Hypophosphatemic rickets is a hereditary form of rickets characterized by low serum phosphate levels and resistance to treatment with ultraviolet radiation or vitamin D ingestion. This disorder was initially called vitamin D resistant rickets, is now called hereditary hypophosphatemic rickets because the primary problem is phosphate wasting rather than true vitamin D resistance.
[Read in detail about rickets and osteomalacia]
In addition to hypophosphatemia, these disorders all have normal glomerular filtration rate, normal serum levels of calcium. Most of these disorders also have high circulating levels of fibroblast growth factor 23 [FGF 23].
Hereditary forms of hypophosphatemic rickets include X-linked, autosomal dominant, and autosomal recessive disease, as well as hypophosphatemic rickets with hypercalciuria. Tumor-induced osteomalacia has similar clinical manifestations to the familial syndromes.
X-linked hypophosphatemia accounts for more than 80% of all familial hypophosphatemia.
Cause and Pathophysiology
X linked hypophosphatemic rickets
In X linked hypophosphatemic rickets, a mutant gene known as PHEX results in the reduced breakdown of FGF 23. FGF23 is known to act on the kidney to cause increased phosphate excretion and decreased alpha-1 hydroxylase activity.
Inadequate levels of inorganic phosphate impair, bone matrix ossification because the formation of mature bone involves the precipitation of hydroxyapatite [calcium phosphate salt] crystals.
It is a dominant disorder with a prevalence of approximately one case per 20,000 live births.
It is most common of all hypophosphatemic rickets.
However, FGF23 does not mediate all of the clinical features of XLH. Enthesopathy and dental abnormalities are mediated by mechanisms other than FGF23. XLH is also characterized by inappropriately low level of calcitriol (1,25-(OH) 2 vitamin D3) due to defect in renal hydroxylation. Determination of the PHEX mutation can confirm the diagnosis.
Autosomal dominant hypophosphatemic rickets
This occurs due to mutations in the FGF23 gene on chromosome 12p13. The mutant protein is resistant to proteases and leads to an increase in serum FGF23. The clinical features and treatment are similar to the X-linked disease.
Autosomal recessive hypophosphatemic rickets.
Patients exhibit isolated renal phosphate wasting. The disorder is caused by mutations in the DMP1 gene. DMP suppresses FGF23 production from the bone.
Hypophosphatemic rickets with hypercalciuria
It is an autosomal recessive disease and is associated with high levels of vitamin D. It is caused by genetic mutations of the renal type 2c sodium-phosphate cotransporter. The gene is located on chromosome 9q34. Rickets and/or osteomalacia is the presenting feature.
Mild forms may present with hypercalciuria and nephrolithiasis without bone disease.
Patients should be treated only with phosphorus supplementation [in contrast to other forms]
Dent’s disease
Dent’s disease results from mutations in the CLCN5 gene in 60% of patients, and in the OCRL1 gene in another 15%. It is an X-linked recessive syndrome. The defect is in the cells of the proximal renal tubule leading to solute-wasting, hypercalciuria,, kidney stones, renal failure, and in some cases rickets.
Clinical Presentation of Hypophosphatemic Rickets
Being a genetic disorder, hypophosphatemic rickets is present from conception. Infant birth weight is generally normal, but early growth may be slower than normal.
The earliest clinical sign of hypophosphatemic rickets slowed growth rate in the first year of life. The child shows reluctance to bear weight when beginning to stand or walk. Short stature is seen as the child grows. Older children may have a history of late dentition or multiple dental abscesses due to a defect in dentin material.
Intellectual development is unaffected. Rachitic changes like widened joint spaces and flaring at the knees, bowing deformities.
An outstanding feature of familial hypophosphatemic rickets is disproportionate short stature.
Adults show osteomalacic changes and calcification of entheses and joint capsules.
Hypertension left ventricular hypertrophy, and craniosynostosis are some other features which can be seen. Hyperparathyroidism may develop due to oral phosphate supplementation. Muscle weakness is rare.
Nephrocalcinosis and hyperparathyroidism are important complications and nephrocalcinosis may result in renal insufficiency.
Differential Diagnoses
- Renal tubular acidosis
- Hereditary hypophosphatemic rickets with hypocalciuria
- Fanconi syndrome
- Hereditary Vitamin D Dependent rickets
- Vitamin D deficient rickets
- Pseudohypoparathyroidism
Lab Studies
- Serum calcium levels are normal or slightly lower
- Severe hypophosphatemia (< 2.5 mg/dL)
- Alkaline phosphatase levels are raised
- Normal to-high PTH levels
- Normal plasma calcidiol concentration, and normal
- Reduced plasma calcitriol concentration
Image Credit:Orthobullets
Imaging studies
X-rays of the wrists, knees, ankles, and long bones. Changes similar to rickets may be found. Bone radiographs show short, squat long bones and coarse, axial skeleton trabeculation.
Image Credit: Medscape
Treatment of Hypophosphatemic Rickets
Standard treatment of hypophosphatemic rickets is the administration of calcitriol. Addition of phosphates has been found not to be beneficial. As noted above, in the case of hypophosphatemic rickets with hypercalciuria, only phosphate supplementation is required. It takes about 6-8 weeks for rickets to show healing.
Patients need to be followed up for serum calcium concentration monitoring and periodic renal ultrasonography studies to note the development of nephrocalcinosis which is now recognized as an iatrogenic result of therapy. Renal creatinine needs to be monitored and dosage adjusted accordingly.
Urinary calcium and phosphate excretion monitoring also are important.
As the healing progresses, the patient’s requirements for calcium deposition and vitamin D decreases and the patient becomes highly susceptible to hypercalcemia during this phase.
Patients respond well but in extreme deformities and delayed diagnoses, surgical corrections may be needed. Dental procedures may be required periodically.
Activity restriction is not required. Contact sports should be avoided till rickets has healed.
Persistent stimulation of parathyroid hormone release despite the administration of calcitriol may require parathyroidectomy.
Amiloride and hydrochlorothiazide are administered to enhance calcium reabsorption and to reduce the risk of nephrocalcinosis.
Most of the adults are asymptomatic and may not benefit from therapy. Some may have calcification of tendons and ligaments. Unnecessary treatment may cause complications. Hence, treatment is only indicated in symptomatic patients for bone pain or non-uniting fractures or those who are to undergo orthopedic surgery in next 3-6 months as this helps in recovery.
Pregnancy is another indication where treatment should be considered to maintain serum phosphorus concentrations.
Prognosis of Hypoph0sphatemic Rickets
Apart from the short stature of most affected adults, the prognosis for a normal lifespan and normal health is good.
Abnormal dentine formation causes late dentition and spontaneous abscess formation.
Acute hypercalcemia (with resulting irritability, confusion, and potential seizures) can occur during treatment. Nephrocalcinosis, the long-term result of aggressive therapy, may be more damaging.
Hypertension has been reported in older children under treatment as a consequence of persistent hyperparathyroidism.
Younger siblings of affected patients should be screened by measuring fasting serum phosphorus, and renal phosphorus excretion.
