Instituto Valenciano de Microbiología

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
CIF B-96337217


Hereditary hypophosphatemic rickets (hypophosphatemia); (Hypophosphatemic rickets Hereditary) - Genes FGF23 and PHEX.


Hereditary hypophosphatemic rickets is a disorder related to hypophosphatemia. In most cases, the signs and symptoms of this disorder begin in early childhood. The characteristics of the disease vary widely, even among affected members of the same family. Individuals with mild disease may have hypophosphatemia without other signs and symptoms. Children with more severe disease show a slow growth and are lower than their peers. Bone abnormalities that may interfere with movement and cause bone pain may develop. The most notable of these anomalies is the calibration of the legs or knees angled outwards. These statements, if untreated, tend to worsen over time. Other signs and symptoms of the disorder may include craniosynostosis, dental anomalies and enthesopathy. In adults, hypophosphatemia is characterized by a softening of the bones known as osteomalacia.

They described various forms of hereditary hypophosphatemic rickets, which differ in their pattern of inheritance and its genetic cause. The most common form of the disease is known as hypophosphatemic rickets X - linked (XLH), which has a dominant inheritance pattern X - linked inheritance Other patterns such as X - linked recessive, autosomal dominant form, autosomal recessive and other forms of the disease are much less frequent. Another rare type of the disease known as hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Besides hypophosphatemia, this disease is characterized by the excretion of high levels of calcium in the urine (hypercalciuria).

This process is due to mutations in the FGF23 and PHEX gene. Genes associated with hereditary hypophosphatemic rickets are involved in maintaining the proper balance of phosphate. Many of these genes, including the PHEX gene directly or indirectly regulate a protein called fibroblast growth factor-23, encoded from the FGF23 gene. This protein normally inhibits the ability of the kidney to reabsorb phosphate in the bloodstream.

FGF23 gene, located on the short arm of chromosome 12 (12p13.3), encoding the protein fibroblast growth factor-23, which occurs in bone cells. This protein is needed to regulate phosphate concentrations in the body. Among its many functions, phosphate plays a critical role in the formation and bone growth in childhood and helps maintain bone strength in adults. Phosphate concentrations are controlled largely by the kidneys. Normally, the kidneys remove excess phosphate in the body by excretion in the urine, mineral reabsorbed into the bloodstream when needed. The fibroblast growth factor-23 signals the kidneys to stop phosphate reabsorption into the bloodstream. They have identified at least three mutations in the FGF23 gene cause the autosomal dominant hypophosphatemic rickets. Mutations in this gene, change the amino acids in the fibroblast growth factor-23, which prevents its cleavage, and as a result, the protein is not inactivated. Hyperactivity fibroblast growth factor-23 reduces phosphate reabsorption by the kidneys, which leads to hypophosphatemia and problems related to bone growth in individuals with autosomal dominant hypophosphatemic rickets.

The PHEX gene, located on the short arm of X (Xp22.2-p22.1) chromosome, encodes an enzyme that is mainly active in bones and teeth. PHEX is believed that the enzyme may be involved in the regulation of fibroblast growth factor-23, but no clutch so far not established a direct link. It is still unclear how the PHEX enzyme helps control the reabsorption of phosphate and what role it plays in the formation and growth of bones. There are more than 200 mutations in the PHEX gene causing the most common form of hereditary hypophosphatemic rickets, hypophosphatemic rickets known as X - linked Although it is unclear how mutations in the PHEX gene lead to hypophosphatemia and other problems in those affected, it is likely that PHEX gene mutations somehow alter the encoding that protein. An increase in fibroblast growth factor-23, reduces phosphate reabsorption by the kidneys, resulting hypophosphatemia. However, because some affected individuals have normal levels of fibroblast growth factor-23, are considering other ways in which a mutated gene PHEX could cause hypophosphatemic rickets X - linked  

This disease can have several patterns of inheritance. When the disease is due to mutations in the PHEX gene, the process is inherited recessive sex - linked, as the gene is located on chromosome X. Having males one X chromosome, the alteration of this single gene is enough for the process is revealed. In women, having two X chromosomes, the mutation must occur on both chromosomes to cause the syndrome. For this reason, males will affect far more often than women, because it is very rare that they have two copies of the altered gene on both chromosomes X. A feature of these processes linked to the X chromosome, it is that parents do not they can pass this genetic trait to their children. Less commonly, the disease can have a recessive inheritance pattern linked to chromosome X. In some families, the disease has an autosomal dominant inheritance, meaning that one copy of an altered gene in each cell is sufficient to express the illness.

The type of hereditary hypophosphatemic rickets with hypercalciuria (HHRH), has an autosomal recessive inheritance pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.  

Tests in IVAMI: in IVAMI perform detection of mutations associated with hereditary hypophosphatemic rickets, by complete PCR amplification of the exons of FGF23 and PHEX gene respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).