Growth Retardation

• 96/10/12

• Data from Up To Date

• 林峻輝

INTRODUCTION

• Short stature is not a disease; it is a term applied to a child who is 2 standard deviations (SD) or more below the mean height for children of that sex and chronologic age (and ideally of the same racial-ethnic group).

• This translates into being below the third percentile for height.

• A single measurement of height is much less useful in assessing growth than is the pattern of growth over a period of time.

• Growth curve in a male with intrinsic shortness. The growth velocity is normal from age 5 onward with the height being below, but parallel to, the third percentile.

• To define any growth point, one must measure children accurately and plot each point (height, weight, and head circumference) precisely.

• One of the more common causes of apparent growth failure (and short stature) is mismeasurement or aberrant plotting of the data.

Prediction of height potential • Somatic growth and biologic maturation are influe

nced by many factors that act independently or in concert to modify a child's genetic potential for growth.

• Although the precise contribution of heredity cannot be quantitated, an estimate of a child's adult height potential can be obtained by calculation of the midparental height, adjusted for the sex of the child:

•   For girls, 13 cm is subtracted from the father's height and averaged with the mother's height.

• For boys, 13 cm is added to the mother's height and averaged with the father's height.

VARIATIONS OF NORMAL GROWTH

• A normal pattern of growth is evidence that the general health of a child or adolescent is good.

• On the other hand, children with just about any subacute or chronic illness may grow slowly.

• Statural growth is a continuous but not linear process. There are three phases of postnatal growth: infantile, childhood, and pubertal.

• Each has its own distinctive pattern.

• The infantile phase is characterized by rapid but decelerating growth during the first two years of life; overall growth during this period is about 30 to 35 cm.

• Infants often cross percentile lines in the first 24 months as they grow toward their genetic potential and get further away from the excesses or constraints of the intrauterine environment.

• The childhood phase is characterized by growth at a relatively constant velocity of 5 to 7 cm per year; there is often slight slowing later in childhood.

• The pubertal phase is characterized by a growth spurt of 8 to 14 cm per year because of the synergistic effects of increasing gonadal steroid and growth hormone secretion.

Idiopathic short stature

• There are certain children whose stature falls below 2 SD of the mean for age, and for whom no endocrine, metabolic or other diagnosis can be made.

• Such children are considered to have idiopathic short stature.

• They have normal (often at the lower limit) growth velocity, no biochemical or other evidence for a specific growth retarding condition, normal serum concentrations of insulin-like growth factor-I (IGF-I) and IGF binding protein-3, and normal growth hormone responses to pharmacologic agents that lead to growth hormone release.

PATTERNS OF ABNORMAL GROWTH

• The most common causes of short stature beyond the first year or two of life are familial (genetic) short stature and delayed (constitutional) growth.

• The latter may have a genetic basis, because there is often another close family member in whom growth was delayed.

• The shortest children often have both of these variants of normal growth.

• Although there is considerable individual variability, the size at birth in children with these disorders is usually normal.

• However, a downward shift in growth begins at three to six months that is often indistinguishable from that in normal children (lag-down growth) but tends to be more severe and more prolonged .

• Many of these children have normal growth velocity by the third or fourth year, and then continue to grow below, but parallel to, the third percentile .

• There are multiple ways in which to categorize slow growth and the resulting short stature, but it is the abnormal growth rate (the trajectory along the growth chart) that is more relevant than the issue of whether a child is short or not (see above).

• I use a classification based upon the relationship between chronologic age, height age, weight age, bone age, and growth rate.

• Intrinsic shortness — Intrinsic shortness is characterized by inherent limitations of bone growth and predicts adult short stature.

• Delayed growth — Delayed growth is defined as a bone age closer to height age than chronologic age and predicts "normal" adult stature.

• Attenuated growth — Attenuated growth is characterized by a growth rate that is so slow that the child progressively deviates from a previously defined growth channel (or percentile).

• Because the height age approximates the bone age, adult height potential is often normal, but only after remedial action is taken for one of the many possible causes.

DISEASES THAT MAY CAUSE GROWTH FAILURE AND SHORT

STATURE • Renal disease • Metabolic acidosis • Cancer • Glucocorticoid therapy • Pulmonary disease • Cardiac disease • Gastrointestinal disease • Immunologic disease • Metabolic and endocrine diseases

• Renal disease — Growth failure in children with renal disease is multifactorial.

• Implicated factors include metabolic acidosis, uremia, poor nutrition secondary to dietary restrictions, anorexia of chronic illness, anemia, calcium and phosphorus imbalance, renal osteodystrophy and potential adverse effects on the serum concentrations of growth factors and their binding proteins.

• Metabolic acidosis alone can also impair growth, as occurs in children with renal tubular acidosis .

• Alkali therapy may lead to attainment and maintenance of normal stature.

• Cancer — Children with cancer may grow poorly before diagnosis because of poor food intake, nausea, vomiting, and increased caloric utilization.

• After diagnosis, anorexia, nausea, and vomiting induced by chemotherapy and radiotherapy also can contribute to impaired growth.

• These effects of treatment often subside by one to two years, and some children then have catch-up growth.

• Late growth failure is common in children who received cranial radiotherapy (and perhaps chemotherapy), because it causes growth hormone (GH), gonadotropin, and sometimes thyrotropin deficiency .

• In younger children, especially girls, cranial radiotherapy can cause precocious puberty and adult short stature.

• Primary hypothyroidism also can occur if the thyroid gland was in the radiation field. Spinal irradiation may result in slow growth of the spine, with relative sparing of limb growth.

• Glucocorticoid therapy — Glucocorticoids exert multiple growth-suppressing effects, interfering with endogenous growth hormone secretion, bone formation, nitrogen retention, and collagen formation .

• The impairment in growth is most pronounced with daily therapy, may be less pronounced with an alternate-day regimen, and even can occur with inhaled glucocorticoids .

• As an example, one report evaluated the effect of seven months of relatively low-dose inhaled beclomethasone dipropionate (400 mcg/day) in 7- to 9-year-old children with mild asthma .

• Treatment had no effect on overnight urinary cortisol excretion, but did reduce growth velocity (0.79 versus 1.14 mm/week).

• At the end of the seven months of therapy, children receiving beclomethasone had grown 1 cm less than those in the placebo group.

• The growth-impairing effects of glucocorticoids may persist after therapy is discontinued.

• In a study of 224 children with cystic fibrosis who previously had been treated for up to four years with either alternate-day prednisone or placebo, mean height after age 18 years (on average six to seven years after cessation of therapy) was significantly lower in boys who had received either high- or low-dose prednisone (170.5 and 170.7 versus 174.6 cm with placebo; p = 0.03) .

• This effect was most pronounced in boys who had started taking prednisone at 6 to 8 years of age.

• In contrast, there was no persistent growth impairment in girls treated similarly.

• Pulmonary disease — Asthma is the most common chronic pulmonary disease in children. Severe asthma alone probably results in slow growth, but it is slowed more by treatment, especially with glucocorticoids.

• Cystic fibrosis is both a pulmonary and gastrointestinal disease. Growth failure is multifactor in this disorder as poor food intake, increased fecal losses becuase of maldigestion or malabsorption, chronic infection, and increased energy requirements (work of breathing) can all contribute.

• Cardiac disease — Growth failure is common in children with severe heart disease of any cause. The major pathogenetic factors are thought to be anorexia and increased basal energy requirements .

• Gastrointestinal disease — Celiac disease is a prime example of a remediable cause of short stature, especially in younger children .

• Children with growth failure resulting from gastrointestinal disease have a greater deficit in weight than height (ie, they are underweight-for-height) in contrast to those with endocrine disorders who are often overweight-for-height .

• Older children with inflammatory bowel disease, especially Crohn's disease, may present with growth failure before the onset of gastrointestinal symptoms.

• Immunologic disease — Renewed interest in immunologic causes of growth retardation has come with the AIDS epidemic. However, it is difficult to attribute growth failure to the infection or its immunologic consequences, because anorexia, malabsorption, diarrhea, severe infections, and failure of one or more organ systems are so common in these patients .

• Growth failure also can occur with other immunological deficiencies such as the severe combined immunodeficiency syndrome. As with HIV infection, multiple factors are probably involved.

• Metabolic and endocrine diseases — Growth failure is common in children and adolescents with many of the inborn disorders of metabolism.

• Among acquired metabolic diseases, the most common is autoimmune diabetes mellitus.

• Diabetes was, in the past, an important cause of short stature and attenuated growth because of caloric deficit resulting from severe glucosuria .

• However, it is now rare because of improvements in therapy.

• Although children with fair-to-good metabolic control have some decrease in insulin-like growth factor-1 (IGF-1) production or action, their growth is usually normal.

• Any disorder associated with vitamin D deficiency or decreased vitamin D action can cause hypophosphatemia and rickets, which is characterized by abnormal epiphyseal development, bowing of the extremities, and poor growth.

• Other common endocrine causes of growth failure and short stature are hypothyroidism, hypopituitarism (isolated GH deficiency or multiple anterior pituitary hormone deficiencies), and hypercortisolism (Cushing's syndrome, exogenous and endogenous).

• GH deficiency usually results from deficiency of growth hormone-releasing hormone (GHRH), but can be because of sellar and parasellar tumors (eg, germinoma ) that destroy the pituitary gland itself.

• These children can have striking catch-up growth after surgical treatment or during GH replacement therapy .

• A rare cause is an inactivating mutation of the GHRH receptor that is inherited in an autosomally recessive manner .

• Hypothyroidism is a well-recognized cause of growth failure that may be an early or the major manifestation of hypothyroidism in children.

• The skeletal age is usually as delayed as the height age; as a result, many children with hypothyroidism have a reasonably normal growth potential.

• Cushing's syndrome in children is most often iatrogenic, because of glucocorticoid therapy for asthma, inflammatory bowel disease, or immunologic renal disease.

• Endogenous Cushing's syndrome is uncommon in children, but should be considered if the child has both weight gain and growth retardation, ie, is overweight-for-height .

DIAGNOSIS OF ENDOCRINE

CAUSES OF GROWTH FAILURE • Hypothyroidism — Thyroid function should al

ways be evaluated, because growth failure may be the first or even the only manifestation of hypothyroidism.

• The evaluation should include measurements of both serum thyrotropin (TSH) and thyroxine; both primary and central hypothyroidism can cause growth failure, and measurement of serum TSH alone will not detect central hypothyroidism.

• Cushing's syndrome — Cushing's syndrome is rare in children except when due to the toxicity of glucocorticoid therapy.

• It is initially a clinical diagnosis that is suggested by the clinical findings and then confirmed by biochemical and imaging tests.

• The following findings were noted in a review of 59 patients with Cushing's syndrome who were between the ages of 4 and 20 years :

• A corticotropin (ACTH)-secreting pituitary adenoma (Cushing's disease) is by far the most common cause, accounting for 50 cases.

• The two major findings are weight gain (90 percent) and growth retardation (83 percent); bone age was normal at diagnosis in most patients.

• Growth hormone deficiency — If growth hormone deficiency is congenital and complete, the diagnosis is relatively easy to confirm.

• Affected children present with severe growth failure, delayed bone age, and very low serum concentrations of growth hormone, IGF-I, and its major binding protein, IGF-binding protein-3.

• The rare children with growth hormone insensitivity have high serum growth hormone concentrations but low serum IGF-I and IGF binding-protein-3 concentrations.

• In its complete form, this condition is called Laron-type dwarfism (complete growth hormone insensitivity).

Treatment of growth hormone deficiency in

children • PREPARATIONS OF GROWTH HORMO

NE FOR THERAPY — Seven pharmacologic preparations are approved for treatment of growth hormone deficiency in children, and others are still being tested:

• Aqueous solutions of growth hormone for subcutaneous administration.

• Several brands of growth hormone have been available for subcutaneous administration for many years, and most information about growth hormone treatment comes from these preparations.

• Most are available in multiple-dose pen devices that materially aid in administration.

• Daily therapy is more effective than three times a week at the same dose .

• The recommended dose of growth hormone in children with growth hormone deficiency is 0.04 mg/kg per day.

• Children with chronic kidney disease or Turner's syndrome are given slightly higher doses because they have a degree of growth hormone resistance.

• Growth hormone encapsulated in biodegradable glycolide microspheres for deep subcutaneous administration.

• This formulation was approved by the United States Food and Drug Administration in January 2000.

• In a study of 74 children with growth hormone deficiency, either 1.5 mg/kg body weight once a month or 0.75 mg/kg twice a month significantly increased linear growth compared with the pretreatment rate, but this formulation was not compared with a subcutaneous formulation .

• Local reactions at the injection site were common; 60 percent of injections resulted in subcutaneous nodules and 36 percent in postinjection pain.

• This product has been removed from the market.

• Synthetic growth hormone-releasing hormone (sermorelin, Geref®) is an approved treatment for children whose pituitaries are capable of releasing growth hormone .

• It is about one-half as expensive as growth hormone but, in the recommended doses, may be somewhat less effective .

• This product has been removed from the market.

• Several growth hormone-releasing peptides (GHRP) or nonpeptide analogs (some active orally) are being evaluated in growth hormone-deficient children and adults .

• It is too early to determine their long-term efficacy and safety.

The End

• Thank for your attention.