Genetic Forms of Calciopenic Rickets

Rickets is a disease involving calcium and phosphate balance disturbances in the pediatric population. A series of hereditary disorders known as vitamin D-dependent rickets are defined as early-onset rickets resulting from either an insufficient response to active vitamin D or an inability to maintain adequate levels of the active forms of vitamin D. According to the age at onset and the pathophysiology of the disease, various clinical signs including growth failure, limb bowing, and joint enlargement may be present. Vitamin D-dependent rickets type 1A, type 1B, type 2A, type 2B, and type 3 are classified as genetic forms. Further studies are crucial for the development of targeted therapies and future mutation-specific therapies.


Introduction
][3] The body converts cholecalciferol, which is produced in the skin upon exposure to the sun or consumed via food but is not biologically active, into active vitamin D through 2 hydroxylation reactions. 4,5The liver is the site of the initial hydroxylation process.The enzyme 25-hydroxylase in the liver converts it to 25-OH vitamin D [25(OH)D or calcidiol].The 1-hydroxylase enzyme produced by the kidneys causes 25(OH)D to go through a second hydroxylation.This transforms it into calcitriol [1,25(OH) 2 D], an active metabolite of vitamin D. 6,7 By attaching to the vitamin D receptor (VDR) and vitamin D binding protein, 1,25(OH) 2 D becomes functional in target cells. 8- 12It is stored in adipose tissue, muscles, and the liver. 13ckets, previously known as rachitis, is a disease characterized by inadequate mineralization of growth plate cartilage and the bone matrix in bone tissue during the period when the growth plates are open. 14,157][18] It is an important cause of morbidity and may lead to delayed growth and motor development, short stature, skeletal deformities, tetany, and seizures. 19ckets can be classified into 3 main categories.[22] Roughly 13% of all cases of rickets are due to hereditary factors.There are 2 main categories of hereditary rickets, and vitamin D-dependent rickets (VDDR) occurs in the gene encoding the vitamin D receptor or as a result of gene abnormalities that affect the encoding of enzymes involved in vitamin D production.More VDDR cases occur in underdeveloped countries. 23On the other hand, due to genetic damage, hypophosphatemic rickets is linked to abnormalities in renal phosphate transport or reabsorption. 24,25netic Forms of Calciopenic Rickets Vitamin D-dependent rickets types 1A and 1B, which are defined by vitamin D insufficiency, and types 2A and 2B, which are characterized by vitamin D resistance, constitute 2 main subgroups of hereditary calciopenic rickets (Figure 1).The clinical and laboratory results reported in cases of hereditary calciopenic rickets are summarized in Table 1. 26,27tamin D-Dependent Rickets Type 1A (MIM 264700) The production of vitamin D and its conversion to an active state are both primarily carried out by the enzyme 1-hydroxylase.An inactivating mutation in CYP27B1, which encodes 1-hydroxylase, causes VDDR1A. 28This mutation prevents 25(OH)D from converting into 1,25(OH) 2 D, which results in rickets. 29inical Findings Clinical findings are similar to those of nutritional rickets.Hypocalcemic seizures, hypotonia, growth retardation, and muscle weakness may be observed in early infancy.30,31 25(OH)D deficiency has been reported to affect the muscles of the lower extremities, which are especially crucial for walking and postural balance.32 Patients are usually clinically normal at birth, but severe signs of rickets may appear in the first 2 years of life.

Laboratory Findings
Laboratory findings seen in VDDR1A are as follows 25,26,33 : levels in VDDR1A are typically low from birth and do not rise with vitamin D therapy. 34,35arathyroid hormone secretion and elevated PTH levels are brought on by deficiencies of vitamin D, calcium, and ionized calcium. 36n some circumstances, otherwise normal 1,25(OH) 2 D levels with hypophosphatemia, hypocalcemia, and elevated PTH levels should be regarded as low. 37 Normal or elevated cyclic adenosine monophosphate (cAMP) in urine • Increased intestinal calcium excretion • Normal 2 D level, that is, normal 24-hydroxylase enzyme activity.

Treatment
Calcitriol, the first-choice treatment, rapidly corrects the clinical, biochemical, and radiological findings of VDDR1A at physiologic doses.The goal of treatment is to increase calcium levels and other biochemical parameters to normal ranges without hypercalciuria, improve radiological findings, increase muscle strength, and ensure normal growth and development.
Calcitriol is started at 10-20 ng/kg/day in 2 doses or 1-2 µg/day, and treatment can be continued at a dose of 0.5-1 µg/day in follow-up.Alfacalcidol can also be used at a dose of 1-3 µg/day.Adding

Main Points
• Rickets is a significant childhood illness that persists despite vitamin D supplementation programs.
• If there are signs and symptoms of rickets despite vitamin D supplementation, clinicians should consider the possibility of vitamin D-dependent rickets.
• The discovery of new mutations that cause hereditary types of rickets is leading to a better understanding of the underlying mechanisms and new therapeutic opportunities.
30-75 mg/kg/day of elemental calcium to calcitriol or alfacalcidol should be recommended at the beginning of treatment.Lifelong treatment is required for patients with VDDR1A.With adherence to treatment, biochemical parameters normalize and adult height with normal linear growth and normal bone mineralization can be achieved. 25,26,38tamin D-Dependent Rickets Type 1B (MIM 600081) A rare autosomal recessive condition, VDDR1B is brought on by homozygous or compound heterozygous mutations in the CYP2R1 gene (cytochrome P450, family 2, subfamily IIR, polypeptide 1; MIM 608713). 39,40In patients presenting with signs of low 25(OH)D levels as also seen in cases of nutritional rickets may cause difficulty in diagnosing VDDR1B.This type of rickets should be considered for patients who have no signs of malabsorption and for whom standard vitamin D doses do not result in an adequate increase in 25(OH)D levels.These patients generally have a milder phenotype compared to those with VDDR1A. 26,41inical Findings Clinical findings are as in VDDR1A (Table 2).42 Laboratory Findings Laboratory findings of VDDR1B are as follows 26,43

Treatment
Treatment may include high doses of vitamin D. 44 There is no standard regarding the dose of vitamin D to be given.In the literature, oral administration of 4000-10 000 U/day or 50 000 U/month intramuscularly for 6 months has been reported.Calcitriol can be used at 10-20 ng/kg/day with 2 oral doses.Patients receiving calcitriol treatment should be followed for the risk of hypercalciuria or nephrocalcinosis.
There is insufficient information in the literature regarding long-term treatment results. 26,43,45tamin D-Dependent Rickets Type 2A (MIM 277440) Vitamin D-dependent rickets type 2A is an inherited autosomal recessive type of rickets characterized by resistance to 1,25(OH) 2 D. 46 It is also called vitamin D-resistant rickets, hereditary 1,25(OH) 2 D-resistant rickets, rickets-alopecia syndrome, hereditary hypocalcemic vitamin D-resistant rickets, and pseudovitamin D-deficiency type 2A.7,26 Clinical Findings Clinical findings are the same as those seen with VDDR1A in addition to total or partial alopecia seen in the majority of cases (Table 2).42 The clinical findings are heterogeneous.Disease manifestations usually occur in infancy or early childhood, but sporadic late-onset cases with milder clinical manifestations may also be seen.
In contrast to other forms of rickets, more than 50% of patients with VDDR2A have sparse body hair and alopecia from birth or the first years of life. 49In patients with alopecia, signs of rickets appear earlier and the clinical course is more severe.The extent of alopecia ranges from hair sparseness to the absence of eyelashes and eyebrows or total alopecia. 49The absence of alopecia in VDDR1A and VDDR1B indicates that calcitriol receptor function rather than vitamin D plays a role in hair follicle development.In some severe cases, patients may die in the first year of life with hypocalcemic convulsions and pulmonary complications. 50,51boratory Findings Laboratory findings in cases of VDDR2A are as follows [51][52][53] : •

Treatment
There is no standard treatment protocol for patients with VDDR2A.It is advised to administer elemental calcium at a dose of 1-3 g/day and calcitriol orally at 1-6 µg/kg/day. 8,20ecommended daily doses are 5000-40 000 IU for vitamin D, 20-200 g for 25(OH)D3, and 17-20 g for 1,25(OH) 2 D3. 27Depending on the specific VDR mutation, responses to medication may change.High doses of elemental intravenous calcium are needed for resistant patients who do not react to vitamin D therapy, such as 400 to 1400 mg/m 2 /day. 54For the majority of patients with VDDR2A, extended hospitalization with intravenous calcium treatment may be required to achieve normocalcemia.

Vitamin D-Dependent Rickets Type 2B (MIM 600785)
Vitamin D-dependent rickets type 2B is an uncommon condition.The clinical and laboratory findings are comparable to those of VDDR2A, but the VDR gene is unaltered.The molecular etiology is still not completely understood.Vitamin D receptor functions and VDR-RXR heterodimer formation were shown to be normal in contrast to VDDR2A patients. 55opecia may accompany clinical and laboratory findings in VDDR2B that are comparable to those of VDDR2A. 56It is possible to distinguish between VDDR2A and VDDR2B by genetic testing.These patients are treated similarly to VDDR2A patients. 25,26tamin D-Dependent Rickets Type 3 Increased inactivation of vitamin D metabolites results in VDDR3.This is induced a p.I301T mutation in the CYP3A4 gene. 57Clinically and experimentally, it is comparable to VDDR1. 58t has been indicated that high-dose vitamin D therapy is beneficial. 54However, there is only one clinical trial in the literature for VDDR3. 57urther studies are crucial for the future development of targeted therapies and mutationspecific therapies.

Figure 1 .
Figure 1.Hereditary forms of calciopenic rickets and vitamin D homeostasis.

Table 1 .
Clinical and Laboratory Findings in Vitamin D-Dependent Rickets (VDDR)

Table 2 .
Clinical Features of Vitamin D-Dependent Rickets Type 1A