Mesomelic dwarfism Dankmeyerґa - possibilities of prenatal identification

Dwarfism is a significant retardation in physical development and growth due to absolute or relative deficiency of somatotropic hormone (GH, growth hormone).

The corresponding diagnosis is established when an adult woman’s height is less than 120 cm, men – 130 cm. Men suffer from dwarfism twice as often as women.

The prevalence of the disease is low; according to various sources, the incidence of dwarfism is 1:3000–1:30000. Currently, most patients with confirmed dwarfism receive hormone replacement therapy to allow them to achieve normal growth rates.

Synonyms: nanism (from the Greek nanos - dwarf), somatotropic insufficiency, nanosomia.

Dwarfism is a significant delay in growth and physical development

Causes and risk factors

The main cause of the disease is a genetic mutation inherited from parents autosomal recessively, dominantly, much less often - linked to the X chromosome, resulting in a disruption in the production of somatotropic hormone.

The following genes are mainly damaged in this disease:

• growth hormone gene GH-1;
• growth hormone receptor gene GHRH-R;
• gene that controls the maturation of pituitary cells, PROP-1;
• the Pit-1 (GHF-1) protein gene, which stimulates the expression of the growth hormone gene, as well as the prolactin gene in the pituitary gland.

The main cause of dwarfism is a genetic mutation

The development of nanism also leads to:

• idiopathic growth hormone deficiency;
• pathologies of the formation of central nervous system organs (holoprosencephaly, septo-optic dysplasia);
• violation of the formation of the pituitary gland at the stage of embryogenesis (a- or hypoplasia, ectopia).

Dwarfism as an independent disease does not have significant consequences; possible complications are associated with concomitant pathology.

In addition to being congenital, dwarfism can be a consequence of acquired growth hormone deficiency. The main reasons in this case are:

• neoplasms of the hypothalamic-pituitary axis (craniopharyngioma, hamartoma, neurofibroma, germinoma, adenoma);
• tumors of brain structures;
• traumatic brain injuries;
• iatrogenic damage to pituitary structures;
• viral and bacterial infections of brain tissue, meninges;
• autoimmune lesions of the hypothalamus, pituitary gland;
• hydrocephalus;
• transient growth hormone deficiency (constitutional or psychosomatic);
• empty sella syndrome (ESTS);
• hemorrhagic or ischemic damage to pituitary tissue;
• exposure to ionizing radiation;
• toxic damage to brain tissue.

In rare cases, nanism is a consequence of the immunity of peripheral tissues to growth hormone at its normal concentration for the following reasons:

• insufficient concentration of growth hormone receptors;
• biologically intact growth hormone;
• high concentration of somatobinding protein;
• tissue resistance to insulin-like growth factor-1 (somatomedin C), which is the most important endocrine mediator of the action of somatotropic hormone.

Causes of short stature in children

Growth retardation in children is a heterogeneous condition. To understand it, a multilateral approach and knowledge of the processes that determine the course of this group of diseases are necessary. Dwarfism is considered to be height in men below 130 cm and in women less than 120 cm. Many endocrine, somatic, genetic and chromosomal diseases are accompanied by growth retardation, as a result of which difficulties arise in identifying the etiology of short stature and prescribing adequate therapy. Most often, stunting is caused by the constitutional characteristics of the child’s growth and development. It is important to understand that growth retardation factors can affect the body from the moment of conception until the physiological process of growth ceases (20–23 years). Growth is one of the most sensitive indicators characterizing a child's health. Growth is a fairly stable indicator, but there is a seasonal dependence and is associated with the course of diseases.

A special feature of a child’s body is its intensive growth: the younger the body, the more intense the growth processes. During the second month of intrauterine development, the length of the embryo increases by approximately 1 cm per day; in the last months of pregnancy, the growth rate decreases to 1.5 mm per day. During the intrauterine period of development, from the moment of formation of the egg until the complete formation of the fetus, its mass increases 612 times. With age, the mass of a person relative to a newborn increases by 20 times, body surface area by 8 times, and body length by 3 times.

The greatest increase in a child's body weight occurs in the first year of life; in subsequent years its intensity decreases. Its second jump is observed during puberty. The growth rates of children and adolescents are gender specific. Boys are characterized by a higher growth rate, while girls have an earlier rate of skeletal maturation after 2–3 years of age, which determines the rapid biological development inherent in all organs and the skeleton of the body. Also, girls earlier reach a certain level of body weight and degree of fat deposition that precedes the onset of menstruation.

The development of a child’s body is based on cell division and an increase in cell volume due to the cytoplasm. The ratio of hyperplasia and hypertrophy changes further, so that in the antenatal period the processes of cell division dominate.

Many factors can influence the processes of growth and development. Genetic and environmental are the most important of them. It is very difficult to recognize the role of genetic factors; it is much easier to identify environmental influences, among them - poor nutrition, vitamin deficiency, physical and emotional stress, acute and chronic diseases, climate and place of residence - all of them can have both positive and negative effects on growth and development of the body.

In recent decades, in the developed countries of the world, there has been a clear trend of acceleration—the acceleration of puberty—children grow faster and reach indicators that are higher than those of people who lived a century ago.

Critical periods of development

Damaging exogenous factors during the period of intrauterine development can be chemicals, including many drugs, ionizing radiation (for example, X-ray in diagnostic doses), hypoxia, fasting, drugs, nicotine, viruses, etc.

Chemicals and drugs that penetrate the placental barrier are especially dangerous for the fetus in the first 3 months of pregnancy, since they are not metabolized and accumulate in high concentrations in the tissues and organs of the fetus. Drugs impair brain development. Starvation and viruses cause malformations and even intrauterine death. Chronic diseases, as well as medications, can affect the growth processes and maturation of the fetus and, subsequently, the child. There are three stages of child growth rates.

Stage I—infancy (up to two years), characterized by very rapid growth. Its pace, first of all, determines the favorable development of the fetus during pregnancy. In the first year the child grows by about 25 cm, in the second year by 10–12 cm.

Stage II—the period of childhood, characterized by relatively constant growth. Regulated primarily by growth hormone (GH). If it is insufficient, normal growth rates (5–7 cm/year) may decrease to 3–4 cm/year.

Stage III—the period of puberty—is characterized by an adolescent growth spurt, caused by an increase in the level of sex hormones; the action of growth hormone is also very important. For girls, this stage begins a year before menarche (12–13 years), for boys at puberty (14–15 years). The pubertal leap can vary within 2–3 years. Growth rates can reach 8–12 cm/year.

At each stage of a child’s life, one of the anabolic hormones exhibits particularly high activity. So, in the first years of life this refers to thyroid hormones (TG). It is at this stage that TG ensure the final maturation of organs and systems and, above all, the central nervous system. At the same time, a high level of TG actively stimulates the secretion of GH, that is, it has a pronounced growth effect.

After 2–4 years of life and before the onset of puberty, linear growth processes prevail. This effect is provided mainly by the anabolic effect of GH. At this stage of life, the growth rate is 5–6 cm per year.

During puberty, the level of sex hormones sharply increases, which stimulate the production of GH, which contributes to the accelerated growth of a teenager (up to 10–15 cm per year). At the same time, sex hormones accelerate the processes of differentiation of skeletal bones, as a result of which the epiphyseal clefts merge and human growth stops. In many ways, the final height of an adult is determined by the timing of the onset and duration of puberty. The timing of the onset and nature of the course of puberty are genetically determined.

Growth retardation and delayed bone age are symptoms of many endocrine diseases, which are characterized by a deficiency of anabolic or excess catabolic hormones.

Intrauterine growth retardation. Diagnosis of intrauterine growth restriction is based on the discrepancy between weight and body length at birth and gestational age. It can manifest itself as a component of one of the hereditary syndromes, or be an isolated condition (in the latter case, the disease can occur sporadically). Risk factors are: multiple pregnancy, toxicosis, maternal malnutrition during pregnancy, smoking, arterial hypertension, intrauterine infection, hemorrhages in the placenta. The functions of the endocrine organs are not impaired, but such newborns have an increased risk of developing hypoglycemia. Indicators of bone maturation vary and may not correlate with the degree of developmental delay. The dynamics of growth are very diverse - some children reach normal levels already in the first year of life, while in others the delay in growth rates is longer and can lead to short stature in the future.

Intrauterine growth retardation is one of the manifestations of “fetal alcohol syndrome,” characteristic of children born to mothers suffering from chronic alcoholism.

Perinatal pathology. Various perinatal pathologies with asphyxia and fetal distress due to trauma during childbirth with breech and leg presentation, the application of obstetric forceps, vacuum extraction, rapid or, conversely, prolonged labor can cause idiopathic deficiency of somatotropic growth hormone (GH).

As the child grows, insufficient weight gain and slower neuropsychic development are observed; the causes of these conditions are very diverse.

Constitutional delay in growth and puberty (late puberty syndrome). Features of growth and development are hereditary. This is one of the most common forms of growth retardation. The etiopathogenesis of constitutional delay of sexual and physical development is not completely clear. GH production in such children is at normal levels.

This variant of short stature occurs in children of both sexes, but more often in boys. As a rule, the father and/or immediate paternal relatives of these children have the same developmental characteristics. Body length and weight at birth do not differ from those of healthy children. The slowest rates of growth occur in the first years of life, and therefore the most pronounced growth retardation occurs in children aged 3–4 years. From the age of 4–5 years, the rate of development is restored (5–6 cm per year), but, having an initially low height, children remain short in stature at school age. “Bone” age is somewhat (on average 2 years) behind the chronological one. This circumstance can explain the late entry into puberty - usually sexual development and the pubertal growth spurt are delayed in these children by 2–4 years, manifesting as a delayed pubertal growth acceleration. These teenagers are sharply behind their peers in their development. During a period when growth rates among peers increase significantly (on average at 11 years old for girls and 13 years old for boys), children with constitutional delay in sexual and physical development continue to grow at the same or even slightly slower rate (up to 4 cm per year) . Late entry into puberty and later closure of growth plates in this case are a favorable factor that improves the prognosis for growth in adulthood. Therefore, in most cases, children do not need treatment. On the contrary, treatment aimed at inducing puberty is accompanied by an acceleration of bone age and may cause premature growth arrest and short stature in adult patients. When carrying out differential diagnosis of growth retardation in boys, it should be remembered that about 80% of adolescents with delayed growth and sexual development have this constitutional feature of growth and development. In some cases, when there are short relatives in the family, this form of delay is combined with elements of family short stature. In such children, the growth prognosis may be less favorable.

Familial short stature (genetic). A fairly common variant of growth retardation, characterized by a hereditary predisposition. As a rule, relatives of children with a similar type of developmental delay have short stature. Its delay is observed from an early age, and the speed corresponds to the lower limit of the norm. At birth, children have normal height and body weight, but after 3–4 years the growth rate is no more than 2–4 cm per year; in rare cases, in the prepubertal period, the growth rate reaches 4–5 cm per year. The fundamental thing is that the “bone” age of these children usually corresponds to or only slightly lags behind the chronological one, and the entry of children into puberty practically corresponds to normal periods, but its pace is also at the lower limit of the norm. The final height of such patients reaches 151 cm in women and 163 cm in men, which, as a rule, falls within the range of permissible fluctuations in target height (average height of parents).

GH secretion and other pituitary functions are not altered in this condition. Heredity factors for familial short stature have not yet been found. It is believed that some patients may have partial resistance to GH, since 5% of patients have heterozygous mutations in the GH receptor gene. The development of familial short stature is also associated with a defect in the SHOX gene; with its point mutation in the pseudoautosomal zone of the X- and Y-chromosomes, the premature formation of a stop codon at position 195 occurs.

It is important to note that the diagnosis of “familial short stature” can be made only in cases where all other causes leading to growth retardation (GH deficiency, syndromic forms, etc.) have been excluded.

Disturbances in growth processes are observed in various diseases, but in pathologies of the endocrine system, their course is the most severe. Almost all hormones directly or indirectly participate in growth processes. Each hormone performs its own function, but their action is not isolated, but is closely related to each other.

STH is a hormone with a direct effect on target cells of peripheral tissues. It has a pronounced protein-anabolic and growth effect, largely determining the rate of development of the body and its final size. Stimulates the transport of amino acids from the blood into cells (via insulin-like growth factors (IGF)). Along with the growth effects, growth hormone has the properties of causing “fast” metabolic effects - increased lipolysis, ketogenesis and glycogenolysis, changes in cell membranes, inhibition of glucose utilization in some tissues, release of insulin by the pancreas, and a general hyperglycemic effect.

GH secretion is subject to daily fluctuations and has a pulsating nature. The highest peaks of GH are observed at night—up to 70% of the daily amount of the hormone is released at night. In addition, GH takes an active part in the body’s adaptive reactions, and, therefore, its level during the day may change for this reason. Thus, an increase in GH is observed during hypoglycemia and physical activity. Amino acids, glucagon, vasopressin, thyroid and sex hormones actively influence the synthesis and release of GH and largely determine its level in the blood.

The growth-stimulating effect of GH is mediated by insulin-like growth factors—hormones that are formed under the influence of GH in the liver and other tissues. There are two types of IFRs: IGF-I and IGF-II. These are structurally similar single-chain proteins similar to proinsulin. Both IGFs are involved in fetal development; in the postembryonic period, IGF-I is of primary importance in the regulation of growth. It stimulates the proliferation of cells in all tissues, primarily cartilage and bone. IGFs act on the hypothalamus and adenohypophysis according to the feedback principle, controlling the synthesis of somatoliberin and somatostatin and the secretion of growth hormone.

Somatotropic insufficiency. Characterized by the most pronounced growth retardation. The frequency is from 1:10000 to 1:15000. The causes of GH deficiency are varied - damage to the hypothalamic or pituitary structures, impaired peripheral sensitivity to the action of the hormone as a result of pathology of the receptor apparatus, synthesis of biologically inactive GH. Somatotropic insufficiency is often combined with loss of other triple hormones—panhypopituitarism. There are idiopathic and organic variants of the disease.

In the idiopathic variant, there are no signs of organic damage to the central nervous system; the pathological process, as a rule, is formed at the level of hypothalamic structures. The disease occurs 2–4 times more often in boys than in girls.

A deficiency of triple hormones determines the clinical picture of this condition. Symptoms of GH deficiency with pronounced proportional growth retardation come to the fore. Without therapy, maximum height in adults does not exceed 120 cm in women, 130 cm in men. At birth and in the first months of life, children with somatotropic insufficiency, according to physical development data, practically do not differ from healthy children. Growth retardation becomes noticeable in the second year of life. Growth rates slow down; after 4 years of life, children add no more than 2–3 cm per year. “Bone” age significantly lags behind chronological age (more than 2 years).

Due to underdevelopment of the skull bones, the facial features are small, with a characteristic doll-like expression. Thin hair, high voice. Often accompanied by secondary excess body weight.

Boys are characterized by a micropenis. Sexual development is delayed and occurs when bone age reaches puberty.

Children with GH deficiency have a tendency to hypoglycemic states (glycogenolysis processes are reduced). Hypoglycemia in some children may be the first sign of the disease and is often detected already in the neonatal period.

In adult patients with congenital somatotropic deficiency, in addition to growth retardation, there is obesity with an abdominal type of fat distribution, decreased muscle mass, osteoporosis, hypercholesterolemia and early atherosclerosis, low levels of physical and intellectual activity. All this significantly worsens the quality of life of patients.

The organic variant is characterized by damage to the hypothalamic-pituitary system due to congenital defects (aplasia or hypoplasia, septo-optic dysplasia, empty sella syndrome, aneurysm) or destructive injuries. The most common cause is a congenital tumor—craniopharyngioma. Along with growth retardation, such patients experience neurological symptoms, signs of increased intracranial pressure, and limited visual fields. As the process progresses and other triple hormones are lost, symptoms of hypothyroidism, hypocortisolism, and hypogonadism appear. This disease is characterized by diabetes insipidus, sometimes transient.

With isolated GH deficiency, the synthesis of triple hormones is not impaired, the course of the disease is milder—the height of adult patients is slightly higher (in women—125 cm, in men—145 cm), there are no symptoms of hypothyroidism, puberty usually occurs 2–4 years later, but proceeds normally, patients are usually fertile. “Bone” age lags behind chronological age, but the differentiation of skeletal bones is impaired to a lesser extent than with panhypopituitarism. At the end of puberty, the growth plates of patients close.

Laron syndrome. Caused by impaired sensitivity of receptors to GH. The clinical picture is identical to that of isolated GH deficiency. Adult patients with this syndrome rarely reach a height of 130 cm. At the same time, the level of GH (basal and stimulated) in patients usually exceeds normal values, reaching in some cases 50–100 ng/ml.

The lack of effect of GH is explained by a decrease in the level of somatomedins (primarily IGF-I), the synthesis of which does not increase with the introduction of exogenous GH. The molecular basis of this condition is the pathology of the growth hormone receptor gene. The secretion of growth hormone by the pituitary gland is not impaired, but there is receptor resistance to GH.

Family cases of the disease have been described, and consanguineous marriages are often registered in these families. We cannot exclude the possibility of development of growth retardation in children, also caused by a violation of the biological activity of growth hormone.

In addition to GH deficiency (or a violation of its mechanism of action), severe growth retardation can be caused by a deficiency of other anabolic hormones—thyroid and sex hormones.

Psychological dwarfism (deprivation, psychosocial dwarfism). May occur in children from disadvantaged families. They develop severe growth retardation, delayed bone age, mental development, a large belly, delayed sexual development, eating behavior, and growth hormone deficiency. When examining such children, transient or functional hypopituitarism and, in particular, a decrease in GH secretion are revealed. Such children are characterized by perverted appetite or gluttony, urinary and fecal incontinence, insomnia, convulsive crying and sudden outbursts of anger. They can be overly passive or aggressive, and their intelligence is at the lower limit of normal or reduced. When these children are isolated from unfavorable conditions, the level of growth hormone is restored on its own, the children begin to grow, but the lag in intellectual development remains for life.

Insulin plays an important role in the regulation of growth processes - it has an anabolic effect, promoting the transport of amino acids into cells, an anti-catabolic effect by inhibiting glyconeogenesis from proteins and amino acids, accelerates the synthesis of RNA and proteins, and provides energy for all anabolic processes.

Chronic insulin deficiency leads to a lack of nutrients and energy needed for growth and formation of the body. The metabolism of not only carbohydrates, but also proteins, lipids, amino acids, and nucleotides is disrupted. Catabolism prevails over anabolism, toxic metabolic products accumulate, which cannot but inhibit the growth and development of the child.

Disturbances occur in the GH system—insulin-like growth factors; partial resistance to GH develops, which is most pronounced in puberty. It maintains hyperglycemia and is one of the reasons for decreased insulin sensitivity.

A characteristic set of symptoms in long-term decompensation of type 1 diabetes mellitus (DM) is Mauriac syndrome. Obesity of the Cushingoid type appears, abdominal enlargement due to hepatomegaly with the presence of fatty hepatosis, a tendency to ketoacidosis and frequent hyperglycemic states, severe growth retardation (up to dwarfism) and puberty (can reach puberty infantilism), delayed bone ossification and osteoporosis (especially in spine), diabetic blush is often observed. Children's intelligence is age appropriate.

Thyroid hormones in physiological quantities have a significant protein-anabolic effect; high concentrations of T3 and T4, on the contrary, have a protein-catabolic effect through the activation of proteinases and enhance glyconeogenesis. In contrast to the effect of GH, thyroid hormones have a greater effect on the differentiation and maturation of tissues, primarily bone, than on the linear growth of the child. At the same time, TGs actively influence the synthesis and secretion of GH and accelerate linear growth.

Deficiency of thyroid-stimulating hormone in patients with panhypopituitarism is the cause of secondary congenital hypothyroidism, which determines a complex of symptoms - mental lethargy, dry skin, bradycardia, hypotension, constipation, late appearance and late change of teeth. Intelligence suffers to a lesser extent than with primary congenital hypothyroidism. This is due to the fact that the thyroid gland in secondary hypothyroidism is not damaged and is able to function normally. The role of stimulator of thyroid function in the prenatal period is assumed by choriogonin (placental lactogen). Thus, the fetal thyroid gland in utero synthesizes a sufficient amount of thyroid hormones for the maturation of the central nervous system. In the postnatal period of life, a pronounced TG deficiency in patients with somatotropic insufficiency worsens the processes of growth and differentiation of skeletal bones.

The vast majority of patients with congenital hypothyroidism are characterized by severe growth retardation and bone age. However, unlike patients with somatotropic insufficiency, this group of patients has disproportionate growth retardation and other characteristic clinical symptoms of the underlying disease, which make it easy to determine the cause of growth retardation.

Sex hormones (SGs) have a powerful anabolic effect, accelerating both linear growth—the pubertal growth spurt—and the differentiation of skeletal bones. The growth effect of sex hormones occurs only in the presence of GH, the level of which increases significantly during this period of life under the influence of sex hormones.

Deficiency of gonadotropic hormones (GTG) is the cause of the development of hypogonadism. Some boys with panhypopituitarism at birth have signs of intrauterine THG deficiency (cryptorchidism and micropenis). Subsequently, all patients develop symptoms of severe hypogonadism—there are no secondary sexual characteristics, and growth plates remain open. A pronounced deficiency of sex hormones and the resulting absence of a pubertal growth spurt in such children further aggravate growth retardation.

Patients with hypogonadism and delayed puberty are also characterized by delayed growth and bone age. However, these symptoms begin to attract attention only in adolescence. In childhood, growth rates and “bone” age, as a rule, correspond to chronological ones.

Severe growth retardation as a result of premature fusion of epiphyseal fissures always occurs in patients with precocious sexual development of any etiology.

Glucocorticoids, activating the processes of gluconeogenesis, have a pronounced catabolic effect. Cortisol also has a negative effect on growth processes because it actively inhibits the secretion of GH.

High levels of glucocorticoids (Cushing's syndrome with long-term use of glucocorticoid drugs), which have a catabolic effect, can also cause growth retardation in children.

Pseudohypoparathyroidism (Albright's syndrome). It is also an endocrine-dependent variant of growth retardation. The parathyroid glands in this syndrome are histologically unchanged and are capable of synthesizing and secreting parathyroid hormone. The disease is caused by a hereditary defect in the cellular receptor apparatus, in particular the kidneys and skeleton. Target cells are resistant to the action of parathyroid hormone. Patients with pseudohypoparathyroidism are characterized by short stature that occurs after the age of 3–4 years, a short neck, short and wide phalanges of the fingers, brachydactyly, most often the 1st, 4th, 5th metacarpal bones, as well as the 1st and 5th th metatarsals; exostoses and thickening of the calvarium, generalized demineralization of bones. Such patients often exhibit calcium deposits and metaplastic bone formation under the skin. Mental retardation, basal ganglia calcification, and cataracts are common. The diagnosis is confirmed by hypophosphaturia and hypocalcemia, low levels of parathyroid hormone in the blood.

Another group consists of patients with growth retardation caused by non-endocrine factors.

There are many conditions characterized by somatogenically caused growth disorders. Congenital and acquired chronic diseases accompanied by hypoxia (diseases of the cardiovascular system - heart and vascular defects, congenital and early carditis); anemia (blood diseases—sickle cell anemia, thalassemia, hypoplastic Fanconi anemia); nutritional disorders—protein deficiency (kwashiorkor), vitamin deficiency, mineral deficiency (zinc, iron); violation of absorption processes (intestinal diseases - Crohn's disease, celiac disease, malabsorption syndrome, cystic fibrosis of the pancreas, chronic gastroenteritis); impaired renal function (kidney disease - chronic renal failure, renal dysplasia, Fanconi nephronophthisis, renal tubular acidosis, nephrogenic diabetes insipidus); liver dysfunction; metabolic diseases (glycogenosis, mucopolysaccharidosis, lipoidosis); pathology of the skeletal system (achondroplasia, hypochondroplasia, osteogenesis imperfecta) - all these conditions can manifest themselves in delayed growth and development of the child.

With these variants of dwarfism, there are no signs of primary dysfunction of the endocrine glands; the “bone” age, as a rule, corresponds to the chronological one. The symptoms of the underlying disease come to the fore, which makes it easy to determine the cause of growth retardation.

Primordial dwarfism (intrauterine, primary). The disease was first described in 1902. The word primordial means that children, being full-term, are already born with short stature (25–30 cm) and insufficient weight (usually less than 2000 g). When analyzing family history, similar cases are often encountered.

The causes of primordial dwarfism are not exactly clear; some consider it to be genetically determined. There is an opinion about the impact of negative factors on the fetus during pregnancy.

At birth, such children show signs of microcephaly, hydrocephalus, and craniofacial dysostosis (disharmonious development of the bones of the skull). During dynamic observation of these children, it is possible to note normal differentiation of bone tissue. The “bone” age of these children corresponds to the chronological one. Growth gains are small, sexual development is age-appropriate. They are capable of creating families and reproducing normal children. Internal organs without pathologies. Studies of the level of growth hormone and other tropic hormones do not reveal any deviations from the norm. These children grow up, but fail to reach borderline normal heights (they are petite people and remain short throughout their lives).

The group of children with primordial dwarfism is heterogeneous. This group unites patients according to one main feature - disruption of growth processes from the period of intrauterine life - genetic syndromes (Hutchinson-Gilford, Seckel, Russell-Silver, etc.), intrauterine infection (rubella, syphilis, toxoplasmosis, cytomegaly), “fetus of an alcoholic” " and etc.

Shereshevsky–Turner syndrome (gonadal dysgenesis). A characteristic feature is severe growth retardation. With the classic version of the syndrome (karyotype 45, XO), the height of patients does not exceed 142–145 cm; with mosaicism (45, XO/46, XX), the height may be slightly higher.

Typical clinical symptoms for karyotype 45, XO are represented by reduced body weight at birth, lymphatic edema of the feet, legs and hands in newborns, low hair growth on the back of the neck, a short neck with wing-shaped folds, a barrel-shaped chest, and widely spaced nipples. Characteristic features include ptosis, epicanthus, and low positioned ears. Growth retardation begins to attract attention from the age of 2–3 years, from this time the growth rate decreases to 2–3 cm per year. “Bone” age, as a rule, up to 11–12 years corresponds to the chronological one; later, due to severe hypogonadism, it lags behind the chronological one. In the classic variant of the disease, secondary sexual characteristics are absent; in mosaicism, they can be expressed to varying degrees. A large number of characteristic dysplastic symptoms, negative or low percentage of sex chromatin confirm the diagnosis.

Nonne syndrome . Close in phenotype to Shereshevsky–Turner syndrome. Along with short stature and wing-shaped folds on the neck, congenital heart and kidney defects, pronounced facial dysmorphia (ptosis, hypertelorism, exophthalmos, micrognathism) is found. The karyotype in this syndrome is normal; both boys and girls are affected.

In boys with growth retardation, constitutional delay of growth and puberty most often occurs - late puberty syndrome or familial short stature. In girls, Shereshevsky–Turner syndrome is most common.

Progeria (Hutchinson-Gilford syndrome). The clinical picture is represented by features of progressive premature aging. Height and weight, normal at birth, lag significantly behind already by the first year of life. The main symptoms develop from 2–3 years of age - total alopecia, atrophy of the sweat and sebaceous glands, absence of the subcutaneous fat layer, scleroderma-like skin changes, pronounced venous network on the head, nail dystrophy, exophthalmos, thin beak-shaped nose, small facial and large brain skull. The voice is thin. Puberty usually does not occur. Intelligence is average or above average. Aseptic necrosis of the femoral head and dislocation of the hip joint are often diagnosed. Characterized by early widespread atherosclerosis of the coronary, mesenteric vessels, aorta, and brain. Life expectancy is on average 12–13 years, the main cause of mortality is acute myocardial infarction, congestive heart failure, and strokes.

Russell-Silver syndrome. It is characterized by intrauterine growth retardation, asymmetry of the body (shortening of the limbs on one side), shortening and curvature of the 5th finger, a “triangular” face, and mental retardation. A third of patients develop premature puberty. Renal anomalies and hypospadias are characteristic.

Seckel syndrome (bird-headed dwarfs). It is characterized by intrauterine growth retardation, microcephaly, hypoplasia of the facial skull with a large nose, low ears (often abnormally developed), mental retardation, clinodactyly of the 5th finger.

Prader-Willi syndrome. Children with this syndrome, along with growth retardation from birth, have severe obesity, cryptorchidism, micropenis, hypospadias, impaired carbohydrate tolerance, and mental retardation.

Lawrence-Moon-Bardet-Biedl syndrome. Includes short stature, obesity, retinal pigmentary degeneration, optic disc atrophy, hypogonadism, and mental retardation. Often there are incomplete forms of the syndrome, with the presence of only some of the described signs.

In conclusion, it is worth noting that constitutional features of a child’s growth and development are the most common, but far from the only cause of growth retardation. Delayed growth and bone age are symptoms of many pathological conditions of the endocrine system with a deficiency of anabolic and excess of catabolic effects. The combined action of hormones ensures normal growth and development processes. The final growth depends on the timing of puberty, its duration and the timing of completion of bone growth. Diagnosis of these conditions is quite difficult, since hormonal dysfunctions do not always manifest themselves clearly and unambiguously, and are often masked by concomitant diseases. The most important clinical problem of growth retardation in children is the differential diagnosis of dwarfism of various etiologies in order to determine the exact variant of short stature, prognosis of the disease and selection of adequate methods of therapy.

Literature

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V. V. Smirnov , Doctor of Medical Sciences, Professor G. E. Gorbunov Russian State Medical University, Moscow

Forms of the disease

Depending on the cause of the disease:

• congenital and acquired nanism;
• organic (due to damage to brain structures) and idiopathic (of unknown etiology, accounting for about 70% of all cases).

In accordance with the level at which the pathology arose, the following forms are distinguished:

• hypothalamic dwarfism;
• pituitary;
• peripheral.

Depending on the severity of somatotropic insufficiency:

• isolated (production or absorption of only somatotropic hormone is impaired);
• combined (GH deficiency is combined with loss of functions of other hormones of the hypothalamic-pituitary system).

Symptoms

The main symptom of the disease is a lag in physical development and short stature while maintaining body proportions. Other symptoms:

• small, “doll-like” facial features;
• sinking nose bridge, massive forehead;
• rounded skull, short neck;
• miniature feet and hands;
• high voice;
• sexual infantilism;
• dryness, flabbiness of the skin, often a marbled pattern;
• emotional infantilism.

The main sign of dwarfism is short stature while maintaining body proportions

In the case of combined involvement of several hypothalamic-pituitary hormones in the pathological process, symptoms of hypothyroidism, hypogonadism, etc. are added to the clinical picture of dwarfism.

So big, but very weak...

Gigantism, like dwarfism, can be the result of many reasons. It is easy to understand that an adult is sick. A height above 2 meters can indicate this. However, gigantism in children is more difficult to recognize. Acceleration of growth can be observed at any age, most often it occurs during the school period. Gigantism can be clearly noticed during puberty, but it can begin at 5 years of age.

Such children get sick more often, get tired quickly and have an awkward figure. Their muscles are poorly developed, they often feel their heartbeat. All these symptoms appear because the internal organs do not grow as quickly as the skeleton. With pituitary gigantism, people suffer from increased intracranial pressure and headaches. This is due to the proliferation of tumor cells and pressure on surrounding tissues.

Gigantism in children is sometimes confused with precocious puberty. In both cases, growth increases rapidly. But with early puberty, bone growth zones close quickly and growth stops. Such teenagers do not become giants.

Diagnostics

Diagnosis of the disease is primarily based on an assessment of the characteristic symptoms:

• retardation in growth and physical development, fully manifested by 2-4 years;
• growth less than 4 cm per year (usually 1-2 cm);
• maintaining the proportionality of the body structure;
• height standard deviation coefficient is less than 2.

The diagnosis of “dwarfism” is established when an adult woman’s height is less than 120 cm, and a man’s height is 130 cm.

Instrumental and laboratory studies:

• magnetic resonance and/or computed tomography (detection of structural changes in the hypothalamus and pituitary gland);
• determination of bone age using the methods of Grolich and Pyle or Tanner and Whitehouse (lag from real age by 2 or more years);
• X-ray examination of the skull (detection of sella turcica anomalies);
• somatotropin-stimulating tests - identifying the peak of GH release in the blood plasma against the background of drug provocation (insulin, clonidine, levodopa, etc.);
• determination of the level of high molecular weight somatomodin binding protein;
• determination of the concentration of insulin-like growth factor.

Characteristic signs

Signs of dwarfism may not appear immediately in children. At birth, children have normal body parameters. Deviations become noticeable when the child reaches 2-3 years of age. At this time, children normally grow by 7-8 cm, but in those who are sick, the lack of the hormone results in an increase in height of only 3-4 cm. At the same time, normal body proportions are still preserved.

Short stature is not the only symptom of dwarfism. These children exhibit the following anomalies:

• steep, protruding forehead;
• small face shaped like a circle;
• the bridge of the nose is flattened;
• muscles are poorly developed;
• the skin is thin, pale and dry;
• fat deposits are distributed unevenly, excess is observed in the abdomen, mammary glands, hips, pubis;
• the genitals are underdeveloped, especially for the male sex (the glands, penis, scrotum are underdeveloped, secondary sexual characteristics are very weak or absent); (subsequently women have no menstruation, secondary sexual characteristics are not expressed).

If short stature is primordial, then timely formation of secondary sexual characteristics is observed, sexual life is possible, as is childbearing. One of the manifestations of dwarfism in some species is the lack of reproductive function. Disturbances in various organs and systems are also possible.

Thus, pituitary changes may be accompanied by insufficiency of thyroid function. Because of this, the following symptoms can be observed: thick layer of skin, brittle hair, tissue swelling, mental underdevelopment. Proportional growth retardation, tissue ossification, and delayed sexual development are constantly manifested.

Among other things, the lack of the hormone in dwarfism slows down the process of ossification and development of teeth, impairs vision, leads to hypotension, contributes to the appearance of wrinkles and aging of the skin, lack of secondary hair growth, late change of teeth, causes underdevelopment of internal organs, bradycardia, and heart problems.

Treatment

Until the mid-80s of the last century, somatotropic hormone preparations obtained by extract from human pituitary tissue were used to treat children suffering from dwarfism. In 1985, this long-standing practice was officially banned due to the inability to produce the required quantities of drugs and the high risk of developing Creutzfeldt-Jakob disease in people receiving such treatment. Currently, dwarfism is treated with recombinant somatotropic hormone obtained in the laboratory using genetic engineering techniques.

During treatment, a clear dose-dependent effect is observed. An indicator of the adequacy of hormone replacement therapy is a stable annual growth: up to 13 cm (according to other sources, 8-10 cm) after the start of treatment, somewhat slowing down subsequently, fixed at 5-6 cm annually.

Currently, most patients with confirmed dwarfism receive hormone replacement therapy to allow them to achieve normal growth rates.

Active treatment is carried out until socially acceptable values ​​of linear growth are achieved. After the growth zones are closed, the drugs are used in maintenance doses (approximately 8-9 times less than growth-stimulating doses) to ensure normal life functions.

I'll grow big, very big!

Few people notice changes in growth as adults, but everyone sees how quickly children change. The baby begins to grow immediately after birth. In the first year he gains 25 cm! Every year this figure decreases. However, during puberty (12–13 years), a period of intense growth is observed again.

All processes in the body are influenced by hormones. The human endocrine system can be compared to an orchestra that has a conductor. All glands produce biologically active substances under the “guidance” of the hypothalamus, which are located in the brain area. The growth process is influenced by the somatotropic hormone of the pituitary gland; under its action, bones lengthen in special areas. It also releases growth factor. It is needed to strengthen muscles. Bone growth zones “close” at different ages in different people. This moment occurs for girls at about 19 years old, and for boys at 25 years old. If closure occurs earlier, then the person will not increase in length. If special zones of bones remain open for a long time, then growth, on the contrary, continues for a long time.

When the amount of somatotropic hormone in the human body decreases, dwarfism develops, and with a large amount of this hormone, a person can grow to gigantic sizes.