Laron's syndrome: what is it, causes, symptoms, treatment, prognosis

What is Laron's Syndrome?

Laron's syndrome Is a group of extremely rare genetic disorders in which the body cannot use growth hormone (abbr. GR) that it produces. Laron's syndrome can be caused by mutations in the gene for the growth hormone receptor (GH) or by mutations in genes involved in the pathway of action in the cell after growth hormone binds to its receptor, preventing the production of insulin-like growth factor 1 (IGF-1, IGF-1), a substance responsible for the effects of growth hormone on the body. Even more rarely, children with a deletion of the GH gene who have been treated with recombinant GH develop antibodies that block the binding of growth hormone to its receptor. Affected children cannot grow normally.

Children with STH deficiency who are treated with IGF-1 before puberty have improved growth, but Unlike children with GH deficiency receiving treatment with recombinant GH, they do not recover from normal growth. Treatment of these conditions is effective only when the growing bones are still open, i.e. before the end of adolescence. IGF-1 insensitivity due to mutation of the IGF-1 receptor mimics Laron's syndrome, but results in less severe growth failure and is somewhat responsive to treatment with recombinant GH.

Laron's syndrome is characterized by short stature and stunted bone growth, and normal to high circulating somatotropin levels. Other common symptoms are delayed puberty, bulging forehead, low blood sugar in infancy and early childhood, and obese in adulthood. With the exception of an extremely rare form of the syndrome, where the IGF-1 gene is defective, but brain development is normal, apparently because IGF-1 can be obtained during the life of the fetus without stimulation of growth hormone in other conditions. Some, but definitely not all, patients with the less rare state of IGF-1 receptor deficiency may have mild intellectual disability.

History

Laron and his colleagues from Israel first reported STH deficiency in 1966, based on observations that began in 1958 and continue to the present. The molecular basis of the syndrome they described - a mutation of the STH gene in some Israeli patients was for the first time described in 1989, and since then, many researchers have found more than 60 different mutations in the gene for this squirrel. Mutations in genes in the pathway of growth hormone action after its binding to growth hormone and associated with various effects of IGF-1 deficiency have been described in the last 15 years.

Signs and symptoms

There is a wide range of symptoms depending on the gene mutations involved (see. section "Causes"). Very few people with an IGF-1 gene mutation have severe intellectual disabilities and intrauterine growth disorders with deafness and micrognathia. GH deficiency results in severe growth failure without adversely affecting intrauterine growth or brain development, and the mutation STAT5b, responsible for an important activator protein, has similar effects on growth but is also associated with severe impairment of immunocompetence. IGFALS mutations affecting an important stabilizing constituent of circulating IGF-1, although associated with very low circulating IGF levels, have only a moderate effect on growth.

Laron syndrome is characterized by a severe but proportionate short stature resulting from a growth disorder that begins at birth. Along with growth retardation, there are teething delays. There is also a disproportion between the growth of the skull and face, the saddle nose and deep-set eyes. Sexual development is moderately delayed in both sexes. In women with these disorders, the onset of menstruation usually occurs between the ages of 16-19. The arms and legs are smaller than usual in proportion to the overall body size. Also, in adult patients, there may be a high voice and obesityespecially in women.

High blood levels of GH are found in children, but may not be evident without stimulation in adults. A high percentage of young patients have low blood sugar (hypoglycemia), which may be associated with seizures in some very young children. Recently, researchers found that the GH-deficient population in Ecuador (where approximately 1/3 of the world's population has been identified with a deficiency in GH receptors) had no cancer and diabetes with molecular evidence of protection against aging changes in their DNA. This may be due to a protective effect against low levels of IGF-1, and in the absence of diabetes despite obesity, due to the absence of counter-regulatory effects of growth hormone.

Causes

Laron's syndrome is inherited as an autosomal recessive genetic disorder and is caused by a mutation in the growth hormone gene or by mutations in genes involved in the pathway of action in the cell after GH binds to its receptor, including STAT5b, IGF-1 and IGFALS.

Recessive genetic disorders occur when a person inherits two copies of an abnormal gene for the same trait, one from each parent. If a person inherits one normal gene and one gene for the disease, the person will be a carrier of the disease, but usually asymptomatic. The risk for two carrier parents who both pass on the altered gene and infect the baby is 25% with each pregnancy. The risk of having a child who will be a carrier, like a parent, is 50% with each pregnancy. The probability for a child to receive normal genes from both parents is 25%. The risk is the same for men and women.

Parents who are close relatives (brother and sister) are at higher risk than unrelated parents who have the same abnormal gene, which increases the risk of having a child with a recessive genetic disorder.

Affected populations

Worldwide, only about 300 cases of Laron's syndrome have been reported due to STH deficiency. The ethnicity of the majority (90%) of the reported cases is known. Of the approximately 250 affected individuals with the syndrome identified worldwide, about two-thirds are Semitic and half of the remainder are of Mediterranean or South Asian origin. The Semitic group includes the Arab, Eastern or Middle Eastern Jewish population and the largest group, genetically homogeneous 100+ Converse in Ecuador (Jews who converted to Christianity during Inquisition).

Symptomatic disorders

Symptoms of the following disorders may be similar to those of Laron's syndrome. Comparisons can be useful for differential diagnosis:

In addition to the genetic forms of Laron's syndrome, the inability to grow normally despite adequate GH production is common in a number of conditions, including chronic illness, malnutrition, kidney disease, liver disease and congenital syndromes.

• Coffin-Siris syndrome Is a disease of unknown cause. It is present at birth and affects both sexes. The disease is mainly characterized by nutritional problems, frequent respiratory infections and poor growth.
• Cockayne Syndrome Is a progressive disorder that manifests itself in the second year of life. It is characterized by increased sensitivity to sunlight and growth retardation.
• Growth hormone deficiency (GDR) in its most severe form is very similar to primary Laron's syndrome, the main difference being that children with Laron's syndrome have high blood levels of GH, and the administration of recombinant GH does not lead to normalization growth. The cause of GHR is often unknown, but genetic defects in the growth hormone receptor that release a hormone from the brain and in the GH molecule, as well as in factors that lead to a deficiency of other hormones along with the hormone growth. It can be treated fairly easily and reliably with recombinant GH injections.
• Hydrocephalus - the condition can be confused with Laron's syndrome due to STH deficiency in infancy due to the bulging of the forehead, the presence the sclera (tunica albuginea) above the iris, the small face relative to the skull, and the bulging veins on head. However, rapid head growth is not seen in Laron's syndrome, as can be seen in hydrocephalus.

There are many more disorders that short stature can cause.

Diagnostics

The diagnosis of Laron's syndrome is usually made when the inability to grow is accompanied by a typical facial appearance and central puffiness, which suggests a GH deficiency, but with the identification of an increased level GR.

Standard treatments

The rare disease drug rhIGF-1 (recombinant IGF-1) has been approved for children in whom growth impairment is associated with GH deficiency or GH-inactivating antibodies.

Treatment of Laron syndrome with recombinant human GH is not effective because the body cannot use the hormone to grow. Recombinant IGF-1 therapy is associated with the risk of hypoglycemia, which can be prevented by feeding. Fortunately, the long-term effects of hypoglycemia were not noticed.

Genetic counseling is also recommended for patients and their families.

Forecast

Long-term prognosis appears to be normal for patients with STH deficiency and post-receptor defects, with the exception of the mutation STAT5b. In fact, subjects with STH deficiency, despite being obese, have an increased sensitivity to insulin and do not develop diabetes, and can also be protected from cancer.

People with a mutation STAT5bare likely to have a low life expectancy as a result of chronic lung diseases.