Graves' disease (GD) and Thyroid Eye Disease (TED) are autoimmune disorders characterized by significant heterogeneity in treatment response. Up to 50% of GD patients relapse after antithyroid drug (ATD) withdrawal, and a substantial portion of TED patients (20-50%) are resistant to first-line glucocorticoid (GC) therapy. This review evaluates the current evidence on epigenetic modifications as predictive biomarkers to guide personalized treatment. We synthesized recent findings (up to 2025) from PubMed, focusing on DNA methylation and microRNAs (miRNAs). For GD, ATD relapse risk is linked to a persistent "epigenetic memory" in T cells, notably the hypomethylation of Th17-associated genes. Circulating miRNA signatures, including miR-346, miR-23b-5p, and miR-92a-3p, also show promise in predicting remission. For TED, GC sensitivity is strongly correlated with specific circulating miRNAs. High pre-treatment levels of miR-146a predict a positive response (100% positive predictive value), while low levels of miR-224-5p predict non-responsiveness. While DNA methylation is confirmed in TED pathogenesis, its predictive role is unstudied. Major research gaps persist, particularly the near-total absence of data on histone modifications as predictive markers and the lack of epigenetic predictors for new biologics treatments, which currently rely on genetic or pharmacokinetic markers. Epigenetic biomarkers represent a promising frontier for stratifying patients and optimizing therapeutic strategies in Graves' autoimmunity.

PURPOSE:Rickets is a rare bone disorder due to altered calcium, vitamin D, and phosphorus metabolism, caused by nutritional deficiencies or, in 13% of cases, genetic origin. Few data are available on an Italian cohort of rickets. METHODS:Twenty-four patients with confirmed low serum phosphorus levels and reduced renal tubular phosphate reabsorption were recruited from different tertiary care centres over the last 5 years. Biochemical, clinical, and anamnestic data were also collected. DNA was extracted and subjected to targeted next-generation sequencing. RESULTS:Twenty-four single-nucleotide variants were identified in the PHEX (eight pathogenic, five likely pathogenic, three variants of uncertain significance), CYP27B1 (two pathogenic, four likely pathogenic), and SLC34A3 (one pathogenic, one likely pathogenic) genes. Five large genomic deletions involving one or more PHEX exons were detected. Eight of 20 PHEX and both SLC34A3 variants were novel, and segregation analysis identified 11 familial and three de novo cases. Biochemical data confirmed high serum alkaline phosphatase and low 25-hydroxyvitamin D3 levels, whereas the main clinical manifestations were short stature (76.1%), bone deformities (85.7%), musculoskeletal pain (71.4%), and muscle weakness (55.5%). CONCLUSIONS:Our study provides clinical and genetic descriptions of rickets in a cohort of Italian patients. Moreover, we expanded the spectrum of mutations associated with the genetic forms of this disorder and suggested a high-throughput sequencing approach to provide a molecular diagnosis for adequate follow-up of patients.

CONTEXT:Mild autonomous cortisol secretion (MACS) is associated with increased risk of vertebral fractures (VFx). OBJECTIVE:The aim was to investigate impact of recovery from MACS on bone health remains unclear. METHODS:Retrospective intervention study (Study 1): 53 patients with MACS were followed for 35.2 ± 18.6 months; 31 patients underwent surgery (Study 1-Group A, 74.2% women, age 63 years [57-67]), while 22 patients received conservative treatment (Study 1-Group B, 45.5% women, age 64 years [61-72]). Prospective randomized study (Study 2): Fifty-one outpatients with MACS were randomly assigned to either adrenalectomy (Study 2-Group A, 21 patients, 67% women, age 63 [56.5-72.5]) or conservative approach (Study 2-Group B, 28 patients, 78% women, age 69 [61-73]) and were followed for 24 months. METHODS:MACS was diagnosed in patients with adrenal incidentalomas (AIs) >1 cm and cortisol after the 1-mg dexamethasone suppression test ≥1.8 µg/dL (50 nmol/L). At baseline and at the end of follow-up we assessed calcium-phosphorus metabolism, bone mineral density (BMD) at the lumbar spine (LS), total hip (TH), and femoral neck (FN) using dual-energy X-ray absorptiometry, and the presence of VFx. RESULTS:Study 1: At the end of the follow-up, Study 1-Group B showed an increased incidence of VFx (n = 11, 50%) than Study 1-Group A (n = 3, 9.7%, P < .005). In both groups, BMD at LS, FN, and TH was comparable between baseline and the end of follow-up. Study 2: After 24 months in Study 2-Group A, but not in Study 2-Group B, calcium and phosphorus levels increased compared with baseline (P = .03 and P = .04, respectively). At the end of follow-up, BMD remained stable across both groups, but Study 2-Group B showed a significantly higher incidence of VFx (n = 7, 25%) than Study 2-Group A (n = 1, 4.8%, P = .04). CONCLUSION:In patients with AI and MACS, adrenalectomy significantly reduces the risk of VFx.

Introduction: Primary hyperparathyroidism (PHPT) is a common endocrine disorder, primarily caused by single adenomas or multiglandular disease. This study evaluates the economic impact of different PHPT treatment approaches from both the Italian National Health Service and societal perspectives. Methods: A micro-costing approach was used to estimate the costs of surgical and non-surgical treatments. Data were gathered through a survey among panel members responsible for the Italian PHPT treatment guidelines, ensuring alignment with national clinical practice. The survey examined various cost components, including diagnostic tests, pre-hospitalization assessments, surgery duration, drug use, healthcare professionals involved, disposable materials, and follow-up care requirements. Results: The total cost for PHPT diagnosis and comorbidity assessment is € 887.96. Parathyroidectomy (PTX) costs € 4,588.00. Non-surgical alternatives, including pharmacological treatment (€ 953.34 annually) and active surveillance (€ 197.42 annually), result in cumulative 30-year costs of € 28,590 and € 5,910, respectively. Since PTX is typically performed at age 55, pharmacological treatment over 30 years incurs an additional € 22,876 per patient compared to surgery. Conclusions: Despite its higher upfront cost, PTX demonstrated long-term cost efficiency due to the relatively low rates of follow-up complications and the absence of recurring annual costs associated with conservative strategies.

OBJECTIVE:Bone densitometry and fracture risk algorithms have proved scarce reliability for fractures risk estimation in patients with diabetic osteopathy. Calcaneal quantitative ultrasound (QUS) is a noninvasive, low-cost technique already acknowledged for fracture risk assessment in patients with primary osteoporosis. Nevertheless, there is limited evidence on the role of QUS in patients with diabetes mellitus (DM). The aim of our study was to evaluate whether calcaneal QUS may effectively estimate long-term risk of fragility fractures in a group of patients with DM. DESIGN:We conducted a retrospective study including 300 patients with type 1 (T1DM) or type 2 DM (T2DM) who underwent calcaneal QUS evaluation in 2013. Information about clinical fragility fractures, DM characteristics, and QUS parameters (broadband ultrasound attenuation, BUA; speed of sound, SOS; stiffness index, SI) were collected through electronic medical records. Ten years later, the patients were asked to participate to an interview about clinical fragility fractures occurring within the decade 2013-2023. PATIENTS AND MEASUREMENT:At baseline, thirty-nine patients (13%) presented with at least one fragility fracture at any site. Fractured patients showed significantly lower QUS parameters than non-fractured (p < 0.0001), both in T1DM (n = 106) and in T2DM (n = 194). In 2023, 231 patients (132 with T2DM and 99 with T1DM) participated to the follow-up interview; 31 patients (13%) referred the occurrence a new clinical fragility fracture, and 14 patients (6%) a major osteoporotic fractures (MOF). Among QUS parameters, BUA was significantly associated to the occurrence of new MOF over 10-years in T2DM (p < 0.01), but not in T1DM. CONCLUSIONS:Calcaneal QUS may represent an effective tool in assessment of fracture risk among patients with T2DM.

L’osteoporosi è una malattia sistemica caratterizzata da ridotta densità minerale e deterioramento della microarchitettura ossea, con conseguente aumento del rischio di fratture da fragilità. Sebbene le terapie farmacologiche antiriassorbitive e anaboliche siano efficaci nella prevenzione delle fratture, il loro impiego può essere associato a eventi avversi, talvolta rari ma clinicamente rilevanti. Le complicanze più documentate dei farmaci antiriassorbitivi includono l’osteonecrosi della mandibola e le fratture atipiche del femore, entrambe legate a una terapia prolungata e alla concomitante presenza di fattori predisponenti. I bisfosfonati orali possono inoltre causare disturbi gastrointestinali, mentre la somministrazione endovenosa è associata a reazioni di fase acuta e, più raramente, a nefrotossicità e fibrillazione atriale. In corso di terapia antiriassorbitiva è possibile inoltre lo sviluppo di un’ipocalcemia, complicanza rara ma potenzialmente rilevante nei pazienti con deficit di vitamina D o insufficienza renale. Le terapie anaboliche, come teriparatide, abaloparatide e romosozumab, presentano un profilo di sicurezza generalmente favorevole, sebbene romosozumab sia stato associato a un possibile incremento del rischio cardiovascolare in pazienti predisposti. Una conoscenza approfondita delle potenziali complicanze delle terapie antiosteoporotiche è essenziale per una valutazione individualizzata del rischio-beneficio. L’identificazione precoce dei fattori predisponenti, un’attenta selezione terapeutica e il monitoraggio regolare sono fondamentali per garantire sicurezza, efficacia e aderenza al trattamento nei pazienti con osteoporosi.

Parathyroid hormone controls calcium and phosphate metabolism. The latter is also regulated by both FGF23 and 1–25(OH)2VitaminD. The polymorphic variant c.716 C > T of the FGF23 gene was previously found to be associated with renal phosphate leak/nephrolithiasis. The aim of our research is to study the metabolism of phosphate in a cohort of patients with primary hyperparathyroidism (PHPT) and its impact on bone and kidney. We have retrospectively compared a large sample of sporadic PHPT patients (339) with historical comparison cohort (HCC 503: Olivetti Study Group and Siena Osteoporosis Study). Moreover, in 51 PHPT patients, phosphate metabolism indexes were also revaluated at least 2 years after surgical cure. The variant c.716 C > T of the FGF23 gene was genotyped in patients and in a small sample of the control group. In PHPT patients we found higher levels of serum calcium, PTH, alkaline phosphatase, beta-C-terminal telopeptide (CTx), urinary calcium, while serum phosphate, 25OH-VitaminD, maximal tubular renal phosphate reabsorption adjusted for glomerular filtration rate (TmPO4/GFR) were lower than what was found in HCC. In PHPT patients fibroblast growth factor 23 (FGF23) levels were higher than in controls. Patients with kidney stones carried the 716 T allele more frequently than patients without it (χ2 7.20, p = 0.027). In PHPT patients revaluated at least 2 years after surgery, we observed a significant reduction of 1–25(OH)2VitaminD and FGF23. According to the median of serum phosphate levels, PHPT patients were subdivided into two subgroups: ≤2.8 mg/dL and > 2.8 mg/dL. The lowest phosphate group had a significantly higher serum calcium, PTH, 1–25(OH)2VitaminD, urinary calcium and a higher prevalence of kidney stones than in the highest phosphate group. The rate of males in the lowest phosphate group was significantly higher than in the highest phosphate group. Our study shows that the regulators of phosphate metabolism in PHPT patients are higher than controls and they significantly reduce after surgical cure. PHPT patients with low serum phosphate have a worse biochemical and clinical phenotype.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

CONTEXT:Current evidence of cardiovascular (CV) risk in primary hyperparathyroidism (PHPT) is still inconsistent. OBJECTIVE:To prospectively investigate changes of early atherosclerosis in patients with PHPT undergoing parathyroidectomy (PTx) or conservative management, according to consensus criteria. METHODS:Biochemical parameters of PHPT, CV risk factors (systolic and diastolic blood pressure, cholesterol [total, high-density, and low-density], triglyceride, HbA1c, HOMA-IR), and carotid intima-media thickness (IMT) and plaque were assessed in 52 consecutive postmenopausal PHPT patients both at baseline and ≥ 24 months after surgery (PTx, n = 22) or conservative management (non-PTx, n = 30). RESULTS:At baseline, PTx and non-PTx showed comparable age, BMI, renal function, and 25(OH)D levels, and did not differ for CV risk factors, IMT and plaques, or for prevalence of smoking, diabetes mellitus, or antihypertensive or statin therapy, while all parameters characterizing PHPT differed. Follow-up duration in PTx was longer than in non-PTx (P = .004). Parameters characterizing PHPT significantly improved ≥ 24 months after surgery, whereas in non-PTx serum phosphate slightly decreased and parathyroid hormone increased. Systolic and diastolic blood pressure increased at follow-up in both groups, while other CV risk factors did not significantly vary. In PTx, IMT did not significantly vary after surgery (0.85 ± 0.14 to 0.89 ± 0.22 mm, P = .366), whereas it significantly increased in non-PTx (0.80 ± 0.18 to 0.93 ± 0.23 mm, P = .008), even adjusting for blood pressure. Plaque prevalence and incidence did not significantly differ in the 2 groups. CONCLUSION:Our results suggest that in postmenopausal patients with PHPT, subclinical atherosclerosis could be halted by PTx, whereas it worsens over time in nonoperated patients with milder disease.

Potassium is a cation involved in the resting phase of membrane potential. Diets rich in fresh fruit and vegetables, whole grains, dairy products, and coffee have high potassium content. The shift from a pre-agriculture diet to today’s consumption has led to reduced potassium intake. Indeed, the Western diet pattern is characterized by a high daily intake of saturated fats, sugars, sodium, proteins from red meat, and refined carbohydrates with a low potassium intake. These reductions are also mirrored by high sodium intakes and a high consumption of acid-generating food, which promote a chronic state of low-grade metabolic acidosis. The low-grade metabolic acidosis is a cause of the bone-wasting effect. Therefore, a long-standing acidotic state brings into play the bone that contributes to the buffering process through an increase in osteoclastic resorption. In consideration of this background, we carried out a review that focused on the pathophysiological mechanisms of the relationship between dietary potassium intake and bone health, underlining the detrimental effects of the Western dietary patterns characterized by low potassium consumption.

Context: The risk of vertebral fractures (VFx) in patients with nonfunctioning adrenal incidentalomas (NFAI) is unknown. Objective: This work aimed to assess in NFAI patients the prevalence and incidence of VFx and a hormonal marker to identify patients at risk. Methods: A retrospective, cross-sectional, and longitudinal study of outpatients was conducted. A total of 306 NFAI patients (cross-sectional arm) and 213 controls were evaluated for VFx prevalence; 85 NFAI patients (longitudinal arm, follow-up 30.3 +/- 17.5 months) were evaluated for VFx incidence. Main outcome measures included serum cortisol after 1 mg-dexamethasone test (F-1mgDST), lumbar spinal (LS), and femoral neck (FN) bone mineral density (BMD) and VFx presence, by radiograph of the spine. Results: Cross-sectional arm: prevalent VFx associated with F-1mgDST with a cutoff of 1.2 mu g/dL (33 nmol/L, area under the curve 0.620 +/- 0.39; P = .002). Compared with controls and NFAI patients with F-1mgDST less than 1.2 mu g/dL (group A), NFAI patients with F-1mgDST greater than or equal to 1.2 mu g/dL (group B) showed a higher VFx prevalence (10.8%, 12.6%, and 29.5%, respectively; P < .001 all comparisons), which was associated with F-1mgDST greater than or equal to 1.2 g/dL (odds ratio 3.02; 95% CI, 1.63-5.58; P < .001) accounting to confounders. Longitudinal arm: the VFx incidence was higher in group B than in group A (19.3% vs 3.6%; P = .05). In group B, all incident VFx occurred in patients without low BMD. The F-1mgDST cutoff for predicting an incident VFx was 1.2 g/dL, although statistical significance was not reached after adjustment for confounders (P = .061). Conclusion: In NFAI patients, F-1mgDST levels greater than or equal to 1.2 mu g/L (33 nmol/L) are associated with prevalent VFx and may identify patients at risk of incident VFx.

Over the past few decades, the worldwide incidence of cutaneous melanoma, a malignant neoplasm arising from melanocytes, has been increasing markedly, leading to the highest rate of skin cancer-related deaths. While localized tumors are easily removed by excision surgery, late-stage metastatic melanomas are refractory to treatment and exhibit a poor prognosis. Consequently, unraveling the molecular mechanisms underlying melanoma tumorigenesis and metastasis is crucial for developing novel targeted therapies. We found that the multiple endocrine neoplasia type 1 (MEN1) gene product Menin is required for the transforming growth factor beta (TGFβ) signaling pathway to induce cell growth arrest and apoptosis in vitro and prevent tumorigenesis in vivo in preclinical xenograft models of melanoma. We further identified point mutations in two MEN1 family members affected by melanoma that led to proteasomal degradation of the MEN1 gene product and to a loss of TGFβ signaling. Interestingly, blocking the proteasome degradation pathway using an FDA-approved drug and RNAi targeting could efficiently restore MEN1 expression and TGFβ transcriptional responses. Together, these results provide new potential therapeutic strategies and patient stratification for the treatment of cutaneous melanoma.

Pregnancy and lactation-associated osteoporosis is a rare form of osteoporosis occurring during late pregnancy and early lactation, featuring fragility fractures, primarily involving the vertebral bodies and leading to back pain. Its management involves osteoporosis treatment, complicated by potential drug-related dangerous effects on the fetus. Nevertheless, many controversies remain regarding diagnosis, prognosis, and treatment options. Herein, we propose a multicentric case series to provide a comprehensive neurosurgical, gynecological, and endocrinological perspective on the management of pregnancy and lactation-associated osteoporotic vertebral fractures. A multicenter retrospective study was conducted at the Neurosurgical Department of Università degli Studi di Napoli Federico II, the Neurosurgical Unit of Hopitaux Universitaires de Genève, and the Spine and Spinal Cord Surgery Unit of the University Hospital of Udine, collecting data from January 2014 to December 2022. The study has been approved by the ethical committee of each hospital. N = 11 patients with an overall number of 31 fractures were eligible, with a mean age of 36. N = 5 (16

BACKGROUND:Adrenocorticotropic Hormone (ACTH)-secreting tumors account for 5- 10% of Cushing syndrome cases and are often difficult to diagnose and treat.CASE REPORT:A 44-year-old man presented with arterial hypertension and weight gain. On the physical examination, he exhibited central obesity, abdominal striae rubrae, and facial plethora. Due to the clinical suspicion of Cushing syndrome, the Nugent test and Liddle-1 test were performed, which showed a lack of cortisol suppression. ACTH levels were also high (138 pg/mL), so pituitary MRI and dynamic tests were performed, including the Corticotropin-releasing Hormone (CRH) stimulation test and Liddle-2. MRI showed a 3 mm pituitary microadenoma, but hormonal testing suggested ectopic ACTH production. Chest CT detected a 10-mm nodule in the upper lobe of the right lung, suspicious for a carcinoid tumor. However, the nodule did not exhibit any enhancement on 68-Gallium-DOTATOC PET-CT, and further, 18-FDG PET-CT was inconclusive. In addition, the nodule was deemed non-biopsiable due to its location. Meanwhile, the patient developed osteoporosis, resulting in two vertebral fractures and one rib fracture, which was treated with zoledronate. Furthermore, the patient developed acute aortic insufficiency. During bioprosthetic valve replacement, the thoracic surgeon performed wedge resection of the right upper lung lobe. The histological examination of the lesion revealed a typical lung carcinoid (1.2x0.9 cm, pT1bNXR0, Ki671%, ACTH positive in 95% of neoplastic elements). ACTH levels dropped to 4 pg/mL on the fourth postoperative day.CONCLUSION:ACTH-secreting tumors are particularly challenging diseases. A comprehensive hormonal and instrumental valuation is often required, necessitating a multidisciplinary approach.

AIM:This guideline (GL) is aimed at providing a clinical practice reference for the management of sporadic primary hyperparathyroidism (PHPT) in adults. PHPT management in pregnancy was not considered.METHODS:This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology (AME) and Società Italiana dell'Osteoporosi, del Metabolismo Minerale e delle Malattie dello Scheletro (SIOMMMS) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for the clinical practice recommendations.RESULTS:The present GL provides recommendations about the roles of pharmacological and surgical treatment for the clinical management of sporadic PHPT. Parathyroidectomy is recommended in comparison to surveillance or pharmacologic treatment in any adult (outside of pregnancy) or elderly subject diagnosed with sporadic PHPT who is symptomatic or meets any of the following criteria: • Serum calcium levels >1 mg/dL above the upper limit of normal range. • Urinary calcium levels >4 mg/kg/day. • Osteoporosis disclosed by DXA examination and/or any fragility fracture. • Renal function impairment (eGFR <60 mL/min). • Clinic or silent nephrolithiasis. • Age ≤50 years. Monitoring and treatment of any comorbidity or complication of PHPT at bone, kidney, or cardiovascular level are suggested for patients who do not meet the criteria for surgery or are not operated on for any reason. Sixteen indications for good clinical practice are provided in addition to the recommendations.CONCLUSION:The present GL is directed to endocrinologists and surgeons - working in hospitals, territorial services or private practice - and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

Abstract Disclosure: V. Favero: None. E. Cairoli: None. C. Eller-Vainicher: None. V. Morelli: None. A.S. Salcuni: None. S. Della Casa: None. G. Muscogiuri: None. C. Columbu: None. F. Pugliese: None. S. Corbetta: None. L. Persani: None. A. Scillitani: None. I. Chiodini: None. Context: The risk of vertebral fractures (VFx) in patients with non-functioning adrenal incidentalomas (NFAI) is unknown. Objective: To evaluate the VFx prevalence and incidence in NFAI patients. Design. Cross-sectional and longitudinal study on retrospective data. Setting. Four Italian endocrinology units. Patients. 306 NFAI patients (cross-sectional arm) and 213 matched control subjects to evaluate VFx prevalence; 85 NFAI patients (longitudinal arm, follow-up 30.3±17.5 months) to evaluate VFx incidence. Main outcome measures: serum cortisol after 1 mg-dexamethasone test (F-1mgDST), bone mineral density (BMD) at spine (LS) and femur (FN), and VFx presence by x-ray. Results:. Cross-sectional arm: prevalent VFx was associated with F-1mgDST with the cut-off set at 1.2 µg/dL (33 nmol/L, area under the curve 0.620±0.39, p=0.002). As compared with controls and with NFAI patients with F-1mgDST <1.2 µg/dL (33 nmol/L, Group NFAI-A), NFAI patients with F-1mgDST ≥1.2 µg/dL (33 nmol/L, Group NFAI-B) showed higher VFx prevalence (10.8%, 12.6% and 29.5%, respectively, p<0.001 for all comparisons), which was independently associated with F-1mgDST ≥1.2 µg/dL (33 nmol/L, odds ratio 3.02, 95% confidence interval 1.63-5.58, p<0.001) regardless for influencing factors including BMD. Longitudinal arm: the VFx incidence was higher in Group NFAI-B than in Group NFAI-A (19.3% vs 3.6%, p=0.05). In NFAI-B group, all incident VFx occurred in patients without low BMD. The F-1mgDST cut-off for predicting an incident VFx was 1.2 µg/dL (33 nmol/L), but the incident VFx was not independently predicted by F-1mgDST ≥1.2 µg/dL (33 nmol/L) after adjusting for possible influencing factors, including BMD and presence of prevalent VFx. Conclusions: In NFAI patients, F-1mgDST levels ≥1.2 µg/L (33 nmol/L) are associated with prevalent VFx and may identify NFAI patients at higher risk of incident VFx Presentation: 6/3/2024

CONTEXT:The risk of vertebral fractures (VFx) in patients with adrenal incidentalomas (AI) and mild autonomous cortisol secretion (MACS) is debated. OBJECTIVE:To evaluate the VFx prevalence and incidence in patients with AI and MACS. METHODS:This cross-sectional and longitudinal study using retrospective data from 4 Italian endocrinology units included 444 patients (cross-sectional arm) and 126 patients (longitudinal arm, 24.9 ± 5.3 months follow-up) to evaluate prevalent and incident VFx, respectively, in patients with MACS (MACS-yes) and without MACS (MACS-no). The main outcome measures were serum cortisol after a 1-mg dexamethasone test (F-1mgDST), bone mineral density (BMD) by dual-energy x-ray absorptiometry at spine (LS) and femur (FN), and VFx presence by x-ray. RESULTS:Cross-sectional arm: 214 and 230 patients were MACS-yes and MACS-no, respectively, based on F-1mgDST >1.8 µg/dL (50 nmol/L). Patients with MACS had higher VFx prevalence (62.6%) than those without MACS (22.9%, P < .001); MACS was associated with prevalent VFx (odds ratio, 5.203; 95% CI, 3.361-8.055; P < .001; relative risk [RR] 2.07), regardless of age, body mass index, gender distribution, LS-BMD, and presence of type 2 diabetes mellitus (T2D). Longitudinal arm: 66 and 60 patients were MACS-no and MACS-yes, respectively. Patients without MACS showed higher number of incident VFx (36.4%) than patients without MACS (10.0%, P < .001); MACS was associated with the presence of an incident VFx (RR 4.561; 95% CI, 1.600-13.003; P = .005) regardless of age, LS-BMD, gender distribution, presence of prevalent VFx, and T2D. Results were confirmed in women and men when separately evaluated. CONCLUSION:Women and men with AI and MACS are at higher risk of VFx.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

IntroductionHypophosphatasia (HPP) is a rare genetic disease caused by inactivating variants of the ALPL gene. Few data are available on the clinical presentation in Italy and/or on Italian HPP surveys. MethodsThere were 30 suspected HPP patients recruited from different Italian tertiary cares. Biological samples and related clinical, biochemical, and anamnestic data were collected and the ALPL gene sequenced. Search for large genomic deletions at the ALPL locus (1p36) was done. Phylogenetic conservation and modeling were applied to infer the effect of the variants on the protein structure. ResultsThere were 21 ALPL variants and one large genomic deletion found in 20 out of 30 patients. Unexpectedly, NGS-driven differential diagnosis allowed uncovering three hidden additional HPP cases, for a total of 33 HPP subjects. Eight out of 24 coding variants were novel and classified as "pathogenic", "likely pathogenic", and "variants of uncertain significance". Bioinformatic analysis confirmed that all the variants strongly destabilize the homodimer structure. There were 10 cases with low ALP and high VitB6 that resulted negative to genetic testing, whereas two positive cases have an unexpected normal ALP value. No association was evident with other biochemical/clinical parameters. DiscussionWe present the survey of HPP Italian patients with the highest ALPL mutation rate so far reported and confirm the complexity of a prompt recognition of the syndrome, mostly for HPP in adults. Low ALP and high VitB6 values are mandatory for the genetic screening, this latter remaining the gold standard not only to confirm the clinical diagnosis but also to make differential diagnosis, to identify carriers, to avoid likely dangerous therapy in unrecognized cases.