Laron’s Syndrome, which is also known as Laron-type dwarfism, is a rare disease; primarily characterized by a short stature. The disease is caused by the body not being unable to utilize human growth hormone. The root cause of this insensitivity is usually a mutated growth hormone receptor. Affected individuals are born near normal size but develop slowly reaching a maximum height averaging between four to four and half feet. Currently, the condition is treatable but not curable.
“In 1958 laboratory and clinical testing began on a group of dwarf children with similar growth defects. This was not the only commonality; however, the group also suffered from high levels of growth hormones with seemingly little response in body development. The breakthrough that identified the uniqueness of this syndrome was a sequence of liver biopsies and subsequent identification of receptor deficiency. Zvi Laron, who is an Israeli researcher and Medical Doctor, first officially reported the disease in 1966.
The primary symptom and presentation of Laron’s Syndrome is dwarfism. Dwarfism can be defined as a medical condition of unusually or abnormally low stature or small size. Dwarfism, however, is not the sole presentation of Laron’s. Other symptoms related to underutilization of growth hormone often present in varying levels and consistencies. For example, over eighty percent of patients have an abnormal or unusual facial shape, aplasia/hypoplasia of the nose, delayed eruption of the teeth, delayed skeletal maturation, high forehead, hypoplastic nasal bridge, microdontia, micrognathia, a reduced number of teeth, and truncal obesity. Still, in addition to those common symptoms, near thirty percent of patients suffer from abnormal elbows, brachydactyly, delayed onset of puberty, hypoglycemia, hypoplasia of the penis, motor function delay, shorter than normal toes, and underdeveloped supraorbital ridges. Finally, five percent of patients present with blue sclerae, depressed nasal ridge, a higher than normal pitched voice, hypercholesterolemia, hypohidrosis, intellectual disabilities, osteoarthritis, and a prematurely aged appearance.
A diagnosis of Laron syndrome is often suspected based on the presence of characteristic signs and symptoms discussed above. Further, a second step of diagnosis is based on clinical and biological findings with hormonal tests to reveal normal or increased level of growth hormone and lower than normal Insulin-Like Growth Factor 1 levels. Specifically, the test performed is an “IGF-1 Generation test”. During the test, a patient receives .03 mg/kg of growth hormone for four consecutive days with baseline/twelve hour/eighty four hour measurements of Insulin-Like Growth Factor 1 recorded. For reference, normal levels of Insulin-Like Growth Factor 1 is between 75 ug/L and 365 ug/L with a Loran’s diagnosis normally confirmed at levels near 50ug/L. These levels, which will fail to rise after external growth hormone administration, are indicative of the cells not utilizing the growth hormone. Next, genetic tests should be performed to make a precise diagnosis. Additional genetic testing can be ordered to confirm the diagnosis and rule out other conditions that cause similar presentations. Genetic testing seeks to identify abnormalities or mutations of the GHR gene. These tests can be used to confirm a diagnosis in most cases.
Laron syndrome is caused by changes, also known as mutations, of the GHR gene. Specifically, an R217X mutation in the growth hormone receptor gene is characteristic of Laron’s. This gene encodes growth hormone receptors. These receptors are proteins found on the outer membrane of cells throughout the body. Growth hormone receptors are designed to recognize and bind growth hormone, which triggers cellular growth and division. When growth hormone is bound to the growth hormone receptors on liver cells; specifically, Insulin-Like Growth Factor 1, which is an important growth stimulating hormone, is produced. Mutations in GHR genes limit the function of growth hormone receptors. This, in-turn, interferes with their ability to bind growth hormone to proteins, thus disrupting normal growth and development of cells and prevents the production of Insulin-Like Growth Factor 1, which causes the many signs and symptoms of Laron syndrome. Most cases of Laron syndrome are inherited in an autosomal recessive manner, which is to say from specific genetic alleles. This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition, but when two carriers of an autosomal recessive condition have children, each child has a twenty-five percent chance to have the condition, a fifty-percent chance to be a carrier like each of the parents, and a twenty-five percent chance to not have the condition while also not being a carrier.
Reports also exist of rare families in which Laron syndrome appears to be inherited in an autosomal dominant manner.In these cases, a person only needs a change in one copy of the responsible genetic mutation in each cell. In some cases, an affected person inherits the mutation from an affected parent. Other cases may result from new or different mutations in the gene. These cases occur in people with no history of the disorder in their family. An affected person has a fifty-percent chance with each pregnancy of passing along the altered gene to his or her child
DRUG THEREPIES AND DOSES –
There is currently no cure for Laron syndrome. Therefore, treatment is primarily focused on improving growth. The only specific treatment available for this condition is subcutaneous injections of a synthetic version of Insulin-Like Growth Factor 1 (the missing stimulated hormone referred to earlier). Insulin-Like Growth Factor 1 stimulates linear growth. Linear growth is best described as the lengthening of skeletal structures promoted at epiphyseal plates and the associated growth in stature. Insulin-Like Growth Factor 1 also improves brain growth and metabolic abnormalities caused by long-term deficiency. It has also been shown to raise blood glucose levels, reduce cholesterol, and increase muscle growth. Treatment generally begins with a confirmed diagnosis and is staged in approach depending on particular Insulin-Like Growth Factor 1 levels in a patient. As a baseline, Dr. Laron used 150 ug/kg once daily (injected subcutaneously) during his earliest work. Since then, other schedules have been tested and developed, most commonly, beginning with 50 ug/kg administered twice daily and raising dosage to 100 ug/ks twice daily depending on individual response to treatment and growth stimulation. The effectiveness of treatment is contingent on the timing of diagnosis and must be started before puberty for appreciable results because of the downtrend of growth hormone production with age. Below are two specific medication products most commonly prescribed.
“Mecasermin (Brand name: Increlex) - Manufactured by Tercica, Inc. FDA-approved indication: Long-term treatment of growth failure in children with severe primary IGF-1 deficiency (Primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to growth hormone.”
“Mecasermin rinfabate (Brand name: Iplex) - Manufactured by Insmed, Inc. FDA-approved indication: Treatment of growth failure in children with severe primary IGF-1 deficiency (Primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to growth hormone .”
Insulin-Like Growth Factor 1 and Growth Hormone levels should be closely monitored in people undergoing this treatment because over-dosage of Insulin-Like Growth Factor 1 can causes a variety of health problems and side-effects. To expound, because of its insulin-like properties, Insulin-Like Growth Factor 1 side effects draw comparisons with insulin. These effects can include hypoglycemic coma, tachycardia, Bell’s palsy, or swelling of the hands. Although, even correct doses of Insulin-Like Growth Factor 1 can lead to side-effects. Most patients suffer from increased adipose tissue and elevated cholesterol because of the treatments effect on fat metabolism and the reduction of lipoprotein.
SURGERY AND LONG TERM TREATMENT OPTIONS –
There are also no reasonable surgical options to combat Laron’s syndrome because of its genetic association. Treatment is limited to correcting the underlying condition early in life. Long-term life expectancy can be normal to above average because, statistically, Laron’s patients have lower rates of cancer and diabetes. There are some precautions that sufferers should take, including: avoiding some activity because of small stature or high impact due to bone formation deficiencies. In summary, long term treatment is simply related to managing symptoms initially caused by Laron Syndrome.”
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