- Email: [email protected]
Chromosomal Syndromes
Chromosomal Syndromes Rita Shiang, PhD KEYWORDS Down syndrome Trisomy 21 Klinefelter syndrome Turner syndrome Aneuploidy Sex chromosomes KEY POINTS Chromosomal aneuploidies are caused by nondisjunction of chromosomes in meiosis or mitosis. Down syndrome is caused by trisomy of chromosome 21. Klinefelter and Turner syndromes are sex chromosome aneuploidies, with an extra X chromosome in the former and a missing X in the latter. Mosaicism is found in Down syndrome, Klinefelter syndrome, and Turner syndrome. The risk of Down syndrome and Klinefelter syndrome increases with maternal age, but this phenomenon is not observed for Turner syndrome. The main features of Down syndrome are cognitive impairment, hypotonia, and characteristic facial features. The 2 main features of Klinefelter syndrome are hypergonadotropic hypogonadism and small testicular volume, although most individuals with Klinefelter syndrome remain undiagnosed. The 2 main features of Turner syndrome are growth retardation, resulting in short stature throughout life, and infertility in later years.
Down syndrome Genetics Down syndrome is the most frequently observed chromosomal aneuploidy caused by trisomy 21 or partial trisomy 21.1,2 Most (90%e95%) cases are caused by de novo chromosomal nondisjunction. About 2% to 6% of cases are caused by translocations of 2 chromosome 21s or a Robertsonian translocation of chromosome 21 fused to another acrocentric chromosome. Another 2% to 3% of cases are mosaic for trisomy 21. The prevalence of this disorder is 1/700 live births, but the risk of having a child with Down syndrome greatly increases with the age of the mother. The risk is 1/1000 at age 30 years and increases to 9/ 1000 at age 40 years.3,4
Clinical features The main features of Down syndrome include cognitive impairment, hypotonia, and characteristic facial features. The IQ of individuals with trisomy 21 is highly variable, and most individuals fall between the moderate to severe range.5,6 IQ is not stable and decreases with age.7 Specific cognitive weaknesses have been identified in expressive language, syntactic/ morphosyntactic processing, and verbal working memory.8 Craniofacial features include brachycephaly, midface hypoplasia, flat or depressed nasal bridge, micrognathia, and epicanthic folds (Fig. 1). In addition, there are outer (dysmorphic
Disclosures: No disclosures or conflicts of interests to report. Department of Human and Molecular Genetics, Virginia Commonwealth University, PO Box 980033, Richmond, VA 23298-0033, USA E-mail address: [email protected] Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 197–203 1061-3315/14/$ - see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cxom.2014.05.003
outer ear and stenosis of the external ear canal), middle (malformation of the eustachian tube), and inner ear anomalies, which can result in hearing loss and cholesteatoma.9 Dental issues include variable tooth morphogenesis and eruption and a greater prevalence and severity of periodontal disease, but lower incidence of caries.10,11 Changes in the oral cavity include macroglossia and a protruding furrowed tongue as well as narrow palate, pharynx, and oropharynx. Many of these craniofacial issues can lead to sleep apnea, and because of a decrease of immune function in individuals with Down syndrome, these can also lead to chronic infections.9 Congenital heart defects are not present in all individuals but contribute greatly to mortality. These anomalies include atrioventricular canal defect, tetralogy of Fallot, and patent ductus arteriosus but particularly atrioventricular septal defects. There are many confounding issues with individuals with trisomy 21. There is a greater risk for leukemia, both acute lymphoblastic leukemia and acute myelogenous leukemia.12 Approximately 45% of individuals with Down syndrome age 45 years or older develop Alzheimer-related dementia.13,14 Individuals with trisomy 21 also have an increased risk of atlantoaxial instability (Fig. 2).15,16 The phenotype can be variable in individuals with mosaic Down syndrome.17 The average life expectancy is 49 years in the white population, although there is racial disparity.18,19
Differential diagnosis Trisomy 18 is an aneuploidy that manifests in severe cognitive delay and heart problems but may also have problems in the digestive, reproductive, and urologic systems. The disorder is often fatal in infancy or early childhood. Males with more than 1 X chromosome also have cognitive delay, distinct facies, and skeletal problems. Individuals with isolated hypotonia have no
oralmaxsurgeryatlas.theclinics.com
198
Shiang associated with cervical instability, with the need for surgical intervention. To prevent any additional problems, radiologic evaluation of the cervical spine should be performed before any procedures requiring anesthesia. The neck should be maintained in a neutral position to prevent any extreme flexion, extension, or rotation.9,15,16 Tracheal stenosis can be more common in children with Down syndrome, which can lead to complications in anesthesia during surgery, such as complicated intubation or greater airway narrowing after intubation or bronchoscopy.9 Comprehensive assessment, including cardiac assessment, should be performed before surgery. Residual cardiac defects such as conduction disturbances and atrial rhythm anomalies can persist throughout the life of the individual, even after successful cardiac repair.20 Complications such as recurrent infections and a higher incidence of pulmonary hypertension, which contribute to increased mortality and morbidity, can also arise.20
Fig. 1 A young child with Down syndrome showing midface hypoplasia, flat or depressed nasal bridge, and epicanthic folds.
other distinctive features and have a normal chromosomal complement. Zellweger syndrome, a disease of peroxisome, also presents with hypotonia, cardiac defects, flat occiput and face, epicanthal folds, and palmer crease, similar to Down syndrome. Differential diagnosis can be made because individuals also present with congenital cataracts, hepatomegaly, contractures, and increased levels of iron and long-chain fatty acids. They also have a normal chromosomal complement. Autism manifests in general development delay in early childhood. A diagnosis of Down syndrome can be made using karyotype analysis or array comparative genomic hybridization.
Klinefelter syndrome Genetics Klinefelter syndrome is the most common sex chromosome aneuploidy in males and is caused by having 1 extra X chromosome (47,XXY) (89.9%). Additional X chromosomes can also be present (48,XXXY [1.1%]; 49,XXXXY [1.8%]), and mosaicism can also exist (46,XY/47,XXY [6.6%]; 47,XXY/48,XXXY [0.2%]). The prevalence was 1 in 660 men in a Danish population.21 The risk increases with maternal age. The disorder is sporadic and usually caused by meiotic or mitotic nondisjunction in germ cells or in the fetus, respectively.
Clinical features Treatment considerations for the oral and maxillofacial surgeon Atlantoaxial instability affects between 10% and 30% of individuals with Down syndrome, only 1.5% of whom need surgical intervention. Os odontoideum has been specifically
The 2 main features found in individuals with Klinefelter syndrome are hypergonadotropic hypogonadism with adults presenting with a high ratio of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels when compared with their testosterone levels and small testicular volume.22 Tall
Fig. 2 A 10-year-old girl noted to have C1-C2 instability on routine screening. (A) Flexion and (B) extension radiographs showing 7 mm of motion. (From Dimar JR, Carreon LY. Spine deformity in Down syndrome. Spine Deform 2012;(Preview Issue):78; with permission.)
Chromosomal Syndromes stature was believed to be a hallmark of the disorder, and growth in childhood and adolescence is accelerated, but mean adult height of affected men is 184.7 cm, which is not greatly different from the mean adult height of unaffected men (182.6 cm) in Denmark.22 Cryptorchidism (14%), gynecomastia (44%), and behavioral and learning problems (36%) are also observed, but not in all individuals.22 Verbal processing seems to be specifically affected.23,24 Other variable features include eunuchoid body habitus, long arms and legs, sparse body hair, and mandibular prognathism (Fig. 3).25 This variable phenotype is seen in Fig. 4, which shows an atypical phenotypic presentation.26 Individuals with Klinefelter syndrome are also at increased risk for metabolic syndrome, osteopenia/osteoporosis, breast cancer, autoimmune disorders, and mortality.26e29 Individuals with more X chromosomes seem to have a more severe phenotype, including additional congenital malformations and greater cognitive involvement.30 Klinefelter syndrome is the most common chromosomal abnormality in azoospermic infertile men.31 Testicular histology through childhood remains normal but with fewer germ cells (Fig. 5).22 By adulthood, there are few seminiferous tubules, with spermatogenesis and hyperplasia of Leydig cells. Undifferentiated and differentiated Sertoli cells can be observed.22 Most individuals with Klinefelter syndrome are undiagnosed. Only 10% of the expected numbers are diagnosed before puberty and 25% in adults, mainly because of infertility or hypogonadism.21 The major reasons for diagnosis of Kleinfelter syndrome are maternal age prenatally, developmental delay before puberty (<11 years old), and small testes in individuals between 11 and 19 years old.30,32 Selective early initiation of testosterone supplementation has been shown to restore the sex dimorphic changes in fat deposition through puberty33 and may also prevent the
199
Fig. 4 An atypical phenotype in an individual with Klinefelter syndrome. This individual presented with relatively large muscle mass, normal masculine body hair distribution, beard, and baldness, but also the typical abdominal obesity. He was diagnosed at the age of 35 years, because of infertility. Height 181 cm, weight 94 kg, karyotype 47,XXY. (From Bojesen A, Høst C, Gravholt CH. Klinefelter’s syndrome, type 2 diabetes and the metabolic syndrome: the impact of body composition. Mol Hum Reprod 2010;16:397; with permission.)
development and persistence of gynecomastia. Thus, early diagnosis would be helpful for early intervention with testosterone, although sperm retrieval is most successful at the onset of puberty and before testosterone therapy.34
Differential diagnosis Individuals with fragile X syndrome also present with intellectual disability and social anxiety, but their physical characteristics include an elongated face, large protruding ears, and macroorchidism. Kallmann syndrome also presents with hypogonadism but is accompanied by a reduced sense of smell. Kallmann syndrome and isolated hypogonadotropic hypogonadism are characterized by low levels of circulating sex hormones. Marfan syndrome also presents with increased height and long limbs but no hypogonadism. Klinefelter syndrome can be distinguished from these other disorders through chromosomal analysis. Fig. 3 Profile of a man with Klinefelter syndrome, showing mandibular prognathism. The arrow points to the parotid region, and in this rare case, parotid gland agenesis was observed. (From Yilmaz YF, Titiz A, Yurur-Kutlay N, et al. Congenital bilateral parotid gland agenesis in Klinefelter syndrome. J Craniomaxillofac Surg 2010;38:249; with permission.)
Treatment considerations for the oral and maxillofacial surgeon Because of the greater prevalence of certain systemic diseases, as noted earlier, appropriate medical evaluation is important before anesthesia and surgery. Individuals with
200
Shiang
Fig. 5 Comparisons of micrographs of testicular specimens from individuals with Klinefelter syndrome at various ages. (Left) Individuals with normal testicular function and (right) affected individuals. Testicular architecture of specimens from unaffected and affected individuals is similar from fetal life until puberty, except that the number of germ cells is severely reduced in the prepubertal Klinefelter syndrome sample. During puberty, gross morphologic changes appear. Normally, spermatogenesis is initiated, but the seminiferous tubules in the affected individual show widespread degeneration and hyalinization. In an adult individual with Klinefelter syndrome, few degenerated tubules may contain germ cells, but most of the testicular tissue is composed of clumps of Leydig cells. Arrows indicate gonocytes. Bars represent 100 mm. GW, gestational week. (From Aksglaede L, Skakkebaek NE, Almstrup K, et al. Clinical and biological parameters in 166 boys, adolescents and adults with nonmosaic Klinefelter syndrome: a Copenhagen experience. Acta Paediatr 2011;100:799; with permission.)
Klinefelter syndrome also manifest with an increase of taurodontism and caries when compared with a control population.35,36 Shovel-shaped incisors have also been reported in patients with Klinefelter syndrome.
Turner syndrome Genetics Turner syndrome is mainly characterized by missing 1 or portions of an X chromosome in females. Many are missing an entire X chromosome (45,X) (45%), and 15% are mosaic of 45,X/ 46,XX. Individuals with Xq isochromosomes or mosaics of Xq isochromosomes make up 11% of the population. The rest have many different variants, including deletions and translocations of the X chromosome, Xp isochromosomes, various combinations of mosaicism, and even karyotypes with Y chromosome material. The prevalence of Turner syndrome was about 1 in
2000 females in a Danish population.37 Turner syndrome occurs sporadically, and nondisjunction in this case is mainly paternal. There is no association with increased maternal age.
Clinical features The 2 main features of Turner syndrome are growth retardation, resulting in short stature throughout life, and infertility in later years.38 Growth failure begins prenatally and is observed by 3 years of age. On average, adult height is 20 cm less than typical height (Fig. 6).39e41 Although individuals with Turner syndrome are not deficient in growth hormone, treatment with growth hormone allows greater height attainment. It remains to be determined if earlier growth hormone therapy increases final height attainment.38 Infertility is caused by ovarian failure, the onset of which is variable but which can begin prenatally. A third of girls have onset of pubertal development, but a smaller percentage have spontaneous menarche (16%).42 Most go on to show ovarian failure, although spontaneous
Chromosomal Syndromes
Fig. 6 Mean height including 2 standard deviations plotted against age of females with Turner syndrome (dark lines) from 5 European cohorts. Mean heights can be compared with unaffected females (light lines). The data were compiled using 5 cohorts, 4 of which included individuals not treated with hormone therapy and one included individuals treated with estrogen but not androgen. (From Lyons AJ, Preece MA, Grant DB. Growth curve for girls with Turner syndrome. Arch Dis Child 1985;60:933; with permission.)
pregnancy does occur in 2% to 5% of individuals who develop spontaneous menarche.42,43 Individuals with Turner syndrome do have estrogen deficiency and higher levels of LH and FSH starting at puberty and continuing in adulthood. Most girls need to be treated with hormone replacement therapy (HRT) to induce puberty. HRT does not seem to affect final outcomes with growth hormone therapy. Other features of Turner syndrome include congenital lymphedema, broad chest with widely spaced nipples, anomalous auricles, low posterior hair
201 line, appearance of webbed neck, cubitus valgus, excessive pigmented nevi, and horseshoe kidney, which occur with varying frequency (Fig. 7).44 Heart anomalies are found in 50% of individuals with Turner syndrome and are the main contributor to an increase in mortality.45 Congenital structural abnormalities of the heart include coarctation of the aorta (COA), bicuspid aortic valve (BAV), and partial anomalous pulmonary venous return. The presence of webbing of the neck, which indicates lymphedema, is significantly associated with BAV and COA.46,47 Aortic dissection can develop in adults with Turner syndrome and is found in 0.6% to 1.4% of individuals, which is a higher incidence than found in the general population.48 Hypertension affects up to 25% of adolescents and 50% of adults. It is mostly systolic and is often nocturnal.49 Other morbidities associated with Turner syndrome include increased rates of diabetes, metabolic syndrome, inflammatory bowel disease, hypothyroidism, and celiac disease. These metabolic and autoimmune issues may be caused by a different body composition in adult women. They weigh more and have greater fat body mass and less lean body mass than women in the general population.41 Scoliosis and kyphosis are identified in 10% to 20% of girls with Turner syndrome. Also, decreased bone mineral density is observed, which results in an increase in fractures, although more fractures are also observed before puberty.50,51 HRT can increase bone mineral density in adults.52,53 The standardized mortality is increased for all individuals with Turner syndrome and is 4.08 for individuals with 45,X; overall mortality is 2.86.37 Mortality is mainly caused by disorders associated with endocrine, nutritional, and metabolic disorders, most likely associated with increased diabetes, congenital anomalies, coronary disease, and cancer.37
Differential diagnosis Noonan syndrome shares many features of Turner syndrome, including short stature, webbed neck, and congenital heart disease. Individuals with Noonan syndrome also present with unusual facies, including hypertelorism and downward slanting eyes, but have normal karyotypes.
Fig. 7 A young woman with Turner syndrome, showing excessive pigmented nevi, micrognathia, and prominent ears (left, profile) as well as a wide short neck (right, frontal view). (From Russell KA. Orthodontic treatment for patients with Turner syndrome. Am J Orthod Dentofacial Orthop 2001;120:316; with permission.)
202
Treatment considerations for the oral and maxillofacial surgeon Individuals with Turner syndrome can have micrognathia (60%) and a high arched palate (35%) (see Fig. 7).38,54 These issues, along with a wide and short neck, and athrogryposis of the temporomandibular joint in some individuals, can complicate tracheal intubation (see Fig. 7). The short trachea along with high bifurcation can also lead to endobronchial intubation and inadvertent endotracheal extubation when the endotracheal tube is under traction. The high incidence of cardiovascular problems indicates preoperative echocardiogram and stress tests. Coarctatation of the aorta mandates strict control of blood pressure. Any metabolic presentations, such as diabetes, also need to be managed during surgery.55,56
References 1. Lejeune J, Turpin R, Gautier M. [Mongolism; a chromosomal disease (trisomy)]. Bull Acad Natl Med 1959;143(11-12):256e65. French. PubMed PMID:13662687. 2. Korbel JO, Tirosh-Wagner T, Urban AE, et al. The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies. Proc Natl Acad Sci U S A 2009;106:12031e6. 3. Centers for Disease Control and Prevention (CDC). Improved national prevalence estimates for 18 selected major birth defectseUnited States, 1999-2001. MMWR Morb Mortal Wkly Rep 2006;54:1301e5. 4. Mikkelsen M, Fischer G, Stene J, et al. Incidence study of Down’s syndrome in Copenhagen, 1960-1971; with chromosome investigation. Ann Hum Genet 1976;40:177e82. 5. Carlier M, Desplanches AG, Philip N, et al. Laterality preference and cognition: cross-syndrome comparison of patients with trisomy 21 (Down), del7q11.23(Williams-Beuren) and del22q11.2 (DiGeorge or velo-cardio-facial) syndromes. Behav Genet 2011; 41:413e22. 6. Levy Y. IQ predicts word decoding skills in populations with intellectual disabilities. Res Dev Disabil 2011;32:2267e77. 7. Patterson T, Rapsey CM, Glue P. Systematic review of cognitive development across childhood in Down syndrome: implications for treatment interventions. J Intellect Disabil Res 2013;57:306e18. 8. Silverman W. Down syndrome: cognitive phenotype. Ment Retard Dev Disabil Res Rev 2007;13:228e36. 9. Ramia M, Musharrafieh U, Khaddage W, et al. Revisiting Down syndrome from the ENT perspective: review of literature and recommendations. Eur Arch Otorhinolaryngol 2014;271(5): 863e9. 10. Anders PL, Davis EL. Oral health of patients with intellectual disabilities: a systematic review. Spec Care Dentist 2010;30(3): 110e7. 11. Bauer D, Evans CA, Begole EA, et al. Severity of occlusal disharmonies in Down syndrome. Int J Dent 2012;2012:872367. 12. Fong CT, Brodeur GM. Down’s syndrome and leukemia: epidemiology, genetics, cytogenetics and mechanisms of leukemogenesis. Cancer Genet Cytogenet 1987;28:55e76. 13. Thase ME, Liss L, Smeltzer D, et al. Clinical evaluation of dementia in Down’s syndrome: a preliminary report. J Ment Defic Res 1982;26:239e44. 14. Wisniewski KE, Wisniewski HM, Wen GY. Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann Neurol 1985;17:278e82. 15. Hwang SW, Jea A. A review of the neurological and neurosurgical implications of Down syndrome in children. Clin Pediatr 2013;52: 845e56. 16. Dimar JR, Carreon LY. Spine deformity in Down syndrome. Spine Deform 2012;(Preview Issue):75e84.
Shiang 17. Papavassiliou P, York TP, Gursoy N, et al. The phenotype of persons having mosaicism for trisomy 21/Down syndrome reflects the percentage of trisomic cells present in different tissues. Am J Med Genet A 2009;149A:573e83. 18. Centers for Disease Control and Prevention (CDC). Racial disparities in median age at death of persons with Down syndromeeUnited States, 1968e1997. MMWR Morb Mortal Wkly Rep 2001;50:463e5. 19. Yang Q, Rasmussen SA, Friedman JM. Mortality associated with Down’s syndrome in the USA from 1983 to 1997: a populationbased study. Lancet 2002;359:1019e25. 20. Meitzner MC, Skurnowicz JA. Anesthetic considerations for patients with Down syndrome. AANA J 2005;73:103e7. 21. Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a National Registry Study. J Clin Endocrinol Metab 2003;88:622e6. 22. Aksglaede L, Skakkebaek NE, Almstrup K, et al. Clinical and biological parameters in 166 boys, adolescents and adults with nonmosaic Klinefelter syndrome: a Copenhagen experience. Acta Paediatr 2011;100:793e806. 23. Rovet J, Netley C, Keenan M, et al. The psychoeducational profile of boys with Klinefelter syndrome. J Learn Disabil 1996;29: 180e96. 24. Graham JM Jr, Bashir AS, Stark RE, et al. Oral and written language abilities of XXY boys: implications for anticipatory guidance. Pediatrics 1988;81:795e806. 25. Brown T, Alvesalo L, Townsend GC. Craniofacial patterning in Klinefelter (47 XXY) adults. Eur J Orthod 1993;15:185e94. 26. Bojesen A, Høst C, Gravholt CH. Klinefelter’s syndrome, type 2 diabetes and the metabolic syndrome: the impact of body composition. Mol Hum Reprod 2010;16:396e401. 27. Bojesen A, Juul S, Birkebaek N, et al. Increased mortality in Klinefelter syndrome. J Clin Endocrinol Metab 2004;89:3830e4. 28. Swerdlow AJ, Hermon C, Jacobs PA, et al. Mortality and cancer incidence in persons with numerical sex chromosome abnormalities: a cohort study. Ann Hum Genet 2001;65:177e88. 29. Swerdlow AJ, Higgins CD, Schoemaker MJ, et al. Mortality in patients with Klinefelter syndrome in Britain: a cohort study. J Clin Endocrinol Metab 2005;90:6516e22. 30. Tartaglia N, Ayari N, Howell S, et al. 48,XXYY, 48,XXXY and 49,XXXXY syndromes: not just variants of Klinefelter syndrome. Acta Paediatr 2011;100:851e60. 31. Mau-Holzmann UA. Somatic chromosomal abnormalities in infertile men and women. Cytogenet Genome Res 2005;111:317e36. 32. Nahata L, Rosoklija I, Yu RN, et al. Klinefelter syndrome: are we missing opportunities for early detection? Clin Pediatr (Phila) 2013;52:936e41. 33. Ratcliffe SG, Butler GE, Jones M. Edinburgh study of growth and development of children with sex chromosome abnormalities IV. In: Evans JA, Hamerton JL, Robinson A, editors. Children and young adults with sex chromosome aneuploidy. Follow-up, clinical and molecular studies. March of Dimes Birth Defects Foundation. Birth Defects Original Article Series, vol. 26. White Plains NY: Wiley-Liss; 1991. p. 1e44. 34. Rives N, Milazzo JP, Perdrix A, et al. The feasibility of fertility preservation in adolescents with Klinefelter syndrome. Hum Reprod 2013;28:1468e79. 35. Schulman GS, Redford-Badwal D, Poole A, et al. Taurodontism and learning disabilities in patients with Klinefelter syndrome. Pediatr Dent 2005;27:389e94. 36. Palin-Palokas T, Alvesalo L, Takala I, et al. Caries occurrence in Klinefelter syndrome men (47,XXY males). Proc Finn Dent Soc 1990;86:143e7. 37. Stochholm K, Juul S, Juel K, et al. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab 2006;91:3897e902. 38. Gravholt CH. Clinical practice in Turner syndrome. Nat Clin Pract Endocrinol Metab 2005;1:41e52. ¨ger H, Rosendahl W, et al. Turner syndrome: 39. Ranke MB, Pflu spontaneous growth in 150 cases and review of the literature. Eur J Pediatr 1983;141:81e8.
Chromosomal Syndromes 40. Lyon AJ, Preece MA, Grant DB. Growth curve for girls with Turner syndrome. Arch Dis Child 1985;60:932e5. 41. Gravholt CH, Weis Naeraa R. Reference values for body proportions and body composition in adult women with Ullrich-Turner syndrome. Am J Med Genet 1997;72:403e8. 42. Pasquino AM, Passeri F, Pucarelli I, et al. Spontaneous pubertal development in Turner’s syndrome. Italian Study Group for Turner’s Syndrome. J Clin Endocrinol Metab 1997;82:1810e3. 43. Mortensen KH, Rohde MD, Uldbjerg N, et al. Repeated spontaneous pregnancies in 45,X Turner syndrome. Obstet Gynecol 2010; 115:446e9. 44. Jones KL. Smith’s recognizable patterns of human malformation. 6th edition. Philadelphia: Elsevier Saunders; 2006. 45. Price WH, Clayton JF, Collyer S, et al. Mortality ratios, life expectancy, and causes of death in patients with Turner’s syndrome. J Epidemiol Community Health 1986;40:97e102. 46. Clark EB. Neck web and congenital heart defects: a pathogenic association in 45 X-O Turner syndrome? Teratology 1984;29:355e61. 47. Loscalzo ML, Van PL, Ho VB, et al. Association between fetal lymphedema and congenital cardiovascular defects in Turner syndrome. Pediatrics 2005;115:732e5. 48. Lin AE, Lippe B, Rosenfeld RG. Further delineation of aortic dilation, dissection, and rupture in patients with Turner syndrome. Pediatrics 1998;102:e12.
203 49. Nathwani NC, Unwin R, Brook CG, et al. Blood pressure and Turner syndrome. Clin Endocrinol (Oxf) 2000;52:363e70. 50. Gravholt CH, Juul S, Naeraa RW, et al. Morbidity in Turner syndrome. J Clin Epidemiol 1998;51:147e58. 51. Gravholt CH, Vestergaard P, Hermann AP, et al. Increased fracture rates in Turner’s syndrome: a nationwide questionnaire survey. Clin Endocrinol (Oxf) 2003;59:89e96. 52. Bertelloni S, Cinquanta L, Baroncelli GI, et al. Volumetric bone mineral density in young women with Turner’s syndrome treated with estrogens or estrogens plus growth hormone. Horm Res 2000; 53:72e6. 53. Sas TC, de Muinck Keizer-Schrama SM, Stijnen T, et al, Dutch Advisory Group on Growth Hormone. Bone mineral density assessed by phalangeal radiographic absorptiometry before and during long-term growth hormone treatment in girls with Turner’s syndrome participating in a randomized dose-response study. Pediatr Res 2001;50:417e22. 54. Russell KA. Orthodontic treatment for patients with Turner syndrome. Am J Orthod Dentofacial Orthop 2001;120(3):314e22. 55. Mashour GA, Sunder N, Acquadro MA. Anesthetic management of Turner syndrome: a systematic approach. J Clin Anesth 2005;17: 128e30. ~o MV. Turner syndrome and anesthesia [review] Rev Bras 56. Maranha Anestesiol 2008;58:84e9 [in Portuguese].
Down syndrome Genetics Down syndrome is the most frequently observed chromosomal aneuploidy caused by trisomy 21 or partial trisomy 21.1,2 Most (90%e95%) cases are caused by de novo chromosomal nondisjunction. About 2% to 6% of cases are caused by translocations of 2 chromosome 21s or a Robertsonian translocation of chromosome 21 fused to another acrocentric chromosome. Another 2% to 3% of cases are mosaic for trisomy 21. The prevalence of this disorder is 1/700 live births, but the risk of having a child with Down syndrome greatly increases with the age of the mother. The risk is 1/1000 at age 30 years and increases to 9/ 1000 at age 40 years.3,4
Clinical features The main features of Down syndrome include cognitive impairment, hypotonia, and characteristic facial features. The IQ of individuals with trisomy 21 is highly variable, and most individuals fall between the moderate to severe range.5,6 IQ is not stable and decreases with age.7 Specific cognitive weaknesses have been identified in expressive language, syntactic/ morphosyntactic processing, and verbal working memory.8 Craniofacial features include brachycephaly, midface hypoplasia, flat or depressed nasal bridge, micrognathia, and epicanthic folds (Fig. 1). In addition, there are outer (dysmorphic
Disclosures: No disclosures or conflicts of interests to report. Department of Human and Molecular Genetics, Virginia Commonwealth University, PO Box 980033, Richmond, VA 23298-0033, USA E-mail address: [email protected] Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 197–203 1061-3315/14/$ - see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cxom.2014.05.003
outer ear and stenosis of the external ear canal), middle (malformation of the eustachian tube), and inner ear anomalies, which can result in hearing loss and cholesteatoma.9 Dental issues include variable tooth morphogenesis and eruption and a greater prevalence and severity of periodontal disease, but lower incidence of caries.10,11 Changes in the oral cavity include macroglossia and a protruding furrowed tongue as well as narrow palate, pharynx, and oropharynx. Many of these craniofacial issues can lead to sleep apnea, and because of a decrease of immune function in individuals with Down syndrome, these can also lead to chronic infections.9 Congenital heart defects are not present in all individuals but contribute greatly to mortality. These anomalies include atrioventricular canal defect, tetralogy of Fallot, and patent ductus arteriosus but particularly atrioventricular septal defects. There are many confounding issues with individuals with trisomy 21. There is a greater risk for leukemia, both acute lymphoblastic leukemia and acute myelogenous leukemia.12 Approximately 45% of individuals with Down syndrome age 45 years or older develop Alzheimer-related dementia.13,14 Individuals with trisomy 21 also have an increased risk of atlantoaxial instability (Fig. 2).15,16 The phenotype can be variable in individuals with mosaic Down syndrome.17 The average life expectancy is 49 years in the white population, although there is racial disparity.18,19
Differential diagnosis Trisomy 18 is an aneuploidy that manifests in severe cognitive delay and heart problems but may also have problems in the digestive, reproductive, and urologic systems. The disorder is often fatal in infancy or early childhood. Males with more than 1 X chromosome also have cognitive delay, distinct facies, and skeletal problems. Individuals with isolated hypotonia have no
oralmaxsurgeryatlas.theclinics.com
198
Shiang associated with cervical instability, with the need for surgical intervention. To prevent any additional problems, radiologic evaluation of the cervical spine should be performed before any procedures requiring anesthesia. The neck should be maintained in a neutral position to prevent any extreme flexion, extension, or rotation.9,15,16 Tracheal stenosis can be more common in children with Down syndrome, which can lead to complications in anesthesia during surgery, such as complicated intubation or greater airway narrowing after intubation or bronchoscopy.9 Comprehensive assessment, including cardiac assessment, should be performed before surgery. Residual cardiac defects such as conduction disturbances and atrial rhythm anomalies can persist throughout the life of the individual, even after successful cardiac repair.20 Complications such as recurrent infections and a higher incidence of pulmonary hypertension, which contribute to increased mortality and morbidity, can also arise.20
Fig. 1 A young child with Down syndrome showing midface hypoplasia, flat or depressed nasal bridge, and epicanthic folds.
other distinctive features and have a normal chromosomal complement. Zellweger syndrome, a disease of peroxisome, also presents with hypotonia, cardiac defects, flat occiput and face, epicanthal folds, and palmer crease, similar to Down syndrome. Differential diagnosis can be made because individuals also present with congenital cataracts, hepatomegaly, contractures, and increased levels of iron and long-chain fatty acids. They also have a normal chromosomal complement. Autism manifests in general development delay in early childhood. A diagnosis of Down syndrome can be made using karyotype analysis or array comparative genomic hybridization.
Klinefelter syndrome Genetics Klinefelter syndrome is the most common sex chromosome aneuploidy in males and is caused by having 1 extra X chromosome (47,XXY) (89.9%). Additional X chromosomes can also be present (48,XXXY [1.1%]; 49,XXXXY [1.8%]), and mosaicism can also exist (46,XY/47,XXY [6.6%]; 47,XXY/48,XXXY [0.2%]). The prevalence was 1 in 660 men in a Danish population.21 The risk increases with maternal age. The disorder is sporadic and usually caused by meiotic or mitotic nondisjunction in germ cells or in the fetus, respectively.
Clinical features Treatment considerations for the oral and maxillofacial surgeon Atlantoaxial instability affects between 10% and 30% of individuals with Down syndrome, only 1.5% of whom need surgical intervention. Os odontoideum has been specifically
The 2 main features found in individuals with Klinefelter syndrome are hypergonadotropic hypogonadism with adults presenting with a high ratio of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels when compared with their testosterone levels and small testicular volume.22 Tall
Fig. 2 A 10-year-old girl noted to have C1-C2 instability on routine screening. (A) Flexion and (B) extension radiographs showing 7 mm of motion. (From Dimar JR, Carreon LY. Spine deformity in Down syndrome. Spine Deform 2012;(Preview Issue):78; with permission.)
Chromosomal Syndromes stature was believed to be a hallmark of the disorder, and growth in childhood and adolescence is accelerated, but mean adult height of affected men is 184.7 cm, which is not greatly different from the mean adult height of unaffected men (182.6 cm) in Denmark.22 Cryptorchidism (14%), gynecomastia (44%), and behavioral and learning problems (36%) are also observed, but not in all individuals.22 Verbal processing seems to be specifically affected.23,24 Other variable features include eunuchoid body habitus, long arms and legs, sparse body hair, and mandibular prognathism (Fig. 3).25 This variable phenotype is seen in Fig. 4, which shows an atypical phenotypic presentation.26 Individuals with Klinefelter syndrome are also at increased risk for metabolic syndrome, osteopenia/osteoporosis, breast cancer, autoimmune disorders, and mortality.26e29 Individuals with more X chromosomes seem to have a more severe phenotype, including additional congenital malformations and greater cognitive involvement.30 Klinefelter syndrome is the most common chromosomal abnormality in azoospermic infertile men.31 Testicular histology through childhood remains normal but with fewer germ cells (Fig. 5).22 By adulthood, there are few seminiferous tubules, with spermatogenesis and hyperplasia of Leydig cells. Undifferentiated and differentiated Sertoli cells can be observed.22 Most individuals with Klinefelter syndrome are undiagnosed. Only 10% of the expected numbers are diagnosed before puberty and 25% in adults, mainly because of infertility or hypogonadism.21 The major reasons for diagnosis of Kleinfelter syndrome are maternal age prenatally, developmental delay before puberty (<11 years old), and small testes in individuals between 11 and 19 years old.30,32 Selective early initiation of testosterone supplementation has been shown to restore the sex dimorphic changes in fat deposition through puberty33 and may also prevent the
199
Fig. 4 An atypical phenotype in an individual with Klinefelter syndrome. This individual presented with relatively large muscle mass, normal masculine body hair distribution, beard, and baldness, but also the typical abdominal obesity. He was diagnosed at the age of 35 years, because of infertility. Height 181 cm, weight 94 kg, karyotype 47,XXY. (From Bojesen A, Høst C, Gravholt CH. Klinefelter’s syndrome, type 2 diabetes and the metabolic syndrome: the impact of body composition. Mol Hum Reprod 2010;16:397; with permission.)
development and persistence of gynecomastia. Thus, early diagnosis would be helpful for early intervention with testosterone, although sperm retrieval is most successful at the onset of puberty and before testosterone therapy.34
Differential diagnosis Individuals with fragile X syndrome also present with intellectual disability and social anxiety, but their physical characteristics include an elongated face, large protruding ears, and macroorchidism. Kallmann syndrome also presents with hypogonadism but is accompanied by a reduced sense of smell. Kallmann syndrome and isolated hypogonadotropic hypogonadism are characterized by low levels of circulating sex hormones. Marfan syndrome also presents with increased height and long limbs but no hypogonadism. Klinefelter syndrome can be distinguished from these other disorders through chromosomal analysis. Fig. 3 Profile of a man with Klinefelter syndrome, showing mandibular prognathism. The arrow points to the parotid region, and in this rare case, parotid gland agenesis was observed. (From Yilmaz YF, Titiz A, Yurur-Kutlay N, et al. Congenital bilateral parotid gland agenesis in Klinefelter syndrome. J Craniomaxillofac Surg 2010;38:249; with permission.)
Treatment considerations for the oral and maxillofacial surgeon Because of the greater prevalence of certain systemic diseases, as noted earlier, appropriate medical evaluation is important before anesthesia and surgery. Individuals with
200
Shiang
Fig. 5 Comparisons of micrographs of testicular specimens from individuals with Klinefelter syndrome at various ages. (Left) Individuals with normal testicular function and (right) affected individuals. Testicular architecture of specimens from unaffected and affected individuals is similar from fetal life until puberty, except that the number of germ cells is severely reduced in the prepubertal Klinefelter syndrome sample. During puberty, gross morphologic changes appear. Normally, spermatogenesis is initiated, but the seminiferous tubules in the affected individual show widespread degeneration and hyalinization. In an adult individual with Klinefelter syndrome, few degenerated tubules may contain germ cells, but most of the testicular tissue is composed of clumps of Leydig cells. Arrows indicate gonocytes. Bars represent 100 mm. GW, gestational week. (From Aksglaede L, Skakkebaek NE, Almstrup K, et al. Clinical and biological parameters in 166 boys, adolescents and adults with nonmosaic Klinefelter syndrome: a Copenhagen experience. Acta Paediatr 2011;100:799; with permission.)
Klinefelter syndrome also manifest with an increase of taurodontism and caries when compared with a control population.35,36 Shovel-shaped incisors have also been reported in patients with Klinefelter syndrome.
Turner syndrome Genetics Turner syndrome is mainly characterized by missing 1 or portions of an X chromosome in females. Many are missing an entire X chromosome (45,X) (45%), and 15% are mosaic of 45,X/ 46,XX. Individuals with Xq isochromosomes or mosaics of Xq isochromosomes make up 11% of the population. The rest have many different variants, including deletions and translocations of the X chromosome, Xp isochromosomes, various combinations of mosaicism, and even karyotypes with Y chromosome material. The prevalence of Turner syndrome was about 1 in
2000 females in a Danish population.37 Turner syndrome occurs sporadically, and nondisjunction in this case is mainly paternal. There is no association with increased maternal age.
Clinical features The 2 main features of Turner syndrome are growth retardation, resulting in short stature throughout life, and infertility in later years.38 Growth failure begins prenatally and is observed by 3 years of age. On average, adult height is 20 cm less than typical height (Fig. 6).39e41 Although individuals with Turner syndrome are not deficient in growth hormone, treatment with growth hormone allows greater height attainment. It remains to be determined if earlier growth hormone therapy increases final height attainment.38 Infertility is caused by ovarian failure, the onset of which is variable but which can begin prenatally. A third of girls have onset of pubertal development, but a smaller percentage have spontaneous menarche (16%).42 Most go on to show ovarian failure, although spontaneous
Chromosomal Syndromes
Fig. 6 Mean height including 2 standard deviations plotted against age of females with Turner syndrome (dark lines) from 5 European cohorts. Mean heights can be compared with unaffected females (light lines). The data were compiled using 5 cohorts, 4 of which included individuals not treated with hormone therapy and one included individuals treated with estrogen but not androgen. (From Lyons AJ, Preece MA, Grant DB. Growth curve for girls with Turner syndrome. Arch Dis Child 1985;60:933; with permission.)
pregnancy does occur in 2% to 5% of individuals who develop spontaneous menarche.42,43 Individuals with Turner syndrome do have estrogen deficiency and higher levels of LH and FSH starting at puberty and continuing in adulthood. Most girls need to be treated with hormone replacement therapy (HRT) to induce puberty. HRT does not seem to affect final outcomes with growth hormone therapy. Other features of Turner syndrome include congenital lymphedema, broad chest with widely spaced nipples, anomalous auricles, low posterior hair
201 line, appearance of webbed neck, cubitus valgus, excessive pigmented nevi, and horseshoe kidney, which occur with varying frequency (Fig. 7).44 Heart anomalies are found in 50% of individuals with Turner syndrome and are the main contributor to an increase in mortality.45 Congenital structural abnormalities of the heart include coarctation of the aorta (COA), bicuspid aortic valve (BAV), and partial anomalous pulmonary venous return. The presence of webbing of the neck, which indicates lymphedema, is significantly associated with BAV and COA.46,47 Aortic dissection can develop in adults with Turner syndrome and is found in 0.6% to 1.4% of individuals, which is a higher incidence than found in the general population.48 Hypertension affects up to 25% of adolescents and 50% of adults. It is mostly systolic and is often nocturnal.49 Other morbidities associated with Turner syndrome include increased rates of diabetes, metabolic syndrome, inflammatory bowel disease, hypothyroidism, and celiac disease. These metabolic and autoimmune issues may be caused by a different body composition in adult women. They weigh more and have greater fat body mass and less lean body mass than women in the general population.41 Scoliosis and kyphosis are identified in 10% to 20% of girls with Turner syndrome. Also, decreased bone mineral density is observed, which results in an increase in fractures, although more fractures are also observed before puberty.50,51 HRT can increase bone mineral density in adults.52,53 The standardized mortality is increased for all individuals with Turner syndrome and is 4.08 for individuals with 45,X; overall mortality is 2.86.37 Mortality is mainly caused by disorders associated with endocrine, nutritional, and metabolic disorders, most likely associated with increased diabetes, congenital anomalies, coronary disease, and cancer.37
Differential diagnosis Noonan syndrome shares many features of Turner syndrome, including short stature, webbed neck, and congenital heart disease. Individuals with Noonan syndrome also present with unusual facies, including hypertelorism and downward slanting eyes, but have normal karyotypes.
Fig. 7 A young woman with Turner syndrome, showing excessive pigmented nevi, micrognathia, and prominent ears (left, profile) as well as a wide short neck (right, frontal view). (From Russell KA. Orthodontic treatment for patients with Turner syndrome. Am J Orthod Dentofacial Orthop 2001;120:316; with permission.)
202
Treatment considerations for the oral and maxillofacial surgeon Individuals with Turner syndrome can have micrognathia (60%) and a high arched palate (35%) (see Fig. 7).38,54 These issues, along with a wide and short neck, and athrogryposis of the temporomandibular joint in some individuals, can complicate tracheal intubation (see Fig. 7). The short trachea along with high bifurcation can also lead to endobronchial intubation and inadvertent endotracheal extubation when the endotracheal tube is under traction. The high incidence of cardiovascular problems indicates preoperative echocardiogram and stress tests. Coarctatation of the aorta mandates strict control of blood pressure. Any metabolic presentations, such as diabetes, also need to be managed during surgery.55,56
References 1. Lejeune J, Turpin R, Gautier M. [Mongolism; a chromosomal disease (trisomy)]. Bull Acad Natl Med 1959;143(11-12):256e65. French. PubMed PMID:13662687. 2. Korbel JO, Tirosh-Wagner T, Urban AE, et al. The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies. Proc Natl Acad Sci U S A 2009;106:12031e6. 3. Centers for Disease Control and Prevention (CDC). Improved national prevalence estimates for 18 selected major birth defectseUnited States, 1999-2001. MMWR Morb Mortal Wkly Rep 2006;54:1301e5. 4. Mikkelsen M, Fischer G, Stene J, et al. Incidence study of Down’s syndrome in Copenhagen, 1960-1971; with chromosome investigation. Ann Hum Genet 1976;40:177e82. 5. Carlier M, Desplanches AG, Philip N, et al. Laterality preference and cognition: cross-syndrome comparison of patients with trisomy 21 (Down), del7q11.23(Williams-Beuren) and del22q11.2 (DiGeorge or velo-cardio-facial) syndromes. Behav Genet 2011; 41:413e22. 6. Levy Y. IQ predicts word decoding skills in populations with intellectual disabilities. Res Dev Disabil 2011;32:2267e77. 7. Patterson T, Rapsey CM, Glue P. Systematic review of cognitive development across childhood in Down syndrome: implications for treatment interventions. J Intellect Disabil Res 2013;57:306e18. 8. Silverman W. Down syndrome: cognitive phenotype. Ment Retard Dev Disabil Res Rev 2007;13:228e36. 9. Ramia M, Musharrafieh U, Khaddage W, et al. Revisiting Down syndrome from the ENT perspective: review of literature and recommendations. Eur Arch Otorhinolaryngol 2014;271(5): 863e9. 10. Anders PL, Davis EL. Oral health of patients with intellectual disabilities: a systematic review. Spec Care Dentist 2010;30(3): 110e7. 11. Bauer D, Evans CA, Begole EA, et al. Severity of occlusal disharmonies in Down syndrome. Int J Dent 2012;2012:872367. 12. Fong CT, Brodeur GM. Down’s syndrome and leukemia: epidemiology, genetics, cytogenetics and mechanisms of leukemogenesis. Cancer Genet Cytogenet 1987;28:55e76. 13. Thase ME, Liss L, Smeltzer D, et al. Clinical evaluation of dementia in Down’s syndrome: a preliminary report. J Ment Defic Res 1982;26:239e44. 14. Wisniewski KE, Wisniewski HM, Wen GY. Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann Neurol 1985;17:278e82. 15. Hwang SW, Jea A. A review of the neurological and neurosurgical implications of Down syndrome in children. Clin Pediatr 2013;52: 845e56. 16. Dimar JR, Carreon LY. Spine deformity in Down syndrome. Spine Deform 2012;(Preview Issue):75e84.
Shiang 17. Papavassiliou P, York TP, Gursoy N, et al. The phenotype of persons having mosaicism for trisomy 21/Down syndrome reflects the percentage of trisomic cells present in different tissues. Am J Med Genet A 2009;149A:573e83. 18. Centers for Disease Control and Prevention (CDC). Racial disparities in median age at death of persons with Down syndromeeUnited States, 1968e1997. MMWR Morb Mortal Wkly Rep 2001;50:463e5. 19. Yang Q, Rasmussen SA, Friedman JM. Mortality associated with Down’s syndrome in the USA from 1983 to 1997: a populationbased study. Lancet 2002;359:1019e25. 20. Meitzner MC, Skurnowicz JA. Anesthetic considerations for patients with Down syndrome. AANA J 2005;73:103e7. 21. Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a National Registry Study. J Clin Endocrinol Metab 2003;88:622e6. 22. Aksglaede L, Skakkebaek NE, Almstrup K, et al. Clinical and biological parameters in 166 boys, adolescents and adults with nonmosaic Klinefelter syndrome: a Copenhagen experience. Acta Paediatr 2011;100:793e806. 23. Rovet J, Netley C, Keenan M, et al. The psychoeducational profile of boys with Klinefelter syndrome. J Learn Disabil 1996;29: 180e96. 24. Graham JM Jr, Bashir AS, Stark RE, et al. Oral and written language abilities of XXY boys: implications for anticipatory guidance. Pediatrics 1988;81:795e806. 25. Brown T, Alvesalo L, Townsend GC. Craniofacial patterning in Klinefelter (47 XXY) adults. Eur J Orthod 1993;15:185e94. 26. Bojesen A, Høst C, Gravholt CH. Klinefelter’s syndrome, type 2 diabetes and the metabolic syndrome: the impact of body composition. Mol Hum Reprod 2010;16:396e401. 27. Bojesen A, Juul S, Birkebaek N, et al. Increased mortality in Klinefelter syndrome. J Clin Endocrinol Metab 2004;89:3830e4. 28. Swerdlow AJ, Hermon C, Jacobs PA, et al. Mortality and cancer incidence in persons with numerical sex chromosome abnormalities: a cohort study. Ann Hum Genet 2001;65:177e88. 29. Swerdlow AJ, Higgins CD, Schoemaker MJ, et al. Mortality in patients with Klinefelter syndrome in Britain: a cohort study. J Clin Endocrinol Metab 2005;90:6516e22. 30. Tartaglia N, Ayari N, Howell S, et al. 48,XXYY, 48,XXXY and 49,XXXXY syndromes: not just variants of Klinefelter syndrome. Acta Paediatr 2011;100:851e60. 31. Mau-Holzmann UA. Somatic chromosomal abnormalities in infertile men and women. Cytogenet Genome Res 2005;111:317e36. 32. Nahata L, Rosoklija I, Yu RN, et al. Klinefelter syndrome: are we missing opportunities for early detection? Clin Pediatr (Phila) 2013;52:936e41. 33. Ratcliffe SG, Butler GE, Jones M. Edinburgh study of growth and development of children with sex chromosome abnormalities IV. In: Evans JA, Hamerton JL, Robinson A, editors. Children and young adults with sex chromosome aneuploidy. Follow-up, clinical and molecular studies. March of Dimes Birth Defects Foundation. Birth Defects Original Article Series, vol. 26. White Plains NY: Wiley-Liss; 1991. p. 1e44. 34. Rives N, Milazzo JP, Perdrix A, et al. The feasibility of fertility preservation in adolescents with Klinefelter syndrome. Hum Reprod 2013;28:1468e79. 35. Schulman GS, Redford-Badwal D, Poole A, et al. Taurodontism and learning disabilities in patients with Klinefelter syndrome. Pediatr Dent 2005;27:389e94. 36. Palin-Palokas T, Alvesalo L, Takala I, et al. Caries occurrence in Klinefelter syndrome men (47,XXY males). Proc Finn Dent Soc 1990;86:143e7. 37. Stochholm K, Juul S, Juel K, et al. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab 2006;91:3897e902. 38. Gravholt CH. Clinical practice in Turner syndrome. Nat Clin Pract Endocrinol Metab 2005;1:41e52. ¨ger H, Rosendahl W, et al. Turner syndrome: 39. Ranke MB, Pflu spontaneous growth in 150 cases and review of the literature. Eur J Pediatr 1983;141:81e8.
Chromosomal Syndromes 40. Lyon AJ, Preece MA, Grant DB. Growth curve for girls with Turner syndrome. Arch Dis Child 1985;60:932e5. 41. Gravholt CH, Weis Naeraa R. Reference values for body proportions and body composition in adult women with Ullrich-Turner syndrome. Am J Med Genet 1997;72:403e8. 42. Pasquino AM, Passeri F, Pucarelli I, et al. Spontaneous pubertal development in Turner’s syndrome. Italian Study Group for Turner’s Syndrome. J Clin Endocrinol Metab 1997;82:1810e3. 43. Mortensen KH, Rohde MD, Uldbjerg N, et al. Repeated spontaneous pregnancies in 45,X Turner syndrome. Obstet Gynecol 2010; 115:446e9. 44. Jones KL. Smith’s recognizable patterns of human malformation. 6th edition. Philadelphia: Elsevier Saunders; 2006. 45. Price WH, Clayton JF, Collyer S, et al. Mortality ratios, life expectancy, and causes of death in patients with Turner’s syndrome. J Epidemiol Community Health 1986;40:97e102. 46. Clark EB. Neck web and congenital heart defects: a pathogenic association in 45 X-O Turner syndrome? Teratology 1984;29:355e61. 47. Loscalzo ML, Van PL, Ho VB, et al. Association between fetal lymphedema and congenital cardiovascular defects in Turner syndrome. Pediatrics 2005;115:732e5. 48. Lin AE, Lippe B, Rosenfeld RG. Further delineation of aortic dilation, dissection, and rupture in patients with Turner syndrome. Pediatrics 1998;102:e12.
203 49. Nathwani NC, Unwin R, Brook CG, et al. Blood pressure and Turner syndrome. Clin Endocrinol (Oxf) 2000;52:363e70. 50. Gravholt CH, Juul S, Naeraa RW, et al. Morbidity in Turner syndrome. J Clin Epidemiol 1998;51:147e58. 51. Gravholt CH, Vestergaard P, Hermann AP, et al. Increased fracture rates in Turner’s syndrome: a nationwide questionnaire survey. Clin Endocrinol (Oxf) 2003;59:89e96. 52. Bertelloni S, Cinquanta L, Baroncelli GI, et al. Volumetric bone mineral density in young women with Turner’s syndrome treated with estrogens or estrogens plus growth hormone. Horm Res 2000; 53:72e6. 53. Sas TC, de Muinck Keizer-Schrama SM, Stijnen T, et al, Dutch Advisory Group on Growth Hormone. Bone mineral density assessed by phalangeal radiographic absorptiometry before and during long-term growth hormone treatment in girls with Turner’s syndrome participating in a randomized dose-response study. Pediatr Res 2001;50:417e22. 54. Russell KA. Orthodontic treatment for patients with Turner syndrome. Am J Orthod Dentofacial Orthop 2001;120(3):314e22. 55. Mashour GA, Sunder N, Acquadro MA. Anesthetic management of Turner syndrome: a systematic approach. J Clin Anesth 2005;17: 128e30. ~o MV. Turner syndrome and anesthesia [review] Rev Bras 56. Maranha Anestesiol 2008;58:84e9 [in Portuguese].