Laron's syndrome: pathogenetic aspects, clinical manifestations and therapeutic approaches

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Introduction. Laron's syndrome is characterized by resistance to somatotropic hormone (STH), which causes dwarfism, and is often accompanied by clinical manifestations such as delayed puberty, hyperinsulinemia and insulin resistance, and obesity. The syndrome is extremely rare in the population, the exact prevalence is unknown, according to the World Health Organization, as of 2021 there are about 500 patients with this disease in the world, which complicates the diagnostic search, the study of Laron syndrome and the search for new therapeutic approaches to treat this pathology.

The purpose of the work. To study the clinical manifestations of Laron's syndrome, to analyze the pathogenesis of its development and the effectiveness of various treatment methods.

Materials and methods of research. Domestic and foreign articles, literary sources devoted to the study of Laron's syndrome, posted on the platforms PubMed, eLibrary, CyberLeninka, published in 2014-2024.

The results of the study. Larone syndrome is a genetically determined disease associated with impaired function of insulin–like growth factor 1 (IGF-1) and its receptors. The disease is characteristic of children born from closely related marriages, with age the degree of growth retardation increases, excess body weight progresses, and there is a disproportion of the face and skull due to hypoplasia of the upper and lower jaw. A "doll-like" face, short stature, slight obesity, and a high-pitched voice create the image of cupid [1].
The pathogenesis of Laron syndrome is currently explained by the following key mechanisms:

1. IGF-1 deficiency. Due to a number of genetic disorders, the patient has IGF-1 deficiency, which leads to STH deficiency. IGF-1 is the main initiator of STH action, which is involved in a number of processes of cell growth, development and division [2].
2. Violation of signal activation, pathology of the receptor apparatus. Altered or insensitive IGF-1 receptors are unable to bind effectively to IGF-1, which leads to insufficient activation of intracellular signaling cascades and negatively affects cell growth, differentiation, and metabolic processes in the body.

IGF-1 deficiency and its impaired signaling lead to a decrease in the patient's height, regardless of the PH level, as well as to metabolic disorders in the metabolism of carbohydrates and lipids, and inadequate absorption of nutrients.
Typical manifestations of Laron's syndrome include:
normal height and weight of children at birth and progressive growth retardation from the first year of life;
Hypoglycemia in infancy;
Disproportionation of the craniofacial skeleton due to hypoplasia of the upper and lower jaw, saddle-shaped nose, protruding forehead, sunken bridge of the nose and blue sclera;
fragility, dystrophy and premature tooth decay;
hair is sparse, it grows slowly;
hands and feet are relatively small;
obesity, high-pitched voice;
Delayed puberty, which is more often manifested in men in the form of micropenia and testicular hypoplasia, patients are fertile;
slow development of motor functions, muscle hypotension, low exercise tolerance [3];
Bone age discrepancy with passport age;
Mental development is usually normal;
congenital malformations;
overweight;
relative hyperinsulinemia and insulin resistance up to the development of diabetes mellitus;
Height: men – 119-142 cm, women - 108-136 cm;

Laboratory and instrumental research methods such as:
measurement of STH concentration in blood serum – the concentration of STH may be normal or elevated because the hormone is not used properly by the body;
Measurement of IGF-1 levels: IGF-1 is synthesized by the liver under the influence of growth hormone. In Laron's syndrome, IGF-1 levels are significantly reduced because the body's cells do not respond to growth hormone [4];
Genetic testing – to confirm the diagnosis, genetic testing is also performed for the presence of mutations in the growth hormone receptor gene, this step allows you to establish the hereditary nature of the disease.;
Provocative tests – In some cases, provocative tests may be performed to assess the body's response to the administration of exogenous growth hormone. For example, a test with arginine or glucagon allows you to evaluate the liver's ability to respond to growth hormone stimulation.;
physical examination of the patient and determination of objective body parameters, analysis of anthropometric data (height, weight at the time of treatment and in dynamics);
Instrumental diagnostics – radiography of the hands to assess bone age and identify abnormalities in bone development, computer and magnetic resonance imaging for targeted diagnosis;
Additional studies to exclude other endocrine diseases (hypothyroidism, hypopituitarism).
Currently, the only method of treating patients with Laron's syndrome is the administration of a drug containing IGF-1 [5], which leads to a rapid "catching up" increase in head circumference (brain growth) and a slow increase in linear growth [6]. Treatment is carried out under the constant supervision of an endocrinologist due to the risk of progression of obesity and other complications (hypoglycemia, headaches, nausea, vomiting, hypertension and edematous syndrome). In addition, prolonged use of IGF-1 causes the body to become resistant to IGF-1. Patients should also follow dietary recommendations: review their diet, taking into account the increased levels of protein and complex carbohydrates.

Conclusion. The study of Laron's syndrome is relevant due to its rare occurrence (1-9 cases per 1 million population), rather complex diagnosis and significant impact on the quality of life of patients. The results of our literature review show that the pathogenesis of Laron syndrome is a complex process involving genetic, hormonal, and metabolic factors. Understanding the pathogenesis of this syndrome helps in the diagnosis and development of treatment approaches aimed at correcting disorders in hormonal metabolism. Early diagnosis and timely initiation of treatment improve the patient's prognosis. According to modern concepts, the treatment of Laron syndrome consists in substitution therapy, which has a number of side effects and is not well tolerated by all patients.
Thus, further research is required to find new pathogenetic mechanisms of the disease and to develop more effective approaches in the treatment of Laron syndrome.

About the authors

Anastasia Sergeevna Serova

Donetsk State Medical University named after M. Gorky

Author for correspondence.
Email: anazdasia15@gmail.com
ORCID iD: 0009-0007-2143-7649
Russian Federation, 16 Ilyich Ave., Donetsk, 283003, Russia, Donetsk People's Republic

Svetlana Nikolaevna Butenko

Donetsk State Medical University named after M. Gorky

Email: sveta_butenko@mail.ru
ORCID iD: 0009-0001-1893-6902

Assistant of the Department of Internal Diseases N 1

Russian Federation, 16 Ilyich Ave., Donetsk, 283003, Russia, Donetsk People's Republic

References

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