Dr Gabriel Uguru
You grew up with dwarfism and no doubt people look at you peculiarly and even have the odd laugh at your expense. Well, guess who is laughing now? You! …That is, if your dwarfism is of the rare type called the Laron syndrome or growth hormone insensitivity or growth hormone receptor deficiency (GHRD). The condition also known by other names including Laron dwarfism, is so rare that only about 500 people worldwide are affected by the syndrome with one-third of them living in Ecuador.
Laron syndrome is caused by mutations in the growth hormone receptor (GHR). Under normal conditions, the GHR binds to the growth hormone (GH), which is secreted in the anterior pituitary gland of the brain, triggering cell growth and divisions, as well as the production of the growth-promoting hormone called insulin-like growth factor-1 (IGF-1). The IGF-1 is produced primarily in the liver, but also in other tissues. It assists GH in promoting bone and tissue growths, but deficiency or mutations in GHR limits the proper use of GH in the body. This leads to shorter stature and other difficulties in metabolic functions, including the efficient use and storage of carbohydrates, proteins and fats.
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Studies have shown that individuals with Laron syndrome have exceptional metabolic system as a result of changes in their hormones when compared with others without the condition. People with Laron syndrome have delayed age-associated cognitive decline as well as lower blood insulin concentrations and higher insulin sensitivity, and as a result, they never get type 2 diabetes.
The good news continues, because, when Laron syndrome sufferers are stressed, their cells unlike “normal stature” people, self-destruct instead of accumulating mutations and DNA damage. This is one of the features that preserve them from getting cancer. Subjects of the Laron syndrome from Ecuador showed very low incidence of type 2 diabetes and cancer, and one case of cancer seen in the study group was found to be nonlethal!
Guevara-Aguirre and coworkers published a report in the 15 February 2017 issue of the Journal of Neuroscience, which shows that low concentrations of the insulin-like growth factor-1 (IGF-1) receptor was the magic bullet. It prevents oxidative DNA damage when the cells were exposed to the oxidising agent, hydrogen peroxide. In fact, in normal circumstances, stress causes a buildup of reactive oxygen species (ROS) in the cells, which are converted to hydrogen peroxide. And when hydrogen peroxide blocks the synthesis of the skin pigment, melanin, less of the pigment is produced, the result is grey hair.
Also, when the GHR is disrupted by mutations, it is unable to attach to the GH to trigger signalling within cells. This means that even when GH is in abundance, cells are unable to produce IGF-1, and cell growths and divisions are not stimulated. This inability to react to GH is called growth hormone insensitivity, and the result is the disruption of the normal growth and function of many different tissues. This anomaly is actually an advantage for people with Laron syndrome in that the insensitivity to GH helps prevent uncontrolled growth and division of cells as commonly seen in cancerous tumours! Thus, Laron syndrome people are conferred protection against cancers.
There is compelling evidence to suggest that insensitivity to GH due to mutations in the GHR gene is the key that confers protection to individuals with Laron syndrome against type 2 diabetes. This is because, GH insensitivity seems to change the response of the body to insulin. Insulin is a hormone that regulates blood glucose levels, and people with Laron syndrome are sensitive to insulin unlike normal stature people who are resistant to the effects of insulin, a feature, which predisposes them to type 2 diabetes.
It has been discovered that in yeast, when mutations occur in genes encoding parts of the growth-promoting pathway, the result is a protection against age-related genomic instability. It has also been reported that defects in the IGF-1 receptor and GH lead to longer longevity and a delay in the appearance of age-related mutations and cancer in mice. And mutations in the IGF-1 signalling pathway increase longevity in worms.
Sadly, there has been no definitive report of increased longevity in humans with Laron syndrome. But as a tradeoff, a report recently published in the 26 April 2024 issue of the journal, Med, shows that people with Laron syndrome have lower blood pressure, lower rate of artery fat buildup, and a less thick carotid artery wall. In a nutshell, they seem to have lower risk of developing cardiovascular disease. This is in complete contradiction to the principle that low levels of IGF-1 are associated with higher risk of developing cardiovascular disease in normal stature people.
Guevara-Aguirre and colleagues who had been studying people with Laron syndrome in Ecuador for the past 30 years, conducted a study involving 24 people with the syndrome. Included in the study were 27 of their relatives, all of them living in Ecuador. The aim of the study was to comprehensively evaluate the function of the cardiovascular (or circulatory system), damage, and associated risk factors in Laron syndrome subjects and their relatives.
The researchers conducted clinical assessments of cardiovascular disease blood markers in Laron syndrome subjects and compared these with those of the relatives, who served as controls. They observed that Laron syndrome subjects have normal levels of GH but low levels of IGF-1 required by GH to promote growths of bones and tissues. Their study indicates that individuals with Laron syndrome have improved levels of cardiovascular disease risk factors compared with their normal stature relatives living in the same area and sharing similar lifestyles and culture.
Lower risks of cardiovascular disease were also found in people with another form of dwarfism called, achondroplasia (discussed in this column in the 26 September 2023 edition of Prime Business Africa). This condition results from a mutation occurring in a single gene important for bone growth, leading to dwarfism.
Similarly, Roberto Salvatori and coworkers studying a group of growth hormone deficient dwarfs from a rural area of Brazil, reported in the 1 June 2006 edition of The Journal of Clinical Endocrinology & Metabolism, that there was no evidence of atherosclerosis in the group. Atherosclerosis is characterised by narrow arteries, which restrict blood flow, increasing the risk of cardiovascular disease and stroke.
It is speculated that the beneficial effects of lower concentration of insulin-like growth factor-1 seen in Laron syndrome subjects could be explored in drug designs targeting the growth hormone receptor in order to combat cardiovascular disease in normal stature individuals.
For every disappointment, there is indeed a blessing!
