Pediatric Annals

Evaluating Short Stature in Children

Isil Halac, MD; Donald Zimmerman, MD

Abstract

Growth reflects general health, which means deceleration may be a sign of larger problems.

Children presenting with hypothyroidism severe enough to cause growth retardation usually have normal or increased weight due to decreased metabolism and water retention. Usually, patients with hypothyroidism exhibit symptoms such as dry hair and skin, cold intolerance, constipation, low energy, and decreased appetite. In evaluation of thyroid disorders, measurement of free thyroxine is generally preferable to measurement of total thyroxine, because free thyroxine is the biologically active moiety. Levels of thyroid-stimulating hormone should also be determined.

GROWTH RETARDATION IN ADOLESCENCE

Evaluation of short stature during puberty demands careful attention to the details of pubertal development. Females have the pubertal growth spurt by the time they enter Tanner stage 3, while males have the pubertal growth spurt by the time they enter Tanner stage 4. The growth spurt in girls occurs approximately 2 years earlier than it does in boys. The peak growth velocity in girls of 8.3 cm per year is slightly slower than that of 9.5 cm per year in boys. Puberty is considered to be delayed for girls still in Tanner stage 1 by age 13 or boys still in Tanner stage 1 by age 14.

As in infancy, growth delay in puberty may be physiologic. Distinguishing normal variants of growth and development from pathologic disturbance of growth requires a detailed history that catalogues the details of the patient's growth, as well as a detailed endocrine review of systems (see Sidebar, page 172) and general review of systems. The review of the gastrointestinal and neurologic systems should be particularly detailed. In adolescence, careful attention must be directed to possible contributions from conditions such as anorexia nervosa or from regimens such as strict weight control in wrestlers. Causes of short stature in this age group also include inflammatory bowel disease, gonadal dysgenesis, craniopharyngioma, germinomas, and Langerhans cell histiocytosis.

In constitutional delay of growth and development (Figure 7, see page 175), pubertal sex steroid secretion is delayed. In turn, the sex-steroid-stimulated increase in GH is delayed, resulting in late occurrence of the pubertal growth spurt. Adolescents with constitutional delay of growth and development have slower growth immediately before the pubertal growth spurt than do adolescents with normal or early puberty. The growth velocity in constitutional delay may fall below 4 cm per year. Extreme growth deceleration may be indistinguishable from that produced by acquired GH deficiency and other serious conditions. In light of the similarity of presentations, significant growth delay in this age group usually warrants a complete evaluation.

The evaluation should include the same studies noted earlier with the addition of FSH, LH, estradici or testosterone, and prolactin.

SUMMARY

A child's growth reflects his or her general state of health. Growth deceleration therefore may result from processes that ultimately threaten much more than height and weight. Accurate height and weight measurements and routine plotting of growth data on standard growth charts are important elements of pediatrie practice. A decrease in length or height percentiles may be physiologic in infancy and in puberty. However, in order to distinguish physiologic from pathologic growth deceleration, a careful history and physical examination needs to be obtained. Quite frequently, laboratory and radiographie studies are needed to distinguish with confidence between causes of slow growth in these phases of life. Such studies are always required to evaluate growth deceleration during childhood, because growth deceleration in this phase is virtually always the result of a pathological process. If constitutional growth delay is diagnosed, reassurance is often adequate treatment, though continued monitoring of growth and bone age is indicated. Growth deceleration due to…

Growth reflects general health, which means deceleration may be a sign of larger problems.

Assessment of growth is an essential component of pediatrie health examination because a large number of disease processes may alter growth velocity. The causes of short stature are summarized in the article by Dr. Miller (see page 1 77). Attention to growth problems may be directed by the pediatrician who observes a significant abnormality in a patient's growth trajectory. In other instances, parents are alarmed by the height discrepancy between their child and the child's peers. Some overzealous parents may be concerned if their child does not have the advantage of tall stature.

GROWTH MEASUREMENT

The growth pattern is the key to the diagnosis of growth problems. Therefore., correct measurement of length or height is crucial. In all instances, children should be measured with bare feet. The length of children younger than age 2 or who are unable to stand should be measured within a firm box in the supine position. The child should lie perpendicular to the surface with the head touching a fixed plate. The head should be positioned so the outer canthus of the eye is vertically aligned above the external auditory canal, or Frankfurt plane. A second adult should maneuver the sliding plate, also perpendicular to the surface on which the child lies, so that it presses on the soles of the patient's feet. Use of other methods, such as marking the top of the head and the bottom of the feet on a paper covering the examination table, is not sufficiently precise in analyzing growth patterns.

Older than 3, height should be measured using a standard stadiometer. The child should stand on a stationary surface with his or her back against a flat surface. Feet, buttocks, thoracic area, and head should touch this surface, and the measurer should ascertain that the patient is not slouching. The head should be positioned in the Frankfurt plane with the outer canthus of the eye aligned with the external auditory canal.

The measurement of height is simple and inexpensive. However, under-measurement is a common reason for referral of patients with putative short stature to the pédiatrie-endocrine clinic. Therefore, medical personnel responsible for assessing children's length or height should be trained to obtain these measurements correctly.

Once height and weight measurements are obtained, they should be plotted on the standard growth charts. It would be ideal to have separate growth charts for different ethnic groups, because there are variations in height between different ethnic groups. The same growth chart is used, however, for all ethnicities. The most recent growth charts in use in the United States are based on a representative sample collected from 1988 to 1994 as part of the National Health and Nutrition and Examination Survey. Once a diagnosis of Turner syndrome, Down syndrome, or chondrodysplasia is made, specific growth charts for these conditions should be used.

Other anthropométrie measurements that may guide the physician to specific diagnoses include the occipito-frontalhead circumference, the upper-to-lower extremity ratio, and the height-toarmspan ratio. The lower segment is the distance from the superior border of the pubic bone to the surface upon which the patient stands or against which the feet are placed. The upper segment is the difference between the height and the lower segment. The armspan may be measured with the patient facing a wall or other flat surface with the arms held perpendicular to the axis of the body. The distance between the distal ends of the middle fingers should be measured.

Age-appropriate upper-to-lower extremity ratios are 1.7 at birth, 1.4 at age 2, 1 at age 10, and 0.9 in adults.1 An abnormally increased upper-to-lower segment ratio is seen in short-limbed dwarfism, chondrodystrophies, hypothyroidism, gonadal dysgenesis, and Klinefelter syndrome, patients with the latter are short in early childhood and tall in adolescence. The upper-to-lower segment ratio is decreased in patients with vertebral abnormalities such as scoliosis and spondyloepiphyseal dysplasia, and in patients with a history of spinal irradiation.

Normal armspan-to-height ratio is 95% ±5% at birth and 97% ±4% at age 6.5. At age 12, this ratio is 100% in boys and 98% in girls, ±4% in both sexes. By age 18, this ratio increases to 103% in boys and 101% in girls, ±2% in both sexes. Increased armspan may be seen in Marfan syndrome, multiple endocrine neoplasia type 2B, homocystinuria, vertebral abnormalities, and eunuchoidism. Short armspan is a common finding in skeletal dysplasias. African Americans have relatively long limbs and as adults, their upper to lower segment ratio is 0.85. 2

NORMAL GROWTH

In prenatal life, growth velocity is highest in the second trimester, peaking at 120 cm per year at 20 weeks of gestation. It declines in the third trimester. At birth, an average fullterm newborn is 50 cm in length and 3.5 kg in weight. During the first 6 months, the infant grows 16 to 17 cm, with another 8 cm increase during the next 6 months. Growth velocity exceeds 10 cm per year in the second year, 8 cm per year in the third year, 7 cm per year in the fourth year, and 6 cm per year in the seventh year. Growth velocity then stabilizes at 5 to 6 cm per year until puberty.

FETAL GROWTH RETARDATION

Intrauterine growth retardation (IUGR) is less likely to result from endocrine dysfunction than is postnatal growth retardation. Infants presenting with thyroid or growth hormone (GH) deficiencies have normal fetal growth and are usually normal in weight and length at birth. Extremely severe GH deficiency (eg, secondary to GH gene defects) and severe GH resistance, as found in patients with Laron syndrome, may cause mild fetal growth retardation.

A rare endocrine cause of felal growth retardation is congenital diabetes mellitus. In this condition, the absence of insulin leads to slowed growth in length and weight in utero. Catch-up growth occurs with replacement of insulin.

Causes of RJGR include placenta! insufficiency, small uterine size, congenital infections, chromosomal abnormalities, skeletal dysplasias, congenital errors of metabolism, teratogenic agents, maternal under-nutrition or severe illness, multiple gestations, and idiopathic causes. Miscellaneous syndromes, such as Russell-Silver syndrome, Seckel syndrome, and Noonan syndrome, are also responsible for IUGR.

Evaluation of IUGR

The medical history should explore maternal illness and exposure to possible pathogens and teratogens. The family history may identify others with a similar growth pattern. If the patient is disproportionate, skeletal radiographs may identify features of skeletal dysplasia, If a number of significant malformations are observed, chromosomal analysis may lead to the diagnosis. Studies to identify intrauterine infections should be initiated. In addition to the usual antibody titers, radiographie studies to detect intracranial calcification should be performed.

In most instances, including those due to multiple gestations, catch-up growth is seen by age 3.3 Compared with children born at normal size, children who are small for gestational age are 5 to 7 times more likely to develop short stature.4 In approximately 10% to 15% of IUGR patients, however, postnatal catch-up growth fails to occur (Figure 1, see page 174). These children may benefit from GH treatment, recently approved by the Food and Drug Administration for this indication.

Russell-Silver Syndrome

Patients with Russell-Silver syndrome most commonly present with IUGR, postnatal growth failure, hemihypertrophy, frontal bossing, small triangular facies, sparse subcutaneous tissue, and shortened and in-curved fifth fingers. Precocious puberty, delayed closure of the fontanelles, and delayed bone age are other features.5 Approximately 10% of the Russell-Silver patients have uniparental disomy 7; in other patients the diagnosis is clinical.6

Prader-Willi Syndrome

Prader- Willi syndrome may be due to deletions of the short arm of chromosome 15 or to uniparental disomy in light of parental imprinting in this chromosomal region. Patients with this syndrome may present with IUGR, but growth retardation is even more prominent in postnatal life. Later in infancy, increased appetite and obesity emerge and become severe. Newborn males may present with hypotonia, microphallus, and cryptorchidism in association with hypogonadism.7

Noonan Syndrome

Noonan syndrome is an autosomaldominant condition that presents with Turner syndrome-like findings, including webbing of the neck, low posterior hairline, ptosis, cubitus valgus, malformed ears, and cardiac abnormalities. In contrast to the prominence of leftsided heart disease in patients with Turner syndrome, patients with Noonan syndrome have right-sided heart disease. In addition, 25% to 50% of patients with Noonan syndrome have mental retardation.8

Seckel Syndrome

Also known as "bird-headed dwarfism," Seckel syndrome is an autosomal-recessive condition presenting with microcephaly, prominent nose, and micrognathia. Adult height reaches approximately 100 cm, and mental retardation is frequent.7

GROWTH RETARDATION DURING INFANCY

The evaluation for growth retardation during infancy should include a detailed medical and family history, including heights of family members and timing of puberty in family members. The physical examination should include careful measurement of head size and of armspan and lower segment. The ratios of armspan to height and upper and lower segments should be calculated. Dysmorphic features should be identified, along with organomegaly and lymphadenopathy.

As shown in Figure 2 (see page 174), there is a prominent decrease in growth percentiles within the first 2.5 years. Subsequently, growth proceeds at a normal velocity. Decreased percentiles in the first 3 years may be physiological and consistent with constitutional growth delay or with familial short stature. If there is a strong family history of genetic short stature or of constitutional growth delay, and if the physical examination is normal (with normal head circumference and body proportions), this growth pattern is quite reassuring.

In children with constitutional delay of growth and development, birth size is normal but growth percentiles subsequently decline. Bone age is delayed in comparison to chronologic age. Dental age is also delayed. After age 3, the child's growth velocity normalizes so height parallels the normal curve. These children enter puberty at older ages than their peers. Growth may continue until the late teens in females and the early 20s in boys, in contrast to 15 or 16 in females and 18 in males with normal pubertal timing. There is often a family history of pubertal delay. Adult height is normal.

Infants with genetic short stature may have growth trajectories similar to the trajectories of infants with constitutional delay of growth and development. They are normal for length and weight at birth, and their length and weight percentiles decline to their genetic potential within the first 2 to 3 years. Unlike those with constitutional delay of growth and development, patients with genetic short stature have nondelayed bone age and normal pubertal timing.

Figure 1.

Figure 1.

Figure 2.

Figure 2.

Figure 3.

Figure 3.

In the setting of a strong family history of short stature or of constitutional delay of growth and development, patients with growth trajectories similar to that shown in Figure 2 can be followed expectantly. If the family history is not strongly positive for these normal variants of growth and development, a laboratory evaluation may be indicated in patients manifesting a decline of two or more major percentile lines.

The initial evaluation should include studies of complete blood count, erythrocyte sedimentation rate, electrolytes, calcium, phosphorus, liverfunction studies, free T4, TSH, IGF-I, IGF-BP3, serum anti-transglutaminase, endomysial antibodies and serum IgA levels, urinanalysis and qualitative stool fat, and bone age x-ray. Karyotype evaluations should be conducted for female patients.

As shown in Figure 3, the weight percentiles decline to a more significant degree than do the height percentiles. When weight is more markedly affected than height, nutritional factors are more likely to play a role. Inadequate nutrition may be due to environmental or social factors, or to failure of the child to take adequate nutrients. Frequent vomiting or failure to absorb or digest nutrients may produce a similar growth pattern.

The history should include a complete nutrition history and a thorough exploration of gastrointestinal symptoms. The examiner should carefully note the interaction between the patient and the caretakers to consider whether psychosocial deprivation is likely. In addition to the work-up described above, blood smear, serum albumin, serum levels of folate and vitamin B 12, stool microscopic examination for ova and parasites, quantitative stool fat, spot stool a-I antitrypsin levels, and sweat chloride should be obtained to rule out gastrointestinal causes. If these tests are normal, patients may require admission to a hospital for observation of food intake and weight gain.

GROWTH RETARDATION IN CHILDHOOD

As Figure 4 shows (see page 175), both height and weight may increase at normal velocities parallel to but below the fifth percentile. This growth curve is quite common in constitutional delay of growth and development. As described above, this diagnosis requires that bone age and pubertal development remain delayed as the patient is followed with regular examinations and repeated bone-age determinations.

A decrease in height percentiles in childhood (Figure 5, see page 175) is usually pathological and requires special attention. Many conditions could present with this growth pattern. As mentioned above, detailed family history, a complete review of systems including medication history (eg, gfucocorticoids), and a detailed physical examination are essential.

The evaluation should include a complete blood count with differential erythrocyte sedimentation rate, serum electrolytes including calcium and phosphate, liver-function tests, serum carotene and folate, prolactin, free thyroxine, TSH, IGF-I, IGF-BP-3, urinalysis, qualitative stool fat, sweat chloride, and bone-age x-ray. Karyotype evaluations also should be done for female patients.

When height percentiles decrease in childhood, the probability of finding a pathologic process as the cause of growth delay is very high. When malnutrition is not a concern and blood counts, blood chemistries, and thyroid function studies are normal, low levels of IGF-I or IGF-BP3 should prompt additional studies to establish whether GH deficiency is present.

Growth hormone has a pulsatile secretion pattern with increased secretion during sleep. Therefore, assessment of GH secretion requires pharmacological GH- stimulation testing. If the GH response is low in two stimulation tests, a diagnosis of GH deficiency is confirmed. Once GH deficiency is diagnosed, central nervous system pathologies need to be ruled out using an MRI of the brain that includes thin sections through the pituitary and hypothalamus and images taken with and without contrast. Brain MRI findings may show hypoplastic pituitary or interrupted stalk in patients with GH deficiency without any gene defects.9 If brain imaging is normal, GH treatment should be offered in association with a discussion of possible GH side effects.

Figure 6 shows growth retardation occuring coincident with or subsequent to excessive weight gain. This pattern is suggestive of excessive glucocorticoid exposure (ie, Gushing syndrome) or hypothyroidism. When investigating possible Gushing syndrome, a careful drug history is essential. Patients with Gushing syndrome have typical clinical features of obesity, hypertension, prominent cheeks with flushed appearance (moon facies), buffalo hump, hypertrichosis, and purplish striae. Excessive glucocorticoids increase the circulating somatomedin inhibitors that lead to decreased somatomedin activity and contribute to impaired growth.10 Glucocorticoids also suppress IGF-I Iranscription in osteoblasts." Urine-free or midnight-serum cortisol may help identify patients with this problem.

Figure 4.

Figure 4.

Figure 5.

Figure 5.

Figure 6.

Figure 6.

Figure 7.

Figure 7.

Children presenting with hypothyroidism severe enough to cause growth retardation usually have normal or increased weight due to decreased metabolism and water retention. Usually, patients with hypothyroidism exhibit symptoms such as dry hair and skin, cold intolerance, constipation, low energy, and decreased appetite. In evaluation of thyroid disorders, measurement of free thyroxine is generally preferable to measurement of total thyroxine, because free thyroxine is the biologically active moiety. Levels of thyroid-stimulating hormone should also be determined.

GROWTH RETARDATION IN ADOLESCENCE

Evaluation of short stature during puberty demands careful attention to the details of pubertal development. Females have the pubertal growth spurt by the time they enter Tanner stage 3, while males have the pubertal growth spurt by the time they enter Tanner stage 4. The growth spurt in girls occurs approximately 2 years earlier than it does in boys. The peak growth velocity in girls of 8.3 cm per year is slightly slower than that of 9.5 cm per year in boys. Puberty is considered to be delayed for girls still in Tanner stage 1 by age 13 or boys still in Tanner stage 1 by age 14.

As in infancy, growth delay in puberty may be physiologic. Distinguishing normal variants of growth and development from pathologic disturbance of growth requires a detailed history that catalogues the details of the patient's growth, as well as a detailed endocrine review of systems (see Sidebar, page 172) and general review of systems. The review of the gastrointestinal and neurologic systems should be particularly detailed. In adolescence, careful attention must be directed to possible contributions from conditions such as anorexia nervosa or from regimens such as strict weight control in wrestlers. Causes of short stature in this age group also include inflammatory bowel disease, gonadal dysgenesis, craniopharyngioma, germinomas, and Langerhans cell histiocytosis.

In constitutional delay of growth and development (Figure 7, see page 175), pubertal sex steroid secretion is delayed. In turn, the sex-steroid-stimulated increase in GH is delayed, resulting in late occurrence of the pubertal growth spurt. Adolescents with constitutional delay of growth and development have slower growth immediately before the pubertal growth spurt than do adolescents with normal or early puberty. The growth velocity in constitutional delay may fall below 4 cm per year. Extreme growth deceleration may be indistinguishable from that produced by acquired GH deficiency and other serious conditions. In light of the similarity of presentations, significant growth delay in this age group usually warrants a complete evaluation.

The evaluation should include the same studies noted earlier with the addition of FSH, LH, estradici or testosterone, and prolactin.

SUMMARY

A child's growth reflects his or her general state of health. Growth deceleration therefore may result from processes that ultimately threaten much more than height and weight. Accurate height and weight measurements and routine plotting of growth data on standard growth charts are important elements of pediatrie practice. A decrease in length or height percentiles may be physiologic in infancy and in puberty. However, in order to distinguish physiologic from pathologic growth deceleration, a careful history and physical examination needs to be obtained. Quite frequently, laboratory and radiographie studies are needed to distinguish with confidence between causes of slow growth in these phases of life. Such studies are always required to evaluate growth deceleration during childhood, because growth deceleration in this phase is virtually always the result of a pathological process. If constitutional growth delay is diagnosed, reassurance is often adequate treatment, though continued monitoring of growth and bone age is indicated. Growth deceleration due to other processes is often treatable. Delineation of the causes of poor growth is particularly important because these disease processes may produce other serious problems.

REFERENCES

1. Carrilo AA, Recker BF. Reference Charts Used Frequently by Endocrinologists in Assessing the Growth and Development of Youth, in: Lifshitz F, ed. Pediatrie Endocrinology. New York, NY: Marcel Dekker; 2003:1001.

2. Shohat M, Rimoin DL. Skeletal Dysplasia. In: Lifshitz F, ed. Pediatrie Endocrinology. New York, NY: Marcel Dekker; 2003:113-132.

3. Horner JM, Thorsson AV, Hintz RL. Growth deceleration patterns in children with constitutional short stature: an aid to diagnosis. Pediatrics. 197 8; 62(4): 529-534.

4. Albertsson-Wikland K, Boguszewski M, Karlberg J. Children born small-for-gestational age: postnatal growth and hormonal status. Harm Res. 1998;49(Suppl 2):7-13.

5. Russell'Silver Syndrome. In: Jones KL, ed. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W.B. Saunders; 1997:96-99.

6. Eggermann T, Wollmann HA, Kuner R, et al. Molecular stuides in 37 Silver-Russell syndrome patients: frequency and etiology of uniparental disomy. Hum Genet. 1997;100(3-4):415-419.

7. Rosenfeld RG, Cohen P. Disorders of growth hormone/insulin-like growth factor secretion and action. In: Sperling MA, ed. Pediatrie Endocrinology. Philadelphia, PA: W.B. Saunders; 2002:211-288.

8. Styne D. The testes disorders of sexual differentionaüon and puberty in the male. In: Sperling MA, ed. Pediatrie Endocrinology. Philadelphia, PA: W.B. Saunders; 2002:565-628.

9. Osorio MG, Mami S, Jorge AA, et al. Pituitary magnetic resonance imaging and function in patients with growth hormone deficiency with and without mutations in GHRHR, GH- 1 , or PROP- 1 genes. J Clin Endoerinol Metab. 2002;87(11):5076-5084.

10. Unterman TG, Phillips LS. Glucocorticoid effects on somatomedins andsomatomedin inhibitors. J Clin Endoerinol Metab. 1985;15(10):1781-1789.

11. Delany AM, Durant D, Canalis E. Glucocorticoid suppression of IGF- 1 transcription in osteoblasts- Mol Endocrinol. 2001;15(10):1781-1789.

10.3928/0090-4481-20040301-08

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