X-linked hypophosphatemia (XLH) is a rare and lifelong phosphate wasting disorder. It is characterized by pathological elevations in concentration and activity of hormones called fibroblast growth factor 23.
The ‘X’ in the “XLH” stands for “X-linked” which implies that XLH is a sex-linked disease, that is passed on from one generation to the other due to a mutation in the X chromosome. Therefore, a factor that increases the likelihood of developing XLH is family history. This means that there is a high chance of developing XLH if your parents or any closely related family member has this condition.
Why does XLH occur?
As stated above XLH occurs due to the presence of a mutated gene on an X-chromosome, so children of carriers are likely to inherit this disease. However, gene mutations are unpredictable. In the context of XLH, gene mutation in the PHEX gene is part of the X chromosome. It causes the body to produce an excess of a hormone called fibroblast growth factor 23 (FGF23) regulates phosphate concentration in the blood. FGF23 inhibits renal phosphate reabsorption as it works on increasing the excretion of phosphate by the kidneys. This causes a lack of phosphate in the blood which leads to bone weakness, muscle damage and fractures.
Sequence of events leading to XLH
Excess FGF23 causes loss of dangerous amounts of phosphate through urine.
This phosphate wasting leads to low levels of phosphorus in the blood. Which causes a condition called hypophosphatemia.
This leads to soft and weak bones which are the prime symptoms of XLH
Since this condition is a sex-linked disease, you may wonder if XLH is prevalent in particular sex. But the answer is not as simple as you think; there is a twist.
1. If the mother is the one who is affected, then 50% of all children will be at risk of their sex.
2. If the father is the one affected, then all daughters will have XLH but none of the sons will have XLH
3. If both parents are affected then all daughters and 50% of sons will be affected
The gene for this disease is located on the X chromosome. Which means it can’t be avoided by anybody as both males and females have a X chromosome. But this condition is more common in females as they have XX chromosomes.
Visible indicators of XLH?
This disease has local and systemic effects including:
Impaired growth
Rickets
Bone abnormalities and bone pain
Constant dental abscesses
Muscular dysfunction.
How is XLH diagnosed?
The initial symptoms of XLH are bone pain, tenderness at joints or undetected fractures which are incidentally found on x-ray. The earliest sign is when children begin to stand when the bowing of the legs can be identified. But over a period of time, slow growth in height may develop which leads to short stature as an adult.
What diagnostic tests can be done to detect XLH? E.g of some Diagnostic tests include:
Blood and urine test: The positive result shows that there is low serum phosphate concentration in the blood and elevated levels of alkaline phosphatase.
Genetic testing: It involves examining a patient's DNA to identify a mutation in their genes, which may be the cause of the disease.
An example of genetic testing used to identify XLH:
Targeted gene panel sequencing was done to identify a novel variant in the PHEX gene of a 24-month-old boy with hypophosphatemic rickets.
Targeted gene panel sequencing was performed to detect mutations in genes associated with hypophosphatemic rickets. Genomic DNA was extracted from the peripheral blood and the library was prepared using the Sequencing Panel. Massively parallel sequencing was performed on this panel. Sequence reads were mapped to UCSC hg19 standard base for comparative analysis. The results of targeted gene panel sequencing revealed a variant in the PHEX gene, which was then confirmed by Sanger sequencing using custom-designed primers.
The variant in the PHEX gene was also found in his mother, who had a short stature. In addition, this variant has been suggested to affect protein function in validation studies using in silico analyses. This proved that the variant in the PHEX gene can be classified as a likely pathogenic variant.
What are the long-term effects of XLH?
While some may think that XLH occurs only during childhood, adults with XLH continue to experience symptoms of the ongoing condition.
Risks at the paediatric level
Delayed and disproportionate growth.
Rickets
Delayed motor development.
Risks for adults:
Fractures
Osteoarthritis
Hearing loss
Disability that impacts ability to work
Common risk for both adults and children:
Short stature
Deformity of weight bearing limbs
Tooth abscess
Bone and joint pain
Joint stiffness
Muscle pain and weakness
Is there any cure for XLH?
XLH is very rare and different compared to other forms of rickets. This is because vitamin C therapy is effective in treating rickets but it does not affect XLH. In spite of that there is still good news because on April 17, 2018, The U.S. Food and Drug Administration approved Crysvita (burosumab-twza) as the first ever drug to treat adults and children ages 1 year and older with x-linked hypophosphatemia (XLH).
“This is the first FDA-approved medication for the treatment of XLH and a real breakthrough for those living with this serious disease”, said Julie Beitz, M.D., director of the Office of Drug Evaluation III in the FDA’s Centre for Drug Evaluation and Research.
The clinical trials done to validate the use of crysvita:
A placebo trial, in which 8% of the adults receiving placebo achieved normal phosphorus levels. In the controlled trial, 94% of the adults receiving Crysvita once a month, achieved normal phosphorus levels. In children, 94 to 100 per cent of patients treated with Crysvita every two weeks achieved normal
phosphorus levels. The X-ray findings associated with XLH showed improvements in both children and adults.
Most common side effects in adults:
Back pain, headache, restless leg syndrome, decreased vitamin D, dizziness and constipation.
Common side effects in children:
Headache, reaction at the injection site, nausea, decrease in vitamin D and fever.
XLH is a rare disease of 1 in 25,000 incidences. But the symptoms and signs such as delayed motor development, short stature and rickets make it easy to diagnose patients. Simple diagnostic tests such as blood and urine samples, and genetic tests are sufficient to detect XLH. Crysvita is an effective cure for XLH as it is able to bring phosphorus levels in the blood back to normal. Despite side effects, crysvita can help patients live happy and content lives as it improves the mobility of the patient. The benefits outweighing the risks prove Crysvita as a successful treatment and a breakthrough in the world of rare diseases
Written by: Aditya Bagwe
Edited by: Svasti Tewari and Sakshi Deshpande
Glossary
Gene mutation- A permanent change in the DNA sequence that makes up the gene.
Bibliography
Beck-Nielsen, Signe Sparre, et al. FGF23 And Its Role in X-Linked Hypophosphatemia-Related Morbidity, Kyowa Kirin Services Ltd Provided Financial Support for the Writing of This Manuscript. Medialis Ltd Provided Medical Writing Support and Were Also Funded by Kyowa Kirin Services Ltd., 26 Feb. 2019, https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1014-8.
What Is XLH?, Ultragenyx Pharmaceutical Inc., 17 Aug. 2020, https://www.xlhlink.com/pat/what-is-xlh/.
Solorzano, Christine Burt. X-Linked Hypophosphatemia (XLH), ENDOCRINE SOCIETY, 23 Jan. 2022, https://www.endocrine.org/patient-engagement/endocrine-library/x-linked-hypophosphatemia.
“FDA Approves First Therapy for Rare Inherited Form of Rickets, x-Linked Hypophosphatemia.” FDA Approves First Therapy for Rare Inherited Form of Rickets, x-Linked Hypophosphatemia , US Food and Drug Administration , 19 Apr. 2018, https://www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-rare-inherited-form-rickets-x-linked-hypophosphatemia.
Jo, Ha Young, and Heirim Lee. Identification of a Novel Variant in the PHEX Gene Using Targeted Gene Panel Sequencing in a 24-Month-Old Boy with Hypophosphatemic Rickets, National Library of Medicine , 31 Mar. 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136512/.
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