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Conditions

Hereditary hypophosphataemic rickets

Hereditary hypophosphataemic rickets is a group of conditions characterised by low serum phosphate, skeletal developmental anomalies and muscle weakness.

Overview

Hereditary hypophosphataemic rickets is a group of genetic conditions in which pathogenic variants in genes encoding hormones, receptors and ion transporters involved in phosphate handling cause lifelong hypophosphataemia and skeletal and non-skeletal clinical manifestations.

Clinical features

Clinical features of hereditary hypophosphataemic rickets include:

  • lifelong hypophosphataemia;
  • renal phosphate wasting;
  • skeletal developmental anomalies and skeletal fragility, leading to a ricketic phenotype and increased fracture risk;
  • bone pain; and
  • muscle weakness;

Depending on the specific cause, other features may also be present, including restricted growth, skeletal dysplasia, dental abnormalities, hearing loss, hypercalciuria and nephrocalcinosis or nephrolithiasis, and secondary hyperparathyroidism. Enthesopathy and osteoarthritis may occur in adulthood.

There are different types of hereditary hypophosphataemic rickets, all of which have variable clinical features and different modes of inheritance and are caused by pathogenic variants in a range of genes, as shown in table 1.

Table 1: Types of hereditary hypophosphataemic rickets by causative gene, inheritance and mechanism

Name (OMIM reference) Gene Inheritance Mechanism
X-linked hypophosphataemic rickets (XLH) (307800) PHEX X-linked dominant Incompletely understood, but it is established that loss-of-function variants in the PHEX gene are associated with elevated expression of FGF 23, primarily in osteocytes, leading to renal phosphate wasting, reduced activation of 25 OH vitamin D to 1,25 di OH D and impaired bone mineralisation.
Autosomal dominant hypophosphataemic rickets (ADHR) (193100) FGF23 Autosomal dominant Gain-of-function variants lead to stabilisation of full-length (32 kDa) FGF 23 by substituting arginine with glutamine or tryptophan within the RXXR subtilisin-like proprotein convertase (SPC) cleavage site. This leads to enhanced FGF 23 activity and consequent renal phosphate wasting, hypophosphataemia and impaired bone mineralisation.
Autosomal recessive hypophosphataemic rickets type 1 (ARHR 1) (241520) DMP1 Autosomal recessive Variants are thought to result in non-functional DMP-1 protein, causing impaired osteocyte maturation and associated excess FGF 23 secretion.
Autosomal recessive hypophosphataemic rickets type 2 (613312) ENPP1 Autosomal recessive It is hypothesised that ENPP1 may regulate osteoblast differentiation, meaning that variants may affect osteocyte differentiation (osteocytes being derived from osteoblasts) and lead to excessive FGF 23 secretion, as occurs in ARHR 1.
Autosomal recessive hypophosphataemic rickets type 3 (also known as Raine syndrome) (259775) FAM20C Autosomal recessive Variants in the conserved C terminal domain of FAM20C are usually lethal. However, some variants are compatible with life and cause a phenotype with craniofacial anomalies, osteosclerosis and in one reported case, high FGF 23 levels.
Hereditary hypophosphataemic rickets with hypercalciuria (HHRH) (241530) SLC34A3 Autosomal recessive Homozygous or compound heterozygous inactivating variants in SLC34A3 lead to excess renal phosphate losses with elevated 1,25 di OH D levels and hypercalciuria secondary to this, leading to nephrolithiasis and distinguishing HHRH from conditions in which the primary anomaly is excess FGF 23 secretion, such as XLH.
Hypophosphataemic rickets and hyperparathyroidism (612089) KL Autosomal dominant KL gene translocation leading to enhanced FGF 23 signalling (klotho being the FGF 23 co-receptor in kidney and parathyroid). This leads to renal phosphate wasting and hyperparathyroidism as well as elevated FGF 23 levels, which would not be predicted to be part of the phenotype. This suggests that klotho may have an additional role in regulating FGF 23 secretion.
Fanconi syndrome and hypophosphataemic rickets (613388) SLC34A1, NPT2 Autosomal recessive The phenotype is renal Fanconi syndrome with hypophosphataemic rickets and severe short stature and, as in HHRH, hypercalciuria and elevated 1,25 di OH D levels.
X–linked recessive hypophosphatemic rickets: Dent disease (300009) CLCN5 X-linked recessive Rare recessive X-linked disorder characterised by hypophosphatemia, hematuria, proteinuria, hypercalciuria, nephrocalcinosis and progressive renal failure.
Hypophosphatemia, nephrolithiasis, osteoporosis (612287) SLC9A3R1, NHERF1 Autosomal dominant The phenotype is hypophosphatemia, decreased renal phosphate resorption and decreased bone mineral density.

Genetics

  • Although hereditary hypophosphataemic rickets can have a wide variety of potential genetic causes as outlined in table 1, it is important to recognise that the most common cause in clinical practice by some significant margin is X-linked hypophosphataemic rickets (XLH). Many of the other causes summarised in table 1 have only been reported in very few cases.
  • If requesting genomic testing for hypophosphataemic rickets in UK NHS practice, the usual test provided will be small gene panel R154.1 Hypophosphataemia or rickets. This panel also includes PHEX, FGF23, DMP1 and ENPP, and tests for rarer genetic causes of hypophosphataemic rickets (such as FAM20C, SLC34A1 and SLC34A3) as well as other genes (specifically ALPL, CYP27B1, CYP2R1, OCRL and VDR).

For more information about genomic testing, see Presentation: Patient with possible hereditary hypophosphataemic rickets.

This condition may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to paediatric endocrinology. Please refer to the local pathway for your region for this condition.

Diagnosis

The diagnosis of hereditary hypophosphataemic rickets is established on the basis of clinical, biochemical and radiological anomalies together with an assessment of family history and genetic testing. Key diagnostic assessments are outlined below:

  • Assess for clinical and radiological features of rickets, such as short stature, lower limb deformities, fractures and a history of lower limb orthopaedic surgery.
  • Biochemical assessment requires discontinuation of any phosphate and vitamin D analogue treatment for 1–2 weeks prior to blood sample collection.
  • Assess for persistent hypophosphataemia by repeat measurement of fasting serum phosphate.
  • Measure hormones regulating mineral metabolism: FGF23, PTH, 25(OH) vitamin D, and 1,25(OH)2 vitamin D.
  • Assess for renal phosphate wasting by measurement of tubular maximum reabsorption of phosphate (TmP) to GFR (TmP/GFR).
  • Exclude acquired causes of hypophosphataemia and renal phosphate wasting, such as intravenous iron therapy and tumour-induced osteomalacia.
  • Genomic testing is required to differentiate between the different forms of hereditary hypophosphataemic rickets, and also to exclude acquired causes such as tumour induced osteomalacia.

For more information about genomic testing, see Presentation: Patient with possible hereditary hypophosphataemic rickets.

This condition may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to paediatric endocrinology. Please refer to the local pathway for your region for this condition.

Inheritance and genomic counselling

Inheritance varies according to which genetic cause is identified. See table 1.

X-linked hypophosphataemic rickets is the most common form of inherited rickets and has an estimated prevalence of between 1:20,000 and 1:60,000.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

Management

Management of patients with hypophosphataemic rickets is complex and should be undertaken in a specialist centre, ideally by a multidisciplinary team with expertise in these conditions. Specific management is dependent on the underlying cause of the hypophosphataemia.

Conventionally, treatment of XLH and ADHR has involved administration of oral phosphate supplements and active vitamin D analogues (calcitriol or alfacalcidol). However, these treatments are imperfect, often exacerbating elevated FGF 23 levels, sometimes driving tertiary hyperparathyroidism, leading to the development of side effects and incomplete resolution of the underlying hypophosphataemia, and failing to normalise skeletal growth and morphology.

Gene-directed therapies and trials

Burosumab (Crysvita) is a recombinant human monoclonal antibody that binds to and inhibits the action of FGF 23, and is licensed for the treatment of XLH. The 2024 NICE guidance ‘Burosumab for treating X-linked hypophosphataemia in adults’ (TA993) states that “burosumab is recommended, within its marketing authorisation, as an option for treating X-linked hypophosphataemia (XLH) in adults”.

This condition may be identified before any symptoms appear, for example through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 20/01/2026
  • Next review due: 20/01/2028
  • Authors: Dr Fadil Hannan, Dr Jeremy Turner
  • Reviewers: Professor Duncan Bassett, Dr Louise Izatt, Professor Márta Korbonits