Clinical and molecular description of the first Italian cohort of 33 subjects with hypophosphatasia Luigia Cinque, Flavia Pugliese, Antonio Stefano Salcuni, Domenico Trombetta, Claudia Battista, et al. Frontiers in Endocrinology, 2023 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.
Italian Association of Clinical Endocrinologists (AME) and International Chapter of Clinical Endocrinology (ICCE). Position statement for clinical practice: prolactin-secreting tumors Renato Cozzi, Maria Rosaria Ambrosio, Roberto Attanasio, Claudia Battista, Alessandro Bozzao, et al. European Journal of Endocrinology, 2022 Prolactinomas are the most frequent pituitary adenomas. Prolactinoma may occur in different clinical settings and always require an individually tailored approach. This is the reason why a panel of Italian neuroendocrine experts was charged with the task to provide indications for the diagnostic and therapeutic approaches that can be easily applied in different contexts. The document provides 15 recommendations for diagnosis and 54 recommendations for treatment, issued according to the GRADE system. The level of agreement among panel members was formally evaluated by RAND-UCLA methodology. In the last century, prolactinomas represented the paradigm of pituitary tumors for which the development of highly effective drugs obtained the best results, allowing to avoid neurosurgery in most cases. The impressive improvement of neurosurgical endoscopic techniques allows a far better definition of the tumoral tissue during surgery and the remission of endocrine symptoms in many patients with pituitary tumors. Consequently, this refinement of neurosurgery is changing the therapeutic strategy in prolactinomas, allowing the definitive cure of some patients with permanent discontinuation of medical therapy.
Prevalence of less severe hypercortisolism in fractured patients admitted in an outpatient clinic for metabolic bone diseases F. Pugliese, A. S. Salcuni, C. Battista, V. Carnevale, G. Guglielmi, et al. Endocrine, 2021 To evaluate the prevalence of less severe hypercortisolism (LSH) in fractured patients, and its association with hypertension, hyperglicemia, dyslipidemia, and obesity. From July 2015 to October 2018 we enrolled all fractured patients admitted in our outpatient center for metabolic bone diseases, after exclusion of patients with secondary osteoporosis apart from diabetes and taking drugs known to affect bone metabolism. In all enrolled patients we collected data regarding gonadal status, history of diabetes, high blood pressure, dyslipidemia, and measured blood pressure, lipid profile, fasting glycaemia. Bone mass was measured with DXA at lumbar spine and femoral neck and the presence of fractures was evaluated with X-ray of thoracic and lumbar spine. All patients performed twice, 1 mg overnight dexametasone suppression test (DST) and, as confirmatory, 2day low-dose DST for diagnosing hypercortisolism. We enrolled 101 fractured patients (75 females, 26 males), aged 65 ± 10.3 years. Five out of 101 (5.0%) patients were diagnosed as LSH. Fifty-five (54.5%) out of 101 were hypertensive, 57 (56.4%) dyslipidemic, 17 (16.8%) hyperglicaemic, 28(27.7%) obese patients. LSH tended to be associated to blood hypertension [5/5 vs 50/96 (Fisher exact test, p = 0.06) hypertensive patients]. Four out five LSH patients were hypogonadic. Our study confirms that a nonnegligible percentage of fractured subjects actually presents an unrecognized hypercortisolism. Accordingly, regardless of age, we suggest to screen for hypercortisolism all patients with established osteoporosis and in particular hypertensive subjects.
Treatment of acromegalic osteopathy in real-life clinical practice: The BAAC (bone active drugs in acromegaly) study Gherardo Mazziotti, Claudia Battista, Filippo Maffezzoni, Sabrina Chiloiro, Emanuele Ferrante, et al. Journal of Clinical Endocrinology and Metabolism, 2020 Background Vertebral fractures (VFs) are a frequent complication of acromegaly, but no studies have been so far published on effectiveness of antiosteoporotic drugs in this clinical setting. Objective To evaluate whether in real-life clinical practice bone active drugs may reduce the risk of VFs in patients with active or controlled acromegaly. Study design Retrospective, longitudinal study including 9 tertiary care endocrine units. Patients and Methods Two hundred and forty-eight patients with acromegaly (104 males; mean age 56.00 ± 13.60 years) were evaluated for prevalent and incident VFs by quantitative morphometric approach. Bone active agents were used in 52 patients (20.97%) and the median period of follow-up was 48 months (range 12-132). Results During the follow-up, 65 patients (26.21%) developed incident VFs in relationship with pre-existing VFs (odds ratio [OR] 3.75; P < .001), duration of active acromegaly (OR 1.01; P = .04), active acromegaly at the study entry (OR 2.48; P = .007), and treated hypoadrenalism (OR 2.50; P = .005). In the entire population, treatment with bone active drugs did not have a significant effect on incident VFs (P = .82). However, in a sensitive analysis restricted to patients with active acromegaly at study entry (111 cases), treatment with bone active drugs was associated with a lower risk of incident VFs (OR 0.11; P = .004), independently of prevalent VFs (OR 7.65; P < .001) and treated hypoadrenalism (OR 3.86; P = .007). Conclusions Bone active drugs may prevent VFs in patients with active acromegaly.
Rare Somatic MEN1 Gene Pathogenic Variant in a Patient Affected by Atypical Parathyroid Adenoma Luigia Cinque, Flavia Pugliese, Celeste Clemente, Stefano Castellana, Maria Pia Leone, et al. International Journal of Endocrinology, 2020 Objective. Atypical parathyroid adenoma is a rare neoplasm, showing atypical histological features intermediate between classic benign adenoma and the rarest parathyroid carcinoma, whose the clinical behaviour and outcome is not yet understood or predictable. Up to date only two cases of atypical adenoma were found associated to a MEN1 syndrome, and only one was proved to carry a pathogenic variant of the MEN1 gene. Design. We report the clinical, histologic, and molecular findings of a 44-year-old woman, presenting with a histologically proved atypical parathyroid adenoma with an apparent aggressive behaviour. Methods and Results. CDC73 gene was screened at germline and somatic levels with no results. Whole exome sequencing performed on DNA extracted from blood leukocytes and tumour tissue revealed a somatic MEN1 gene heterozygous variant, c.912+1G > A, of the splicing donor site of exon 6. On immunohistochemistry, downregulation of the menin protein expression in the neoplastic cells was also observed. Conclusions. We report the second case of a rare association of a somatic MEN1 gene mutation in a patient with atypical parathyroid adenoma. We suggest that MEN1 gene could be an underestimate genetic determinant of these rare histological entities, and we highlight the utility of a complete genetic screening protocol, by the use of next-generation sequencing technology in such undetermined clinical cases with no frank clinical presentation.
Adrenal function and skeletal regulation Iacopo Chiodini, Claudia Battista, Elisa Cairoli, Cristina Eller-Vainicher, Valentina Morelli, et al. Multidisciplinary Approach to Osteoporosis from Assessment to Treatment, 2018 The hormones produced by the adrenal gland have important effects on the bone both in physiological and pathological conditions. The role of cortisol secretion on the bone physiology during growth is not fully understood. During the adult life, the degree of the cortisol secretion, still in the normal range, seems to directly correlate with the bone mineral density in elderly individuals and in osteoporotic women. The overt and subclinical cortisol excess leads to an increased risk of fracture partially independent of the bone mineral density reduction and possibly related to a reduced bone quality. The individual sensitivity to cortisol due to the different polymorphisms of the glucocorticoid receptor (GR) or of the 11β-hydroxysteroid dehydrogenase may modulate the effect of glucocorticoids (GCs) on the bone, thus explaining, at least in part, the wide interindividual variability of the skeletal consequences of the hypercortisolism. The adrenal androgens excess in congenital adrenal hyperplasia (CAH) importantly affects the bone, leading not only to an early growth acceleration but to a reduction in the final adult height. On the other hand, the reduction of the adrenal androgens during aging has been considered among the pathophysiological mechanisms of the osteoporosis in the elderly, but the effects of the restoration of the androgen levels in the aging-related osteoporosis are conflicting. Finally, the presence of mineralocorticoid receptors has been demonstrated in osteoblast, osteoclast, and osteocyte, and an association exists between indexes of bone strength and some genes involved in aldosterone pathways. In keeping, the condition of hyperaldosteronism has been associated with an increased fracture risk.
Primary aldosteronism as a cause of secondary osteoporosis Antonio Stefano Salcuni, Vincenzo Carnevale, Claudia Battista, Serena Palmieri, Cristina Eller-Vainicher, et al. European Journal of Endocrinology, 2017 Objective Patients with primary aldosteronism (PA) have a high prevalence of osteoporosis (OP) and fractures (Fx). We evaluated the presence of PA in patients admitted to our metabolic bone disease outpatient clinic. Design Study conducted on an in- and outpatient basis in a referral Italian endocrinology unit. Methods A total of 2632 patients were evaluated. 2310 were excluded because they were taking drugs known to affect bone or mineralocorticoids metabolism or were diagnosed to have a secondary cause of osteoporosis. The remaining 322 subjects (304 females, 18 males) took part in the study. Bone mineral density (BMD) and thoracic and lumbar spine vertebral morphometry were performed by dual X-ray absorptiometry. All patients were screened for PA with aldosterone-to-renin ratio. In those who had positive results, confirmatory tests were performed. Results Among 322 subjects, 213 were osteoporotics and 109 were not. PA was diagnosed in eleven out of 213 osteoporotic patients (5.2%) and one out of 109 non-osteoporotic subjects (0.9%, P = 0.066). PA was observed in the 26.1% of patients with the concomitant presence of osteoporosis, hypertension and hypercalciuria. Compared with patients without PA, patients with PA had mean values of urinary calcium excretion, 4.8 ± 2.5 mmol/day vs 7.6 ± 3.2 mmol/day, P < 0.001 and serum PTH levels, 5.4 pmol/L vs 7.3 pmol/L, P < 0.01, significantly higher. Conclusions PA should be considered among the causes of secondary OP.
MEN1 gene mutation with parathyroid carcinoma: First report of a familial case Luigia Cinque, Angelo Sparaneo, Antonio S Salcuni, Danilo de Martino, Claudia Battista, et al. Endocrine Connections, 2017 Background The occurrence of parathyroid carcinoma in multiple endocrine neoplasia type I (MENI) is rare and the 15 cases of malignant parathyroid tumor reported so far have been associated with MENI in individuals and not with multiple members within a family. Methods We report on a 61-year-old male, operated for a 7.3 cm parathyroid carcinoma infiltrating the esophagus. In his brother, a 4.6 cm parathyroid carcinoma was diagnosed histologically, while in the daughter, neck ultrasonography revealed 2 extrathyroidal nodules, yet to be excised. Results Screening of the MEN1 gene identified a known germline heterozygous missense mutation (c.1252G>A; p.D418N) in exon 9, in all affected subjects. Conclusions The occurrence of parathyroid carcinoma in more than one affected member of a single MEN1 family represents the first reported familial case. This suggests that additional constitutional genetic mutations may contribute to the variation in malignant potential and clinical behavior of parathyroid tumors in MEN1.
Bone involvement in aldosteronism Antonio Stefano Salcuni, Serena Palmieri, Vincenzo Carnevale, Valentina Morelli, Claudia Battista, et al. Journal of Bone and Mineral Research, 2012
