Parents in Korea and other Asian countries are unusually concerned about their children's height. That is partly because Asians tend to be shorter than people in the West. Still, this interest in height has given rise to the academic term "heightism" in sociology, referring to social prejudice and discrimination based on height.

According to a survey in Korea, shocking reports exist that as many as 30 percent of children and adolescents use various dietary supplements, drugs, and even devices with unclear scientific evidence to increase their height. On average, these children's targeted height is 181 centimeters for males and 169 centimeters for females, six to eight centimeters taller than the median Korean adult height.

Most patients with rare diseases are very short, even as adults. There are many reasons for this. Some are born small because they don’t grow well in the womb. After birth, they don't have the growth to catch up, so they grow very short, which is even more heartbreaking for their parents. In very unusual cases, some rare diseases make people taller than others. I’ll cover them another time. Growth (height, weight, head circumference) and development (motor, social, cognitive, language, etc.) should be harmonious and considered normal.

Fortunately, new medications are being developed to prevent and treat stunting for some rare diseases. In this article, I will focus on three rare diseases for which new drugs have been approved in recent years.

A case in point is achondroplasia.

Achondroplasia is inherited in an autosomal dominant manner, with an incidence of 1 in 25,000 new births. Most cases occur without a family history. The risk increases according to the father’s age. In patients who marry later in life, 50 percent of their children will develop the condition.

Based on prenatal ultrasound findings, chondrodysplasia can be suspected from the second trimester of pregnancy onward. At birth, the characteristic findings are already present. The baby has a large head with a protruding forehead, a low nasal bridge, short fingers, and trident-like fingers. A relatively long and narrow torso with short limbs (especially the proximal limbs close to the torso are disproportionately short) is characteristic.

They have been very disproportionately short from childhood (the final adult height is 131±5.6 cm in males and 124±5.9 cm in females). Intelligence is normal, and pregnancy is possible in adulthood. If the potentially fatal complications, such as hydrocephalus and cervical spinal cord injury, are detected early and managed well, the child can lead a normal life.

Some such celebrities are working as actors in foreign countries. Surgical procedures to lengthen the limbs have been the mainstay of treatment for short stature. However, in 2021, vosoritide (Voxzogo in product name) was approved in the United States and Europe for children with open growth plates aged five and older. In 2023, it was expanded to include children of all ages. The drug is said to increase height by about 1.6 centimeters per year. The drug is based on correcting the molecular pathology of the signal transduction system. It is yet to be approved in Korea.

The second disease is X-linked hypophosphatemic rickets. The frequency is believed to be 1 in 25,000 newborns. It is caused by a mutation in a gene called PHEX, located on the female sex chromosome X. Women who are carriers also develop symptoms. This is known as X-linked dominant inheritance.

Low blood phosphate levels characterize the disease due to the excretion of phosphate in the urine. About 85 percent of the phosphate filtered by the kidneys must be reabsorbed back into the blood, and the genetic abnormality is in the reabsorption mechanism. If an adequate supply of phosphate is not made, it leads to rickets.

In children, the mineralization of the growth plate cartilage is also impaired, resulting in stunted growth and leg deformity. It’s also known as vitamin D-resistant rickets because it doesn’t improve with routine vitamin D administration. It’s clinically asymptomatic immediately after birth, but the deformity of the lower limbs becomes evident between six months and two years of age when children usually start to stand, walk, and bear weight. The child walks with a waddling gait.

In adults, pain can be associated with osteomalacia. Fractures are more prone to occur, and arthritis or excessive calcification of the tendons, where they attach to the muscles, can cause severe pain. Premature tooth loss and periodontitis are common. It also causes shortness of stature, and if left untreated, it’s estimated that people can reach 130 to 165 centimeters.

The traditional treatment has been phosphate and vitamin D, but many unmet needs exist. In 2018, a new treatment, burosumab (Crysvita in product name), was approved in the U.S. and Europe. The drug is an orphan drug developed based on a change in a biomarker. In Korea, reimbursement for select patients was approved in 2023.

The third disease, hypophosphatasia, is a genetic, biochemical metabolic disorder. It is an alkaline phosphatase deficiency, an enzyme essential for muscle metabolism and bone formation, resulting in impaired bone regeneration and mineralization. There are six to seven different forms of the disease, depending on the time of onset and severity of symptoms, with the most lethal forms occurring during the perinatal and infancy period. It is a very deadly disease with an incidence of 1 in 100,000 newborns, but early detection can be life-saving as there are treatments available.

From birth to six months of age, craniosynostosis, decreased mineralization, rickety ribs, pulmonary insufficiency, complications from hypercalcemia, anorexia, impaired growth, and decreased muscle tone are seen. Rarely, vitamin B6-dependent convulsions are present. The primary (incisors) teeth are usually lost before the age of five years and are accompanied by short stature, duck gait, skeletal deformities, bone pain, and fractures. In 2015, an enzyme treatment called asfotase alfa (Strensiq in product name) was approved in the United States and Europe. In Korea, it was approved for reimbursement in 2020 in select patients. This drug is a type of enzyme replacement therapy that replaces the deficient enzyme.

All orphan drugs used to treat the aforementioned diseases are too expensive for individuals to pay for, so most are covered by the government through special calculations and medical benefits. It takes a considerable amount of time for new drugs to be approved overseas and introduced in Korea.

While this can be frustrating for patients, countries with limited financial resources have no choice but to prioritize by identifying unmet medical needs in clinical practice, such as whether there are existing affordable alternatives, the severity of the disease, and the number of patients. That explains why it is important to introduce new drugs developed by foreign countries quickly, but it is more important to develop new drugs domestically.

Professor Yoo Han-wook, Department of Pediatrics at CHA University Bundang Medical Center

Professor Yoo graduated from Seoul National University College of Medicine and trained at the Jewish Genetics Center at Mount Sinai Hospital in the United States from 1989 to 1992 before becoming a board-certified medical geneticist. He served as the director of the Medical Genetics Clinic at Asan Medical Center in Seoul and the director of the Pediatric Hospital. He is currently a professor of pediatrics at CHA University Bundang Medical Center. He has served as president of the Korean Society of Pediatric Endocrinology, chairman of the Korean Society of Medical Genetics and Genomics, director of the Center for Genomic Research on Congenital Malformations and Genetic Diseases at the Ministry of Welfare, and chairman of the planning committee for the Conquering Rare and Difficult Diseases Project at the Korea Health Industry Development Institute.