Short Stature

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 date.[4] 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, or a female with primary amenorrhea, mandates a karyotype to exclude this disorder.

Age

Individuals of any age can be affected.

Individuals with normal variant short stature have an excellent prognosis.

Treatment of patients with classic growth hormone deficiency (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.

A study by Bourgeois et al, using data from the National Health and Nutrition Examination Survey, reported a link between adult short stature and higher blood pressure. It was found that, starting in the fourth decade of life, taller subjects tended to have significantly lower systolic arterial blood pressure and pulse pressure, but higher diastolic arterial pressure, than shorter persons. Moreover, the effects of height on blood pressure were determined to increase with age.[5]

A Japanese study, by Shimizu et al, indicated that short stature in middle-aged men places them at an inflammatory disadvantage. The study, which involved 3016 men aged 30-59 years, found height to be inversely proportional to white blood cell count, particularly in men with a body mass index of 23 kg/m2 or above.[6]

A study by Quitmann et al indicated that children and adolescents with current short stature are more likely to have internalizing problems and a lower self- and parent-reported health-related quality of life than do those who have previously been diagnosed with short stature but who have reached a height greater than -2SDs by the time of evaluation.[7]

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 patient education resources, see the Growth Hormone Deficiency Center, as well as Short Stature in Children, Growth Hormone Deficiency, Growth Failure in Children, Understanding Growth Hormone Deficiency Medications, and Growth Hormone Deficiency FAQs.

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 one 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.

• GI

  • 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 growth failure (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.

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 below).

    Proper use of a wall-mounted stadiometer.

  • 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. Fifth finger clinodactyly is seen in Silver-Russell syndrome.

• 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.

  • Growth hormone deficiency (GHD) or panhypopituitarism should be considered as a cause of short stature in such patients.

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)

A study by Kärkinen et al indicated that in persons who, after age 3 years, have a height standard deviation score (SDS) below -3, short stature most often has a pathologic cause. Such was the case for 76% of girls and 71% of boys in the report, with causes including syndromes (most frequent etiology; 20% of the total 785 subjects in the study), organ disorders (16%), GHD (12%), small for gestational age without catch-up growth (9%), and skeletal dysplasias (7%). The investigators also found that the greater the severity of short stature and the mismatch with target height, the greater the chance that a growth-related pathology exists, especially a syndrome or skeletal dysplasia.[8]  

Laboratory studies used to assess the major causes of short stature in children include the following:

• Measurement of serum levels of insulinlike growth factor-I (IGF-I), formerly named somatomedin C, and IGF binding protein-3 (IGFBP-3)

  • These are useful tests for growth hormone deficiency (GHD), except in pubertal patients and those with history of a brain tumor.

  • 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 GHD.

• Karyotype by G-banding

  • The 45,X pattern defines patients with Ullrich-Turner syndrome.

  • Because 10% of patients with Ullrich-Turner syndrome possess a mosaic karyotype (eg, 45,X; 46,XX), counting at least 30 cells reduces the possibility of failing to identify a patient with mosaic Turner syndrome (TS).

• Measurement of 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 to exclude cystic fibrosis (CF): Consider this test in patients who are short and have a history of meconium ileus or pulmonary symptoms.

• Serum transferrin and prealbumin concentrations for undernutrition

Murray et al estimated that through the use of genetic studies, such as copy number variant analysis, targeted gene panels, and whole-exome sequencing, a molecular diagnosis could be derived for 25-40% of children initially diagnosed with idiopathic short stature.[10]  

Perform anteroposterior radiography of left hand and wrist to assess bone age (see image below).

Bone age comparison between an 8-year-old boy (left) and a 14-year-old adolescent boy (right).

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.

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.

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.

• Peak GH level is higher if the patient has been recently exposed to sex steroids, but controversy among pediatric endocrinologists persists regarding the use of sex steroid priming prior to stimulation testing.

Perform all GH provocative testing under the supervision of a pediatric endocrinologist. Please refer to Hyposomatotropism for further details of these tests.

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.[2, 3] Published clinical studies that have focused on this particular issue have been inconclusive. These reports 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 double-blinded, randomized study from the National Institutes of Health 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.[11]

Other randomized studies have shown variable results, with some demonstrating benefit[12]  and others not.[13, 14]  A study by Schena et al indicated that in children with short stature who are not GH deficient (ie, those with idiopathic short stature), long-term treatment with rhGH yields results similar to those in GH-deficient children who undergo this therapy, although this study did not have an untreated control group and pretreatment growth velocity data for the patients was missing.[15]  Thus, the risk-benefit ratio for treatment of children with idiopathic short stature is not well defined.

In a randomized, 1-year, placebo-controlled trial, Shemesh-Iron et al found improved height perception in boys with idiopathic short stature who received growth hormone. By the end of 3 additional years, in which all members of the study received growth hormone, there were improvements in the Rosenberg Self-Esteem Scale (RSES) and Single-Category Implicit Association Test for height (SC-IAT-H) scores but not in the Pediatric Quality-of-Life Inventory (PedsQL) or Child Behavior Checklist (CBCL) scores.[16]

However, a prospective, observational study by González Briceño et al found that PedsQL scores, as well as scores on the Quality of Life in Short Stature Youth (QoLISSY) questionnaire, improved in children with short stature who were treated with GH, indicating significant increases in emotional and social quality of life. The investigators could not rule out a placebo effect, since this was not a placebo-controlled trial. (Time may also have been a factor, since the above scores can improve with increased patient maturity.) Nonetheless, the authors reported that improvement in QoLISSY questionnaire results moderately correlated with increases in height standard deviation scores (SDS).[17]

Along with questions regarding the benefits of GH therapy, there is also controversy regarding GH dosing. Fixed dosing based on weight has long been used. However, a 2-year, open-label, randomized trial that measured the response to somatotropin (rDNA origin) therapy based on serum insulinlike growth factor-I (IGF-I) levels in children with GH deficiency and in children with idiopathic short stature suggested that IGF-based dosing of GH may safely provide superior growth outcome in both groups.[18]

Recombinant human GH has been used for over 4 decades, with a good track record of safety. A preliminary report from the French part of the European Union Safety and Appropriateness of GH treatments in Europe (EU SAGhE) study showed increased overall mortality in adults treated with rhGH during childhood, raising concerns about the long-term safety of this therapy.[19] Data from Belgium, The Netherlands, and Sweden, however, did not show a similar distribution of causes of death.[20] After reviewing information from the EU SAGhE study and other sources, the US Food and Drug Administration (FDA) recommended continued rhGH prescription and use according to the labeled recommendations.[21]

A study by Miller et al suggested that in males with GHD or idiopathic short stature, combined treatment with GH and aromatase inhibitor (with the latter known to delay epiphyseal fusion) allows ongoing growth over a 2-year period. In the patients with idiopathic short stature, the mean height SDS was -2.15 at baseline, -1.04 before initiation of aromatase inhibitor therapy, and -0.65 after 2 years of concomitant aromatase inhibitor treatment.[22]

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.

The following consultations are indicated:

• 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.

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.

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

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.

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

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 below).

Comparison of the growth patterns between idiopathic short stature and constitutional growth delay.

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.

A 2016 update to 2003 guidelines for GH and insulinlike growth factor-I treatment in children and adolescents with GH deficiency, idiopathic short stature, or primary insulinlike growth factor-I deficiency, from the Pediatric Endocrine Society, suggests the use of “a shared decision-making approach to pursuing GH treatment for a child with” idiopathic short stature. The update also states that the “decision can be made on a case-by-case basis after assessment of physical and psychological burdens, and discussion of risks and benefits,” and recommends that GH therapy not be used routinely in every child with a height standard deviation score at or below -2.25. It also suggests that, due to response overlap between dosing groups, the GH dose be initiated at 0.24 mg/kg/wk, “with some patients requiring up to 0.47 mg/kg/week.”[23]

Medication administered depends on the etiology of the short stature.

Class Summary

These agents improve symptoms associated with growth hormone deficiency (GHD).

Somatropin (Humatrope, Nutropin, Genotropin, Saizen, Tev-Tropin, Norditropin)

hGH produced via recombinant DNA technology in Escherichia coli; widely available since 1985. Currently, only 1 of the 10 largest reported clinical studies has demonstrated that therapy can increase final adult height in patients with normal variant short stature. This most recent NIH-funded study was randomized, placebo controlled, and took place over 14 y. Investigators demonstrated average gain in height did not exceed 4 cm when rhGH treatment of normal variant short stature began prior to puberty and continued through completion of puberty. They did not identify any clinical feature that, prior to start of therapy, could predict whether an individual patient would respond to rhGH and to what degree. Whether several years of daily injections are worth the potential, but not promised, relatively small increase in final adult height remains a personal and individual decision involving the patient, patient's family, and physician.

Class Summary

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.

Mecasermin (Increlex)

Recombinant human insulinlike growth factor-1 (rhIGF-1) indicated for long-term treatment of GF in children with severe primary IGFD (primary IGFD defined as basal serum IGF-I level and height SD scores ≤ -3, normal or elevated serum GH level). IGF-I is essential for normal growth of children's bones, cartilage, and organs by stimulating uptake of glucose, fatty acids, and amino acids into tissues. IGF-I is the principal hormone for linear growth and directly mediates GH actions. Primary IGFD is characterized by absent IGF-I production despite normal or elevated GH release.