SCIENTIFIC BACKGROUND

CLCN5DMP1ENPP1FAM20CFGF23PHEXSLC34A1SLC34A3SLC9A3R1

The most common form of hypophosphatemia or hereditary hypophosphatemic rickets without hypercalciuria is caused by causative variants in the PHEX gene, which codes for the phosphate-regulating endopeptidase. The disease is inherited in an X-linked manner; however, females and males are equally affected. Penetrance is 100% and prevalence is 1:20,000. In addition to hypophosphatemia, growth retardation, rickets, osteomalacia, bone abnormalities, bone pain, spontaneous dental abscesses, hearing loss, enthesopathy, osteoarthritis, muscle dysfunction, impaired renal phosphate reabsorption, and impaired vitamin D metabolism are seen.

 

The clinical presentation of X-linked hypophosphatemia (XLH) is highly variable, ranging from isolated hypophosphatemia to severe lower extremity deformity. The diagnosis is often made in the first two years of life when lower extremity deformity becomes apparent as a child starts to walk. However, due to the highly variable clinical presentation, the diagnosis is sometimes not made until adulthood. There is evidence that the type of genetic alteration correlates with the severity of the disease. For example, patients with larger deletions tend to be more severely affected than patients with missense variants. This may explain the large phenotypic variability.

 

Low serum phosphate levels and reduced tubular phosphate reabsorption in children suggests hypophosphatemia caused by variants in the PHEX gene. Clinically, progressive deformities of the lower extremities with decreasing length growth can be observed, as well as changes in the metaphyses of the lower extremities visible on x-ray. In addition, patients with XLH are prone to spontaneous dental abscesses.

 

Externally, the skeletal changes in nutritional rickets cannot be distinguished from hereditary forms of rickets. However, there is a biochemical distinction: in hypophosphatemic rickets, serum concentrations of calcium and 25-hydroxy vitamin D (calcidiol, the storage form of vitamin D) are within the normal range, unlike in nutritional rickets. In contrast, di-hydroxy vitamin D (calcitriol, active vitamin D) is reduced in hypophosphatemic rickets.

 

In addition to variants in the PHEX gene, other genetic and acquired disorders can also cause renal phosphate loss. These include variants in the FGF23, DMP1, ENPP1, SLC34A3, SLC9A3R1, SLC34A1, CLCN5, and FAM20C genes, and conditions such as McCune-Albright syndrome (GNAS gene), Schimmelpenning-Feuerstein-Mims syndrome (KRAS, HRAS, and NRAS genes), Fanconi syndrome, and tumor-induced osteomalacia.

 

Treatment options include administration of active vitamin D analogs and phosphate supplementation to correct 1,25 (OH) 2 vitamin D deficiency and compensate for renal phosphate loss. In addition, therapy with KRN23/burosumab, a recombinant human monoclonal antibody against FGF23, has been approved in Europe since 2018.

 

References

Beck-Nielsen et al. 2019, Orphanet Journal of Rare Diseases 14:58 / www.orpha.net / Ruppe M.D. 2017, GeneReviews® [Internet], www.ncbi.nlm.nih.gov/books/NBK83985/

 

GENES

CLCN5DMP1ENPP1FAM20CFGF23PHEXSLC34A1SLC34A3SLC9A3R1
How to order

LATEST ARTICLES

Cystic fibrosis (CF) is a life-threatening, progressive, inherited condition that causes severe damage to the body, primarily affecting the organs of...

Read more

Down syndrome is a genetic condition caused by the presence of an extra copy of chromosome 21. It affects physical growth, facial features, and cogni...

Read more

Every year on April 25th, DNA Day celebrates the discovery of DNA’s double helix and the advances we’ve made in understanding genetics. D...

Read more

Neurodevelopmental disorders (NDDs) have diverse genetic origins, making diagnosis challenging. A new study analyzing over 1,100 pediatric patients f...

Read more

Colorectal cancer (CRC) remains one of the most prevalent and deadly cancers worldwide, with a significant number of cases presenting at an advanced ...

Read more

Carrier screening is a genetic test designed to identify whether an individual carries a gene with changes (mutations) associated with inherited diso...

Read more

Trisomy 13, also known as Patau syndrome, is a genetic condition in which cells in the body have three copies of chromosome 13 instead of two. The co...

Read more

The human brain develops through a complex series of events, with genes carefully regulating the formation of neurons and glial cells. A recent study...

Read more

Rare diseases affect between 300 and 400 million people worldwide – more than cancer and AIDS combined [1, 2], but despite this, many people face a...

Read more

Rosalind Elsie Franklin was a brilliant and meticulous research scientist whose interdisciplinary work made fundamental contributions to various area...

Read more