Pituitary Nanism (hypopituitarism) in children

Metabolic effects of growth hormone (STH) are complex and manifest depending on the point of application. Growth hormone is the main hormone that stimulates linear growth. It promotes the growth of bones in length, the growth and differentiation of internal organs, the development of muscle tissue.

Deficiency of growth hormone develops due to a primary disturbance of the secretion of growth hormone at the level of the pituitary gland, or as a result of a violation of hypothalamic regulation.

[1], [2], [3]

Causes of the hypophyseal nanism in the child

The growth of the body is controlled by a fairly large number of factors. To the lag in growth can cause genetic defects in endocrine regulation, somatic chronic diseases, social unhappiness. Hormonal regulation of growth processes is carried out by the interaction of somatotropin, thyroid hormones, insulin, glucocorticoids, adrenal androgens, sex hormones. Insufficiency of one of them (a decrease in secretion or a violation of reception) can determine one or another clinical variant of the lag in growth.

The etiology of hypopituitarism is very diverse.

• Congenital growth hormone deficiency.
  • Hereditary (pathology of the growth hormone gene, pituitary transcriptional factor, STG-RG-receptor gene).
  • Idiopathic deficiency of STG-RG.
  • Defects in the development of the hypothalamic-pituitary system.
• Acquired deficiency of growth hormone.
  • Tumors of the hypothalamus and pituitary gland (craniopharyngoma, hamartoma, neurofibroma, germinoma, pituitary adenoma).
  • Tumors of other parts of the brain (glioma of the visual crossover).
  • Injuries.
  • Infectious diseases (viral, bacterial encephalitis and meningitis, nonspecific hypophysitis).
  • Suprasellar arachnoid cysts, hydrocephalus.
  • Vascular pathology (an aneurysm of the vessels of the pituitary gland, a pituitary infarction).
  • Irradiation of the head and neck.
  • Toxic effects of chemotherapy.
  • Infiltrative diseases (histiocytosis, sarcoidosis).
  • Transitional (constitutional delay in growth and pubertal, psychosocial nanism).
• Peripheral resistance to the action of growth hormone.
  • Pathology (mutations) of the STG-receptor gene (Laron's syndrome, dwarfism of African pygmies).
  • Biologically inactive growth hormone.
  • Resistance to insulin-like growth factor (IGF-1).

[4], [5]

Pathogenesis

Lack of growth hormone leads to a decrease in synthesis in the liver, kidneys and other organs of insulin-like growth factors (stimulators of protein synthesis), fibroblast growth factor (stimulates the division of cartilage cells, connective tissue of joints, joints), epidermal skin growth factor, platelet growth factors, leukocytes, erythropoietin, nerves, etc. A consequence of this is a decrease in the growth rates of the skeleton, muscles, internal organs. Decreased utilization of glucose, inhibited lipolysis, gluconeogenesis. Reduced secretion of gonadotropins, TSH, ACTH leads to a decrease in the function of the thyroid gland, adrenal cortex, gonads.

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

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

[6], [7], [8], [9], [10]

Symptoms of the hypophyseal nanism in the child

For patients without visible damage to the pituitary gland, against a backdrop of sharp growth retardation, delay in growth rate and bone maturation, normal proportions of the body are characteristic. For each child with a growth deficit, the pediatrician should make a growth curve. Some children notice growth retardation by the end of the year, but more often the lag in growth becomes obvious and reaches three standard deviations from the average growth of peers by 2-4 years. Characteristic of small features, thin hair, high voice, round head, short neck, small hands and feet. Body constitution is infantile, flabby dry skin with a yellowish tinge. Sexual organs are underdeveloped, secondary sexual characteristics are absent. Sometimes symptomatic hypoglycemia is noted, usually on an empty stomach. Intellect, as a rule, does not suffer.

With the development of destructive processes in the hypothalamic-pituitary region, nanism develops at any age. At the same time, growth stops, asthenia occurs. Sexual maturation does not occur, but if it has already begun, it can regress. Sometimes there are symptoms of diabetes insipidus - thirst, polyuria. A growing tumor can cause headache, vomiting, visual disturbances, seizures. Usually, growth retardation precedes the appearance of neurological symptoms.

[11], [12], [13], [14], [15], [16]

Diagnostics of the hypophyseal nanism in the child

The detection of growth retardation is primarily based on anthropometry data: the standard deviation (SD) of growth is below -2 for the chronological age and sex, the growth rate is less than 4 cm per year, proportional to the physique.

Instrumental research

A delay in bone age is characteristic (more than 2 years in relation to chronological age). Morphological changes in the hypothalamic-pituitary region are revealed in MRI (hypoplasia or aplasia of the pituitary gland, pituitary-leg eruption syndrome, neurohypophysis ectopy, accompanying anomalies).

[17], [18], [19]

Laboratory research

Diagnosis of insufficiency of growth hormone includes stimulation tests. A single determination of the growth hormone in the blood for diagnosis of somatotropic insufficiency does not have diagnostic significance due to the episodic nature of the secretion. Growth hormone is thrown into the blood by somatotrophs every 20-30 minutes. STG-stimulating tests are based on the ability of various drugs to stimulate the secretion of growth hormone, including insulin, arginine, dopamine, STG-RH, clonidine. Clonidine is administered at a dose of 0.15 mg / m ^{2 of} the body surface, blood samples are taken every 30 minutes for 2.5 hours. Total growth hormone deficiency is diagnosed in the case of a release of growth hormone against a stimulation background of less than 7 ng / ml, partial deficiency at peak of the emission 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 diagnostic tests for the verification of nanism. The STG deficiency is closely correlated with the decreased levels of IGF-1, IGF-2 and IGF-binding protein-3.

Differential diagnosis

Differential diagnosis of somatotropic insufficiency is performed with a constitutional delay in growth and puberty. The child of parents, in whose anamnesis there is a delay in growth and pubertal, with a high degree of probability will inherit this developmental character.

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. Stimulant tests reveal a significant release of growth hormone (more than 10 ng / ml), but the integrated daily growth hormone secretion is reduced. The pubertal is delayed by the terms of the lag of the bone age. The timing of achieving the final growth is shifted in time, the final growth is usually normal without hormonal therapy.

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

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

The hormonal characteristic includes a high or normal basal level of growth hormone in the blood, a hyperergic reaction of growth hormone against the background of STH stimulating samples, low levels of IGF and IGF-binding protein-3 in the blood.

For the diagnosis of Laron's syndrome IGF-1 stimulating test is used - introduction of the growth hormone preparation and determination of the levels of IGF-1 and IGF-SB-3 initially and one day after the end of the test. Children with Laron's syndrome do not have an increase in IGF with stimulation, in contrast to children with pituitary abscess.

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

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

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

Clinical symptoms - nannism, barrel chest, widely spaced nipples, low hair growth on the back, pterygopal folds on the neck, short neck, gothic palate, ptosis, micrognathia, valgus deviation of the elbow joints, multiple pigment nevi, lymphatic edema of the hands and feet newborns.

Concomitant diseases - aortic and aortic valve defects, urinary system defects, autoimmune thyroiditis, alopecia, tolerance to carbohydrates.

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

Syndrome Noonan. The disease is sporadic, but autosomal dominant inheritance is possible. The phenotype is similar to that of the Shereshevsky-Turner syndrome. The karyotype is normal. They note cryptorchidism and delay of puberty in boys, defects in the right heart. In 50% of patients, mental retardation is delayed. The final height of boys - 162 cm, girls - 152 cm.

Cornelia de Lange syndrome includes a delay in growth from birth, delayed mental development, intergrown eyebrows, ptosis, curved long eyelashes, microgenia, a small nose with anteriorly opened nostrils, thin lips, low ears, hypertrichosis, low growth of hair on forehead and neck , syndactyly, restriction of elbow joint mobility, asymmetry of the skeleton. Cryptorchidism.

The Silver-Russell syndrome includes intrauterine growth retardation, asymmetry of the skeleton, shortening and curving of the V finger, triangular face, narrow lips with lowered corners, premature pubertal, congenital dislocation of the hips, renal anomalies, hypospadias, mental retardation (in some patients).

Progeria - the Hutchinson-Gilford syndrome - is represented by features of premature aging, developing from 2-3 years of age, life expectancy on the average is 12-13 years.

In many chronic diseases, significant growth retardation occurs. Hypoxia, metabolic disorders, prolonged intoxication lead to the impossibility of realizing the biological effects of hormones that regulate growth processes, despite their sufficient concentrations in the body. At the same time, the growth rate slows down, as a rule, from the beginning of the somatic disease, there is a delay in sexual development, the bone age is moderately behind the chronological age. Such diseases include:

• diseases of the osseous system - achondroplasia, hypochondroplasia, imperfect osteogenesis, mesolitic dysplasia;
• bowel disease - Crohn's disease, celiac disease, malabsorption syndrome, cystic fibrosis of the pancreas;
• malnutrition - protein deficiency (kwashiorkor), vitamin deficiency, mineral deficiency (zinc, iron);
• kidney disease - chronic renal failure, renal dysplasia, Fanconi nephronophytosis, renal tubular acidosis, nephrogenic diabetes insipidus;
• diseases of the cardiovascular system - heart and vascular malformations, congenital and early carditis;
• metabolic diseases - glycogenoses, mucopolysaccharidosis, lipoids;
• disease of the blood - sickle-cell anemia, thalassemia, hypoplastic AF;
• diseases of the endocrine system - hypothyroidism, gonadal dysgenesis, Cushing's syndrome, PPR, uncompensated diabetes mellitus.

Treatment of the hypophyseal nanism in the child

With somatotropic insufficiency, 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"), norditropine ("NovoNordisk") are allowed for use. Indication for their purpose is a growth hormone deficiency confirmed by hormonal tests. The treatment of pituitary nanism continues until the closure of growth zones or the achievement of socially acceptable growth. For girls this is 155 cm, for boys - 165 cm.

Contraindications - malignant neoplasms, progressive growth of intracranial tumors.

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

In children with panhypopituitarism, in addition to treatment with growth hormone, replacement therapy with other hormones - sodium levothyroxine, glucocorticosteroids, desmopressin - is required. When gonadotropins are deficient, sex hormones are prescribed. In children with panhypopituitarism, with late-started treatment with growth hormone, the stimulation of puberty is carried out in a remote period to realize the child's growth potential.

Forecast

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

[20], [21], [22], [23], [24], [25]