RESUMEN
Introduction: Hypophosphatasia (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. Methods: There 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. Results: There 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. Discussion: We 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.
Asunto(s)
Hipofosfatasia , Adulto , Humanos , Hipofosfatasia/diagnóstico , Hipofosfatasia/epidemiología , Hipofosfatasia/genética , Filogenia , Biología Computacional , Diagnóstico Diferencial , Italia/epidemiología , Enfermedades RarasRESUMEN
BACKGROUND: Autosomal dominant hypocalcemia (ADH) is an endocrine disorder caused by activating mutations of the calcium-sensing receptor (CASR) gene which plays a major role in maintaining calcium homeostasis. Biochemical features of ADH are hypocalcemia and hypercalciuria with inappropriately low levels of parathyroid hormone (PTH). We report on two four-generation families affected by ADH. AIM: To identify mutations of CASR gene in subjects affected by familial idiopathic hypoparathyroidism. To perform functional assays of identified CASR variants by transient transfection on HEK293 cells. RESULTS: We identified two CASR variants (Q681R and P221L): the Q681R variant was novel while the P221L had been previously published. Functional assays on the Q681R variant showed that it did not alter the whole expression nor the correct plasmamembrane localization, but enhanced the signaling function, increasing the sensitivity of the receptor as compared to the WT. CONCLUSIONS: We report two activating CASR mutations in two families affected by ADH and the functional assays performed on the novel variant Q681R. Our work enlarged the spectrum of mutations of the CASR and contributed to a better elucidation of the protein function.
Asunto(s)
Calcio/metabolismo , Hipercalciuria/genética , Hipocalcemia/genética , Hipoparatiroidismo/congénito , Hipoparatiroidismo/genética , Hormona Paratiroidea/deficiencia , Receptores Sensibles al Calcio/genética , Adulto , Anciano , Señalización del Calcio , Análisis Mutacional de ADN , Femenino , Células HEK293 , Homeostasis , Humanos , Hipercalciuria/metabolismo , Hipocalcemia/metabolismo , Hipoparatiroidismo/metabolismo , Mutación , Linaje , Receptores Sensibles al Calcio/metabolismo , TransfecciónRESUMEN
Clinical pathways (CPs) are multidisciplinary clinical governance tools necessary for the care management of the patients, whose aim is to outline the best practicable path within a health organization related to an illness or to a complex clinical situation. The COVID-19 pandemic emergency has created the need for an organizational renewal of care pathways based on the principles of "primary health care" recommended by the WHO. In Italy, the Hospitals and Local Health Authorities (ASL) have tried to guarantee the continuity of non-deferrable treatments and the maximum safety of both patients and health professionals. This study analyzes the organizational and managerial responses adopted in pathology-specific care pathways to assess how CPs as diagnostic tools responded to the COVID-19 pandemic in the first two waves. Twenty-four referents of Operational Units (UU OO) from Hospitals (AO) and Local Health Authorities (ASL) of the Lazio Region (Central Italy) that apply four different CPs responded to a survey, which analyzes the managerial and organizational responses of CPs in regard to different contexts. Results show that the structural and organizational adjustments of the CPs have made it possible to maintain an adequate level of care for specific treatment processes, with some common critical aspects that require improvement actions. The adjustments found could be useful for dealing with new outbreaks and/or new epidemics in order to try to mitigate the potential negative impact, especially on the most vulnerable patient categories.
Asunto(s)
COVID-19 , Vías Clínicas , Humanos , Italia/epidemiología , Pandemias , SARS-CoV-2RESUMEN
BACKGROUND: It is a well-known fact that the information obtained from a survey can be used in a healthcare organizational analysis; however, it is very difficult to compare the different results found in the literature to each other, even through the use of metanalysis, as the methodology is often not consistent. METHODS: Data from a survey analyzing the organizational and managerial responses adopted in pathology-specific clinical pathways (CPs) during the first two waves of the COVID-19 pandemic were used for constructing a decisional matrix, a tool called SPRIS system, consisting of four different sheets. The first sheet reports the results of the survey and, using a streetlight color system, identifies strengths and weaknesses; the second one, by assigning a priority score, establishes the priority of intervention on each of the strengths and weaknesses identified; the third sheet reports the subjective items of the questionnaire in order to identify threats and opportunities and their probability of happening; in the last sheet, a SWOT Analysis is used to calculate the performance index of the whole organization. RESULTS: The SPRIS system, applied to data concerning the adaptation of four CPs to the COVID-19 pandemic, showed that, whereas all the CPs had a good performance index, some concerns remained unsolved and need be addressed. CONCLUSIONS: The SPRIS system showed to be an easily constructed tool that is able to give an overview of the organization analyzed by the survey and to produce an index that can be used in a direct quality comparison between different services or organizations.
Asunto(s)
COVID-19 , Planificación Estratégica , COVID-19/epidemiología , Vías Clínicas , Atención a la Salud , Humanos , Pandemias , Encuestas y CuestionariosRESUMEN
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.
Asunto(s)
Neoplasias Hipofisarias/diagnóstico , Neoplasias Hipofisarias/terapia , Prolactinoma/diagnóstico , Prolactinoma/terapia , Niño , Consenso , Dopaminérgicos/efectos adversos , Dopaminérgicos/uso terapéutico , Endocrinología , Medicina Basada en la Evidencia , Femenino , Humanos , Hiperprolactinemia/etiología , Hiperprolactinemia/terapia , Italia , Masculino , Procedimientos Neuroquirúrgicos/métodos , Neoplasias Hipofisarias/etiología , Embarazo , Prolactinoma/etiología , RadioterapiaRESUMEN
Normocalcemic primary hyperparathyroidism (NPHPT) is diagnosed in the setting of elevated PTH concentrations with consistently normal albumin-adjusted and ionized serum calcium levels, in absence of secondary causes for elevated PTH concentrations. In order to confirm persistence of the hyperparathyroid state, PTH levels should be elevated on at least two occasions over a 3 to 6 months period. The prevalence of NPHPT depends on the population studied. Data from different studies are often not comparable; indeed, different criteria have been used to exclude secondary hyperparathyroidism. Notwithstanding such limits, the prevalence of NPHPT in studies including ionized calcium dosage was between 0.5% and 0.7%. Available data suggest that patients with NPHPT are likely to have more skeletal, kidney and metabolic complications compared to healthy subjects, but almost all studies suffer from possible misclassification of patients due to lack of ionized calcium dosage. The management of NPHPT is controversial in part due to lack of solid data about the natural history. However, surgical treatment is currently performed more frequently than in the past, although studies do not show, so far, a clear benefit from intervention.
Asunto(s)
Hiperparatiroidismo Primario , Hiperparatiroidismo Secundario , Calcio , Humanos , Hiperparatiroidismo Primario/diagnóstico , Hormona Paratiroidea , PrevalenciaRESUMEN
The aim of the study was to investigate the relationship between quantitative ultrasound (QUS) parameters extracted from the analysis of the ultrasound (US) signal and the geometric properties of the bones. One hundred and one subjects in the age range of 20-7 4yr (mean: 52+/-12 yr) have been measured by QUS at the phalanges for the evaluation of amplitude-dependent speed of sound (AD-SoS), bone transmission time (BTT), US peak amplitude (UPA), signal dynamic (SDY), slope, energy, and fast wave amplitude (FWA). Hand radiograph, lumbar spine dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT), and femoral neck DXA forearm peripheral QCT were performed on all patients. BTT is related to cortical thickness (CTh) (r=0.62, p<0.0001), and FWA is related to medullary canal thickness (r=-0.64, p<0.0001). Other parameters are related to both medullary canal thickness (AD-SoS: r=-0.21; UPA: r=-0.53; SDY: r=-0.56; slope: r=-0.64; energy: r=-0.44, p<0.05) and CTh (AD-SoS: r=0.54, p<0.0001; UPA: r=0.51; SDY: r=0.38; slope: r=0.32; energy: r=0.56, p<0.001). Linear multivariate models indicate that BTT, UPA, and energy measured at the phalanges carry independent information on CTh of the bone, whereas FWA, SDY, and slope are related only to medullary canal thickness.
Asunto(s)
Densidad Ósea , Falanges de los Dedos de la Mano/diagnóstico por imagen , Osteoporosis/diagnóstico , Absorciometría de Fotón , Adulto , Anciano , Femenino , Fémur , Humanos , Imagenología Tridimensional , Modelos Lineales , Vértebras Lumbares , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Tomografía Computarizada por Rayos X , Ultrasonografía , Adulto JovenRESUMEN
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.
RESUMEN
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 56.00â ±â 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; Pâ <â .001), duration of active acromegaly (OR 1.01; Pâ =â .04), active acromegaly at the study entry (OR 2.48; Pâ =â .007), and treated hypoadrenalism (OR 2.50; Pâ =â .005). In the entire population, treatment with bone active drugs did not have a significant effect on incident VFs (Pâ =â .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; Pâ =â .004), independently of prevalent VFs (OR 7.65; Pâ <â .001) and treated hypoadrenalism (OR 3.86; Pâ =â .007). CONCLUSIONS: Bone active drugs may prevent VFs in patients with active acromegaly.
Asunto(s)
Acromegalia/tratamiento farmacológico , Conservadores de la Densidad Ósea/uso terapéutico , Enfermedades Óseas/tratamiento farmacológico , Fracturas de la Columna Vertebral/prevención & control , Acromegalia/complicaciones , Acromegalia/epidemiología , Adulto , Anciano , Densidad Ósea/efectos de los fármacos , Enfermedades Óseas/epidemiología , Enfermedades Óseas/etiología , Femenino , Humanos , Italia/epidemiología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pautas de la Práctica en Medicina/estadística & datos numéricos , Estudios Retrospectivos , Fracturas de la Columna Vertebral/epidemiologíaRESUMEN
OBJECTIVE: Data on trabecular bone mass in acromegaly are controversial. All the studies are cross-sectional and bone mineral density (BMD) has been evaluated largely by dual X-ray absorptiometry (DXA), which is influenced by bone enlargement. In this study we assessed in acromegalic patients the effects overtime of GH excess on trabecular bone mass measured by single-energy quantitative computed tomography (QCT) which is not influenced by bone size. DESIGN: Longitudinal retrospective study. PATIENTS: A total of 46 acromegalic patients followed-up for 48 months (median), subdivided into four groups: group A (eugonadal patients with active disease: n = 13), group B (hypogonadal patients with active disease; n = 9), group C (eugonadal patients with controlled disease; n = 10), group D (hypogonadal patients with controlled disease; n = 14). MEASUREMENTS: Serum GH and IGF-I levels, spinal trabecular BMD, and vertebral fractures were evaluated in all patients. BMD variations were reported as change (Delta) in Z-values (Z-QCT) measured at baseline and end of follow-up per year (Delta Z-QCT). RESULTS: Delta Z-QCT was greater in group A vs. group B and D (P =0.002 and P = 0.0001, respectively) and in group C vs. group D (P =0.009). Multivariate regression analysis showed that hypogonadal status (beta = -0.69; P = 0.001) and baseline duration of hypogonadism (beta = 0.44; P = 0.02) but not baseline duration of acromegaly, length of follow-up and disease activity, were significantly associated with Delta Z-QCT. CONCLUSIONS: This longitudinal study suggests that the effect of chronic GH excess on spinal trabecular bone mass seems to be anabolic in active eugonadal patients but not in hypogonadal ones.
Asunto(s)
Acromegalia/patología , Acromegalia/fisiopatología , Densidad Ósea/fisiología , Columna Vertebral/patología , Columna Vertebral/fisiopatología , Absorciometría de Fotón , Acromegalia/tratamiento farmacológico , Adulto , Anciano , Densidad Ósea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Hormona del Crecimiento/sangre , Hormona del Crecimiento/farmacología , Hormona del Crecimiento/uso terapéutico , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios RetrospectivosRESUMEN
OBJECTIVE: Subclinical hypercortisolism (SH) is suggested to exert a deleterious effect on bone. This effect and the role of gonadal status in male subjects are not fully elucidated. We evaluated bone mineral density (BMD) and prevalence of vertebral fractures in eugonadal male subjects with adrenal incidentalomas (AI) and without SH. DESIGN: This 12-month observational multicentre study was performed between January and December 2006 on inpatient basis in three referral Italian centres. PATIENTS: Eighty-eight consecutive eugonadal male patients with AI and 90 matched control subjects were studied. MEASUREMENTS: All subjects underwent the determination of BMD by dual-energy X-ray absorptiometry at lumbar spine (LS) and femoral neck (FN), and spinal radiograph. In AI patients SH was diagnosed in the presence of two of the following: urinary free cortisol > 193.1 nmol/l, cortisol after 1 mg dexamethasone suppression test > 82.8 nmol/l, ACTH levels < 2.2 pmol/l. RESULTS: As compared to patients without SH (SH-, n = 66) and controls, patients with SH (SH+, n = 22) had lower BMD at LS (Z-score: SH+, -1.04 +/- 1.84; SH-, 0.19 +/- 1.34, Controls 0.20 +/- 1.28, P = 0.001 and FN (Z-score: SH+, -0.63 +/- 1.01; SH-, 0.01 +/- 1.01, Controls 0.26 +/- 1.06, P = 0.002) and higher prevalence of fractures (SH+, 72.7%; SH-, 21.2%, Controls 20.0%, P = 0.0001). Multivariable analyses showed that SH was associated to BMD at LS (beta = -0.378, P = 0.0001) and vertebral fractures (OR = 7.81, 95% CI 1.96-31.17, P = 0.004). CONCLUSION: In eugonadal male patients with AI, SH is associated with low BMD and high prevalence of vertebral fractures.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/complicaciones , Adenoma Corticosuprarrenal/complicaciones , Síndrome de Cushing/complicaciones , Hallazgos Incidentales , Vértebras Lumbares/lesiones , Fracturas de la Columna Vertebral/epidemiología , Neoplasias de la Corteza Suprarrenal/fisiopatología , Adenoma Corticosuprarrenal/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Densidad Ósea/fisiología , Estudios de Casos y Controles , Síndrome de Cushing/fisiopatología , Fracturas del Cuello Femoral/epidemiología , Humanos , Hidrocortisona/metabolismo , Italia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Prevalencia , Factores de Riesgo , Testículo/fisiopatologíaRESUMEN
BACKGROUND: Hypercortisolism is known to cause osteoporosis. OBJECTIVE: To evaluate the prevalence of subclinical hypercortisolism in participants referred for evaluation of osteoporosis. DESIGN: Cross-sectional study. SETTING: Two community hospitals and research institutes in Italy. PATIENTS: 219 patients without clinically overt hypercortisolism or other secondary causes of osteoporosis who were referred for evaluation of osteoporosis between January 2005 and December 2005. MEASUREMENTS: Bone mineral density was measured by using dual-energy x-ray absorptiometry, and hypercortisolism was assessed with serum cortisol levels after a dexamethasone suppression test. Also measured were 24-hour urinary free cortisol levels and midnight plasma cortisol levels. RESULTS: Seven of 65 patients with T-scores of 2.5 or less and vertebral fractures had subclinical hypercortisolism (prevalence, 10.8% [95% CI, 3.23% to 18.31%]). This prevalence was 4.8% (CI, 1.32% to 8.20%) among patients with osteoporosis. In multivariable analyses adjusted for age, sex, and body mass index, a positive dexamethasone suppression test result was associated with the presence of osteoporosis (odds ratio, 3.37 [CI, 1.78 to 6.43]; P < 0.001) and vertebral fractures (odds ratio, 1.70 [CI, 1.04 to 2.79]; P = 0.035). LIMITATIONS: The study was conducted in a referral setting; its findings may not apply to the general population. CONCLUSIONS: Subclinical hypercortisolism may be more common than is generally recognized in patients with osteoporosis in whom secondary causes of osteoporosis have been excluded.
Asunto(s)
Hiperfunción de las Glándulas Suprarrenales/complicaciones , Osteoporosis/complicaciones , Hiperfunción de las Glándulas Suprarrenales/diagnóstico , Hiperfunción de las Glándulas Suprarrenales/epidemiología , Anciano , Densidad Ósea , Estudios Transversales , Dexametasona , Femenino , Humanos , Hidrocortisona/sangre , Hidrocortisona/orina , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Osteoporosis/etiología , Pruebas de Función Adreno-Hipofisaria , Prevalencia , Factores de Riesgo , Fracturas de la Columna Vertebral/etiologíaRESUMEN
INTRODUCTION: Three single-nucleotide polymorphisms in the calcium-sensing receptor gene (CASR) encoding the missense substitutions A986S, R990G, and Q1011E have been associated with normal variation in extracellular calcium homeostasis, both individually and in haplotype combination. The aim of this study was to examine haplotype associations in primary hyperparathyroidism (PHPT). PATIENTS AND METHODS: Patients with sporadic PHPT (n = 237) were recruited from endocrine clinics and healthy controls (n = 433) from a blood donor clinic, and levels of serum calcium, albumin, and PTH were measured. In PHPT patients, urinary calcium/creatinine clearances and bone mineral density at spine and femoral neck were measured and the presence of kidney stones and vertebral fractures identified. The CASR single-nucleotide polymorphisms were haplotyped by allele-specific sequencing. RESULTS: Four haplotypes (ARQ, SRQ, AGQ, and ARE) of eight were observed, in keeping with significant linkage disequilibrium, but haplotype frequencies did not show significant Hardy-Weinberg disequilibrium. The SRQ haplotype was more common in PHPT (125 of 474 alleles) than in controls (170 of 866 alleles, P = 0.006) and showed a significant (P = 0.006) gene-dosage effect. There was no significant association between haplotype and bone mineral density or fractures, but association with kidney stones was significant (P = 0.0007). In the stone-forming subgroup, the SRQ haplotype was underrepresented and AGQ overrepresented. Patients bearing the AGQ haplotype had an odds ratio of 3.8 (95% confidence interval, 1.30-11.3) for presentation with renal stones compared with the rest. CONCLUSION: Our data indicate that the CASR SRQ haplotype is significantly associated with PHPT in our population. Within the PHPT patient population, the AGQ haplotype is significantly associated with kidney stones.
Asunto(s)
Haplotipos , Hiperparatiroidismo Primario/genética , Cálculos Renales/genética , Receptores Sensibles al Calcio/genética , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de RegresiónRESUMEN
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.
Asunto(s)
Hiperaldosteronismo/complicaciones , Hiperaldosteronismo/diagnóstico por imagen , Osteoporosis/diagnóstico por imagen , Osteoporosis/etiología , Absorciometría de Fotón/métodos , Anciano , Estudios Transversales , Femenino , Fracturas Óseas/diagnóstico por imagen , Fracturas Óseas/etiología , Humanos , Masculino , Persona de Mediana Edad , Admisión del Paciente/tendenciasRESUMEN
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.
RESUMEN
Primary hyperparathyroidism (PHPT) is associated with hypovitaminosis D as assessed by serum total 25-hydroxyvitamin D (TotalD) levels. The aim of this study is to evaluate whether this is also the case for the calculated bioavailable 25-hydroxyvitamin D (BioD) or free 25-hydroxyvitamin D (FreeD), and whether the vitamin D status is influenced by genetic background. We compared vitamin D status of 88 PHPT patients each with a matched healthy family member sharing genetic background, i.e., first-degree relative (FDR), or not, namely an in-law relative (ILR). We compared TotalD and vitamin D-binding protein (DBP), using the latter to calculate BioD and FreeD. We also genotyped two common DBP polymorphisms (rs7041 and rs4588) likely to affect the affinity for and levels of vitamin D metabolites. TotalD was lower (p < 0.001) in PHPT (12.3 ± 6.6 ng/mL) than either family member group (FDR: 19.4 ± 12.1 and ILR: 23.2 ± 14.1), whether adjusted for DBP or not. DBP levels were also significantly lower (p < 0.001) in PHPT (323 ± 73 mg/L) versus FDR (377 ± 98) or ILR (382 ± 101). The differences between PHPT and control groups for TotalD, BioD, and FreeD were maintained after adjustment for season, gender, and serum creatinine. 25-hydroxyvitamin D, evaluated as total, free, or bioavailable fractions, is decreased in PHPT. No difference was seen between first-degree relative and in-law controls, suggesting that neither genetic nor non-genetic background greatly influences the genesis of the hypovitaminosis D seen in PHPT.
Asunto(s)
Familia , Hiperparatiroidismo Primario/genética , Polimorfismo de Nucleótido Simple , Deficiencia de Vitamina D/genética , Proteína de Unión a Vitamina D/genética , Vitamina D/análogos & derivados , Adulto , Anciano , Femenino , Humanos , Hiperparatiroidismo Primario/sangre , Hiperparatiroidismo Primario/complicaciones , Masculino , Persona de Mediana Edad , Estaciones del Año , Factores Sexuales , Vitamina D/sangre , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/complicacionesRESUMEN
Inactivating mutations of the multiple endocrine neoplasia 1 (MEN1) gene cause MEN1 syndrome, characterized by primary hyperparathyroidism (pHPT), and parathyroid and gastro-entero-pancreatic pituitary tumors. At present, only 14 cases of malignant parathyroid tumor have been associated with the syndrome, with 6 cases carrying an inactivating mutation of the MEN1 gene. The present study presents the case of a 48-year-old female who presented with multigland pHPT and multiple pancreatic lesions. The patient underwent surgery several times for the excision of parathyroid hyperplasia, carcinoma and adenoma. The MEN1 gene was screened, revealing three variants (in cis) at the intron/exon 3 boundary (IVS2-3G>C, c.497A>T and c.499G>T) detected on the DNA of the proband, not shared by her relatives. RNA sequencing revealed that the IVS2-3C>G variant caused the skipping of the exon 3. Therefore, the present study reports on a novel rare association of MEN1 syndrome and parathyroid carcinoma. The reported splicing mutation was previously identified in subjects who always developed malignant lesions; thus, a possible genotype-phenotype association may be considered.
RESUMEN
CONTEXT: Mutations of the HRPT2 gene have recently been implicated in the development of parathyroid carcinoma. OBJECTIVE: The objective of this study was early diagnosis of parathyroid tumor in a family with germline HRPT2 mutation. PATIENTS, METHODS, AND RESULTS: In a 40-yr-old male previously treated for parathyroid atypical adenoma, we screened the 17 translated HRPT2 exons and their exon-intron boundaries and found a germline frameshift mutation in exon 7 (685delAGAG) predicting a premature stop codon at nucleotides 767-769. Nine family members (age, 33.9 +/- 19.8 yr, mean +/- SD) also carry the mutation, but eight have had normal serum calcium. Biochemical and ultrasonographic evaluation uncovered a 27-yr-old hypercalcemic carrier niece with an atypical parathyroid adenoma, and a 43-yr-old normocalcemic carrier sister was found by ultrasonography to have an extrathyroidal nodule, which proved to be parathyroid carcinoma. The index case, 12 yr after surgery, was normocalcemic, but ultrasonography revealed an extrathyroidal nodule in the contralateral hemithyroid tissue that proved to be atypical adenoma. CONCLUSIONS: Our report confirms that germline mutations of HRPT2 gene may be associated with multiple parathyroid neoplasms. Our experience suggests that longitudinal surveillance by serum biochemistry alone may not be 100% sensitive, and addition of routine neck ultrasonography is a readily accepted adjunct that may facilitate earlier disease detection in some families.
Asunto(s)
Mutación del Sistema de Lectura , Mutación de Línea Germinal , Hiperparatiroidismo/genética , Neoplasias de las Paratiroides/diagnóstico , Neoplasias de las Paratiroides/genética , Proteínas Supresoras de Tumor/genética , Adenoma/diagnóstico , Adenoma/genética , Adenoma/cirugía , Adulto , Anciano , Calcio/sangre , Cromatografía Líquida de Alta Presión , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de las Paratiroides/cirugía , Linaje , Reacción en Cadena de la Polimerasa , Sensibilidad y EspecificidadRESUMEN
Somatostatin analogues (SSAs) have shown limited and variable antiproliferative effects in neuroendocrine tumours (NETs). Whether tumour control by SSAs depends on grading based on the 2010 WHO NET classification is still unclear. The aim of this study is to evaluate the efficacy of long-acting SSAs in NETs according to Ki67 index. An observational Italian multicentre study was designed to collect data in patients with gastro-entero-pancreatic or thoracic NETs under SSA treatment. Both retrospective and prospective data were included and they were analysed in line with Ki67 index, immunohistochemically evaluated in tumour samples and graded according to WHO classification (G1 = Ki67 index 0-2%, G2 = Ki67 index 3-20%, G3 = Ki67 index > 20%). Among 601 patients with NET, 140 with a histologically confirmed gastro-entero-pancreatic or thoracic NET or NET with unknown primary were treated with lanreotide autogel or octreotide LAR. An objective tumour response was observed in 11%, stability in 58% and progression in 31%. Objective response and tumour stability were not significantly different between G1 and G2 NETs. Progression free survival was longer but not significantly different in G1 than G2 NETs (median: 89 vs 43 months, p = 0.15). The median PFS was significantly longer in NETs showing Ki67 < 5% than in those showing Ki67 ≥ 5% (89 vs 35 months, p = 0.005). SSA therapy shows significant antiproliferative effects in well differentiated low/intermediate-proliferating NETs, not only G1 but also in G2 type. A Ki67 index of 5% seems to work better than 3% to select the best candidates for SSA therapy.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Antígeno Ki-67/metabolismo , Tumores Neuroendocrinos/tratamiento farmacológico , Octreótido/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Diferenciación Celular/efectos de los fármacos , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/patología , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
Although adrenal incidentalomas (AI) are not associated with clinically evident syndromes, some patients display biochemical features of subclinical hypercortisolism (SH). Previous studies indicated a negative effect of SH on bone in AI patients, but the prevalence of vertebral fractures and the roles of SH and gonadal status in volumetric bone mineral density are unknown. In 70 female AI patients and 84 controls, the prevalence of vertebral fractures and spinal bone mineral density (by quantitative computed tomography) were evaluated. Subjects were subdivided according to menopausal status into groups Pre (21 patients and 23 controls) and Post (49 patients and 61 controls); there were 14 and 35 patients without SH (SH(-)) and 7 and 14 patients with SH (SH(+)) in groups Pre and Post, respectively. The prevalence of fractures was higher in SH(+) than in controls and in SH(-) subjects in both groups Pre [SH(+), 42.9%; controls, 0% (P = 0.001); SH(-), 7.1% (P = 0.049)] and post [SH(+), 78.6%; controls, 37.7% (P = 0.006); SH(-) 42.9% (P = 0.024)]. In group Post, the mean z-score quantitative computed tomography values were lower in SH(+) patients (-0.78 +/- 0.29) than in controls (0.06 +/- 0.14; P = 0.011) and SH(-) patients (0.02 +/- 0.19; P = 0.034). Evaluation of spinal bone is indicated in female AI patients with SH.