Evidence for interaction between the TCO and NMTC1 loci in familial non-medullary thyroid cancer.

BACKGROUND: Familial non-medullary thyroid cancer (fNMTC) is a complex genetic disorder that is more aggressive than its sporadic counterpart. Thus far, three genetic loci have been implicated in susceptibility to fNMTC by linkage analysis. METHODS: We used linkage analysis to test the significance of two of the known susceptibility loci for fNMTC, TCO on 19p13 and NMTC1 on 2q21 in 10 fNMTC families, nine of which present with cell oxyphilia, a rare histological phenotype associated with TCO. Furthermore, we used two-locus linkage analysis to examine the possibility that the TCO and NMTC1 loci interact to increase the risk of NMTC. RESULTS: The 10 families provided evidence for linkage at both TCO and NMTC, with LOD scores of 1.56 and 2.85, respectively. Two-locus linkage analysis, using a multiplicative risk model for the development of NMTC, achieved a maximum LOD of 3.92, with an LOD of 4.51 when assuming 70% of families were linked, indicating that the segregation in these families is consistent with an interaction model. Most of this evidence came from a large Tyrolean family that singularly achieved a two-locus LOD of 3.21. CONCLUSIONS: These results provide further evidence that susceptibility genes for fNMTC exist at 19p13 and 2q21, and furthermore, raise the possibility that in a subset of fNMTC pedigrees, these loci interact resulting in significantly increased risk of NMTC for patients that carry both susceptibility loci.

Effects of growth hormone (GH) replacement on bone metabolism and mineral density in adult onset of GH deficiency: results of a double-blind placebo-controlled study with open follow-up.

It is known that GH stimulates bone turnover and that GH-deficient adults have a lower bone mass than healthy controls. In order to evaluate the influences of GH replacement therapy on markers of bone turnover and on bone mineral density (BMD) in patients with adult onset GH deficiency, a double-blind placebo-controlled study of treatment with recombinant human GH (rhGH; mean dose 2.4 IU daily) in 20 patients for 6 months and an extended open study of 6 to 12 months were conducted. Eighteen patients, fourteen men and four women, with a mean age of 44 years with adult onset GH deficiency were evaluated in the study. Compared with placebo, after 6 months serum calcium (2.39 +/- 0.02 vs 2.32 +/- 0.02 mmol/l, P = 0.037) and phosphate (0.97 +/- 0.06 vs 0.75 +/- 0.05 mmol/l, P = 0.011) increased and the index of phosphate excretion (0.03 +/- 0.03 vs 0.19 +/- 0.02, P < 0.001) decreased significantly, and there was a significant increase in the markers of bone formation (osteocalcin, 64.8 +/- 11.8 vs 17.4 +/- 1.8 ng/ml, P < 0.001; procollagen type I carboxyterminal propeptide (PICP), 195.3 +/- 26.4 vs 124.0 +/- 15.5 ng/ml, P = 0.026) as well as those of bone resorption (type I collagen carboxyterminal telopeptide (ICTP), 8.9 +/- 1.2 vs 3.3 +/- 0.5 ng/ml, P < 0.001; urinary hydroxyproline, 0.035 +/- 0.006 vs 0.018 +/- 0.002 mg/100 ml glomerular filtration rate, P = 0.009). BMD did not change during this period of time. IGF-I was significantly higher in treated patients (306 +/- 45.3 vs 88.7 +/- 22.5 ng/ml, P < 0.001). An analysis of the data compiled from 18 patients treated with rhGH for 12 months revealed similar significant increases in serum calcium and phosphate, and the markers of bone turnover (osteocalcin, PICP, ICTP, urinary hydroxyproline). Dual energy x-ray absorptiometry (DXA)-measured BMD in the lumbar spine (1.194 +/- 0.058 vs 1.133 +/- 0.046 g/cm2, P = 0.015), femoral neck (1.009 +/- 0.051 vs 0.936 +/- 0.034 g/cm2, P = 0.004), Ward's triangle (0.881 +/- 0.055 vs 0.816 +/- 0.04 g/cm2, P = 0.019) and the trochanteric region (0.869 +/- 0.046 vs 0.801 +/- 0.033 g/cm2, P = 0.005) increased significantly linearly (compared with the individual baseline values). At 12 months, BMD in patients with low bone mass (T-score < -1.0 S.D.) increased more than in those with normal bone mass (lumbar spine 11.5 vs 2.1%, P = 0.030, and femoral neck 9.7 vs 4.2%, P = 0.055). IGF-I increased significantly in all treated patients. In conclusion, treatment of GH-deficient adults with rhGH increases bone turnover for at least 12 months. BMD in the lumbar spine and the proximal femur increases continuously in this time (open study) and the benefit is greater in patients with low bone mass. Therefore, GH-deficient patients exhibiting osteopenia or osteoporosis should be considered candidates for GH supplementation. However, long-term studies are needed to establish that the positive effects on BMD are persistent and are associated with a reduction in fracture risk.

[Double photon absorptiometry in renal osteodystrophy]. / Doppel-Photonen-Absorptiometrie bei renaler Osteopathie.

Bone mineral content (BMC) of the lumbar spine (L2-L4), femoral neck, Ward's triangle and the trochanteric region was measured in 52 consecutive patients on maintenance haemodialysis. In the whole group the median BMC value as percentage of sex- and age-matched normal means was significantly decreased only in Ward's triangle (91.7%; p less than 0.02). In patients with chronic interstitial nephritis there was a significant decrease in bone density in Ward's triangle and the trochanteric region (p less than 0.02). There was no correlation between BMC and time on dialysis or intact parathormone. BMC value did not predict the type of renal osteodystrophy, according to Delling. 17 patients underwent a second investigation after one year. There was a slight fall in mean BMC of the lumbar spine (-0.9%) and Ward's triangle (-1.1%). The fall in mean BMC of the trochanteric region was pronounced (-3.2%). We believe that the observed low demineralisation, which was more pronounced in patients with interstitial nephritis, may be attributable to early and carefully monitored therapy with vitamin D metabolites.

Bone disorders following total gastrectomy.

Bone disorders following gastrectomy were studied by measuring absolute and relative bone mineral density of the Wards triangle, serum 1,25-(OH)2-D, alkaline phosphatase, and total serum calcium. The subjects were 20 males who had undergone total gastrectomy not more than three months previously (group A1). Seventeen of these patients were reviewed three years later (group A2). Absolute and relative bone density were significantly lower in group A2 than in A1 (0.52 +/- 0.011 g/cm2 versus 0.6 +/- 0.014 g/cm2, P < 0.01 and 85.5 +/- 1.4% age-matched control versus 95 +/- 1.3%, P < 0.01). 1,25-(OH)2-D was significantly lower in group A2 than in group A1 (14.3 +/- 0.97 pg/ml versus 20.6 +/- 1.02 pg/ml, P < 0.01). There was no difference in alkaline phosphatase and calcium serum concentration. The mean weight loss was 6.26 +/- 0.57% over the follow-up period, and weight loss correlated with absolute and relative bone density (r = -0.74, P < 0.01). There was a positive correlation between 1,25-(OH)2-D and absolute or relative bone density (r = 0.67, r = 0.62 and P < 0.01). These data suggest that bone density decrease has already occurred three years after total gastrectomy and is positively correlated to 1,25-(OH)2-D deficiency. As no differences in serum alkaline phosphatase and serum calcium concentration were found, these factors are of little value for the early detection of postgastrectomy bone disorders, whereas weight loss is a valuable screening parameter.