For every abnormal blood test and biochemical abnormality medical students and doctors learn lists of causes, at the bottom of which are rare diseases (often caused by a single gene defect). This has been relatively academic in the past, but recently targeted biologic therapies have started to become available for these rare diseases. X-linked hypophosphatemia is one of those rare disorders, affecting on average 1/20,000. XLH was until recently managed with supportive therapy and often referred to as Vitamin D Resistant Rickets. In today's medical landscape, doctors and healthcare professionals can connect and share their experiences and expertise in the diagnosis and treatment of XLH patients. XLH is caused by mutations in the Phosphate regulating gene with Homology to Endopeptidases located on the X chromosome (PHEX) gene. Sometimes XLH is due to a de novo mutation in the PHEX gene. This gene encodes an endopeptidase, expressed in teeth and bones and is important in regulating the synthesis of fibroblast growth factor 23 (FGF-23), which in turn regulates renal reabsorption of phosphate. PHEX gene mutations lead to increased expression of FGF-23 and subsequently renal phosphate wasting and low serum phosphate concentration.

How do XLH patients present?

XLH usually manifests in childhood in the first two years of life and when a child starts to walk. Common features are progressive bowing of the lower extremities and slow growth velocity with short stature. Affected children might also complain of bone and joint pain and over time develop rachitic bone deformities. Examples of these deformities are epiphyseal swelling, genu varum and valgus, rachitic rosary (figure 2) and thickened frontal and parietal bones. Bowing of the legs (figure 1) can also be seen.

Fig 1: Note the bowing of the legs in this 2 year old child

Image created by Michael L. Richardson, M.D. Sept 28th, 2004de: Bild:Rachitis.jpg Originally from en.wikipedia; description page is/was here., CC BY-SA 1.0, https://commons.wikimedia.org/w/index.php?curid=59299

Fig 2: Rachitic rosary (beading of ribs/nodularity at costochondral junctions) in hypophosphatemic rickets

By Frank Gaillard CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=14717832 Hypophosphatemia usually leads to elevated levels of 1,25(OH)₂D. However, XLH patients tend to have low to normal levels of this active vitamin D metabolite. This can be explained by the fact that FGF-23 also regulates Vitamin D metabolism as it decreases the synthesis and increases the catabolism of 1,25(OH)₂D. This also explains why XLH patients do not respond to traditional Vitamin D supplementation as a management option in the way nutritional rickets does. The main laboratory findings that are characteristic for XLH is low-serum phosphate and low to normal levels of 1,25(OH)2D. Other findings includenormal serum calcium and 25-hydroxyvitamin D, normal parathyroid hormone level, elevated alkaline phosphataseand inappropriately normal or low serum levels of calcitriol. Urine and blood samples will show a reduced tubular resorption of phosphate corrected for glomerular filtration rate (TmP/GFR).  Molecular genetic testing can also be used to identify pathogenic variants of the PHEX gene. It is important to not misdiagnose and mismanage this form of rickets, as XLH patients do not respond to traditional Vitamin D supplementation. Mismanagement whilst bones are still growing can lead to permanent skeletal defects. Phosphate wasting is the most important pathological defect, which is why this disorder is managed by oral replacement of phosphate. This should be combined with supplementing the active vitamin D metabolite Calcitriol (which also reduced the risk of hyperparathyroidism associated with phosphate therapy). XLH is known to have a heterogenous response to therapy, with children on optimal therapy from a young age still developing bone deformities later on and needing orthopaedic surgical procedures to correct these. Newer therapies have now been developed to treat the underlying pathophysiology. The NICE evidence committee recently concluded that there is enough evidence to suggest that the monoclonal antibody Burosumab would provide meaningful clinical benefits in the treatment of XLH. Join in discussions in  MedShr’s Paediatric Osteomalacia and XLH Discussion Group – connect with a global community of experts, and GPs discussing this rare disorder. Join the group here