Hypophosphatemic rickets

Other names:hypophosphatemia ;VDRR ;vitamin D-resistant rickets

Hypophosphatemic rickets (previously called vitamin D-resistant rickets) is a disorder in which the bones become painfully soft and bend easily, due to low levels of phosphate in the blood. Phosphate is a mineral that is essential for the normal formation of bones and teeth.

Rickets due to low serum phosphate concentrations, the cause of which can be nutritional or genetic. This condition is characterized by normal parathyroid hormone concentrations, usually caused by renal phosphate wasting occurring in isolation or as part of a renal tubular disorder, and characterized by resistance to treatment with ultraviolet radiation or vitamin d.

Epidemiology

X-linked hypophosphatemic rickets is the most common form of rickets that runs in families. It affects about 1 in 20,000 newborns. Each of the other forms of hereditary hypophosphatemic rickets has been identified in only a few families.

Onset

Symptoms usually begin in early childhood and can range in severity.

Types

Researchers have described several forms of hereditary hypophosphatemic rickets, which are distinguished by their pattern of inheritance and genetic cause. The most common form of the disorder is known as X-linked hypophosphatemic rickets (XLH). It has an X-linked dominant pattern of inheritance. X-linked recessive, autosomal dominant, and autosomal recessive forms of the disorder are much rarer.

Another rare type of the disorder is known as hereditary hypophosphatemic rickets with hypercalciuria (HHRH). In addition to hypophosphatemia, this condition is characterized by the excretion of high levels of calcium in the urine (hypercalciuria).

Cause

Hypophosphatemic rickets is almost always hereditary and may be caused by mutations in any of several genes. The specific gene involved determines the way it is inherited. Most commonly, it is caused by a mutation in the PHEX gene. Other genes that can be responsible for the condition include the CLCN5, DMP1, ENPP1, FGF23, and SLC34A3 genes. The genes associated with hereditary hypophosphatemic rickets are involved in keeping a proper balance of phosphate in the body. Many of these genes directly or indirectly regulate a protein that normally inhibits the kidneys' ability to reabsorb phosphate into the blood. Mutations affecting the function of these genes increase the production (or reduce the breakdown) of the protein, causing the protein to be overactive. The overactivity of the protein reduces phosphate reabsorption by the kidneys, leading to the features of the condition.

Rarer, sporadic, acquired cases are sometimes associated with benign (non-cancerous) mesenchymal tumors that decrease resorption of phosphate.

Inheritance

Hypophosphatemic rickets is most often inherited in an X-linked dominant manner. This means that the gene responsible for the condition is located on the X chromosome, and having only one mutated copy of the gene is enough to cause the condition.

Because males have only one X chromosome (and one Y chromosome) and females have two X chromosomes, X-linked dominant conditions affect males and females differently. Both males and females can have an X-linked dominant condition. However, because males don't have a second, working copy of the gene (as females do), they usually have more severe disease than females.

If a father has the mutated X-linked gene:

• all of his daughters will inherit the mutated gene (they will all receive his X chromosome)
• none of his sons will inherit the mutated gene (they only inherit his Y chromosome)
• If a mother has the mutated X-linked gene, each of her children (both male and female) has a 50% chance to inherit the mutated gene.

Less commonly, hypophosphatemic rickets is inherited in an X-linked recessive, autosomal dominant, or autosomal recessive manner.

Signs and symptoms

The symptoms of hypophosphatemic rickets usually begin in infancy or early childhood. Specific symptoms and severity can vary greatly among affected children. The condition can be so mild that there are no noticeable symptoms, or so severe that it causes bowing of the legs and other bone deformities; bone pain; joint pain; and short stature. Other symptoms may include premature closure of the skull bones in babies (craniosynostosis); limited joint movement; and dental abnormalities. If left untreated, symptoms worsen over time.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormal calcium-phosphate regulating hormone level
• Abnormality of dental enamel(Abnormal tooth enamel)
• Bowing of the long bones(Bowed long bones)
• Delayed eruption of teeth(Delayed eruption)
• Dolichocephaly(Long, narrow head)
• Exostoses(Formation of new noncancerous bone on top of existing bone)
• Joint stiffness(Stiff joint)
• Pectus excavatum(Funnel chest)
• Short stature(Decreased body height)

30%-79% of people have these symptoms

• Craniosynostosis
• Scoliosis

Diagnosis

Begin clinical laboratory evaluation of rickets with assessment of serum calcium, phosphate, and alkaline phosphatase levels. In hypophosphatemic rickets, calcium levels may be within or slightly below the reference range; alkaline phosphatase levels will be significantly above the reference range. Carefully evaluate serum phosphate levels in the first year of life, because the concentration reference range for infants (5.0-7.5 mg/dL) is high compared with that for adults (2.7-4.5 mg/dL). Serum parathyroid hormone levels are within the reference range or slightly elevated, while calcitriol levels are low or within the lower reference range. Most importantly, urinary loss of phosphate is above the reference range.

The renal tubular reabsorption of phosphate (TRP) in X-linked hypophosphatemia is 60%; normal TRP exceeds 90% at the same reduced plasma phosphate concentration. The TRP is calculated with the following formula: 1 - [Phosphate Clearance (CPi) / Creatinine Clearance (Ccr)] X 100

Treatment

Treatment involves taking phosphate and calcitriol in order to raise phosphate levels in the blood and promote normal bone formation.

Prognosis

The long-term outlook (prognosis) for people with hypophosphatemic rickets is good. With appropriate management, normal health and normal lifespan are expected. If the condition is not treated (especially while children are growing), skeletal deformities may be permanent.

NIH genetic and rare disease info

• NIH info on Hypophosphatemic rickets

Hypophosphatemic rickets is a rare disease.