HVDRR is a rare recessive genetic disorder caused by mutations in the VDR that result in end organ resistance to 1,25-(OH)2D3 action. The major defect caused by the mutant VDR is a decrease of intestinal calcium and phosphate absorption, which leads to decreased bone mineralization and rickets. Since 1978, more than 50 families exhibiting signs and/or symptoms of HVDRR have been studied (Table 3). Usually, the diagnosis of HVDRR has been based on high circulating levels of 1,25-(OH)2D3 and resistance of cultured skin fibroblasts to 1,25-(OH)2D3 treatment. Many cases have been analyzed for [3H]1,25-(OH)2D3 binding to the VDR and/or transactivation of reporter genes by the VDR, which revealed that the disease was caused by heterogeneous mutations in the VDR gene. A number of cases of HVDRR have not yet been examined for mutations in the VDR gene. Since some of these cases presented late in life, it is possible they may have been due to nonhereditary or acquired resistance to 1,25-(OH)2D3. Analysis of the syndrome of HVDRR provides many interesting insights into vitamin D physiology and the role of the VDR in mediating 1,25-(OH)2D3 action. Our analysis of the findings leads us to make the following observations. At the time of this writing, eight missense mutations have been found in the VDR DBD that prevent the receptor from activating gene transcription even though 1,25-(OH)2D3 binding is normal. Six missense mutations have been identitled in the LBD that cause reduced or complete hormone insensitivity either by decreasing hormone affinity and/or interfering with heterodimerization with RXR. Four mutations have been found that introduce premature termination codons, which truncate the VDR and lead to complete hormone resistance. Two unique splice site mutations have been demonstrated that also introduce premature termination codons. A partial deletion encompassing exons 7-9 of the VDR gene has also been described. Despite the many pleiotropic processes regulated by 1,25(OH)2D3, children with HVDRR exhibit only symptoms that relate to their calcium deficiency and/or alopecia. We conclude that in vivo, the pleiotropic actions of vitamin D can be compensated for by other mechanisms but the calcemic effects cannot. The improvement in rickets after chronic intravenous calcium infusion or oral calcium raises interesting questions about the role of vitamin D in bone homeostasis. Correction of hypocalcemia and secondary hyperparathyroidism leads to healing of the rickets, as assessed by x-ray and bone biopsy. Thus, although there are many well defined actions of vitamin D on osteoblasts, the response to normalization of serum calcium suggests that 1,25-(OH)2D3 action on osteoblasts is not essential to form normal bone. The implication is that 1,25-(OH)2D3 action on bone is mainly due to its effects on intestinal mineral absorption to provide calcium and phosphate for bone formation. The same conclusion was reached by Underwood and DeLuca (273), who showed that the development of rickets is prevented in totally vitamin D-deficient rats by calcium and phosphate infusions in the absence of vitamin D. The ramifications for therapy are that normalization of serum calcium by intravenous and/or oral calcium supplements will bypass the defective intestinal VDR and heal the rickets. Although 1,25-(OH)2D3 is an inhibitor of PTH production, in the HVDRR children, normalizing serum calcium by intravenous infusion is sufficient to suppress their PTH overproduction and does not require 1,25-(OH)2D3 action. In addition, intravenous calcium therapy without phosphate is adequate to correct all of the metabolic abnormalities in children with HVDRR. This suggests that the hypophosphatemia in these patients is mainly the result of secondary hyperparathyroidism and not inadequate intestinal phosphate absorption. A number of interesting issues concerning alopecia and HVDRR are worth noting. Since VDRs have been found in hair follicles (27, 28), 1,25-(OH)2D3 action through the VDR appears to be essential for the differentiation of this structure during embryogenesis. Also, Marx et al. (26) have shown that there is some correlation between the severity of rickets and the presence of alopecia. HVDRR patients with alopecia tend to be nonresponsive to calciferols while those without alopecia tend to be responsive to high doses of vitamin D. The alopecia or some degree of hair loss appears to be associated primarily with DBD mutations or premature stop mutations, which usually result in complete hormone unresponsiveness and total resistance. A few patients with LBD mutations did not develop alopecia. Interestingly, the patient from family F48 had alopecia despite not having a mutation in the VDR. Alopecia remains unchanged in patients that undergo successful therapy or that show spontaneous improvement. In families with a history of HVDRR, the absence of body hair in newborns provides initial evidence for the disease. Interestingly, alopecia usually has not been found in other conditions related to defective vitamin D action, including 1α-hydroxylase deficiency (VDDR I) and other forms of vitamin D deficiency. In HVDRR, the hair follicles appear normal on microscopic examination, but without hair shafts present. We suspect that 1,25-(OH)2D3 action is necessary for the establishment of the hair synthetic machinery at a critical stage in development. A prenatal diagnosis of HVDRR is now possible in pregnant women from high-risk families. Cultured cells from chorionic villus samples or amniotic fluid have been used to ascertain whether the fetus has HVDRR using [3H]1,25-(OH)2D3 binding, induction of 24-hydroxylase activity, and RFLP analyses (271, 272). The mechanism for the spontaneous improvement in some HVDRR children as they get older is an interesting dilemma. One hypothesis that explains the normalization of the 1,25-(OH)2D3 endocrine system, in the face of inactive VDRs, is that some other transcription factor can substitute for the defective vitamin D system. Possibly RAR, RXR, or TR can substitute for a nonfunctional VDR and activate the appropriate target genes to reverse the hypocalcemia and restore the bones to normal. This hypothetical explanation remains untested. However, Whitfield et al. (157) have shown in vitro that addition of RXR can rescue mutant VDR with defects in the dimerization domain and restore hormone responsiveness. HVDRR is a relatively rare disease compared with androgen (239)- and thyroid (158)- resistant syndromes, which occur more frequently in the population. On the other hand, only a few cases of glucocorticoid (241), mineralocorticoid (242), and estrogen (240) resistance have been reported, while progesterone resistance has not been described. It is therefore interesting to speculate on the reasons for these differences in prevalence of diseases caused by mutations in the steroid hormone receptors. We believe that HVDRR is relatively rare because it is a true recessive disease. Heterozygotes are asymptomatic and for these rare mutations to affect both alleles in an individual, consanguinity is usually required. On the other hand, the number of cases of androgen resistance (androgen insensitivity syndrome or AIS) is greater, in part, because the AR gene is on the X-chromosome and a single mutation would result in the disease in the hemizygous male population. Females with two copies of the AR gene appear phenotypically normal even when one allele is mutated. Males acquire the mutant AR gene from their asymptomatic, heterozygotic mothers and consanguinity is not required. Thyroid hormone resistance (generalized resistance to thyroid hormone or GRTH), on the other hand, is often caused by dominant negative mutations in which one defective allele inactivates the normal allele (158). Like androgen resistance, only a single mutant TR allele is necessary to cause thyroid resistance. In contrast, dominant negative mutations have not been described in HVDRR where heterozygotes exhibit a normal phenotype. Since TR and VDR are thought to act through a common heterodimerization partner, RXR, one might speculate that the difference between GRTH and HVDRR due to a dominant negative mechanism might be due to the ability of TRs to form homodimers while VDRs do not. Few reports of glucocorticoid and mineralocorticoid resistance have been described (241, 242). Total resistance is likely to be lethal while mild cases might be more prevalent in the population than one might expect but are not diagnosed because they are not as easily recognized as androgen insensitivity syndrome, GRTH, and HVDRR (241). Mutations in ER and PR are rarely recognized although a single case of defective ER has been described in a male patient (240). The rarity of clinical cases was originally thought to be due to lethality of the mutation but, since knockout mice survive, this may also be due to lack of ascertainment or interference with successful pregnancy.
