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Biomedical subjects

K Kruse

Publications and source records attributed to K Kruse.

At least 55 records · Page 3Linked to original sources
PubMed1995

A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia.

A single heterozygous nucleotide exchange in exon M2 of the gene encoding the parathyroid hormone-parathyroid hormone-related peptide (PTH-PTHrP) receptor was identified in a patient with Jansen-type metaphyseal chondrodysplasia, which changes a strictly conserved histidine residue at position 223 in the receptor's first intracellular loop to arginine. Constitutive, ligand-independent adenosine 3',5'-monophosphate accumulation was observed in COS-7 cells expressing the mutant PTH-PTHrP receptor but not in cells expressing the wild-type receptor. This finding explains the severe ligand-independent hypercalcemia and hypophosphatemia, and most likely the abnormal formation of endochondral bone, in this rare form of short-limbed dwarfism.

Amino Acid Sequence↗
PubMed1995

Pathophysiology of calcium metabolism in children with vitamin D-deficiency rickets.

OBJECTIVE: To improve understanding of the biochemical events in vitamin D-deficiency rickets (VDR). METHODS: We investigated 51 untreated patients, 2 to 36 months of age, during three stages of VDR. Nineteen of these patients were also studied during therapy with 5000 to 10,000 U vitamin D3 (cholecalciferol) and 0.5 to 1 gm calcium. Together with calcium and inorganic phosphate in serum and urine, we measured (1) parathyroid hormone (PTH) secretion (intact serum PTH) and action on the kidney (urinary adenosine 3',5'-cyclic monophosphate (cAMP)/creatinine ratio; (2) serum alkaline phosphatase level; (3) urinary hydroxyproline/creatinine ratio; and (4) serum 1,25-dihydroxyvitamin D (1,25(OH)2D) level. RESULTS: The untreated patients had secondary hyperparathyroidism (high serum PTH and urinary cAMP/creatinine ratio), low calcium and phosphate concentrations in serum, and increased bone turnover (elevated serum alkaline phosphatase and OHP/creatinine ratio), whereas serum 1,25(OH)2D was low, normal, or even slightly elevated. Serum calcium level was positively correlated to serum 1,25(OH)2D and to OHP/creatinine ratio, indicating that normocalcemia in untreated rickets (stage 2) is at least partially maintained by 1,25(OH)2D-induced calcium mobilization from bone. There was no correlation between serum calcium and serum PTH, or between serum PTH and urinary cAMP/creatinine ratio or serum phosphate, indicating disturbed regulation and action of PTH. During vitamin D treatment, serum 1,25(OH)2D values increased to supranormal concentrations in association with the restoration of the physiologic relationship of PTH to serum calcium and phosphate concentrations and urinary cAMP/creatinine ratio. CONCLUSION: Circulating 1,25(OH)2D has an important role in the pathophysiology of VDR before and during treatment, mainly by influencing the bone and kidney response to endogenous PTH.

Alkaline Phosphatase↗
PubMed1995

Healing of rickets during vitamin D therapy despite defective vitamin D receptors in two siblings with vitamin D-dependent rickets type II.

We report the healing of severe rickets despite hypocalcemia in two siblings with absent vitamin D receptors; long periods of treatment with excessive doses of vitamin D led to relative hypoparathyroidism and a return to normal of calcium metabolism during calcitriol treatment. This finding suggests that some other regulating factor may substitute for the defective vitamin D receptor.

Dose-Response Relationship, Drug↗
PubMed1995

Increased urinary excretion of collagen crosslinks in girls with Ullrich-Turner syndrome.

Skeletal abnormalities and "osteoporosis" are frequent features of Ullrich-Turner syndrome (UTS), but their cause remains largely unknown. In this study, we compared the urinary excretion of hydroxyproline (OHP), pyridinoline (PYD) and deoxypyridinoline (DPD) in 28 girls (bone age 3.5-11.0 years, mean 7.4 years) with UTS and 30 healthy prepubertal children (chronological age 3.9-10.9 years, mean 7.6 years). Expressed relative to the square of the height, the excretion of both collagen crosslinks was significantly higher in UTS than in controls (23.4% for PYD, 33.6% for DPD, p < 0.05). In contrast, no significant difference was found for OHP. The molar PYD/DPD ratio was significantly lower in UTS children than in controls (mean (+/- SD) 3.4 (+/- 0.41) versus 3.8 (+/- 0.55); p = 0.004). While the higher excretion of collagen crosslinks reflects enhanced bone resorptive activity in UTS, the lower PYD/DPD ratio might be due to structural alterations in collagen.

Adolescent↗
PubMed1995

Dose-dependent responses in insulin-like growth factors, insulin-like growth factor-binding protein-3 and parameters of bone metabolism to growth hormone therapy in young adults with growth hormone deficiency.

There is increasing awareness that growth hormone (GH) replacement therapy is also essential in adult patients with growth hormone deficiency (GHD). There are little data available on the dose requirements for replacement therapy in this age group. In childhood, the growth response to GH therapy can serve as an indicator for correct replacement dose. Because this indicator does not exist in adults, we analyzed growth factors and biochemical markers of bone metabolism by specific radioimmunoassays in a group (n = 12) of adult patients (age, 20.0-31.6 years) with GHD with childhood onset before and after a 4-week treatment period (daily, s.c.) with recombinant, human GH at different doses (0.125, 0.25 and 0.5 IU/kg body weight/week). Comparing the basal levels to those on low-dose GH (0.125 IU/kg/week) and on a high dose (0.5 IU/kg/week), the following results were obtained. Insulin-like growth factor-I (IGF-I) in serum: basal, 68.6 +/- 37 ng/ml; low dose, 176.9 +/- 65 ng/ml (p < or = 0.05); high dose, 380.6 +/- 200 ng/ml (p < or = 0.01). IGF-binding protein-3 in serum: basal, 2.13 +/- 0.58 mg/l; low dose, 3.23 +/- 0.84 mg/l (p < or = 0.01); high dose, 3.97 +/- 0.82 mg/l. Osteocalcin in serum: basal, 3.88 +/- 1.27 ng/ml; low dose, 7.01 +/- 2.20 ng/ml (p < or = 0.01); no further increase. Procollagen-I peptide in serum: basal, 113.6 +/- 36.7 microgram/l; low dose, 211.6 +/- 90.4 microgram/l (p < or = 0.01); no further increase.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Pseudohypoparathyroidism type Ib is not caused by mutations in the coding exons of the human parathyroid hormone (PTH)/PTH-related peptide receptor gene.

Pseudohypoparathyroidism type Ib (PHP-Ib) is thought to be caused by a PTH/PTH-related peptide (PTHrP) receptor defect. To search for receptor mutations in genomic DNA from 17 PHP-Ib patients, three recently isolated human genomic DNA clones were further characterized by restriction enzyme mapping and nucleotide sequencing across intron/exon borders. Regions including all 14 coding exons and their splice junctions were amplified by polymerase chain reaction, and the products were analyzed by either temperature gradient gel electrophoresis or direct nucleotide sequencing. Silent polymorphisms were identified in exons G (1 of 17), M4 (1 of 17), and M7 (15 of 17). Two base changes were found in introns, 1 at the splice-donor site of the intron between exons E2 and E3 (1 of 17) and the other between exons G and M1 (2 of 17). Total ribonucleic acid from COS-7 cells expressing minigenes with or without the base change between exons E2 and E3 showed no difference by either Northern blot analysis or reverse transcriptase-polymerase chain reaction. Radioligand binding was indistinguishable for both transiently expressed constructs. A missense mutation (E546 to K546) in the receptor's cytoplasmic tail (3 of 17) was also found in 1 of 60 healthy individuals, and PTH/PTHrP receptors with this mutation were functionally indistinguishable from wild-type receptors. PHP-Ib thus appears to be rarely, if ever, caused by mutations in the coding exons of the PTH/PTHrP receptor gene.

Adolescent↗
PubMed1994

[Calcitriol administration during pregnancy in a partial DiGeorge anomaly].

A 23-year-old pregnant woman was known since birth to have partial DiGeorge syndrome with idiopathic hypoparathyroidism and clinically suspected thymus hypoplasia. The hypocalcaemia had until recently been treated with 1000 IU vitamin D3 daily. During the 9th week of pregnancy the serum calcium level was 1.9 mmol/l, the phosphate one 1.58 mmol/l and parathormone 5.6 pg/ml. To ensure better control, calcitriol was given (1.25-[OH]2-vitamin D3, initially 1 microgram daily and then, from the 22nd week of pregnancy onward, 1.5 micrograms daily), as well as calcium gluconate and lactate (initially 300 mg daily, then 900 mg daily). The serum calcium level at that time was between 2.0 and 2.5 mmol/l. Because of toxaemia of pregnancy the patient was hospitalized and confined to bed during the 37th week, whereupon the serum calcium level rose from 2.2 to 2.7 mmol/l, but a decrease in calcitriol dosage resulted in a decrease to within normal limits within one day. A girl was delivered by section in the 39th week: she had normal serum calcium and phosphate levels and appeared healthy.

Adult↗
PubMed1994

Teratogenic effects in a case of maternal treatment for acute myelocytic leukaemia--neonatal and infantile course.

Experience with the use of cytotoxic drugs in the first trimester of pregnancy is limited. We report on the clinical phenotype and infantile development of a girl born to a 36-year-old mother. Before recognition of pregnancy, the latter had been treated for acute myelocytic leukaemia receiving cytarabine, daunorubicin and doxorubicin at conception and cytarabine and thioguanine at about 35-37 days post conception. At delivery, there were severe brachycephaly, hypoplasia of the anterior cranial base and the midface as well as synostoses of both coronal and metopic sutures. Further findings included bilateral four-finger hands with hypoplastic thumbs and absent radii. This phenotype is reminiscent of the Baller-Gerold syndrome. The child, at present 15 months old, has had to undergo two operations for fronto-orbital advancement because of insufficient growth of the mid-face, nasal airway hypoplasia and increased intracranial pressure. Motor milestones are slightly retarded--neurodevelopment is otherwise normal. These findings are discussed in the context of the few previous reports and are particularly important for future genetic counselling.

Abnormalities, Drug-Induced↗
PubMed1993

Endocrine and molecular biological studies in a German family with Albright hereditary osteodystrophy.

We examined a German family with five members affected by Albright hereditary osteodystrophy (AHO). The only patient with pseudohypoparathyroidism type Ia (PHP-Ia) presented clinically with latent tetany, mental retardation, round face, short stature, brachymetacarpia and calcifications of subcutaneous tissue, heart and brain, whereas all other four members with pseudopseudohypoparathyroidism (pseudo-PHP) showed only subcutaneous calcifications and brachymetaphalangia. The PHP-Ia patient exhibited hypocalcaemia, hyperphosphataemia, elevated immunoreactive parathyroid hormone (PTH), and a blunted response of cyclic adenosine monophosphate (cAMP) in plasma and urine to synthetic 1-38 hPTH. In addition, latent primary hypothyroidism was found. In contrast, all tested healthy family members as well as the patients with pseudo-PHP exhibited normal calcium metabolism including cAMP response to exogenous PTH. In Northern blot experiments all patients with AHO, regardless whether affected by PHP-Ia or pseudo-PHP, revealed significantly reduced mRNA levels coding for the alpha subunit of the G protein that stimulates adenylyl cyclase (Gs alpha), when compared with healthy family members. In contrast, there was no significant difference between healthy and affected subjects with regard to the levels of the mRNA coding for the alpha subunit of Gi alpha-2, the main inhibitory G protein of adenylyl cyclase. The results indicate that reduced expression of Gs alpha is a useful genetic marker in some families with AHO, regardless whether patients are affected by PHP-Ia or by pseudo-PHP.

Adolescent↗
PubMed1993

Calcium metabolism in the Jansen type of metaphyseal dysplasia.

The Jansen type of metaphyseal dysplasia (JMD) is a rare disorder characterized by growth disturbance and progressive metaphyseal changes initially reminiscent of rickets or primary hyperparathyroidism. Seven of the 16 patients described until now presented with hypercalcaemia of unknown origin. We report studies of calcium metabolism in a hypercalcaemic girl with JMD during the first 3 years of life. The patient presented with hypercalcaemia, hypercalciuria, elevated urinary phosphate and cyclic adenosine monophosphate (AMP) excretion as well as increased 1,25-dihydroxyvitamin D concentrations in serum despite suppressed or low normal values of circulating intact parathyroid hormone (PTH) and PTH related peptide (PTHrP). Measurements of biochemical indices of bone turnover indicated increased bone resorption without sufficient compensatory bone formation. The study suggests that the hypercalcaemia in our patient was caused by an unknown factor, which is not PTH or PTHrP, with osteolytic activity and stimulatory effect on the proximal kidney tubule.

Bone Diseases, Developmental↗
PubMed1993

Elevated 1,25-dihydroxyvitamin D serum concentrations in infants with subcutaneous fat necrosis.

Two infants with subcutaneous fat necrosis had hypercalcemia that normalized during glucocorticoid treatment. The combination of hypercalcemia, normal concentration of 25-hydroxyvitamin D, an elevated concentration of 1,25-dihydroxyvitamin D, a suppressed parathyroid hormone level, and low-normal bone turnover indicated abnormal 1,25-dihydroxyvitamin D production with increased intestinal absorption of calcium. Unregulated production of 1,25-dihydroxyvitamin D by the granulomatous cells of fat necrosis may cause hypercalcemia.

Adipose Tissue↗
PubMed1993

Single strand conformation polymorphism analysis of androgen receptor gene mutations in patients with androgen insensitivity syndromes: application for diagnosis, genetic counseling, and therapy.

Recent studies indicate that mutations in the androgen receptor gene are associated with androgen insensitivity syndromes, a heterogeneous group of related disorders involving defective sexual differentiation in karyotypic males. In this report, we address the possibility of rapid mutational analysis of the androgen receptor gene for initial diagnosis, genetic counseling, and molecular subclassification of affected patients and their families. DNA from peripheral blood leukocytes of six patients from five families with various degrees of androgen insensitivity was studied. Exons 2 to 8 of the androgen receptor gene were analyzed using a combination of single strand conformation polymorphism analysis and direct DNA sequencing. Female family members were also studied to identify heterozygote carriers. Point mutations in the AR gene were identified in all six patients, and all mutations caused amino acid substitutions. One patient with incomplete androgen insensitivity was a mosaic for the mutation. Four of the five mothers, as well as a young sister of one patient, were carriers of the mutation present in the affected child. Our data show that new mutations may occur in the androgen receptor gene leading to sporadic androgen insensitivity syndrome. Molecular genetic characterization of the variant allele can serve as a primary tool for diagnosis and subsequent therapy, and can provide a basis for distinguishing heterozygous carriers in familial androgen resistance. The identification of carriers is of substantial clinical importance for genetic counseling.

Adolescent↗