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Introduction: Direct comparisons of both short-term and long-term auxological outcomes of growth hormone therapy (GHT) between growth hormone deficiency (GHD) and small for gestational age (SGA) are scarce., Methods: One hundred three patients with GHD and 53 patients with SGA treated at our tertiary center were investigated. Short-term and long-term outcomes were compared between these groups using multivariable linear regression models with adjustment for age, sex, and height at therapy start, also allowing for sex-specific group comparisons., Results: Mean delta height standard deviation scores (SDS) after 1 year of treatment were significantly higher in GHD (0.90, CI: 0.82-0.99) compared to SGA (0.67, CI: 0.54-0.79) (p = 0.003) with no sex difference. As expected, the mean increase in height SDS at final height (FH) was significantly higher in GHD (2.21, CI: 2.00-2.42) compared to SGA (1.05, CI: 0.75-1.35) (p < 0.001), leading to a target height corrected FH of -0.39 SDS (CI: -0.62 to -0.15) in GHD and -1.22 SDS (CI: -1.57 to -0.87) in SGA (p < 0.001). Girls with GHD had a better long-term outcome, as did boys with SGA when compared to the respective opposite sex. The cut-off of delta height of 0.5 SDS during the first year had a low sensitivity to detect long-term non-responders. We found a relation between short-term and long-term outcomes in GHD but not in SGA (adjusted R2 = 0.66 vs. 0.01)., Conclusion: In contrast to GHD, we observed practically no relationship between 1st-year and long-term outcomes in SGA patients treated with GH., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Objectives: The aim of this project was to develop a rectal formulation of metyrapone suitable for application in an infant hospitalised with McCune-Albright syndrome (MAS)-related Cushing syndrome and to provide a detailed description of the formulation protocol including quality control parameters., Methods: Suppositories with a drug load of up to 100 mg metyrapone were prepared. Mass variation, content uniformity and drug release were analysed according to the guidelines set out by the European Pharmacopoeia. Monitoring of the drug content for 6 weeks allowed for estimation of the storage stability at 2-8°C., Results: A protocol for the reproducible preparation of suppositories with intended metyrapone content of 30-100 mg was established. The suppositories were well tolerated by the patient and the clinical outcome is promising. The suppository preparations complied with the regulations from the European Pharmacopoeia. Further, a stability of the rectal formulation of at least 1 month was confirmed, facilitating medication supply for home care., Conclusions: An adequate and easy to follow protocol for preparation of high-quality metyrapone suppositories, with sufficient stability for practical use and fulfilling major pharmaceutical quality parameters, was established. The protocol can be easily replicated by skilled personnel in a community pharmacy facilitating treatment of the infant in home care., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

A female toddler was diagnosed at age ten months with peripheral precocious puberty and hypercortisolism related to McCune Albright Syndrome with additional systemic complications. We present the first successful, long-term use of metyrapone as suppositories, with striking clinical and biochemical improvement and no side-effects., (The Author(s). Published by S. Karger AG, Basel.)

Objectives: The aim of this study is to analyze height after cessation of growth (final height [FH]) and its evolution over the last decades in X-linked hypophosphatemia (XLH) patients in France, as the data on natural history of FH in XLH are lacking., Design: We performed a retrospective observational study in a large cohort of French XLH patients with available data on FH measurements., Materials and Methods: We divided patients into 3 groups according to their birth year: group 1 born between 1950 and 1974, group 2 born between 1975 and 2000, and group 3 born between 2001 and 2006, respectively, and compared their FHs., Results: A total of 398 patients were included. Mean FHs were the following: for group 1, -2.31 ± 1.11 standard deviation score (SDS) (n = 127), 156.3 ± 9.7 cm in men and 148.6 ± 6.5 cm in women; for group 2, -1.63 ± 1.13 SDS (n = 193), 161.6 ± 8.5 cm in men and 153.1 ± 7.2 cm in women; and for group 3, -1.34 ± 0.87 SDS (n = 78), 165.1 ± 5.5 cm in men and 154.7 ± 6 cm in women. We report a significant increase in mean FH SDS over 3 generations of patients, for both men and women (P < .001). Final height SDS in male (-2.08 ± 1.18) was lower than in female (-1.70 ± 1.12) (P = .002)., Conclusion: The FH of XLH patients in France increased significantly over the last decades. Even though men's FHs improved more than women's, men with XLH remain shorter reflecting a more severe disease phenotype. While the results are promising, most patients with XLH remain short leaving room for improvement., Competing Interests: Conflict of interest: D.-A.E. reports receiving travel grants and honoraria from Novo Nordisk, Pfizer and Merck Serono. A.L. and A.R. report receiving research grants, consulting fees and/or honoraria from Kyowa Kirin, Alexion, Novo Nordisk, Pfizer, and Merck Serono. All disclosures mentioned are unrelated to this research project. The other authors have no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Severe short stature is a feature of acrodysostosis, but data on growth are sparse. Treatment with recombinant human growth hormone (rhGH) is used in some centers to increase final height, but no studies have been published so far. Our objective was to conduct a multicenter, retrospective, cohort study to investigate growth in individuals with both types of acrodysostosis, treated with rhGH or not; we used the new nomenclature to describe acrodysostosis, as this disease belongs to the large group of inactivating PTH/PTHrP signaling disorders (iPPSD); acrodysostosis refers to iPPSD4 (acrodysostosis type 1 due to PRKAR1A mutations) and iPPSD5 (acrodysostosis type 2, due to PDE4D mutations)., Methods: We present auxological data from individuals with genetically characterized iPPSD4, and participants with clinical features of iPPSD5., Results: We included 20 and 17 individuals with iPPSD4 and iPPSD5, respectively. The rhGH-treated iPPSD4 patients (n = 9) were smaller at birth than those who did not receive rhGH (median - 2.2 SDS vs. - 1.7 SDS); they showed a trend to catch-up growth during rhGH therapy (median 0.5 SDS in the first year). The rhGH-treated patients (n = 5) reached a better final height compared to those who did not receive rhGH (n = 4) (median - 2.8 SDS vs. - 3.9 SDS), suggesting that rhGH is efficient to increase height in those patients. The difference in target height to final height ranged between 1.6 and 3.0 SDS for iPPSD4 not treated with rhGH (n = 4), 2.1-2.8 SDS for rhGH-treated iPPSD4 (n = 5), 0.6-5.5 SDS for iPPSD5 not treated with rhGH (n = 5) and 2.5-3.1 for rhGH-treated iPPSD5 (n = 2)., Conclusion: Final height may be positively influenced by rhGH in patients with acrodysostosis/iPPSD. Our rhGH-treated cohort started therapy relatively late, which might explain, at least in part, the limited effect of rhGH on height., (© 2023. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Background: Maternal inactivating GNAS mutations lead to pseudohypoparathyroidism 1A (PHP1A), newly classified as inactivating parathyroid hormone (PTH)/PTHrP-signaling disorder type 2 of maternal inheritance (iPPSD2). Patients present with resistance to PTH and other hormones, subcutaneous ossifications, brachydactyly, short stature, and early-onset obesity. They can be born small for gestational age (SGA) and may present with growth hormone (GH) deficiency. The use of recombinant human GH (rhGH) therapy has been sporadically reported, yet we lack data on the long-term efficacy and safety of rhGH, as well as on adult height., Objective: Our multicenter, retrospective, observational study describes growth in patients treated with rhGH in comparison with untreated iPPSD2/PHP1A controls., Methods: We included 190 patients, of whom 26 received rhGH. Height, weight, body mass index at various time points, and adult height were documented. We analyzed the effect of rhGH on adult height by using linear mixed models., Results: Adult height was available for 11/26 rhGH-treated individuals and for 69/164 controls. Patients treated with rhGH showed a gain in height of 0.7 standard deviation scores (SDS) after 1 year (CI +0.5 to +0.8, P < .001) and of 1.5 SDS after 3 years (CI +1.0 to +2.0, P < .001). Additionally, there was a clear beneficial impact of rhGH on adult height when compared with untreated controls, with a difference of 1.9 SDS (CI +1.1 to +2.7, P < .001). Body mass index SDS did not vary significantly upon rhGH therapy., Conclusion: Recombinant human growth hormone treatment of iPPSD2/PHP1A patients with short stature improves growth and adult height. More studies are needed to confirm long-term efficacy and safety., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Background: Achondroplasia, caused by a pathogenic variant in the fibroblast growth factor receptor 3 gene, is the most common skeletal dysplasia. The Lifetime Impact of Achondroplasia Study in Europe (LIAISE; NCT03449368) aimed to quantify the burden of achondroplasia among individuals across a broad range of ages, including adults., Methods: Demographic, clinical and healthcare resource use data were collected from medical records of achondroplasia patients enrolled in 13 sites across six European countries in this retrospective, observational study. Descriptive statistics or event rates per 100 person-years were calculated and compared across age groups as well as by history of limb lengthening. Patient-reported outcomes (quality of life [QoL], pain, functional independence, work productivity and activity impairments) were evaluated using questionnaires at the time of enrolment. An exploratory analysis investigated correlations between height (z-score or centimetres) and patient-reported outcomes., Results: Overall, 186 study patients were included, with a mean age of 21.7 ± 17.3 years (range 5.0-84.4). At least one complication or surgery was reported for 94.6% and 72.0% of patients, respectively, at a rate of 66.6 and 21.5 events per 100 person-years. Diverse medical and surgical complications were reported for all ages in a bimodal distribution, occurring more frequently in the youngest and oldest age groups. A total of 40 patients had previously undergone limb lengthening (capped at 20% per the study protocol). The most frequent surgery types varied by age, in line with complication profiles. Healthcare resource use was high across all age groups, especially among the youngest and oldest individuals, and did not differ substantially according to history of limb lengthening. Compared to general population values, patients reported impaired QoL particularly for physical functioning domains. In addition, patients reported difficulty carrying out daily activities independently and pain starting in childhood. Patient height correlated with multiple patient-reported outcomes., Conclusions: The findings of this study suggest that, across an individual's lifetime, achondroplasia is associated with multisystem complications, reduced QoL and functionality, and increased pain. These results highlight the large amount of healthcare resources that individuals with achondroplasia require throughout their lifespans and provide novel insights into current achondroplasia management practices across Europe. Trial registration ClinicalTrials.gov, NCT03449368, Submitted 14 December 2017 - prospectively registered, https://clinicaltrials.gov/ct2/show/record/NCT03449368., (© 2023. The Author(s).)

Background: X-linked hypophosphatemia (XLH) is characterized by increased serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphatemia and insufficient endogenous synthesis of calcitriol. Beside rickets, odonto- and osteomalacia, disproportionate short stature is seen in most affected individuals. Vitamin D analogs and phosphate supplements, i.e., conventional therapy, can improve growth especially when started early in life. Recombinant human growth hormone (rhGH) therapy in XLH children with short stature has positive effects, although few reports are available. Newly available treatment (burosumab) targeting increased FGF23 signaling leads to minimal improvement of growth in XLH children. So far, we lack data on the growth of XLH children treated with concomitant rhGH and burosumab therapies., Results: Thirty-six patients received burosumab for at least 1 year after switching from conventional therapy. Of these, 23 received burosumab alone, while the others continued rhGH therapy after switching to burosumab. Children treated with burosumab alone showed a minimal change in height SDS after 1 year (mean ± SD 0.0 ± 0.3 prepubertal vs. 0.1 ± 0.3 pubertal participants). In contrast, rhGH clearly improved height during the first year of treatment before initiating burosumab (mean ± SD of height gain 1.0 ± 0.4); patients continued to gain height during the year of combined burosumab and rhGH therapies (mean ± SD height gain 0.2 ± 0.1). As expected, phosphate serum levels normalized upon burosumab therapy. No change in serum calcium levels, urinary calcium excretion, or 25-OHD levels was seen, though 1,25-(OH) 2 D increased dramatically under burosumab therapy., Conclusion: To our knowledge, this is the first study on growth under concomitant rhGH and burosumab treatments. We did not observe any safety issue in this cohort of patients which is one of the largest in Europe. Our data suggest that continuing treatment with rhGH after switching from conventional therapy to burosumab, if the height prognosis is compromised, might be beneficial for the final height., (© 2022. The Author(s).)

The heterogeneity of "rare bone disorders" can be explained by the number of molecules and regulatory pathways which are responsible for bone health and normal stature. In this article, the most important basic principles behind bone homeostasis from development to structure and regulation of the growing skeleton are summarized. The aim is to provide the reader with some theoretical background to understand the nature of the different main groups of disorders affecting bone stability, longitudinal growth and disturbances of calcium and phosphate homeostasis.

Diagnosing and treating hypercalcemia during pregnancy can be challenging due to both the physiological changes in calcium homeostasis and the underlying cause for the hypercalcemia. During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus' calcium requirements. Here we discuss the diagnostic challenges, management, and patient perspective of hypercalcemia during pregnancy in two particular cases and in other rare conditions causing hypercalcemia.

Objective: Pseudohypoparathyroidism and related disorders belong to a group of heterogeneous rare diseases that share an impaired signaling downstream of Gsα-protein-coupled receptors. Affected patients may present with various combination of symptoms including resistance to PTH and/or to other hormones, ectopic ossifications, brachydactyly type E, early onset obesity, short stature and cognitive difficulties. Several years ago we proposed a novel nomenclature under the term of inactivating PTH/PTHrP signaling disorders (iPPSD). It is now of utmost importance to validate these criteria and/or improve the basis of this new classification., Design: Retrospective study of a large international series of 459 probands and 85 relatives molecularly characterized., Methods: Information on major and minor criteria associated with iPPSD and genetic results were retrieved from patient files. We compared the presence of each criteria according to the iPPSD subtype, age and gender of the patients., Results: More than 98% of the probands met the proposed criteria for iPPSD classification. Noteworthy, most patients (85%) presented a combination of symptoms rather than a single sign suggestive of iPPSD and the overlap among the different genetic forms of iPPSD was confirmed. The clinical and molecular characterization of relatives identified familial history as an additional important criterion predictive of the disease., Conclusions: The phenotypic analysis of this large cohort confirmed the utility of the major and minor criteria and their combination to diagnose iPPSD. This report shows the importance of having simple and easily recognizable signs to diagnose with confidence these rare disorders and supports a better management of patients.

Hypophosphatasia (HPP) is an inborn error of metabolism caused by loss-of-function mutations in the biomineralization-associated alkaline phosphatase gene, encoding tissue-nonspecific alkaline phosphatase (TNSALP). Symptoms include skeletal hypomineralization and extra-skeletal manifestations such as pyridoxine (B6)-responsive seizures due to impaired cerebral B6 passage. Since the introduction of enzyme replacement therapy (ERT), skeletal manifestations and B6-responsive seizures were reported to improve significantly. Nevertheless, there is an increasing evidence of B6-independent neurological manifestation of HPP including HPP-associated encephalopathy. Here, we present for the first time the brain alterations of an infant with neonatal HPP who died of neurological complications at the age of 5 months despite early initiation of ERT. CSF analysis showed normal concentrations of biogenic amines reflecting sufficient intracellular B6 availability. Postmortem histopathology revealed severe, localized affection of the cerebral cortex including cortical lesions in layers 2 and 3 in direct proximity to TNSALP-expressing neurons and hippocampal sclerosis. Our findings confirm that TNSALP deficiency may lead to a severe encephalopathy. We hypothesize that HPP-associated encephalopathy resistant to currently available ERT may develop in addition and probably independently of typical B6-responsive seizures in some patients. Prospective, controlled studies with close neurological follow-up including brain imaging are needed to identify patients at risk for severe neurological symptoms despite ERT., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Objective: Young women with Turner syndrome (TS) are known to be at risk for loss to medical follow-up. Recent literature indicates that there are disparities regarding transition readiness between different chronic conditions. So far, studies in young women with TS investigating their transition readiness compared to youths with other chronic conditions with no or minor neurocognitive challenges have not been reported., Methods: Patients (n = 52), 26 patients with Turner syndrome (mean age 17.24 ± 2.10) and 26 controls with type 1 diabetes or a rheumatic disease (mean age 17.41 ± 2.44), were recruited from specialized paediatric endocrine outpatient clinics. The Transition Readiness Assessment Questionnaire TRAQ-GV-15 was used to compare transition readiness scores between TS and controls. In addition, information on individual handling of the questionnaire was obtained. Descriptive statistics and nonparametric methods were used to analyse the data., Results: Significant differences for transition readiness scores were found between the two study groups. The global TRAQ-GV-15 score was significantly lower for females with TS. In particular, subscale 1 'autonomy' of the TRAQ-GV-15 showed lower scores in patients with TS. Patients with TS needed significantly more help and more time to complete the questionnaire., Conclusion: Special attention should be given to young women with Turner syndrome in the preparation for the transitional phase. By incorporating the assessment of transition readiness specialists will find it easier to identify underdeveloped skills and knowledge gaps in their patients. Unless a multidisciplinary young adult clinic is established, an older age than 18 years at transfer to adult endocrine care might be beneficial., (© 2020 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Background: The acid-labile subunit (ALS) is a crucial factor in the tertiary complex. IGF-I and IGFBP-3 are routinely measured during the diagnostic work-up for growth hormone deficiency (GHD). The aim of the study is to evaluate the relevance of serum ALS as an additional biomarker in the diagnosis of GHD., Methods: Ninety-one children undergoing standard diagnostic work-up for GHD were included in this retrospective study. Inclusion criteria were evidence-based auxological cutoffs, IGF-I and IGFBP-3 <-2 SDS at first presentation, at least 1 growth hormone (GH) stimulation test, and IGF-I, IGFBP-3, and ALS measurements on the same day. Statistical analysis was performed by ROC as well as by odds ratio calculations., Results: Forty-seven of 90 participants presented with peak GH values under the cutoff of 7 ng/mL. AUC from a model containing only IGF-I was 0.76 and 0.68 when using only ALS. A model containing IGF-I, IGFBP-3, and ALS (AUC = 0.77) did not improve the result compared to the combination of IGF-I/IGFBP-3 (0.77) or IGF-I/ALS (0.76). Furthermore, the variation in the outcome (GH peak

Turner syndrome (TS) is a common genetic disorder in females with high incidence of ascending aortic dilatation and even dissection occurring as early as in the second decade. Known risk factors (RF) are bicuspid aortic valves (BAV), coarctation of the aorta (CoA), and arterial hypertension. Since 10% of dissections occur in patients without RF, an intrinsic aortic wall abnormality has been postulated. This study aimed to investigate the elasticity of the ascending aorta as a surrogate marker of aortic wall texture. Forty-six pediatric patients with genetically proven TS were prospectively examined for the morphology of their aortic valve, and size and elasticity indices of the adjacent aorta. Cohorts of 46 female subjects with tricuspid aortic valves (TAV) and ten non-syndromic females with BAV were investigated as separate control groups. Comparison of healthy controls with TS patients revealed significantly deteriorated elasticity indices in those with TS. Furthermore, normalized aortic dimensions were greater in TS patients, but dilatations of the ascending aorta with z-score levels above two were restricted to those with BAV (14/46). Deteriorated elasticity indices were measured in TS patients, independent of aortic dilatation, BAV, and CoA, and were comparable to those of patients with isolated, non-syndromic BAVs. By measuring elasticity levels as a surrogate for aortic wall texture, we were able to gather evidence that TS presents with an intrinsic abnormality of the ascending aorta even in patients without concomitant BAV, CoA or dilatations as early as in childhood.

Background: Previous studies have shown that only a minority of patients with Turner syndrome (TS) have adequate medical care after transfer to adult care., Aim of This Study: To assess the status of medical follow-up and quality of life (QoL) in adult women diagnosed with TS and followed up until transfer. To compare the subjective and objective view of the medical care quality and initiate improvements based on patients' experiences and current recommendations., Methods: 39 adult women with TS out of 64 patients contacted were seen for a clinical and laboratory check, cardiac ultrasound, standardized and structured questionnaires (SF-36v2 and Beck depression inventory)., Results: 7/39 of the patients were not being followed medically at all. Only 2/39 consulted all the specialists recommended. Comorbidities were newly diagnosed in 27/39 patients; of these, 11 related to the cardiovascular system. Patients in our cohort scored as high as the mean reference population for SF-36v2 in both mental and physical compartments. Obese participants had lower scores in the physical function section, whereas higher education was related to higher physical QoL scores. Adult height slightly correlated positively with physical health., Conclusion: Medical follow-up was inadequate in our study cohort of adults with TS. Even though their medical follow-up was insufficient, these women felt adequately treated, leaving them vulnerable for premature illness. Initiatives in health autonomy and a structured transfer process as well as closer collaborations within specialities are urgently needed., (© 2018 The authors.)

Turner syndrome (TS), although considered a rare disease, is the most common sex chromosome abnormality in women, with an incident of 1 in 2500 female births. TS is characterized by distinctive physical features such as short stature, ovarian dysgenesis, an increased risk for heart and renal defects as well as a specific cognitive and psychosocial phenotype. Given the complexity of the condition, patients face manifold difficulties which increase over the lifespan. Furthermore, failures during the transitional phase to adult care result in moderate health outcomes and decreased quality of life. Guidelines on the optimal screening procedures and medical treatment are easy to find. However, recommendations for the treatment of the incriminating psychosocial aspects in TS are scarce. In this work, we first reviewed the literature on the cognitive and psychosocial development of girls with TS compared with normal development, from disclosure to young adulthood, and then introduce a psychosocial approach to counseling and treating patients with TS, including recommendations for age-appropriate psychological diagnostics. With this work, we aim to facilitate the integration of emphasized psychosocial care in state-of-the-art treatment for girls and women with TS., (© 2017 The authors.)

Background: A female infant was admitted to hospital due to failure to thrive. She presented hypercalcemia (4.09 mmol/L, normal range: 2.2-2.65 mmol/L), high 25-hydroxyvitamin D (283 nmol/L, normal range: 75-250 nmol/L), 1,25-dihydroxyvitamin D in the upper normal range, and low parathyroid hormone. Vitamin D intoxication was suspected. The patient had received routine rickets prophylaxis., Methods: Williams-Beuren syndrome was genetically excluded. Sequencing of CYP24A1 showed 2 mutations: c.443T>C and c.1186C>T., Results: The patient's clinical status improved after intravenous rehydration, cessation of supplementation, and on a low-calcium diet. 25-Hydroxyvitamin D concentrations normalized within days, while 1,25-dihydroxyvitamin D remained in the upper normal range. We also investigated our patient's bone health., Conclusion: The patient was hospitalized initially on suspicion of vitamin D intoxication but proved to be a case of compound heterozygosity. Data on the long-term clinical and biochemical evolution of patients with idiopathic infantile hypercalcemia are sparse. Our follow-up showed seasonal variations of vitamin D and calcium parameters, with no influence on kidney function or bone health for the investigated period., (© 2016 S. Karger AG, Basel.)

Background: The measurement of insulin-like growth factors (IGF-I) and insulin-like growth factor-binding protein (IGFBP-3) often serves as first-line testing in children with growth disorders. The role of acid-labile subunit (ALS) as a screening parameter for homozygous or heterozygous mutations of the ALS gene still has to be determined., Methods: IGF-I, IGFBP-3, and ALS were measured in 252 samples from children and adolescents. Reference curves were fitted using generalized additive model for location, scale and shape (GAMLSS) models and SD-Scores were calculated. Bootstrap analysis was used to quantify the uncertainty of the estimated percentiles. Bland-Altman plots were used to investigate the discrepancy between our newly estimated standard deviation scores (SDS) and SDS calculated on the basis of previous reference data., Results: We present reference data for enzyme-linked immunosorbent assay (ELISA) measurements based on recommended internal standard for IGF-I, IGFBP-3, and ALS suitable for calculation of SD-scores. The Bland-Altman plot shows a rough agreement between the previous SDS calculation and our new one only for SDS around 1; for SDS at -2, an average difference of 0.83 SD was noticed., Conclusion: Our IGF-I reference values for the interval of interest in diagnosing growth hormone deficiency (GHD) (prepubertal age) are solid as proved by bootstrap analysis. The difference in calculated SD scores by using data provided previously highlights the importance of using labor and method specific reference data.

Introduction: Regulation of phosphate homeostasis is essential for mineralization and enchondral ossification. Fibroblast growth factor 23 (FGF23) and its obligatory co-receptor Klotho (KL) play a key role in this process by influencing both renal phosphate reabsorption and vitamin D metabolism. In disease, excessive action of FGF23 leads to hypophosphatemic rickets, while its deficiency causes tumoral calcinosis. Although osteocytes and osteoblasts are widely seen as the primary source of FGF23 under physiological conditions, the origin of systemic FGF23 remains controversial. In this study, we investigated the expression of FGF23 and KL in porcine growth plate cartilage, adjacent tissues, and parenchymal tissues., Materials and Methods: Tissue samples were obtained from 4- to 6-week-old piglets. mRNA expression was quantified by real-time PCR and normalized to 18S rRNA. Immunohistochemical staining was performed for FGF23, KL, collagen type X, and FGF receptor 1. Growth plate chondrocyte subpopulations were acquired by collagenase digestion of growth plate explants and subsequent density gradient centrifugation., Results: We could detect both FGF23 and KL mRNA and protein in growth plate chondrocytes. FGF23 expression was mainly found in hypertrophic and resting chondrocytes. Furthermore, significant expression of both genes was observed in bone, liver, and spleen., Conclusion: These data challenge previous expression analyses, in particular theories of bone as the exclusive source of FGF23. Moreover, significant expression of FGF23 and KL within the growth plate and adjacent tissues imply a potential local role of FGF23 in chondrocyte differentiation and tissue mineralization.

Case Report: A female patient with consanguineous parents presented with severe symptomatic hypocalcemia (1.62mmol/l) at the age of 4 months. Treatment with oral 1,25-(OH)2-vitamin D and calcium carbonate was started and serum calcium concentrations were stabilized at the lower end of the normal range. Subsequently she developed normally and had no evidence for additional abnormalities. Over the next 6 years of observation, serum levels of PTH were always low but detectable (5.3-2.5pg/ml; normal: 15-65pg/ml) resulting in the diagnosis of isolated hypoparathyroidism. Disturbances in the vitamin-D metabolism, autoimmune polyendocrine syndrome (APS), chromosomal anomalies or mutations in the calcium-sensing receptor gene (CaSR) were excluded. Nucleotide sequence analysis of PTH revealed the presence of a homozygous point mutation (c.68C>A) in exon 2 that introduces a premature termination codon (p.Ser23X in the Pre- sequence of PTH) resulting in a non-functional PTH-precursor., Conclusion: A novel, homozygous PTH mutations was identified, which is obviously a very rare cause of isolated hypoparathyroidism (IHP). Although activating CaSR mutations are the most common cause of hypoparathyroidism, analysis of the PTH gene should be considered in those IHP patients in whom a CaSR has been excluded, particularly if the parents are likely to be consanguineous., (Copyright © 2012 Elsevier Inc. All rights reserved.)