Hypophosphataemia

X-linked hypophosphataemia (XLH) is the predominant hereditary form and the reference phenotype for this spectrum. XLH typically presents with rickets in early childhood and osteomalacia in adults; the diagnosis is most often made in the first years of life, when lower-limb bowing emerges with weight-bearing. Milder XLH may declare later, in adolescence or adulthood. The rarer non-XLH forms diverge from this picture. In autosomal dominant hypophosphataemic rickets, phosphate wasting can begin later and occasionally remits. In hereditary hypophosphataemic rickets with hypercalciuria, hypercalciuria and raised 1,25-dihydroxyvitamin D distinguish the biochemistry. Across the spectrum the skeletal phenotype ranges from isolated biochemical hypophosphataemia to severe lower-limb deformity, and may include growth restriction, dental abscesses and craniosynostosis. Some rarer entities are syndromic, adding extraskeletal features such as proximal tubular dysfunction or distinctive craniofacial findings.

XLH is the most common hereditary form with an estimated prevalence of about 5 per 100,000 children. The other genetic forms are individually rarer, and their frequencies are not well established.

The genetic forms of hypophosphataemia can be divided into FGF23-mediated and FGF23-independent disorders of renal phosphate wasting. The most common cause is X-linked hypophosphataemia (XLH), resulting from pathogenic variants in the PHEX gene that lead to increased FGF23 activity and renal phosphate wasting. Autosomal dominant hypophosphataemic rickets is also FGF23-mediated and is caused by pathogenic variants in the FGF23 gene that increase the stability of biologically active FGF23. FGF23-independent forms include hereditary hypophosphataemic rickets with hypercalciuria, caused by pathogenic variants in SLC34A1 and SLC34A3. Additional genes underlie a range of rarer syndromic entities.

Inheritance varies by gene. XLH, the predominant form, is X-linked dominant: an affected father transmits the variant to all daughters and no sons, whereas an affected mother transmits it to about half her children of either sex. In XLH, disease severity can differ between males and females despite the X-linked dominant inheritance pattern. Both sexes may be significantly affected, but females often show greater clinical variability owing to random X-chromosome inactivation. As a result, manifestations range from mild biochemical abnormalities to severe skeletal disease even among affected members of the same family. Other genetic forms of hypophosphataemia are inherited in an autosomal dominant or an autosomal recessive manner.

Diagnosis combines persistent hypophosphataemia, reduced renal phosphate reabsorption (low TmP/GFR), and assessment of serum FGF23, calcium, 1,25-dihydroxyvitamin D and urinary calcium. This biochemical profile distinguishes FGF23-mediated from FGF23-independent forms and helps narrow the differential diagnosis. Molecular genetic testing can then confirm the underlying genetic cause and establish the specific disease entity.

Main differential diagnoses include:

• Nutritional rickets: vitamin D or dietary phosphate deficiency; no monogenic cause.
• Tumour-induced osteomalacia: acquired FGF23 excess from a mesenchymal tumour; phenotypically mimics XLH.
• syndrome: generalised proximal tubular dysfunction with phosphaturia; acquired or syndromic causes.
• Hereditary vitamin D–dependent rickets: rickets with impaired vitamin D metabolism or action, typically without isolated renal phosphate wasting; CYP27B1, VDR.

• Identification of the underlying pathogenic variant confirms the clinical diagnosis, clarifies which form of hereditary hypophosphataemia is present, provides the basis for accurate genetic counselling and predictive testing.
• A confirmed molecular diagnosis can inform condition-specific surveillance and clinical management, including differentiation between FGF23-mediated and FGF23-independent forms and their associated treatment strategies; specific measures are determined by the treating physicians in consultation with the affected individual and their family.

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