In our study, we present a case of 52-year-old woman with recurrent renal stones, who was subsequently diagnosed as having MSK and tertiary hyperparathyroidism. Although hyperparathyroidism is reported in a few patients with MSK, the exact association is still controversial. Our study indicates that MSK might be the primary factor, and parathyroid adenoma might occur secondary to long-term negative calcium balance caused by MSK, which highlights the importance of early detection, treatment, and further prevention of complications of MSK. Given the key role of the GDNF and RET interaction in kidney and urinary tract development, we also analyzed and found RET G691S/S904S polymorphism in this patient, but additional studies are required to explore the exact mechanism of the RET gene in MSK with hyperparathyroidism.
MSK is a kidney malformation and is often combined with impaired renal tubular functions, such as concentration defects, and partial or complete distal renal tubular acidosis (dRTA). Fabris et al.  showed that over 80% of patients with MSK had complete or incomplete dRTA. Chemical analyses of the stone in patients with MSK showed that 67% of them were mainly calcium phosphate and 33% were calcium oxalate which further confirmed the prevalence of distal tubular acidosis in patients with MSK . Some proposed that dRTA played a key role in the pathogenesis of MSK, which could lead to hypercalciuria, hypocitraturia, and stone formation. In our case, our patient had recurrent renal stones, urinary tract infection, hypokalemia, morning urine pH > 5.5, and acidosis, which were consistent with MSK and dRTA. Hyperparathyroidism is also reportedly associated with a few patients with MSK [3, 6], but the exact association between the two diseases is still controversial as both diseases can manifest as kidney stones and excessive urinary calcium excretion. Some scholars believe that hyperparathyroidism is a cause of MSK and triggers nephrolithiasis in these patients , while others believe that MSK could be the primary factor, and parathyroid adenoma might occur secondary to long-term negative calcium balance caused by high urinary calcium . In our case, nephrocalcinosis preceded the onset of hyperparathyroidism, while the level of PTH continued to rise after parathyroidectomy. Thus, we hypothesized the tertiary hyperparathyroidism in this patient, as proved by parathyroid pathology, is secondary to MSK, due to long-term distal tubular acidosis and negative calcium balance caused by high urinary calcium.
As MSK is considered a congenital disease, it is speculated that the GDNF and RET genes, which play a key role in the kidney–urinary tract development and nephrogenesis, might be the reasonable candidates for MSK. Torregrossa et al.  analyzed GDNF and RET genes of 55 patients with sporadic MSK and found eight patients with MSK had heterozygous variations of GDNF gene c.-45G>C, c.-27 + 18G>A. RET encodes a receptor tyrosine kinase, expressed primarily in neural crest and urogenital precursor cells. It is a developmentally important gene, required for kidney morphogenesis, maturation of peripheral nervous system lineages, and for differentiation of spermatogonia. In RET knockout mice, the loss of the RET protein results in anomalies of renal embryogenesis, which indicates that the RET protein is required for the development of the urinary excretory system. Primary hyperparathyroidism (PHPT) may occur as part of a complex syndrome or as an isolated disorder. Syndromic PHPT includes MEN types 1 to 4 (MEN1 to MEN4). RET gene mutations were also found in 97% of patients with MEN2A, who have an increased risk for parathyroid adenoma or hyperplasia, medullary carcinoma of the thyroid, and pheochromocytoma . Intriguingly, Diouf et al.  reported the case of a woman with MSK combined with MEN2A, that is, hyperparathyroidism and medullary thyroid carcinoma (MTC), due to RET C634Y mutation. In addition, sporadic forms of parathyroid tumors may arise because of somatic gene abnormalities. To date, reports have shown that more than 10% of patients with hyperparathyroidism may have a germline mutation involving the MEN1, RET, cell division cycle 73 (CDC73), calcium-sensing receptor (CASR), cyclin-dependent kinase inhibitor (CDNK1B), or PTH genes. Thakker  suggested that the patients with hyperparathyroidism in whom there is a high suspicion of a genetic etiology (for example, young age at onset, multigland disease, parathyroid carcinoma, or atypical parathyroid adenoma) should be offered genetic counseling and germline mutation testing. In our patient, the RET gene polymorphisms G691S (exon 11) and S904S (exon 15) were identified, but no GDNF variants were found. It was shown that the nonsynonymous RET G691S polymorphism is able to increase downstream signaling compared with RET wild type [12, 13]. Moreover, some studies have demonstrated that the oncogenic activity of RET pathogenic genes in MTC is enhanced by the presence of G691S, suggesting a possible modifier role of this nonsynonymous RET polymorphism [14, 15]. Previous studies  have shown that the polymorphisms G691S and S904S of RET are in linkage disequilibrium with each other. Robledo et al.  analyzed the polymorphisms G691S and S904S of RET in 104 patients with MEN2A, and found the homozygous for these polymorphisms were, on average, 10 years younger at the time of diagnosis compared with heterozygous and wild-type homozygous, indicating that the G691S/S904S variants of RET have a modifier effect on the age at onset of MEN2A. However, the exact mechanism of RET G691S/S904S polymorphism in the pathogenesis of MSK and hyperparathyroidism still remains to be uncovered.
Considering the pivotal role of incomplete dRTA in MSK, Fabris et al.  recommended orally administered alkali citrate in patients with MSK with at least one urine abnormality, and found quite positive effects: the stone rate decreased from 0.58 to 0.10 per year, a 50% decrease in their calciuria, and a 75% rise in their citrate levels, with an improvement in their bone mineral density. Other therapeutic measures include drinking plenty of water, reducing dietary sodium and proteins, and increasing vegetable and fruit intake. For patients with very frequently recurring stones, the minimally invasive percutaneous nephrolithotomy can be an option . The progression of MSK is slow and prognosis is usually good. End-stage renal disease in our patient can probably be attributed to persistent kidney damage as a result of long-term uncorrected dRTA, years of undiagnosed hyperparathyroidism, recurrent kidney stones requiring multiple admissions, and repeated episodes of urinary tract infections, all of which complicated the course of this apparently benign disease and resulted in total loss of kidney function. Early detection, treatment, and further prevention of complications will slow the kidney damage and prevent the need of renal replacement therapy in patients with MSK.