J Pediatr Endocrinol Metab. Age, height, weight, BMI z-score, and BA/CA were similar in the PA and control groups . Olesen T, Egeblad M, Dige-Petersen H, Ahlgren P, Nielsen AM, Vesterdal J. Somatic manifestations in children suspected of having been maltreated. The bone age (also called the skeletal age) is measured in years. In our opinion, this method could be useful also to obtain information about: defects in condrogenesis and/or osteogenesis (commonly found in hypochondroplasia); irregularity of metaphyseal regions and enlargement of the metaphyseal region of the ulna and of the radius (commonly found in subjects with rickets or metaphyseal chondrodysplasias); shortening of the fourth metacarpus, triangularization of radius distal epiphysis, pyramidalization of carpus distal line, or translucency of radius (commonly found in LeriWeil and Turner Syndrome); shortening of the fourth and fifth metacarpus (commonly found in pseudohypoparathyroidism); Harris lines (expression of a temporary arrest of long bones growth); and. Variability in the order of ossification of the bony centers of the hand and wrist. Conclusions: Hormonal effects associated with adiposity and sexual maturity likely influence skeletal maturation. They can be seen on an X-ray because they're softer and contain less mineral, making them appear darker on an X-ray image than the rest of the bone. In a recent poll, only 1 in 5 parents believed it is unsafe for children to take medicine past its expiration date, while many did not know how to properly dispose medicine. The child's hand/ wrist X-ray is interpreted based on the appearance . Although most children with short or tall stature do not have a pathologic condition, extremes of height, especially beyond three standard deviations, require further workup. Then, the remaining centers progressively appear (Figure 1) (80). /content/kidshealth/misc/medicalcodes/parents/articles/xray-bone-age, diseases that affect the levels of growth hormones, such as growth hormone deficiency, hypothyroidism, precocious puberty, and adrenal gland disorders, orthopedic or orthodontic problems in which the timing and type of treatment (surgery, bracing, etc.) Furthermore, the impact of being overweight or obese on bone age could be identified correctly by BoneExpert. In many European countries, the increase in illegal immigration and above all the immigration of children and adolescents unaccompanied by parents and without identity documents posed important doubts and stressed the need for new procedures aimed at ensuring a better assistance and protection for young people. Children with short stature and no identified cause and children with certain other identifiable causes of short stature should be referred to a pediatric endocrinologist. (1991) 10:61620. Bone Age and Maturity in Association with Anthropometric Measurements doi: 10.1159/000329372, 11. doi: 10.2214/ajr.108.3.511, 108. Age Determination Procedures for Custody Decisions. Br J Sports Med. Although several body areas have been studied over the years in order to define a standardized and universal method (3, 6), the wrist and knee areas represent the gold standard procedures (3, 7). Thereafter, the pisiform and the sesamoid become recognizable. Effective dose and energy imparted in diagnostic radiology. N Engl J Med. Although aromatase inhibitors have been used in children with idiopathic short stature, long-term effectiveness and safety data are not available.27. Eur J Pediatr. then every 6 months. Assessments of skeletal maturity in prepubertal children are primarily based on the epiphyseal size of the phalanges as they relate to the adjacent metaphyses. doi: 10.1515/JPEM.1994.7.2.141, 129. This evaluation is more detailed than a simple comparison and takes into consideration a detailed analysis of structural characteristics of different bones with the assignment of a score to each element (3, 113, 114). Although several bones have been studied to better define bone age, the hand and wrist X-rays are the most used images. In: Geary DF, Schaefer F, editors. Clin Immunol. Bone age may be used either in normal variants of delayed growth patterns with delayed puberty and accelerated growth patterns with early puberty, where it may be more consistent with height age and adult height prediction may be more consistent with genetics. Bone age assessment: automated techniques coming of age? Bone age delay is also associated with genetic syndromes such as trisomy 21, Turner syndrome, and RussellSilver syndrome (10, 4648). doi: 10.1056/NEJM199409083311002, 24. Cambridge. Projected height can be estimated by projecting the current growth curve to adulthood in children with normal bone age, or by using a bone age atlas in those with delayed bone age. Between six and 18 months of age, children exhibit catch-up or catch-down growth until they reach their genetically determined growth curve based on midparental height. The pattern of growth in children with constitutional tall stature from birth to age 9 years. Rofo. Automatic determination of Greulich and Pyle bone age in healthy Dutch children. It is administered through daily injections over several years. (1999) 81:1723. (2009) 94:223944. Tanner JM HM, Goldstein H, Cameron N. Assessment of Skeletal Maturity and Prediction of Adult Height (TW3 Method). Salsberry PJ, Reagan PB, Pajer K. Growth differences by age of menarche in African American and White girls. doi: 10.1159/000184848, Keywords: skeletal development, height, X ray, children, bone age, Citation: Cavallo F, Mohn A, Chiarelli F and Giannini C (2021) Evaluation of Bone Age in Children: A Mini-Review. Aust Orthod J. As sex steroid levels rise during puberty, bone maturation accelerates. J Pediatr. http://www.who.int/childgrowth/standards/en/. doi: 10.1159/000185511, 141. (1996) 167:13958. Horm Res. doi: 10.1093/qjmed/hcs230, 66. A difference between a child's bone age and their chronological age might indicate a growth problem. Biological maturation of youth athletes: assessment and implications. Horm Res. For example if a girl will have a normal timed puberty and a final height of 55, she would be expected to grow along the 50th percentile through childhood. [7][8] Features of bone development assessed in determining bone age include the presence of bones (have certain bones ossified yet), the size and shape of bones, the amount of mineralization (also called ossification), and the degree of fusion between the epiphyses and metaphyses. Chronological age vs. bone age in 169 children with Cystic Fibrosis Dots under the line represented a delay in bone age. (2011) 12:1848. Hand Bone Age. Endocr Rev. (2016) 170:16370. [] The other applications of BA include height prediction and estimation of age in children seeking asylum in other countries and in competitive sports where chronological age (CA) may be unknown. Braz Oral Res. During puberty, the contours of the epiphyses begin to overlap, or cap, the metaphyses. Principal pros and cons related to the different methods utilized for the definition of skeletal age [82, 85, 94, 95, 97, 98, 102, 116, 121, 122, 123, 126, 129,132, 135,137, 138]. p. 70932. Greulich WW. It is defined by the age expressed in years that corresponds to the level of maturation of bones. 69. Recent studies show that organs like the liver can also be used to estimate age and sex, because of the unique feature of liver. Hackman L, Black S. The reliability of the Greulich and Pyle atlas when applied to a modern Scottish population. Pediatricians have relied on methods for determining skeletal maturation for >75 years. [24] This technique was created to avoid errors in estimating bone age though to arise from focusing on only one area of the body. doi: 10.1097/YIC.0000000000000109, 44. Of these, 5477 participants (2975 female [54.3%]) had bone measurements from at least 1 age after peak height velocity . Bone age is delayed | Children's Hospital Colorado The image in the reference atlas that most closely resembles the patient's x-ray is then used to assign a bone age to the patient. (2012) 102:1742. Means and standard deviations of weight, height, chronological age, SA, P-TW3 and P-KR were determined by group 1 and 2 (model and validation groups) and by sex, for all 497 (group 1 = 252; group . doi: 10.1007/s00247-019-04435-z. Midparental height growth velocity should be calculated to evaluate a child's growth vs. potential height. GreulichPyle distinguished two standard templates: 31 and 27 radiographic images, in male and female individuals, respectively, which illustrate different phases of bone maturation between 0 and 18 or 19 years, respectively. doi: 10.1109/42.108597, 128. (2016) 37:13587. The BayleyPinneau method uses a series of tables that are indexed according to gender, chronological age, and skeletal age. Horm Res. Aust Orthod J. Pediatr Endocrinol Rev. Giovanni XXIII Children's Hospital, Italy, University of Modena and Reggio Emilia, Italy, Children's Hospital at Montefiore, United States. Ann Hum Biol. 93. (2016) 52:5238. [4] Other uses of bone age measurements include assisting in the diagnosis of medical conditions affecting children, such as constitutional growth delay, precocious puberty, thyroid dysfunction, growth hormone deficiency, and other causes of abnormally short or tall stature. doi: 10.1136/bjsports-2015-094623, 67. Evaluation of Short and Tall Stature in Children | AAFP Arch Dis Child. Pediatric Endocrine Associates | Growth Delay Treatments The bones on the X-ray image are compared with X-rays images in a standard atlas of bone development, which . doi: 10.1016/S0022-3476(73)80481-0, 19. doi: 10.1016/j.jpeds.2013.11.065, 23. The Local. doi: 10.1080/03014460500087725, 119. Statistical Confirmation of a Method of US Determination of Bone Age doi: 10.1297/cpe.23.27, 55. World Health Organization growth charts should be used for children younger than two years, and the Centers for Disease Control and Prevention growth charts should be used for children older than two years. (2003) 59:77987. There have been two updates since the first publication of the TW method in 1962: the TW2 method in 1975 and the TW3 method in 2001. Taranger J, Karlberg J, Bruning B, Engstrom I. doi: 10.1136/adc.2005.090134, 121. In order to achieve a greater accuracy and diagnostic reproducibility, it is important that bone age determination has the lowest intra- and interoperator variability. doi: 10.1136/bjsports-2012-091296. A comparison between the appearance of a patient's bones to a standard set of bone images known to be representative of the average bone shape and size for a given age can be used to assign a "bone age" to the patient. As well, height prediction methods might be affected by ethnicity-related differences, thus either underestimating or overestimating adult height, with wide variations in accuracy. doi: 10.1038/oby.2010.305, 51. [15] An alternative approach to the atlas method just described is the so-called "single-bone method" where maturity scales are assigned to individual bones. doi: 10.1001/archpedi.1993.02160360071022, 96. TW2 and TW3 bone ages: time to change? A score is assigned to each bone based on maturation and sex of the patient. Hum Biol. Presentation, diagnosis, and therapy. (2005) 35:42933. Vignolo M, Naselli A, Magliano P, Di Battista E, Aicardi M, Aicardi G. Use of the new US90 standards for TW-RUS skeletal maturity scores in youths from the Italian population. doi: 10.1159/000184846, 130. van Rijn RR, Lequin MH, Thodberg HH. Herman TE, Crawford JD, Cleveland RH, Kushner DC. Between 1931 and 1942, Greulich and Pyle evaluated the hand and wrist radiographs obtained from about 1,000 white people of Cleveland (Ohio, USA) belonging to mediumhigh social classes (9, 10, 106). Nebesio TD, Eugster EA. New technology for bone age determination includes computer-automated readings and assessments obtained from alternative imaging modalities. PDF The applicability of the Greulich & Pyle Atlas for bone age assessment (2000) 94:2128. Ashizawa K, Kumakura C, Zhou X, Jin F, Cao J. RUS skeletal maturity of children in Beijing. Comparison of Bone Age Assessments by Gruelich-Pyle, Gilsanz - LWW (1997) 82:16037. Arch Dis Child. Albanese A, Stanhope R. Predictive factors in the determination of final height in boys with constitutional delay of growth and puberty. Online software Boneureka assessing bone age based on metacarpal length The bone ages of hand and elbow were different at puberty, and the elbow was a more reliable location for bone-age assessment at puberty. In 1991, Pietka et al. Bone age in children of diverse ethnicity. doi: 10.1111/j.1651-2227.1988.tb10615.x, 46. Bone Age Advancement in Prepubertal Children - Wiley Online Library J Pediatr Gastroenterol Nutr. Tanner JM. BoneXpert is the first AI-based bone age assessment solution introduced in 2008. doi: 10.1016/j.ajodo.2006.07.037, 99. Discrepancies between bone age and biological age can be seen in people with stunted growth, where bone age may be less than biological age. Therefore, newer methods, such as artificial intelligence, might be used with the aim to guide endocrinologists and radiologists in the daily routine approach. Viii + 339 pp. A renal anomaly? Mansourvar M, Ismail MA, Raj RG, Kareem SA, Aik S, Gunalan R, et al. 41. Endocrine effects of inhaled corticosteroids in children. The issue here is the size of the standard deviation (SD) of the difference between bone age and chronological age, which is 15 months or more. As kids grow, their growth plates look thinner on X-rays and eventually disappear (called "closed growth plates"). doi: 10.1016/j.gcb.2008.09.020, 30. In order to improve the accuracy and reproducibility of this method, changes and improvements have been made over the years. J Pediatr. (2009) 12:7026. Is the assessment of bone age by the Greulich-Pyle method reliable at forensic age estimation for Turkish children? Skeletal age of individuals with Down syndrome. It may take more than four years for a preterm infant who is born small for gestational age to attain a normal height.24, Recombinant growth hormone is approved for a variety of conditions that cause short stature, including Turner syndrome, chronic renal failure, Prader-Willi syndrome, small for gestational age, Noonan syndrome, short stature homeobox-containing gene deficiency, and idiopathic short stature. BMD increased with age in children of both sexes (r = 0 . (1997) 24:13116. Cox LA. J Forensic Dent Sci. Using an atlas-based method gives a great possibility of intra- and interoperator variability (142). Hochberg Z. Endocrine Control of SkeletalMaturation. Zhang H, Geng N, Wang Y, Tian W, Xue F. Van Wyk and Grumbach syndrome: two case reports and review of the published work. Bull RK, Edwards PD, Kemp PM, Fry S, Hughes IA. Bone age is measured in years, most often using the Greulich-Pyle scale. In particular, estrogens and oral contraceptives or creams containing testosterone or estrogens can cause an early closure of the growth plate. (1952) 40:42341. Data Sources: We searched PubMed, Agency for Healthcare Research and Quality, Cochrane Database of Systematic Reviews, and National Guidelines Clearinghouse. Am J Hum Biol. Images of hand and wrist x-rays in four female subjects compatible with physiological skeletal maturation in different ages: A (4 years), B (8 years), C (12 years), D (16 years). Applicability of the Greulich and Pyle skeletal age standards to black and white children of today. (1997) 131(1 Pt 1):3440. Am J Hum Biol. Thus, the variability in the bone age at onset of puberty was greater than the variability in the chronological age at onset of puberty ( Fig. These changes can be seen by x-ray and other imaging techniques. doi: 10.1097/00004032-199811000-00005, 87. Khan KM, Miller BS, Hoggard E, Somani A, Sarafoglou K. Application of ultrasound for bone age estimation in clinical practice. Bone growth estimation using radiology (GreulichPyle and Tanner-Whitehouse Methods). Awais M, Nadeem N, Husen Y, Rehman A, Beg M, Khattak YJ. (2010) 13:35560. 5. For specific medical advice, diagnoses, and treatment, consult your doctor. (1993) 21:148. During late puberty, the fusion of the epiphyses to the metaphyses in the long bones of the hand tends to occur in a characteristic pattern: (3) fusion of the proximal phalanges, and. Bone age and factors affecting skeletal maturation at diagnosis of paediatric Cushing's disease. (1970) 108:5115. ( p =0.67). A Comparison of Skeletal Age of Thalassaemic Patients of 9-15 Years (2014) 23:2734. doi: 10.1111/j.1365-2265.2010.03799.x, 33. (1997). 68. By A. F. Roche, W. C. Chumlea, and D. Thissen. Introduction. [5][17] The reason for imaging only the left hand and wrist are that a hand is easily x-rayed with minimal radiation[18] and shows many bones in a single view. Samadi M, Rashid RJ, Ghaffari S, Shoaran M. Study on bone age in pediatric patients with congenital heart disease and its relation with cyanosis and pulmonary artery pressure. Data obtained in this study were introduced in a computerized system that analyzes 111 maturity indicators of the hand and wrist area in relation to sex and age, morphology, contiguity ratios, and through linear measurements of some bone segments (125, 126). X-Ray Exam: Bone Age Study (for Parents) - Nemours KidsHealth In: Preedy V, editor. As a child grows the epiphyses become calcified and appear on x-rays, as do the carpal and tarsal bones of the hands and feet, separated on x-rays by a layer of invisible cartilage where most of the growth is occurring. [19] Further, most people are right-hand dominant and the left hand is therefore less likely to be deformed due to trauma. Bass S, Pearce G, Bradney M, Hendrich E, Delmas PD, Harding A, et al. Acta Paediatr Scand. In the United States, the most common technique for estimating a person's bone age is to compare an x-ray of the patient's left hand and wrist to a reference atlas containing x-ray images of the left hands of children considered to be representative of how the skeletal structure of the hand appears for the average person at a given age. As these cartilaginous zones become obliterated, the epiphyses are said to be "closed" and no further lengthening of the bones will occur. In the case of too much growth hormone, a child may have a bone age that is older than their chronological age suggesting that they are growing abnormally fast. Tanner JM. The bone mineral density (BMD) of the lumbar spine (L1-L4) was measured by dual energy x-ray absorptiometry (Hologic QDR 1000) in 135 healthy caucasian children, aged 1-15 yr, and values were correlated with age, height, weight, body surface, bone age, pubertal status, calcium intake, vitamin D supplementation, and serum bone gla protein. Nowadays, many methods are available to evaluate bone age. Obesity (Silver Spring). IEEE Trans Med Imaging. Tall stature is defined as a height more than two standard deviations above the mean for age (greater than the 97th percentile). Chronological age and bone age were 8.7 4.0 and 8.8 4.3 years, respectively, for the entire population. FCa, CG, AM, and FCh have contributed to the conception and the design of the manuscript. doi: 10.1097/MPG.0b013e31818cb4b6, 32. [1][2][21], The Tanner-Whitehouse (TW) technique of estimating bone is a "single-bone method" based on an x-ray image of a patient's left hand and wrist. [2][5], To assign a bone age to the patient under review, a radiologist compares the patient's hand and wrist x-ray to images in the Greulich and Pyle atlas. [3] Large differences between a person's bone age and their chronological age may indicate a growth disorder. This process is characterized by a predictable sequence of development and progression of ossification centers. Maes M, Vandeweghe M. A valuable improvement of adult height prediction methods in short normal children. Each bone segment begins its maturation first in the primary ossification center and then, through different stages of enlargement and remodeling, reaches the final shape; many bones, like long bones, have many centers of maturation (epiphysis). PDF Research Article Reliability of the Greulich & Pyle Method for Bone Age Bone Age to Chronological Age Ratio - SUPPRELIN LA Other causes include renal, hepatic, and gastrointestinal diseases, and other genetic syndromes.1015, The initial evaluation of short stature (Figure 1) should include a history and physical examination, accurate growth assessment, calculation of the growth velocity and midparental height, and radiography to evaluate bone age.16 Drugs known to cause short stature include steroids (chronic use), attention-deficit/hyperactivity disorder medications, and anticonvulsants. Available online at: https://treaties.un.org/Pages/ViewDetails.aspx?src=IND&mtdsg_no=IV-1&chapter=4&clang=_en. (2001) 50:6248. It was documented that GP standards are highly inaccurate in children born in America from African or European parents (84). Br J Radiol. Look for a Mllerian anomaly as well. Table 5 lists the indications for referral.2,6,22. (1980) 37:110311. Available online at: https://www.rch.org.au/immigranthealth/clinical/Birth_date_issues/. doi: 10.1590/S0004-27302007000300021, 64. United Nations Treaty Collection. Heyman R, Guggenbuhl P, Corbel A, Bridoux-Henno L, Tourtelier Y, Balencon-Morival M, et al. (1997) 48:18490. The determination of bone age is important to properly assess and guide the evaluation of short or tall stature, impaired or accelerated growth, and delayed or early puberty (10). (2006) 91:420514. Clin Endocrinol Oxford. Following the growth charts from the CDC, the average height of adult woman at age 20 is 64-65 in (163 cm). doi: 10.1118/1.598153. Over the years, numerous standardized methods have been developed to evaluate a skeletal maturity score for the hand and wrist radiographs (3, 5, 9092). doi: 10.1002/ajhb.1310010206, 126. Softer body tissues, such as the skin and muscles, allow the X-ray beams to pass through them. In particular, the method of medical age assessment proposed consisted of taking X-rays of wisdom teeth and MRI scans of knee joints, which are then analyzed by dentists and radiologists. Meet the board: Jessica L. Peck, DNP, APRN, CPNP-PC, CNE, CNL, FAANP, FAAN. It is defined by the age expressed in years that corresponds to the level of maturation of bones. They look darker on the image. (2009) 58:38290. doi: 10.1111/j.1651-2227.2011.02476.x, 74. Apart from the ability to assess the chronological age of a person, the evaluation of growth remaining in a person can be extremely beneficial to a clinician in different circumstances, as previously discussed. A number of factors can help determine your body age. Moreover, weight gain and obesity are one of the most important causes of pediatric advanced bone age; the mechanisms underlying these alterations are not fully clarified, although insulin resistance and hormonal factors produced by adipose tissue might play an important role (50, 51). At birth, long bones present different centers of ossification that proliferate continuously until the terminal or epiphyseal part of the bone melt definitively with the diaphyseal one. X-ray exam: bone age study. Available online at: http://www.ice.gov/doclib/foia/dro_policy_memos/agedeterminationproceduresforcustodydecisionsaug202004.pdf. They should stay still for 23 seconds so the X-ray image is clear. As well, hypophyseal alterations secondary to malformation, tumor, or infiltrative pathologies may also be associated with bone age delay consequently to a secondary GH deficiency or hypothyroidism. doi: 10.1016/j.forsciint.2012.08.030, 105. Although useful and easy to use, this method might be affected by several causes of errors. Over the years, this system has been refinished by moving from an initial system known as TannerWhitehouse method 1 (TW1) to two subsequent methods known as TannerWhitehouse 2 (TW2) and 3 (TW3) (3, 113, 114). [Paternal height (cm) 13 cm + maternal height (cm)] 2, [Paternal height (in) 5 in + maternal height (in)] 2, [Paternal height (cm) + 13 cm + maternal height (cm)] 2, [Paternal height (in) + 5 in + maternal height (in)] 2, Constitutional delay of growth and puberty, Normal growth velocity, history of delayed puberty in parents, History and physical examination, bone age, Short parents, projected height consistent with midparental height, normal growth velocity, Midparental height, growth velocity, bone age; consider targeted laboratory evaluation, Height < 2 standard deviations below the mean for age with no identified pathology, normal growth velocity and bone age, Abdominal pain, malabsorption, anemia; short stature may be the only symptom, Tissue transglutaminase and total immunoglobulin A measurements; consider referral for endoscopy and biopsy, History of renal disease, poor weight gain, Abdominal pain, bloody stool, poor weight gain, Erythrocyte sedimentation rate and C-reactive protein measurements, referral for endoscopy and biopsy, Short limbs; long, narrow trunk; large head with prominent forehead, History of head trauma or cranial irradiation, central nervous system infection, IGF-1 and IGFBP-3 measurements, referral for growth hormone stimulation, other pituitary function tests, Hypoglycemia, birth length may be normal, height and bone age progressively delayed; jaundice, microphallus, midline craniofacial abnormalities, IGF-1 and IGFBP-3 measurements; referral for growth hormone stimulation, magnetic resonance imaging, other pituitary function tests, Mental retardation if not identified early, Newborn screening, thyroid-stimulating hormone and free thyroxine (T4) measurements, Born small for gestational age, normal height not achieved by 2 to 4 years of age, Focused laboratory testing to evaluate organic causes, consider referral to pediatric endocrinologist, History of poor nutrition, weight loss precedes height loss, Short stature, webbed neck, characteristic facies, short metacarpals, broad chest with widely spaced nipples, hyperconvex fingernails and toenails; may be normal appearing; decreased growth velocity and delayed puberty, Follicle-stimulating hormone, karyotyping, Erythrocyte sedimentation rate, C-reactive protein, Thyroid-stimulating hormone, free thyroxine (T4), Tissue transglutaminase and total immunoglobulin A, Serum luteinizing hormone, follicle-stimulating hormone, testosterone, Children with intrauterine growth retardation who do not catch up to the growth curve by 2 years of age, Height more than 3 standard deviations below the mean for age, No onset of puberty by 14 years of age for boys or 13 years of age for girls, Projected height more than 2 standard deviations (10 cm [4 in]) below the midparental height, Bone age more than 2 standard deviations below chronologic age, Diagnosis of conditions approved for recombinant growth hormone therapy, Family history of early puberty, bone age greater than chronologic age, Projected height within 5 cm (2 in) of midparental height, bone age greater than chronologic age, normal growth velocity after catch-up growth, Rapid childhood growth, goiter, tachycardia, hypertension, diarrhea, fine tremor, exophthalmos, Thyroid-stimulating hormone and free thyroxine (T4) measurements, Body mass index greater than the 95th percentile, slightly early onset of puberty, modest overgrowth/tall stature, minimally advanced bone age, Pituitary gigantism (excess growth hormone), Coarse facial features, mandibular prominence, broad root of nose, broad hands and feet, excessive sweating, hypertension, glucose intolerance, Measurement of insulinlike growth factor 1 and insulinlike growth factor binding protein 3, brain/pituitary magnetic resonance imaging, glucose suppression test, Girls: breast development before 8 years of age, Measurements of luteinizing hormone, follicle-stimulating hormone, estradiol, and testosterone, Boys: testicular enlargement (> 3 mL) before 9 years of age, Measurement of 17-hydroxyprogesterone, human chorionic gonadotropin, dehydroepiandrosterone, estradiol, and testosterone; bone age, Macrocephaly, macroglossia, ear pits, renal abnormality, omphalocele, umbilical hernia, hepatosplenomegaly, Insulin and glucose measurements, advanced bone age, karyotyping, renal ultrasonography, echocardiography, Marfan-like habitus, developmental delay, inferior subluxation of lens, Homocysteine and methionine measurements, dilated eye examination, Delayed puberty; infertility; small, firm testes; gynecomastia; high-pitched voice; learning disability, Measurements of luteinizing hormone, follicle-stimulating hormone, and testosterone; karyotyping, Increased arm span, thin extremities, superior subluxation of lens, hypotonia, kyphoscoliosis, cardiac valvular deformities, aortic root dilation, Clinical diagnosis using Ghent criteria, testing for, Large, protruding ears; long face; high-arched palate; hyperextensible fingers; pes planus; soft skin; macro-orchidism, Clinical suspicion based on dysmorphic features, testing for, Large head; long, thin face; broad forehead; prominent, narrow jaw; downward slanting palpebral fissures; feeding difficulties from birth; facial flushing; hypotonia, Clinical suspicion based on dysmorphic features, renal ultrasonography, echocardiography, advanced bone age, Small chin, broad forehead, hypertelorism, long philtrum, camptodactyly, Clinical suspicion based on dysmorphic features, renal ultrasonography, brain magnetic resonance imaging, advanced bone age (from birth).
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