: effect of growth hormone treatment. Horm Res 1998;50:141-6. 15. Davies TI, Rayner PHW. Functional appliance therapy in conjunction with growth hormone treatment: a case report. Br J Orthod 1995;22:361-5.
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16. Russell KA. Orthodontic treatment for patients with Turner syndrome. Am J Orthod Dentofacial Orthop 2001;120:314-22. 17. Pirinen S. Endocrine regulation of craniofacial growth. Acta Odontol Scand 1995;53:179-85. 18. Simmons KE. Growth hormone and craniofacial changes: preliminary data from studies in Turner’s syndrome. Pediatrics 1999;104:1021-4. 19. Thilander B. Basic mechanism in craniofacial growth. Acta Odontol Scand 1995;53:144-51. 20. Edler RJ. Cephalometric parameters in hypopituitary patients. Br J Orthod 1979;6:19-22. 21. Cantu G, Buschang PH, Gonzalez JL. Differential growth and maturation in idiopathic growth-hormone-deficient children. Eur J Orthod 1997;19:131-9.
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22. Lewinson D, Bialik GM, Hochberg Z. Differential effects of hypothyroidism on the cartilage and the osteogenic process in the mandibular condyle: recovery by growth hormone and thyroxine. Endocrinology 1994;135:1504-10. 23. Yamaguchi T, Maki K, Shibasaki Y. Growth hormone receptor gene variant and mandibular height in the normal Japanese polulation. Am J Orthod Dentofacial Orthop 2001;119:650-3. 24. Livne E, Laufer D, Blumenfeld I. Comparison of in vitro response to growth hormone by chondrocytes from mandibular condyle cartilage of young and old mice. Calcif Tissue Int 1997;61:62-7. 25. Visnapuu V, Peltomaki T, Ronning O, Vahlberg T, Helenius H. Growth hormone and insulin-like growth factor I receptors in the temporomandibular joint of the rat. J Dent Res 2001;80:1903-7.