Hereditary hypophosphataemic rickets
Hereditary hypophosphataemic rickets is a group of conditions caused by various pathogenic genetic variants. They are characterised by 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 associated clinical manifestations.
Clinical features
Clinical features of hereditary hypophosphataemic rickets include:
- skeletal developmental anomalies and skeletal weakness 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, nephrolithiasis and anomalies of dentition.
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. |
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.
Inheritance and genomic counselling
Inheritance varies according to which genetic cause is identified. See table 1.
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 activated vitamin D metabolites (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. It is not routinely commissioned for NHS use and is only available through the self-funding route, or through a managed access programme that is only available through a limited number of centres.
Resources
For clinicians
- NHS England: National Genomic Test Directory
- US National Library of Medicine: ClinicalTrials.gov database
References:
- Haffner D, Francesco E, Eastwood DM and others. ‘Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia‘. Nature Reviews Nephrology 2019: volume 15, issue 7, pages 435–455. DOI: 10.1038/s41581-019-0152-5