Pituitary nanism (hypopituitarism) in children

The metabolic effects of somatotropic hormone (STH) are complex and manifest themselves depending on the point of application. Growth hormone is the main hormone stimulating linear growth. It promotes bone growth in length, growth and differentiation of internal organs, and development of muscle tissue.

Growth hormone deficiency develops as a result of a primary disruption in the secretion of growth hormone at the pituitary gland or as a result of a disruption in hypothalamic regulation.

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Causes of pituitary anism in a child.

The growth of the organism is controlled by a large number of factors. Growth retardation can be caused by genetic defects in endocrine regulation, somatic chronic diseases, and social disadvantage. Hormonal regulation of growth processes is carried out by the interaction of somatotropin, thyroid hormones, insulin, glucocorticoids, adrenal androgens, and sex hormones. Insufficiency of one of them (reduced secretion or impaired reception) can determine one or another clinical variant of growth retardation.

The etiology of hypopituitarism is very diverse.

• Congenital growth hormone deficiency.
  • Hereditary (pathology of the growth hormone gene, pituitary transcription factor, STH-RH receptor gene).
  • Idiopathic GH-RH deficiency.
  • Defects in the development of the hypothalamic-pituitary system.
• Acquired growth hormone deficiency.
  • Tumors of the hypothalamus and pituitary gland (craniopharyngioma, hamartoma, neurofibroma, germinoma, pituitary adenoma).
  • Tumors of other parts of the brain (optic chiasm glioma).
  • Injuries.
  • Infectious diseases (viral, bacterial encephalitis and meningitis, nonspecific hypophysitis).
  • Suprasellar arachnoid cysts, hydrocephalus.
  • Vascular pathology (aneurysms of the pituitary vessels, pituitary infarction).
  • Head and neck irradiation.
  • Toxic effects of chemotherapy.
  • Infiltrative diseases (histiocytosis, sarcoidosis).
  • Transient (constitutional delay in growth and puberty, psychosocial dwarfism).
• Peripheral resistance to the action of growth hormone.
  • Pathology (mutations) of the growth hormone receptor gene (Laron syndrome, African pygmy dwarfism).
  • Biologically inactive growth hormone.
  • Insulin-like growth factor (IGF-1) resistance.

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Pathogenesis

Growth hormone deficiency leads to decreased synthesis of insulin-like growth factors (protein synthesis stimulators), fibroblast growth factor (stimulates division of cartilage cells, connective tissue of ligaments, joints), epidermal growth factor of the skin, platelet growth factors, leukocytes, erythropoietin, nerves, etc. in the liver, kidneys and other organs. Glucose utilization decreases, lipolysis and gluconeogenesis are inhibited. Decreased secretion of gonadotropins, TSH, ACTH leads to decreased function of the thyroid gland, adrenal cortex, gonads.

Combined deficiency of growth hormone, TSH and prolactin, caused by a genetic defect of the Pit-1 gene (or pituitary-specific transcription factor), leads to the appearance of symptoms of hypothyroidism against the background of significant growth retardation; bradycardia, constipation, dry skin, and lack of sexual development may be observed.

Genetic defect of the Prop-1 gene is accompanied by deficiency of prolactin, TSH, ACTH, luteotropic (LH) and follicle-stimulating hormone (FSH) secretion along with growth hormone deficiency. When Pit-1 and Prop-1 genes are disrupted, growth hormone deficiency develops first, followed by disruption of secretion of other adenohypophysis hormones.

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Symptoms of pituitary anism in a child.

Patients without visible pituitary gland damage against the background of a sharp growth retardation, growth rate delay and bone maturation are characterized by normal body proportions. The pediatrician should draw a growth curve for each child with growth deficiency. Growth retardation is noticed in some children by the end of the year, but more often the growth retardation becomes obvious and reaches three standard deviations from the average height of peers by 2-4 years. Small facial features, thin hair, high voice, round head, short neck, small hands and feet are characteristic. The body type is infantile, flabby dry skin with a yellowish tint. The genitals are underdeveloped, secondary sexual characteristics are absent. Symptomatic hypoglycemia is sometimes noted, usually on an empty stomach. Intelligence, as a rule, does not suffer.

With the development of destructive processes in the hypothalamic-pituitary region, dwarfism develops at any age. In this case, growth stops, asthenia occurs. Puberty does not occur, and if it has already begun, it can regress. Sometimes symptoms of diabetes insipidus appear - thirst, polyuria. A growing tumor can cause headaches, vomiting, visual impairment, convulsions. Usually, growth retardation precedes the appearance of neurological symptoms.

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Diagnostics of pituitary anism in a child.

The identification of growth retardation is primarily based on anthropometric data: the standard deviation (SD) coefficient of growth is below -2 for chronological age and sex, the growth rate is less than 4 cm per year, and the body type is proportional.

Instrumental research

Delayed bone age is typical (more than 2 years relative to chronological age). Morphological changes in the hypothalamic-pituitary region are revealed by MRI (hypoplasia or aplasia of the pituitary gland, rupture syndrome of the pituitary stalk, ectopia of the neurohypophysis, concomitant anomalies).

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Laboratory research

Diagnosis of growth hormone deficiency includes stimulation tests. A single determination of growth hormone in the blood for the diagnosis of somatotropic deficiency has no diagnostic value due to the episodic nature of secretion. Growth hormone is released into the blood by somatotrophs every 20-30 minutes. STH-stimulating tests are based on the ability of various drugs to stimulate the secretion of growth hormone, these include insulin, arginine, dopamine, STH-RH, clonidine. Clonidine is prescribed at a dose of 0.15 mg / m ² of body surface, blood samples are taken every 30 minutes for 2.5 hours. Total somatotropic deficiency is diagnosed in the case of growth hormone release against the background of stimulation less than 7 ng / ml, partial deficiency - at the peak of release from 7-10 ng / ml.

Determination of insulin-like growth factors - IGF-1, IGF-2 and IGF-binding protein-3 - is one of the most diagnostically significant tests for verifying dwarfism. STH deficiency closely correlates with reduced levels of IGF-1, IGF-2 and IGF-binding protein-3.

Differential diagnosis

Differential diagnostics of somatotropic insufficiency is carried out with constitutional growth and puberty retardation. A child of parents with a history of growth and puberty retardation is highly likely to inherit this development pattern.

Such children have normal weight and height at birth, grow normally up to 2 years, then the growth rate decreases. Bone age, as a rule, corresponds to the age of growth. The growth rate is not less than 5 cm per year. Stimulation tests reveal a significant release of growth hormone (more than 10 ng/ml), but the integrated daily secretion of growth hormone is reduced. Puberty is delayed by the period of delay in bone age. The timing of achieving final height is shifted in time, final height is usually normal without hormonal therapy.

The most difficult differential diagnosis is with syndromic forms of short stature:

Laron syndrome is a syndrome of receptor insensitivity to growth hormone. The molecular basis of this disease is various types of mutations in the STH receptor gene. In this case, the secretion of growth hormone is not impaired, but there is receptor insensitivity to growth hormone at the level of target tissues. Clinical symptoms are similar to those in children with congenital growth hormone deficiency.

Hormonal characteristics include high or normal basal levels of growth hormone in the blood, hyperergic growth hormone response to STH-stimulating tests, low levels of IGF and IGF-binding protein-3 in the blood.

To diagnose Laron syndrome, an IGF-1 stimulating test is used - the introduction of a growth hormone preparation and determination of IGF-1 and IGF-BP-3 levels initially and one day after the end of the test. In children with Laron syndrome, there is no increase in IGF against the background of stimulation, unlike children with pituitary dwarfism.

Already at the first stage of differential diagnostic search in children with growth retardation, clinical examination allows identifying patients with syndromic dwarfism, since many forms of chromosomal pathology are characterized by a typical phenotype. However, this is not a very simple task, since there are more than 200 known congenital genetic syndromes accompanied by short stature.

Shereshevsky Turner syndrome is a gonadal dysgenesis syndrome. Frequency is 1:2000-1:2500 newborns. Chromosomal abnormalities:

• complete monosomy 45X0 (57%);
• isochromosome 46X(Xq) (17%);
• mosaic monosomy 45X0/46XX;
• 45Х0/47ХХХ (12%);
• mosaic monosomy with the presence of Y chromosome 45X0/45XY (4%), etc.

Clinical symptoms include dwarfism, barrel chest, widely spaced nipples, low hair growth on the back of the neck, alar folds on the neck, short neck, gothic palate, ptosis, micrognathia, valgus deviation of the elbows, multiple pigmented nevi, lymphedema of the hands and feet in newborns.

Associated diseases: aortic and aortic valve defects, urinary system defects, autoimmune thyroiditis, alopecia, impaired carbohydrate tolerance.

To stimulate growth, treatment with recombinant growth hormone is indicated. Sexual development is possible against the background of replacement therapy with estrogen and progesterone preparations.

Noonan syndrome. The disease is sporadic, but autosomal dominant inheritance is possible. The phenotype is similar to that of Shereshevsky-Turner syndrome. The karyotype is normal. Cryptorchidism and delayed puberty in boys, defects of the right heart are noted. Mental retardation is observed in 50% of patients. The final height of boys is 162 cm, girls - 152 cm.

Cornelia de Lange syndrome includes growth retardation from birth, mental retardation, fused eyebrows, ptosis, long, curved eyelashes, microgenia, a small nose with anteriorly open nostrils, thin lips, low-set ears, hypertrichosis, low hair growth on the forehead and neck, syndactyly, limited elbow mobility, skeletal asymmetry, cryptorchidism.

Silver-Russell syndrome includes intrauterine growth retardation, skeletal asymmetry, shortening and curvature of the fifth finger, triangular face, narrow lips with drooping corners, premature puberty, congenital dislocation of the hips, renal anomalies, hypospadias, and mental retardation (in some patients).

Progeria - Hutchinson-Gilford syndrome - is characterized by features of premature aging that develop from the age of 2-3 years, with an average life expectancy of 12-13 years.

Many chronic diseases are associated with significant growth retardation. Hypoxia, metabolic disorders, and prolonged intoxication lead to the impossibility of realizing the biological effects of hormones that regulate growth processes, despite their sufficient concentrations in the body. In this case, the growth rate slows down, as a rule, from the onset of a somatic disease, there is a delay in sexual development, and bone age moderately lags behind chronological age. Such diseases include:

• diseases of the skeletal system - achondroplasia, hypochondroplasia, osteogenesis imperfecta, mesolithic dysplasia;
• bowel diseases - Crohn's disease, celiac disease, malabsorption syndrome, cystic fibrosis of the pancreas;
• nutritional disorders - protein deficiency (kwashiorkor), vitamin deficiency, mineral deficiency (zinc, iron);
• kidney diseases - chronic renal failure, renal dysplasia, Fanconi nephronophthisis, renal tubular acidosis, nephrogenic diabetes insipidus;
• cardiovascular diseases - heart and vascular defects, congenital and early carditis;
• metabolic diseases - glycogenoses, mucopolysaccharidoses, lipoidoses;
• blood diseases - sickle cell anemia, thalassemia, hypoplastic FA;
• endocrine system diseases - hypothyroidism, gonadal dysgenesis, Cushing's syndrome, PPR, uncompensated diabetes mellitus.

Treatment of pituitary anism in a child.

In case of somatotropic deficiency, constant replacement therapy with human growth hormone is necessary. Since 1985, recombinant growth hormone preparations have been used. Genotropin (Pfaizer), Saizen (Serono), Humatrop (Ely Lilly), Norditropin (NovoNordisk) are approved for use. The indication for their use is a growth hormone deficiency confirmed by hormonal tests. Treatment of pituitary dwarfism continues until the growth zones are closed or a socially acceptable height is achieved. For girls, this is 155 cm, for boys - 165 cm.

Contraindications: malignant neoplasms, progressive growth of intracranial tumors.

The criterion for the effectiveness of treatment of pituitary dwarfism is an increase in the child's growth rate. In the first year, the child gains height from 8 to 13 cm, then 5-6 cm per year. Treatment with growth hormone does not lead to accelerated maturation of the skeleton, and puberty begins at the appropriate bone age.

In children with panhypopituitarism, in addition to treatment with growth hormone, replacement therapy with other hormones is necessary - sodium levothyroxine, glucocorticosteroids, desmopressin. In case of gonadotropin deficiency, sex hormones are prescribed. In children with panhypopituitarism with late treatment with growth hormone, stimulation of puberty is carried out in the remote period to realize the child's growth potential.

Forecast

Replacement therapy with growth hormone preparations and timely administration of thyroid, adrenal, and sex hormone preparations determine a favorable prognosis for life and working capacity in children with congenital forms of hypopituitarism. In acquired destructive processes in the pituitary gland, the prognosis depends on the nature of the pathological process and the results of surgical intervention.

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