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ACVR1 Gene Responsible for Fibrodysplasia ossificans progressiva (FOP)
Scientists have identified a gene that turns muscle into bone - one of the rarest disorders that affects about one in two million individuals.
The disease named by scientists as Fibrodysplasia ossificans progressiva (FOP) is a connective tissue disorder in which bone grows in tendons, ligaments, and muscles. It begins early in childhood and has no cure.
Researchers led by Frederick Kaplan at the University of Pennsylvania first established that the FOP is likely to be caused by a mutated gene that affects bone morphogenetic proteins (BMPs), which control the formation and repair of the skeleton.
This insight led them to a gene called ACVR1, which controls one of the three main receptors for BMP that determine how cells respond to its signals, the online edition of The Times reported.
In patients with FOP, a tiny mutation in one of the two copies of the ACVR1 gene changes the meaning of its genetic message, so a faulty protein is made, it said.
The discovery of the single gene offers new hope of a first effective therapy for the disorder, they said.
By providing insights into the genetic signals that govern bone growth, the research should also improve understanding and treatment of a wide range of more common skeletal conditions. These include osteoporosis, spinal injuries and sports injuries.
In the longer term, it could also allow scientists to make bone in the laboratory, for treating fractures that fail to heal and skeletal malformations.
Fibrodysplasia Ossificans Progressiva (FOP) is misdiagnosed
"The irony here is that diagnosis of FOP has distinguishing features and is obvious just by asking a few simple questions," he said. "Instead, with misdiagnosis of this rare disease, the result was anxiety and pain for the patient."
By University of California - San Francisco, [RxPG]A new research study shows how common a medical misdiagnosis can be and how severely it can exacerbate a disease. Focusing on a rare, genetic and disabling disease known as fibrodysplasia ossificans progressiva, or FOP, researchers designed the study as an examination of the frequency of misdiagnosis and the complications associated with it.
FOP is a disorder of connective tissue that ultimately results in massive bone formation across the body's major joints, eventually rendering movement impossible. The disorder affects one in two million people worldwide, and there are 200 known cases in the U.S.
The study found that FOP is misdiagnosed 87 percent of the time, takes an average of four years to be accurately diagnosed, and often is inaccurately identified as cancer. The inaccurate diagnoses have led to painful biopsies and incorrect treatments that in themselves often worsened the condition of the patient, speeding permanent loss of mobility.
"It is unfortunate that individuals afflicted with this rare disabling disease have suffered further serious problems due to incorrect diagnoses by their physicians," said Joseph Kitterman, MD, lead investigator and professor of pediatrics at the University of California, San Francisco.
In addition to Kitterman, the team included researchers from the University of Pennsylvania, the International FOP Association, and the University of California, Davis.
Based on study findings, the researchers estimate that only 10 percent of doctors have ever heard of FOP.Only eight percent of the 184 medical textbooks that they reviewed contained adequate descriptions of FOP.
An accurate diagnosis of the disease can be made based on the clinical findings of tumor-like swellings on the head, neck, back or shoulders in association with malformations of the great (big) toes, according to Kitterman. However, the study showed that physicians often misdiagnosed the condition because the patient was not fully examined or the physician was not aware of FOP.
The disease is distinguished by the unique characteristics of toe malformations and missing joints which are present at birth, but their significance is almost never appreciated, Kitterman noted.
"The irony here is that diagnosis of FOP has distinguishing features and is obvious just by asking a few simple questions," he said. "Instead, with misdiagnosis of this rare disease, the result was anxiety and pain for the patient."
The study found that patients often endured painful deep muscle biopsies and permanent complications due to misdiagnosis, with almost half reporting permanent loss of mobility that resulted from invasive procedures.
No condition other than FOP is associated with malformed toes and rapid tissue swellings during childhood, Kitterman said.
"FOP can look like cancer. Inspection of the toes, however, would instantly reveal a different disease," said co-investigator Frederick Kaplan, MD, an international FOP expert at the University of Pennsylvania and director of one of the few research centers in the world investigating the disease.
"The disease is easy to diagnose once the physician knows what to look for," he added.
The study findings showed that it took an average of six physicians to accurately diagnose FOP. Those consulted most frequently were orthopedic surgeons, pediatricians, general practitioners, oncologists, rheumatologists and internists.
The research team reviewed the experiences of 138 patients with FOP from around the world. The extremely high rate of misdiagnoses was worldwide, with cancer cited most often. Sixty-seven percent of the study patients had unnecessary invasive procedures, and 68 percent received inappropriate therapies.
The next steps in finding a cure for FOP are to define the metabolic pathways that influence the disease and identify the gene that causes it, according to the researchers.
Penn Researchers Discover Gene That Creates Second Skeleton
specifying Cause of Fibrodysplasia Ossificans Progressiva (FOP) Will boost Development of Treatments for FOP and Common Bone Disorders
Researchers at the University of Pennsylvania School of Medicine have said to have located the "skeleton key," a gene that, when damaged, which causes the body's skeletal muscles and soft connective tissue to undergo a metamorphosis into bone, which in progress locks joints in place and rendering movement highly impossible. Identifying the gene that causes fibrodysplasia ossificans progressiva (FOP), one of the rarest and most disabling genetic conditions known to humans and a condition that imprisons its childhood victims in a "second skeleton," has been the focus at Penn's Center for Research in FOP and Related Disorders for the past 15 years. This important discovery is relevant, not only for patients with FOP, but also for those with more common skeletal conditions.
Senior authors Eileen M. Shore, PhD, and Frederick S. Kaplan, MD, both from the Penn Department of Orthopaedic Surgery, and their international consortium of colleagues, report their findings in the advanced online edition of Nature Genetics. "The discovery of the FOP gene is relevant to every condition that affects the formation of bone and every condition that affects the formation of the skeleton," says Kaplan.
The discovery of the FOP gene was the result of sincere and hard work by the Penn scientists and their colleagues in the International FOP Research Consortium over many years. It involved the identification and clinical examination of multigenerational families, often in remote regions of the world; genome-wide linkage analysis; identification of candidate genes; and finally, the DNA sequencing and analysis of those candidate genes. The team found that FOP is caused by a mutation of a gene for a receptor called ACVR1 in the bone morphogenetic protein-signaling pathway.
Kaplan describes FOP as the "Mount Everest" of genetic skeletal disorders. His lifelong ambition, as he puts it "is to conquer the summit of this daunting mountain range and see this emerging knowledge turned into novel therapies that can dramatically improve the life of these children. This is nothing less than a campaign for physical independence and personal freedom for these kids. If the knowledge helps us to see farther to help others, that will be great, but this work is for and about the children."
One in Two Million individuals,
FOP is one of the rarest known case in the history of medicine, found in only one in 2 million individuals, but, as Kaplan says, quoting from William Harvey who discovered the circulation of the blood, "Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path." Of an estimated 2500 total FOP patients worldwide, there are approximately 600 known patients, and the FOP research group at Penn knows nearly all of them. Says Kaplan, "They are our children, our family."
Early in life, because of a possible molecular short-circuit in the wound repair system of the body, tendons, ligaments, and skeletal muscle begin an inexorable transformation into an armament of bone, imprisoning its childhood victims in a second skeleton. "FOP bone is perfectly normal in every way, except it should not be there," says Kaplan. "There are absolutely no other known examples of one normal organ system turning into another. its like a place for mass production of bones that never stops "
Children with FOP are seem to be normal at birth, except for telltale malformations of the great toes that look like congenital bunions. Early in childhood, painful swellings that are often mistaken for tumors seize the skeletal muscles and transform them into bone. Eventually, ribbons, sheets, and plates of bone cross the joints, lock them in place, and render movement impossible. Attempts to remove the extra bone leads to explosive growth of new bone. Even the slightest trauma such as very small injuries , bruises, childhood immunizations, and injections for dental work can cause the muscles to turn to bone.
For now, there is no effective prevention or treatment for the molecular sabotage of FOP. The discovery of the FOP gene and the unique mutation that causes FOP provides a highly specific target for future drug development that is what promises the altering not just the symptoms of the disease, but the disease itself.
Penn Team progresses on earlier Findings
The Penn team originally surmised that FOP was caused by a mutation of a gene in the bone morphogenetic protein (BMP) signaling pathway, one of the most highly conserved signaling pathways in nature. BMPs are regulatory proteins involved in the embryonic formation and post-natal repair of the skeleton.
Indeed, the FOP gene encodes a BMP receptor called Activin Receptor Type IA, or ACVR1, one of three known BMP Type I receptors. BMP receptors are protein switches that help determine the fate of the stem cells in which they are expressed. The ACVR1 protein is 509 amino acids long, and in FOP the amino acid histidine is substituted for the amino acid arginine at amino acid position 206 in all affected individuals.
FOP is the first human genetic disease ascribed to ACVR1. "Our identification of ACVR1 as a critical regulator of endochondral bone formation during embryogenesis and in post-natal tissues will undoubtedly re-focus thinking and stimulate new research directions," says Shore. "This discovery will surely have a major impact on the study of skeletal biology and regenerative medicine.
"This single amino acid substitution is predicted to change the sensitivity and activity of the receptor," continues Shore. "As is the case for most genes, every cell has two copies of the ACVR1 gene. In FOP patients, one of the two ACVR1 gene copies harbors a mutation that causes the ACVR1 protein to be incorrectly made."
In FOP, the ACVR1 gene is damaged by the substitution of a single genetic letter at a specific location in the gene. The single nucleotide substitution changes the meaning of the genetic message encoded by the ACVR1 gene. "Thus, the substitution of one genetic letter for another out of six billion genetic letters in the human genome - the smallest and most precise change imaginable - is like a molecular terrorist that short circuits a functioning set of muscles and connective tissues and transforms them into a second skeleton - in essence turning a light bulb into an atom bomb," says Kaplan.
ACVR1 is an important BMP signaling switch in cartilage cells of the growth plates of growing bones, especially in the hands and feet, as well as in the cells of skeletal muscle. In previous studies in chickens and zebrafish, other researchers have found that an artificially made "trigger happy" copy of the ACVR1 gene (similar, but not identical to the FOP gene mutation) makes muscle cells behave like bone cells, upregulating BMP4 expression; downregulating BMP antagonist expression (such as noggin); expanding cartilage elements in growing bone, eventually inducing extra bone growth; and stimulating joint fusion - clinical and molecular features nearly identical to those seen in individuals with FOP.
In the definitive genetic linkage analysis described in one of the the Nature Genetics paper, which located the FOP gene to a region on chromosome 2, the researchers used a subset of families in whom all affected individuals had unambiguous features of classic FOP, features that included typical congenital malformations of the great toes and a predictable pattern of extra-skeletal bone formation that mimics the embryonic patterns by which the normal skeleton forms. The researchers have found that every person with classic FOP has the identical mutation in the ACVR1 gene.
the future is promising
Computer modeling of the three-dimensional structure of the mutant ACVR1 protein suggests altered activation of this form of ACVR1. "Presumably, the FOP mutation causes a molecular short circuit or promiscuous activation of the receptor, but the detailed molecular Physiology
is still being deciphered," says Kaplan. "Such knowledge will be essential to develop treatments and an eventual cure for FOP."
"To really understand the physiological consequences, we have begun to develop a genetically engineered mouse with the FOP mutation," notes Shore.
The ACVR1 gene and protein have been encoded in the molecular machinery of vertebrate DNA for nearly as 400 million years suggesting that nature needs to maintain an arginine at codon 206 to support the normal functions of cells, tissues, and organs. Now it will be important to develop an animal model with the same mutation in ACVR1 that is found in people who have FOP. The ACVR1 gene is highly conserved throughout vertebrate evolution, from fish to mice to humans, but whether or not a mouse will develop FOP now has to be seen.
"We now know the cause for FOP at the genetic level, and we expect that it will not be long before we understand the mechanism at the molecular level," says Kaplan. "That knowledge may someday be used, not just for understanding and treating FOP, but for treating many common disorders that affect the skeleton - conditions such as non-genetic forms of extra bone growth that may occur following total hip replacement, head injuries, spinal cord injuries, sports injuries, blast injuries from war, and even osteoarthritis and damaged heart valves. Perhaps someday we will be able to harness the gene mutation that causes the renegade bone formation in FOP and make bone in a controlled way - for patients who have severe osteoporosis, for those with severe bone loss from trauma, for those with fractures that fail to heal or spinal fusions that are slow to heal, or for those with congenital malformations of the spine and limbs. We have reached a summit on our epic journey to understand FOP - knowledge we desperately need to help the kids and that will likely help many others. We still have a long way to go, but finally we can see a therapeutic horizon above the clouds, and the view is promising."
Disclaimer :This research news has been taken from a reputed news website. It has not been modified or recreated in way, as to preserve the authenticity of it. No Copyright Infringement is intended. This information is posted here for read-only basis. No part of this news is to be reproduced elsewhere, unless due credit is given to the original source and author.
Research Finds Firstborns Gain the Higher I.Q.
By BENEDICT CAREY
Published: June 22, 2007
The eldest children in families tend to develop higher I.Q.’s than their siblings, researchers are reporting today, in a large study that could settle more than a half-century of scientific debate about the relationship between I.Q. and birth order.
Family Influence The average difference in I.Q. was slight — three points higher in the eldest child than in the closest sibling — but significant, the researchers said. And they said the results made it clear that it was due to family dynamics, not to biological factors like prenatal environment.
Researchers have long had evidence that firstborns tended to be more dutiful and cautious than their siblings, and some previous studies found significant I.Q. differences. But critics said those reports were not conclusive, because they did not take into account the vast differences in upbringing among families.
Three points on an I.Q. test may not sound like much. But experts say it can be a tipping point for some people — the difference between a high B average and a low A, for instance. That, in turn, can have a cumulative effect that could mean the difference between admission to an elite private liberal-arts college and a less exclusive public one.
Moreover, researchers said yesterday that the results — being published today in separate papers in two journals, Science and Intelligence — would lead to more intensive study into the family dynamics behind such differences. Though the study was done in men, the scientists said the results would almost certainly apply to women as well.
“I consider these two papers the most important publications to come out in this field in 70 years; it’s a dream come true,” said Frank J. Sulloway, a psychologist at the Institute of Personality and Social Research at the University of California, Berkeley.
Dr. Sulloway, who was not involved in the study but wrote an editorial accompanying it, added that “there was some room for doubt about this effect before, but that room has now been eliminated.”
Effects of birth order are notoriously difficult to study, and some critics are still dubious. Joseph Lee Rodgers, a psychologist at the University of Oklahoma and a longtime skeptic of such effects, said the new analysis was not conclusive.
“Past research included hundreds of reported birth order effects” that were not legitimate, Dr. Rodgers wrote in an e-mail message. “I’m not sure whether the patterns in the Science article are real or not; more description of methodology is required.”
In the study, Norwegian epidemiologists analyzed data on birth order, health status and I.Q. scores of 241,310 18- and 19-year-old men born from 1967 to 1976, using military records. After correcting for factors that may affect scores, including parents’ education level, maternal age at birth and family size, the researchers found that eldest children scored an average of 103.2, about 3 percent higher than second children (100.3) and 4 percent higher than thirdborns (99.0).
The difference was an average, meaning that it varied by family and showed up in most families but not all.
The scientists then looked at I.Q. scores in 63,951 pairs of brothers, and found the same results. Differences in household environments did not explain elder siblings’ higher scores.
Because sex has little effect on I.Q. scores, the results almost certainly apply to females as well, said Dr. Petter Kristensen, an epidemiologist at the University of Oslo and the lead author of the Science study. His co-author was Dr. Tor Bjerkedal, an epidemiologist at the Norwegian Armed Forces Medical Services.
To test whether the difference could be due to biological factors, the researchers examined the scores of young men who became the eldest in the household after an older sibling had died. Their scores came out the same, on average, as those of biological firstborns.
“This is quite firm evidence that the biological explanation is not true,” Dr. Kristensen said in a telephone interview.
Social scientists have proposed several theories to explain how birth order might affect intelligence scores. Firstborns have their parents’ undivided attention as infants, and even if that attention is later divided evenly with a sibling or more, it means that over time they will have more cumulative adult attention, in theory enriching their vocabulary and reasoning abilities.
But this argument does not explain a consistent finding in children under 12: among these youngsters, later-born siblings actually tend to outscore the eldest on I.Q. tests. Researchers theorize that this precociousness may reflect how new children alter the family’s overall intellectual resource pool.
Adding a young child may, in a sense, diminish the family’s overall intellectual environment, as far as an older sibling is concerned; yet the younger sibling benefits from the maturity of both the parents and the older brother or sister. This dynamic may quickly cancel and reverse the head start the older child received from his parents.
One possibility, proposed by the psychologist Robert Zajonc, is that older siblings consolidate and organize their knowledge in their natural roles as tutors to junior. These lessons, in short, benefit the teacher more than the student.
Another potential explanation concerns how siblings find a niche in the family. Some studies find that both the older and younger siblings tend to describe the firstborn as more disciplined, responsible, high-achieving. Studies suggest — and parents know from experience — that to distinguish themselves, younger siblings often develop other skills, like social charm, a good curveball, mastery of the electric bass, acting skills.
“Like Darwin’s finches, they are eking out alternative ways of deriving the maximum benefit out of the environment, and not directly competing for the same resources as the eldest,” Dr. Sulloway said. “They are developing diverse interests and expertise that the I.Q. tests do not measure.”
This kind of experimentation might explain evidence that younger siblings often live more adventurous lives than their older brother or sister. They are more likely to participate in dangerous sports than eldest children, and more likely to travel to exotic places, studies find. They tend to be less conventional than firstborns, and some of the most provocative and influential figures in science spent their childhoods in the shadow of an older brother or sister (or two or three or four).
Charles Darwin, author of the revolutionary “Origin of Species,” was the fifth of six children. Nicolaus Copernicus, the Polish-born astronomer who determined that the sun, not the earth, was the center of the planetary system, grew up the youngest of four. The mathematician and philosopher René Descartes, the youngest of three, was a key figure in the scientific revolution that began in the 16th century.
Firstborns have won more Nobel Prizes in science than younger siblings, but often by advancing current understanding, rather than overturning it.
“It’s the difference between every-year or every-decade creativity and every-century creativity,” Dr. Sulloway said, “between innovation and radical innovation.”
Norditropin(R) Approved For Treatment Of Children With Short Stature Associated With Turner Syndrome
Novo Nordisk announced that Norditropin(R) (somatropin [rDNA origin] injection) received approval from the U.S. Food and Drug Administration (FDA) for the treatment of children with short stature associated with Turner syndrome. Turner syndrome is a rare chromosomal condition caused by complete or partial absence of the second sex chromosome (X chromosome) in females. This occurs in approximately 1 in 2,500 live female births, and in as many as 10 percent of all miscarriages worldwide. Short stature is the most common feature associated with Turner syndrome affecting the majority of patients (90 - 100 percent depending on the chromosomal abnormalities).
"Treatment of short stature in girls with Turner syndrome is the second new indication granted this summer for Norditropin, which recently received an approval to treat children with short stature associated with Noonan syndrome," said Martin Soeters, president of Novo Nordisk Inc. "Novo Nordisk is committed to our biopharmaceutical business unit, and we will continue to conduct research in rare disorders where there are currently treatment gaps."
This FDA approval signifies advancement in dosing capabilities, giving physicians the option of dosing at higher than existing treatment options. Results from a pivotal clinical trial illustrated that treatment with Norditropin at the higher dosing level of .067 mg/kg/day resulted in 80 percent of Turner syndrome patients reaching a normal adult height compared to only 53 percent at a lower dosing level.
"I know first hand from my practice that short stature can be a social and self image concern for girls with Turner syndrome," said Judith Ross, M.D., Professor, Department of Pediatrics at Thomas Jefferson University, Philadelphia. "Clinical data for Norditropin in girls with Turner syndrome show for the first time that a higher dose Norditropin treatment regimen results in growth to a height that is considered normal compared to the general population. This higher dose option gives physicians more dosing flexibility and a greater chance of successfully treating short stature."
About Turner Syndrome
Turner syndrome is a rare chromosomal disorder of females characterized by short stature and the lack of sexual development at puberty. Among affected females, physical features may include a short neck with a webbed appearance, heart defects, kidney abnormalities and various other malformations. Several medical problems occur more frequently in individuals with Turner syndrome than in the general population, including a heightened incidence of osteoporosis, cardiac malfunction diabetes and an increased risk of ear and hearing disorders. However, there is variability in the degree to which girls with Turner syndrome are affected by any of its manifestations.
Clinical Features and Complications
Many characteristic features are associated with Turner syndrome. Their presence and severity vary greatly from individual to individual and can include
-- Narrow, high-arched palate (roof of the mouth)
-- Misshapen ears and other ear disorders
-- Low hairline
-- Webbed neck
-- Broad chest -- Scoliosis (curvature of the spine)
-- Cubitus valgus (arms that curve out slightly at the elbows)
-- Heart Defects
About Norditropin
Norditropin(R) (somatropin [rDNA origin] injection) is indicated for the treatment of children with short stature associated with Turner syndrome, the treatment of children with short stature associated with Noonan syndrome, and treatment of children with growth failure due to inadequate secretion of endogenous growth hormone and for replacement of endogenous growth hormone in adults with growth hormone deficiency (GHD) who meet either of the following two criteria:
1) Adult Onset: Patients who have GHD, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or
2) Childhood Onset: Patients who were growth hormone deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes.
In general, confirmation of the diagnosis of adult GHD in both groups usually requires an appropriate growth hormone stimulation test.
Important Safety Information
Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses or in patients with active proliferative or severe non- proliferative diabetic retinopathy. Norditropin should not be used in patients with known hypersensitivity to somatropin or any of its excipients.
Somatropin should not be used or should be discontinued with any evidence of active malignancy. Patients with preexisting malignancy should be monitored carefully for any progression or reoccurrence.
Somatropin should not be used to treat patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or acute respiratory failure as increased mortality may occur.
Deaths have been reported in patients with Prader-Willi syndrome who are severely obese or have severe respiratory impairment and are treated with somatropin. Unless patients with Prader-Willi syndrome also have a diagnosis of GHD, Norditropin is not indicated for the treatment of patients who have growth failure due to genetically confirmed Prader-Willi syndrome.
Blood glucose levels should be monitored periodically as treatment with somatropin may decrease insulin sensitivity. Patients with preexisting diabetes or glucose intolerance should be monitored closely during somatropin therapy. Doses of insulin or oral agents may need to be adjusted for patients with diabetes on somatropin therapy.
Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or vomiting has been reported in a small number of patients treated with somatropin products. Symptoms usually occurred within the first eight (8) weeks after initiation of somatropin therapy and generally resolve after cessation of therapy or a reduction of the somatropin dose. Funduscopic examination should be performed routinely before initiating and periodically during the course of somatropin therapy. If papilledema is observed by funduscopy during somatropin treatment, treatment should be discontinued.
Pediatric patients may develop slipped capital femoral epiphyses more frequently if they have endocrine disorders or during rapid growth. Any child having onset of a limp or complaints of hip or knee pain during somatropin therapy should be carefully evaluated. Progression of scoliosis can occur in patients who experience rapid growth. Somatropin has not been shown to increase the occurrence of scoliosis.
In patients with GHD, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Patients treated with somatropin should therefore have periodic thyroid function tests and thyroid hormone replacement therapy should be initiated or adjusted as needed.
Somatropin inhibits 11Beta-hydroxysteroid dehydrogenase type 1 (11BetaHSD-1) in adipose/hepatic tissue, and may significantly impact the metabolism of cortisol and cortisone. In patients treated with somatropin, previously undiagnosed central (secondary) hypoadrenalism may be unmasked requiring glucocorticoid replacement therapy. In addition, patients treated with glucocorticoid replacement therapy especially with cortisone acetate and prednisone for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses.
Careful monitoring is advisable when somatropin is administered in combination with other drugs known to be metabolized by CP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine) or other hormone replacement therapy.
The safety and effectiveness of Norditropin in patients age 65 years and older has not been evaluated in clinical studies. Elderly patients may be more sensitive to the actions of somatropin and may be more prone to develop adverse reactions.
Common somatropin-related adverse reactions include injection site reactions/rashes, lipoatrophy and headaches, glucose intolerance, fluid retention and unmasking of latent central hypothyroidism.
Most serious adverse reactions include intracranial hypertension, diabetic retinopathy, glucose intolerance, slipped capital femoral epiphysis, progression of preexisting scoliosis, sudden death in pediatric patients with Prader-Willi syndrome with risk factors including severe obesity, history of upper airway obstruction or sleep apnea and unidentified respiratory infection, intracranial tumors as a 2nd tumor in patients who had been treated for a 1st neoplasm.
In clinical studies wherein children with Turner Syndrome were treated, the most frequently reported adverse events were common childhood diseases including influenza-like illness, otitis media, upper respiratory tract infection, otitis externa, gastroenteritis and eczema.
Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear and hearing disorders. Somatropin treatment may increase the occurrence of otitis media in patients with Turner Syndrome.
Scientists at the University of California, San Diego (UCSD) School of Medicine have uncovered a novel pathway by which hormones elevated in inflammation, cancer and cell injury act on cells to stimulate their growth.
The research team led by Joan Heller Brown, Ph.D., professor and chair of the department of Pharmacology
at UCSD, has demonstrated in a mouse model that a newly discovered subtype of the phospholipase C (PLC) family of enzymes, called PLC-epsilon, has the unique ability to activate a second and distinct signaling pathway that cells require for proliferation. The study is currently on line in advance of publication by the Proceedings of the National Academy of Science (PNAS.)
The studies reported in the PNAS demonstrate that "in the cell, hormones that activate small G proteins are highly dependent on PLC- to generate second messengers," said Heller Brown. "In addition, and more surprisingly, we discovered that this enzyme is required for cell growth because it serves a second function when activated by hormones."
Many intracellular signaling proteins work as molecular "switches." The reception of a signal activates them and causes them to pass the signal through the cell, after which they can be switched off until another signal is received. G proteins are a commonly used form of switch, activated by the binding of guanine nucleotides. PLC's normal role is delivering signals from outside the cell to inside the cell by generating "second messengers" that tell cells to contract and secrete. But these signals alone are not enough to cause cells to increase their growth. The first author of the paper, Simona Citro, Ph.D., and colleagues found that PLC- uniquely activates a second and distinctly different signaling cascade. This second signal catalyzes activation of a Ras family of small G proteins associated with cell growth.
"In combination with the first set of signals, this can lead to cell proliferation and could contribute to inflammation or cancer if left unchecked," said Citro.
"PLC plays a critical role in physiological processes including heart function, cell secretion and blood pressure control, so one would not normally want to block its activity," added Heller Brown. The UCSD researchers' discovery may enable scientists to target this novel PLC isoform or inhibit only its second function, preventing pathological responses while leaving PLC's critical positive role intact.
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