Search

Chromosomal 8p23 deletion syndrome is recognized as a malformation syndrome with clinical symptoms of facial anomalies, microcephaly, mental retardation, and congenital heart defects. The responsible gene for the heart defects in this syndrome has been identified as GATA4on 8p23.1. Two patients with interstitial deletions of 8p23.1 were investigated; one patient showed moderate developmental delay and Ebstein anomaly, and the other showed mild delay and typical atrioventricular septum defect. The precise deletion sizes, 17 and 2.9 Mb, were determined by FISH analyses using BAC clones as probes. The latter deletion was the smallest deletion including GATA4in the previously reported patients, and the critical regions and genes for clinical manifestation of 8p23 deletion syndrome, including facial anomalies, microcephaly, behavioral abnormality, and developmental delay, were discussed. © 2008 WileyLiss, Inc.

FGF-23 was recently shown to be involved in the development of several hypophosphatemic diseases, including X-linked hypophosphatemic rickets/osteomalacia (XLH) and tumor-induced rickets/osteomalacia (TIO). FGF-23 is processed between Arg179 and Ser180, and only full-length FGF-23 was shown to cause hypophosphatemia. Two assays for FGF-23 have been reported. One assay detects only full-length FGF-23. In contrast, the C-terminal assay recognizes both full-length and processed C-terminal fragment of FGF-23. However, discrepant results concerning circulatory levels of FGF-23 in patients with TIO and XLH have been reported using these two assays. We simultaneously measured FGF-23 levels in 13 patients with adult-onset hypophosphatemic osteomalacia and 29 patients with XLH by these two assays. The full-length assay indicated that FGF-23 was above the upper limit of the reference range in all patients with osteomalacia and in 24 of 29 patients with XLH. However, the C-terminal assay in dicated that FGF-23 was within the reference range in 3 of 13 patients with osteomalacia and 16 of 29 patients with XLH. In addition, there was no correlation between FGF-23 levels measured by these assays in patients with XLH whose FGF-23 was within the reference range by C-terminal assay. These results indicate that FGF-23 within the reference range by C-terminal assay does not rule out an increase in full-length FGF-23. In addition, because FGF-23 was high in most of these hypophosphatemic patients, these results support the notion that FGF-23 plays a major role in the development of hypophosphatemia in patients with TIO and XLH.

We treated an extremely tall 13-year-old girl with a growth hormone (GH)-secreting macroadenoma and GH levels of 120–495 ng/ml with a combination of preoperative octreotide infusion, surgery and postoperative octreotide infusion plus estrogen, which resulted in reduced tumor size prior to surgery, reduced GH levels and completely suppressed growth after surgery. 20K GH is produced by alternative splicing of 22K GH mRNA and the ratio of 20K GH to 22K GH is within a small range in the normal population and high in a GH-secreting tumor. The 20K/22K GH ratio in this patient was persistently elevated during each phase of the treatment and may serve as a sensitive index of tumor-derived GH secretion.

Pycnodysostosis (Pycno) is an autosomal recessive osteosclerotic skeletal dysplasia that is caused by the markedly deficient activity of cathepsin K. This lysosomal cysteine protease has substantial collagenase activity, is present at high levels in osteoclasts, and is secreted into the subosteoclastic space where bone matrix is degraded. In vitro studies revealed that mutant cathepsin K proteins causing Pycno did not degrade type I collagen, the protein that constitutes 95% of organic bone matrix. To determine the in vivo effects of cathepsin K mutations on bone metabolism in general and osteoclast‐mediated bone resorption specifically, several bone metabolism markers were assayed in serum and urine from seven Pycno patients. Two markers of bone synthesis, type I collagen carboxy‐terminal propeptide and osteocalcin, were normal in all Pycno patients. Tartrate‐resistent acid phosphatase, an osteoclast marker, was also normal in these patients. Two markers that detect type I collagen telopeptide cross‐links from the N and C termini, NTX and CTX, respectively, were low in Pycno. A third marker which detects a more proximal portion of the C terminus of type I collagen in serum, ICTP, was elevated in Pycno, a seemingly paradoxical result. The finding of decreased osteoclast‐mediated type I collagen degradation as well as the use of alternative collagen cleavage sites by other proteases, and the accumulation of larger C‐terminal fragments containing the ICTP epitope, established a unique biochemical phenotype for Pycno.

Pycnodysostosis (Pycno) is an autosomal recessive osteosclerotic skeletal dysplasia that is caused by the markedly deficient activity of cathepsin K. This lysosomal cysteine protease has substantial collagenase activity, is present at high levels in osteoclasts, and is secreted into the subosteoclastic space where bone matrix is degraded. In vitro studies revealed that mutant cathepsin K proteins causing Pycno did not degrade type I collagen, the protein that constitutes 95% of organic bone matrix. To determine the in vivo effects of cathepsin K mutations on bone metabolism in general and osteoclast‐mediated bone resorption specifically, several bone metabolism markers were assayed in serum and urine from seven Pycno patients. Two markers of bone synthesis, type I collagen carboxy‐terminal propeptide and osteocalcin, were normal in all Pycno patients. Tartrate‐resistent acid phosphatase, an osteoclast marker, was also normal in these patients. Two markers that detect type I collagen telopeptide cross‐links from the N and C termini, NTX and CTX, respectively, were low in Pycno. A third marker which detects a more proximal portion of the C terminus of type I collagen in serum, ICTP, was elevated in Pycno, a seemingly paradoxical result. The finding of decreased osteoclast‐mediated type I collagen degradation as well as the use of alternative collagen cleavage sites by other proteases, and the accumulation of larger C‐terminal fragments containing the ICTP epitope, established a unique biochemical phenotype for Pycno.

Hypoparathyroidism is a clinical disorder characterized by hypocalcemia and hyperphosphatemia in the absence of renal failure and hypomagnesemia. The causes of hypoparathyroidism can be classified as two groups: (i) insufficient parathyroid hormone (PTH) secretion in relation to the serum calcium level (hypoparathyroidism); and (ii) impaired PTH action (pseudohypoparathyroidism). The main emphasis in this report is to distinguish subgroups based on the etiology and pathophysiology of the various aspects of the disease.

To determine the effect of intranasal administration of salmon calcitonin on glucocorticoid-induced osteoporosis in children with nephrosis, we gave 100 U of calcitonin intranasally on alternate days with 1α-hydroxyvitamin D3to five children, 8 to 12 years of age, with frequently relapsing nephrosis. Four patients with osteoporosis, 10 to 14 years of age, were treated only with 1α-hydroxyvitamin D3and served as control subjects. Both groups were treated with an almost equal amount of glucocorticoids previously and during this study period. Bone mineral content of the spine was measured by a quantitative computed tomographic technique. The bone mineral content was preserved in both cortical and spongeous areas of the vertebrae during the 16-month period in the calcitonin-treated group but was decreased significantly in the control group. Urinary hydroxyproline and calcium excretion decreased significantly in the calcitonin-treated group. The serum calcium and phosphorus concentrations and the parathyroid function did not change significantly in either group. We conclude that calcitonin suppressed bone resorption and might be useful for the long-term treatment of osteoporosis, in combination with 1α-hydroxyvitamin D3, in children with nephrosis requiring long-term glucocorticoid therapy.

Abstract. The activity of stimulatory guanine nucleotide regulatory protein (Ns) in the erythrocyte membrane was assayed by the reconstitution method using plasma membrane of cyc−S49 mouse lymphoma cells in 18 patients with type I pseudohypoparathyroidism (PHP-I), 2 with pseudopseudohypoparathyroidism (PPHP) and 30 normal subjects, in parallel with other clinical parameters. The Ns activity as expressed by per cent of pooled standard (mean ± se) was 78.9 ±6.1 in PHP-I patients, which was significantly lower (P< 0.01) than the value in normal subjects, 99.5 ± 2.4. In PHP-I patients, the Ns activities (Y) were in significant correlation with three clinical parameters examined (X), i.e., with body height in standard deviation score from the mean of the normal population at the corresponding age, Y = 89.4 + 10.4X (r = 0.616, P< 0.01); with urinary cAMP excretion in relation to creatinine [cAMP(nmol)/Cr(mg)], Y = 56.3 + 7.2X (r = 0.501, P< 0.05); and with TSH levels in plasma (μU/ml), Y = 129–3X (r = 0.639, P< 0.01). The Ns activities of PPHP were as low as 53.8 and 60.0. The decrease of Ns activity in the cell membrane may be implicated in the development of the clinical symptoms such as short stature, decrease in urinary excretion of cAMP and latent or manifest primary hypothyroidism in PHP-I and possibly in skeletal abnormality in PPHP.

The function of 1,25-dihydroxyvitamin D3in bone development is to regulate the differentiation or proliferation of osteoblastic, osteoclastic, and chondrocytic lineage, affecting bone mineralization and linear bone growth. An A(T/C)G substitution exists in the first of the two putative translation initiation sites in exon 2 of the vitamin D receptor (VDR) gene. We studied the relationship between exon 2 polymorphism and height in 90 healthy Japanese female subjects aged 18-20 y, who had attained final height, in 159 healthy Japanese aged 13 y, and 24 children with constitutional short stature aged 6-10 y less than -1.5 SD in height, mostly with parents of normal height. Exon 2 polymorphism was analyzed by PCR-single strand conformation polymorphism, PCR-direct sequencing, and PCR-restriction fragment length polymorphism. The frequency of the exon 2 polymorphism was genotype CC (ACG/ACG), 0.37; genotype CT (ACG/ATG), 0.51; and genotype TT (ATG/ATG), 0.12 in 249 normal subjects. The mean height of female subjects aged 18-20 y with the genotype CT was 160.3 ± 4.3 cm (mean ± SD), whereas that with CC was 4.4 cm lower (p < 0.0001), and that with TT was 2.7 cm lower (p = 0.0302). At age 13 y, this trend was observed, and the mean height SD score of subjects with the genotype CT was taller than homozygotes (CC/CT; p = 0.0363 and CT/TT; p = 0.0208) in 159 subjects. Genotype CT in 24 children with constitutional short stature was less frequent than other genotypes (CC, 0.62; CT, 0.21; TT. 0.17) (?2p value, 0.0171). In conclusion, the exon 2 polymorphism affecting the VDR mRNA and protein is one of the major determinants of adult height at least in female Japanese, which was noted at the age of 13 y examined in both sexes.

Minagawa M, Yasuda T, Kobayashi Y, Niimi H. Transient pseudohypoparathyroidism of the neonate. Eur J Endocrinol 1995:133:151–5. ISSN 0804–4643We report three neonates with transient hypoparathyroidism with elevated parathyroid hormone (PTH) levels to clarify further the pathogenesis of late neonatal hypocalcemia and calcium homeostasis. Clinical signs were seizures starting at the age of 10 and 11 days. The biochemical features were characterized by transient hypocalcemia and hyperphosphatemia due to a high transport maximum of the phosphate/glomerular filtration rate, despite high PTH levels. All had normal magnesium and calcidiol levels (at least 5 μg/l) for their age, and this precludes hypoparathyroidism due to low magnesium levels and hyperparathyroidism due to overt vitamin D deficiency. To diagnose pseudohypoparathyroidism type I, intravenous human PTH (1–34) infusions were performed; however, they showed brisk responses of plasma and/or urine cyclic AMP in response to the PTH infusion, but the phosphaturic response to the PTH was sluggish compared to the controls. All three showed an increase in serum alkaline phosphatase activity, suggesting PTH stimulation of osteoblasts. They were treated initially with calcium lactate or (1α)-hydroxycalciol/calcitriol. Their hypoparathyroid condition, however, was transient: they maintained normal serum calcium and PTH levels without medication before the age of 6 months. The etiology, possibly intracellular signal transduction distal to cyclic AMP and/or distinct from adenylate cyclase in the kidney, is developmental and the condition was resolved completely within 6 months of age. We have termed this condition "transient pseudohypoparathyroidism of the neonate".M Minagawa, Department of Pediatrics, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260, Japan

The circadian changes in blood and urine minerals and parathyroid function assessed by nephrogenous cyclic AMP (NcAMP) and a highly sensitive midregion specific parathyroid hormone (PTH) radioimmunoassay (RIA) were investigated for 26 hours in ten healthy 23 to 53-year-old males (group 1) with normal food intakes. Also, we studied another six male and four female adults between 600 and 1200 h as fasting controls (group 2). The blood calcium (Ca) levels were the highest at 630 h in both groups and decreased thereafter, and the diurnal variation of NcAMP reflected that of serum Ca, showing a low value in the morning. There were significant negative correlations between total Ca and NcAMP in both groups 1 and 2 (r=−0.323, n=130, p<0.01; r=−0.525, n=60, p<0.01), suggesting that the blood Ca level is the major determinant of parathyroid function and that NcAMP is a good indicator of blood Ca related PTH secretion in healthy individuals. This last relationship was not seen between Ca and midregion PTH levels presumably owing to slow clearance of PTH fragments from the circulation. However, midregion PTH perhaps because of its long half life, not NcAMP, shows a significant inverse relation to urinary Ca excretion (mg/dIGF) in the diurnal variation in healthy individuals (r=−0.560, n=130, p<0.01). The circadian pattern (s) of serum phosphate (P) consisted of a minium level at 900–1100 h followed by two peaks, at 1400–1600 h and 2200–2400 h. Thus, this study conducted in healthy individuals under physiologic condition clearly demonstrated that the NcAMP level reflects blood Ca related PTH secretion and that urinary Ca excretion seems to be determined by the sum of PTH secretion.

Novel heterodinuclear ethylplatinum complexes with a 1,2-bis(diphenylphosphino)ethane (dpe) ligand (dpe)EtPt-MLn(MLn= MoCp(CO)3, WCp(CO)3, Mn(CO)5, Co(CO)4) have been synthesized and characterized. The dinuclear complexes show higher activity for β-H elimination reaction than a mononuclear PtEtCl(dpe), and in the case of Pt-Mo and Pt-W complexes the reaction proceeds with retention of the dinuclear structure.

Reactions of a Pt-Mo heterodinuclear hydride complex, (dpe)HPt-MoCp(CO)3with alkynes at room temperature lead to facile reductive elimination giving HMoCp(CO)3accompanied by the formation of Pt(alkyne)(dpe). When terminal alkynes are employed, further Markovnikov addition of HMoCp(CO)3to the coordinated alkyne takes place to give new heterodinuclear alkenyl complexes (dpe)(μ-H2C=CR)Pt-MoCp(μ-CO)(CO).