Achondroplasia, a representative rare genetic disorder that causes short stature, is entering a new era in treatment.
The average height of men with achondroplasia is about 130 cm, while women average around 120 cm. However, new therapies are emerging that could increase height by up to 20 cm.
Why, then, are patients with achondroplasia shorter in stature?
Professor Lee Beom-hee of the Department of Pediatrics at Asan Medical Center (Credit: YouTube channel "Medical School Library")
Professor Lee Beom-hee of the Department of Pediatrics at Asan Medical Center explained on the YouTube channel “Medical School Library” that “achondroplasia is caused by a gain-of-function mutation in FGFR3,” adding that “this leads to overactivation of the MAPK pathway, an important signaling pathway involved in bone growth.”
The MAPK pathway normally promotes cell growth and development. While one might expect overactivation of this pathway to increase growth, the opposite occurs. Professor Lee noted, “Noonan syndrome and neurofibromatosis are also diseases characterized by overactivation of the MAPK pathway,” adding that “this overactivation actually suppresses growth.”
Achondroplasia is often diagnosed within months after birth. During infancy, when rapid growth occurs, affected children typically exhibit characteristic physical features, such as shortened limbs and a relatively larger trunk and head, facilitating early diagnosis.
How, then, is achondroplasia currently treated?
Professor Lee explained, “Because the arms and legs are short, limb-lengthening surgery may be necessary. Knee deformities can also develop, making the role of orthopedic specialists important.” He added, “Some patients use growth hormone therapy, but it is generally not considered highly effective.”
Recently, more effective drugs targeting the underlying disease mechanism of achondroplasia have been developed.
Among them are CNP (C-type natriuretic peptide) analog therapies. CNP is a naturally occurring protein involved in bone growth regulation that promotes cartilage cell proliferation and bone formation by blocking inhibitory signals in the growth plate. Professor Lee explained, “Many CNP analog therapies have recently been developed,” adding that “CNP enters cells and suppresses the overactivated MAPK pathway.”
Achondroplasia pathway graphic captured from the “Medical School Library” YouTube channel.
Korea has already approved a first-generation CNP analog therapy, Voxzogo (vosoritide), which is currently undergoing the national health insurance reimbursement process. Professor Lee said, “This drug is a CNP analog targeted therapy that selectively suppresses overactivation of the MAPK pathway,” adding that “when administered from as early as four months of age, patients may grow about 20 cm taller compared to those who do not receive treatment.”
While Voxzogo requires daily injections, another newly approved therapy in the U.S., Yuviwel (navepegritide), is administered once weekly.
In addition to short stature, children with achondroplasia may also develop rare but serious complications. One such condition is foramen magnum stenosis, in which the junction between the skull and spine narrows, compressing nerves.
Professor Lee emphasized the importance of neurosurgical management, stating, “If a child with achondroplasia experiences a sudden increase in head circumference, compression of the spinal cord causing leg stiffness or paralysis, or breathing difficulties, decompression surgery may be necessary.”
Kim Kyoung-Won
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