IGF deficiency: GH deficiency
a deficiency of IGF levels and concomitant alterations in serum concentrations of IGFBPs suggests an abnormality of GH secretion or activity and makes necessary a thorough evaluation of hypothalamic-pituitary-IGF function.
Thus, even in children below the 5th percentile in height (which, obviously, applies to 5% of the normal population), documentation of a normal height velocity (above the 25th percentile for several years) makes the diagnosis of IGF deficiency and GHD highly unlikely.
Stimulation tests have often been divided into “screening tests” (exercise, fasting, levodopa, clonidine), which are characterized by ease of administration, low toxicity, low risk, and low specificity) and “definitive tests” (arginine, insulin, glucagon).
It is generally accepted that a child must “fail” provocative tests with at least two separate stimuli to be considered as having GHD.
Despite the many problems with GH measurements described above, there continues to be a value in determination of GH secretory capacity in the diagnostic evaluation of a child with IGF deficiency. Documentation of normal (or increased) GH levels is necessary in discriminating between primary and secondary IGF deficiency. The documented presence of GH deficiency should alert the clinician to the possibility of other pituitary deficiencies.
An alternative means of diagnosing GHD is the assessment of IGF-I and -II and their binding proteins. [261] [262] [264] [290] GHD then becomes part of the differential diagnosis of IGF deficiency, which includes hypothalamic dysfunction, pituitary insufficiency, and GHI. With the development of sensitive and specific assays for IGF-I, IGF-II, and the IGFBPs, it has become clear that these peptides accurately reflect integrated GH status of pediatric patients. Furthermore, IGF-I and -II normally circulate in serum in sufficiently high levels that assay sensitivity is not an issue. Serum levels of both peptides are relatively constant during the day so that provocative testing or multiple sampling is not necessary. Even when these caveats are considered, the correlation between serum IGF-I levels and provocative or spontaneous GH measurements is imperfect. In a group of children younger than 10 years of age, IGF-I levels were below -2 SD in only 8/15 children with a diagnosis of GHD based upon provocative testing (53.3% sensitivity), and normal in 47/48 children with a normal GH response (97.9% specificity).[
The utility of IGFBP-3 assays in the diagnosis of GHD was evaluated by Blum and colleagues,[488] who found that serum IGFBP-3 levels were below the 5th percentile for age in 128/132 of children (97%) diagnosed with GHD by conventional criteria (height less than 3rd percentile, height velocity less than 10th percentile, and peak serum GH less than 10 μg/L.
Recommendations by the GH Research Society (GRS)[1276] for defining GHD recognize no “gold standard” for that diagnosis and propose that in a child with slow growth, whose history and auxology suggest GHD ( Table 23-9 ), testing for GH/IGF-I deficiency requires the measurement of IGF-I and IGFBP-3 levels as well as GH provocation tests (after hypothyroidism has been excluded).
Some patients with auxology suggestive of GHD, however, may have IGF-I and/or IGFBP-3 levels below the normal range on repeated tests but GH responses in provocation tests above the “cutoff” level. Such children do not have classical GHD but nonetheless may have an abnormality of the GH-IGF axis and, after the exclusion of systemic disorders affecting the synthesis or action of IGF-I, could be considered for GH treatment.
TABLE 23-9 -- KEY HISTORY AND PHYSICAL EXAMINATION FINDINGS THAT MAY INDICATE THAT GROWTH HORMONE DEFICIENCY COULD BE PRESENT (THE GRS 2000 CRITERIA[1276])
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Children with Turner's syndrome and short stature should not be required to undergo GH testing to qualify for GH therapy, because such treatment is not predicated on abnormal GH secretion.
The diagnosis of GHD in a newborn is especially challenging. The presence of micropenis in a male newborn should always lead to an evaluation of the GH-IGF axis
There remains a large cadre of short children in whom the cause of their diminished stature is unknown or “idiopathic.” Many children and early adolescents are short (<3rd>. Such children usually have normal GH secretory dynamics, although provocative tests may be blunted under some circumstances. GH-dependent peptides are frequently (but not invariably) lower than expected on a chronologic though often not skeletal age basis. Treatment with exogenous GH usually augments linear growth. These children have often been considered variants of normal growth and, if untreated, may achieve a final adult height within the range considered acceptable for the family. It should be noted, however, that many of these children are as short as those with GHD and so cannot simply be considered “normal, short children.” The etiology of the slowed childhood growth and frequently delayed pubertal spurt has not been established in most of these children. As this is the largest group of short children, continuing efforts are underway to develop a rational categorization and to develop the means of defining these children within the possible abnormalities of the GH-IGF axis. Multiple groups of patients are included in this broad category, including those with constitutional delay of growth and maturation and so-called genetic or familial short stature. The genetic characterization of the former syndrome, with an emphasis upon the timing and tempo of pubertal onset and progression, is beyond the scope of this chapter. Familial short stature, while not usually in the range of the dramatic genetic syndromes resulting in extremely poor growth described above, generally results in an adult whose height is close to or below the bottom of the normal range, but appropriate for family. It must be noted that this should not be considered totally reassuring, because there is growing recognition of subtle genetic defects contributing to growth failure and masquerading as “benign” familial short stature. ISS is the remaining large but uncharacterized group of children. These children presumably have more subtle disorders of the hypothalamic-pituitary-IGF axis [907] [928] than those described in the discussion of primary IGFD (see Table 23-10 ). Heterozygous mutations throughout the growth system, a relatively greater preponderance of blockers of the GH-signaling cascade, such as enhanced intracellular phosphatase activity and production of such signaling factors as SOC2 and CIS, and gene-mediated alterations in patterns of GH or IGF production await to be described.
The term constitutional delay [1285] [1286] describes children with a normal variant of maturational tempo characterized by short stature but relatively normal growth rates during childhood, delayed puberty with a late and attenuated pubertal growth spurt, and attainment of normal adult height. Most children with constitutional delay begin to deviate from the normal growth curve during the early years of life and by age 2 years are at or slightly below the 5th percentile for height.[1287] During midchildhood years, height SDS may gradually drift lower, but this does not appear to affect adult height outcome.
Final height, though usually within the normal population range, is often in the lower part of the parental height target zone, [1289] [1290] [1291] with few patients exceeding that target height. The predicted final height, especially when the skeletal age is extremely delayed, is greater than that usually achieved, but is difficult to reliably anticípate.
TABLE 23-11 -- CRITERIA FOR PRESUMPTIVE DIAGNOSIS OF CONSTITUTIONAL DELAY OF GROWTH AND MATURATION
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Genetic (Familial) Short Stature
Nonetheless, a constellation of clinical findings describes a normal variant referred to as genetic short stature (GSS) (or familial short stature) that differs from the syndrome of constitutional delay of growth and maturation discussed above. In GSS, childhood growth 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 chronologic age. Parental height is short (both parents are often below the 10th percentile) and pubertal maturation is normal. Final heights in these individuals are short and in the target zone for the family.[1291] The GH-IGF system is normal, but exogenous GH therapy during middle childhood years may increase linear growth velocity substantially without disproportionate augmentation of skeletal maturation. Whether long-term GH treatment enhances final height outcome, however, is not clear.
Growth hormone in idiopatic short stature
Growth Hormone Therapy
Gains in Height
Available data suggest that growth hormone therapy increases adult height between 3 and 6 cm in children with idiopathic short stature, but such growth requires long-term therapy. In studies demonstrating the efficacy of growth hormone therapy for this indication, the mean duration of therapy was four to seven years.6,8,9,29 A meta-analysis of the efficacy of growth hormone
therapy in children with idiopathic short stature identified only four controlled studies and six uncontrolled studies with data regarding adult height.6 After growth hormone therapy (at doses
of 0.25 to 0.40 mg per kilogram of body weight per week) or observation for a mean of 5.3 years
in 118 patients in controlled studies, the adult height in the group that was treated with growth
hormone was 5 to 6 cm greater than that of the untreated controls and 3.6 to 4.6 cm greater than the height predicted at baseline. In the eight uncontrolled studies with data regarding adult height for 246 patients, growth hormone treatment (at a dose of 0.14 to 0.33 mg per kilogram per week) for a mean of 4.7 years resulted in a gain of 3.8 to 4.5 cm in adult height above the height predicted at baseline. Higher doses of growth hormone may confer a greater benefit. A European study compared adult heights of 17 patients treated with growth hormone that was administered six times a week at a mean dose of 0.37 mg per kilogram per week for 7.0 years to that of 17 patients treated with a dose of 0.24 mg per kilogram per week for 6.1 years.9 In comparison with their baseline predicted adult height, the children who were treated with
the higher dose had a significantly greater gain in adult height (7.2 cm, as compared with 5.4 cm for the group that received a lower dose). Moreover, daily administration of growth hormone has been shown to be more efficacious than administration three times per week.
A recent economic analysis, based on the approved dosing guidelines and published efficacy data regarding adult height, calculated that the current cost of growth hormone therapy for five years is $52,000 per incremental inch of height gained.50 Because of the exorbitant cost and the large number of children whose height falls below the 1.2 percentile who theoretically qualify for therapy, the use of growth hormone in idiopathic short stature generates questions about the equitable distribution of health care resources and the economic effect on the health care system
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