Xunwu Meng

Tumor-induced osteomalacia: an important cause of adult-onset hypophosphatemic osteomalacia in China: Report of 39 cases and review of the literature.

Tumor‐induced osteomalacia (TIO) is an acquired form of hypophosphatemia. Tumor resection leads to cure. We investigated the clinical characteristics of TIO, diagnostic methods, and course after tumor resection in Beijing, China, and compared them with 269 previous published reports of TIO. A total of 94 patients with adult‐onset hypophosphatemic osteomalacia were seen over a 6‐year period (January, 2004 to May, 2010) in Peking Union Medical College Hospital. After physical examination (PE), all patients underwent technetium‐99m octreotide scintigraphy (99Tcm‐OCT). Tumors were removed after localization. The results demonstrated that 46 of 94 hypophosphatemic osteomalacia patients had high uptake in 99Tcm‐OCT imaging. Forty of them underwent tumor resection with the TIO diagnosis established in 37 patients. In 2 patients, the tumor was discovered on PE but not by 99Tcm‐OCT. The gender distribution was equal (M/F = 19/20). Average age was 42 ± 14 years. In 35 patients (90%), the serum phosphorus concentration returned to normal in 5.5 ± 3.0 days after tumor resection. Most of the tumors (85%) were classified as phosphaturic mesenchymal tumor (PMT) or mixed connective tissue variant (PMTMCT). Recurrence of disease was suggested in 3 patients (9%). When combined with the 269 cases reported in the literature, the mean age and sex distribution were similar. The tumors were of bone (40%) and soft tissue (55%) origins, with 42% of the tumors being found in the lower extremities. In summary, TIO is an important cause of adult‐onset hypophosphatemia in China. 99Tcm‐OCT imaging successfully localized the tumor in the overwhelming majority of patients. Successful removal of tumors leads to cure in most cases, but recurrence should be sought by long‐term follow‐up.

Aromatase deficiency in a Chinese adult man caused by novel compound heterozygous CYP19A1 mutations: Effects of estrogen replacement therapy on the bone, lipid, liver and glucose metabolism

OBJECTIVES Aromatase deficiency is a rare disorder resulting in estrogen insufficiency in humans. It has been reported in remarkably few men with loss-of-function mutations in the CYP19A1 gene encoding the aromatase, a cytochrome P450 enzyme that plays a crucial role in the biosynthesis of estrogens from androgens. We investigated a non-consanguineous family including an adult man with clinical features of aromatase deficiency, and studied the effects of estrogen replacement in the man. METHODS We investigated the clinical and biochemical phenotype, performed CYP19A1 mutational analysis in the family and 50 unrelated persons, studied the effects of CYP19A1 mutations on aromatase protein structure, functionally characterized the mutations by cell-based aromatase activity assays, and studied the effects of estrogen replacement on the bone, lipid, liver and glucose metabolism. RESULTS The man with clinical features of aromatase deficiency had novel compound heterozygous CYP19A1 mutations (Y81C and L451P) that were not found in 50 unrelated persons. Three-dimensional modeling predicted that Y81C and L451P mutants disrupted protein structure. Functional studies on the basis of in vitro expression showed that Y81C and L45P mutants significantly decreased the aromatase activity and catalytic efficiency. Estrogen replacement in the man increased bone mineral density, accelerated bone maturation, improved lipid profile and liver steatosis, and improved glucose levels but not insulin resistance. CONCLUSIONS We have identified two novel CYP19A1 missense mutations in an aromatase-deficient man. Estrogen replacement in the man shows great impact on recovering the impairments in the bone, lipid, liver and glucose metabolism, but fails to improve insulin resistance.

Novel and Recurrent Mutations of WISP3 in Two Chinese Families with Progressive Pseudorheumatoid Dysplasia

Background The WNT1-inducible signaling pathway protein 3 (WISP3), which belongs to the CCN (cysteine-rich protein 61, connective tissue growth factor, nephroblastoma overexpressed) family, is a secreted cysteine-rich matricellular protein that is involved in chondrogenesis, osteogenesis and tumorigenesis. WISP3 gene mutations are associated with progressive pseudorheumatoid dysplasia (PPD, OMIM208230), an autosomal recessive genetic disease that is characterized by the swelling of multiple joints and disproportionate dwarfism. Methodology/Principal Findings Four PPD patients from two unrelated Chinese families were recruited for this study. The clinical diagnosis was confirmed by medical history, physical examinations, laboratory results and radiological abnormalities. WISP3 mutations were detected by direct DNA sequence analysis. In total, four different mutations were identified, which consisted of two missense mutations, one deletion and one insertion that spanned exons 3, 5 and 6 of the WISP3 gene. One of the missense mutations (c.342T>G/p.C114W) and a seven-base pair frameshift deletion (c.716_722del/p.E239fs*16) were novel. The other missense mutation (c.1000T>C/p. S334P) and the insertion mutation (c.866_867insA/p.Q289fs*31) had previously been identified in Chinese patients. All four cases had a compound heterozygous status, and their parents were heterozygous carriers of these mutations. Conclusions/Significance The results of our study expand the spectrum of WISP3 mutations that are associated with PPD and further elucidate the function of WISP3.

Novel mutations of CYP27B1 gene lead to reduced activity of 1α-hydroxylase in Chinese patients.

Pseudovitamin D-deficiency rickets (PDDR) is an autosomal recessive disorder resulting from a defect in renal 25-hydroxyvitamin D 1α-hydroxylase, the key enzyme in the pathway of vitamin D metabolism. We identified ten different mutations in the 1α-hydroxylase gene (CYP27B1) in eight Chinese families with PDDR by DNA-sequence analysis. Six of them are novel missense mutations: G57V, G73W, L333F, R432C, R459C, and R492W; three are novel deletion mutations: c48-60del, c1310delG, and c1446delA; and an insertion mutation c1325-1332insCCCACCC reported previously. Functional assay revealed that the missense mutants identified in this study retain 5.5-12.1% 1α-hydroxylase activity of the wild type. The study describes nine novel mutations in addition to 37 known mutations of CYP27B1 gene and shows the correlation between these mutations and the clinical findings of 1α-hydroxylase deficiency.

Clinical phenotypes of Chinese primary hyperparathyroidism patients are associated with the calcium-sensing receptor gene R990G polymorphism

OBJECTIVE The purpose of this study was to investigate the distribution of the A986S and R990G polymorphisms of the calcium-sensing receptor (CASR) gene in the Chinese population and whether there is an association between genetic variants and the risk of developing primary hyperparathyroidism (PHPT) and its associated clinical phenotypes. METHODS A total of 164 Chinese Han PHPT patients (M/F: 51/113) and 230 healthy controls (M/F: 50/180) were enrolled. The common clinical parameters of PHPT patients including biochemical markers, bone mineral density (BMD), kidney stone occurrence, and pathology results were analyzed. Genotyping was conducted for both the patients and controls, and it was carried out using standard procedures. RESULTS The R990G variant was more frequently present than the A986S variant in this group of Chinese PHPT patients. The R allele increased the risk of PHPT (odds ratio=1.134, 95% CI: 1.008, 1.277, and P=0.036). Patients with either the RR or RG genotype had lower blood calcium levels and higher alkaline phosphate levels than patients with the GG genotype. The lumbar BMD T-score was -2.20 (-2.63, -0.32) in patients with the GG genotype, and it was significantly lower in patients with the RR+RG genotype (-2.53 (-3.70, -1.72) P=0.036). Patients with the R allele had a significantly higher incidence of hyperplasia (25.0%) and carcinomas (7.1%) than those with the GG genotype (5.3 and 0% respectively; P=0.025). The prevalence of osteoporosis and parathyroid carcinomas was higher in Chinese PHPT patients with the R allele. CONCLUSION The R990G polymorphism is most frequently present in the Chinese population and among patients with PHPT. Additional studies in the Chinese population are needed to elaborate the relationship between genetics and PHPT.

Surgical Treatments of Tumor-Induced Osteomalacia Lesions in Long Bones: Seventeen Cases with More Than One Year of Follow-up.

BACKGROUND Tumor-induced osteomalacia is a rare and fascinating paraneoplastic syndrome usually caused by a small, benign phosphaturic mesenchymal tumor. Most tumors are treated surgically, but we are unaware of any reports that compare the results of curettage and segmental resection for lesions in long bones. METHODS Seventeen patients (ten male and seven female) with tumor-induced osteomalacia lesions in long bones, who underwent surgical treatment from December 2004 to August 2013 in our hospital, were included in this retrospective study. The mean follow-up (and standard deviation) was 35 ± 27 months (range, twelve to 116 months). The characteristics of the tumor and the effects of different surgical treatments (curettage compared with segmental resection) were evaluated. RESULTS All patients showed typical clinical characteristics of tumor-induced osteomalacia, including elevated serum fibroblast growth factor-23 (FGF-23); 82% of tumors were in the epiphysis, and 82% grew eccentrically. The mean maximum diameter of the tumors was 2.4 ± 2.0 cm. The complete resection rates were similar for curettage (67%) and segmental resection (80%). However, the recurrence rate after curettage (50%) was higher than that after segmental resection (0%). The complete resection rate for secondary segmental resection (75%) was not different from that for primary segmental resection (83%). All of our cases of tumor-induced osteomalacia were caused by phosphaturic mesenchymal tumors. After successful removal of tumors, serum FGF-23 returned to normal within twenty-four hours and serum phosphorus levels returned to normal at a mean of 6.5 ± 3.5 days. CONCLUSIONS Most lesions in long bones are located in the epiphysis, so curettage is first suggested to maintain joint function. If curettage is incomplete or there is a recurrence, secondary segmental resection should be considered curative. Changes of serum FGF-23 and phosphorus levels before and after the operation may be of prognostic help.

CHAPTER 22 – Clinical Presentation of Primary Hyperparathyroidism: India, Brazil, and China

The pattern of presentation of hyperparathyroidism has changed in the West such that nearly 70–80% patients are asymptomatic and do not usually suffer from its skeletal or renal complications. In contrast, primary hyperparathyroidism presents its traditional manifestations in the East and in some regions of the Southern Hemisphere. In these regions, it is associated with more symptoms, large parathyroid tumors, and a higher incidence of parathyroid cancers. Many of the similarities between traditional primary hyperparathyroidism of the West and contemporary primary hyperparathyroidism of the East are explained by the differences in prevailing surveillance patterns and vitamin D and calcium nutrition of the populations. The higher prevalence of parathyroid cancers may be a reflection of an exaggerated growth behavior of abnormal parathyroid tissue partly influenced by vitamin D and calcium nutritional status of the individual. It is reasonable to infer that more severe bone disease—such as osteitis fibrosa cystica, brown tumors, and pathologic fractures are likely only when excess parathyroid hormone secretion is accompanied by profound and prolonged vitamin D and calcium malnutrition. Continued observations and comparisons of patients with primary hyperparathyroidism from different parts of the world are likely to provide even greater insights into this ever-changing disease.

Epidemiology of osteoporosis in mainland China.

As the NIH Consensus Development Panel on Prevention, Diagnosis, and Therapy of Osteoporosis suggested in 2001, osteoporosis is a skeletal disorder characterized by compromised bone strength that predisposes a person to an increased risk of fracture. In recent decades, osteoporosis has been acknowledged to be an important disease in the world. The incidence and prevalence of osteoporosis have been investigated all over the world, including China. Owing to the improvement of peoples livelihood and the development of social health care, the average lifespan expectancy increased from 35 years in 1945 to 71 years in 1998 in mainland China. The percentage of elderly population in China increased gradually. People older than 60 years and 65 years of age accounted for 6.1% and 3.5%, respectively, in 1964. However, these percentages are predicted to become 20.0% and 12.9% in 2025. Furthermore, China holds more than 20% of the world population. So osteoporosis and its major complication, fracture, have become one of the important public health problems. Li et al. [1] reported a survey conducted in five administrative areas in 2002 in which 5593 Chinese of Han nationality above 40 years of age from five areas including the Jilin (northern), Shanghai (east), Guangdong (southern), Chengdu (southwest), and Beijing (northeast) were enrolled in the study. Bone mineral density (BMD) was measured by dual-energy X-ray aborptiometry (DEXA). A BMD below the average value of the peak bone mass of young normal people by 2.5 SD is defined as osteoporosis. The prevalence rate of osteoporosis was 11.5 % in males and 19.9% in females, respectively, and the total prevalence rate was 16.1%. Fracture is common among the elderly population with osteoporosis, and it is one of the most severe complications of osteoporosis. Several surveys were conducted on the prevalence of vertebral fracture in mainland China. The prevalence of vertebral fracture in the aforementioned five

A compound heterozygous mutation in SLC34A3 causes hereditary hypophosphatemic rickets with hypercalciuria in a Chinese patient

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare metabolic disorder inherited in an autosomal recessive fashion and characterized by hypophosphatemia, short stature, rickets and/or osteomalacia, and secondary absorptive hypercalciuria. HHRH was recently mapped to chromosome 9q34, which contains the gene SLC34A3 which encodes the renal proximal tubular sodium-phosphate cotransporter NaPi-IIc. Here we describe a 29-year-old man with a history of childhood rickets who presented with increased renal phosphate clearance leading to hypophosphatemia, hypercalciuria, low serum parathyroid hormone (PTH), elevated serum 1,25-dihydroxyvitamin D (1,25(OH)2D) and recurrent nephrolithiasis. We performed a mutation analysis of SLC34A3 (exons and adjacent introns) of the proband and his parents to determine if there was a genetic contribution. The proband proved to be compound heterozygous for two missense mutations in SLC34A3: one novel mutation in exon 7 c.571G>C (p.G191R) and one previously identified mutation in exon 13 c.1402C>T (p.R468W). His parents were both asymptomatic heterozygous carriers of one of these two mutations. We also performed an oral phosphate loading test and compared serum phosphate, intact PTH, and intact fibroblast growth factor 23 (iFGF23) in this patient versus patients with other forms of hypophosphatemic rickets, the results of which further revealed that the mechanism of hypophosphatemia in HHRH is independent of FGF23. This is the first report of HHRH in the Chinese population. Our findings of the novel mutation in exon 7 add to the list of more than 20 reported mutations of SLC34A3.