Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders

Hypophosphatemic bone and kindney disease

The diseases of this group are characterized by renal phosphate wasting. Skeletal abnormalities develop secondarily.

Test Strategy

Diagnostic starts with affirmation of renal phosphate wasting, the exclusion of secondary hypophosphatemias, the assessment of family history and than proceeds towards differentiation of the form of genetic disorder.

Pathogenesis

The picture shows phosphate regulation by the phosphatonin, FGF23, which is secreted by osteocytes. Secretion of this phosphaturic hormone is enhanced by calcitriol and hyperphosphatemia, and it is reduced by proteins encoded by genes DMP1, PHEX1, and ENPP1. At the basolateral membrane of proximal tubulus cells, the hormone activates the FGF receptor 1 and klotho. This starts an intracellular signal cascade that finally inactivates luminal phosphate transporters, reduces phosphate reabsorption, and increases phosphate excretion.

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From this graph it can be deduced that inactivating mutation in genes DMP1, PHEX1, and ENPP1 enhance phosphaturia by increased FGF23 secretion. The hyperphosphaturic FGF23 effect is also increase by activating mutations in the KL (klotho) and FGFR1 genes and of course in FGF23 itself. Further downstream the signal cascade inactivating mutations in genes responsible for intracellular signal transduction and the phosphate transporters cause hyperphosphaturia independent of or even downregulated FGF23 levels.

Management

Diet

The dietary recommendations include phosphate-rich food which is in particular milk and milk products, but also protein-rich food like meat and fish contain a lot of phosphate. Also some energy drinks and preservatives are phophate enriched.

Medicament

Drugs to substitute phosphate losses are available. Also vitamin D preparations are considered in hypophosphatemmic rickets. The rational of vitamin D is to improve bone development it also has a positive effect on enteral phosphate resorption but it has to be kept in mind that active vitamin D also increases FGF23which may further increase phophate losses in low FGF23 hyperphophatemias.

Symptomatic

AS the disease is characterized with kidney stone formation and bone deformation orthopedic and urological treatment might be necessary.

Systematic

Disturbances in phosphate metabolism
Hyperphosphatemic familial tumoral calcinosis
Hypophosphatasia
Hypophosphatemic bone and kindney disease
Disorders of the renal phosphate transporters
Hypophosphatemic rickets with hypercalciuria
SLC34A3
Idiopathic basal ganglia calcification 1
SLC20A2
Nephrolithiasis/osteoporosis, hypophosphatemic, 1
SLC34A1
Nephrolithiasis/osteoporosis, hypophosphatemic, 2
SLC9A3R1
FGF23-induced hypophosphatemic rickets
Autosomal dominant hypophosphatemic rickets
FGF23
Autosomal recessive hypophosphatemic rickets type 1
DMP1
Autosomal recessive hypophosphatemic rickets type 2
ENPP1
X-linked dominant hypophosphatemic rickets
PHEX
Fanconi-type hypophosphatemic rickets
Nephrolithiasis/osteoporosis, hypophosphatemic, 1
SLC34A1
X-linked recessive hypophosphatemic rickets
CLCN5
OCRL
Hypophosphatemic rickets with hyperparathyroidism
KL
Osteoglophonic dysplasia
FGFR1
Raine syndrome
FAM20C
X-linked dominant hypophosphatemic rickets
PHEX

References:

1.

Econs MJ et al. (1997) Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder.

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2.

et al. (2000) Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23.

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3.

Shimada T et al. (2001) Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia.

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4.

Strewler GJ et al. (2001) FGF23, hypophosphatemia, and rickets: has phosphatonin been found?

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5.

Tenenhouse HS et al. (2002) Novel phosphate-regulating genes in the pathogenesis of renal phosphate wasting disorders.

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6.

Scriver CR et al. (1977) Hypophosphatemic nonrachitic bone disease: an entity distinct from X-linked hypophosphatemia in the renal defect, bone involvement, and inheritance.

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7.

Scriver CR et al. (1981) Autosomal hypophosphataemic bone disease responds to 1,25-(OH)2D3.

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Update: Sept. 26, 2018