[Perioperative enhanced recovery after surgery program for Ivor Lewis esophagectomy : First experiences of a high-volume center]. / Perioperatives "Enhanced-recovery-after-surgery"-Programm der Ivor-Lewis-Ösophagektomie : Erste Erfahrungen eines High-volume-Zentrums.

BACKGROUND AND OBJECTIVE: Transthoracic esophagectomy is generally accepted as the standard of surgical care for patients with esophageal cancer. Despite improvements in the perioperative management this surgical procedure is associated with a clinically relevant morbidity. Fast-track protocols (synonym: enhanced recovery after surgery, ERAS) are conceived to perioperatively maintain the physiological homoeostasis and thereby to accelerate postoperative rehabilitation and reduce morbidity. In this prospective observational study the initial experiences of a high-volume center with the implementation of an ERAS protocol after transthoracic esophagectomy were analyzed. MATERIAL AND METHODS: A total of 26 patients with esophageal cancer and a low index of comorbidities prior to hybrid Ivor Lewis esophagectomy were included in this study. According to an ERAS protocol all patients underwent a standardized perioperative treatment pathway aiming to discharge the patients from the inpatient treatment on postoperative day 10. The primary outcome parameter was the rate of major complications (Clavien-Dindo IIIb/IV), which was compared to a cohort of 52 non-ERAS patients. RESULTS AND CONCLUSION: The ERAS programs with the various core elements can be implemented in patients scheduled for transthoracic esophagectomy, although the organizational and personnel expenditure of this fast-track protocol is high. The length of hospital stay appears to be reduced without compromising patient safety. The limiting variable of the ERAS protocol remains the early and adequate enteral feeding load of the gastric conduit before discharge on postoperative day 10.

Long-term Surveillance of Children with Congenital Hypothyroidism: Data from the German Registry for Congenital Hypothyroidism (AQUAPE "Hypo Dok").

BACKGROUND: The German study group for quality assurance in pediatric endocrinology and the University of Ulm have established a software ("Hypo Dok") for the documentation of longitudinal data of patients with congenital primary hypothyroidism (CH). Aim of this study was to analyse the long-term follow-up of patients with CH and to compare treatment with current guidelines. METHODS/PATIENTS: Anonymised data of 1,080 patients from 46 centres were statistically analysed. RESULTS: Newborn screening result was available at a mean age of 7.3 days. Confirmation of the diagnosis was established at 8.4 days and therapy was started at 11 days. The average screening TSH was 180.0 mIU/L. During the first 3 months mean levothyroxine (LT4) dose was 10.7 µg/kg/day or 186.0 µg/m²/day. Weight-, BMI- and height-SDS did not differ significantly from the normal population. Only 25% of the patients (n=262) underwent formal EQ/IQ-testing. Their average IQ was 98.8 ± 13.2 points. DISCUSSION: In Germany screening, confirmation and start of treatment of CH are within the recommended time frame of 14 days. Initial LT4-doses are adequate. The auxological longterm outcome of young CH patients is normal. The implementation of standardized IQ testing has to be improved in routine patient care. CONCLUSION: Longitudinal data of patients with CH was analysed and compared to current guidelines. Confirmation and start of treatment are according to the recommendations. However standardised IQ testing requires improvement.

Artificially low cortical bone mineral density in Turner syndrome is due to the partial volume effect.

UNLABELLED: We aimed to show that the decrease in the cortical bone mineral density (BMD) in the radius in Turner syndrome (TS) is artificially caused by the partial volume effect. We confirmed that the partial volume effect-corrected cortical BMD is not decreased in TS compared to in the healthy controls. Other factors are responsible for the increased fracture rate in TS. INTRODUCTION: Decreased cortical bone mineral density (BMD) has been reported in Turner syndrome (TS), using peripheral quantitative computerised tomography, and it is perceived as one of the major factors leading to increased fracture risk. We tested the hypothesis that low cortical BMD in the radius is caused artificially by the partial volume effect. METHODS: A cross-sectional study was conducted at the university hospital referral centre between March and October 2013. Thirty-two participants with TS who consented to the study were included (mean age 15.3 ± 3.2 years). We assessed the cortical BMD in the radius as well as the tibia, where the cortex is thicker compared with the radius. RESULTS: Whereas the cortical BMD was decreased in the radius (mean ± SD Z-score -0.6 ± 1.5, p = 0.037), it was increased in the tibia (mean Z-score 0.83 ± 1.0, p < 0.001). After correcting the cortical BMD for the partial volume effect, the mean Z-score was normal in the radius in TS (0.4 ± 1.3, p = 0.064). The corrected cortical BMD values were similar in the radius and tibia (1108 ± 52 vs. 1104 ± 48, group difference p = 0.75). CONCLUSIONS: The cortical BMD is not decreased in TS. The partial volume effect is responsible for previous findings of decreased cortical BMD in the radius. Altered bone geometry or other factors rather than low cortical BMD likely play a role in the increased fracture risk in TS.

Musculoskeletal pain: a new algorithm for differential diagnosis of a cardinal symptom in pediatrics.

Musculoskeletal pain (MSP) is a common childhood complaint associated with multiple differential diagnoses, including cancer. Considering the expanding spectrum of diagnostics, evaluat-ing a young patient with MSP is a challenge today, particularly for non-specialists in a primary care setting. Since childhood cancer is rare and most cardinal symptoms mimic rather non-serious diseases, misdiagnosis is not uncommon, but of significant prognostic relevance. To build the appropriate bridge between primary and secon-dary care for a child presenting with MSP, thereby preventing treatment delay and longterm sequelae, initial evaluation should follow a comprehensive, multidisciplinary, systematic and stepwise approach, which unites the patient's individual anamnestic, psychosocial, and clinical charac-teristics. After a systematic review of the literature, we generated multidisciplinarily quality-assured recommendations for efficient, rational and cost-effective primary care assessment of pediatric MSP. The algorithm promotes the identification and structured interpretation of the patient's individual clinical clues. It should serve the primary care physician to recognize when further intervention, rather than reassurance and follow-up, is needed using the minimum amount of testing to make an appropriate, prompt diagnosis in the clinical situation "child presenting with MSP". A German version of this algorithm has been published in the Guideline-Portal of The Association of the Scientific Medical Societies ("Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften", AWMF) in November 2013.

[Childhood and adolescent obesity--consequences for the locomotor system and treatment options. Musculoskeletal complications of overweight children and adolescents]. / Kindliche Adipositas - Folgen für den Bewegungsapparat und Therapieansätze. Muskuloskelettale Komplikationen bei Übergewicht und Adipositas im Kindes- und Jugendalter.

The aim of this article is to present the most relevant musculoskeletal complications known to be associated with being overweight or obese in childhood and adolescence in order to help the clinicians and physiotherapists in the diagnostic and management of these patients. Various musculoskeletal problems like slipped capital femoral epiphysis and Blount disease are well-known complications. More recent studies describe the effects of overweight on musculoskeletal pain and controversial influences on fracture rates. Reduced physical activity is a contributing factor in obesity, but also effects bone mineral accrual. Reduced postural stability and increased falls may be the reason for increased fracture rates. Furthermore these data show relevant changes of locomotion studied by gait analysis. Longitudinal kinematic studies may be needed to understand the entire aspect of gait development in overweight children. Obesity is still a serious health problem and has a relevant impact on the development of a child's musculoskeletal system. Obesity affects the locomotor sytem both functionally and structurally. Future studies are necessary to help us better understand the pathophysiology and development of optimal therapeutic strategies.

Measuring procedures to determine the Cobb angle in idiopathic scoliosis: a systematic review.

BACKGROUND: Scoliosis of the vertebral column can be assessed with the Cobb angle (Cobb 1948). This examination is performed manually by measuring the angle on radiographs and is considered the gold standard. However, studies evaluating the reproducibility of this procedure have shown high variability in intra- and inter-observer agreement. Because of technical advancements, interests in new procedures to determine the Cobb angle has been renewed. This review aims to systematically investigate the reproducibility of various new techniques to determine the Cobb angle in idiopathic scoliosis and to assess whether new technical procedures are reasonable alternatives when compared to manual measurement of the Cobb angle. METHOD: Systematic review. Studies examining procedures used to determine the Cobb angle were selected. Two review authors independently selected studies for inclusion, extracted data and assessed risk of bias. Statistical results of reliability and agreement were summarised and described. RESULTS: Eleven studies of new measuring procedures were included, all reporting the reproducibility. The new procedures can be divided into computer-assisted procedures, automatic procedures and smartphone apps. CONCLUSIONS: All investigated measuring procedures showed high degrees of reliability. In general, digital procedures tend to be slightly better than manual ones. For all other measurement procedures (automatic or smartphone), results varied. Studies implementing vertebral pre-selection and observer training achieved better agreement.

Functional deficits and morphological changes in the neurogenic bladder match the severity of spinal cord compression.

UNLABELLED: Following spinal cord injury (SCI), loss of spinal and supraspinal control results in desynchronisation of detrusor vesicae (parasympathicus) and external urethral sphincter (sympathicus) activity. Despite recovery of lower urinary tract function being a high priority in patients with SCI, effective treatment options are unavailable largely because mechanisms are poorly understood. PURPOSE AND METHODS: We used a clinically relevant model of thoracic SCI compression injury in adult female Wistar rats and confirmed that lesion volumes following severe injuries were significantly greater compared to moderate injuries (p < 0.05). Between 1-9 weeks, we assessed recovery of bladder function as well as return of locomotor function using the Basso, Beattie and Bresnahan (BBB) score. Bladder morphometrics and overall intramural innervation patterns, as assessed with ß-III tubulin immunohistochemistry, were also examined. RESULTS: Despite variability, bladder function was significantly worse following severe compared to moderate compression injury (p < 0.05); furthermore, the degree of bladder and locomotor dysfunction were significantly correlated (r = 0.59; p < 0.05). In addition, at 9 weeks after SCI we saw significantly greater increases in bladder dry weight (p < 0.05) and wall thickness following severe compared to moderate injury as well as increases in intramural axon density (moderate: 3× normal values; severe 5×; both p < 0.05) that also correlated with injury severity (r = 0.89). CONCLUSION: The moderate and severe compression models show consistent and correlated deficits in bladder and locomotor function, as well as in gross anatomical and histopathological changes. Increased intramural innervation may contribute to neurogenic detrusor overactivity and suggests the use of therapeutic agents which block visceromotoric efferents.

Introduction of a new standardized assessment score of spine morphology in osteogenesis imperfecta.

PURPOSE: Osteogenesis imperfecta (OI) is a rare hereditary disease leading to multiple bone deformities and fractures. In the absence of causal therapy, a symptomatic approach is based on treatment with bisphosphonates and physiotherapy. The clinical and radiological manifestations vary. Therefore, standardization and quantification for an objective comparison, especially during therapy, are required. In this paper, radiological changes of the spine are quantified according to their clinical relevance to define a scoring system that transfers the morphological changes into a single value representing the severity of the disease. MATERIALS AND METHODS: 268 lateral spine X-rays of 95 patients with OI (median age 5.6 years) were assessed. The findings were classified based on their clinical relevance. RESULTS: The three criteria, vertebral compression, thoracolumbar kyphosis and deformity type, were quantified in a new grading system. Based on this, a "severity classification" (1 to 5) was defined with implications for diagnostics and treatment. A mathematical formula that takes into account the three criteria and their correlations to clinical relevance, resulting in a "severity score", was developed. CONCLUSION: "Severity classification" and "severity score" introduce a new concept for a standardized evaluation of spine X-rays in patients with OI. For both scientific and routine purposes, it provides the user with a simple and easy-to-handle tool for assessing and comparing different stages of severity prior to and during therapy with detailed accuracy.

[Standardized x-ray reports of the spine in osteogenesis imperfecta]. / Standard zur Befundung von Röntgenaufnahmen der Wirbelsäule bei Patienten mit Osteogenesis imperfecta.

PURPOSE: In this study we present a standard for radiological reports in patients with osteogenesis imperfecta (OI). The parameters can be used to describe X-rays of the lateral spine and give an impartial description of anatomical structures during a treatment with bisphosphonates. MATERIAL AND METHODS: In this retrospective analysis we included 48 patients with OI (31 female, 17 male [1.5 months - 19 years, mean age 9.0 years]). Lateral spine X-rays were analyzed by 2 radiologists before and during treatment. The parameters of the standardized report are degree of kyphoscoliosis, compression of single vertebrae, predominant type of vertebral deformities and extent of vertebral compression (score 1 - 5). RESULTS: There was no clear trend in the change of compression of single vertebrae. Some vertebrae with ventral compression showed an upgrowth to vertebrae with harmonic compression. Other deformities showed only marginal changes. In 26 patients the kyphoscoliosis improved (mean 10 degrees), in 36 patients the thoracic vertebrae compression increased and in 30 patients the vertebral height in the lumbar spine increased. The improvement of vertebral height was 1 point in the thoracic and lumbar spine. CONCLUSION: We propose a standardized report of X-rays of the lateral spine in patients with OI with quantitative and semiquantitative parameters using morphological criteria. These include compression of single vertebrae, degree of kyphoscoliosis, vertebral deformities and the severity of vertebral compression in the thoracic and lumbar spine.

Insulin binding to antibodies is a risk factor for inexplicable severe hypoglycaemia in children with type-1 diabetes mellitus.

BACKGROUND: Type-1 diabetic individuals differ with regard to both, the formation of circulating insulin antibodies, and the incidence of severe hypoglycaemia. AIM OF THE STUDY: To assess the association of insulin binding to antibodies with the incidence of severe hypoglycaemia. PATIENTS AND METHODS: In a cross sectional study, 73 children with type-1 diabetes mellitus (median age 14 years, duration of diabetes 6 years) were investigated, 22 of whom had experienced severe hypoglycaemia during the past 18 months, and 51 had never experienced severe hypoglycaemia. Of the patients with severe hypoglycaemia 16 had experienced severe unexplained hypoglycaemias, and 6 had experienced severe hypoglycaemias which were explicable (by missed meals, unplanned physical exercise etc.). Insulin binding was measured in a blinded central laboratory by radioimmunoassay, and expressed as ratio bound/unbound insulin; a binding >15% was considered relevant insulin binding. RESULTS: A total of 38 patients displayed relevant insulin binding (17 of whom had experienced severe hypoglycaemia), and 35 patients did not (5 of whom had experienced severe hypoglycaemia; p=0.0055, Fisher's exact test). Patients with relevant insulin binding were younger (12.2 vs 14.5 years, p=0.006) than patients without relevant insulin binding. From the 16 patients with inexplicable severe hypoglycaemia, 15 displayed relevant insulin binding, compared to 2 of the 6 patients with explicable severe hypoglycaemia (p=0.009). The association of any severe hypoglycaemia, and of inexplicable severe hypoglycaemia, with relevant insulin binding was significant (odds ratio 4.8 (95%CI 1.5-15.2), and 22.1(95%CI 2.7-179.6), p<0.006). Patients with/without relevant insulin binding, or with/without severe hypoglycaemia, did not differ significantly regarding sex, duration of diabetes, number of insulin injections per day, HbA1c and C-peptide levels (ANOVA). CONCLUSION: Insulin binding to antibodies >15% appears to be a strong risk factor for inexplicable severe hypoglycaemias in type-1 diabetic children.

[Bisphosphonate therapy for children and adolescents with primary and secondary osteoporotic diseases]. / Bisphosphonat-Therapie bei Kindern und Jugendlichen mit primären und sekundären osteoporotischen Erkrankungen.

Bisphosphonates have a set place in the treatment of osteoporosis in adults. For the last 10 years they have also been used in pediatrics. Due to inhibition in differentiation and reduction in osteoclasts, both pamidronate and alendronate, the most commonly used preparations, cause an increase in bone density. Most experience comes from the i.v. treatment of forms with severe courses of osteogenesis imperfecta (OI). There is an increase in bone substance, a decrease in rate of fractures and a reduction in pain with higher mobility of those effected. In addition to the use of drugs, intramedullary nailing and physiotherapy are important therapeutic standards. Bisphosphonates are also used for other diseases involving bone remodeling, such as juvenile idiopathic osteoporosis or familial hyperphosphatemia. Acute side effects usually occur with the first infusion, involve "flu-like" symptoms and are self limiting. The question of long-term side effects cannot be answered with the currently available data.

Clinical characteristics of type 2 diabetes mellitus in overweight European caucasian adolescents.

AIM: To present the clinical features of Type 2 diabetes mellitus (T2DM) in overweight European Caucasian children and adolescents. METHODS: We report the clinical characteristics of 16 non-syndromal overweight European Caucasian adolescents with T2DM (10 boys, 6 girls, SDS-BMI in median +2.8, range +1.6 to +3.4) treated in 5 specialised centres for obesity and diabetes. RESULTS: None of the adolescents manifested with ketoacidosis. 13 were asymptomatic (3 adolescents with polyuria), 12 showed features of metabolic syndrome (dyslipidaemia or hypertension), 8 demonstrated acanthosis nigricans and 12 had relatives with T2DM. 11 adolescents were extremely obese and all patients were pubertal. Mean age at diagnosis was 14.2 years (range 11.0 - 16.9). Median insulin was 19 microU/ml, insulin resistance index (HOMA) 8.5, C-peptide 2.3 ng/ml, HbA1c 6.9 %, fasting blood glucose 176 mg/dl and blood glucose at 2 hours with the oGTT 229 mg/dl at manifestation. Fasting blood glucose and HBA1c were in the normal range in 4 and 6 adolescents respectively, while oGTT always fitted the diagnosis of T2DM. CONCLUSION: Since T2DM occurred in Caucasian overweight adolescents and is frequently asymptomatic, it is essential that clinicians perform diagnostic procedures to identify T2DM in high-risk groups of overweight Caucasian adolescents (extreme obesity, features of metabolic syndrome, relatives with T2DM).

Biochemical markers of growth hormone (GH) sensitivity in children with idiopathic short stature: individual capacity of IGF-I generation after high-dose GH treatment determines the growth response to GH.

OBJECTIVE AND PATIENTS: To assess multiple dose-response relationships between three GH doses (1.5, 3.0 and 6.0 IU/m2) and nine different biochemical markers of GH sensitivity in a well-defined group of 17 children with idiopathic short stature (ISS). DESIGN AND MEASUREMENTS: Serum levels of IGF-I, IGF-II and IGFBP-3, and peripheral markers leptin, C-terminal propeptide of type I collagen (PICP) and N-terminal propeptide of type III collagen (PIIINP), alkaline phosphatase (AP) and osteocalcin (OC) were measured at the start and after 2 and 12 weeks of periods of no treatment, GH 1.5 IU/m2 and GH 3.0 IU/m2. Twelve-week washout periods were applied between the 12-week GH-treatment periods. High-dose GH treatment was given during the second year of study and all serum markers were measured at start, after 2 and 12 weeks and 1 year of GH 6.0 IU/m2. In 18 non-GH-treated children with ISS the same parameters were measured yearly. The bone resorption marker urinary deoxypyridinoline (DPD) was measured during 12-h day and night periods at start and after 2 weeks GH 1.5, 3.0 and 6.0 IU/m2. RESULTS: All markers were GH dependent, but the timing of maximal response varied among different markers. Height SDS at start, age at start and IGF-II at baseline were inversely related to the first-year growth response (r = -0.73, P = 0.001; r = -0.53, P = 0.03; and r = -0.53, P = 0.03, respectively). Some statistically significant correlations between biochemical responses on low GH doses (1.5 or 3.0 IU/m2) and second-year growth response were found, but these showed no consistent pattern. However, all changes in IGF-I SDS after GH 6.0 IU/m2 measured either after 2 or 12 weeks or 1 year correlated significantly with the second-year growth response (r = 0.55, P = 0.02; r = 0.81, P = 0.001; and r = 0.86, P < 0.001, respectively). Baseline or GH-stimulated levels of peripheral markers did not correlate with the growth response. CONCLUSION: The individual capacity of IGF-I generation after high-dose GH treatment (6.0 IU/m2) determines the growth response on high-dose GH treatment. Peripheral markers do not seem to play a role in growth prediction of children with ISS.

The bone behind a low areal bone mineral density: peripheral quantitative computed tomographic analysis in a woman with osteogenesis imperfecta.

Areal bone mineral density (BMD) is the most widely used densitometric parameter. However, this approach makes it difficult to understand the structural basis of bone diseases, because a large number of bone properties are integrated into a single number. This is exemplified in the present case of a 27-year-old woman with osteogenesis imperfecta type I. Peripheral quantitative computed tomographic analysis at the radial metaphysis and at the radial diaphysis revealed a decreased areal BMD at both sites (z score -3.9 and -3.4, respectively). Yet, the structural basis for this decrease was different for the two locations: At the distal radius areal BMD was decreased because volumetric BMD was very low, whereas bone size was above the mean of the reference range. At the proximal radius areal BMD was decreased, because bone size was very low but volumetric BMD was above average. Bone mineral content of the radial diaphysis was very low for forearm muscle size, a finding which is compatible with Frost's hypothesis that the mechanostat setpoint is increased in osteogenesis imperfecta.

On longitudinal bone growth, short stature, and related matters: insights about cartilage physiology from the Utah paradigm.

Precursor cell division in growing cartilage determines human height, the lengths of the spine and limb bones, the alignment of joints, spines and limbs, and the ratio of spinal length to limb length. That division also helps to determine the sizes and shapes of joints, apophyses and epiphyses. Ideas about what controls those facts are changing. To former views, in which mainly genetic and humoral factors controlled them, the Utah paradigm of skeletal physiology adds long-overlooked biomechanical including muscular factors. These three kinds of factors would collaborate in controlling the precursor cell division that determines the above skeletal features. Problems with that control clearly cause or help to cause many clinical disorders. Examples include short stature, gigantism, premature and delayed skeletal maturation, some changes in fracture patterns associated with puberty, joint malalignments, congenital hip dysplasia, scoliosis, limb torsions, the ball-and-socket ankle, and some skeletal abnormalities in Marfan's syndrome and the osteochondrodystrophies. The physiology such things depend on has matured sufficiently to justify a review for pediatricians, endocrinologists and other clinical specialists, and many basic scientists.

A new and accurate prediction model for growth response to growth hormone treatment in children with growth hormone deficiency.

OBJECTIVE: To identify parameters which predict individual growth response to recombinant human GH (rhGH) therapy and to combine these parameters in a prediction model. DESIGN: Fifty-eight prepubertal patients with GH deficiency (17 females) participated in this prospective multicenter trial with 1 year of follow-up. METHODS: Auxological measurements, parameters of GH status and markers of bone metabolism were measured at baseline and at 1, 3 and 6 months after the start of rhGH treatment. Correlations with height velocity during the first 12 months of treatment (HV+12) were calculated. Prediction models were derived by multiple regression analysis. RESULTS: The model which best predicted HV+12 combined the following parameters: pretreatment bone age retardation as a fraction of chronological age, pretreatment serum levels of IGF-I, urinary levels of deoxypyridinoline (a marker of bone resorption) after 1 month of treatment and height velocity after 3 months of treatment. This model explained 89% of the variation in HV+12 with a standard deviation of the residuals of 0.93 cm/year. Defining successful rhGH therapy as a doubling of pretreatment height velocity, the model had a specificity of 90% and a sensitivity of 100% in predicting therapeutic success. CONCLUSIONS: This model is an accurate and practicable tool to predict growth response in GH-deficient children. It may help to optimize rhGH therapy by individual dose adjustment and contribute to improved overall outcomes.

The "muscle-bone unit" in children and adolescents: a 2000 overview.

In former views hormones, calcium, vitamin D and other humoral and nonmechanical agents dominated control of postnatal bone strength (and "mass") in children and adolescents. However later evidence that led to the Utah paradigm of skeletal physiology revealed that this control depends strongly on the largest mechanical loads on bones. Trauma excepted, muscles cause the largest loads and the largest bone strains, and these strains help to control the biological mechanisms that determine whole-bone strength. That makes the strength of children's load-bearing bones depend strongly on growing muscle strength and how bones respond to it. Most hormones and other nonmechanical agents that affect bone strength can help or hinder that "bone strength-muscle strength" relationship but cannot replace it. In addition some agents long thought to exert bone effects by acting directly on bone cells, affect muscle strength too. In that way they could affect bone strength indirectly. Such agents include growth hormone, adrenalcorticosteroid analogs, androgens, calcium, genes, vitamin D and its metabolites, etc. Thus bone and muscle do form a kind of operational unit. It is part of the Utah paradigm that supplements earlier views with later evidence and concepts. The paradigm explains how the "bone strength-muscle strength" relationship works. This article provides an overview of that physiology, and some of its implications for pediatric endocrinologists.

Chemiluminescence immunometric assay for measuring osteocalcin in healthy children.

Osteocalcin (OC) was measured in serum samples from 92 children and adolescents (57 females, 35 males) by a two-site chemiluminescence immunometric assay (Nichols Institute Diagnostics, USA), which recognizes the 1-19 region of the whole molecule as well as the large N-terminal midregion fragment representing the main part of OC in serum. The highest OC levels are measured between the age of 10-15 years. The linear correlations between OC and alkaline phosphatase were 0.65 (p < .01) for total alkaline phosphatase (TAP) and 0.61 (p < 0.1) for bone alkaline phosphatase (BAP).

Posterior pituitary ectopia: another hint toward a genetic etiology.

We report the MR and clinical findings of two patients with growth hormone deficiency and posterior pituitary ectopia (PPE). Possible causes of PPE are discussed.

Asp361Val Mutant of alkaline phosphatase found in patients with dominantly inherited hypophosphatasia inhibits the activity of the wild-type enzyme.

Hypophosphatasia is characterized by the hypomineralization of bone associated with the mutation of the tissue-nonspecific alkaline phosphatase (TNSALP) gene. Although the disease is usually autosomal recessive, an autosomal dominant form is also recognized. Approximately 50 mutations have been found in the TNSALP gene in patients with hypophosphatasia. However, the mutations identified to date do not seem to account for the dominantly inherited form of the disease. We have examined a German family in which the father and all 4 children were affected with hypophosphatasia, whereas the mother was healthy. The affected members of this family showed premature loss of deciduous teeth at or shortly before 2 yr of age and low levels of serum ALP with elevated levels of urinary phosphoethanolamine. DNA analysis by direct sequencing revealed a heterozygous missense mutation that caused the conversion of amino acid Asp to Val at position 361 (D361V) in the patients. Another substitution was detected in exon 12 (Val to Ala conversion at codon 505: V505A) in 1 allele of the mother and 3 children, indicating no association of the substitution with the disease. Reconstruction experiments demonstrated that the D361V mutant protein lost its enzymatic activity and that it inhibited the function of wild-type enzyme when coexpressed in COS-7 cells. On the other hand, the V505A mutant exhibited enzymatic activities equal to those of the wild-type ALP. It is likely that the mutant D361V protein forms dimers with the wild-type protein, and the protein-protein interaction contributes to the dominant effect of the mutant D361V. The mutation that causes D361V is the first one proven to be associated with the dominant form of hypophosphatasia.