AUTHOR AND EDITOR INFORMATION

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Longitudinal growth assessment is essential in child care. Short stature can be promptly recognized only with accurate measurements of growth and critical analysis of growth data.

Short stature, optimally defined relative to the genetic endowment of the individual, is recognized by comparing an individual child’s height with that of a large population of a similar genetic background and, more particularly, using the mid-parental target height (see History).

Growth failure (GF) is often confused with short stature. By definition, GF is a pathologic state, whereas short stature is often a normal variant. Regardless of the genetic background, short stature may be a sign of a wide variety of pathologic conditions or inherited disorders. Thus, accurate longitudinal growth assessment is a fundamental aspect of health maintenance in children. Reviewing the patient's growth chart is critical to evaluating short stature. Deviation from a prior growth pattern appropriate for the genetic background often heralds new pathology. In addition, analysis of the prior growth pattern helps distinguish normal growth from pathologic variants of short stature.

Compared with a well-nourished, genetically relevant population, short stature is defined as a standing height more than 2 standard deviations (SDs) below the mean (or below the 2.5 percentile) for gender. Skeletal maturation is typically determined by the bone age, which is assessed using anteroposterior radiography of the left hand and wrist. Gender-specific reference data for standing height, head circumference, and weight have been published for most developed countries (see References), most ethnic subpopulations (including Asians and African Americans), and the most common genetic disorders (eg, Down syndrome, Ullrich-Turner syndrome, achondroplasia).

The causes of short stature can be divided into 3 broad categories: chronic disease (including undernutrition genetic disorders), familial short stature, and constitutional delay of growth and development. Endocrine diseases are rare causes of short stature (see Frequency). The hallmark of endocrine disease is linear GF that occurs to a greater degree than weight loss. Most short children evaluated by clinicians in developed countries have familial short stature, constitutional growth delay, or both. Short stature and constitutional growth delay are diagnoses of exclusion.

The hallmarks of familial short stature (also referred to as genetic short stature) include bone age appropriate for chronologic age, normal growth velocity, and predicted adult height appropriate to the familial pattern (using the Bayley-Pinneau or Tanner-Goldstein-Whitehouse tables). By contrast, constitutional growth delay is characterized by delayed bone age, normal growth velocity, and predicted adult height appropriate to the familial pattern (see Image 2). Patients with constitutional growth delay typically have a first-degree or second-degree relative with constitutional growth delay (eg, menarche reached when older than 15 y, adult height attained in male relatives when older than 18 y).

Pathophysiology

Short stature may be normal. Obtaining the family history of growth patterns and direct measurement of the parents is crucial to determine the genetic potential for growth in the child.

Short stature can also be the sign of a wide variety of pathologic conditions or inherited disorders when it results from GF or premature closure of the epiphysial growth plates. Therefore, pathophysiology depends on the underlying cause. For detailed discussions of the disorders included in the differential diagnoses of short stature, see Differentials.

Frequency

United States

By definition, 2.5% of the population is short. However, the number of children with poor linear growth is higher given the frequency of chronic diseases of childhood. The Utah Growth Study is the largest population-based survey of growth in children published to date¹. These investigators assessed height and growth velocity in nearly 115,000 American children. Among the 555 children with short stature (defined as height below the third percentile) and poor growth rate (defined as growth velocity <5 cm annually), only 5% had an endocrine disorder. In addition, 48% of the children with growth hormone deficiency (GHD) or Turner syndrome (TS) in this large cohort had been undiagnosed or untreated.

Parents often suspect an endocrine disorder (eg, GHD) as the major cause of short stature in their child. In fact, the Utah Growth Study confirms that most (95%) children with poor growth (velocity <5 cm/y) do not have an endocrine disorder.

International

Unfortunately, malnutrition remains the most common cause of GF worldwide. Supporting lay and professional efforts to reverse this preventable cause of short stature in besieged communities must be a high priority of all governments and health care professionals.

Race

Normal variations in stature are often related to ethnic background. For example, tall for a Cambodian individual may be short for a Norwegian individual. However, the major causes of short stature (ie, malnutrition, recurrent illness, parasites) are not race specific.

Sex

• Boys who are short are more likely to come to medical attention than girls who are short. Notwithstanding the legitimate debate regarding this ascertainment bias, boys do appear more likely to have idiopathic GHD or constitutional delay of growth and development.
• Ullrich-Turner syndrome (ie, TS) affects only females. The evaluation of a short female mandates a karyotype to exclude this disorder.

Age

Individuals of any age can be affected.

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Key data to obtain for the evaluation of short stature include the child's weight and length at birth; prior growth pattern; and the final (or current) heights and weights of parents, siblings, and grandparents.
• • Whenever possible, obtain the original birth records to document length, weight, and fronto-occipital circumference at birth.
  • Assessing the heights of both parents is absolutely essential.
  • Generally, men overreport their height, and women underreport their weight.
  • Ideally, measure each parent’s height in the clinic for optimal calculation of the mid-parental target height, according to 1 of several formulas, among which the author prefers the following:

    Target height in cm for a girl = [mother's height in cm + (father's height in cm - 13)]/2
    
    Target height in cm for a boy = [(mother's height in cm + 13) + father's height in cm)]/2

• Document pubertal timing in first-degree relatives.
• • At a minimum, determine the age at onset of menarche for the child's mother and the age of adult height attainment for the father.
  • Most parents can usually recall these 2 milestones, which have proven reliable predictors of pubertal timing and tempo in parent-child pair studies of puberty. 
• Review of symptoms by organ system provides additional clues to the etiology underlying short stature.
• • Gastrointestinal
  
  
  • Diarrhea, flatulence, or borborygmi (frequent, discomforting, or even audible peristalsis) suggest malabsorption.
  • Vomiting can suggest an eating disorder or a CNS disorder (eg, dysgerminoma).
  • Consider dietary intake and composition. In particular, ask about intake of carbonated beverages, juices, and other casual intake.
  • Pain or abdominal discomfort suggests inflammatory bowel diseases.
  • Cardiac disease: Signs include peripheral edema, murmurs, and cyanosis.
  • Chronic infections: Poor wound healing and opportunistic infections are signs of potential immune deficiency.
  • Pulmonary
  
  
  • Sleep apnea can be a cryptic cause of short stature.
  • Other chronic diseases that may result in short stature include severe asthma associated with chronic steroid use and cystic fibrosis (CF).
  • Neurologic
  • Visual field deficits often herald pituitary neoplasms.
  • Vomiting, early morning nausea, polyuria, or polydipsia is often associated with masses of the CNS.
  • Renal
• • Polyuria and polydipsia are important symptoms of hypothalamic and pituitary disorders.
  • Chronic renal disease is a common cause of GF.
  
  
  • Social
  
  
  • Participation in sports that require weight control (eg, wrestling, crew, gymnastics) may be associated with anorexia nervosa or bulimia induced by the patient, peers, or coaches.
  • Growth is often impaired in refugees and in children emerging from foster care or certain international adoption settings.
  • The growth pattern with adequate nutrition in a loving environment over time is critical to distinguish pathologic GF from normal variant short stature in such patients.

Physical

Endocrinologists rely heavily on accurate and reliable height assessment.

• Measure standing height in triplicate using a calibrated wall-mounted stadiometer.
  
  • Although no particular brand is endorsed, one well-accepted device is available from Harpenden Ltd of Wales (see Image 1).
  • In infants, length is determined in triplicate using a tabletop recumbent stadiometer.
  • The mean value of the triplicate data serves as the true measurement.
• In children who cannot completely stand or recline (eg, those with spina bifida, those with contractures), arm span provides a reliable alternative for longitudinal assessment of long bone growth.
• • Ascertain arm span by facing the child against a flat firm surface (usually the wall), fully extending the arms, and measuring the maximal distance between the tips of the middle fingers.
  • If this positioning is physically impossible, a flexible tape measure may be rolled along the dorsal aspect of the arms and upper back to determine arm span.
• Documenting growth velocity over time complements the initial height assessment.
• • Calculate growth velocity as the change in standing height over at least 6 months (in children) or in length over at least 4 months (in infants).
  • Poor linear growth is defined as linear growth velocity more than 2 SDs below the mean for gender, genetic composition, and chronologic age.
• Weigh all patients.
• In infants, determine the fronto-occipital circumference.
• In patients in whom short-limb dwarfism is suspected, the sitting height can be obtained by measuring the upper body segment, or crown to pelvis, as the child sits upright on a platform-mounted stadiometer (or on the floor with a wall-mounted stadiometer).
• • Alternatively, the lower segment can be determined by measuring from the superior midline brim of the symphysis pubis to the floor, with the child standing (feet placed together).
  • The upper-to-lower segment ratio (US/LS) should be close to 1.
  • The ratio is more than 1 in children with shortened limbs, as it is in individuals with hypochondroplasia or achondroplasia.
• Palpate for thyroid enlargement and firmness, which can be associated with Hashimoto thyroiditis, the most common cause of acquired hypothyroidism.
• Test visual fields for signs of pituitary and hypothalamic tumors, initially by gross confrontation.
• Inspect fourth metacarpals, which are shortened in persons with pseudohypoparathyroidism, Ullrich-Turner syndrome, and Albright hereditary osteodystrophy.
• Inspect mucous membranes for ulcerative stomatitis, typical of Crohn disease and various trace mineral and vitamin deficiencies.
• • Pretibial ulcerations are also observed in persons with Crohn disease and ulcerative colitis.
  • Rectal tags and clubbing are also typical in individuals with Crohn disease.
• Confirm the history with direct measurements whenever possible. For example, measure both biologic parents' heights during the clinic visit.
• Both the arm span and US/LS ratio can be informative regarding the cause of short stature. Patients with short-limb dwarfism usually have an US/LS ratio that remains above 1.3.  Newborns typically display a ratio of 1.7, which gradually drops to approximately 1 during prepubertal growth and remains close to 1 in adulthood. 
• Arm span also reveals a decrement in growth, which is otherwise indiscernible in a child with spinal deformation (eg, myelomeningocele).
• Carefully examine the midface.
• • A single, central, maxillary incisor reflects a defect in midline facial development.
  • Similarly, a bifid uvula suggests the possibility of a submandibular cleft palate, which may be palpable, yet not visible on inspection.
  • Associated anomalies of midline structures, such as the pituitary gland, are common in patients with major midline facial anomalies.
  • GHD or panhypopituitarism should be considered as a cause of short stature in such patients.

Causes

• The nonendocrine causes of short stature (see Other Problems to be Considered) can be divided into 3 major categories, as follows:
• • Constitutional delay of growth and sexual development
  • Familial short stature
  • Chronic diseases of childhood: Among the chronic conditions, malnutrition remains the leading cause of short stature worldwide.
• Genetic causes of short stature are as follows:
  
  
  • Down syndrome (trisomy 21)
  • Ullrich-Turner syndrome (45,XO)
  • Lerí-Weill dyschondrosteosis (SHOX gene)

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Causes of Growth Failure in Children (Partial List)

Endocrine
Hypothyroidism
Primary - Hashimoto thyroiditis, Pendred syndrome
Secondary - Thyrotropin (thyroid-stimulating hormone [TSH]) deficiency
Tertiary - Thyrotropin-releasing hormone (TRH) deficiency
Other - Iatrogenic or environmental radioablation, neoplasm
GHD (complete absence) or insufficiency (partial absence)
Neurosecretory GHD
Panhypopituitarism (combined anterior pituitary hormone deficiencies)
Growth hormone-releasing hormone (GHRH) deficiency
Poorly controlled type 1 diabetes mellitus - Mauriac syndrome
Chronic hypernatremia - Hypothalamic adipsia, diabetes insipidus
Hypercortisolism - Cushing syndrome, iatrogenic glucocorticoid administration
Hypocortisolism - DAX1 gene mutation, autoimmune adrenalitis (Addison disease) (However, note that adrenocorticotropic hormone deficiency alone has been associated with tall stature; short stature results from hypocortisolism only in persons with salt wasting.)

Normal Variant Short Stature (Also Called Familial Short Stature)

Genetic (unknown defect)
Silver-Russell syndrome
Shwachman-Diamond syndrome

Pulmonic
CF
Severe asthma
Chronic obstructive pulmonary disease
Restrictive lung disease

Cardiac
Hypoxemia
Congestive heart failure
Low cardiac output states
Precocious puberty

Renal
Chronic renal insufficiency
Renal failure
Renal tubular acidosis

Psychosocial dwarfism
Chronic neglect
Starvation

WORKUP

Section 5 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Laboratory studies used to assess the major causes of poor linear growth in children include the following:
  
  
  • Measurement of serum levels of insulinlike growth factor-1 (IGF-I), formerly named somatomedin C, and insulinlike growth factor-binding protein-3 (IGFBP-3)
    
    
    • These are useful tests for GHD, except in patients with brain tumors or during puberty.
    • Patients with certain CNS neoplasms may have normal serum growth factor levels despite having GHD, particularly during puberty.
    • Consider provocative tests of pituitary function in any patient with normal thyroid function suspected to be GH deficient.
    • Interpret a low serum IGF-I concentration cautiously because poor nutrition is associated with low serum IGF-I concentration.
    • The serum IGFBP-3 concentration has greater specificity than serum IGF-I concentration in the diagnosis of GH deficiency.
  • Karyotype by G-banding
    
    
    • The 45,XO pattern defines patients with Ullrich-Turner syndrome.
    • Because 10% of patients with Ullrich-Turner syndrome possess a mosaic karyotype (eg, 45,XO; 46,XX), counting at least 30 cells reduces the possibility of failing to identify a patient with mosaic TS.
  • Measuring serum levels of GH
    
    
    • Beyond the first months of life, endogenous GH is secreted in a pulsatile fashion. These intermittent peaks are greatest after exercise, after meals (as blood glucose levels decrease), and during deep sleep. Therefore, measuring a single random serum GH value is of no use in the evaluation of the short child. Beyond the neonatal period, values obtained during the daytime are unlikely to be detectable.
    • Although a random serum GH value of more than 10 mg/dL generally excludes GHD, a random low serum GH concentration does not confirm the diagnosis of GHD.
• Other useful tests include the following:
  
  
  • CBC count for hematologic disease
  • Wintrobe sedimentation rate for inflammatory bowel disease
  • Antiendomysial immunoglobulin A (IgA) and immunoglobulin G (IgG), transglutaminase IgG, and antigliadin IgG titers for sprue (gluten enteropathy) (Antiendomysial IgA titers are more sensitive, and IgG titers are more specific.)
  • Serum total thyroxine (total T4) and thyrotropin (TSH) levels to test for hypothyroidism
    
    
    • Determination of serum free T4 concentration is necessary in patients in whom TSH deficiency, TRH deficiency, or thyroxine-binding globulin (TBG) deficiency is suspected.
    • Directly assay free T4 levels using equilibrium dialysis.
    • Many reference laboratories report a value termed the free thyroxine index, which is calculated by multiplying the total T4 by an internal standard; however, if free T4 assessment is needed, measure it directly.
  • Sweat chloride testing: Consider this test in patients who are short and have a history of meconium ileus or pulmonary symptoms to exclude CF.
  • Serum transferrin and prealbumin concentrations for undernutrition

Imaging Studies

• Perform anteroposterior radiography of left hand and wrist to assess bone age (see Image 3). Chondrodysplasia of the distal radial epiphysis (Madelung deformity) suggests Lerí-Weill dyschondrosteosis.
• Perform renal and cardiac ultrasonography in all patients with Ullrich-Turner syndrome. The most commonly associated anomalies include horseshoe kidney and bicuspid aortic valve.

Other Tests

• Perform hearing tests in all patients with Ullrich-Turner syndrome.
• Use Bayley-Pinneau or Tanner-Goldstein-Whitehouse methods.
  
  
  • These methods are often used to predict final adult height and become more accurate with advancing bone age.
  • Within 5 years of epiphyseal closure, the predicted height may fall within ±5 cm of the final adult height, with 95% confidence.
  • The Bayley-Pinneau method can be used with a bone age as young as 6 years; however, the prediction is less accurate at the younger ages.

Procedures

• Several provocative tests have been developed for the evaluation of suspected GHD, including the following:
• • Insulin-induced hypoglycemia is the most powerful stimulus for GH secretion; however, this test also carries the greatest potential for harm and is the only GH provocative test that has been associated with fatalities.
  • Alternate GH secretagogues used successfully in combination as 2 serial tests include arginine, levodopa, propranolol with glucagon, exercise, clonidine, or epinephrine.
• Perform all GH provocative testing under the supervision of a pediatric endocrinologist.
• Please refer to Hyposomatotropism for further details of these tests.

TREATMENT

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Medical Care

Medical care depends on the etiology of the short stature.

• Recombinant human growth hormone (rhGH) administration has not been proven to remarkably improve final adult height in children with normal variant short stature.
  
  
  • Nine inconclusive clinical studies that focused on this particular issue have been published to date.
  • Published studies were flawed because of  the following:
    
    
    • Selection bias due to high drop-out rates from treatment regimens (presumably due, in part, to the parents' or health care provider's dissatisfaction with results of therapy in these individuals)
    • Lack of key design elements for a proper clinical trial (eg, placebo controls, double blinding, randomization)
    • Inadequate follow-up study to final adult height
  • A recent study from the National Institutes of Health was double blinded randomly and suggests GH has a small effect on adult height in children with normal short stature if they are treated with GH injections for many years.
  • In the absence of better clinical outcomes, do not use rhGH therapy to treat children with normal variant short stature.

Surgical Care

• Surgical care depends on the underlying cause of short stature.
• Brain tumors that cause hyposomatotropism may require neurosurgical intervention, depending on the tumor type and location (see Hyposomatotropism).
• Limb-lengthening procedures have been performed but carry enormous morbidity and mortality risks and are not recommended.

Consultations

• Consult a pediatric cardiologist, radiologist, and audiologist for patients with Ullrich-Turner syndrome.
• Consult a psychologist for patients with eating disorders.
• Perform all GH provocative testing under the supervision of a pediatric endocrinologist.

Diet

• Optimize nutrition in patients with GI disease.
• Obtain psychologic or psychiatric consultation for patients with eating disorders.
• Forced energy intake in children with normal variant short stature has not been demonstrated to improve short-term growth or final adult height.

Activity

• Do not restrict activity in children with normal variant short stature.

MEDICATION

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Medication administered depends on the etiology of the short stature.

Drug Category: Growth Hormone

These agents improve symptoms associated with GHD.

Drug Category: Insulin-like growth factor-I

Indicated for long-term treatment of severe, primary insulin-like growth factor-I (IGF-I) due to mutations of the growth hormone receptor (GH-R) or GH-R downstream signaling pathways.

FOLLOW-UP

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Further Inpatient Care

• Although many hospitalized patients are short, therapy directed at the illness underlying their short stature is the best course in the inpatient setting.

Further Outpatient Care

• The proper evaluation of short stature is conducted in an outpatient setting with a calibrated stadiometer.
  
  
  • The most useful information in the evaluation of a child with short stature is the child's growth pattern (see Image 2).
  • In children younger than 3 years, track length and weight at 3-month intervals.
  • Standing height and weight can be tracked at 6-month intervals in older children.

Deterrence/Prevention

• Growth evaluation is a useful means of detecting chronic disease in children.

Complications

• Short stature may be the harbinger of an occult chronic disease of childhood. Normal variant short stature may be associated with a bone mineral density that is lower than in the remainder of the (taller) population. Whether this healthy subset of the population is at higher risk of osteoporosis remains unclear.

Prognosis

• Individuals with normal variant short stature have an excellent prognosis.
• Treatment of patients with classic GHD with rhGH can be expected to yield a height consistent with genetic potential, provided that therapy is initiated at least 5 years prior to the onset of puberty. Whether cotreatment with rhGH and a gonadotropin-releasing hormone analog (eg, leuprolide) to inhibit puberty results in greater adult height in patients with classic GHD remains controversial.
• Treatment of hypothyroidism at least 5 years before the onset of puberty is essential to attain a height consistent with the genetic potential.
• Any chronic illness can reduce the adult height achieved if treatment of the condition is initiated late.

Patient Education

• Superb resources prepared by health care professionals for lay audiences include the following:
• • The MAGIC Foundation (Major Aspects of Growth in Children)
  • The Hormone Foundation of The Endocrine Society
  • The Turner Syndrome Society
  • The Human Growth Foundation
• In addition, the following are examples of informative Web sites for specific diseases that bring parents and researchers together in the ongoing effort to improve care:
• • National Organization for Rare Disorders
  • Shwachman-Diamond Syndrome
• For excellent patient education resources, visit eMedicine's Growth Hormone Deficiency Center. Also, see eMedicine's patient education articles Short Stature in Children, Growth Hormone Deficiency, Growth Failure in Children, Understanding Growth Hormone Deficiency Medications, and Growth Hormone Deficiency FAQs.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Patients with mosaic Ullrich-Turner syndrome grow significantly better than patients with classic Ullrich-Turner syndrome. The patient with mosaic syndrome may grow above the third percentile of the normal female population (see Image 4), thereby escaping the clinician's notice. In particular, girls with mosaic Ullrich-Turner syndrome may not come to attention until puberty, when they can present with primary amenorrhea. Despite a near-normal growth rate during childhood, the final adult height of a patient with mosaic TS may be lower than the third percentile of the normal population.
• Because girls may not have any symptoms of Ullrich-Turner syndrome, the clinician should have a high index of suspicion for this disorder in any girl with unexplained short stature, webbed neck, peripheral edema, coarctation of the aorta, delayed puberty, or any 2 of the following: nail dysplasia, high arched palate, short fourth metacarpal, or strabismus.
• The delayed diagnosis of a brain tumor associated with failure to thrive or grow is commonly associated with litigation.
• Delay in the diagnosis of acquired hypothyroidism can result in litigation.

MULTIMEDIA

Section 10 of 11  

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• Miscellaneous
• Multimedia
• References

Media file 1:  Proper use of a wall-mounted stadiometer.
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Media type:  Photo

Media file 2:  Comparison of the growth patterns between idiopathic short stature and constitutional growth delay.
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Media type:  Graph

Media file 3:  Bone age comparison between an 8-year-old boy (left) and a 14-year-old adolescent boy (right).
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Media type:  X-RAY

Media file 4:  Growth chart for Turner syndrome. Note that the upper limit overlaps the range for girls of normal height.
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Media type:  Graph

Media file 5:  A single, central, maxillary incisor reflects a defect in midline facial development.
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Media type:  Illustration

REFERENCES

Section 11 of 11

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17. Horton WA, Hall JG, Scott CI, Pyeritz RE, Rimoin DL. Growth curves for height for diastrophic dysplasia, spondyloepiphyseal dysplasia congenita, and pseudoachondroplasia. Am J Dis Child. Apr 1982;136(4):316-9. [Medline].
18. Horton WA, Rotter JI, Rimoin DL, Scott CI, Hall JG. Standard growth curves for achondroplasia. J Pediatr. Sep 1978;93(3):435-8. [Medline].
19. Hunter AG, Hecht JT, Scott CI Jr. Standard weight for height curves in achondroplasia. Am J Med Genet. Mar 29 1996;62(3):255-61. [Medline].
20. Li H, Leung SS, Lam PK, et al. Height and weight percentile curves of Beijing children and adolescents 0-18 years, 1995. Ann Hum Biol. Sep-Oct 1999;26(5):457-71. [Medline].
21. Lyon AJ, Preece MA, Grant DB. Growth curve for girls with Turner syndrome. Arch Dis Child. Oct 1985;60(10):932-5. [Medline].
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Article Last Updated: May 23, 2007