Rudolph's Pediatrics, 22nd Ed.

CHAPTER 522. Growth and Growth Impairment

Edward O. Reiter

Growth is a complex process that involves the interaction of multiple, diverse factors and represents the sum of these influences on cell replication and programmed cell death (apoptosis) and on cell differentiation. Growth is ultimately governed by the genome of a person and its interactions with external factors, such as nutrition and psychosocial well-being. Linear height growth may occur as a continuous process or with periodic bursts of growth and arrest.1-3 During 1 year of growth monitoring, there may be marked seasonal variations of height and weight gain with several monthly bursts of weight and then height growth.4 Despite the complexity, healthy children usually grow linearly in a remarkably predictable manner. Change from a normal growth pattern often is the first manifestation of a disease, either an endocrine or a nonendocrine disorder that can involve almost any organ system. Frequent and accurate assessment of growth therefore is of primary importance in the care of children.

CHARACTER OF NORMAL GROWTH

Growth rates differ during intrauterine life, early and middle childhood, and adolescence. During gestation, growth averages 1.2 to 1.5 cm per week but increases dramatically to a midgestational peak of 2.5 cm per week with a decline to 0.5 cm per week immediately before birth. Growth velocity during the first 2 years of life averages about 15 cm per year and slows to approximately 6 cm per year during middle childhood. The peak height velocity during the pubertal growth spurt is 7 to 11 cm/yr. The time of puberty onset and consequently the age at the pubertal growth spurt varies among healthy children. On average, girls begin and complete puberty earlier than do boys and thus stop growing earlier (at 14 to 15 years of age compared with 16 to 17 years for boys). This accounts for the approximately 13-cm difference in the adult heights of women and men. Despite variations in the age of onset of puberty, among most healthy children, final height is not influenced by the chronological time of onset of the pubertal growth spurt. Growth ceases after fusion of long bone and vertebral epiphyses. This occurs when chondrocyte proliferation in the growth plate slows and senescent changes occur in a process seemingly intrinsic to the biology of the growth plate.5,6

Because heredity is a significant determinant of growth, it is important to relate a patient’s height to that of siblings and parents. Mean parental height is calculated, and 6.5 cm is added for boys or subtracted for girls. The 2-SD (standard deviation) range for this calculated parental target height is approximately 10 cm. The possibility of an underlying pathological condition must be considered when a child’s growth pattern clearly deviates from that of the parents.7

MEASUREMENTS

Accurate height measurements are necessary for the evaluation of growth. Measurement of supine length should be used for children younger than 2 years and erect height used for older children (see http://depts.washington.edu/growth/module5/text/contents.htm for detailed instructions; eFigs. 522.1 and e522.2 ). Supine length can be readily determined in a box constructed with an inflexible board against which the head is placed and a movable footboard on which the feet are placed perpendicular to the plane of the infant’s supine length. Under ideal conditions, the child is relaxed, the legs are fully extended, and the head is positioned so that a perpendicular plane to the long axis of the trunk is made by a line connecting the outer canthus of the eyes and the external auditory meatus. This is called the Frankfurt plane.

For older children who are physically capable, standing height is measured with a sturdy wall-mounted device. The traditional measuring device with a flexible arm mounted to a weight balance is notoriously unreliable and should be avoided. As with supine length, the position of the child is crucial to accuracy and reproducibility. The child should be fully erect with heels together; with the head in the Frankfurt plane; and the back of the head, thoracic spine, buttocks, and heels touching the measuring device. An effort should be made to correct discrepancies related to lordosis or scoliosis. Because erect height undergoes daytime lowering, serial measurements ideally should be made at the same time of day.

To estimate height velocity, two measurements (preferably made by the same person) no less than 4 months apart should be used; even when every effort is made to obtain accurate height measurements, measurement every 9 to 12 months is preferable to minimize error.

ASSESSMENT OF MEASUREMENTS (USE OF GROWTH CHARTS)

The National Center for Health Statistics has recently provided a set of 16 new growth charts (8 each for males and females) representing revisions of 14 existing charts and introducing new charts for body mass index (BMI = wt/ht2www.cdc.gov/growth charts).8

These charts allow comparison of an individual child’s growth with that of a normal U.S. population, graphically displayed in percentiles. Despite their utility, these charts are less useful in children below the 3rd or above the 97th percentiles. In these situations, computing standard deviation scores (SDS) are useful to quantitatively describe the growth delay. Height SDS for age is calculated as follows: SDS equals height minus mean height for healthy children at this age and sex, divided by the SD of height for healthy children at this age and sex. During adolescence, when variation in growth rate and maturational tempo can be large, these approaches can also be misleading. To address this issue, Tanner and colleagues developed growth charts combining longitudinal data to construct the curve shapes with percentile widths obtained in a large cross-sectional survey, thus accounting for variability in the timing of puberty.9

Carefully documented height velocity data are invaluable in assessing a child for abnormalities of growth. Although there is considerable variability in normal height velocity among children of different ages, between the age of 2 years and the onset of puberty, children normally grow with remarkable fidelity relative to the normal growth curves. Any crossing of height percentiles during this time period warrants further evaluation. Syndrome-specific growth curves have been developed for several clinical conditions associated with growth failure, such as Turner syndrome, Russell-Silver syndrome, and Down syndrome (http://www.ndss.org/index.php?option=com_content&view=article&id=71&Itemid=91- and http://www.magicfoundation.org/www/docs/7/; accessed January 20, 2009).

APPROACH TO THE EVALUATION OF GROWTH IMPAIRMENT

Evaluation of growth impairment initially requires discrimination between the child who fails to gain weight, with resulting growth deceleration, and those with a disorder of linear growth, as described in Chapters 29 and 30.

Table 522-1. Classification of Growth Retardation

Primary Growth Abnormalities

Osteochondrodysplasias

Pseudohypoparathyroidism

Chromosomal abnormalities

Intrauterine growth retardation

Secondary Growth Disorders

Malnutrition

Chronic disease

Endocrine disorders

Hypothyroidism

Cushing disease

Rickets

IGF deficiency (see Tables 523-1 and 523-2)

Idiopathic Short Stature

Genetic short stature

Constitutional delay of growth and maturation

Heterozygous defects of the GH receptor

CLASSIFICATION OF GROWTH DISORDERS AND DIFFERNTIAL DIGNOSIS OF GROWTH IMPAIRMENT

When disorders of linear growth appear to be caused by abnormalities intrinsic to the growth plate, they are called primary growth abnormalities (Table 522-1). The best examples of this category would be an osteochondrodysplasia, including disorders such as achondroplasia, hypochondroplasia, SHOX (short stature homeobox)-deficient skeletal dysplasia,10-215 and mutations in the natriuretic peptide receptor (NPR-B).10-215 These disorders are characterized by abnormalities in the size and structure of cartilage and bone. A variety of other chromosomal syndromes are associated with growth impairment, including trisomy 21 (Down syndrome), gonadal dysgenesis (Turner syndrome), Prader-Willi syndrome, and many others. These are further discussed in Chapters 176 and 179. Children with a history of in utero growth impairment (IUGR-SGA) are at risk for growth impairment following birth, as discussed in Chapter 47. Often the underlying cause of abnormal fetal growth is unclear, but deficits in IGF-I expression may be the underlying factor since the concentration of IGF-I in cord or fetal blood usually is low in SGA regardless of the apparent cause of growth failure. After birth, 10% to 15% of SGA infants continue to have attenuated growth with persistent height deficits through childhood and adolescence, contributing up to 20% of the total population of short children.240-261

Secondary growth disorders refer to growth failure caused by chronic disease or endocrine disorders. Malnutrition from any cause leads to alterations in the GH/IGF system, which probably mediates the growth failure observed in undernutrition. Serum levels of IGF-I are decreased despite normal or elevated GH levels,262-283 but in generalized malnutrition (marasmus), GH levels may be normal or low.284Consequently, malnutrition may be considered a form of GH insensitivity, with serum IGF-I levels reduced despite normal or elevated GH levels. GHBP levels, as a reflection of GH receptor content, are decreased.285,286 Gastrointestinal disorders, especially Crohn disease and celiac disease, are associated with growth impairment that is often associated with a decrease in serum IGF-1.287-292 Even with appropriate therapy, impaired linear growth results in deficits of final height among approximately 30% of children with Crohn disease.293 Gluten withdrawal is a highly effective treatment for celiac disease and results in rapid catch-up growth and decreased clinical symptoms during the first 6 to 12 months of treatment.287,294 In chronic liver disease, decreased food intake and malabsorption may lead to growth impairment, but with severe disease, alterations of the GH-IGF system with evidence of GH resistance appears to mediate the growth failure.295–304 After the patient receives a liver transplant, linear growth accelerates but may be delayed by drug therapy or complications of transplantation.298,299 In children with cyanotic congenital heart disease, growth failure correlates with the degree of hypoxemia.

Growth impairment is also common in those with congestive heart failure, usually due to inadequate caloric intake. Impaired growth almost invariably occurs among children with altered renal function305-308and may be the presenting sign in children with either uremia or renal tubular acidosis. Children with hematologic disorders such as thalassemia and sickle cell disease often have growth failure, which may be more apparent due to associated delayed onset of puberty. Therapy with repeated transfusions, and the hemosiderosis that can result, can cause endocrine deficiencies, such as hypothyroidism, gonadal failure, hypogonadotropic hypogonadism, and GH resistance.309-317 Children with diabetes mellitus grow normally unless they do not maintain reasonable glycemic control. Children with a variety of inborn errors of metabolism have poor growth. Growth impairment may also occur with some pulmonary disorders. In severe asthma, use of aerosolized glucocorticoids appears to minimize the growth-retarding effects of glucocorticoid therapy, but systemic absorption can still affect growth, depending on the specific drug and dose used.318-329 Children with cystic fibrosis often have retarded growth and delay in sexual maturation unless they receive aggressive nutritional supplementation. Growth failure can accompany any chronic infection or inflammatory disease in childhood. For juvenile rheumatoid arthritis, studies suggest that this may be due to a decrease in IGF-1 production mediated by IL-6.13 Although these disorders are not due to GH deficiency, many may be amenable to therapy with GH as discussed in Chapter 523.

Disorders that result from abnormalities in either GH secretion or of the GH-dependent peptide IGF-I are classified as IGF deficiency syndrome (IGFD). Key history and physical examination findings that increase the likelihood of GH deficiency are listed in Table 522-2.

Deficiency of growth hormone, IGFD, and other endocrine disorders causing growth impairment are further discussed in Chapter 523Idiopathic short stature (ISS) is a term used to describe variants of normal growth, including constitutional delay of growth and maturation and genetic short stature, that are not clearly related to other secondary disorders or to abnormalities in the GH-IGF axis. These are discussed separately.

DIAGNOSTIC EVALUATION

Evaluation for growth failure is considered for the following patients:

• Any child whose height is more than 3 SD below the mean height for age (approximated by means of measuring the vertical distance on a growth chart from the mean to the third percentile (–2 SD) and multiplying this value by 1.5).

• Any child, regardless of absolute height, who has a subnormal growth rate that is falling away from the normal growth channel.

• Any child whose height percentile clearly differs from that of midparental height.

If a child meets these criteria, evaluation includes a complete medical history with a genetic pedigree, documentation of the stature of ancestors, and a search for evidence of perinatal insult. Adequacy of diet; stooling and urination patterns; presence of respiratory, gastrointestinal, and infectious disease symptoms; and headaches and other symptoms suggestive of an intracranial lesion are determined. Specific attention is focused on the medical and social history during periods in which growth failure occurred.

The child’s weight and height are compared. Among children who are underweight for height, a chronic systemic disease is more likely than is hypopituitarism or an endocrine abnormality. An endocrine disorder is more likely among short children whose weight percentile is greater than their height percentile (ie, “pudgy, short”). Evidence of disproportionate body segments suggests a disorder such as a chondrodysplasia. In this regard, other measurements of the body are useful. They include occipitofrontal head circumference; lower body segment, or distance from the top of the pubic symphysis to the floor; upper body segment, or sitting height (height of stool is subtracted from standing height); and arm span. Published standards for these body-proportion measurements show the age-related changes. For example, the upper-to-lower-segment ratio drops from 1.7 for neonates to slightly less than 1.0 for adults.

Table 522-2. The Growth Hormone Research Society 2000 Criteria of Key History and Physical Examination Findings Suggestive of Growth Hormone Deficiency*

In the neonate, hypoglycemia, prolonged jaundice, microphallus, or traumatic delivery

Cranial irradiation

Head trauma or central nervous system infection

Consanguinity and/or an affected family member

Craniofacial midline abnormalities

Severe short stature (< –3 SD)

Height < –2 SD and a height velocity over 1 year < –1 SD

A decrease in height SD of more than 0.5 over 1 year in children over 2 years of age

A height velocity below –2 SD over 1 year

A height velocity more than 1.5 SD below the mean sustained over 2 years

Signs indicative of an intracranial lesion

Signs of multiple pituitary hormone deficiency (MPHD)

*Data from GH Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. J Clin Endocrinol Metab. 2000;85:3990-3993.

If no diagnostic clues are forthcoming from the history and physical examination, selected laboratory tests are performed to screen for some of the silent causes of growth failure, as detailed in Table 522-3 and Figure 522-1. Although this has no specific diagnostic value, radiography of the hand and wrist to assess “bone age” is useful because it provides a reflection of somatic maturity.11 The bone age reflects the degree of growth-plate senescence and thus is a useful adjunct in estimating growth opportunity. The ossification centers of the left hand and wrist appear and progress in a predictable sequence in healthy children; therefore, they can be compared with the normal age and sex standards of Greulich and Pyle.12

Table 522-3. Screening Tests for Children with Growth Failure

Plasma levels of IGF-I and IGFBP-3, which are GH-dependent, are measured before complete pituitary function testing is undertaken. The widespread clinical use of these measurements reflects the central role of the IGF system in childhood growth. A clearly normal IGF-I concentration renders GH deficiency unlikely. However, a low value does not prove GH deficiency, because such values occur in malnutrition, hypothyroidism, and many other chronic illnesses. In general, IGFBP-3 levels are similar to IGF-1 levels, although malnutrition does not seem to lower IGFBP-3 production comparably. Overall, abnormal values of these GH-dependent peptides strongly suggest either GH deficiency or resistance to GH action.

Those children with growth impairment and for whom history, physical examination, and laboratory screening tests yield no clues other than low or borderline levels of IGF-1 and IGFBP-3 should undergo pituitary function testing. Because GH is secreted episodically, adequacy of GH production cannot be determined with random blood samples. Two or more pharmacological provocative tests are required, because failure to respond to a single stimulus is not sufficient evidence to confirm the diagnosis of GH deficiency (see Table 522-4). Values obtained with any single test may not reflect true GH secretory capacity. Although maximal poststimulus serum GH values of 7 to 10 ng/mL or less have generally been accepted as evidence of impaired GH secretion, most endocrinologists accept that these cutoff values are arbitrary.15 Children who secrete GH normally may not secrete GH during testing, and children with deficiency may muster what appear to be good responses during testing; thus, stimulated GH secretion is not necessarily a gold standard.16 Alternative approaches such as measuring serum GH with round-the-clock blood sampling is expensive and inconvenient, precluding their general use for clinical testing. In suspected isolated GHD, two GH-provocation tests are always required, but in those with defined central nervous system (CNS) pathology, history of irradiation, multiple pituitary hormone deficiencies, or a genetic defect, one GH test may suffice.16

FIGURE 522-1. Clinical and biochemical assessment of a child with growth failure. Primary screening evaluation is to establish IGF deficiency. Subsequent studies localize causation at hypothalamic or pituitary dysfunction or GH resistance. IGF, insulin-like growth factor; IGFBP3, insulin-like growth factor binding protein 3; IUGR, intrauterine growth retardation.

Documentation of abnormal pituitary GH secretion raises the possibility of intracranial tumors and the potential for deficiency of other pituitary hormones. Table 522-5 lists tests that are useful in the complete evaluation of pituitary function. Children with isolated GH deficiency have normal serum thyroxine levels, and their TSH level does not differ from normal. ACTH deficiency can be evaluated by measuring cortisol in the serum during an insulin-induced hypoglycemia GH-provocative test, or it can be evaluated indirectly by assessing post-ACTH cortisol levels. Abnormalities of gonadotropin secretion are difficult to detect before puberty. Magnetic resonance imaging studies may show characteristic developmental abnormalities in the hypothalamic-pituitary area such as an abnormal (attenuated or absent) pituitary stalk, ectopia of the posterior pituitary (situated in the stalk or abutting the median eminence), and hypoplasia of the anterior pituitary (eFig. 522.3 ).

Table 522-4. Clinical Tests of Growth Hormone Secretion

IDIOPATHIC SHORT STATURE (ISS)

Many children and early adolescents are short (< 3rd percentile) and have slowed linear growth velocity(< 25th percentile), sometimes with delayed skeletal maturation and an impaired or attenuated pubertal growth spurt, but have no chronic illnesses or apparent endocrinopathies. Such children usually have normal GH secretory dynamics, though provocative tests may be blunted under some circumstances. IGF-1 and IGFBP-3 are frequently lower than expected on a chronological though often not skeletal age basis. The etiology of the slowed childhood growth and frequently delayed pubertal spurt has not been established but presumably is due to a variety of subtle disorders of the hypothalamic-pituitary-IGF axis that are not identified using standard tests (see eTable 522.1 ).25,178 Multiple groups of patients are included in this broad category, including those with constitutional delay of growth and maturation (“late bloomers”) and those with familial short stature.

CONSTITUTIONAL DELAY OF GROWTH AND MATURATION (CDGM)

The term constitutional delay describes children with a variant of maturational tempo characterized by short stature but normal growth rates during childhood, delayed puberty with a late and attenuated pubertal growth spurt, and attainment of normal adult height. Diagnostic criteria are listed in Table 522-6. Toddlers with constitutional delay deviate from the normal growth curve and by age 2 years are at or slightly below the fifth percentile for height.185Final height, though usually within the normal population range, is often in the lower part of the parental-height-target zone with few patients exceeding that target height.186-188 The predicted final height, especially when the skeletal age is extremely delayed, is greater than that usually achieved but is difficult to reliably anticipate.189-191 These children also tend to be thin (though certainly not uniformly) and may be hypermetabolic, possibly contributing to impaired anabolism.192

Table 522-5. Tests of Pituitary Function Useful in Determining Whether a Child Has Hypopituitarism

Table 522-6. Criteria for Presumptive Diagnosis of Constitutional Delay of Growth and Maturation

No history of systemic illness

Normal nutrition

Normal physical examination, including body proportions

Normal thyroid function tests and levels of GH/IGF axis peptides

Normal CBC, sedimentation rate, electrolytes, BUN, creatinine

Height at or below the third percentile but with annual growth rate > fifth percentile for age

Delayed Puberty

Males: failure to achieve Tanner G2 stage by age 14 years or P2 by 15 years

Females: failure to achieve Tanner B2 stage by age 13 years

Delayed Bone Age

Normal predicted adult height

Males: > 163 cm (64″)

Females: > 150 cm (59″)

Often these children have delayed skeletal ages, normal or slightly low serum IGF-I but usually normal IGFBP-3 levels for skeletal age, and normal GH-provocative tests (if pretreated with gonadal steroids). Low serum levels of IGF-I and IGFBP-3 or a poor GH response to provocative testing (after priming with gonadal steroids) require investigation for possible underlying pathology, such as intracranial tumors. When CDGM occurs in the context of familial short stature (see below) children may experience both a delayed adolescent growth spurt and a short adult height.

GENETIC (FAMILIAL) SHORT STATURE

Familial height impacts the growth of an individual, and evaluation of a specific growth pattern must be placed in the context of familial growth and stature. A constellation of clinical findings describes a normal variant referred to as genetic short stature (GSS) or familial short stature, which differs from the syndrome of constitutional delay of growth and maturation discussed above. In GSS, childhood height is at or below the 5th percentile, but the velocity is generally normal. The onset and progression of puberty are normal or even slightly early and more rapid than normal so that skeletal age is concordant with chronological age. Parental height is short (both parents are often below the 10th percentile), and pubertal maturation is normal. Adult heights in these individuals are short and in the target zone for the family.188 The GH-IGF system is normal, but exogenous GH therapy during middle childhood years may substantially increase linear growth velocity without disproportionate augmentation of skeletal maturation.