Researchers have described several forms of hereditary hypophosphataemic rickets, which are distinguished by their pattern of inheritance and genetic cause. The most common form of the disorder is known as X-linked hypophosphataemia (XLH). It has an X-linked dominant pattern of inheritance. XLH affects globally 22,000-40,000 new births each year.
X-linked recessive hypophosphataemia (XLRH), autosomal dominant hypophosphataemic rickets (ADHR), and autosomal recessive forms of the disorder are much rarer.
Another rare type of the disorder is known as hereditary hypophosphataemic rickets with hypercalciuria (HHRH). In addition to hypophosphatemia, this condition is characterised by the excretion of high levels of calcium in the urine (hypercalciuria).
Phosphate wasting is also a prominent feature of tumour-induced osteomalacia (TIO), which is caused by rare, mostly benign mesenchymal tumours that overexpress fibroblast growth factor 23 (FGF23)
Besides these well-defined conditions, there may be further Mendelian hypophosphataemia’s, such as hypophosphataemic bone disease and autosomal recessive hypophosphatemia without hypercalciuria.
In children the first thing that is noticed is that there is some bowing of the legs. It can be missed initially as normal toddlers can have a degree of normal ‘physiological’ bowing but this is normally mild. There are other clues however. The children may walk late or have pain in their legs. There may be swelling of the ankles, knees and wrists and they may start to walk with a waddling gait. These are all signs of rickets and many times children are misdiagnosed as having vitamin D deficiency rickets.
Normally the diagnosis of rickets is made by radiographs. Once rickets is diagnosed and vitamin D deficiency is ruled out then the diagnosis of hypophosphataemic rickets is confirmed using paired urine and blood tests. This looks at how much phosphate is being lost in the urine on the background of a low blood phosphate level (inappropriate phosphate wasting). Other clues to the diagnosis is that the children often have tooth abscesses or there may be affected family members.
The key to making the diagnosis is the doctor thinking about this as a possibility. Sometimes the phosphate can be in the lower part of the normal range and children can go for many months and years before someone looks more closely.
After establishing the clinical diagnosis, the genetic diagnosis can be made. Most of the time it is due to a mutation in PHEX but there are other genetic causes of hypophosphataemic rickets.