Hereditary Hypophosphatemic Rickets: Types, Clinical Features and Treatment

Introduction

Vitamins and minerals are essential components of the human body. They serve as building block components of human life. These components aid various functions of cell organelles, cellular functions, and structures of different organs. Calcium and phosphate are one of the most important minerals of the human body. These two minerals maintain functions like the formation of bone and neuromuscular functions. The regulation of the balance of minerals and formation of bone and tooth structs are aided by vitamin D. Irregularities of such components from childhood are responsible for structural damage and growth retardation. Rickets is a condition associated with calcium, phosphate, and vitamin D regulation disorder.

What Are Rickets?

Rickets is a musculoskeletal disorder of children characterized by the defective formation of bones. The peak incidence of rickets is seen in children aged between 6 to 23 months. Even adolescent adults are also affected by this condition. The mean age group of affected children is 2 to 11 years. Softening and weakening of bones is the key clinical feature of this disorder. Along with these developmental delays, muscle tenderness can be seen. Based on etiology rickets can be of two types:

1) Calcipenic Rickets: This type of rickets is caused by vitamin D deficiency. The following factors cause this type of rickets:

• Malnutrition is the key factor for such a condition caused by vitamin D deficiency.

• Conditions like celiac disease and cystic fibrosis cause improper absorption of vitamin D.

• The genetic defect of vitamin D metabolism is also associated with these conditions. This is of four types and they are the following:

1. 1. Vitamin D-Dependent Rickets Type I A: This is an autosomal recessive type caused by the mutation of the CYP27B1 gene.
   2. Vitamin D-Dependent rickets type I B: This also belongs to the autosomal recessive type caused by mutation of the CYP2R1 gene.
   3. Vitamin D-Dependent Rickets Type II A: VDR gene mutations are associated with this autosomal recessive condition.
   4. Vitamin D-Dependent Rickets Type II B: Overexpression of nuclear protein is associated with this condition.

2) Phosphopenic Rickets: This condition is caused by the low level of phosphate in the blood. Increased urinary phosphate loss and defective phosphate metabolism cause such conditions. Hereditary hypophosphatemic rickets belongs to this category.

What Are Hereditary Hypophosphatemic Rickets?

This is a genetic condition characterized by a low level of phosphate in the blood. The level of phosphate in the blood is maintained by fibroblast growth factor 23 (FGF23, a type of growth factor), parathyroid hormone, and calcitriol (a steroid hormone). This FGF23 binds with the cellular membrane receptor 1c (FGFR1c). This molecule again interacts with Klotho protein compounds and maintains the cellular level of phosphate ions. On the other hand, defective phosphate ion excretion in the urine is associated with the improper functioning of calcitriol and parathyroid hormone. This condition is comprised of three genetic disorders. These are:

1. X-linked Hypophosphatemic Rickets: This autosomal dominant disorder was first described by Albright in 1939. The incidence rate of this disorder is 1 in every 20000 persons. Around 80 percent of familial hypophosphatemic rickets belong to this category only. Mutation of the phosphate-regulating gene with homologies to endopeptidase (PHEX) on the X chromosome is responsible for this condition. This causes downregulation in the functioning of FGF23 and decreased phosphate reabsorption in kidneys. Also, the function of the fibroblasts is impaired.
2. Autosomal Dominant Hypophosphatemic Rickets: This type of rickets is divided into two subgroups. One subgroup is seen in children, and another is seen in adolescents. The mutation of the FGF23 gene is associated with this, which causes increased excretion of phosphate ions through urine.
3. Autosomal Recessive Hypophosphatemic Rickets: This is caused by a gene mutation associated with the functioning of dentin matrix protein 1. The impaired functioning of this protein is responsible for the improper proliferation of osteocytes and downregulation of FGF-23. Increased loss of phosphate ions is caused by this. Recently mutation of ectonucleotide pyrophosphatase/phosphodiesterase (an enzyme responsible for the breakdown of ATP) enzyme is also seen in some cases. Malformation of the enzymatic activity of this enzyme is responsible for calcification in the capillary bed.
4. Hereditary Hypophosphatemic Rickets With Hypercalciuria: This type of disorder is caused by the mutation of the SLC34A3 gene. This gene maintains the function of sodium-phosphate cotransporter, which in turn regulates the phosphate transport in the kidneys and the intestine. The presence of excessive amounts of calcium in the urine is the key clinical feature of this condition.

What Are the Features?

The clinical manifestations of such disorders include:

• Frontal bossing, unusual prominence of the forehead.

• Short structure limbs, specifically lower limbs, are deformed.

• Poorly developed muscles and muscle weakness.

• Joint pain, pain during movement.

• Coxa vara is a deformity of the lower limb where the angle between the hip bone and the head of the femur bone is reduced.

• Genu valgum or inward bending of the knees.

• Genu varum or outward bending of knees, but in this condition, ankles and feet touch each other.

• Dental abnormalities include the poor formation of enamel, the late eruption of teeth, and the malformation of teeth structures in these conditions.

What Are the Treatment Options?

As these, all are genetic disorders. Curing these condition is impossible. Life-long supportive therapy for the patients is needed. But certain therapeutic steps can be taken, such as:

• For the treatment of X-linked hypophosphatemic, phosphate is generally administered at 20 to 40 milligrams per kilogram per day in three to five divided doses. Calcitriol is also administered.

• These patients also suffer from hyperparathyroidism and vitamin D deficiency. For which vitamin D supplements can be given.

• Recently, a new drug Burosumab (a human monoclonal antibody against FGF-23) has been used.

Conclusions:

Hereditary hypophosphatemic rickets is a rare hereditary disorder. Different genes are involved in the disruption of phosphate levels. Bone deformities, skeletal malformations, and developmental delays are the clinical features of this condition. Assessment of phosphate levels in the blood and urine analysis help diagnose such conditions. The application of hormones and modern medicines like Burosumab can be useful to cure such problems.