Short Stature

Experimental drug can encourage bone growth in children with dwarfism

Short Stature | Johns Hopkins Medicine

Researchers at Johns Hopkins Medicine, the Murdoch Children's Research Institute in Australia and seven other medical institutions report that an experimental drug called vosoritide, which interferes with certain proteins that block bone growth, allowed the average annual growth rate to increase in a study of 35 children and teenagers with achondroplasia, a form of dwarfism. The patients' average boost in height to about 6 centimeters (2.4 inches) per year is close to growth rates among children of average stature, and the side effects of the drug were mostly mild, according to the researchers.

Results of the four-year study are summarized online June 18 in the New England Journal of Medicine.

“An increase in the annual growth rate alone may have a positive effect on some patients' quality of life. For other patients, now and in the future, our hope is that the altered bone growth throughout the body could ease such problems as sleep apnea, neurological and leg and back problems, and improve their quality of life,” says Julie Hoover-Fong, M.D.

, Ph.D., associate professor and director of the Greenberg Center for Skeletal Dysplasias at the Johns Hopkins McKusick-Nathans Institute of Genetic Medicine. “Right now, the results of the study show an impact on growth, and this effect is sustained, at least over nearly four years in this trial. The potential long-term benefit will take more time to observe.

Achondroplasia, although rare, is the most common form of dwarfism worldwide, affecting an estimated 1 in 15,000-40,000 live births. The condition is caused by mutations in a gene called FGFR3 that result in the excess production of proteins that slow bone growth. The disorder is marked by disproportionate short stature with shortened limbs, near normal-sized torsos and enlarged heads.

About 20% of people with achondroplasia inherit the mutations, meaning most children born with it have parents of average height. People with achondroplasia are prone to develop sleep apnea, chronic ear infections, neurological problems, spinal stenosis and bowed legs, frequently requiring surgical treatments to relieve pain and other symptoms.

“About half of these children will need spinal or other surgery, and this can mean a lot of time away from school as the child recovers and rehabilitates after surgery, which can affect important social connections,” says Ravi Savarirayan, M.B.B.S., M.D., clinical geneticist and group leader of skeletal biology and disease at Murdoch Children's Research Institute.

There are no treatments able to reverse achondroplasia or treat the genetic culprit itself. However, growth hormone has been approved to treat the condition in Japan and occasionally is used off label elsewhere, but is not considered very effective in achondroplasia.

Vosoritide is a synthetic version of a protein present in humans called C-type natriuretic peptide.

It is designed to bind to a specific receptor on the surface of chondrocytes, a type of cartilage cell found in the growth plates of bones.

Once joined, the vosoritide-receptor connection sends a signal inside the fibroblast to stanch the flow of negative growth factors that were triggered by the mutation in the FGFR3 gene.

“This is the first therapeutic option that targets the molecular cause of the condition,” says Hoover-Fong.

For the currently reported study, conducted between January 2014 and July 2018, investigators enrolled 35 children ages 5-14 and followed them for a midpoint of 42 months. There were 19 girls and 16 boys, including two Hispanics, seven Asians and two African Americans.

To enroll in the study, participants had previously been monitored for six months to determine their baseline growth rate. Then, for six months, participants received a daily vosoritide injection through the skin at doses ranging from 2.5-30 micrograms/kilogram.

Over the four-year study, two participants discontinued the trial because of anxiety with daily injections. One left the trial because their growth plates closed, and another withdrew for unknown reasons.

A fifth was withdrawn when doctors found during a routine electrocardiography that a participant had Wolff-Parkinson-White syndrome, a condition in the electrical circuits of heart muscles that causes rapid heartbeat.

At the end of six months, 30 participants opted to continue taking vosoritide. Participants who had earlier received the lowest doses of the drug received increased dosages, up to 15 micrograms/kg, and the other participants continued to receive their initial doses of 15 and 30 micrograms/kg. One of the 30 patients withdrew from the study to undergo limb-lengthening surgery.

Overall, the researchers found that, on average, the childrens' annual growth rate increased from below 4 centimeters per year to just below 6 centimeters per year. “They grew nearly 2 centimeters more, on average, per year, and this rate comes close to the annual growth of average stature people,” says Hoover-Fong.

The research team also found that the growth rate increase lasted over the nearly four-year study.

Moving forward, Hoover-Fong says all the remaining study participants will receive vosoritide until they reach their final adult height or they choose to withdraw from the study.

She says the sweet spot of vosoritide dose seems to be at 15 micrograms/kilogram as participants who received 30 micrograms/kilogram did not gain any growth velocity beyond those who received 15.

All 35 study participants had at least one side effect, considered mild and reversible, including injection site pain, swelling, headache, cough and low-grade fever.

One child was admitted to a hospital for surgery to remove their tonsils and adenoids, which is common in achondroplasia to treat sleep apnea, and another had enlarged tonsils.

One child had a congenital cyst in the neck and another had a fluid-filled cyst in the spinal cord.

“Importantly, none of the children experienced an anaphylactic reaction to the drug and none developed a low blood pressure problem that required medical intervention, which was a concern with this type of drug,” says Hoover-Fong.

Some of the participants were averse to needle sticks, but this became less of a problem as the study went on, she says.

There are ongoing clinical trials of vosoritide, including a randomized, double-blind, placebo-controlled study in more than 100 children and teenagers with achondroplasia worldwide. It is expected to end in 2019, and a global study of the drug in 70 children younger than 5 years is ongoing.

At least four other experimental drugs that target different molecular bone growth receptors or pathways are currently being tested in children and teenagers with achondroplasia at Johns Hopkins and elsewhere.

The cost of vosoritide has not been determined.

Story Source:

Materials provided by Johns Hopkins Medicine. Note: Content may be edited for style and length.

Journal Reference:

  1. Ravi Savarirayan, Melita Irving, Carlos A. Bacino, Bret Bostwick, Joel Charrow, Valerie Cormier-Daire, Kim-Hanh Le Quan Sang, Patricia Dickson, Paul Harmatz, John Phillips, Natalie Owen, Anu Cherukuri, Kala Jayaram, George S. Jeha, Kevin Larimore, Ming-Liang Chan, Alice Huntsman Labed, Jonathan Day, Julie Hoover-Fong. C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia. New England Journal of Medicine, 2019; DOI: 10.1056/NEJMoa1813446


Johns Hopkins Klinefelter Syndrome Center

Short Stature | Johns Hopkins Medicine

From the 1889 opening of The Johns Hopkins Hospital, to the opening of the School of Medicine four years later, there emerged the concept of combining research, teaching and patient care. This model, the first of its kind, would lead to a national and international reputation for excellence and discovery.

Today, Johns Hopkins uses one overarching name—Johns Hopkins Medicine—to identify its entire medical enterprise.

This $5 billion system unites the physicians and scientists of the Johns Hopkins University School of Medicine with the health professionals and facilities that make up the broad, integrated Johns Hopkins Health System.

The Johns Hopkins Hospital and its affiliated hospitals and clinics has been ranked #1 by US News and World Report for the last 20 years. Its commitment to medical education, clinical care and research has made it one of the premier international institutions.

Mission: We are a comprehensive multidisciplinary health care system designed to care for boys and men with KS. Our medical specialists act as a team to provide the most up to date services to maintain the long-term health of men with KS.

The goals of the clinic are:

  • To be the premier center for the clinical care of men with sex chromosomal disorders
  • To develop standardized testing procedures for this population
  • To develop treatment guidelines for men with sex chromosomal disorders
  • To expand the scientific knowledge on the diagnosis, pathophysiology and treatment of the syndrome

Klinefelter syndrome is a group of conditions that affects the health of males who are born with at least one extra X chromosome. Chromosomes, found in all body cells, contain genes. Genes provide specific instructions for body characteristics and functions.

For example, some genes determine height and hair color. Other genes influence language skills and reproductive functions. Each person typically has 23 pairs of chromosomes. One of these pairs (sex chromosomes) determines a person’s sex. A baby with two X chromosomes (XX) is female.

A baby with one X chromosome and one Y chromosome (XY) is male.

Most males with Klinefelter syndrome, also called XXY males, have two X chromosomes instead of one. The extra X usually occurs in all body cells. Sometimes the extra X only occurs in some cells, resulting in a less severe form of the syndrome. This is called a mosaicism, and is very common. Rarely, a more severe form occurs when there are two or more extra X chromosomes.

What are the signs and symptoms of Klinefelter syndrome?

Signs and symptoms can vary. Some males have no symptoms but a doctor will be able to see subtle physical signs of the syndrome. Many males are not diagnosed until puberty or adulthood. As many as two-thirds of men with the syndrome may never be diagnosed. Many men with mosaicism for XXY males do not have all of the signs and symptoms listed below.

Infants and young boys may have:

  • Problems at birth, such as testicles that haven’t dropped into the scrotum or a hernia*
  • A small penis
  • Weak muscles
  • Speech and language problems, such as delayed speech
  • Problems with learning and reading
  • Problems fitting in socially
  • Mood and behavioral problems

Adolescents may ALSO have:

  • Small, firm testicles
  • Enlarged breasts, called gynecomastia
  • Long legs but a short trunk
  • Above-average height
  • Reduced muscle bulk
  • Sparse facial and body hair
  • Delayed puberty
  • Low energy levels

Adults may ALSO have:

  • Low testosterone (male hormone) levels
  • Infertility from a lack of sperm
  • Decreased sex drive
  • Problems getting or keeping an erection
  • Other difficulties, such as being unable to make plans or solve problems

* when an internal organ bulges through a body cavity wall

How is Klinefelter syndrome diagnosed?

Diagnosis is a physical examination, hormone testing, and chromosome analysis. The syndrome can also be diagnosed before birth but testing is not routinely done at that time.

Health Problems Associated with Klinefelter Syndrome

Klinefelter syndrome can lead to weak bones (osteoporosis), varicose veins, and autoimmune diseases (when the immune system acts against the body), such as lupus or rheumatoid arthritis.

XXY males have an increased risk for breast cancer and cancers that affect blood, bone marrow, or lymph nodes, such as leukemia.

They also tend to have excess fat around the abdomen (which raises the risk of health problems), heart and blood vessel disease, and type 2 diabetes.

What is the treatment for Klinefelter syndrome?

Treatment can help males overcome many of the physical, social, and learning problems that are part of the syndrome. Males with Klinefelter syndrome should be seen by a team of health care providers.

The team may include endocrinologists, general practitioners, pediatricians, urologists, speech therapists, genetic counselors, and psychologists. Surgery may be needed to reduce breast size.

With treatment, men can lead very normal lives.

Experts recommend testosterone replacement, starting during puberty, for proper development of muscles, bones, male sex characteristics such as facial hair, and sexual function.

Continued treatment throughout life helps prevent long-term health problems. Testosterone replacement does not cure infertility, however.

Infertility treatments require specialized—and costly—techniques, but some men with Klinefelter syndrome have been able to father children.


Shuler: Johns Hopkins Should Live Up To Its Values

Short Stature | Johns Hopkins Medicine

The following are AFL-CIO Secretary-Treasurer Liz Shuler's prepared remarks at a rally in support of nurses at Johns Hopkins Hospital: 

Sisters and brothers, Johns Hopkins Hospital was founded 130 years ago on the ideals of “respect, dignity and integrity.” Its philanthropist namesake specifically set aside funds for a hospital that would “treat the poor without charge” no matter the patient’s “age, sex or color.”

Today, Johns Hopkins Hospital is abandoning its values!

A recent report from NNU and the AFL-CIO found that over the past decade, Johns Hopkins has filed more than 2,400 lawsuits in Maryland courts over payments for alleged medical debt from former patients. In more than 400 of those cases, the hospital won the right to garnish patients’ wages or bank accounts.

Johns Hopkins hardly needs help. It’s a multi-billion-dollar business! In 2017 alone, it received nearly $165 million in tax breaks—and here’s the kicker—$25 million in what’s known as “rate reimbursements”….to provide care to low-income patients who don’t have health insurance or cannot cover their out-of-pocket costs.

Charity care is something Johns Hopkins is REQUIRED to offer by the state of Maryland. Yet, it falls short of that obligation! Many Johns Hopkins patients would ly qualify for help to pay their health care bills, but say the hospital never even told them it was an option!

It’s no wonder Johns Hopkins consistently ranks last or next to last among Maryland hospitals in charity care relative to the reimbursements it receives from the state.

And listen to this: Of the 10 zip codes with the highest number of residents being sued by Johns Hopkins, 9 have poverty rates higher than the state average, and 5 have child poverty rates more than double the state average.

These lawsuits disproportionately harm African-Americans, the families who live side by side with the hospital. John Hopkins is a bad neighbor!

Despite our report and the media attention it got…despite widespread community criticism and outrage…and despite recent announcements from two other large hospitals—Mary Washington Healthcare in Fredericksburg, Virginia, and Methodist Le Bonheur [bawn-er] in Memphis, Tennessee—Johns Hopkins is STILL continuing its egregious medical debt practices!

That’s why we’re calling on Johns Hopkins to:

  • Cancel all medical debt lawsuits filed against low-income patients!

  • End the practice of garnishing wages!

  • Increase the amount of charity care it provides!

  • And guarantee that ALL patients are informed of the opportunity to qualify for free or reduced medical care!

We’re demanding no less than fair treatment! We’re demanding justice in Baltimore and beyond! We’re demanding that Johns Hopkins Hospital lives up to its values! 

Sisters and brothers, is that too much to ask?

Johns Hopkins—it’s time to end these egregious practices NOW!