pediatrics
Growth Hormone Deficiency in Children
Diagnosis of Growth Hormone Deficiency
Auxologic assessment (height and weight data recorded on a growth chart) Imaging studies Insulin-like growth factor 1 (IGF-1) levels and IGF binding protein type 3 (IGFBP-3) levels Usually confirmation by provocative testing Evaluation of other pituitary hormones and for other causes of poor growth Current consensus guidelines for diagnosis of growth hormone deficiency require integration of growth criteria, medical history, laboratory testing, and imaging test results. Growth is assessed;data for height and weight should be plotted on a growth chart (auxologic assessment) for all children. (For children 0 to 2 years, seeWorld Health Organization [WHO] Growth Charts; for children 2 years and older, seeCenters for Disease Control and Prevention [CDC] Growth Charts.) Measurement of IGF-1 and IGFBP-3 levelsbegins the assessment of the GH/IGF-1 axis. IGF-1 reflects GH activity, and IGFBP-3 is the major carrier of IGF peptides. Levels of IGF-1 and IGFBP-3 are measured because GH levels are pulsatile, highly variable, and difficult to interpret. IGF-1 levels vary by age and should be interpreted relative to bone age rather than to chronologic age. IGF-1 levels are lowest in infancy and early childhood (< 5 years) and thus do not reliably discriminate between normal and subnormal in these age groups. At puberty, IGF-1 levels rise and normal levels help exclude GH deficiency. Low IGF-1 levels in older children suggest GH deficiency; however, IGF-1 levels are low in conditions other than GH deficiency (eg, emotional deprivation, Evaluation , In children with low levels of IGF-1 and IGFBP-3, GH deficiency is usually confirmed by measuring GH levels. Because basal GH levels are typically low or undetectable (except after the onset of sleep), random GH levels are not useful and assessment of GH levels requires Provocative testing . However, provocative testing is nonphysiologic, subject to laboratory variation, and poorly reproducible. Also, the definition of a normal response varies by age, sex, and testing center and is based on limited evidence. Treatment of GH deficiency should not be based solely on the results of provocative testing. Imaging studiesare done when growth is abnormal; bone age should be determined from an x-ray of the left hand (by convention). In GH deficiency, skeletal maturation is usually delayed to the same extent as height. With GH deficiency, evaluating the pituitary gland and hypothalamus with MRI is indicated to rule out calcifications, tumors, and structural anomalies. Screening laboratory testsare done to look for other possible causes of poor growth, including Hypothyroidism (eg, thyroid-stimulating hormone, thyroxine) Renal disorders (eg, electrolytes, creatinine levels) Inflammatory and immune conditions (eg, tissue transglutaminase antibodies, C-reactive protein) Hematologic disorders (eg, complete blood count with differential) for specific syndromes (eg, Diagnosis ) may be indicated by physical findings or if growth pattern differs significantly from family. If GH deficiency is highly suspected, additional tests of pituitary function are done (eg, ACTH, 8 AM serum cortisol level, LH, FSH, and prolactin levels). Random growth hormone levels are of little use in diagnosing growth hormone deficiency. Because GH responses are typically abnormal in patients with diminished thyroid or adrenal function, provocative testing should be done in these patients only after adequate hormone replacement therapy. Theinsulintolerance test is the best provocative test for stimulating GH release but is rarely done because of the risks of hypoglycemia. Other provocative tests are less dangerous but also less reliable. These include tests usingarginineinfusion (500 mg/kg IV given over 30 minutes),clonidine(0.15 mg/m2orally [maximum 0.25 mg]),levodopa(10 mg/kg orally for children; 500 mg orally for adults), andglucagon(0.03 mg/kg IV [maximum 1 mg]). GH levels are measured at different times after drug administration depending on the drug. Because no single test is 100% effective in eliciting GH release ( Provocative testing reference ), two GH provocation tests are done (typically on the same day). GH levels generally peak 30 to 90 minutes after administration of The GH response that is considered normal is somewhat arbitrary. Generally, any stimulated GH level > 10 ng/mL (> 10 mcg/L) is sufficient to rule out classic GH deficiency. GH deficiency may be considered for responses < 10 ng/mL (< 10 mcg/L; some centers use a lower cutoff, eg, 7 ng/mL [7 mcg/L]) to two pharmacologic stimuli, but results must be interpreted in the context of auxologic data. Because of the arbitrary nature of thresholds for normal results on provocative GH tests, children with otherwise unexplained short stature and normal provocative GH test results may be considered to have GH deficiency if they meet most of the following criteria: Height > 2.25 standard deviations (SD) below the mean for age or > 2 SD below the midparental height percentile Growth velocity < 25th percentile for bone age Bone age > 2 SD below the mean for age Low seruminsulin-like growth factor 1 (IGF-1) and IGF binding protein type 3 (IGFBP-3) levels Other clinical features suggesting growth hormone deficiency Because GH levels rise during puberty, many children who fail provocative GH stimulation testing before puberty may have normal results after puberty or when primed with gonadal steroids. To avoid unnecessary treatment of children with constitutional delay, sex steroid priming before provocative GH testing may be considered in prepubertal boys > 11 years of age and in prepubertal girls > 10 years of age with adult height prognosis within -2 standard deviations of the reference population mean. Priming protocols for both boys and girls suggest beta-estradiol2 mg (1 mg for body weight < 20 kg) orally on each of the two nights before the test or, for boys, a depot formulation oftestosterone50 to 100 mg IM 1 week before the test. Provocative testing may not detect subtle defects in the regulation of GH release. For example, in children with short stature secondary to GH secretory dysfunction, results of provocative testing for GH release are usually normal. However, serial measurements of GH levels over 12 to 24 hours indicate abnormally low 12- or 24-hour integrated GH secretion. However, this test is expensive and uncomfortable and thus is not the test of choice for GH deficiency. If diminished GH release is confirmed, tests of secretion of other pituitary hormones and (if abnormal) hormones of their target peripheral endocrine glands along with pituitary imaging studies must be done if not done previously. 1.Kamoun C, Hawkes CP, Grimberg A: Provocative growth hormone testing in children: How did we get here and where do we go now?J Pediatr Endocrinol Metab34(6):679–696, 2021. doi: 10.1515/jpem-2021-0045 