RESUMO
AIM: To describe baseline characteristics and follow-up data in patients with lipodystrophy syndromes treated with metreleptin in a national reference network, in a real-life setting. PATIENTS AND METHODS: Clinical and metabolic data from patients receiving metreleptin in France were retrospectively collected, at baseline, at 1 year and at the latest follow-up during treatment. RESULTS: Forty-seven patients with lipodystrophy including generalized lipodystrophy (GLD; n = 28) and partial lipodystrophy (PLD; n = 19) received metreleptin over the last decade. At baseline, the median (interquartile range [IQR]) patient age was 29.3 (16.6-47.6) years, body mass index was 23.8 (21.2-25.7) kg/m2 and serum leptin was 3.2 (1.0-4.9) ng/mL, 94% of patients had diabetes (66% insulin-treated), 53% had hypertension and 87% had dyslipidaemia. Metreleptin therapy, administered for a median (IQR) of 31.7 (14.2-76.0) months, was ongoing in 77% of patients at the latest follow-up. In patients with GLD, glycated haemoglobin (HbA1c) and fasting triglyceride levels significantly decreased from baseline to 1 year of metreleptin treatment, from 8.4 (6.5-9.9)% [68 (48-85) mmol/mol] to 6.8 (5.6-7.4)% [51(38-57) mmol/mol], and 3.6 (1.7-8.5) mmol/L to 2.2 (1.1-3.7) mmol/L, respectively (P < 0.001), with sustained efficacy thereafter. In patients with PLD, HbA1c was not significantly modified (7.7 [7.1-9.1]% [61 (54-76) mmol/mol] at baseline vs. 7.7 [7.4-9.5]% [61(57-80) mmol/mol] at 1 year), and the decrease in fasting triglycerides (from 3.3 [1.9-9.9] mmol/L to 2.5 [1.6-5.3] mmol/L; P < 0.01) was not confirmed at the latest assessment (5.2 [2.2-11.3] mmol/L). However, among PLD patients, at 1 year, 61% were responders regarding glucose homeostasis, with lower baseline leptin levels compared to nonresponders, and 61% were responders regarding triglyceridaemia. Liver enzymes significantly decreased only in the GLD group. CONCLUSIONS: In this real-life setting study, metabolic outcomes are improved by metreleptin therapy in patients with GLD. The therapeutic indication for metreleptin needs to be clarified in patients with PLD.
Assuntos
Lipodistrofia Generalizada Congênita , Lipodistrofia , Adolescente , Adulto , Humanos , Leptina/análogos & derivados , Leptina/uso terapêutico , Lipodistrofia/tratamento farmacológico , Lipodistrofia Generalizada Congênita/tratamento farmacológico , Pessoa de Meia-Idade , Estudos Retrospectivos , Síndrome , Adulto JovemRESUMO
Transcription factor SOX10 plays a role in the maintenance of progenitor cell multipotency, lineage specification, and cell differentiation and is a major actor in the development of the neural crest. It has been implicated in Waardenburg syndrome (WS), a rare disorder characterized by the association between pigmentation abnormalities and deafness, but SOX10 mutations cause a variable phenotype that spreads over the initial limits of the syndrome definition. On the basis of recent findings of olfactory-bulb agenesis in WS individuals, we suspected SOX10 was also involved in Kallmann syndrome (KS). KS is defined by the association between anosmia and hypogonadotropic hypogonadism due to incomplete migration of neuroendocrine gonadotropin-releasing hormone (GnRH) cells along the olfactory, vomeronasal, and terminal nerves. Mutations in any of the nine genes identified to date account for only 30% of the KS cases. KS can be either isolated or associated with a variety of other symptoms, including deafness. This study reports SOX10 loss-of-function mutations in approximately one-third of KS individuals with deafness, indicating a substantial involvement in this clinical condition. Study of SOX10-null mutant mice revealed a developmental role of SOX10 in a subpopulation of glial cells called olfactory ensheathing cells. These mice indeed showed an almost complete absence of these cells along the olfactory nerve pathway, as well as defasciculation and misrouting of the nerve fibers, impaired migration of GnRH cells, and disorganization of the olfactory nerve layer of the olfactory bulbs.
Assuntos
Surdez/genética , Predisposição Genética para Doença/genética , Síndrome de Kallmann/genética , Neuroglia/patologia , Condutos Olfatórios/patologia , Fatores de Transcrição SOXE/genética , Animais , Análise Mutacional de DNA , Surdez/patologia , Feminino , França , Galactosídeos , Células HeLa , Humanos , Indóis , Síndrome de Kallmann/patologia , Masculino , Camundongos , Mutação/genética , Plasmídeos/genéticaRESUMO
Multiple endocrine neoplasia syndrome type 1 (MEN1), which is secondary to mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Although genotype-phenotype studies have so far failed to identify any statistical correlations, some families harbor recurrent tumor patterns. The function of MENIN is unclear, but has been described through the discovery of its interacting partners. Mutations in the interacting domains of MENIN functional partners have been shown to directly alter its regulation abilities. We report on a cohort of MEN1 patients from the Groupe d'étude des Tumeurs Endocrines. Patients with a molecular diagnosis and a clinical follow-up, totaling 262 families and 806 patients, were included. Associations between mutation type, location or interacting factors of the MENIN protein and death as well as the occurrence of MEN1-related tumors were tested using a frailty Cox model to adjust for potential heterogeneity across families. Accounting for the heterogeneity across families, the overall risk of death was significantly higher when mutations affected the JunD interacting domain (adjusted HR = 1.88: 95%-CI = 1.15-3.07). Patients had a higher risk of death from cancers of the MEN1 spectrum (HR = 2.34; 95%-CI = 1.23-4.43). This genotype-phenotype correlation study confirmed the lack of direct genotype-phenotype correlations. However, patients with mutations affecting the JunD interacting domain had a higher risk of death secondary to a MEN1 tumor and should thus be considered for surgical indications, genetic counseling and follow-up.
Assuntos
Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/mortalidade , Mutação , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas/genética , Família , Feminino , Seguimentos , Humanos , Masculino , Neoplasia Endócrina Múltipla Tipo 1/metabolismo , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Fatores de RiscoRESUMO
The thyroid is the organ with the highest selenium content per gram of tissue because it expresses specific selenoproteins. Since the discovery of myxoedematous cretinism and thyroid destruction following selenium repletion in iodine- and selenium-deficient children, data on links between thyroid metabolism and selenium have multiplied. Although very minor amounts of selenium appear sufficient for adequate activity of deiodinases, thus limiting the impact of its potential deficiency on synthesis of thyroid hormones, selenium status appears to have an impact on the development of thyroid pathologies. The value of selenium supplementation in autoimmune thyroid disorders has been emphasized. Most authors attribute the effect of supplementation on the immune system to the regulation of the production of reactive oxygen species and their metabolites. In patients with Hashimoto's disease and in pregnant women with anti-TPO antibodies, selenium supplementation decreases anti-thyroid antibody levels and improves the ultrasound structure of the thyroid gland. Although clinical applications still need to be defined for Hashimoto's disease, they are very interesting for pregnant women given that supplementation significantly decreases the percentage of postpartum thyroiditis and definitive hypothyroidism. In Graves' disease, selenium supplementation results in euthyroidism being achieved more rapidly and appears to have a beneficial effect on mild inflammatory orbitopathy. A risk of diabetes has been reported following long-term selenium supplementation, but few data are available on the side effects associated with such supplementation and further studies are required.
Assuntos
Hipotireoidismo/prevenção & controle , Selênio/metabolismo , Selênio/farmacologia , Glândula Tireoide/metabolismo , Suplementos Nutricionais , Doença de Hashimoto/metabolismo , Humanos , Iodeto Peroxidase/imunologia , Glândula Tireoide/efeitos dos fármacosRESUMO
OBJECTIVE: The adipogenic PPARG-encoded PPARγ nuclear receptor also displays essential placental functions. We evaluated the metabolic, reproductive, and perinatal features of patients with PPARG-related lipodystrophy. METHODS: Current and retrospective data were collected in patients referred to a National Rare Diseases Reference Centre. RESULTS: 26 patients from 15 unrelated families were studied (18 women, median age 43 years). They carried monoallelic PPARG variants except a homozygous patient with congenital generalized lipodystrophy. Among heterozygous patients aged 16 or more (n = 24), 92% had diabetes, 96% partial lipodystrophy (median age at diagnosis 24 and 37 years), 78% hypertriglyceridaemia, 71% liver steatosis, and 58% hypertension. The mean BMI was 26 ± 5.0â kg/m2. Women (n = 16) were frequently affected by acute pancreatitis (n = 6) and/or polycystic ovary syndrome (n = 12). Eleven women obtained one or several pregnancies, all complicated by diabetes (n = 8), hypertension (n = 4), and/or hypertriglyceridaemia (n = 10). We analysed perinatal data of patients according to the presence (n = 8) or absence (n = 9) of a maternal dysmetabolic environment. The median gestational age at birth was low in both groups (37 and 36 weeks of amenorrhea, respectively). As expected, the birth weight was higher in patients exposed to a foetal dysmetabolic environment of maternal origin. In contrast, 85.7% of non-exposed patients, in whom the variant is, or is very likely to be, paternally-inherited, were small for gestational age. CONCLUSIONS: Lipodystrophy-related PPARG variants induce early metabolic complications. Our results suggest that placental expression of PPARG pathogenic variants carried by affected foetuses could impair prenatal growth and parturition. This justifies careful pregnancy monitoring in affected families.
Assuntos
Hipertensão , Hipertrigliceridemia , Lipodistrofia , Pancreatite , Recém-Nascido , Humanos , Feminino , Gravidez , Adulto , PPAR gama/genética , Estudos Retrospectivos , Doença Aguda , Placenta , PartoRESUMO
OBJECTIVES: High ankle-brachial index (ABI) (>1.40) is associated with poor cardiovascular disease (CVD) prognosis. Concomittant peripheral artery disease (PAD) is frequent, although undetectable with the ABI in this situation. We assessed the prognostic value of a high ABI according to the coexistence of occlusive PAD in diabetics. METHODS: In this retrospective longitudinal study, we reviewed the data of 403 consecutive diabetic patients (hospitalized in tertiary care teaching hospital) who had a Doppler assessment of their lower limbs between 1999 and 2000. They were classified as "normal" when Doppler waveform patterns (DWP) were normal and ABI within the 0.91 to 1.39 range, "occlusive-PAD (O-PAD)" when ABI ≤0.90, or in case of abnormal DWP with normal ABI, "isolated medial calcinosis (IMC)" if ABI ≥1.40 with normal DWP, and "mixed disease (MD)" when ABI ≥1.40 with abnormal DWP. The primary outcome was the occurrence of any of the following events: death, stroke or transient ischemic attack (TIA), and acute coronary syndrome. RESULTS: The patients (65.6 ± 13.2 years, 54.6% females) were classified as normal (14.4%), O-PAD (48.4%), IMC (16.4%), and MD (20.8%). During a mean follow-up of 6.5 years, the event-free survival curves of O-PAD and MD groups showed equally poorer prognosis than the IMC and normal groups. Adjusted for age, sex, diabetes type and duration, traditional CVD risk factors, chronic kidney disease, CVD history and treatments, the presence of occlusive disease (hazard ratio [HR]: 2.21, 1.16-4.22, P = .016), but not medial calcinosis, was significantly associated with the primary outcome. CONCLUSIONS: In diabetics with ABI >1.40, only those with concommittant occlusive PAD have poorer prognosis.
Assuntos
Índice Tornozelo-Braço , Arteriopatias Oclusivas/complicações , Diabetes Mellitus Tipo 2/complicações , Doença Arterial Periférica/complicações , Síndrome Coronariana Aguda/etiologia , Idoso , Arteriopatias Oclusivas/diagnóstico , Arteriopatias Oclusivas/mortalidade , Arteriopatias Oclusivas/fisiopatologia , Distribuição de Qui-Quadrado , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/fisiopatologia , Intervalo Livre de Doença , Feminino , Humanos , Ataque Isquêmico Transitório/etiologia , Estimativa de Kaplan-Meier , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/mortalidade , Doença Arterial Periférica/fisiopatologia , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Fatores de Tempo , Ultrassonografia DopplerRESUMO
Immunotherapy often incurs side-effects, mainly involving the skin, digestive tract and endocrine system. The most frequent endocrine side-effects involve the pituitary and thyroid glands. Cases of insulin-dependent diabetes, whether autoimmune or not (type 1 or 1B) have been reported with PD-1/PD-L1 inhibitors, alone or in association with anti-CTLA-4 antibodies, and were systematically associated with sudden-onset insulinopenia, frequently leading to ketoacidosis or fulminant diabetes, requiring first-line insulin therapy. This adverse effect has not so far been reported with anti-CTLA-4 monotherapy.
Assuntos
Diabetes Mellitus/induzido quimicamente , Imunoterapia/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Consenso , Diabetes Mellitus/epidemiologia , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , PrognósticoRESUMO
Tyrosine kinase inhibitors (TKI) interfere with glucose metabolism. Contrasting effects have been reported, even for a given molecule. Hyperglycemia rates range between 15 and 40%; nilotinib seems to be the molecule most liable to induce diabetes. Metabolic effects range from metabolic syndrome to onset of diabetes, requiring treatment based on insulin resistance, although pathophysiology is unclear. It is noteworthy that fulminant diabetes has never been reported under TKIs. TKIs may lead to hypoglycemia in type 1 or 2 diabetes. Several cases have been reported of improvement in glycemia and in HbA1c, with reduction or even termination of insulin therapy, mainly under imatinib and sunitinib. Fasting glucose levels should be checked before, during and after treatment, plus HbA1C in diabetic patients, with reinforced self-monitoring. These side-effects are transient and never contraindicate continuation of TKIs. Dyslipidemia under TKI has been reported, concerning both LDL-cholesterol and triglycerides. Although variations seem to be slight, lipid assessment is recommended before, during and after treatment.
Assuntos
Antineoplásicos/efeitos adversos , Doenças Metabólicas/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Consenso , Dislipidemias/induzido quimicamente , Dislipidemias/epidemiologia , Dislipidemias/terapia , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Hipoglicemia/terapia , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/terapia , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidoresRESUMO
Using mTOR inhibitors (mTORi) as anticancer drugs led to hyperglycemia (12-50%) and hyperlipidemia (7-73%) in phase-III trials. These high rates require adapted treatment in cancer patients. Before initiating mTORi treatment, lipid profile screening should be systematic, with fasting glucose assay in non-diabetic patients and HbA1C in diabetic patients. After initiation, lipid profile monitoring should be systematic, with fasting glucose assay in non-diabetic patients, every 2 weeks for the first month and then monthly. The HbA1C target is≤8%, before and after treatment initiation in known diabetic patients and in case of onset of diabetes under mTORi. LDL-cholesterol targets should be adapted to general health status and cardiovascular and oncologic prognosis. If treatment is indicated, pravastatin should be prescribed in first line; atorvastatin and simvastatin are contraindicated. Fenofibrate should be prescribed for hypertriglyceridemia>5g/l resisting dietary measures adapted to oncologic status. In non-controllable hypertriglyceridemia exceeding 10g/l, mTORi treatment should be interrupted and specialist opinion should be sought.
Assuntos
Antineoplásicos/efeitos adversos , Doenças Metabólicas/induzido quimicamente , Serina-Treonina Quinases TOR/antagonistas & inibidores , Consenso , Dislipidemias/induzido quimicamente , Dislipidemias/epidemiologia , Dislipidemias/terapia , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Hipoglicemia/terapia , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/terapia , Neoplasias/complicações , Neoplasias/tratamento farmacológicoRESUMO
The present final consensus statement of the French Society of Endocrinology lays out the assessments that are to be systematically performed before and during anticancer treatment by immunotherapy, tyrosine kinase inhibitors or mTOR inhibitors, even without onset of any endocrinopathy. It also discusses the CTCAE adverse event grading system in oncology and the difficulty of implementing it for endocrine side-effects of these anticancer treatments. Notably, this is why certain treatment steps applied in other side-effects (e.g., high-dose corticosteroids, contraindications to immunotherapy, etc.) need to be discussed before implementation for endocrine side-effects.
Assuntos
Antineoplásicos/efeitos adversos , Doenças do Sistema Endócrino/induzido quimicamente , Doenças do Sistema Endócrino/diagnóstico , Imunoterapia/efeitos adversos , Neoplasias/complicações , Animais , Consenso , Doenças do Sistema Endócrino/epidemiologia , Humanos , Neoplasias/tratamento farmacológicoRESUMO
CONTEXT: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. OBJECTIVE: The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA). DESIGN: This was a multicenter, international, collaborative study. SETTING: The study was conducted in 34 university endocrinology and genetics departments in nine countries. PATIENTS: Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis. MAIN OUTCOME MEASURES: Presence/absence and description of AIP gene mutations were the main outcome measures. INTERVENTION: There was no intervention. RESULTS: Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations. CONCLUSIONS: AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.
Assuntos
Adenoma/genética , Neoplasias Hipofisárias/genética , Proteínas/genética , Adenoma/patologia , Adulto , Idoso , Estudos de Coortes , Feminino , Frequência do Gene , Mutação em Linhagem Germinativa/genética , Hormônio do Crescimento/metabolismo , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação/fisiologia , Neoplasias Hipofisárias/patologia , Prolactinoma/genética , Prolactinoma/metabolismo , Prolactinoma/patologiaRESUMO
Germline mutations of the MEN1 gene cause multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder characterized by tumors of the parathyroids, the pancreas, and the anterior pituitary. Paraganglioma (PGL) is a rare endocrine tumor, which can be sporadic or genetically determined. To date, PGL has never been reported as a feature of MEN1.We report here a patient presenting three features of MEN1 syndrome (hyperparathyroidism, pancreatic neuroendocrine tumor, and adrenocortical adenoma) associated with PGL. Genetic analysis of MEN1 gene revealed a new missense mutation in exon 5 (AGGî²AAG), causing the substitution of arginine by lysine at codon 275. Screening for other genetic disorders (SDHx, TMEM127, MAX, CDKN1B) causing PGL was negative. Immunohistochemical analyses showed normal levels of succinate dehydrogenase (SDH)A and SDHB in the PGL. The proband's sister, bearing the mutation, had primary hyperparathyroidism. It was the first typical MEN1 syndrome reported with an extra-adrenal PGL.
Assuntos
Anormalidades Múltiplas/diagnóstico , Neoplasias do Córtex Suprarrenal/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Paraganglioma/diagnóstico por imagem , Proteínas Proto-Oncogênicas/genética , Anormalidades Múltiplas/genética , Neoplasias do Córtex Suprarrenal/genética , Análise Mutacional de DNA , Feminino , Humanos , Mutação de Sentido Incorreto , Neoplasias Pancreáticas/genética , Paraganglioma/genética , Linhagem , Radiografia , SíndromeRESUMO
CONTEXT: Mutations in CHD7, a gene previously implicated in CHARGE (coloboma, heart defect, choanal atresia, retardation of growth and/or development, genital hypoplasia, ear anomalies) syndrome, have been reported in patients presenting with Kallmann syndrome (KS) or congenital hypogonadotropic hypogonadism (CHH). Most mutations causing CHARGE syndrome result in premature stop codons and occur de novo, but the proportion of truncating vs nontruncating mutations in KS and CHH patients is still unknown. OBJECTIVE: The objective of the study was to determine the nature, prevalence, mode of transmission, and clinical spectrum of CHD7 mutations in a large series of patients. DESIGN: We studied 209 KS and 94 CHH patients. These patients had not been diagnosed with CHARGE syndrome according to the current criteria. We searched for mutations in 16 KS and CHH genes including CHD7. RESULTS: We found presumably pathogenic mutations in CHD7 in 24 KS patients but not in CHH patients. Nontruncating mutations (16 missense and a two-codon duplication) were more prevalent than truncating mutations (three nonsense, three frame shift, and a splice site), which contrasts with patients presenting with typical CHARGE syndrome. Thus, the clinical spectrum associated with CHD7 mutations may be partly explained by genotype/phenotype correlations. Eight patients also had congenital deafness and one had a cleft lip/palate, whereas six had both. For 10 patients, the presence of diverse features of the CHARGE spectrum in at least one relative argues against a de novo appearance of the missense mutation, and this was confirmed by genetic analysis in five families. CONCLUSION: Considering the large prevalence and clinical spectrum of CHD7 mutations, it will be particularly relevant to genetic counseling to search for mutations in this gene in KS patients seeking fertility treatment, especially if KS is associated with deafness and cleft lip/palate.
Assuntos
Síndrome CHARGE/epidemiologia , Síndrome CHARGE/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Síndrome de Kallmann/epidemiologia , Síndrome de Kallmann/genética , Adolescente , Adulto , Criança , Pré-Escolar , Saúde da Família , Feminino , Mutação da Fase de Leitura , Genótipo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Prevalência , Adulto JovemRESUMO
OBJECTIVE AND BACKGROUND: Most primary hyperparathyroidism (pHPT) patients do not conform to the guidelines for parathyroidectomy established by an international panel of specialists and have a mild pHPT. This group is typically defined as 'asymptomatic'. The primary aim of this study was to determine symptom improvement in this 'asymptomatic' group after parathyroidectomy. Secondly, we aimed to create a preoperative clinical score predicting postoperative symptom resolution. DESIGN: A prospective nonrandomized study included patients with mild pHPT. METHODS: A questionnaire (22 items) was given to 'asymptomatic' patients preoperatively and at 3, 6, and 12 postoperative months. A logistic regression was performed to create a preoperative clinical score. RESULTS: One hundred and sixteen patients were included. Postoperatively, HPT was resolved in 98% of patients. Twelve of 22 nonspecific symptoms were improved at 1 year. Subgroups analysis showed a greater improvement in patients <70 years and those with a serum calcium level ≥2.6 mmol/l preoperatively. A clinical score, based on age and five symptoms, was established to predict the clinical improvement after surgery in mild pHPT patients with a positive predictive value of 81%. CONCLUSION: Patients with asymptomatic pHPT have clinical improvement of their symptoms postoperatively even after 1 year. Younger patients and those with higher preoperative calcium levels show the best improvement.
Assuntos
Hiperparatireoidismo Primário/cirurgia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Cálcio/sangue , Creatinina/sangue , Feminino , Seguimentos , Humanos , Hidroxicolecalciferóis/sangue , Hiperparatireoidismo Primário/psicologia , Masculino , Pessoa de Meia-Idade , Paratireoidectomia , Período Pós-Operatório , Estudos Prospectivos , Resultado do TratamentoRESUMO
Familial isolated pituitary adenoma (FIPA) occurs in families and is unrelated to multiple endocrine neoplasia type 1 and Carney complex. Mutations in AIP account only for 15-25% of FIPA families. CDKN1B mutations cause MEN4 in which affected patients can suffer from pituitary adenomas. With this study, we wanted to assess whether mutations in CDKN1B occur among a large cohort of AIP mutation-negative FIPA kindreds. Eighty-eight AIP mutation-negative FIPA families were studied and 124 affected subjects underwent sequencing of CDKN1B. Functional analysis of putative CDKN1B mutations was performed using in silico and in vitro approaches. Germline CDKN1B analysis revealed two nucleotide changes: c.286A>C (p.K96Q) and c.356T>C (p.I119T). In vitro, the K96Q change decreased p27 affinity for Grb2 but did not segregate with pituitary adenoma in the FIPA kindred. The I119T substitution occurred in a female patient with acromegaly. p27(I119T) shows an abnormal migration pattern by SDS-PAGE. Three variants (p.S56T, p.T142T, and c.605+36C>T) are likely nonpathogenic because In vitro effects were not seen. In conclusion, two patients had germline sequence changes in CDKN1B, which led to functional alterations in the encoded p27 proteins in vitro. Such rare CDKN1B variants may contribute to the development of pituitary adenomas, but their low incidence and lack of clear segregation with affected patients make CDKN1B sequencing unlikely to be of use in routine genetic investigation of FIPA kindreds. However, further characterization of the role of CDKN1B in pituitary tumorigenesis in these and other cases could help clarify the clinicopathological profile of MEN4.