HHRH is a rare metabolic disorder with an autosomal recessive inheritance pattern, Tieder et al. were the first to describe the clinical phenotype of HHRH in a consanguineous Bedouin family(1). It is c characterized by hypophosphatemia, short stature, rickets and/or osteomalacia, and secondary absorptive hypercalciuria. Hypophosphataemia stimulates renal 1-alpha-hydroxylase, which increases 1.25 dihydroxyvitamin D synthesis, ith resultant suppression of parathyroid hormone (PTH) and increased intestinal absorption of calcium resulting in an increased renal filtered calcium load and hypercalciuria. which helps differentiate HHRH from autosomal dominant hypophosphataemic rickets (ADHR) and X-linked hypophosphataemia (XLH). In this case, the main clinical manifestations were bilateral genu varus deformity and short stature, but the patient did not present with bone pain, and investigations suggested hypophosphataemia, rickets and renal calculi. The TRP and phosphorus profiles were significantly lower than normal in patients with hypophosphatemic rickets or osteochondrosis, and although this patient had higher than normal values, she had low blood and urine phosphorus. Therefore, gene sequencing was performed to determine the cause.
Bergwitz et al.(2) performed a genomewide linkage scan combined with homozygosity mapping in the large consanguineous Bedouin kindred in which Tieder et al.(1). The candidate gene region was narrowed down to the 1.6MB region on chromosome 9q34, and the mutant gene was identified as SLC34A3, which enforces the type 2C sodium phosphate cotransport protein (NPT2c), which, together with NPT2a, is expressed in the apical region of proximal renal tubule cells under the control of PTH and fibroblast growth factor 23(FGF23). And reabsorption of phosphate from glomerular filtrate(3, 4).
Clinically, HHRH patients with homozygous or complex heterozygous SLC34A3/NPT2c mutations usually present with hypophosphatemia, rickets, or osteomalacia after reduced renal phosphate reabsorption, and often develop kidney stones or renal calcification. Hypophosphatemia caused appropriate elevation of 1,25(OH)2-vitamin D, increased calcium absorption, suppression of parathyroid, and hypercalciuria(5, 6).In contrast, mutations carrying the LRP5 gene(c.C3917T, p.A1306V) are variants of unknown clinical significance and are associated with osteoporosis-pseudoglioma syndrome, which often presents clinically with vitreoretinal abnormalities, generalised hypotonia, osteoporosis, glioma, short stature and microcephaly. Some of the clinical manifestations described above were present in the patient in this case.
Since HHRH is an autosomal recessive genetic disease, the typical manifestations of the disease require double-allelic mutation. The loss of just one SLC34A3 allele does not necessarily lead to abnormal laboratory results. Therefore, the patient must inherit the mutation from both parents to obtain the complete presentation of the disease. In one study(7), heterozygous patients presented with the mildness of clinical symptoms, usually mild or absent hypophosphatemia, and no skeletal deformities, with recurrent kidney stones and hypercalciuria as the main manifestations compared with homozygous patients. In homozygous patients, hypophosphatemia and kidney stones are more common. In this case report, the patient had homozygous gene mutation, and the patient had hypophosphatemia, rickets, short stature, and kidney stones, which was consistent with the report. The LRP5 mutation, which is also an autosomal recessive disorder, causes short stature in patients with early onset of clinical symptoms, and there is no definitive conclusion as to whether the two genetic variants overlap.
The disease can affect both sexes, but some women may have no clinical manifestations and only have reduced renal tubular reabsorption of phosphorus (mutation carriers). A review of the patient's siblings and parents blood phosphorus results revealed that one of the patient's sisters also had low blood phosphorus but was not yet clinically active, possibly because: (1) the patient's sister may be a carrier of the mutation but has not yet reached the age of onset; and (2) there is genetic and clinical heterogeneity for homozygous mutations in the gene. Subsequently, genetic testing of the parents of the proband and the sister who showed only Hypophosphatemia on laboratory tests, confirmed the presence of a heterozygous mutation in the gene in the affected parents and homozygous gene mutation in the sister. Therefore, whether there is clinical heterogeneity in the case for the homozygous gene mutation c.C1402T (p.R468W) in the SLC34A3 gene warrants further investigation.
The patient in this study had a homozygous mutation, in which the base C in position 1402 of the coding region of the gene was mutated to T, resulting in the mutation of amino acid R (arginine) to amino acid W (tryptophan) at position 468 of the amino acid encoded by the gene. The mutation is therefore likely to interfere with the normal function of the protein, leading to the development of the disease. However, HHRH is easily overlooked or underdiagnosed. Genetic evaluation of patients with familial hypercalciuria, hypophosphataemia and kidney stones is needed to further understand the prevalence and treatment of this rare disease. Biochemical, renal ultrasound and genetic screening should also be considered for first-degree relatives of patients with HHRH to increase the confidence in the diagnosis of the disease.
Early and accurate diagnosis of HHRH has important therapeutic significance. Tinder et al.(8) emphasized the importance of correct diagnosis, as long-term phosphate therapy alone can reverse clinical and biochemical abnormalities of HHRP, while treatment with active vitamin D metabolites may aggravate the disease, leading to hypercalcemia, nephrocalcinosis, and renal damage. Blood phosphorus is restored to nearly normal by phosphorus supplementation, which is conducive to fracture healing, and phosphorus supplementation can reduce blood calcium. A report(9) reported a 14-year-old Turkish boy with severe rickets since age 2 years. Laboratory analysis showed hypophosphatemia, normocalcemia, increased alkaline phosphatase activity, and normal serum PTH. Serum 1,25(OH)2D3 was markedly increased. Trabecular bone biopsy showed osteomalacia. At 10 years of age, high doses of vitamin D (40.000U/ D) and phosphate (1.1g/ D) for 20 days resulted in symptomatic kidney stones.
In one case report(10), genetic testing was performed on a 32-year-old woman with a painful valgus knee deformity and after a definitive diagnosis of HHRH, She was started on phosphate supplementation and suspended vitamin D. She subsequently showed significant improvement in her left knee pain. Six months after starting phosphate supplementation, she underwent a simple left total knee arthroplasty (TKA), which significantly improved the patient's quality of life after the procedure. And in this article, it is proposed that corrective surgery (such as osteotomy and total knee arthroplasty) can be performed for patients who develop physical deformities without timely and definitive diagnosis and intervention of HHRH, but that phosphate supplementation should be given for at least 6 months before surgery to ensure that bone mineralisation does not continue to be compromised, otherwise, poor bone healing and mineralisation may occur, leading to further irreversible defects.
However, it is currently controversial(11) whether oral phosphate supplements alone are safe for long-term treatment in terms of renal calcification, whether renal phosphate leakage will last for life, and whether treatment can be stopped after long-term treatment. It is not clear which genetic and biochemical indicators best predict the risk of renal calcification in the HHRH family, so there is a large amount of data needed to support how oral phosphate therapy should be monitored.