Although this one had not been assigned to me, I am answering it as well since it deals with an endocrinology topic: vitamin D. In this case there are important data such as the history of intestinal resection, hypocalcemia and hypophosphoremoia; this should lead us to think in a vitamin D deficit due to malabsorption and therefore, in an osteomalacia. The rest of the data: previous fracture, pain and the X-ray support the diagnosis.

A 74-year-old patient with bowel resection following mesenteric thrombosis comes to consult for fatigue and bone pain. He had suffered a Colles' fracture three months earlier. Laboratory tests showed anemia of 9.5 g/dl, microcytic, albumin 3.5 g/di, calcium 7.5 mg/dl, phosphate 2.0 mg/dl and alkaline phosphatase 224 IU (normal up to 120 IU). Radiographs of the femur show radiolucent bands perpendicular to the cortex on the inner side of the upper femur. What is the most likely diagnosis?

Hypophosphatemic rickets: A case of recurrent pathological fractures.

Renal phosphate-wasting disorders are the most common form of hereditary rickets and osteomalacia in western countries, but are rarely reported in India. Therefore, we report here a case of hypophosphatemic rickets. To report a case of hypophosphatemic rickets presenting with recurrent pathological fractures. A 34-year-old premenopausal lady presented with recurrent pathological fractures, bone pain, and muscle weakness since 14 years of age. A thorough history was taken followed by clinical examination, and relevant biochemical and radiological investigations were done. Height was 125 cm, arm span 145 cm, body weight 30 kg, and body mass index (BMI) 19.2 kg/m(2). Dental caries, kyphoscoliosis, shortening of left lower limb, bilateral coxa vara deformity of knee, muscle weakness, and bone tenderness were present. Calcium was 9.4 mg/dL, phosphorus: 1.8 mg/dL, albumin: 4.0 gm/dL, alkaline phosphatase: 360 U/L, creatinine: 0.4 mg/dL, a normal ammonium chloride (NH4Cl) loading test,24-hour urine calcium excretion: 102 mg/day, 25-hydroxyvitamin D3 [25(OH)D3]: 21.6 ng/mL, intact parathyroid hormone (PTH): 43.74 pg/mL, fraction excretion of phosphate (PO4): 40%, tubular maximum reabsorption of phosphate per unit of glomerular filtrate (TmP/GFR): 0.65 mg/dL, and fibroblast growth factor (FGF)23: 321.4 RU/mL. Skeletal X-rays showed multiple old fractures and pseudofractures. Magnetic resonance imaging (MRI) of the whole body showed no evidence of tumor. Fludeoxyglucose ((18)F)-positron emission tomography (FDG-PET) computed tomography (CT) scan revealed metabolically active marrow with multiple areas of fracture and FDG-avid lesions in both lungs but no CT-based findings. Hypophosphatemic rickets or osteomalacia, possibly hereditary, is a rare cause of recurrent pathological fractures.

Primary hyperparathyroidism in women: a tale of two cities--New York and Beijing.

The Western world has been used to describing disease on its terms, as if it is a prototype for the same disease found anywhere else in the world. It is unusual that one can test the hypothesis that a common disease can present in markedly different ways, depending on the country in which it is studied. We have had the opportunity to compare and contrast primary hyperparathyroidism in the United States and in China as seen in New York City and in Beijing. The cohort of subjects in each case was well over 100, and the experience extends to well over a decade of observations. In the United States, primary hyperparathyroidism typically presents as asymptomatic hypercalcemia in women within 10 years of menopause. Most often, it is discovered accidentally in the course of a routine multichannel chemistry screening test. The serum calcium is 10.5 + 0.1 mg/dL, within 1 mg/dL above the upper limit of normal, 10.2; the serum parathyroid hormone level is 118 + 9 pg/mL (within 1.5-2-fold above the normal limit, 65). The average 25-hydroxyvitamin D level is 21 ng/mL, in the lower range of normal. The classical clinical manifestations of primary hyperparathyroidism, stone and bone disease, have become much less common than earlier descriptions of the disease in the United States through the 1950s. Overt radiological bone disease (osteitis fibrosa cystica) is almost never seen, whereas stone disease is reduced in incidence from a high of 60% in the 1940s to current estimates of 15-20% now. Most patients are asymptomatic; skeletal involvement is detected only by measuring skeletal calcium by bone densitometry. Primary hyperparathyroidism in China presents much differently. Patients are younger, with an average age of 37. The serum calcium level is much higher, averaging about 12 mg/dL. PTH is over 20 times the upper limits of normal. The average 25-hydroxyvitamin D concentration is much lower than in the United States population, 8.8 ng/mL. Radiological evidence for osteitis fibrosa cystica is seen in 60% of patients; virtually all patients have osteoporosis. Thirty-five percent of patients suffer pathological fractures, most often of the femur or humerus. Forty-two percent demonstrate kidney stones, with half showing bilateral disease. Constitutional features of weakness and easy fatigability are always present. There are both facile and rather subtle explanations for this dramatically different presentation of the same disease in the United States (New York City) and China (Beijing).

[Parathyroid carcinoma: report of a case].

A case of parathyroid carcinoma is presented. A 46-year-old female was admitted to our hospital for fractures of both femurs on July 29, 1983. Laboratory data revealed a serum calcium level of 15.2 mg/dl, serum phosphate level of 1.2 mg/dl, serum immunoreactive parathyroid hormone 9.35 ng/ml (less than 0.5), and % tubular reabsorption of phosphate of 57%. X-ray examination showed marked osteitis fibrosa cystica. The diagnosis of primary hyperparathyroidism was made. A hard tumor was palpable on the left anterior side of her neck. Neck exploration was carried out on August 10. The tumor was found to be localized in contact with the left lower lobe of the thyroid gland. Parathyroid carcinoma was strongly suspected, because the tumor severely adhered to surrounding tissues, thus the tumor was resected en bloc. The histopathological diagnosis was typical parathyroid carcinoma. Postoperative course and the treatment of the fractures were uneventful, and she was discharged able to walk five months after the operation. No evidence of recurrence or metastasis has been seen during the eighteen months since the operation. This is the 80th case in the Japanese literature to our knowledge and the clinical features of these 80 cases revealed an average age of 41.5 years old; male/female ratio of 32/48; average weight of tumor of 8.65 g, palpable neck mass in 72%, bone disease in 64%, and renal disease in 34%.

Osteomalacia revisited : a report on 28 cases.

The aim of this study was to analyse the clinical manifestations and the most frequent causes of osteomalacia (OM) in a group of 28 patients diagnosed with this disorder during a 20-year period. OM was diagnosed by bone biopsy and/or by Bingham and Fitzpatrick criteria (two of the following: low calcium, low phosphate, elevated total alkaline phosphatase [total AP] or suggestive radiographs). Of these patients, 13 had vitamin D deficiency OM (VD-OM), 14 hypophosphatemic OM (HypoP-OM) and one had OM-associated hypophosphatasia. Deficient sun exposure and celiac disease were the most frequent etiologies of VD-OM, whereas most HypoP-OM were hereditary forms. The main clinical symptoms were polyarthralgias (89%), frequently associated with fractures (75%). Fifty seven percent had densitometric criteria of osteoporosis. Patients with VD-OM showed significantly higher total AP and PTH serum values, but lower vitamin D, serum calcium, calciuria and bone mass than patients with HypoP-OM. Conversely, HypoP-OM patients had significantly lower serum phosphate and higher phosphaturia than patients with VD-OM. Briefly, high total AP, low serum calcium and low serum phosphate were observed in 85%, 65% and 15%, respectively, of patients with VD-OM, being observed in 64%, 14% and 100%, respectively, of HypoP-OM patients. Nearly 50% of these latter showed increased FGF23 levels. In conclusion, in this study, the frequencies of HypoP-OM and VD-OM were similar. The most frequent laboratory abnormalities were increased total AP and decreased serum phosphate. A urinary calcium loss of less than 50 mg/dl was highly discriminatory for VD-OM and a serum phosphate less than 2.3 mg/dl was also high discriminatory for HypoP-OM. Low densitometric values and fractures were frequent among these patients.

Osteitis fibrosa cystica

Blood tests on patients with OFC generally show high levels of calcium (normal levels are considered to range between 8.5 and 10.2 mg/dL, parathyroid hormone (levels generally above 250 pg/mL, as opposed to the "normal" upper-range value of 65 pg/mL), and alkaline phosphatase (normal range is 20 to 140 IU/L). X-rays may also be used to diagnose the disease. Usually, these X-rays will show extremely thin bones, which are often bowed or fractured. However, such symptoms are also associated with other bone diseases, such as osteopenia or osteoporosis. Generally, the first bones to show symptoms via X-ray are the fingers. Furthermore, brown tumors, especially when manifested on facial bones, can be misdiagnosed as cancerous. Radiographs distinctly show bone resorption and X-rays of the skull may depict an image often described as "ground glass" or "salt and pepper". Dental X-rays may also be abnormal.

[Hypertrophic osteoarthropathy and hypophosphatemic osteomalacia associated with tumor].

Hypertrophic osteoarthropathy and hypophosphatemic osteomalacia are both associated with neoplasm and unusual clinical syndromes. Although the etiologies of these conditions are unknown, their clinical courses are interesting, so we are reporting two cases of these conditions separately. Case 1: A 20-year-old man had an osteogenic sarcoma originating in the 2nd thoracic vertebra which was developing in the mediastinal region. He had complained of numbness and swelling in the left arm and of clubbing of the fingers of both hands. A chest radiograph showed a billiard-ball-sized, round opacity in the left upper mediastinal region. Periosteal new bone formation was demonstrated symmetrically in both humeri, radii, ulnae, femurs, tibiae, fibulae and metacarpals. Case 2: A 30-year-old man had complained of lower back, hip, knee and ankle pain and muscle weakness of five years' duration and was admitted to the National Yokosuka Hospital. Surum phosphorus was 0.7 mg/dl, alkaline phosphatase was 24.9 K.A. and glucosuria was noted. He had a fibrous xanthoma on the right thigh, and after removal of the tumor, his symptoms improved dramatically and pertinent laboratory data returned to normal. However, ossification of the ligaments of the spine subsequently developed.

Osteonecrosis of the jaw (ONJ) and atypical femoral fracture (AFF) in an osteoporotic patient chronically treated with bisphosphonates.

The aim of the study is to report the rare association of two complications of long-term treatment of osteoporosis with bisphosphonates in the same Caucasian elderly patient. A female patient of Italian descent, age 87 years, consulted in February 2013. She had a history of osteoporosis and had taken alendronate weekly for 7 years (1999-2006). Due to low back pain, an orthopedist had indicated i.v. zoledronic acid, 5 mg/year for 3 years (2006-2008). She received occasional supplements of ergocalciferol. In 2009, she suffered a fall and sustained a subtrochanteric fracture of the left femur. She was operated on and recovered uneventfully. In 2012, she consulted a dentist due to loose teeth. She underwent the removal of a molar and was given a denture. She had discomfort when using the prosthesis, and developed an ulceration in the gum of the mandible, which exposed the bone and did not heal for 2 months. After radiologic studies, the diagnosis was osteonecrosis of the jaw. She improved after surgical debridement and local and systemic antibiotics. In early 2013, laboratory tests were normal except for a slight elevation of serum PTH and CTX-I. Calcitriol 0.25 mcg/day was prescribed; after 3 months serum calcium, phosphate, PTH, and CTX-I showed no variation. Two years later, she experienced acute low back pain after a fall; MRI showed recent crushing of D12, and chronic deformities of D11 and L1. Bone densitometry of her right hip (DXA) showed a T-score of -2.3 at the femoral neck. An X-ray film of the right femur showed diffuse thickening of both cortices. She was treated with nasal calcitonin and analgesics. After the back pain subsided, she was treated with s.c. denosumab. Although the association of ONJ and AFF was known in cancer patients treated with high doses of bisphosphonates, it is very rare in patients with osteoporosis receiving these drugs at usual doses. Only three cases have been reported, all in oriental women. This appears to be the first reported case in a Caucasian woman.

A case report of disabling bone pain after long-term kidney transplantation.

A 77-year-old man, who received a renal transplant 13 years before for IgA glomerulonephritis, was referred after he developed bilateral mid-tibial aching pain that did not improve with simple analgesia. He had recently been changed from low-dose cyclosporine to tacrolimus, but the pain did not improve when this was reversed. He had a history of focal prostatic adenocarcinoma, cryptococcal lung infection, osteoporosis treated with alendronate for 2 years and multiple squamous cell carcinomas, including one requiring left neck dissection and radiotherapy. Upon physical examination, he had gouty tophi and marked bilateral tibial tenderness but had no other clinical findings. Laboratory investigations included an elevated intact parathyroid hormone value of 7.9 pmol/L (1.6 to 6.9), bone specific alkaline phosphatase of 22 µg/L (3.7 to 20.9), urinary deoxypyridinoline/creatinine ratio of 7.2 nmol/mmol (2.5 to 5.4) and C-reactive protein. Chest X-ray and tibial X-rays were normal, but there was marrow oedema and a prominent periosteal reaction on magnetic resonance imaging. A radionuclide bone scan showed increased symmetrical, linear uptake in both tibiae and the left femur, and uptake was also noted in both clinically asymptomatic humeri. Tibial bone biopsy disclosed small deposits of poorly differentiated metastatic cancer and a follow-up chest CT revealed a lung lesion. It was concluded that the bone pain and periostitis was caused by primary lung cancer with metastatic disease to bone, and an associated hypertrophic osteoarthropathy.

Osteitis Fibrosa Cystica and pathological fractures-the classic but neglected skeletal manifestation of primary hyperparathyroidism: a case report.

Osteitis fibrosa cystica is the classic manifestation of primary hyperparathyroidism (PHPT), occurs after prolonged exposure of bone to high serum parathyroid hormone (PTH) level. It has become increasingly rare due to early detection of PHPT. A 37-year-old woman was referred to our institution for fixation of multiple fractures of upper and lower extremities that had been reoccurring in the past 5 years. Her medical history showed right-shoulder, left-elbow, and right-femur fractures after a fall 5 years previously. One month ago, she sustained fractures of the right distal humerus, left tibia, and left femur without history of trauma. Upon arrival to our hospital, a thorough review of her plain radiographs demonstrated brown tumors at multiple sites, along with a salt-and-pepper appearance of the skull and a rugger-jersey spine, compatible with osteitis fibrosa cystica. Patient was diagnosed with PHPT, confirmed by high-corrected serum calcium (13.6 [8.6-10.0] mg/dl), low serum phosphate (2.2 [2.5-4.5] mg/dL), high serum alkaline phosphatase (1482 [35-105] U/L), and significantly elevated parathyroid hormone (PTH 3850 [15-65] pg/mL). A histologically confirmed, 2.5-cm parathyroid adenoma was removed by parathyroidectomy. Ten days later, closed reduction and internal fixation of the left proximal femoral shaft was performed. Pain and ambulation were significantly improved 6 months postoperatively. At the 1.5-year follow-up, fracture unions and complete mineralization of brown tumors were noted; the patient could ambulate with neither pain nor an assistive device. PHPT has become more asymptomatic in countries where routine calcium screening is performed. Nevertheless, the classic skeletal involvement, osteitis fibrosa cystica, should not be overlooked, particularly in young patients who present with a low-energy fracture.

[Prostatic osteocondensing metastases and osteomalacia. Value of histomorphometric study. Preliminary results].

A clinical, biochemical and histomorphometric study of non-decalcified bone with measurement of calcification rate was carried out in 10 patients with sclerotic bone metastases from prostatic carcinoma. The patients were under oestrogen therapy, and a change of treatment was being considered. The histomorphometric study showed that 3 patients had osteomalacia. These patients differed from the others in that the pain they experienced in bones was stronger, more diffuse and more often permanent. All three had fracture of the femoral neck. They had hypocalcaemia, hypophosphataemia, hypocalciuria and increased serum alkaline phosphatase, but only phosphataemia was significantly lower than in non-osteomalacia patients. Osteomalacia was cured by vitamin D and calcium in one patient. Osteomalacia can only be reliably diagnosed in these patients by histomorphometry. This examination may be proposed to patients with sclerotic bone metastasis of prostatic origin, under hormonal therapy, presenting with diffuse skeletal pain or bone fragility without osteolysis, and with hypocalcaemia or hypophosphataemia.

X-linked hypophosphatemia

Diagnosis Begin clinical laboratory evaluation of rickets with assessment of serum calcium, phosphate, and alkaline phosphatase levels. In hypophosphatemic rickets, calcium levels may be within or slightly below the reference range; alkaline phosphatase levels will be significantly above the reference range. Carefully evaluate serum phosphate levels in the first year of life, because the concentration reference range for infants (5.0-7.5 mg/dL) is high compared with that for adults (2.7-4.5 mg/dL). Serum parathyroid hormone levels are within the reference range or slightly elevated, while calcitriol levels are low or within the lower reference range. Most importantly, urinary loss of phosphate is above the reference range. The renal tubular reabsorption of phosphate (TRP) in X-linked hypophosphatemia is 60%; normal TRP exceeds 90% at the same reduced plasma phosphate concentration. The TRP is calculated with the following formula:

[Evaluation of clinical and humoral data in 148 patients with Piaget's bone disease].

Pain was present in 113 out of a total of 148 patients with Paget's bone disease who were evaluated. The symptom was originated by: a) bone, in 56.6 % of the cases; b) joints, in 32.7 %; c) skull compression in 7.1 % and spine compression in 3.5 % of the cases. Bone deformities were seen in 50.7 % of patients. Of this total, 41.4 % were localized in femorae. Pathological fractures were found in 16.9 % of patients. Of this total, 44.0 % were localized in femore and 19.2 % in the humerae. The localization of Paget's bone disease in the humerus appears to be specially risky due to the high percentage of fractures found in the present study as well as the frequency of the sarcomatous degeneration described in the literature. Two patients (1.4 %) developed an osteogenic sarcoma in bones previously affected by Paget's disease. It was localized in the tibia in one case and in iliac bone in the other. Frequent associated diseases were osteoporosis, verified in 31.8 % of the patients, arthritis deformans in 28.6 % and nephrolithiasis, verified in 31.8 % of the patients, arthritis deformans in 28.6 % and nephrolithiasis in 12.2 %. Associated neoplastic diseases were mammary cancer in 6.5 % of 77 women and colonic cancer in 2.0 of 148 patients of both sexes. The diagnosis has been made previously or during the period of the present study. The effects of the extent of Paget's bone disease as well as the effect of Paget's skull complication on serum alkaline phosphatase and urinary total hydroxyproline were investigated. Serum alkaline phosphatase and urinary total hydroxyproline were higher in polyostotic then in oligostotic patients although the difference was not significant for serum alkaline phosphatase in a group of 50 polyostotic with skull lesions versus 16 oligostotic with skull lesions. There was a significant increase of serum alkaline phosphatase in groups of 29 polyostotic without skull lesions versus 45 oligostotic without skull lesions (p < 0.001) and in groups of 50 polyostotics with skull lesions versus 29 polyostotics with skull lesions (p < 0.05), and of 16 oligostotic withh skull lesions versus 45 oligostotics without skull lesions (p < 0.02). There was a significant increase of urinary total hydroxyproline in a group of 46 polyostotics with skull lesions versus 15 oligostotics with skull lesions (p < 0.01) and of 25 polyostotics without skull lesions versus 41 oligostotics without skull lesions (p < 0.001), as well of 46 polyostotics with skull lesions versus 25 polyostotics without skull lesions (p < 0.005) and 15 oligostics with skull lesions versus 41 oligostotics without skull lesions (p < 0.02). Although the differences should be referred to a greater number of patients, the results suggest that the effects of Paget skull lesions are more evident on serum alkaline phosphatase than on urinary total hydroxyproline.

Refractory diffuse bony pain 20 years after jejunoileal bypass.

Osteomalacia can be a late but unrecognized complication following jejunoileal bypass. We describe a 53-year-old man who underwent jejunoileal bypass for morbid obesity twenty years earlier who suffered from progressive diffuse bony pain refractory to nonsteroidal anti-inflammatory drugs. He was initially diagnosed with a malignancy with bone metastasis. However, pertinent laboratory data were notable for hypocalcemia (7.5 mg/dL, albumin 4.1 mg/dL) with low urinary calcium excretion (14 mg/day), hypophosphatemia (2.0 mg/dL) with low urinary phosphate excretion (53 mg/day), hypomagnesemia (1.5 mg/dL) with low urine magnesium excretion (23 mg/day), low 1, 25 (OH)2 vitamin D3, and elevated serum alkaline phosphatase and intact parathyroid hormone (iPTH). These laboratory findings pointed to a defect in calcium, phosphate, and magnesium handling in the gastrointestinal tract. Bone biopsy of the iliac crest clearly demonstrated typical changes of osteomalacia with excessive osteoid accumulation and reduced mineralization. His clinical symptoms were refractory to oral 1, 25 (OH)2 vitamin D3 and calcium supplementation but significantly improved with the addition of intermittent intravenous active 1, 25 (OH)2 vitamin D3, calcium, phosphate, and magnesium supplementation. Osteomalacia is an easily misdiagnosed late complication of jejunoileal bypass. Early recognition can avoid circuitous diagnosis and inappropriate management.

Hypocalcemia with bony metastases in prostate cancer.

A 65 year old man presented with a two-month history of low back pain and fatigue and urinary symptoms over the preceding month. He was found to have had a hepatomegaly & a large nodular prostate on rectal examination. Investigations revealed a normal full blood count and renal profile, raised alkaline phosphatase and Prostate Specific Antigen (PSA), and low serum Calcium. A bone scan was performed which revealed widespread bony metastases in the axial and appendicular skeleton resulting in a 'superscan', consistent with prostatic metastases. We recommend that calcium levels be checked in all patients with prostate cancer and metastatic bone disease as this may have a bearing on their symptoms and the use of bisphosphonate therapy.

Chinese herbs and bone disease.

We treated a patient with an unusual bone disease at least partly associated with Chinese herbs. Seven years after 65-year-old man had begun to consume Chinese herbs, multifocal osteoarthralgias were noted, and the patient was hospitalized for renal dysfunction (serum creatinine, 2.8 mg/dl; urea nitrogen, 19 mg/dl). Fanconi syndrome also was apparent. A renal biopsy specimen showed tubulo-interstitial fibrosis. Chinese herbs were discontinued and prednisolone was started, but bone and joint pain as well as renal function gradually worsened. Four years later, creatinine was 9.0 mg/dl and alkaline phosphatase was 571 IU/l. As bone scintigraphy revealed localized asymmetric lesions, Paget's disease of bone was suspected at first. However, neither osteosclerosis nor hypertrophy was seen in radiographs. Based on a bone specimen histology we diagnosed as mixed-type renal osteodystrophy including osteomalacia and osteitis fibrosa. Mosaic pattern of cement lines was not present. This case was not compatible with either Paget's disease or typical renal osteodystrophy as seen in dialysis patients. Etidronate disodium was effective in alleviating bone symptoms. The patient's bone disorder may be a new disease at least partly related to Chinese herbs independently of nephropathy.

InternalMed_Harrison

Clinical Manifestations Diagnosis is often made in asymptomatic patients because they have elevated ALP levels on routine blood chemistry testing or an abnormality on a skeletal radiograph obtained for another indication. The skeletal sites most commonly involved are the pelvis, vertebral bodies, skull, femur, and tibia. Familial cases with an early presentation often have numerous active sites of skeletal involvement.

[Changes in mineral metabolism in stage 3, 4, and 5 chronic kidney disease (not on dialysis)].

With progression of chronic kidney disease (CKD), disorders of mineral metabolism appear. The classic sequence of events begins with a deficit of calcitriol synthesis and retention of phosphorus. As a result of this, serum calcium decreases and parathyroid hormone (PTH) is stimulated, producing in the bone the high turnover (HT) bone disease known as osteitis fibrosa while on the other extreme we find the forms of low turnover (LT) bone disease. Described later and initially associated with aluminum intoxication, these diseases are now seen primarily in older and/or diabetic patients, who in a uremic setting have relatively low levels of PTH to maintain normal bone turnover. Osteomalacia is also included in this group, which after the disappearance of aluminum intoxication is rarely observed. LT forms of hyperparathyroidism facilitate the exit of calcium (Ca) and phosphorus (P) from bone, whereas the adynamic bone limits the incorporation of Ca and P into bone tissue. Therefore, both forms facilitate the availability of Ca and P, which ends up being deposited in soft tissues such as arteries. The link between bone disease and vascular calcifications in CKD is now a well-established phenomenon. 2. Diagnostic strategies Calcium, Phosphorus They have little capacity to predict underlying bone disease, but their regular measurement is decisive for therapeutic management of the patient, especially in the dose titration stages of intestinal phosphorus binders, vitamin D analogs or calcimimetics. Ideally, Ca++ should be used, but total Ca is routinely used. It is recommended to adjust albumin levels in the event of hypoalbuminemia (for each g/dL of decrease in albumin, total serum Ca decreases 0.9 mg/dL). The following formula facilitates rapid calculation of corrected total calcium: Corrected total Ca (mg/dL) = total Ca (mg/dL) + 0.8 [4-albumina (g/dL)]. Parathyroid hormone "Intact" PTH is the biochemical parameter that best correlates with bone histology (levels measured with the Allegro assay from Nichols Institute Diagnostics, no longer available). Various assays are currently available that use antibodies against different fragments of the molecule, but they have significant intermethod variability and have not been validated. A whole PT assay (1-84) is currently unavailable. A consensus to establish uniform criteria for PTH measurement remains to be established. During the dose titration stages of intestinal phosphorus binders, vitamin D analogs or calcimimetics, more frequent measurement may be required based on clinical judgment. Calcifediol (25(OH)D3) It is important to maintain adequate levels of 25(OH)D3 (> 30 ng/mL), since they will be the substrate for production of 1- 25(OH)2 D3, and their deficiency aggravates hyperthyroidism. Determining 25(OH)D3 levels every 6-12 months is a recommended guideline. Other markers of bone turnover (osteocalcin, total and bone alkaline phosphate, free pyridolines in serum, and C-terminal telopeptide of collagen) do not improve the predictive power of PTH and therefore their systematic use is not justified. Radiologic studies Radiologic studies are of little diagnostic utility, because biochemical changes precede radiologic changes. Systematic radiologic evaluation of the skeleton in asymptomatic patients is not justified at present. They are useful as the first step in the study to detect vascular calcifications and amyloidosis due to b2-microglobulin and in symptomatic and at risk patients to detect vertebral fractures. Bone densitometry: Dual energy x-ray absorptiometry (DEXA) is the standard method to determine bone mineral density (usually in the femoral neck and vertebrae). It provides information on changes in bone mineral content, but not on the type of underlying bone disease. It is useful for follow-up of bone mass or for the study of bone mass changes in the same patient. Its value as a predictor of the risk of fracture has not been demonstrated in patients on kidney replacement therapy or with advanced chronic kidney disease. It is indicated in patients with fractures or risk factors for osteoporosis. Bone biopsy: The "gold standard" for diagnosis of bone disease. With improved knowledge of the value of noninvasive parameters, its use is infrequent. Pathological fractures in the presence or absence of minor trauma. Symptomatic patients in the presence of incongruent clinical parameters. A typical case is the presence of unexplained hypercalcemia from systemic disease, with inconclusive serum PTH values (between 120-450 pg/mL as an estimated range). Evaluation and follow-up of cardiovascular calcifications There are no consensuated clinical practice guidelines for the evaluation and follow-up of extraosseal calcifications in CKD. The clinical tools for evaluation and follow-up of cardiovascular disease are used based on clinical judgment. The periodicity of follow-up has not been established . 3. Recommended biochemical values The biochemical values recommended in clinical practice guidelines for the evaluation of bone mineral metabolism are summarized in Figure 3. The recommended PTH values do not fully coincide with the K/DOQI guidelines. The wide variability in PTH values depending on the assays used has led us to expand the recommended PTH range in stage 3 and 4 CKD. 4. Treatment 4.1. Diet. The recommended diet for the patient with CKD is traditionally based on protein restriction and phosphorus restriction for control of mineral metabolism. A favorable circumstance is that there is a close relationship between protein and phosphorus intake. In CKD stages 3, 4 and 5, it is recommended to restrict phosphorus intake to between 0.8-1 g/day when serum levels of phosphorus and PTH are above the recommended range. This is approximately equivalent to a diet of 50-60 g of protein. This reasonable antiproteinuric strategy that also restricts phosphorus intake is nutritionally safe. What should we tell them to eat? In a practical and oversimplified way, we recommend the following daily intake: Animal proteins: 1 serving (100-120 g), dairy products: 1 serving (equivalent to 200-240 mL of milk or 2 yoghourts), bread, cereals, pastas (1 cup of pasta, rice or legumes + some bread or cookies), vegetables and fruits relatively freely, but with moderation. 4.2. Medication Vitamin D supplements should be provided if serum levels are less than 30 ng/mL. In Spain, vitamin D3 (cholecalciferol) is marketed as Vitamin D3 Berenguer 2,000 IU/mL of solution. Combinations of calcium with cholecalciferol are also available. Most of the dosage forms contain approximately 500 mg of Ca+ and 400 IU of cholecalciferol. Alternatively, calcifediol (25(OH)D3), as Hidroferol 100 mcg/mL, has been used, although the dose range is very variable and has not been established. 4.3. Phosphorus binders. Use if hyperphosphatemia occurs. Start with calcium-containing phosphorus binders (calcium carbonate or calcium acetate), which also provide calcium if dietary intake is inadequate. Do not exceed 1.5 g of Ca++ per day. The most used are calcium carbonate and calcium acetate. Calcium acetate shows a similar binding potency to calcium carbonate but with a lesser calcium overload, and thus would have certain advantages as well as its greater effect at different pH ranges. However, gastric intolerance is more frequent with this dosage form. Aluminum hydroxide may sometimes be required to control phosphoremia or the occurrence of hypercalcemia. Serum aluminum values should be maintained below 30 mcg/L. Avoid use for longer than 6 months and daily doses greater than 1.5 g. Sevelamer is associated with an increased risk of acidosis and has not been approved for use in predialysis stages. Lanthanum carbonate has been recently marketed in Spain, although its indication for use in the predialysis stage of CKD is still not approved. 4.4. Vitamin D derivatives. Indicated when PTH levels are elevated. A prerequisite for their use is that Ca and P serum levels are adequately controlled. Vitamin D derivates available in Spain are 1,25(OH)2D3 (Calcitriol)and 1a(OH)D3 (a-Calcidiol). Doses should be titrated until PTH levels are normalized. Phosphate binder doses often need to be increased because these vitamin D derivatives increase intestinal absorption of calcium and phosphorus. Low doses do not cause hypercalcemia or hyperphosphatemia and do not worsen the course of renal function. Recommended doses: Calcitriol 0.25 mcg every 48 hours and alpha-Calcidiol 0.50 mcg every 48 hours. Soon to be available on the Spanish market is the oral dosage form of paricalcitol (recommended initial dose of 1 mcg/24 h), with a lesser hypercalcemic and hyperphosphoremic effect. Clinical use of calcimimetics in the predialysis state is not yet recommended and is currently under investigation.

[A Case of atypical Femoral Fracture after Dosing Denosumab].

For the management of patients with castration-resistant prostate cancer with bone metastases, bisphosphonates and denosumab are used to prevent skeletal related events. Osteonecrosis of the jaw and hypocalcemia have been reported in patients treated with denosumab, but there have been few reports of atypical femoral fracture (AFF). Here, we report a case of AFF after dosing denosumab. A 69-year-old man with prostate-specific antigen (PSA) level of 13.08 ng/ml was diagnosed with adenocarcinoma of the prostate, cT3a, N0, M1b, with Gleason score of 4+4=8 and bone metastases to pubis and ischium. Combined-androgen blockade therapy and denosumab were initiated in April 2014. Forty-eight months later, he had left knee pain. He had a magnetic resonance imaging of his left knee, but it showed no obvious findings. However, he had pain in the bilateral thighs and visited the department of orthopedics at our hospital. Pelvic X-ray showed thickening of the bone cortex at the lateral boarders of bilateral femur, and femoral CT showed faint fracture line in bilateral femur. He was diagnosed with AFF, and denosumab was discontinued. Ourcase suggests that we must considerthe possibility of AFF when pain around the thigh occurs after dosing denosumab.

Multiple myeloma

Signs and symptoms Because many organs can be affected by myeloma, the symptoms and signs vary greatly. Fatigue and bone pain are the most common symptoms at presentation. The CRAB criteria encompass the most common signs of multiple myeloma: Calcium: serum calcium >0.25 mmol/l (>1 mg/dl) higher than the upper limit of normal or >2.75 mmol/l (>11 mg/dl) Renal insufficiency: creatinine clearance <40 ml per minute or serum creatinine >1.77 mol/l (>2 mg/dl) Anemia: hemoglobin value of >2g/dl below the lowest limit of normal, or a hemoglobin value <10g/dl Bone lesions: osteolytic lesions on skeletal radiography, CT, or PET/CT Bone pain

[Aetiologic features of osteoporosis in male patients aged less than 50 years: study of 28 cases with a comparative series of 30 patients over the age of 50].

To study the aetiologic factors of osteoporosis (OP) in young male patients, we conducted a retrospective study of male osteoporosis observed in our department during the past 20 years. Patients included in the study were over 16 years of age and had a fracture or a decreased bone mineral density with a T score (assessed at the spine or at the spine and femoral neck) below -2.5 SD. The age and circumstances of diagnosis, serum and 24-hour urinary calcium and phosphorus investigations, hormonal measurements (including parathyroid hormone, thyroid hormones, cortisol and testosterone), bone biopsy and the final diagnosis were analyzed. One hundred and nineteen patients responded to the defined diagnosis criteria. Twenty-eight were less than 50 years of age (group I or young male osteoporosis). Data were compared with those of 30 patients more than 50 years of age (group II). In group I, an aetiology was found in 17 out of 28 cases (60.7%) (secondary osteoporosis: OP II), while 11 out of 28 patients (39.3%) had primary or idiopathic osteoporosis (OP I). In group II, the frequency of OP I was 19 out of 30 cases (63.3%) and 11 out of 30 patients (36.6%) had OP II. However, the frequency of OP II did not differ significantly between the two groups (P = 0.11). The aetiology in group I was either hypogonadism (6 out of 17), alcoholism (2 out of 17), mastocytosis (2 out of 17), primary biliary cirrhosis (1 out of 17), osteogenesis imperfecta (1 out of 17), idiopathic hypercalciuria (1 out of 17), corticosteroid treatment (1 out of 17) or ankylosing spondylitis (1 out of 17). Multiple causes were found in 5 out of 17 cases. The causes of osteoporosis in group II included hypogonadism (2 out of 11), alcoholism (2 out of 11), idiopathic hypercalciuria (2 out of 11), glucocorticosteroid therapy (6 out of 11) and rheumatoid arthritis (1 out of 11). Our results were compared to those of the various series reported in the literature which, though focusing on male osteoporosis, often included elderly patients. To determine whether osteoporosis in young male is more often OP II, further prospective studies are required.

Hypocalcemia

Mechanism Physiologically, blood calcium is tightly regulated within a narrow range for proper cellular processes. Calcium in the blood exists in three primary states: bound to proteins (mainly albumin), bound to anions such as phosphate and citrate, and as free (unbound) ionized calcium; all of these forms are ionised. Only the unbound calcium is physiologically active. Normal blood calcium level is between 8.5 to 10.5 mg/dL (2.12 to 2.62 mmol/L) and that of unbound calcium is 4.65 to 5.25 mg/dL (1.16 to 1.31 mmol/L). Diagnosis Because a significant portion of calcium is bound to albumin, any alteration in the level of albumin will affect the measured level of calcium. A corrected calcium level based on the albumin level is: Corrected calcium (mg/dL) = measured total Ca (mg/dL) + 0.8 * (4.0 - serum albumin [g/dL]). Since calcium is also bound to small anions, it may be more useful to correct total calcium for both albumin and the anion gap.

[The diagnostic value of radiological, nuclear medicine and biochemical methods for detection of bone metastases in carcinoma of the prostate (author's transl)].

785 combined diagnostic procedures are reported which were carried out on 353 patients with microscopically proven carcinoma of the prostate in order to detect metastases. X-ray films of the thorax, spine and pelvis were taken. Also bone-scintigraphy was done with 87MSr or 99MTc-polyphosphate. Additionally the alcaline, acid and prostate phosphatases were determined. A diagnostic coincidence between radiological results and bone-scan was found in 95.1% of cases. The bone-scan was false negative in 3.7%. Only in 1.2% metastases were detected earlier by the bone-scan than by x-ray examinations. Referring to the number of studies identical results were found. In roentgenologically detected metastases an increased serum level of the alcaline phosphatase was found in 61%, of the acid phosphatase in 31% and of the prostate-phosphatase in 25%.

Treatment approach for the older, unfit patient with myeloma from diagnosis to relapse: perspectives of a European hematologist.

Mrs. A. is a 73-year-old woman who has developed increasing fatigue and lower back pain over the past year. The pain limits her exercise tolerance such that she can now walk only 1 block. She is a retired schoolteacher who does volunteer efforts in her community but has limited her activities due to fatigue. Karnofsky performance status is 70%. She has a history of chronic hypertension treated with a diuretic, adult-onset diabetes mellitus treated with metformin, and hypothyroidism treated with levothyroxine. Initial evaluation reveals anemia, renal dysfunction, an elevated total protein, and an L2 compression fracture on lumbosacral radiographs. Results of initial and subsequent evaluation are shown below, and she is referred to a hematologist for further evaluation, which revealed the following: calcium 9.0 mg/dL, creatinine 3.2 mg/dL with estimated creatinine clearance using the Modification of Diet in Renal Disease equation of 15 mL/min, hemoglobin 9.6 g/dL, total protein 11 g/dL, albumin 3.2 g/dL, immunoglobulin A (IgA) λ M protein 6.8 g/dL, total IgA 7.2 g/dL, IgG 0.4 g/dL, IgM 0.03 g/dL, free κ <0.01 mg/L, free λ 1000 mg/L, free light chain ratio <0.01, β-2-microglobulin 4.2, viscosity 3.0, lactate dehydrogenase 200 U/L, urine protein electrophoresis: 125 mg/dL with 30% M protein, and urine immuno-electrophoresis: λ light chain. Skeletal bone survey showed lytic lesions in femurs and humeri and diffusely in ribs bilaterally as well as compression fractures at T4, T6, and L2. Bone marrow biopsy revealed λ-restricted plasma cells comprising 50% of the bone marrow core. Fluorescence in situ hybridization testing on marrow showed that del(17p) was present in 80% of the plasma cells. Mrs. A. is informed of the diagnosis of multiple myeloma and the need for therapy. She requests consultation with 2 of the leading world experts. However, she wants to be treated near her home and does not want treatment on a clinical trial.

[Hypophosphatemic osteomalacia caused by urinary mesenchymal tumor: A case report].

This case report concerns a 34-year-old woman who had been diagnosed with ankylosing spondylitis (AS), fibromyalgia syndrome (FMS), osteoarthritis (OA), lumbar disc herniation and the like in different hospitals during the past 18 months. She had progressive osteoarthrosis, significant muscle weakness, gait abnormalities in weightbearing areas, however without typical inflammatory low back pain, while the treatment with non-steroidal anti-inflammatory drugs (NSAIDs) was invalid, with normal inflammation index, negative results for rheumatic factor (RF) and human leukocyte antigen (HLA)-B27, and normal erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). She had hyphosphatemia, normal serum calcium, 1,25-(OH)2-D3 reduction, elevated alkaline phosphatase (ALP) and normal parathyroid hormone (PTH), however with elevated urinary phosphorus. Finally, the medial thigh nodule was found in the subcutaneous of her inner leg by careful examination and imaging scans including B-ultrasound and PET/CT. The final pathology confirmed that the nodule was phosphate urinary mesenchymal tumors. After the tumor was removed, the patient was treated with anti-osteoporosis and phosphorus supplementation. The symptoms of bone pain and muscle weakness were alleviated, and hypophosphatemia was corrected. It was confirmed that the patient had low-phosphorus osteomalacia due to tumor. Tumor-induced hypophosphatemia osteomalacia (TIO) was a rare paraneoplastic syndrome which was caused by excessive phosphorus excretion induced by the tumor, and was thus categorized as an acquired hypophosphatemic osteomalacia. TIO had an occult onset and was associated with a high rate of misdiagnosis, although TIO has some typical clinical features. Early diagnosis, correctly positioning of the tumor, and surgical resection can achieve good outcomes.

Approach to the treatment of the older, unfit patient with myeloma from diagnosis to relapse: perspectives of a US hematologist and a geriatric hematologist.

Mrs. A. is a 73-year-old woman who has developed increasing fatigue and lower back pain over the past year. The pain limits her exercise tolerance such that she can now walk only 1 block. She is a retired schoolteacher who does volunteer efforts in her community but has limited her activities due to fatigue. Karnofsky performance status is 70%. She has a history of chronic hypertension treated with a diuretic, adult-onset diabetes mellitus treated with metformin, and hypothyroidism treated with levothyroxine. Initial evaluation reveals anemia, renal dysfunction, an elevated total protein, and an L2 compression fracture on lumbosacral radiographs. Results of initial and subsequent evaluation are shown below, and she is referred to a hematologist for further evaluation, which revealed the following: calcium 9.0 mg/dL, creatinine 3.2 mg/dL with estimated creatinine clearance using the Modification of Diet in Renal Disease equation of 15 mL/min, hemoglobin 9.6 g/dL, total protein 11 g/dL, albumin 3.2 g/dL, immunoglobulin A (IgA) λ M protein 6.8 g/dL, total IgA 7.2 g/dL, IgG 0.4g/dL, IgM 0.03 g/dL, free κ <0.01 mg/L, free λ 1000 mg/L, serum free light chain ratio <0.01, β-2-microglobulin 4.2, viscosity 3.0, lactate dehydrogenase 200 U/L, urine protein electrophoresis: 125 mg/dL with 30% M protein, and urine immunofixation: λ light chain. Skeletal bone survey showed lytic lesions in femurs and humeri and diffusely in ribs bilaterally as well as compression fractures at T4, T6, and L2. Bone marrow biopsy revealed λ-restricted plasma cells comprising 50% of the bone marrow core. Fluorescence in situ hybridization testing on marrow showed that del 17p was present in 80% of the plasma cells. Mrs. A. is informed of the diagnosis of multiple myeloma and the need for therapy. She requests consultation with 2 of the leading world experts. However, she wants to be treated near her home and does not want treatment on a clinical trial.

[Hypophosphatemic osteomalacia in adults].

Hypophosphataemic osteomalacia occurred in a 38-year-old woman. The leading clinical symptom was severe bone pain. X-ray studies demonstrated fractures of the iliac crest and pubic and ischiadic bone, as well as Looser's zones and demineralization of the skeleton. Computerized densitometry of the bone revealed a 31% reduction of hydroxyapatite. Histological evaluation showed nearly absence of osteoclasts and extensive demineralisation of the bone. Hypophosphataemia (0.48 mmol/l), increased urinary phosphate clearance (36 ml/min), reduced renal-tubular reabsorption for phosphate (73%) and increased alkaline phosphatase (355 U/l) were present. Parathyroid hormone and 1,25-dihydroxyvitamin D were normal. No inborn errors, disturbances of the calcium metabolism or paraneoplastic signs could be detected. Defective renal tubular reabsorption of phosphate is likely to be the underlying cause of the disease. Phosphate supplementation and intermittent vitamin D administration remains the therapy of choice.

Traumatic fracture in a healthy man: benign or pathologic?

To describe the challenge of determining the correct diagnosis in a healthy adult male patient with a recent femoral fracture and a history of multiple bone fractures. We present clinical, radiologic, laboratory, and histopathologic details in a patient with a history of recurrent fractures associated with minimal trauma. Moreover, the various types of osteopetrosis are reviewed. A 34-year-old African American man was in his usual state of good health when he fell hard on concrete. Immediately after the fall, he was able to bear weight, although pain prompted him to seek medical care. Besides a personal history of multiple fractures, he had no other medical problems. He had never smoked, denied illicit drug use, and had no family history of bone disorders or recurrent fractures. Findings on physical examination were unremarkable. Radiography disclosed an incomplete femoral fracture and osteosclerosis. Bone survey revealed diffuse, symmetric osteosclerosis of both the axial and the appendicular skeleton. The long bones showed areas of almost complete obliteration of the medullary canal, along with prominent hyperostosis. Additionally, a "bone-within-bone" appearance to the thickened endosteum was noted. A bone scan demonstrated numerous areas of symmetric radiotracer uptake. Laboratory analyses were unremarkable, including a complete blood cell count, electrolytes, serum protein electrophoresis, thyrotropin, and parathyroid hormone. Total alkaline phosphatase was mildly elevated at 162 U/L (normal range, 35 to 130). Seven needles were broken during attempts to perform a bone biopsy. Histologic examination showed normal bone marrow with "woven" bone and areas of primary spongiosa within mature osteoid. Autosomal dominant osteopetrosis type 2 was diagnosed on the basis of his clinical presentation and the radiologic and pathologic findings. The preliminary diagnosis for this patient's condition was Paget's disease, and determining the correct diagnosis of osteopetosis prevented the administration of inappropriate therapy. In addition, this case report reminds the clinician that genetic disease may manifest in adulthood.

[Different forms of clinical presentation of an autosomal dominant hypophosphatemic rickets caused by a FGF23 mutation in one family].

In this report we describe different forms of clinical presentation of an autosomal dominant hypophosphatemic rickets (ADHR) in 4 members of the same family as well as the treatment used in these patients and their response to it. Patient No 1: a 60 year old female who consulted for bone pain: Bone densitometry showed osteoporosis. Laboratory assays showed hypophosphatemia with low renal phosphate threshold, high total alkaline phosphatase, normal intact PTH and normal serum calcium. With neutral phosphate and calcitriol, the biochemical parameters normalized and bone densitometry improved significantly in less than a year. Patient No 2 her grand daughter consulted at 1 year and 8 months of age for growth retardation (height at percentile 3) and genu varum. Laboratory assays showed low serum phosphate and high total alkaline phosphatase; thickening and irregular epiphyseal borders of the wrists were observed radiologically. She began treatment with calcitriol and phosphorus with normalization of laboratory parameters and increase in growth (height increasing to percentile 50 after 20 months of therapy). Patient No 3: mother of patient No 2, she had no clinical manifestations and normal densitometry but presented low serum phosphate (1.9 mg/dl) that normalized with neutral phosphate therapy. Patient No 4: he was the youngest son of Patient No 1, who had had hypophosphatemic rickets, by age 5; his serum phosphate normalized without treatment At age 29, he presented normal serum phosphate and bone densitometry. Genomic DNA analysis performed in patient No 3, showed missense mutation with substitution of arginine at position 179 for glutamine. The family was catalogued as having autosomal dominant hypophosphatemic rickets/osteomalacia.

[Prostatic osteocondensing metastases. The value of examining for osteomalacia].

Bone pains observed in patients undergoing estrogen therapy, and presenting with osteoblastic metastases from prostatic cancer are usually related to unsuccessful treatment. In some patients, these pains may result from osteomalacia--ie incomplete mineralization of the new bone--because of the drainage of calcium by the osteoblastic metastases. A clinical, biological and histomorphometric study of bone specimens without decalcification was conducted in ten patients with osteoblastic disease secondary to prostatic carcinoma, who were under estrogen therapy, and for whom a change of therapy was contemplated. The study reports three cases of osteomalacia. Their bone pains were more intense, more diffuse and more permanent than those registered by patients without osteomalacia. All three had had previous fractures of the neck of the femur and a low urinary and serum calcium and phosphorus content. The discovery of osteomalacia by histomorphometric study is important because it allows effective, etiological treatment of the bone pains in these patients.

Ranson criteria

Acute pancreatitis not secondary to gallstones At admission: Blood glucose > 11.11 mmol/L (> 200 mg/dL) Age > 55 years Serum LDH > 350 IU/L Serum AST > 250 IU/L WBC count > 16000 cells/mm3 Within 48 hours: Serum calcium < 2.0 mmol/L (< 8.0 mg/dL) Hematocrit decreased by > 10% Oxygen (hypoxemia with PaO2 < 60 mmHg) BUN increased by 1.8 or more mmol/L (5 or more mg/dL) after IV fluid hydration Base deficit (negative base excess) > 4 mEq/L Sequestration of fluids > 6 L Acute pancreatitis secondary to gallstones At admission: Glucose > 220 mg/dl Age > 70 years LDH > 400 IU/L AST > 250 IU/ 100 ml WBC count > 18000 cells/mm3 Within 48 hours: Serum calcium < 8 mg/dL Hematocrit decreased by > 10% Base deficit > 4 mEq/L BUN increased by > 2 mg/dL Sequestered fluid > 6L

[Bone density and laboratory parameters of bone metabolism in patients with terminal heart disease].

The purpose of this study was to assess bone mineral density (BMD) and parameters for bone metabolism in patients with end-stage heart disease awaiting heart transplantation to determine whether these patients are at increased risk of bone disease. 39 adult men (mean age 52.3, range 21-65 years) with ischemic (41%), idiopathic (43.5%), valvular (2.5%) and diverse (13%) end-stage heart disease were studied prior to heart transplantation. BMD was measured using dual-energy x-ray absorptiometry at the lumbar spine (L2-L4) and at the upper femur (Ward's triangle and femoral neck). Renal and bone biochemical profiles, parathyroid hormone (PTH), 25-OH-vitamin D3, testosterone, alkaline bone phosphatase, osteocalcin, and deoxypyridinoline and calcium excretion were measured. No fractures were found. Mean z-scores were -1.06 +/- 2.02 (mean +/- SD) at the lumbar spine, -1.12 +/- 2.03 at the femoral neck and -0.25 +/- 1.06 at Ward's triangle. Significantly decreased values were seen at the lumbar spine and at the femoral neck compared to age matched healthy controls. Mean values of serum creatinine and parathyroid hormone were elevated (114.4 +/- 29.5 mumol/l and 84.3 +/- 67.8 ng/l, respectively). 7 (18%), 10 (26%) and 22 (56%) of the 39 patients had values beneath the normal range of 25-OH-vitamin D3, testosterone and osteocalcin respectively. Mean urinary deoxypyridinoline/creatinine ratios were elevated (9.46 +/- 8.52 nmol/mmol, normal range 2.5-5). No correlation existed between osteocalcin and urinary deoxypyridinoline/creatinine ratio. Using a multiple linear regression model, serum PTH and cardiac ejection fraction (EF) weakly predicted BMD at the femoral neck (r2 = 0.26). (1.) Lumbar spine and femoral neck BMD are low in patients awaiting heart transplantation. (2.) A low EF and a high PTH weakly correlate with a decrease in BMD at the femoral neck. (3.) In patients with end-stage heart failure the coupling of bone formation to bone resorption is frequently disturbed. (4.) Testosterone and 25-OH-vitamin D3 levels are low in a number of patients and in such cases replacement therapy may be appropriate.

Fluoride therapy in postmenopausal osteopenic women: effect on vertebral and femoral bone density and prediction of bone response.

Fifty-two postmenopausal women (mean age 60 +/- 5 years) with low BMD (less than -2SD of young adult values) but who had not experienced previous crush fracture were treated with 50 mg of sodium fluoride (NaF), 1 g of calcium and 400 IU of vitamin D2 per day for 2 years. Repeated vertebral and femoral BMD measurements were made and compared with those of a control group consisting of 16 untreated women. Serum alkaline phosphatase and osteocalcin, blood and urinary fluoride levels were measured regularly to determine their predictive value on bone response. 18 of 52 (35%) of the treated patients experienced side effects (29% gastric, 4% lower extremity pain syndrome) but only in 6 cases (12%) was it necessary to discontinue treatment. In neither of the two groups was any fracture recorded (vertebral or otherwise). Among the 43 women who were treated for at least 2 years, 21 (49%) were considered to have responded (i.e., with an increase of vertebral BMD greater than 0.043 g/cm2). There was a mean linear increase in BMD in this group of 0.0041 g/cm2 per month (i.e., 5.5% per year). On the other hand in the non-responder group and in the control group, vertebral BMD either remained stable or decreased. However no difference was detected between the two groups (treated and controls) at the femoral site after 2 years; both groups showed a significant decrease in BMD. The responders had a lower initial osteocalcin level and treatment led to a relatively greater increase in osteocalcin.(ABSTRACT TRUNCATED AT 250 WORDS)


The first step is to detect the mutation and once detected, if the mother is a carrier, to proceed with PGD.

An 8-year-old girl (index case) is clinically diagnosed as having neurofibromatosis type 1 (NF1) or Von Recklinghausen's disease with multiple neurofibromas, café-au-lait spots, and Lisch nodules. Her father (not diagnosed with NF1) died in a traffic accident at the age of 38 years. On examination, the mother presents two café-au-lait spots and attends the genetic counseling consultation with her new partner where a preimplantation genetic diagnosis (PGD) is proposed. Is PGD indicated in this case?

Yes, as the mother has 2 café-au-lait spots, she is a carrier and PGD is indicated with these data.

It is indicated after detection of the causative mutation in the index case and eventually in his mother.

It is not indicated because NF1 responds to mutations in the neurofibromin gene (17q11.2), with recessive inheritance.

No, two café-au-lait spots are not diagnostic and your new partner is very unlikely to be a carrier (NF1 is a rare disease).

With these data, PGD is indicated, consisting of selecting embryos in vitro, to implant in the maternal uterus those without the mutation.

Preimplantation genetic diagnosis

Germany Before 2010, the usage of PGD was in a legal grey area. In 2010, the Federal Court of Justice of Germany ruled that PGD can be used in exceptional cases. On 7 July 2011, the Bundestag passed a law that allows PGD in certain cases. The procedure may only be used when there is a strong likelihood that parents will pass on a genetic disease, or when there is a high genetic chance of a stillbirth or miscarriage. On 1 February 2013, the Bundesrat approved a rule regulating how PGD can be used in practice. Hungary In Hungary, PGD is allowed in case of severe hereditary diseases (when genetic risk is above 10%). The preimplantation genetic diagnosis for aneuploidy (PGS/PGD-A) is an accepted method as well. It is currently recommended in case of multiple miscarriages, and/or several failed IVF treatments, and/or when the mother is older than 35 years. Despite being an approved method, PGD-A is available at only one Fertility Clinic in Hungary.

Preimplantation genetic diagnosis

PGD is also now being performed in a disease called hereditary multiple exostoses (MHE/MO/HME). In addition, there are infertile couples who carry an inherited condition and who opt for PGD as it can be easily combined with their IVF treatment. Pregnancy chances Preimplantation genetic profiling (PGP) has been suggested as a method to determine embryo quality in in vitro fertilization, in order to select an embryo that appears to have the greatest chances for successful pregnancy. However, as the results of PGP rely on the assessment of a single cell, PGP has inherent limitations as the tested cell may not be representative of the embryo because of mosaicism. Furthermore, a study found that diagnoses of the biopsies from the same embryos at two separate laboratories matched up only 50% of the time.

Preimplantation genetic diagnosis

The world's first PGD was performed by Handyside, Kontogianni and Winston at the Hammersmith Hospital in London. Female embryos were selectively transferred in five couples at risk of X-linked disease, resulting in two twins and one singleton pregnancy. The term preimplantation genetic screening (PGS) refers to the set of techniques for testing whether embryos (obtained through IVF/ICSI) have abnormal chromosomes' number. In other words, it tests if an embryo is aneuploid or not. PGS is also called aneuploidy screening. PGS was renamed preimplantation genetic diagnosis for aneuploidy (PGD-A) by Preimplantation Genetic Diagnosis International Society (PGDIS) in 2016. The PGD allows studying the DNA of eggs or embryos to select those that carry certain mutations for genetic diseases. It is useful when there are previous chromosomal or genetic disorders in the family and within the context of in vitro fertilization programs.

Preimplantation genetic diagnosis

the disease. Males on the other hand only require one copy of the mutant X allele for the disease to occur in one's phenotype and therefore, the male offspring of a carrier mother has a 50% chance of having the disease. Reasons may include the rarity of the condition or because affected males are reproductively disadvantaged. Therefore, medical uses of PGD for selection of a female offspring to prevent the transmission of X-linked Mendelian recessive disorders are often applied. Preimplantation genetic diagnosis applied for gender selection can be used for non-Mendelian disorders that are significantly more prevalent in one sex. Three assessments are made prior to the initiation of the PGD process for the prevention of these inherited disorders. In order to validate the use of PGD, gender selection is based on the seriousness of the inherited condition, the risk ratio in either sex, or the options for disease treatment.

Preimplantation genetic diagnosis

Preimplantation genetic haplotyping Preimplantation genetic haplotyping (PGH) is a PGD technique wherein a haplotype of genetic markers that have statistical associations to a target disease are identified rather than the mutation causing the disease. Once a panel of associated genetic markers have been established for a particular disease it can be used for all carriers of that disease. In contrast, since even a monogenic disease can be caused by many different mutations within the affected gene, conventional PGD methods based on finding a specific mutation would require mutation-specific tests. Thus, PGH widens the availability of PGD to cases where mutation-specific tests are unavailable.

Novel phenotypes of NF1 patients from unrelated Chinese families with tibial pseudarthrosis and anemia.

Neurofibromatosis type 1 (NF1) is an autosomal dominant, multi-system, neurocutaneous disorder, manifested with neurofibromas and Cafe´-au-lait spots. Germline mutations in NF1 gene are associated with Neurofibromatosis type 1. NF1 gene encodes neurofibromin, a RAS-specific GTPase activating protein. In our study, we present a clinical molecular study of four Chinese probands with NF1 from four unrelated families, showing extreme phenotypic variation with rare phenotype. In family 1, the proband is a 16 months old girl with multiple café-au-lait spots throughout her whole body. In family 2, the proband is a 6 months old girl with several café-au-lait spots mostly in her trunk and in lower limbs. In family 3, the proband is a 4 months old boy with several café-au-lait spots, tibial pseudarthrosis, and chronic iron deficiency anemia. In family 4, the proband is a 14 years old boy with multiple café-au-lait spots of variable sizes. Targeted exome capture based next generation sequencing and Sanger sequencing identified a novel mutation and three previously reported mutations in these four probands. These four mutations in NF1 gene were causing disease phenotypes in these four probands and was absent in unaffected family members and in healthy controls. According to the variant interpretation guideline of American College of Medical Genetics and Genomics (ACMG), these four mutations, are classified as "likely pathogenic". Our result expands the mutational spectrum of the NF1 gene associated with neurofibromatosis type1.

Preimplantation genetic diagnosis

Cancer predisposition A more recent application of PGD is to diagnose late-onset diseases and (cancer) predisposition syndromes. Since affected individuals remain healthy until the onset of the disease, frequently in the fourth decade of life, there is debate on whether or not PGD is appropriate in these cases. Considerations include the high probability of developing the disorders and the potential for cures. For example, in predisposition syndromes, such as BRCA mutations which predispose the individual to breast cancer, the outcomes are unclear. Although PGD is often regarded as an early form of prenatal diagnosis, the nature of the requests for PGD often differs from those of prenatal diagnosis requests made when the mother is already pregnant. Some of the widely accepted indications for PGD would not be acceptable for prenatal diagnosis.

[A case of growth hormone deficiency combined with neurofibromatosis Type 1 and its gene analysis].

Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic disorder caused by NF1 gene mutations. Café au lait spots, neurofibromatosis, Lisch nodules, axillary freckling, dermal neurofibromas and skeletal dysplasia are the most common manifestations for this disease. A 11-year-old boy visited Third Xiangya Hospital, Central South University due to growth-retardation. He was eventually diagnosed as NF1 with growth hormone deficiency. A novel heterozygous splicing mutation c.6579+2 T>C (IVS 34+2 T>C) of NF1 gene was identified in the patient and his mother. Considering NF1 may present with short stature due to growth hormone deficiency, all children with short stature combined with café au lait spots should be screened for NF1, which may assist the clinical diagnosis and the genetic counseling.

[Mastenbroek controversy or how much ink is spilled on preimplantation genetic screening subject].

Preimplantation genetic screening (PGS) of in vitro fertilization (IVF) embryos has been used for advanced maternal age, repeated miscarriages and repeated implantation failure indications. Several non-randomized studies have been published, showing increased implantation rates, decreased miscarriages and trisomy rates. So PGS seemed to improve prognosis for this particular population. In 2004, a prospective randomized study tempered those results, being unable to demonstrate any significant difference of live birth rate with and without PGS in case of advanced maternal age. In July 2007, another multicenter randomized double-blind trial definitely reopened the controversy, reporting that PGS did not increase but instead significantly reduced pregnancy and live birth rates after IVF in women 35 years of age or older. The debate about efficiency and usefulness of PGS is ongoing and other powered randomized studies will be needed to conclude about real PGS usefulness.

[Anxiety disorders in type 1 neurofibromatosis: A case report].

Neurofibromatosis type 1 (NF1), also known as Von Recklinghausen disease, is one of the most frequent human genetic diseases, with a prevalence of one case in 3000 births, an autosomal dominant mode of inheritance, and a high rate of new mutations. NF1 has markedly variable clinical expression, with manifestations ranging from mild lesions to several complications and functional impairment. The complications are age-specific. Psychiatric disorders are more frequent in NF1 than in the general population, especially in children. They include dysthymia, depressive mood, anxiety, and personality disorders. Bipolar mood disorders or schizophrenia are rather rare. The majority of studies have focused on physical health and neurocognitive function in NF1, whereas psychiatric disorders associated with this disease remain unclear and poorly documented. This report is based on a clinical case and discusses the relationship between neurofibromatosis type 1 and psychiatric disorders, particularly anxiety disorders. This case concerns a 13-year-old girl, the first child of healthy and non-consanguineous parents. The patient's history showed normal psychomotor and psychoaffective development. Her father and paternal grandmother had isolated café-au-lait spots. In June 2013, a subcutaneous mass appeared in her right thigh. She consulted a neurologist and was explored. The physical examination revealed signs of NF1. She had café-au-lait spots on the trunk and extremities, and a neurofibroma in the right thigh. Bilateral ophthalmic examination revealed multiple Lish nodules. After 1 month, a psychiatric consultation was requested for sad mood and night terrors. Obsessive compulsive disorder and generalized anxiety disorder were diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. The current psychiatric literature does not provide full explanations of anxiety symptoms associated with NF1. Some authors have tried to explain the link between NF1 and psychiatric disorders, and several etiopathogenic hypotheses have been discussed. In our case, a concomitant diagnosis of NF1 and anxiety disorders was made at the age of 13. However, anxiety symptoms started to appear before age 4; they increased gradually and occupied the foreground. This would strengthen the hypothesis of genetic determinism in NF1 patients. The question that arises is: is it a fortuitous association of psychiatric disorders and NF1 or are they psychiatric manifestations induced by a multisystem disease? More detailed investigations are necessary to clarify the etiopathogenic and psychopathological mechanisms that would cause psychiatric comorbidity associated with NF1.

[Ethical aspects of preimplantation genetic diagnosis (PGD)].

The controversy surrounding PGD has not abated in recent times. This is especially the case for PGD-based tissue typing, which is used to select a future child who could serve as a stem cell donor for an older sick sibling. We examine three types of ethical argument cited against PGD in general, and specifically against tissue-typing PGD. These arguments focus on the moral status of the early embryo, the eugenics issue, and the charge that the future child is being exploited. We conclude that none of these three arguments is unassailable, and that it is the reproductive freedom of couples considering PGD that should prevail.

Next Generation Sequencing Identified a Novel Multi Exon Deletion of the <i>NF1</i> Gene in a Chinese Pedigree with Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a genetic disease involving neurocutaneous abnormalities. Neurofibromatosis type 1 is an autosomal dominant disorder characterized by the neurofibromas and café-au-lait spots. Mutation in the <iNF 1</i gene causes NF1. The <iNF 1</i gene encodes neurofibromin. In this study, we found a 31-year-old Chinese boy with NF1. He presented only with café-au-lait spots over the whole body. The proband's mother had a severe phenotype with neurofibroma and café-au-lait macules over her whole body, mostly in the facial region. A novel multi exon deletion c.(4661+1_4662-1)_(5748+1_5749-1)del; [EX36_39DEL] on the <iNF 1</i gene has been identified in the proband. Quantitative real-time polymerase chain reaction (qPCR) confirmed that this mutation is co-segregated well and was inherited from the proband's mother. The mutation was absent in the proband's father and normal individuals. The novel multi exon deletion results in the formation of a truncated NF1 protein that caused the NF1 phenotype in this family. Our present study also emphasized the significance of rapid, accurate and cost-effective screening for the patient with NF1 by next generation sequencing (NGS).

Preimplantation genetic diagnosis: does age of onset matter (anymore)?

The identification and avoidance of disease susceptibility in embryos is the most common goal of preimplantation genetic diagnosis (PGD). Most jurisdictions that accept but regulate the availability of PGD restrict it to what are characterized as 'serious' conditions. Line-drawing around seriousness is not determined solely by the identification of a genetic mutation. Other factors seen to be relevant include: impact on health or severity of symptoms; degree of penetrance (probability of genotype being expressed as a genetic disorder); potential for therapy; rate of progression; heritability; and age of onset. In the original applications of PGD, most, if not all of these factors were seen as necessary but none was seen as sufficient for determining whether a genetic condition was labelled 'serious'. This, however, is changing as impact on health or severity of symptoms is coming to eclipse the other considerations. This paper investigates how age of onset (primarily in the context of the United Kingdom (UK)) has become considerably less significant as a criterion for determining ethically acceptable applications of PGD. Having moved off the threshold of permitting PGD testing for only fatal (or seriously debilitating), early-onset diseases, I will investigate reasons for why age of onset will not do any work to discriminate between which adult-onset diseases should be considered serious or not. First I will explain the rationale underpinning age of onset as a factor to be weighed in making determinations of seriousness. Next I will challenge the view that later-onset conditions are less serious for being later than earlier-onset conditions. The final section of the paper will discuss some of the broader disability concerns at stake in limiting access to PGD based upon determinations of the 'seriousness' of genetic conditions. Instead of advocating a return to limiting PGD to only early-onset conditions, I conclude that the whole enterprise of trying to draw lines of what is to count as a 'serious' condition is itself problematic and in certain ways morally misleading.

Preimplantation genetic diagnosis

Another problematic case is the cases of desired non-disclosure of PGD results for some genetic disorders that may not yet be apparent in a parent, such as Huntington disease. It is applied when patients do not wish to know their carrier status but want to ensure that they have offspring free of the disease. This procedure can place practitioners in questionable ethical situations, e.g. when no healthy, unaffected embryos are available for transfer and a mock transfer has to be carried out so that the patient does not suspect that he/she is a carrier. The ESHRE ethics task force currently recommends using exclusion testing instead. Exclusion testing is based on a linkage analysis with polymorphic markers, in which the parental and grandparental origin of the chromosomes can be established. This way, only embryos are replaced that do not contain the chromosome derived from the affected grandparent, avoiding the need to detect the mutation itself.

Case Report for Two Siblings Carrying Neurofibromatosis Type 1 with a Rare <i>NF1</i>: c.5392C>T Mutation.

Neurofibromatosis type 1 (NF1) is a neurocutaneous syndrome caused by mutations on the <iNF1</i gene, which is located at chromosome 17q11.2. Although an autosomal dominant inheritance pattern is well-established, about half of new cases are the result of <ide novo NF1</i mutations. Neurofibromatosis type 1 has an incidence rate of 1/2600-3000 individuals, making it a major public health problem. The product of the <iNF1</i gene, the neurofibromin protein, is known to play a critical role in cellular differentiation and in tumor suppression. Due to widespread expression of neurofibromin in numerous tissues, particularly in cutaneous and nervous systems, <iNF1</i mutations cause a wide variety of clinical symptoms, including cutaneous and ocular lesions such as café au lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, iris Lisch nodules, choroidal freckling and internal tumors. In this article, we report the cases of two siblings with NF1, a 21-year-old male and his 24-year-old sister, who have the same c.5392C>T mutation on the <iNF1</i gene (p.Gln1798 Ter). Café au lait macules and freckling were the prominent clinical features in both siblings. However, a plexiform neurofibroma was also observed on the left arm of the sister, which is known to carry potential risk for malignant transformation. Although the mutation was previously described once, to the best of our knowledge, no case report has been published since then.

[Preimplantation genetic diagnosis (PGD) of hereditary cancer syndromes].

Advances in molecular biology techniques made possible genotype analysis from one or several cells. This can be used in preimplantation genetic diagnosis (PGD) not only of chromosomal aneuploidy but also of single gene diseases as well as hereditary cancer syndromes. PGD can be a benefit for those cases when the risk of transfer of pathological alteration from parent to offspring is unwelcome. We submit three cases of PGD with the results.

NF1 frameshift mutation (c.6520_6523delGAGA) association with nervous system tumors and bone abnormalities in a Chinese patient with neurofibromatosis type 1.

Neurofibromatosis type 1, also known as NF1 or von Recklinghausen's disease, is a common neurocutaneous syndrome that presents with multiple café-au-lait patches, skinfold freckling, dermatofibromas, neurofibromas, and Lisch nodules. The mutations of the gene NF1, encoding the protein neurofibromin, have been identified as the cause of this disease. Here, we report a clinical and molecular study of a Chinese patient with multiple café-au-lait skin freckles, dermatofibroma, central and peripheral nervous system tumors, and bone abnormalities attributed to NF1. The patient showed >6 café-au-lait spots on the body and multiple dermatofibromas. A brain glioma and multiple nerve sheath tumors inside and outside the vertebral canal were identified by magnetic resonance imaging, which also showed multiple intercostal nerve schwannomas and hydrocephalies above the cerebellar tentorium. Talipes equinus was also apparent. A mutation analysis of the NF1 gene revealed a novel frameshift mutation in exon 43, consisting of a heterozygous deletion of four nucleotides (GAGA) between positions 6520 and 6523. No NF1 mutations were detected in the patient's parents or younger brother. These results extend the list of known mutations in this gene. The absence of the NF1 mutation in the healthy family members suggests that it is responsible for the NF1 phenotype. To our knowledge, this frameshift mutation represents a novel NF1 case, and may be associated with nervous system tumors and bone abnormalities.

The case for a parental duty to use preimplantation genetic diagnosis for medical benefit.

This article explores the possibility that there is a parental duty to use preimplantation genetic diagnosis (PGD) for the medical benefit of future children. Using one genetic disorder as a paradigmatic example, we find that such a duty can be supported in some situations on both ethical and legal grounds. Our analysis shows that an ethical case in favor of this position can be made when potential parents are aware that a possible future child is at substantial risk of inheriting a serious genetic condition. We further argue that a legal case for a duty to use PGD for medical benefit can be made in situations in which potential parents have chosen to conceive through in vitro fertilization and know that any children conceived are at substantial risk of having a serious genetic condition.

Preimplantation genetic diagnosis

In the case of families at risk for X-linked diseases, patients are provided with a single PGD assay of gender identification. Gender selection offers a solution to individuals with X-linked diseases who are in the process of getting pregnant. The selection of a female embryo offspring is used in order to prevent the transmission of X-linked Mendelian recessive diseases. Such X-linked Mendelian diseases include Duchenne muscular dystrophy (DMD), and hemophilia A and B, which are rarely seen in females because the offspring is unlikely to inherit two copies of the recessive allele. Since two copies of the mutant X allele are required for the disease to be passed on to the female offspring, females will at worst be carriers for the disease but may not necessarily have a dominant gene for the disease. Males on the other hand only require one copy of the mutant X allele for the disease to occur in one's phenotype and therefore, the male offspring of a carrier mother has a 50% chance of

Neurofibromin 1

Clinical significance Mutations in NF1 are primarily associated with neurofibromatosis type 1 (NF1, also known as von Recklinghausen syndrome). NF1 is the most common single gene disorder in humans, occurring in about 1 in 2500-3000 births worldwide. NF1 is an autosomal dominant disorder, but approximately half of NF1 cases arise from de novo mutations. NF1 has high phenotypic variability, with members of the same family with the same mutation displaying different symptoms and symptom intensities. Café-au-lait spots are the most common sign of NF1, but other symptoms include lisch nodules of iris, cutaneous neurofibromas (CNF), plexiform neurofibromas (PN), skeletal defects, optic nerve gliomas, life-threatening malignant peripheral nerve sheath tumors (MPNST), attention deficits, learning deficits and other cognitive disabilities.

A novel NF1 mutation  in a Chinese patient with giant café-au-lait macule in neurofibromatosis type 1  associated with a malignant peripheral nerve sheath tumor and bone abnormality.

Neurofibromatosis  type 1 (NF1; OMIM#162200) is a common neurocutaneous disorder that is  characterized by multiple café-au-lait, skinfold freckling, Lisch nodules, and  neurofibromas. Mutations in the NF1 gene, which encodes the  neurofibromin protein, have been identified as  the pathogenic gene of NF1. In this study, we present a clinical and molecular  study of a Chinese patient with giant café-au-lait in NF1. The patient showed  >6 café-au-lait spots on the body, axillary freckling, and multiple  subcutaneous neurofibromas. He also had a malignant  peripheral nerve sheath tumor and bone abnormalities. The germline mutational  analysis of the NF1 gene revealed a novel missense mutation in exon 13.  It is a novel heterozygous nucleotide G>A transition at position 2241 of the NF1 gene. We found no mutation in malignant peripheral nerve sheath  tumor DNA from this patient. This expands the database for NF1 gene  mutations in NF1. Its absence in the normal chromosomes suggests that it is  responsible for the NF1 phenotype. To our knowledge, this is the first  case of giant café-au-lait macule in NF1 associated with a malignant peripheral  nerve sheath tumor and bone abnormality.

[Preimplantation genetic diagnosis].

Preimplantation genetic diagnosis (PGD) purpose is to assess the genetic status of 3 day-old embryos. Thus, PGD offers to couples "at-risk" of transmitting a genetic disorder an earlier option to prenatal diagnosis. The first successful PGD was reported in 1990 but in France, PGD has been authorized only since 2000. Worldwide, 7,000 PGD have been performed, leading to the birth of more than one hundred unaffected children. New applications are introduced regularly and the number of diagnoses available is increasing at a rapid rate. In France the practice of PGD is strictly supervised by the bioethical law. However, indications vary considerably in countries where the absence of law authorizes all the practices, raising sometimes serious ethical issues.

Gene diagnosis of infantile neurofibromatosis type I: A case report.

Neurofibromatosis is an autosomal dominant genetic disorder with various manifestations. Systemic multiple neurofibromatosis is rare in infancy. The disease is difficult to identify in the early stage, and it is prone to misdiagnosis and missed diagnosis. In the presence of lower limb swelling with subcutaneous nodules of unknown cause, café-au-lait spots, and axillary freckles, this disease must be considered. This report presents the clinical manifestations, early detection, diagnosis and treatment, and prognosis of infantile neurofibromatosis type I (NF1). The clinical manifestations, imaging examinations, and gene results of a 3-mo-old male infant with NF1 were analyzed retrospectively. He had "swelling of both legs" at the onset and developed café-au-lait spots, axillary freckles, and multiple neurofibromas later. He had a family history of similar conditions. Gene detection showed a heterozygous mutation of c.4537C>T in the <iNF1</i gene, leading to a nonsense mutation of amino acids (p.R1513x), which originated from the mother of the infant. He was diagnosed with NF1. Gene diagnosis plays an important role in the early diagnosis of NF1.

[Examples of preimplantation genetic diagnosis versus prenatal diagnosis in carriers of genetic abnormalities: advantages and disadvantages].

Preimplantation genetic diagnosis (PGD) is a method for identifying genetic abnormalities in embryos obtained via in-vitro fertilisation before their implantation. There are many indications for PGD, which offers an alternative to prenatal diagnosis, although each modality has its advantages and drawbacks. In three female patients there were clear indications for PGD: carriage of the gene for myotubular myopathy, a balanced complex chromosomal translocation, and a Robertsonian translocation in the male partner, respectively. The first patient eventually abandoned PGD and chose prenatal diagnosis. She had a total of three abortions. A twin pregnancy with a so-called foetal reduction resulted in the birth of a genetically normal child. The second patient had one spontaneous abortion and subsequently underwent two PGD cycles, resulting in an uncomplicated pregnancy and the delivery of a genetically normal child. The third patient had one genetically normal child and six spontaneous abortions. She then underwent the PGD procedure successfully and is expecting twins; the pregnancy has been uncomplicated. During preconception counselling of couples at high genetic risk, physicians should be aware of PGD as an alternative to prenatal diagnosis.

Independent NF1 and PTPN11 mutations in a family with neurofibromatosis-Noonan syndrome.

Neurofibromatosis-Noonan syndrome (NFNS), an entity which combines both features of Noonan syndrome (NS) and neurofibromatosis type 1 (NF1), was etiologically unresolved until recent reports demonstrated NF1 mutations in the majority of patients with NFNS. The phenotypic overlap was explained by the involvement of the Ras pathway in both disorders, and, accordingly, clustering of the NF1 mutations in the GTPase-activating protein (GAP) domain of neurofibromin was observed in individuals with NFNS. We report on an 18-month-old girl with typical findings suggestive of NS in combination with multiple café-au-lait spots and bilateral optic gliomas suggestive of NF1. The patient was found to carry a de novo PTPN11 mutation p.T2I as well as the maternally inherited NF1 mutation c.4661+1G>C. Her otherwise healthy mother and brother, who also had the NF1 mutation, showed few café-au-lait spots as the only sign of neurofibromatosis. Since our patient's unique NF1 mutation results in skipping of exon 27a and thus involves the same region, Gap-related domain, that had been shown to be associated with NFNS, her phenotype could have been misleadingly attributed to the NF1 mutation only. Contrarily, absence of both cutaneous neurofibromas and NS features in her relatives with the same NF1 mutation, suggests that the index patient's typical NFNS phenotype is caused by an additive effect of mutations in both NF1 and PTPN11. In contrast to previous findings, we speculate that absence of cutaneous neurofibromas is not solely associated with the recurrent 3-bp in-frame deletion in exon 17.

[BETWEEN USAGE AND POLEMIC, AN ARGUMENT IN FAVOUR OF CLARIFYING THE TERMINOLOGY FOR PREIMPLANTATION GENETIC DIAGNOSIS].

Over 30 years ago, preimplantation genetic diagnosis (PGD) was developed to help couples at risk of transmitting a serious genetic disease to their offspring. Today, the range of medical and non-medical uses of PGD has expanded considerably and some raise much controversy. This is the case, for example, with In-Vitro Fertilization to select embryos as 'saviour siblings' or to screen for susceptibility and predisposition to late onset diseases or conditions of variable penetrance. The situation is even more problematic in the case of sex selection or selection of traits that are culturally valued or discredited (such as deafness, behavioral traits, or height). The debate surrounding PGD has been employing terms to describe these particular uses that have contributed to a focus on the negative effects, thus preventing a distinction between the abuses and the benefits of this reproductive technology. In this context, this paper proposes a terminological clarification that would allow distinguishing medical and non-medical use and, therefore, the issues relevant to each. A more accurate and less generic nomenclature could prevent a conflation of different levels of ethical, clinical and social issues under the single term 'PGD'. For the vast majority of medical uses, we propose to keep: 'preimplantation genetic diagnosis (PGD)', which emphasizes that it is a genetic diagnosis. For non-medical uses, we suggest: 'preimplantation genetic trait selection (PGTS)'.

Preimplantation genetic haplotyping

Advantages Once a panel of associated genetic markers has been established for a particular disease it can be used for all carriers of that disease. In contrast, since even a monogenic disease can be caused by many different mutations within the affected gene, conventional PGD methods based on finding a specific mutation would require mutation-specific tests. Thus, PGH widens the availability of PGD to cases where mutation-specific tests are unavailable.

An Update on Neurofibromatosis Type 1: Not Just Café-au-Lait Spots and Freckling. Part II. Other Skin Manifestations Characteristic of NF1. NF1 and Cancer.

Neurofibromatosis type 1 (NF1) is the most common neurocutaneous syndrome and probably the one best known to dermatologists. Although the genetic locus of NF1 was identified on chromosome 17 in 1987, diagnosis of the disease is still based primarily on clinical observations. The 7 diagnostic criteria of the National Institutes of Health, which were established in 1988, include 3 skin manifestations (café-au-lait spots, freckling on flexural areas, and cutaneous neurofibromas). The age at which these diagnostic lesions appear is variable: onset can be late in some patients while others never develop certain symptoms. Definitive diagnosis may therefore be delayed by years. Although the appearance of the characteristic café-au-lait spots and freckling in the early years of childhood are very suggestive of the disease, these signs are not pathognomonic and, in isolation, do not constitute sufficient evidence to establish a definitive diagnosis. Thus, other diagnoses should be considered in patients whose only symptoms are café-au-lait spots and freckling. By contrast, the presence of multiple cutaneous neurofibromas or at least 1 plexiform neurofibroma is a very specific indication of NF1. Identification of the different types of neurofibroma allows us to confirm the diagnosis and initiate appropriate management.

[Prenatal and preimplantation genetic diagnosis: decision tree, new practices?].

Preimplantation genetic diagnosis (PGD) purpose is to assess the genetic status of 3 day-old embryos. PGD offers thus to couples "at-risk" of a genetic disorder an earlier option to prenatal diagnosis (PND). At the beginning, PGD's indications, patients and law were very closed to PND, but PGD specificities are gradually raising. Particularly, indications vary considerably in countries where the absence of law authorizes all the practices. Some of these applications are moreover raising serious ethical issues. Even in France, where this activity is particularly supervised, the recent modification to the law marks this evolution.

Preimplantation genetic diagnosis

Information on clinic websites In a study of 135 IVF clinics, 88% had websites, 70% mentioned PGD and 27% of the latter were university- or hospital-based and 63% were private clinics. Sites mentioning PGD also mentioned uses and benefits of PGD far more than the associated risks. Of the sites mentioning PGD, 76% described testing for single-gene diseases, but only 35% mentioned risks of missing target diagnoses, and only 18% mentioned risks for loss of the embryo. 14% described PGD as new or controversial. Private clinics were more likely than other programs to list certain PGD risks like for example diagnostic error, or note that PGD was new or controversial, reference sources of PGD information, provide accuracy rates of genetic testing of embryos, and offer gender selection for social reasons. See also Bioethics Designer baby Family-based QTL mapping Sperm sorting Notes and references

Atypical hematologic and renal manifestations in neurofibromatosis type I: coincidence or pathophysiological link?

Neurofibromatosis type 1 (NF1) is an autosomal dominant, multi-system, neurocutaneous disorder that predisposes to the development of benign and malignant tumors with a birth incidence rate of 1 in 2500-3000. 50% of cases are sporadic. The diagnosis is exclusively based on clinical assessment with clinical diagnostic criteria such as café-au-lait spots, neurofibromas, axillary or groin freckling, Lisch nodules, optic pathway glioma, bony dysplasia and first-degree relative with NF1. We report a family with NF1 in which two members presented atypical clinical features in addition to the classical diagnostic criteria. Three relatives affected by NF1, a father and two of his three sons, are described. The clinical diagnosis was originally worn in all three cases, with the association many spots café-au -lait over the entire body and some axillary freckling as well as first-degree relative. One case presented an Acute Myeloid Leukemia (AML) type 2 at 10 years of age diagnosed before the revelation of bicytopenia associated pallor and isolated asthenia. A second case presented a nephrotic syndrome at 4 years of age due to the association of hydrops with headache and asthenia. Direct sequencing of NF1 led to identify the familial mutation, a previously unreported heterozygous missense mutation c.3443C > A, p.Ala1148Glu in exon 20 which segregated with all three affected patients. The family described in this report confirms the high clinical variability of NF1, even intrafamilial, and raises the question as to whether rare features such as AML and nephrotic syndrome are associated with NF1. Some NF1 patients presenting glomerular diseases or AML have rarely been reported, but due to the small number of cases described the mechanisms underlying these associations are poorly understood. However, it seems important to be aware of the possible occurrence of nephritic syndrome and/or malignant blood diseases in NF1 patients.

Preimplantation genetic diagnosis

were exclusively transferred on day two of development as the culture medium used was incapable of reliably growing embryos past this stage. Since the biopsy was to be performed on day three, the first diagnoses were all performed in one day, with transfer of the embryos late on day three. A comparison of day two and day three transfers indicated that this would not adversely affect pregnancy rates. The worry of embryos arresting was so high that some transfers took place in the early hours of day four so that the embryos were removed from culture as soon as possible. There were many evenings at the Hammersmith when a transfer was performed at 1 a.m. on day four and researchers returned to the laboratory at 7 a.m. to start the next case. Winston helped deliver most of the first PGD babies.