Hypophosphataemia means low levels of phosphate in the blood. Phosphate is a mineral that is essential for the normal formation of bones and teeth.

In most cases, the signs and symptoms of hereditary hypophosphataemic (hypo-phos-phat-emic) rickets begin in early childhood. The characteristics of the disease vary widely, even among affected members of the same family. Mildly affected individuals may have hypophosphataemia without other signs and symptoms. Severely affected children experience slow growth and are shorter than their peers. They develop bone abnormalities that can interfere with movement and cause bone pain.

The most noticeable of these abnormalities are bowed legs or knock knees (a condition in which the lower legs are positioned at an outward angle). These abnormalities become apparent with weight-bearing activities such as walking. If untreated, they tend to worsen with time.

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Other signs and symptoms of hereditary hypophosphataemic rickets can include premature fusion of the skull bones (craniosynostosis) and in rare cases structural defects to the base of the skull and cerebellum (chiari malformation).

Dental abnormalities such spontaneous abscessing without trauma or poor hygiene as a result of defects in the dentin along with enlarged pulp chambers may also occur.

The disease may also cause abnormal bone growth where ligaments and tendons attach to joints (enthesopathy). In adults, hypophosphataemia is characterised by a softening of the bones known as osteomalacia.

What is the most common hereditary hypophosphataemic rickets?

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.

What are ultra rare hereditary hypophosphataemic rickets?

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 mosaicism or mendelian hypophosphataemia’s, such as hypophosphataemic bone disease and autosomal recessive hypophosphatemia without hypercalciuria.

How are you diagnosed?

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.