Growth hormone (GH) deficiency is the most frequent deficiency of the pituitary hormone in children and can be isolated or accompanied by the deficiency of other pituitary hormones. GH deficiency in children generally produces abnormally slow growth and short stature, with normal proportions. The diagnosis consists in the measurement of pituitary hormone levels and MRI to detect structural abnormalities of the pituitary gland or brain tumors. The treatment usually consists of specific hormone replacement and the elimination of any causative tumor.
Patients with GH deficiency associated with generalized hypopituitarism will also have the deficiency of one or more of other pituitary hormones (eg, follicle-stimulating hormone, luteinizing hormone, adrenocorticotrophic hormone [ACTH], thyrotrophin, antidiuretic hormone [ADH]).
GH deficiency can occur alone or in association with generalized hypopituitarism. In both cases, GH deficiency can be acquired or congenital (and includes hereditary genetic causes). Rarely, GH is not deficient but GH receptors are abnormal (insensitivity to GH).
The isolated deficiency of GH is estimated to occur in 1/4000 to 1 / 10,000 children. It is usually idiopathic, but about 25% of patients have an identifiable etiology. Congenital causes include abnormalities of the GH1-releasing hormone receptor and GH1 gene and certain malformations of the CNS. Acquired causes include therapeutic CNS radiation (high doses of radiation can cause generalized hypopituitarism), meningitis, histiocytosis, and brain injury. Irradiation of the spine, be it prophylactic or therapeutic, may additionally compromise the potential growth of the vertebrae and put weight gain at risk.
The generalized hypopituitarism can have genetic causes, which involve hereditary or sporadic mutations that affect the cells of the pituitary gland. In these cases, there may also be abnormalities of other organ systems, especially defects in the midline, such as cleft palate or septo-optic dysplasia (which may include the absence of septum pellucidum, optic nerve atrophy, and hypopituitarism). Generalized hypopituitarism can also be acquired by many types of lesions that affect the hypothalamus or pituitary gland; examples include tumors (eg, most commonly craniopharyngioma), infections (eg, tuberculosis, toxoplasmosis, meningitis), and infiltrating disorders. The combination of bone lesions or lytic cranial with diabetes insipidus suggests a histiocytosis of Langerhans cells (seeHistiocytosis of Langerhans cells ).
Signs and Symptoms
The manifestations depend on the age of the patient, the underlying etiology, and the specific hormone deficiencies.
GH deficiency usually manifests as lack of growth sometimes along with delayed teeth development. The height is below the 3rd percentile and the growth rate is < 6 cm / year before 4 years, < 5 cm / year between 4 and 8 years and < 4 cm / year before puberty. Although of short stature, children with hypopituitarism retain the proportions between the upper and lower segments of the body. Skeletal maturation, assessed through the determination of bone age, is > 2 years less than the chronological age.
Other abnormalities may be present, depending on the underlying defect, and the child may have a delay or absence of pubertal development. Weight gain may be out of proportion with growth, resulting in relative obesity. Newborns who have congenital defects of the pituitary gland or hypothalamus may have hypoglycemia (which may also occur in older children), midline defects (eg, cleft palate), or micropenis, as well as other manifestations. endocrine deficiencies.
- Clinical evaluation, which includes growth criteria and other clinical history
- Factor concentrations like growth insulin -1 (IGF-1) and IGF binding protein type 3 (IGFBP-3)
- In general, confirmation with provocation tests
- Evaluation of other pituitary hormones and other causes of poor growth
The current consensus guidelines for the diagnosis of GH deficiency require the integration of the results of growth criteria, clinical history, laboratory tests, and images.
The growth is evaluated; height and weight data should be plotted on a growth chart (auxological evaluation) in all children.
The measurement of IGF-1 and IGFBP-3 levels begins the evaluation of the GH / IGF-1 axis.
In intermediate or late infancy, IGF-1 concentrations that reflect GH activity should be measured, because GH concentrations are highly variable and difficult to interpret. Because IGF-1 levels are elevated at puberty, they should be interpreted in relation to bone age rather than chronological age. The finding of normal concentrations of IGF-1 helps to exclude a deficiency of GH. However, IGF-1 concentrations are low in diseases other than GH deficiency, such as psychosocial deprivation, malnutrition, and hypothyroidism.
During infancy and early childhood, IG-1 levels are usually low and therefore do not allow a reliable distinction between normal and subnormal values in these age groups. However, levels of IGFBP-3 (the main IGF peptide transporter), unlike IGF-1, are less affected by malnutrition and allow discrimination between normal and subnormal in younger children.
In children with low IGF-1 and IGFBP-3 levels, GH deficiency is usually confirmed by measuring GH concentrations. As the typical basal GH concentrations are low or undetectable (except in the period after sleep conciliation), random concentrations of GH are not useful and their evaluation requires provocation tests (see Growth hormone deficiency in children). : Proof of provocation ). However, these tests are not physiological, are subject to laboratory errors and are not reproducible. In addition, the definition of a normal response varies by age, sex, and testing center and is based on limited evidence.
Imaging studies are performed when the growth is abnormal, bone age must be determined with a left-hand x-ray (by convention). In GH deficiency, skeletal maturation is usually delayed by the same proportion as height. With GH deficiency, evaluation of the pituitary gland and sella with CT or MRI should be indicated to exclude calcifications and tumors. The sella turcica is abnormally small in 10 to 20% of patients.
Laboratory screening tests are done to look for other possible causes of low growth, which include
- Hypothyroidism (eg, thyrotrophin, thyroxine)
- Kidney disorders (electrolytes, creatinine levels)
- Inflammatory and immune conditions (eg, tissue anti-transglutaminase antibodies, ESR)
- Hematological disorders (eg, blood count with differential)
Genetic testing for specific syndromes (eg, Turner syndrome) may be indicated by physical findings or if the growth pattern differs significantly from the family. If severe GH deficiency is suspected, additional tests of pituitary function are performed (eg, ACTH, serum cortisol level at 8 a.m., luteinizing hormone, follicle-stimulating hormone, and prolactin levels).
Proof of Provocation
As the GH responses are usually abnormal in patients with decreased thyroid or adrenal function, they should only undergo provocation testing after implementing adequate hormone replacement.
The insulin tolerance test may be the most effective provocation test for the stimulation of GH secretion but it is rarely done because it is risky. Other provocative tests are less dangerous but also less reliable. These include tests that use infusion of arginine (500 mg / kg IV administered in 30 min), clonidine (0.15 mg / m 2 VO [maximum 0.25 mg]), levodopa (10 mg / kg VO for children; 500 mg VO for adults) and glucagon (0.03 mg / kg IV [maximum 1 mg]). GH levels are measured at different times after drug administration depending on the drug.
Since no test is 100% effective in stimulating GH secretion, two provocative tests are performed (usually on the same day). GH concentrations usually reach a maximum value between 30 and 90 minutes after insulin administration or from the beginning of the insulin infusion, between 30 and 120 minutes after the administration of levodopa, between 60 and 90 minutes after the clonidine, and 120 to 180 minutes after the glucagon. The response of the GH that is considered normal is somewhat arbitrary. In general, whenever a stimulated concentration of GH> 10 ng / mL is detected, this should be considered sufficient to discard a GH deficiency. GH deficiency can be considered for responses <10 ng / mL (some centers use a lower cutoff, eg, 7 ng / mL) to two pharmacological stimuli, but the results should be interpreted in the context of auxological data. Because GH levels increase during puberty,
Provocation tests may not detect subtle defects in the regulation of GH secretion, for example in children with short stature due to a dysfunction in GH secretion, in which the results of these tests are usually normal. However, serial measurements of GH concentrations for 12 to 24 hours indicate an abnormally low integrated GH secretion over a 12 or 24 hour period. However, this test is expensive and uncomfortable and therefore is not the test of choice for GH deficiency.
If the decrease in GH secretion is confirmed, tests of secretion of other pituitary hormones and (if abnormal) hormones on which they act in the corresponding peripheral endocrine glands should be performed together with imaging studies of the pituitary gland if previously made.
- Recombinant GH supplements
- Sometimes, replacement of other pituitary hormones
Recombinant GH is indicated in all children with short stature and documented GH deficiency. The dose usually ranges between 0.03 and 0.05 mg/kg subcutaneously once a day. With the treatment, the height growth rate usually increases up to 10 to 12 cm/year in the first year and, although it increases more slowly thereafter, it remains above the speed prior to treatment. The therapy is continued until reaching an acceptable height or until the growth rate falls below 2.5 cm/year.
Adverse effects of GH therapy are few but include idiopathic intracranial hypertension (pseudotumor cerebri-see idiopathic intracranial hypertension ), dislocation of the epiphysis of the femoral head (see Upper femoral epiphysiolysis (EFS) ) and transient mild peripheral edema. Before the development of recombinant GH, GH extracted from pituitary glands was used. Very rarely, this preparation produced Creutzfeldt-Jakob disease between 20 and 40 years after treatment (see Creutzfeldt-Jakob Disease (CJD) ). The GH extracted from the pituitary gland was used for the last time in the decade of the 1980s.
Controversies exist as to whether children with short stature with clinical characteristics of GH deficiency but with normal GH secretion and normal concentrations of IGF-1 should be treated with GH. Many experts recommend a therapeutic trial with GH for 6 to 12 months, and its continuation only if a doubling of growth or an increase of 3 cm/year is observed with respect to the height growth rate prior to treatment. Other experts reject this test because it is expensive and experimental, can cause adverse effects, labels healthy children as abnormal and generate ethical and psychosocial dilemmas in a current called “altruism”.
When other pituitary hormone deficiencies accompany GH deficiency, additional hormone replacement is required. Cortisol and thyroid hormone should be replenished throughout childhood, adolescence, and adulthood when circulating levels of these hormones are low. Diabetes insipidus usually requires lifelong treatment with desmopressin in the form of tablets or intranasal. When the patient does not experience puberty in a normal manner, treatment with gonadal sex steroids should be indicated.
GH therapy in children with short stature secondary to radiotherapy of the pituitary gland for the treatment of cancer is associated with the theoretical risk of causing cancer recurrence. However, the studies did not show a higher than expected incidence of new cancers or a higher recurrence rate. It is likely that the replacement of GH could be instituted safely for at least one year after the completion of antineoplastic treatment.
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