Changes in the production of hormones by the adrenal glands result in a variety of health effects. With their excessive activity, puberty occurs faster. If disturbances affect the medulla of the glands, the person develops arterial hypertension. Decreased adrenal function can lead to the development of Addison's disease, or, as it is also called, bronze disease. It is characterized by: skin pigmentation, exhaustion, decreased blood pressure, low sugar levels. With bronze disease, the body's resistance decreases. Dysfunction of the endocrine system can also manifest itself in changes in the activity of the gonads. Hormone production increases, mainly due to the development of malignant tumors. When the functions of the gonads decrease, a disease such as eunuchoidism is diagnosed. This disease manifests itself in excessive growth of the limbs with their abnormal lengthening, the appearance of a tendency towards obesity, underdevelopment of the genital organs and the absence of some secondary sexual characteristics.
430 Chapter 13 Neuroendocrine diseases
growth hormone and IGF-1, growth hormone level against the background of OGTT
more than 2 ng/ml, MRI or CT signs of pituitary adenoma.
Newborns with Sotos syndrome (cerebral gigantism) are characterized by an increase in body weight and length, a convex forehead, dolichocephaly, macrocephaly, high Gothic palate, hypertelorism with anti-Mongoloid arrangement of the palpebral fissures, and prognathia. Such children experience mental retardation and impaired motor coordination. Skin and
soft tissues are somewhat thickened. With age, body growth increases
occurs, but puberty usually occurs earlier, as a result of which the epiphyses of the tubular bones close. This is why most patients with Co-syndrome
Tosa in adulthood have normal growth.
The clinical picture of Beckwith-Wiedemann syndrome is well reflected by another accepted name for the syndrome - EMG syndrome (omphalocele, macroglossia, gigantism - from the English. Exomphalos, Macroglossia, Gigantism). Indeed, a newborn with Beckwith-Wiedemann syndrome has large sizes, omphalocele, macroglossia, hyperplasia of the medullary layer of the kidneys, hyperplastic
gap of pancreatic islet cells, which often becomes the cause
development of hypoglycemia.
The typical appearance of patients with Marfan syndrome or Marfan-like syndromes (homocystinuria, MEN 2b syndrome,
congenital contractural arachnodactyly), primarily
due to a decrease in the upper segment of the body (sitting height) in relation to the lower, exceeding the arm span of the body length and arachnodactyly.
For the clinical picture of MEN 2b syndrome, see the section “Syn-
"drome of multiple endocrine neoplasia type 2."
For the clinical picture of Klinefelter's syndrome, see
"Delayed puberty syndrome."
In addition, high growth is associated with an increased risk of developing
development of certain diseases and disorders: idiopathic scoliosis and other postural disorders, varicocele, spontaneous pneumothorax, depression, osteoporosis, etc.
Etiology
Constitutional tallness.
Endocrine diseases.
GDM or decompensated diabetes in the mother during pregnancy.
Somatotropinoma of the pituitary gland (pituitary gigantism) and other causes of hypersecretion of growth hormone.
PPS syndrome.
Thyrotoxicosis syndrome.
Exogenous-constitutional obesity.
Hypogonadism syndrome.
Hereditary syndromes including somatotropinoma
pituitary gland
MEN 1 syndrome (Wermer syndrome).
McCune-Albright syndrome.
Carney syndrome.
Familial acromegaly.
Hereditary syndromes characterized by tall stature.
Sotos syndrome (cerebral gigantism).
Weaver-Smith syndrome.
Beckwith-Wiedemann syndrome.
Simpson–Golabi–Bemel syndrome.
Marfan syndrome.
MEN syndrome 2b.
Homocystinuria.
Congenital contractural arachnodactyly (Beals syndrome).
Fragile X syndrome (Martin–Bell syndrome).
ACTH resistance syndromes.
Familial glucocorticoid deficiency 1st type.
Syndrome "3A" (Allgrove syndrome).
Syndromes of androgen/estrogen resistance and aromatase deficiency (testicular feminization syndrome, etc.).
Congenital generalized lipodystrophy (lipoatro-
physical diabetes, Seip–Lawrence syndrome, Berardinelli–Seip syndrome).
Neurofibromatosis type I (Recklinghausen's disease).
Klinefelter's syndrome.
XYY syndrome (prison basketball team syndrome)
Diagnostics
If a newborn has excess body length, the first step should be
The first step is to look for diabetes in the mother. If the mother does not have diabetes
it is necessary to exclude congenital diseases, first of all
including Sotos and Beckwith-Wiedemann syndromes.
Diagnostic algorithm
In childhood, tall stature is diagnosed according to the algorithm presented in Fig. 13-1.
Be sure to find out: the height of parents and siblings; height and weight at birth; rate of growth throughout life.
Physical examination
During the physical examination, the following is carried out:
measurement of height, growth rate, body weight;
assessment of the presence of stigmata of disembryogenesis (congenital features maxillofacial area, ears, etc.);
intellectual development;
432 Chapter 13 Neuroendocrine diseases
Rice. 13-1. Diagnostic algorithm.
sexual development;
the ratio of the length of the upper body to that of the lower;
ratio of arm span to body length.
Laboratory and instrumental studies
Include:
determination of karyotype;
hormonal blood test(IGF-1, TSH);
bone age assessment;
calculation of estimated final growth;
urine test for homocysteine;
molecular genetic research.
In table 13-6 indicates the main principles of diagnosis
main diseases causing tall stature.
Table 13-6. Principles for diagnosing the main diseases causing tall stature
Research, |
||
Disease |
allowing |
Result |
confirm the diagnosis |
||
Somatotropinoma |
Growth hormone levels |
Growth hormone levels in the background |
pituitary gland |
against the background of OGTT, MRI/CT |
OGTT >2 ng/ml, MRI or CT- |
pituitary gland |
signs of pituitary adenoma |
|
Determination of karyotype |
Identification of additional |
|
Klinefelter |
X chromosomes in men |
|
XYY syndrome |
Determination of karyotype |
Identification of additional |
Y chromosomes in men |
||
Homocystinuria |
Urine test for homocysteine |
Level up |
homocysteine in urine |
Diagnosis of other diseases that cause tall stature is based on the characteristic clinical picture and the results of molecular genetic studies.
Treatment of constitutional tall stature
Therapy is considered appropriate if the expected window
final growth of more than three standard deviations (for individuals
Caucasian race is more than 195 cm for boys and 180 cm for girls). The indications for prescribing pharmacotherapy are:
idiopathic scoliosis and psychosocial problems associated with high growth.
To treat tall stature, pre-pubertal growth can be slowed down.
growth so that timely puberty begins at a lower height, or reduce pre-pubertal growth, accelerating the onset
puberty.
Sex hormone therapy is aimed at accelerating the onset of puberty. If treatment is started early, the likelihood of reduced final height increases. The most appropriate time to prescribe therapy is prepuberty
434 Chapter 13 Neuroendocrine diseases
period (bone age for girls - 10, for boys - 12.5 years).
Therapy after the onset of puberty is no longer as effective.
tivna. The administration of sex hormones at bone ages greater than 14 years can lead to an increase in final height.
Treatment of constitutional tall stature with somatostatin analogues and growth hormone receptor antagonists is not yet used in widespread clinical practice.
Treatment of girls
Girls with constitutional tallness are prescribed
ethinyl estradiol orally 0.15–0.3 mg 1 time per day. If necessary, the dose of ethinyl estradiol can be increased to 0.5 mg/day if the patient tolerates the drug well. Application of con-
jugated estrogens (7.5–10 mg/day) are also quite effective
effective. If uterine bleeding occurs, cyclic use of sex hormones is indicated; dydrogesterone orally 10 mg 2 times a day is added to estrogens from the 16th to 25th day of the menstrual cycle or norethisterone orally 5 mg once a day from the 16th to 25th day. th day of the menstrual cycle. Treatment must be continued until the epiphyses are closed, otherwise
growth may continue after estrogen withdrawal.
If ethinyl estradiol is poorly tolerated, estradiol valerate can be replaced (the dose is increased gradually from 2 to 6 mg/day).
Treatment of boys
In practice, the need to treat boys with testosterone drugs is extremely rare.
Testosterone (mixture of esters) intramuscularly 250 mg once a day
week or 500 mg once every 2 weeks for 6–12 months.
Treatment of tall stature in other diseases
Sex hormones are used to limit growth in syn-
drome of Marfan.
For Beckwith-Wiedemann and Sotos syndromes, symptomatic
matic treatment.
Treatment of pituitary somatotropinoma - see “Acromegaly and pituitary gigantism”.
Treatment of MEN 2b syndrome - see “Multiple endocrine neoplasia syndrome type 2”.
Treatment of Klinefelter syndrome - see “Delayed puberty syndrome”, “Klinefelter syndrome” (hypergonadal
tropic hypogonadism).
SHORT STALLING SYNDROME
Classification
Idiopathic growth hormone deficiency.
Idiopathic growth hormone deficiency (classical
Neurosecretory dysfunction (NSD).
Growth hormone deficiency of organic origin: congenital
given and acquired form.
Other causes of short stature
Idiopathic short stature: familial, non-familial.
Clinically defined syndromes with chromosomal aberration: Turner, Down, gonadal dysgenesis.
Clinically defined syndromes without chromosomal aberration: Silver-Russell, Noonan, Recklinghausen, de Lange,
Williams, Bloom, Prader-Willi, Rubinstein.
Intrauterine growth retardation with postnatal short stature, without stigmata.
Intrauterine growth restriction with postnatal short stature
loss, with stigmas: due to perinatal infections,
maternal drug use, smoking or alcohol abuse, etc.
Skeletal dysplasia: achondroplasia, hypochondroplasia, osteogenesis imperfecta, etc.
Diseases of bone metabolism: mucopolysaccharidosis, mucolipidosis, etc.
Metabolic diseases: glycogen storage disease,
lipid storage disease, phenylketonuria, etc.
Iatrogenic short stature.
Diagnostics
See “Growth Measurement and Evaluation.”
Growth deficiency is determined using percentile tables of variation.
ants of normal height. Analyze the child's growth curve with
taking into account the boundaries of his final height, calculated on the basis of the average height of his parents:
predicted final height for a boy = [(father's height + mother's height + 13 cm)/2] ± 10 cm predicted final height for a girl =
[(father’s height + mother’s height – 13 cm)/2] ± 10 cm.
If the extrapolated final height of a child based on birth data
hundred at the time of examination, taking into account bone age, is lower
limits of the calculated final growth interval, then it follows
talk about pathologically low growth.
Assessing the proportionality of the skeleton is important first of all
to exclude various forms of skeletal dysplasia as causes of short stature. In particular, it is advisable to calculate the “upper/lower segment” coefficient and arm span.
The degree of ossification of the epiphyseal growth zones is an important criterion in the diagnosis of dwarfism and the prognosis of final growth.
With primary growth deficiency, the delay in bone maturation is either absent or mild (skeletal dysplasia, syndromic forms of dwarfism, intrauterine growth retardation,
436 Chapter 13 Neuroendocrine diseases
genetic short stature). For secondary growth deficiency,
especially for pituitary dwarfism, significant
lag in bone age from chronological age (>2 years).
X-ray examination of the skull carried out in order to visualize the shape and size of the sella turcica and the condition of the skull bones. With pituitary dwarfism, the sella turcica is often small in size. Characteristic changes in the sella turcica are observed in craniopharyngioma: thinning and porosity of the ster-
nok, widening of the entrance, supra or intrasellar foci usually
message. With increased intracranial pressure, increased digital impressions and divergence of cranial sutures are visible.
At CT and MRI of the brain in patients with idiopathic
hypopituitarism is revealed by morphological and structural
Toural changes: hypoplasia of the pituitary gland, rupture or thinning of the pituitary stalk, ectopia of the neurohypophysis, empty sella syndrome. CT and MRI of the brain are indicated for any suspicion of intracranial pathology (space-occupying process).
Constitutional growth retardation and puberty (CGRP) and familial short stature (or normal variant short stature)
growth) fit into the concept of normal growth options.
Children from parents with short stature, as a rule, are short in stature to the same extent as their parents, due to genetically programmed growth potentials. Children from parents with a history of
severe growth retardation and puberty, with a high degree of probability
will inherit this developmental pattern.
Children with CGRP have normal height and body weight at birth, grow normally until 1–2 years of age, then the growth rate decreases.
and the growth curve is slightly below the 3rd percentile
and parallel to it. Bone age usually corresponds to
age of growth, growth rate - at least 5 cm per year. In samples for
stimulation reveals a significant release of GH (>10 ng/ml),
but the integrated daily secretion of GH in the blood is reduced. Pu-
bertat is normal, but delayed due to bone age lag and occurs when bone maturation is reached in boys at 11.5–12 years, in girls at 10.5–11 years. The timing of achieving final growth is shifted in time; final growth is usually
normal and without hormonal therapy.
There is evidence of effective treatment with recombinant hormones
human growth monopoly of children with CGRP, intrauterine growth retardation, familial short stature, Turner, Russell-Silver, Prader-Willi syndromes, Fanconi anemia, Itsenko-Cushing disease, glycogenosis, with a condition after irradiation for leukemia and brain tumors, after kidney transplantation, with chronic renal failure,
skeletal dysplasias. At the same time, there is no reliable data on the higher final growth of children with CGRP receiving
treated with growth hormone than those who did not receive it, despite
that over a certain period of time (2–3 years) treatment with GH
significantly accelerates the growth rate.
In boys with CCRP over 12 years of age with a delay in bone age of at least 2 years from the chronological age, short-term treatment with short courses of small doses of anabolic steroids (nerobolil♠, retabolil♠) is possible. Wherein
Strict monitoring of the child’s growth is necessary (at least once every
6 months). If bone maturation progresses rapidly, treatment is discontinued.
Pituitary dwarfism (somatotropic insufficiency)
A single measurement of GH in the blood for the diagnosis of somatotropic insufficiency has no diagnostic value due to the pulsed nature of GH secretion and the possibility of obtaining extremely low (zero) basal values
GH even in healthy children. In this regard, spontaneous
secretion of growth hormone in the blood, determine the peak of GH release against the background of stimulation, examine IGFs and their binding proteins in the blood.
Provocative tests are based on the ability to differentiate
ny pharmacological drugs stimulate the secretion and release of GH by somatotrophs. In clinical practice, the most widely used tests are insulin, clonidine, GH-releasing hormone, arginine, levodopa, pyridostigmine bromide (Table 13-7).
Total somatotropic insufficiency is diagnosed when the peak release of GH against the background of stimulation is less than 7 ng/ml, partially
significant deficiency - at the peak of GH release from 7 to 10 ng/ml.
A necessary condition for carrying out GH-stimulating
samples - euthyroid state of the thyroid gland. In case of hypothyroidism, it is necessary
We are taking a preliminary course of treatment with thyroid drugs for 3–4 weeks. In addition, obese children have a reduced GH response to stimulation.
For simultaneous assessment of several pituitary functions
tions, it is convenient to conduct combined tests with various gi-
pothalamic releasing hormones [insulin + thyrotropin-releasing hormone
(TRH) + luliberin (LHRH test), GH releasing hormone + TRH +
LHRH test, GH releasing hormone + corticoliberin (CRH) +
LHRH + TRH test]. For example, when testing with GH-releasing hormone + thyroliberin + luliberin, GH-releasing hormone (1 μg/kg), thyroliberin (7 μg/kg, maximum 400 μg), luliberin (100 μg) are sequentially injected into the intravenous cannula. The presence of basal low levels of TSH and free T4 in combination with the absence or prolonged response of TSH to TRH indicates concomitant secondary hypothyroidism. Absence of gonadotropin release response to LHRH (increase more than 2 times the basal level) in combination with low
basal levels of sex hormones indicates secondary
hypogonadism.
Chapter 13 Neuroendocrine diseases |
||||||
Table 13-7. Somatotropin-stimulating tests |
||||||
A drug |
Mechanism |
Dose, method |
Side effects |
|||
actions |
introduction |
|||||
blood samples |
||||||
introductions |
||||||
Activation |
0.1 U/kg, i.v. |
Hypoglycemia |
||||
hypothalamic |
||||||
ski neurons, |
||||||
stimulating |
||||||
secretion of growth hormone |
||||||
releasing- |
||||||
Clonidine |
Neurotransmit- |
0.15 mg/m2, |
Arterial |
|||
ter, adrenergic |
hypotension, |
|||||
logical agonist |
drowsiness |
|||||
Hypothalamic |
1 mcg/kg, i.v. |
|||||
releasing- |
skiy releasing- |
|||||
Levodopa |
Neurotransmit- |
|||||
ter, dopaminer- |
(body mass |
|||||
gic ago- |
headache |
|||||
nist. Stimulate- |
||||||
no release |
(body mass |
|||||
STG releasing- |
||||||
(body mass |
||||||
L-arginine |
Metabolic |
Hypoglycemia, |
||||
hydrochloro- |
stimulant, |
redness |
||||
amino acid. |
||||||
Stimulates |
solution |
|||||
liberation |
||||||
STG releasing- |
||||||
IV, infusion |
||||||
during |
||||||
Glucagon |
Relative |
100 µg/m2, |
||||
hypoglycemia |
maximum |
vomiting, late |
||||
hypoglycemia |
||||||
The most diagnostically significant constants in identifying
GH deficiency in children - IGF, in particular IGF-1 (somatomedin C) and IGF-2.
To treat pituitary dwarfism, genetically engineered human growth hormone preparations are used as HRT. Currently, the following somatotropin preparations are approved for use in Russia:
genotropin ♠ (Genotropin♠);
norditropin Simplex♠ (Norditropin Simplex♠);
Saizen ♠ (Saizen♠);
humatrope ♠ (Humatrope♠);
Rastan ♠ .
skin daily at 20:00–22:00.
Treatment must be continued until the growth zones are closed or until
achieving socially acceptable growth.
When pituitary dwarfism is combined with multiple adenohypophysial hormone deficiency, appropriate
HRT with thyroid drugs (L-thyroxine), glucocorticoids
dami (hydrocortisone), sex steroids.
Shereshevsky–Turner syndrome (gonadal dysgenesis)
Short stature is the most common clinical manifestation
phenomenon of Shereshevsky-Turner syndrome. This syndrome should be suspected primarily in girls with unexplained growth retardation. Considering the mosaic forms of syndro-
Shereshevsky–Turner ma (45 ХО/46 ХХ, 45 ХО/46 Х i(Хq), 46
Xi(Xq), 45 XO/46 X, rX, etc.) with a minimal set of typical clinical symptoms or even their absence, all girls with growth retardation (height SDS ≤2 SDS) are required to have a karyotype study at the first stage of the diagnostic search.
The growth pattern in girls with Shereshevsky–Turner syndrome is represented by moderate intrauterine growth retardation
(average length and body weight of newborns is approximately 1 SD
below normal values and averages 48.3 cm and 2800 g, respectively), at a relatively normal rate
growth from birth to 3 years of life, progressive decline
The average height for Shereshevsky–Turner syndrome is
on average 142.0–146.8 cm.
In addition to growth retardation, clinical symptoms include
lymphatic edema of the hands and feet during the neonatal period,
a short neck with wing-shaped folds of varying expression
ness, low hair growth on the back of the neck, ptosis of the eyelids (usually
bilateral), micrognathia, epicanthus, Gothic palate, deformed
mation of the ears, barrel-shaped chest with widely spaced nipples, scoliosis, valgus deviation of the elbow-
joints, Madelung deformity, shortening and thickening of the fingers, typical dermatoglyphics, nail dysplasia, multiple pigmented nevi.
Provocative tests for growth hormone stimulation are performed only in patients with Shereshevsky–Turner syndrome, whose
the growth curve deviates from that for this syndrome.
Most patients have a normal growth hormone response to stimulation during childhood. Reduced levels of growth hormone in
period of puberty are probably associated with low levels of sexual
Recurrence of a brain tumor (there is no supporting data, and currently this is not given much importance).
Leukemia (seen in children undergoing chemotherapy or radiation therapy; it is unclear whether it increases Therapy, -i; and. 1. A branch of clinical medicine that studies the causes and mechanisms of development of internal diseases, their diagnosis, treatment and prevention. From Greek therapeia - treatment. 2. The totality of diff. conservative methods of treating diseases without surgery. Treatment methods: medications (pharmacotherapy), including antibacterial (chemotherapy, antibiotic therapy) and hormonal (hormone therapy); serums and vaccines (vaccine and serotherapy)
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47. Should children with idiopathic hyperplasia (i.e., in the absence of GH deficiency) be treated with growth hormone?
The FDA recently approved the use of srota hormone in children with idiopathic short stature and expected final height.< 160 см у мальчиков и < 150 см у девочек. Однако целесообразность такого лечения в отсутствие нарушений секреции ГР оспаривается многими детскими эндокринологами. Результаты кратковременных исследований, включавших небольшие группы детей, свидетельствуют об увеличении скорости роста при лечении ГР в таких случаях. Там же, где детей наблюдали до достижения окончательного роста, были получены противоречивые результаты. Однако большинство исследователей подчеркивают незначительное увеличение окончательного роста, которого можно добиться, к тому же, ценой значительных финансовых затрат. Таким образом, применять ГР у таких детей можно лишь после детального обсуждения с ребенком, членами его семьи я опытным детским эндокринологом, хорошо знающим больного.
48. How do growth dynamics differ in children with an excess of glucocorticoids and with exogenous obesity?
With an excess of glucocorticoids, both iatrogenic (often) and endogenous (rarely), the growth of children slows down. This is due to the direct effect of glucocorticoids on metabolism - stimulation of breakdown and lipolysis and inhibition of collagen synthesis. They also suppress the pulsed secretion of GH by the pituitary gland and the production of IGF-1 by target tissues. All this often leads to short stature in children. In addition, in such children the weight-to-height ratio increases and develops ожирение!}. On the other hand, with exogenous obesity, growth is usually accelerated, and such children are usually taller than their peers.
49. What conditions are characterized by accelerated growth in childhood?
Excessive growth in childhood occurs in a relatively small number of conditions. These include familial tall stature (where the child's final height roughly matches that of the parents), constitutional tall stature, hormonal disorders and genetic syndromes.
50. What is constitutional tallness?
With constitutional tallness, the bone height is ahead of the chronological height, the growth rate is increased, and sexual development begins earlier than usual; the expected final height in such cases corresponds to the height of the parents. Obesity and heredity may play a role in the pathogenesis of this condition.
General provisions. There is no generally accepted definition of the concepts of “excessive growth” and “giant growth”. The data cited by some authors does not take into account the height of the parents, which in some cases is of decisive importance in clarifying the question of the presence of a pathological process. If the child's height is 1.5-2 standard deviations greater than the expected average height (taking into account the age of the child and the height of the parents), further examination is indicated to exclude a pathological process. The influence of acceleration, which parents often consider the first reason for the increased growth of their child (“the child is growing by leaps and bounds”), is overestimated.
Constitutional tall height. In families where children are constitutionally tall, in addition to the fact that the parents themselves are above average height, there are other tall relatives. Body length is determined by numerous genes, so it is not surprising that, thanks to the accumulation of genetic factors that favorably influence height, children of tall parents grow even larger.
The concept of "selection" is reluctantly applied to people. However, it is believed that tall women determine the selection of partners.
Children's body length at birth is above average and approximately parallel to the 97th percentile. Standard deviations from the average values do not change significantly. The differentiation of the skeleton is within the limits of normal fluctuations, and since the growth rate is greater, an increase in body length occurs to a certain extent, which worries parents, especially during the pubertal period of accelerated growth. The children are healthy. No endocrine disorders could be detected. Posture disorders are more common, and in girls - motor disharmony, aggravated by stiffness of movement. During the maximum pubertal growth acceleration (at approximately 12 years of age), orthostatic dysregulation becomes more frequent. Due to excessive growth, the well-being of many girls is significantly impaired, which is primarily due to the attitude of others. Boys of the same age, since the pubertal growth spurt, often differ even more from their peers, and from the point of view of growth physiology, they are 2 years younger. Thus, unusual differences in growth rates occur among 12- and 13-year-old students in mixed school classes. Dressing these teenagers is becoming increasingly difficult because sizes are trendy. clothes are aimed at average performance. Sometimes it should be questioned whether the psychological difficulties of excessively tall girls are as great as their mothers indicate, since the latter often project onto the behavior of their daughters the difficulties that they once had in adolescence.
"Constitutional acceleration of development", or early normal puberty. While the manifestation of constitutional developmental delay (see p. 186) is now well known, it is rarely suspected that almost as often early development, occurring within the framework of physiological fluctuations, with acceleration of skeletal differentiation and growth already in childhood, may occur. In this case, puberty begins earlier and growth ends earlier (about differentiation with premature puberty). These somewhat taller, early maturing children are not paid attention to and are almost never shown to the doctor, turning to him only in case of simultaneous familial tall stature, which is reminiscent of the fact of treatment in case of more frequently observed familial short stature. The prognosis for bone age is relatively good.
Endocrine diseases and gigantism. 1. Pituitary gigantism, or infantile acromegaly. This extremely rare disease in childhood is associated with autonomous or excessive production of somatotropin-releasing factor (GH-RH), as well as secondary (or primary) eosinophilic adenoma of the anterior pituitary gland. In most cases, high growth is combined with symptoms of acromegaly. Due to the rarity of this disease, it should be taken into account in the differential diagnosis only in cases where there is no family history of tall stature or obvious symptoms of acromegaly are present. It has not been established whether diabetes mellitus develops more often in young patients with acromegaly. Plasma GH levels are elevated and do not decrease (as normal) in response to glucose infusion.
2. Hyperthyroidism. Hyperfunction of the thyroid gland may be accompanied by excessive growth and accelerated differentiation of the skeleton; other symptoms are decisive in the differential diagnosis.
3. Pubertas praecox, pseudopubertas praecox. Characteristic and decisive in the differential diagnosis are a pronounced advance in bone age with a not so strong acceleration in length growth, premature appearance of sexual characteristics and closure of the epiphyseal zones, ultimately leading to short stature.
Chromosomal aberrations. Klinefelter syndrome. Tallness becomes noticeable only during the slow course of puberty. During the examination, attention is drawn, as in no other case, to the small and often dense testicles.
2. Other sex chromosome abnormalities are not noticeable at first because of increased body length, but later the height of adult patients increases in most cases.
Clinical syndromes characteristic of gigantism:
Marfan syndrome. This is a pathology of connective tissue (mesoderm) of unknown etiology to date.
Genetics. Autosomal dominant inheritance; 15% of new mutations are noted.
Symptoms 1. Tallness: Patients with Marfan syndrome tend to be unusually disproportionately tall. The tallest patient recorded was 7 feet (213 cm).
2. A more important sign than high growth are characteristic skeletal changes:
A) shift in body proportions - the ratio of the length of the upper body segment to the lower one is shifted towards the latter, i.e. the ratio is reduced;
B) the ratio of length to width of tubular bones, shifted towards length, increasing the so-called metacarpal index. It is determined as follows: using an x-ray of the hand, the ratio of the length to the minimum width of the II, III, IV and V metacarpal bones is determined, the average value of these 4 numbers is calculated, which normally ranges from 7 to 8; if the index is greater than 8.5, there is a reasonable suspicion of the presence of Marfan syndrome;
B) arachnodactyly, which manifests itself, in particular, when covering the distal part of the forearm. If the patient is able to place the thumb next to the terminal phalanx of the small finger, a suspicion of Marfan syndrome arises;
D) scoliosis, funnel chest, chicken breast;
D) insufficiency of the supporting apparatus of the lens, its trembling, subluxation or spherical lens with severe myopia; high risk of retinal detachment;
E) other mesenchymal symptoms: hyperextension of joints, aortic insufficiency. A dissecting aortic aneurysm is possible. Emphysema and spontaneous pneumothorax additionally indicate the presence of Marfan syndrome.
Differential diagnosis. Homocystinuria may resemble Marfan syndrome primarily in ophthalmological symptoms, but here we cannot talk about phenotypically completely similar diseases. The detection of increased urinary excretion of homocysteine is of important differential diagnostic significance.
Treatment. For exceptionally high expected growth or changes in the spine, treatment with estrogen is indicated, and in boys, testosterone.
The prognosis depends critically on cardiovascular symptoms.
Literature. If Marfan syndrome is suspected, it is recommended to review the extensive information presented by McCushick. It is simply impossible to do without his monograph if there is an assumption about the presence of erased forms of the disease.
Sotos syndrome. Tall stature with general manifestations of non-progressive cerebral symptoms and craniofascial signs. Accelerated growth in length, enlargement of the head, and often skeletal differentiation begin at birth.
Genetics and pathogenesis are unknown.
The frequency is low, but due to the lack of accurate data on the geographical pattern of the disease, it may be higher than expected.
Symptoms Tall, macrocephaly with partially acromegaloid features, often intellectual underdevelopment. Mild hydrocephalus and, accordingly, expansion of the ventricles of the brain (not caused by pressure). Sometimes there are cerebral seizures. A typical change in the facial skeleton, along with mild acromegaloid symptoms (without increased GH production), is characterized by an antimongoloid position of the eyes, as well as hypertelorism. In most cases, skeletal maturation is clearly accelerated. The final height is at the upper limit of normal. As for the neurological status, the most precise movements are impaired.
Differential diagnosis. It is possible to distinguish Sotos syndrome from early maturation observed with hydrocephalus of the third ventricle, when there is only accelerated differentiation of the skeleton without premature appearance of sexual characteristics, only on the basis of determining the level of gonadotropins or sex steroid hormones in the plasma. However, often the changes in the facial skeleton are so distinct that the diagnosis can only be made using physiognomy.
Treatment. As a rule, the cerebrospinal fluid pressure is not increased. Due to the fact that the final height does not exceed the upper limit of normal, there is no need for hormonal therapy.
Forecast. There is no information regarding the further development of the patients. The general consensus is that cerebral changes do not progress.
Treatment of constitutional gigantism in girls. Mechanism of action. In 1962 and 1963 Whitelaw et al reported successful treatment of tall stature with estrogens. This method was initially introduced only for the treatment of pre-pubescent girls. Meanwhile, it has been shown that it can be successfully used even after the onset of puberty. The effect of estrogens on growth cannot be explained from any one point of view. There are two didactic positions.
In addition to the reduction in expected final height in adrenogenital syndrome or pubertal syndrome, estrogen-induced premature onset of the pubertal growth spurt means earlier closure of the epiphyseal zones. If this happens 2 years earlier, then the theoretically predicted growth decreases by the increase in body length that would have occurred during these 2 years, since the factors influencing growth act 2 years less.
Estrogens influence skeletal maturation while having relatively little effect on length growth. However, with later treatment after the maximum pubertal growth acceleration, estrogens also negatively affect length growth. Based on the latest research, it becomes obvious that along with the acceleration of skeletal maturation, and therefore the earlier closure of the epiphyseal growth zones, the introduction of estrogens also has a negative effect on the growth process itself. When treated with high doses of estrogen, the level of somatomedin in plasma is significantly reduced. At present, it can be assumed that in this case we are talking specifically about the suppression of the secretion of this humoral growth factor by high concentrations of estrogens.
According to the first hypothesis, a decrease in final height is achieved by an earlier course of sexual development. The second hypothesis indicates inhibition of the growth process due to a decrease in the effect of somatomedin while simultaneous estrogen-induced acceleration of the closure of the epiphyseal zones.
It has long been controversial whether the magnitude of final height can be influenced after the onset of puberty, when the chance to accelerate the onset of maturation has been lost. Prader, Birich and our group were able to unequivocally confirm this possibility. The discrepancy between Whitelaw's observations and more recent data may be explained by the different dosages of estrogens used. Whitelaw often used high doses of estrogen - 30-60 mg of estradiol per month, although this is a very weak estrogen, which roughly corresponds in effect to estrogen conjugates. Consequently, Whitelaw used estrogens in doses that corresponded to 1.5 mg of commonly commercially available estrogen conjugates per day. Biric, who managed to obtain good results also when starting treatment already during puberty, used five times daily doses. The doses used by Biric correspond approximately to equivalent doses used with success by other authors after the onset of puberty.
The possibility of treatment with relatively small doses of estrogens before the onset of puberty has been clearly established, but the responsibility for possible psychological complications associated with artificially induced premature onset of puberty should be recognized. After the onset of the physiological course of puberty, in accordance with the treatment methods currently used in most cases, approximately a fivefold dose is required. One can hardly expect psychological problems.
Carrying out treatment. It is not the intention here to fully outline the various treatment regimens. The "Pediatrics Manual" presents the technique used by Birich. Our group uses conjugated estrogens before the onset of puberty in average doses of 1.25 mg/day, but after a few months this dose increases by 2-4 times. At a later start of treatment, when the endogenous production of estrogen is already obvious, treatment is carried out with ethinyl estradiol (0.5 mg / day), from the 20-25th day a gestagen is added, and from the 25-30th (or 31st) day break in treatment.
At a panel discussion on the treatment of constitutional tallness at the German Society of Pediatrics in September 1974 in Hamburg, intermittent estrogen treatment (as we do) was considered less justified. Continuous treatment is recommended, which corresponds to the technique proposed by Prader and Birich.
The discussion about estrogen treatment tactics is discussed here in detail in order to clearly show that there are no uniform recipes for the treatment of constitutional tallness. However, the treatment regimen with conjugated estrogens indicated by Birich is fully consistent with modern concepts.
Treatment success. The average reduction in actual final height compared to expected is 4-7 cm. This average is based on very heterogeneous results from individual observations. The success of treatment in each case is definitely unpredictable. However, data from the Zurich working group indicate that growth inhibition is greater the earlier treatment is started after the onset of physiological puberty. Currently, treatment is not recommended before the first signs of maturation appear.
Side effect. It is necessary to distinguish between truly constant or frequently observed symptoms accompanying treatment with theoretically expected consequences. Observed side effects include nausea or vomiting at the beginning of treatment, weight gain (4-6 kg), as well as severe pigmentation of the nipples, especially when using synthetic estrogens. After cessation of treatment, a delay in menstruation is often observed, but this amenorrhea, as observations show, has a short duration (2 - maximum 6 months). Transient lactation is occasionally observed.
No one has yet reported a tendency to thrombosis as a side effect, which should be expected theoretically based on the experience of using drugs that inhibit ovulation. Suggestions that long-term treatment may lead to partial suppression of cyclic hypothalamic functions with impaired ovulation have also not been confirmed. However, Wettenhall and Crawford report normal pregnancies in previously treated patients. Whether treated girls have the fertility seen in the normal population can only be proven on the basis of extensive statistical data.
Treatment of threatened abortion with stilbestrol can cause adenocarcinoma of the cervix or vagina in the child of a mother treated in this way with a probability of 1: 250. To date, the occurrence of tumors in connection with the treatment of tall stature with estrogens has not been observed. Stilbestrol, which has estrogenic activity but is not physiological, is not used, nor is treatment carried out in pregnant women, in whom such side effects may be feared. The associated emotions regarding estrogen treatment for constitutional tallness are unfounded. However, such observations call for caution.
Conclusion. The attitude towards the treatment of constitutional tall stature with estrogens is formed by every doctor who is interested in this based on familiarity with the literature. Participants in the aforementioned discussion were unanimous in the opinion that such treatment is at the stage of clinical trials and should only be carried out by a doctor with the necessary experience and knowledge in the field of endocrinology and growth physiology. Opinions also coincided in that treatment should initially be carried out only in centers that also guarantee follow-up of patients. Various indications for treatment are given. The Hamburg group only accepts girls with a predicted height of 185 cm or more for treatment. Knorr and Stendzik adhere to the same boundaries. Biric considers an expected height of 181 cm to be an indication for treatment. Prader points out that, if certain prerequisites are present, treatment is indicated for an expected height above 175 cm.
The exception to this rule is for us cases with the presence of juvenile scoliosis and significant obvious mental development disorders. In this case, one should take into account the emotionality of tall mothers who would like to protect the child from the problems they experienced in their time. During a discussion at the European Society of Pediatric Endocrinology in Paris, Josso said: "Don't treat the parents."
Treatment of constitutional gigantism in boys. The question of such treatment arises much less frequently than in girls. In accordance with Prader's recommendation, parenteral treatment with testosterone preparations is carried out (initially 250, then 500-1000 mg per month). This results in an acceleration of skeletal maturation and a decrease in predicted final height by an average of 5.4 cm. As Zachmann and Prader point out, there are large individual differences in the effectiveness of treatment. A manifestation of inhibition of gonadotropin production by exogenous sex steroid hormones is a clear decrease in the size of the testicles. According to Prader, normalization occurs within 12-18 months after stopping treatment.
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Complaints about high growth less common than short, since many parents are proud that their children are tall. However, some teenagers (mostly girls) become concerned and consider themselves too tall during the puberty growth spurt. The reasons for tall stature are given below.
Causes of premature development or high growth:
I. Obesity:
- Puberty occurs earlier, so the final height centile is lower than in childhood
II. Secondary:
- Hyperthyroidism
- Excess of sex hormones - premature puberty for any reason
- Excess of adrenal hormones and androgens - congenital adrenal hyperplasia
- True (excessive secretion of GH)
III. Syndromes:
- Tall and too long legs:
Marfan syndrome
homocystinuria
Klinefelter syndrome (47 XXY and XXY karyotype)
Proportional tall height at birth:
maternal diabetes
primary hyperinsulinism
Beckwith syndrome
Sotos syndrome is accompanied by an enlarged head, characteristic facial features and learning difficulties
Centile intervals of height and weight of childrenIn most cases high growth inherited from tall parents. Overeating in childhood, which causes obesity, stimulates early development and leads to high growth. However, since in this case puberty usually occurs slightly earlier than average, the final height may not be very high.
Secondary endocrine diseases are rare. Both congenital adrenal hyperplasia and early puberty lead to early fusion of the epiphyses, so that after early rapid growth, its rate decreases and final growth is not much greater than normal.
Marfan syndromes(loose fibrous connective tissue disease) and Klinefelter's (XXY) cause tall stature with disproportionately long legs, and XXY condition is also associated with infertility and learning difficulties.
Tall kids may feel uncomfortable with being treated like adults because they look older than their chronological age. Prepubertal or early pubertal overgrowth in adolescent girls can be managed using estrogen therapy to induce early epiphyseal fusion.
However, since this is a treatment leads to varied results and has dangerous side effects, it is rarely used. In cases of particularly pronounced tall stature, the possibility of surgical destruction of the epiphyses on the legs may be considered.
