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Evaluation of Short Stature in Children

Heba Ismail, MB BCh; and Kathryn Ness, MD, MSCI Abstract
Normal growth in children is a reection of general health and is the result of a complex interaction between genetic, nutritional, and hormonal factors. From conception through infancy, growth is mostly driven by maternal nutrition and the in utero environment. Genetic factors, growth and thyroid hormones, ghrelin, and sex steroids have a more prominent inuence later. Normal growth is not linear; it is marked by periods of growth spurts, particularly during puberty, separated by periods of slow or immeasurable growth. There is often a period of growth deceleration observed before the onset of puberty, with maximal pubertal growth spurts occurring at Tanner stage III for girls and Tanner stage IV for boys. This is caused primarily by the combined effect of the increased amplitude of growth hormone pulses and sex steroids. Short stature (SS), which is the subject of this review, is dened as a length or height more than 2 standard deviations below the mean for age and gender, which corresponds to a percentile below 2.5%. Taking a thorough patient history and completing a comprehensive physical examination are some of the most important diagnostic tools for pediatricians to use in the diagnosis of SS, and in making appropriate referrals as needed.

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EDUCATIONAL OBJECTIVES

1. Distinguish normal growth from pathological short stature. 2. Identify key components in the history and physical exam in the evaluation of short stature. 3. Outline the diagnostic evaluation, indications for growth hormone therapy and indications for referral to a specialist.
Heba Ismail, MB BCh, is a third-year pediatric endocrine fellow, Division of Pediatric Endocrinology, Department of Pediatrics, Seattle Childrens Hospital. Kathryn Ness, MD, MSCI, is an Assistant Professor, Division of Pediatric Endocrinology, Department of Pediatrics, Seattle Childrens Hospital. Address correspondence to: Heba Ismail, MB BCh, Division of Pediatric Endocrinology, Seattle Childrens Hospital, 4800 Sand Point Way NE, M/S OC.7.820, Seattle, WA 98105; email: Hebatullah.Ismail@seattlechildrens.org. Disclosure: The authors have no relevant financial relationships to disclose. doi: 10.3928/00904481-20131022-08

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ormal growth is a reection of general health and is the result of a complex interaction between genetic, nutritional, and hormonal factors. From conception through infancy, growth is mostly driven by maternal nutrition and the in utero environment. Genetic factors, growth and thyroid hormones, ghrelin, and sex steroids have a more prominent inuence later.1 The predominant pathway in the subsequent regulation of growth is the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis. GH is released by the anterior pituitary in a pulsatile fashion. This results in the production of IGF-1, IGF binding protein 3, and acid labile subunit in the liver. IGF1 then acts directly on the growth plates and other target organs to promote linear growth (see Figure 1).2 Normal growth is not linear; it is marked by periods of growth spurts, particularly during puberty, separated by periods of slow or immeasurable growth.3 There is often a period of growth deceleration observed before the onset of puberty, with maximal pubertal growth spurts occurring at Tanner stage III for girls and Tanner stage IV for boys.4 This is caused primarily by the combined effect of the increased amplitude of GH pulses and sex steroids. Short stature (SS), which is the subject of this review, is dened as a length or height more than 2 standard deviations (SDs) below the mean for age and gender, which corresponds to a percentile below 2.5%. MEASUREMENTS AND GROWTH CHARTS Measurements Accurate measurements and plotting on the appropriate growth chart (GC) in addition to a thorough history and physical examination are the most important diagnostic tools. Misdiagnosis of SS is commonly caused by measurement errors, incorrect plotting, or plotting on

Figure 1. Growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis. ALS = acid labile subunit; GHRH = growth hormone releasing hormone; IGFBP3 = insulin-like growth factor binding protein 3.

the incorrect GCs. Therefore, it is important to review proper measurement techniques rst. For supine length measurement in children younger than 2 years, the child should be relaxed with the legs fully extended. The head should be positioned against a rm box with an inexible board and the feet placed perpendicular to the plane of supine length against an adjustable footboard.4 In patients older than 2 years who are capable of standing erect, it is best to use a wall-mounted Harpenden stadiometer. The child should be placed in a fully erect position with the head in a neutral position and the back of the head, thoracic spine, buttocks, and heels touching the vertical axis of the stadiometer; the heels should be together (see Figure 2).5 The length and height should be measured by a trained person at least three times with the average being recorded in the GC. It is very important to minimize measurement error by performing three measurements. Skeletal proportions also should be assessed during the physical examination by the clinician once SS is suspected (see section on disproportionate SS).

Growth Charts The Centers for Disease Control and Prevention (CDC) GCs are used for monitoring normal growth. Since 2010, the CDC has recommended that the World Health Organization GCs be used in the United States for infants and children younger than 2 years.6 It should be noted that when transitioning from length to height charts, about 2 cm are lost in this transition. It is very important for pediatricians to use the appropriate GCs in certain situations, such as in children with Turner,7,8 Down, or Williams syndromes and achondroplasia. In premature infants, if standard GCs are used for plotting length/height, then correction for gestational age should be made through age 40 months. Growth Velocity and Growth Velocity Curves Because growth is not linear, repeated measurements are more informative than a single measurement. Growth velocity (GV) is dened as the change in growth over time, with a period of at least 3 months, but ideally 6 months,

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Image courtesy of Heba Ismail, MB BCh.

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ditional helpful approach to determine whether SS is normal or pathological is to classify causes by body proportions and weight for length/height. In patients with CDGP and familial SS, the weight for length/height is typically normal and so are body proportions. However, in most pathological cases of SS, body proportions and/or weight for length/height are usually abnormal. The determination of proportionality is important in cases of SS to identify cases of disproportionate SS. Upper to lower segment (US/LS) ratios as well as arm span to height need to be assessed. Generally, the lower body segment is measured from the top of the symphysis pubis to the oor, with the upper segment being calculated from the difference between the total height and the lower segment. Arm span is the distance between the tips of the middle ngers with the arms raised and stretched to a horizontal position.9 There are published standards for body proportion measurements relative to patient age.10 The US/LS ratio is increased in patients with rickets, achondroplasia, and chondrodystrophies and, sometimes, hypothyroidism and Turner syndrome, whereas a decreased US/LS ratio is observed in patients with vertebral anomalies, severe scoliosis, and spinal irradiation. The arm span/height is usually decreased in patients with skeletal dysplasias, including achondroplasia and hypochondroplasia. In patients with proportionate SS with decreased weight for height, malnutrition is likely the cause, either primary or secondary to a systemic or chronic condition, such as inammatory bowel disease, celiac disease with malabsorption,11,12 or cardiac, pulmonary, or renal diseases.13,14 Weight for height under the 5th percentile is a good indicator for malnutrition. Children with endocrine disorders, such as hypothyroidism, Cushing syndrome, and GH deciency (GHD) or insensitivity, usually present with proportionate SS but with increased weight for length or height. Children with precocious puberty, virilizing forms of congenital adrenal hyperplasia, and rare cases of longstanding untreated hyperthyroidism15 can present with accelerated early growth and tall stature as children but eventually stop growing earlier than their peers with resultant proportionate SS caused by earlier epiphyseal closure. Idiopathic short stature (ISS) is a term used to describe children with SS of unknown etiology. It is dened as a height less than 2 SDs of the mean for age and gender (a more strict denition of < 2.25 SDs is used when considering GH therapy) with a predicted adult height of less than 63 inches for boys and less than 59 inches for girls.16 These children usually have proportionate SS. More recently, studies suggest that short stature homeobox gene mutations are responsible for up to 4% of cases of ISS.17 Children with chromosomal abnormalities who present with SS include Noonan syndrome, Turner syndrome, and pseudohypoparathyroidism with a high index of suspicion in the presence of classic clinical features. Children who were born small for gestational age (SGA) and who have not caught up in terms of growth by age 2 years should be evaluated further and are usually eligible for GH therapy.18 EVALUATION Evaluation includes proper history taking, a thorough physical examination including accurate measurements, and radiologic and laboratory workup. History Growth history is essential including previous growth parameters and percentiles if available, frequency of increase in shoe and clothing size, and timing of dental eruption. A nutritional history is
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Figure 2. Figure indicating the proper measurement of height for parents and practitioners. (From Centers for Disease Control and Prevention5)

needed for reliable calculation of GV in children older than 2 years. Although most electronic health records software will calculate GV for the clinician, it can be easily calculated by using the following formula: (current height previous height) 12/number of months in between measurements. There are GV curves available for age and gender; however, they are not supported by the CDC. If GV is less than the 5th percentile for age and gender, the child should be investigated further and referred to a pediatric endocrinologist. Normal Short Stature Familial SS and constitutional delay of growth and puberty (CDGP) are considered normal growth variants. GV is usually normal in both of these conditions, but it should be easy to differentiate them based on several ndings (see Table). Pathological Short Stature Pathological causes of SS are classied and listed in the Sidebar. An ad-

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TABLE.

Differences Between Familial SS and CDGP

Familial SS
Parents height Parents pubertal onset Growth velocity Onset of puberty Bone age Final adult height Short (one or both) Normal Normal Normal Normal Short

CDGP
Average Delayed Slow or normal Delayed Delayed Normal

CDGP = constitutional delay of growth and puberty; SS = short stature.

always helpful, especially in cases of suspected malnutrition or anorexia. Relevant endocrine-related history should include signs of pubertal development and timing and symptoms suggestive of hypothyroidism, such as excessive weight gain, fatigue, constipation, excessive hair loss or dry skin, and cold intolerance. A medical history should begin with a perinatal history that includes birth weight (especially a history of SGA or intrauterine growth retardation), length, head circumference, mode of delivery (high risk for pituitary deciencies in breech and traumatic deliveries), and maternal health (substance abuse, smoking, or infections). A medical history should also include a history of irradiation to the head and neck region, systemic conditions, and prescribed medications, specically brain stimulants and steroids. A thorough review of systems should include a history of repeated ear infections (suggestive of Turner syndrome), gastrointestinal symptoms (suggestive of malabsorption), central symptoms such as headaches or blurry vision (pituitary deciencies), symptoms of hypoglycemia (suggestive of pituitary deciencies), and symptoms suggestive of a chronic systemic illness. A family history is very important and should include a history of endocrine problems and systemic conditions,
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but most importantly it should include a history of parental and sibling heights, as well as pubertal development. Parental height is used to predict the childs height based on the midparental height (MPH). An MPH is an approximation of a childs adult height potential adjusted for gender based on parental height. MPH can be calculated from the following formulae: for girls: (paternal height [cm] 13 cm + maternal height [cm])/2 and for boys: (maternal height [cm] + 13 cm + paternal height [cm])/2. Most children will attain adult height within approximately 10 cm or 4 inches of their MPH. PHYSICAL EXAMINATION A thorough physical examination should include examination for dysmorphic features (eg, Turner syndrome) and the presence of midline defects (pituitary deciencies). Pubertal staging is important as is a genital examination to evaluate for microphallus or cryptorchidism in boys (suggestive of central pituitary deciencies). It is important to assess for signs of nutritional deciencies or psychosocial deprivation as is commonly seen in children recently adopted from abroad. An evaluation for body proportions should be performed during the examination, as well as an evaluation for scoliosis or other skeletal deformities.

LABORATORY WORKUP Once the diagnosis of SS is established clinically, the following studies are recommended to screen for different causes of SS and diagnose ISS:16 1) complete metabolic panel including electrolytes, creatinine, bicarbonate, calcium, phosphorus, and alkaline phosphatase; 2) a complete blood count and sedimentation rate to rule out a chronic inammatory condition such as inammatory bowel disease; 3) antitissue transglutaminase immunoglobulin A and total immunoglobulin A levels to screen for celiac disease; 4) thyroid-stimulating hormone, total thyroxine (T4), or free T4 by direct dialysis to rule out hypothyroidism; 5) serum IGF-1 and IGF binding protein 3 to screen for GHD (steady measurable levels compared to pulsatile GH levels); 6) karyotype should be obtained in girls with ISS or features suggestive of Turner syndrome and also considered in boys with genital abnormalities; and 7) bone age (BA) in children 2 years or older. BA is obtained from a simple Xray of the left hand and wrist19 and is considered a rough estimate of skeletal maturity. It allows an estimation of predicted height and whether the childs growth is consistent with genetic potential. In CDGP and most endocrine hormonal deciencies, BA is delayed. In general, further testing must be individualized and guided by history and physical examination as well as abnormal screening laboratory results. A patient with low growth factors should be evaluated further with GH provocative testing.2 Other tests to consider, after discussion with an endocrinologist, include brain magnetic resonance imaging in established GHD or suspected central abnormalities, whereas a skeletal survey is indicated if disproportionate SS or skeletal abnormalities are detected on physical examination.

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SIDEBAR.

Pathological Causes of Short Stature

Common endocrine causes of short stature - Hypothyroidism - Poorly controlled diabetes mellitus - Growth hormone deciency - Growth hormone resistance - IGF-1 deciency - Cushing syndrome - Precocious puberty Idiopathic short stature Malnutrition Chronic disease Osteochondrodysplasias Genetic syndromes - Turner syndrome - Noonan syndrome - Down syndrome - Prader-Willi syndrome - Russell-Silver syndrome Small for gestational age
IGF-1 = insulin-like growth factor 1.

Referral A pediatric endocrine referral is warranted in the following situations: 1) conditions for which rhGH therapy has been US Food and Drug Administration approved; 2) height more than 2 to 2.5 SDs below the mean for chronologic age and gender; 3) heights that are crossing downward more than two major percentiles; 4) children with SS who have not started puberty by age 14 years for boys and 13 years for girls; 5) children with an abnormal GV for chronologic age and pubertal stage; 6) growth percentiles and rate below the expected MPH percentile; 7) children with an abnormally delayed bone age (>2 SDs below chronologic age); and 8) proportionate SS with increased weight for height. Finally, a referral is warranted to a clinical geneticist in cases of disproportionate SS. GH Therapy Currently, the use of rhGH is FDAapproved in the following conditions: GHD, Turner syndrome, chronic renal failure, Prader-Willi syndrome, SGA without catch-up growth after age 2 years, wasting syndrome secondary to HIV infection, Noonan syndrome, and ISS (use remains debatable). GH Therapy Guidelines Treatment is usually continued until the GV is less than 2 cm/year and/or BA shows fused growth plates although it can sometimes be continued through adulthood.4 Regardless of etiology, greater height gains are associated with younger age at the initiation of rhGH. Obstructive sleep apnea should be excluded and treated before the initiation of GH therapy, especially in those patients with Prader-Willi syndrome, as the risk of sudden death is increased.20 Benets of rhGH therapy in children with ISS include an increased height of approximately 3.5 cm after approximately 4 years of therapy,16 a possible psychological benet, improved muscle

tone and power in patients with PWS, and improved muscle mass in patients with wasting syndrome. Patients with GHD may have near normalization of their nal adult height. However, there are important drawbacks to the use of rhGH, including the cost of about $25,000 to $30,000 per year (cumulative ~$100,000$120,000) as well as hundreds or thousands of daily injections over the course of several years, which can be stressful. Once treatment is started, important side effects of therapy need to be evaluated for periodically, including arthralgias and myalgias; slipped capital femoral epiphysis; worsening of current scoliosis; benign intracranial hypertension; glucose intolerance in patients with relative insulin deciency at initiation; peripheral edema; benign and selflimited prepubertal gynecomastia and premature thelarche; tonsillar hypertrophy; pancreatitis; and, nally, a debatable increased risk for cancer.21 Other Forms of Therapy Androgens,22,23 concomitant pubertal suppression,24 aromatase inhibitors,25 and recombinant IGF-1 therapy26,27 are sometimes used in special situations. FOLLOW-UP It is important that all children with growth concerns be monitored on a regular basis by their provider, including monitoring of height, weight, GV, and pubertal development at least every 3 to 6 months. If treatment has been started, side effects of therapy should be evaluated. It is also important to inquire about quality of life related to growth concerns. Most pediatric endocrinologists will monitor the effects of treatment with GV in addition to annual BA and periodic monitoring of growth factors. Although not often the case, the primary care provider is sometimes responsible for close clinical and laboratory monitoring of these patients in parts of the country where there are no or very few
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TREATMENT MANAGEMENT OF SS Counseling It is important for the provider to understand how the family and child view stature and what the exact concerns are. Most commonly, reassurance is sufcient in normal variants of SS. If the child is being bullied, it is important to address this issue by proper counseling and a strong support system. In cases of ISS, it should be emphasized that the mean increase in adult height caused by recombinant human GH (rhGH) therapy is about 3.5 cm to 7.5 cm without strong evidence that taller stature is associated with improved quality of life.16 Furthermore, the response to rhGH is often highly variable. The costs, side effects, benets, and number of injections should be discussed before the initiation or consideration of therapy.

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pediatric endocrinologists available on a regular basis. In conclusion, although a challenge, the diagnosis and initial management of SS in the primary care setting can be very rewarding, both to the provider and the families. This is particularly so when short stature can be reversed with therapy or in certain instances of normal variants with patients, where reassurance can be provided. REFERENCES
1. Touwslager RN, Gielen M, Derom C, et al. Determinants of infant growth in four age windows: a twin study. J Pediatr. 2011;158:566. 2. Rosenfeld RG, Cohen P: Disorders of Growth/Insulin-like Growth Factor Secretion and Action. In: Sperling MA ed. Pediatric Endocrinology. 3rd ed. Philadelphia, PA: Saunders Elsevier; 2008: 283-286. 3. Lampl M, Johnson ML, Frongillo EA Jr. Mixed distribution analysis identies saltation and stasis growth. Ann Hum Biol 2001; 28:403. 4. Cooke D, Divall S, Radovick S: Normal and Aberrant Growth. In: Williams Textbook of Endocrinology. 12th ed. Philadelphia, PA: Saunders Elsevier; 2011: 935-1053. 5. Centers for Disease Control and Prevention. Measuring Childrens Height and Weight Accurately At Home. www.cdc.gov/ healthyweight/assessing/bmi/childrens_bmi/ measuring_children.html. Accessed Oct. 11, 2014. 6. Grummer-Strawn LM, Reinold C, Krebs NF, Centers for Disease Control and Prevention (CDC). Use of World Health Organization and CDC growth charts for children aged 0-59 months in the United States. MMWR Recomm Rep 2010; 59:1. 7. Turner Syndrome Society of the United States. TS Growth Chart. Available at: turnersyndrome.org/resources/publication/ ts-growth-chart. Accessed October 21, 2013. 8. Lyon AJ, Preece MA, Grant DB. Growth curve for girls with Turner syndrome. Arch Dis Child. 1985 Oct;60(10):932-935. 9. Dimeglio, A. Biometric measurements. In: Morrissy RT, Weinstein SL, eds. Lovell and Winters Pediatric Orthopaedics. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2006:35. 10. Bayer LM, Bayley L. Growth Diagnosis: Selected Methods for Interpreting and Predicting Physical Development from One Year to Maturity. Chicago: University of Chicago Press; 1959. 11. Damen GM, Boersma B, Wit JM, Heymans HS. Catch-up growth in 60 children with celiac disease. J Pediatr Gastroenterol Nutr 1994; 19:394. 12. Brain CE, Savage MO. Growth and puberty in chronic inammatory bowel disease. Baillieres Clin Gastroenterol 1994; 8:83. 13. Balfour-Lynn L. Growth and childhood asthma. Arch Dis Child 1986; 61:1049. 14. Betts PR, Magrath G. Growth pattern and dietary intake of children with chronic renal insufciency. Br Med J 1974; 2:189. 15. Conwell LS. Graves diseaseacceleration of linear growth. J Pediatr Endocrinol Metab. 2009; 22:289. 16. Cohen P, Rogol AD, Deal CL, et al. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab 2008; 93:4210. 17. Rappold G, Blum WF, Shavrikova EP, et al. Genotypes and phenotypes in children with short stature: clinical indicators of SHOX haploinsufciency. J Med Genet 2007; 44:306. 18. Clayton PE, Cianfarani S, Czernichow P, Johannsson G, Rapaport R, Rogol A. Consensus Statement: Management of the Child Born Small for Gestational Age through to Adulthood: A Consensus Statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society. J Clin Endocrinol Metab. 2007;92:804-810. 19. Greulich WW, Pyle SI. Radiographic Atlas of Skeletal Development of the Hand and Wrist, Stanford University Press, Stanford 1950. 20. Fillion M, Deal C, Van Vliet G 2009 Retrospective study of the potential benets and adverse events during growth hormone treatment in children with Prader-Willi syndrome. J Pediatr 154: 230233 21. Bell J, Parker KL, Swinford RD, et al. Longterm safety of recombinant human growth hormone in children. J Clin Endocrinol Metab. 2010;95:167-177. 22. Rosenfeld RG, Northcraft GB, Hintz RL. A prospective, randomized study of testosterone treatment of constitutional delay of growth and development in male adolescents. Pediatrics. 1982;69:681-687. 23. Clayton PE, Shalet SM, Price DA, et al. Growth and growth hormone responses to oxandrolone in boys with constitutional delay of growth and puberty (CDGP). Clin Endocrinol (Oxf). 1988;29:123-130. 24. Carel JC. Management of short stature with GnRH agonist and co-treatment with growth hormone: a controversial issue. Mol Cell Endocrinol. 2006;254-255, 226-233. 25. Mauras N, Gonzalez de Pijem L, Hsiang HY, et al. Anastrozole increases predicted adult height of short adolescent males treated with growth hormone: a randomized, placebo-controlled, multicenter trial for one to three years. J Clin Endocrinol Metab. 2008;93:823-831. 26. Cohen P, Germak J, Rogol AD, Weng W, Kappelgaard AM, Rosenfeld RG, on behalf of the American Norditropin Study Group 2010 Variable degree of growth hormone (GH)- and insulin-like growth factor (IGF)sensitivity in children with idiopathic short stature (ISS) compared to GH-decient (GHD) patients: evidence from an IGFbased dosing study of short children. J Clin Endocrinol Metab 95:20892098 27. Chernausek SD, Backeljauw PF, Frane J, et al. for the GH Insensitivity Syndrome Collaborative Group. Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deciency due to growth hormone insensitivity. J Clin Endocrinol Metab. 2007;92:902-910.

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