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Familial benign hypercalcemia (FBH) and neonatal hyperparathyroidism (NHPT) are disorders of calcium homeostasis that are associated with missense mutations of the calcium-sensing receptor (CaR). We have undertaken studies to characterize such CaR mutations in FBH and NHPT and to explore methods for their more rapid detection. Nine unrelated kindreds (39 affected, 32 unaffected members) with FBH and three unrelated children with sporadic NHPT were investigated for mutations in the 3,234-bp coding region of the CaR gene by DNA sequencing. Six novel heterozygous (one nonsense and five missense) mutations were identified in six of the nine FBH kindreds, and two de novo heterozygous missense mutations and one homozygous frame-shift mutation were identified in the three children with NHPT. Our results expand the phenotypes associated with CaR mutations to include sporadic NHPT. Single-stranded conformational polymorphism analysis was found to be a sensitive and specific mutational screening method that detected > 85% of these CaR gene mutations. The single-stranded conformational polymorphism identification of CaR mutations may help in the distinction of FBH from mild primary hyperparathyroidism which can be clinically difficult. Thus, the results of our study will help to supplement the clinical evaluation of some hypercalcemic patients and to elucidate further the structure-function relationships of the CaR.

This paper describes a woman with pseudopseudohypoparathyroidism (PPHP) who had intractable lymphoedema and also abnormal dermatoglyphics. The findings were quite distinct from those in two previously reported cases of pseudohypoparathyroidism (PHP). Dermatoglyphics may prove useful in the diagnosis of PPHP but may also provide a clue to the factors which distinguish PPHP from PHP.

Objectives. To determine whether women with fibromyalgia are at increased risk of developing osteoporosis or osteomalacia. Methods. Forty premenopausal women with fibromyalgia and 37 age-matched female controls were studied. Broadband ultrasound attenuation (BUA) and velocity of sound (VOS) were measured at the calcaneum and bone mineral density was measured at the forearm and lumbar spine using dual-energy X-ray absorptiometry. Serum calcium, alkaline phosphatase, c-glutamyl transferase, 25-hydroxyvitamin D and plasma viscosity were measured in all subjects and parathyroid hormone was measured in subjects recruited in the latter part of the study. Results. Seventeen patients with fibromyalgia syndrome and seven controls had 25-hydroxyvitamin D concentrations

this paper describes some radiological features of osteogenesis imperfecta and temporary brittle bone disease. both conditions cause fractures in early childhood that the parents cannot explain. they can underlie the finding of unsuspected fractures when x-rays are done for other reasons, including fractures of different ages. both can readily be confused with non-accidental injury.in these disorders any type of fracture can occur; no fracture pattern makes bone disease more or less likely. metaphyseal fractures, often regarded as specific for non-accidental injury, also have a wide range of other causes including several bone diseases. osteopenia cannot be reliably used in diagnosis, not least because it can be absent in some bone diseases such as osteogenesis imperfecta. wormian bones, if present in excess, are a valuable pointer to osteogenesis imperfecta but their absence does not eliminate this diagnosis.there is growing evidence for the identification of temporary brittle bone disease as a distinctive disorder with its own characteristic clinical and radiological findings.

AIMS: To determine the causes of death in patients with osteogenesis imperfecta, excluding infants with the perinatal lethal form (type II). METHODS: Seventy nine patients with known osteogenesis imperfecta were identified, 37 of whom had been seen clinically in life. Causes of death were identified from death certificates, postmortem reports, medical records, hospital consultants, relatives, and the Brittle Bone Society's records. RESULTS: Patients with the milder types of osteogenesis imperfecta, I and IV, often had a normal lifespan and died of unrelated illnesses such as myocardial infarction and malignancy. In some of these patients and in many patients with the more severe type III disease, it was clear that osteogenesis imperfecta contributed significantly to death, almost certainly to many of the respiratory deaths and to deaths from cardiac failure due to kyphoscoliosis. Osteogenesis imperfecta also caused six deaths, directly or indirectly, due to basilar invagination of the skull. Osteogenesis imperfecta may have contributed to deaths from intracranial bleeding. Apparently minor traumatic incidents may have disastrous consequences in patients with this disorder. CONCLUSIONS: Prompt care for respiratory infections and prevention of trauma in patients with osteogenesis imperfecta is essential.

Fractures of the distal forearm are widely regarded as the result of “fragility”. We have examined the extent to which patients with Colles’ fractures have osteopenia. We measured the bone mineral density (BMD) in the contralateral radius of 235 women presenting with Colles’ fractures over a period of two years. While women of all ages had low values for ultra-distal BMD, the values, in age-matched terms, were particularly low among premenopausal women aged less than 45 years. This result was not due to the presence of women with an early menopause. This large survey confirms and extends the findings from earlier small studies. We consider that it is particularly important to investigate young patients with fractures of the distal forearm to identify those with osteoporosis, to seek an underlying cause and to consider treatment.

Background: The Immediate Discharge Document is a tool used to communicate patient discharge information between hospitals and general practitioners. The standard of information provided may be variable, and sometimes delayed in arriving at the GP practice. Typed communication from the hospital can also be slow. This can result in difficulty managing patients in the community following their discharge. Our aim was to assess the quantity of information provided on Immediate Discharge Documents, and to assess the time scale taken for GPs to receive written communications from hospitals regarding patient discharges. An audit was initiated using a tool devised from Scottish Intercollegiate Guidelines Network Publication no 5 and involving four general practices within City of Perth, Scotland. Data was collected over a 28-day period in June/July 2001, by examining Immediate Discharge Documents relevant to each practice population received during this period, and by noting the time of arrival of a final typed summary. Data was analysed by Tayside Audit Resource for Primary Care. A total of 244 Documents were audited. Most significant results include basic administrative detail lacking in up to 30%. Of total documents, 13% failed to record a main condition or diagnosis; 93% recorded drug information, but only in 28% were follow up plans clear; 60% were received within five days of discharge, whilst final typed summaries were received from the hospitals within four weeks only in 51%. Conclusion: These results show there to be room for improvement with regard communication of patient discharge information, in regard to both the content of information provided and the time it takes to arrive. We require to raise awareness of this problem amongst hospital colleagues involving clinical governance and audit staff, with the objective to improve the quality and timescale of information transfer. Where this piece fits It is known that effective information transfer between health professionals is vital to optimise patient care. This work gives further impetus to improve the current standard of communication, and confirms a significant time delay that it takes information to reach GPs from the hospital setting.

We report 3 patients referred to the bone clinic after spinal fractures. Dual energy X-ray absorptiometry showed severe osteoporosis. Each patient was found to have a history of prostatic carcinoma and long-term treatment with goserelin. We suggest that all patients who have received androgen deprivation therapy for more than 1 year should be evaluated by bone densitometry.

To ascertain whether patients with Colles’ fracture should be investigated for osteoporosis and the risk of future fractures, we measured the bone mineral density of the distal radius of the other arm in 31 women patients and compared the results with those of a control group of 289 normal women. We divided the patients into two groups, those younger than 66 years and those older. In 25 patients we found values for bone mineral density which were lower than one standard deviation below the mean value for their age. Younger patients had a deficit greater than that expected for their ages. We believe that women with Colles’ fracture should be evaluated routinely for osteoporosis, particularly if they are under 66 years of age.

Using readily available biochemical assays of plasma and urine constituents, we have defined discriminant functions useful as a guide to the differential diagnosis of patients with hypercalcemia. The decreasing rank order of contribution of the variables to the discriminant functions was as follows: plasma albumin, plasma phosphate, plasma chloride, log10 (calcium excretion per liter of glomerular filtrate), and log10 (plasma gamma-glutamyltransferase). Discriminant functions have been defined for patients with values for plasma creatinine above and below 185 mumol/L, and for practical conditions in which plasma and urine samples, or plasma samples only, are available.

Osteogenesis imperfecta (OI) is a group of closely related inherited diseases characterized by abnormal bone fragility. The current clinical classification system delineates 6 types, one of which (type II) is so severe that mortality is 100%, either intrauterine or perinatal. The types are differentiated by clinical groups, by severity, and by the presence or absence of other features such as blue sclerae or dentinogenesis imperfecta. There are no known previous studies of mortality in OI.From a registry created in association with the Brittle Bone Society, 743 patients with OI in England and Wales were observed in the period 1980-1993. These were classified into 3 groups (type IA, type III, and types IB, IVA, and IVB combined). Average annual mortality rates were determined in each group by sex and attained age. These rates were compared with 1981 rates in the population of England and Wales, matched by sex and age. Results are given in terms of exposures, observed and expected deaths, and 2 indices of excess mortality: mortality ratios and excess death rates per 1000 person-years.In type IA, 51.5% of the OI cases overall, there was no significant excess mortality (mortality ratio 108%, based on 15 deaths). In type III, on the other hand, excess mortality was very high in children and still significantly high at ages 15-34 years. In the combined group of types IB, IVA, and IVB, the mortality ratio was 157% in patients aged 45 and up (not significant at the 95% confidence level), but higher ratios at younger ages were significant, even though based on a total of only 5 deaths.

Recent studies show that structural parameters of bone, obtained from computerized image analysis of radiographs, can improve the noninvasive determination of bone strength when used in conjunction with bone density measurements. The present study was designed to assess the ability of image features alone to predict the mechanical characteristics of bones. A multifactorial model was used to incorporate simultaneously a number of characteristics of the image, including periodicity and spatial orientation of the trabeculae. Fifteen pairs (29 specimens) of unembalmed human distal radii were used. The cancellous bone structure was determined using computerized spectral analysis of their radiographic images and the bones were tested to failure under compression. Multilayered perceptron neural networks were used to integrate the various image parameters reflecting the periodicity and the spatial distribution of the trabeculae and to predict the mechanical strength of the specimens. The correlation between each of the isolated image parameters and bone strength was generally significant, but weak. The values of mechanical parameters predicted by the neural networks, however, had a very high correlation with those observed, namely 0.91 for the load at fracture and 0.93 for the ultimate stress. Both these correlations were superior to those obtained with dual-energy X-ray absorptiometry and with the cross-sectional area from CT scans: 0.87 and 0.49 respectively. Our observation suggests that image parameters can provide a powerful noninvasive predictor of bone strength. The simultaneous use of various parameters substantially improved the performance of the system. The multifactorial architecture applied is nonlinear and possibly more effective than traditional multicorrelation methods. Further, this system has the potential to incorporate other non-image parameters, such as age and bone density itself, with a view to improving the assessment of the risk of fracture for individual patients.

To ascertain whether patients with Colles' fracture should be investigated for osteoporosis and the risk of future fractures, we measured the bone mineral density of the distal radius of the other arm in 31 women patients and compared the results with those of a control group of 289 normal women. We divided the patients into two groups, those younger than 66 years and those older. In 25 patients we found values for bone mineral density which were lower than one standard deviation below the mean value for their age. Younger patients had a deficit greater than that expected for their ages. We believe that women with Colles' fracture should be evaluated routinely for osteoporosis, particularly if they are under 66 years of age.

Very limited information is available on the normal size of the anterior fontanelle but this measurement may be of value in the early diagnosis for example of bone diseases, and of hypothyroidism. The purpose of this study was to provide a reference range applicable to the first two years of life, using a larger sample population than previous studies. Measurements were made of the anterior-posterior and transverse dimensions in 334 full term infants between birth and the age of 24 months. Despite the wide variation, both in size and age of closure, it proved possible to define a reference range and also, for the first time, to present a centile chart.

Summary Osteogenesis imperfecta (OI) is often regarded as a form of osteoporosis. However, the bone fragility is the result of defective collagen and earlier work has demonstrated that cortical thickness, in bones not previously fractured, is usually normal. We have now measured the bone mineral content of the distal forearm in 61 adult patients with well characterized OI. Three patients with the Silence type III disorder had bone mass values well below the reference interval. For the 47 type I patients and 11 type IV patients, the bone mass was significantly lower than normal (P < 0.001). However 70% of patients had values within the reference interval. One cannot therefore exclude the diagnosis of OI by finding normal values with densitometry. Diagnostic difficulties do not occur in type III patients and our main objective was to recruit as many individuals as possible with OI types I and IV. In the type IV disease, the diagnosis can be particularly difficult without a positive family history. Since the evaluation of bone density by subjective examination of radiographs is a much less precise procedure, most patients with type I and IV OI would be expected to have 'normal' appearances with this assessment. Osteogenesis imperfecta cannot be excluded on the basis of apparently normal bone density or cortical thickness with routine radiographs.

Summary OBJECTIVES We assessed whether the obesity observed in growth hormone deficient adults is maintained by a reduction in energy expenditure. We studied the effects of exogenous growth hormone on energy expenditure and body composition. DESIGN We performed an open study with growth hormone administered at 0 5 units per kilogram ideal body weight per week for 3 months. PATIENTS Seven growth hormone deficient adults were studied. Thirty-eight healthy volunteers had their resting metabolic rate measured, with seven of them proceeding to have their total energy expenditure assessed. MEASUREMENTS Total energy expenditure was measured by the doubly labelled water method (D2018), resting metabolic rate by ventilated hood indirect calorimetry, and fat free mass from the dilution volume of oxygen-18. Body composition and components of energy expenditure were assessed before, at 2 weeks and at the end of the 3-month treatment period on exogenous growth hormone. RESULTS Growth hormone deficient adults did not have a low total energy expenditure compared to healthy controls (13 12 vs 12 75 MJ/24 h) with only one patient expending less than 10 MJ/24 h. None had a resting metabolic rate lower than the 95% confidence limits of normality. The amount of energy expended on physical activity and thermogenesis was significant (6 54 MJ/24 h) and was similar to healthy controls (6 47 MJ/24 h). Resting metabolic rate increased by 15 9% after 14 days on exogenous growth hormone and was elevated 12-1% after 3 months treatment but the ratio to fat-free mass remained unaltered. Total energy expenditure increased by 13 4% after 14 days therapy. Fat-free mass increased significantly after 3 months treatment by (mean) 4 5 kg with no change in fat mass and no loss in body weight. CONCLUSIONS Obesity maintenance in growth hormone deficient adults is not a consequence of reduced total energy expenditure or a reduced exercise energy output. There was also no evidence for an energy sparing mechanism. Energy expenditure was increased by exogenous growth hormone but was not associated with a loss in fat mass or body weight suggesting the need for dietetic advice for those already obese at the outset of therapy.

Summary Fourteen patients with Marfan syndrome, defined according to present criteria, had bone mineral content of the distal forearm measured by single photon absorptiometry. Patients were matched for age and sex with a large local group of healthy volunteers. While further work is needed with other methods of densitometry with measurements at other sites, our results provide no evidence that there is an increased incidence of osteoporosis in Marfan syndrome. Previous reports of an association were probably due to incorrect clinical diagnosis or confusion with clinically similar syndromes known to cause osteoporosis.

We determined the rate of change of bone mineral content (BMC) in the distal forearm of 89 healthy postmenopausal women by single-photon absorptiometry. The BMC measurements were taken at 6- or 12-monthly intervals for up to 4 years. Urinary oestrogen excretion and anthropometry were assessed at the time of the first BMC measurement. Urinary oestradiol glucuronide (E2G) excretion was related to the rate of change of 'proximal' BMC in women 1-7 years past the menopause (r = 0.52, p less than 0.01). Body mass index was less highly correlated with the rate of change of BMC in these women (r = 0.41, p less than 0.05). We conclude that urinary E2G excretion could contribute to a screening procedure for the assessment in women soon after the menopause of the risk of osteoporotic fracture in later life.

Summary Blood was collected by venepuncture from nine healthy subjects over a ten minute period before applying a standard tourniquet, and over a ten minute period afterwards. Plasma ionised calcium was unaltered by the tourniquet, whereas total calcium, total protein and albumin in serum increased modestly. However, there was no effect on total calcium adjusted for albumin. Even without albumin adjustment the change in total calcium was negligible within one minute of the application of the tourniquet. We consider that in ordinary clinical practice, there is no need to perform venepuncture for calcium assays without a tourniquet.

Using readily available biochemical assays of plasma and urine constituents, we have defined discriminant functions useful as a guide to the differential diagnosis of patients with hypercalcemia. The decreasing rank order of contribution of the variables to the discriminant functions was as follows: plasma albumin, plasma phosphate, plasma chloride, log10 (calcium excretion per liter of glomerular filtrate), and log10 (plasma gamma-glutamyltransferase). Discriminant functions have been defined for patients with values for plasma creatinine above and below 185 mumol/L, and for practical conditions in which plasma and urine samples, or plasma samples only, are available.

Most patients with dominantly inherited osteogenesis imperfecta have blue sclerae and relatively mild symptoms. However, in a small group of families the patients have normal sclerae and this disorder has been classified as Type 4 osteogenesis imperfecta. This paper reports the clinical and radiographical features of 48 patients from 16 families with Type 4 osteogenesis imperfecta and compares the findings with those of the classical disorder with blue sclerae (Type 1 osteogenesis imperfecta). The two types are similar in usually causing a mild disease but with a wide range of severity, and in both types the rate of fracture declines in adolescence. There are, however, some significant differences apart from the colour of the sclerae. In Type 4 the first fracture more commonly occurs at birth, dentinogenesis imperfecta is more frequent than in Type 1 and bruising and nose-bleeds are less common. As in Type 1, the radiographic appearances of the bones may be normal. It is important that Type 4 osteogenesis imperfecta should be recognised because of the need for competent genetic counselling, because the management may be different from that appropriate for Type 1 and because it may be mistaken for idiopathic juvenile osteoporosis or child abuse.

1. A group of 129 patients with chronic alcoholism were assessed for their nutritional status with respect to certain minerals and vitamins, and compared with control subjects.2. In all subjects the plasma values were normal for calcium, magnesium and zinc.3. As in other studies a seasonal variation was found in the plasma levels of 25-hydroxyvitamin D in the control subjects and the alcoholic subjects; in all seasons lower levels were found in the alcoholics than in the controls, but none of the alcoholic patients had results in the range found in osteomalacia.4. The alcoholic subjects had low levels of ascorbic acid both in the plasma and in the leucocytes.5. Although vitamin A and β-carotene levels were within the reference range, the results in alcoholics were found to be lower than in the control subjects.6. We suggest that subclinical vitamin deficiencies other than thiamine deficiency contribute to the cerebral impairment frequently found in alcoholism.

Osteomalacia due to vitamin D deficiency is common in elderly women. It has been suggested that ultraviolet light may have a place in its prevention but our studies with Vita-Lite fluorescent tubes have given no support to the view that these can play a useful role in the promotion of vitamin D synthesis.

To study the problem of new bone formation in myelosclerosis bone biopsies have been performed in cases of polycythaemia vera, which may be regarded as a pre-myelosclerotic condition, and in primary myelosclerosis; morphological studies of bone and reticulin were made and osteoid and bone matrix was quantitatively assessed. Relevant metabolic studies were also carried out, but were predominantly normal. No new bone formation was detected in polycythaemia vera and some bone was osteoporotic; no significant increase in osteoid was found. With the use of polarized light it was found that new bone formation in myelosclerosis resulted from the ossification of wavy argyrophilic fibres in marrow: the presence of a dense network of these wavy fibres was a pre-requisite of new bone formation and ossification of the non-refractile branched reticulin fibres was not observed.

Summary A survey is reported of the genetic advice given to 272 families with osteogenesis imperfecta. An appreciable number of families were not given advice by anyone even though they had asked for it, and only one quarter of the families had been referred to a clinical genetic specialist. Overall approximately one third of the information recollected as having been received was incorrect but genetic specialists were clearly more successful than other doctors.

For a group of normal medical students, we examined the effect of posture on the concentration of a number of constituents in plasma. On standing, there is a significant increase in plasma total protein, albumin, calcium, alkaline phosphatase, bilirubin, and cholesterol--all proteins or substances bound to protein. Although it is possible to make an allowance for postural variations in plasma calcium, no correction is possible for changes in protein concentrations and care is needed whenever the precise values are important, as in the follow-up of patients with the nephrotic syndrome.

SUMMARY We have determined the blood groups and HLA haplotypes in 15 members in four generations of a large kindred with familial benign hypercalcaemia (familial hypocalciuric hypercalcaemia). No linkage was seen between the disorder and ABO or Rh blood groups or the HLA antigens.

1. The case is reported of a woman aged sixty-five with widespread osteosclerosis as a feature of IgA myelomatosis. 2. Improvement was noted after treatment by cyclophosphamide and prednisolone. 3. Only two previously reported cases of myeloma with osteosclerosis of comparable extent have been found, but in forty-seven other cases in the literature some sclerosis has been noted. 4. The finding of sclerotic lesions should not rule out multiple myeloma.

SummaryHypercalcaemia is ordinarily treated by treatment of the underlying disorder. In some cases, as in malignant disease, in vitamin D poisoning and after a failed parathyroidectomy, the hypercalcaemia itself needs to be treated. A large number of methods have been advocated for this, but phosphate is the drug of choice in most patients. This paper outlines its use, mode of action and side effects and reviews the other methods proposed for the management of hypercalcaemia.

Summary Three women with hypoparathyroidism are described who developed severe symptomatic hypercalcaemia while being treated with alphacalcidol (1 alpha-hydroxycholecalciferol; One-Alpha). One sustained permanent renal damage. Alphacalcidol may have advantages over calciferol in its speed of action but poisoning may be more likely to occur. Frequent follow-up checks on the plasma calcium is needed for any patient on alphacalcidol. For long-term management calciferol may still be the drug of choice.

A preterm infant of 25 weeks’ gestation developed at 4 months of age an “impressed” fracture of the right femur. In another preterm infant of 27 weeks’ gestation, multiple fractures of the radius and metacarpalia were observed at age 5 months. Also a full term twin showed multiple rib fractures. Additional radiological findings were: generalized skeletal osteopenia, cupping and fraying of the metaphyses of the long bones, and subperiosteal new bone formation. Further symptoms were repeated apnoic attacks, anemia, neutropenia, and low serum levels of both copper and coeruloplasmin. Alimentary copper deficiency was diagnosed and oral copper substitution (CuCl2 1,2–2,0 µmol/kg/d) initiated. This resulted in complete healing of the fractures and a prompt improvement in other symptoms.

Summary Many official bodies give advice on desirable intakes of calcium but no clear evidence of a calcium deficiency disease in otherwise normal people has ever been given. In Western countries the usual calcium intake is of the order of 800–1000 mg/day; in many developing countries figures of 300–500 mg/day are found. There is no evidence that people with such a low intake have any problems with bones or teeth. It seems likely that normal people can adapt to have a normal calcium balance on calcium intakes as low as 150–200 mg/day and that this adaptation is sufficient even in pregnancy and lactation. Inappropriate concern about calcium intake may divert attention and resources from more important nutritional problems.

The mean paternal age at birth of 80 presumed mutant cases of dominant osteogenesis imperfecta (OI) was significantly higher than that of population controls and remained so after adjusting for maternal age. There was also an increase in mean maternal age (not significant) which disappeared after adjusting for paternal age. No significant increase in maternal or paternal age was found in cases having OI either of a dominant type with an affected parent or of a type (Sillence type III) usually regarded as recessive. We conclude that, as in certain other dominant conditions, the risk of mutant OI increases with paternal age. However, the rate of increase of risk with paternal age appears to be considerably lower than, for example, in achondroplasia. The overall risk of fresh dominant mutation in older fathers may therefore be lower than has previously been suggested.

One of the facultative symptoms of osteogenesis imperfecta is short stature. In determining whether the many fractures are responsible for this observation, we measured hand length from X-rays of 67 osteogenesis imperfecta patients and related them to the corresponding body size. Patients with the type I disorder had mostly a normal, well-proportioned body size. Only the older ones revealed hand lengths greater than would have been expected. All type III patients had small stature, mostly unproportioned. Also the predicted stature calculated from hand length showed pathological values. Type IV patients showed great variation. The majority had normal, proportioned body size, although tended to be below the 50th percentile.