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Background X‐linked hypophosphatemic rickets (XLHR) is a rare genetic disease, often delayed in diagnosis due to the low degree of suspicion and limited access to sophisticated diagnostic tools that confirm the diagnosis, such as genetic testing. Methods Through a cross‐sectional and observational study, 26 patients with a previously presumptive diagnosis of X‐linked hypophosphatemic rickets (based on clinical history, laboratory findings, and physical examination), were followed for approximately 12 months. During 12 months of follow‐up, only 16 patients underwent genetic testing and enrolled in the study. Previous data were analyzed, such as clinical history (e.g., gender, current age, age of clinical diagnosis, age of admission to hospital, family history, and previous orthopedic surgery), physical exam, imaging tests (e.g., radiological changes) and laboratory tests (e.g., tubular maximum reabsorption rate of phosphate to glomerular filtration rate, alkaline phosphatase, and phosphate levels) at the time of the patient’s admission to IEDE and UFRJ, to corroborate and substantiate our research. These data were extracted from the medical records of the patients. Results Among the 16 patients analyzed by molecular biology techniques, the new generation sequencing (NGS), using DNA samples from oral swabs, we obtained seven variants never previously described, which were verified by Sanger sequencing. Among the seven variants never previously described, the most common coding impact was the nonsense mutation. We found two frameshift, one intronic splicing variant, three nonsense, and one deletion splice junction loss. Among patients with new mutations who presented data in the medical record, 100% showed a reduction in TmP/GFR (average of 1.98 mg/dl), the most sensitive laboratory parameter at the time of diagnosis, as well as serum phosphorus (100% had hypophosphatemia on arrival at the referral hospitals––average of 2.4 mg/dl and median 2.3 mg/dl). We also performed NGS on three mothers of the patients with identified mutations. Among these mothers, only one tested negative for the mutation and no family history was reported as well. This mother had serum phosphate of 3.5 mg/dl (normal range: 2.5–4.5 mg/dl) at the time of genetic test collection. The others had a positive test, low serum phosphorus at the time of the molecular test, in addition to a positive family history. Conclusion This study describes seven new variants in the PHEX gene and aims to increase the knowledge of the scientific community about the types of mutations involving this gene, increasing information on the genetic basis of this condition, enabling future considerations about genotype–phenotype correlation, in addition to diagnosis accurate and early.

RESUMOObjetivamos descrever e analisar uma família com seis casos de hiperparatireoidismo familiar isolado (HFI), uma rara doença hereditária de padrão autossômico dominante, caracterizada por hiperparatireoidismo primário sem associação com outras doenças ou tumores endocrinológicos. O diagnóstico foi realizado através da demonstração de hipercalcemia, aumento dos níveis de paratormônio e tumores de paratireóide à histopatologia, excluindo-se neoplasias endócrinas múltiplas do tipo 1 (NEM 1) e do tipo 2a (NEM 2a), além da síndrome hiperparatireoidismo/tumor de mandíbula (HPT/TM). Analisamos a descrição dos exames diagnósticos iniciais, a abordagem cirúrgica, os laudos histopatológicos pós-operatórios e suas evoluções. A primeira paciente operada neste instituto há 20 anos, recidivou onze anos após, e possuía uma irmã com diagnóstico prévio, o que motivou a investigação de outros familiares. A observação do caráter familial nesses pacientes contribuiu para a facilitação diagnóstica e encaminhamento terapêutico dos mesmos, assim como a orientação clínica e genética à família. ABSTRACT Familial Isolated Primary Hyperparathyroidism -Description and Analyses of Six Cases.Our objective is to evaluate and describe one family with six cases of familial isolated primary hyperparathyroidism (HFI), a rare hereditable disorder with an autossomal dominant mode of inheritance. It is characterized by a primary hyperparathyroidism without association with other endocrine tumors or diseases. The HFI diagnosis relied on the demonstration of hypercalcemia, inappropriately high levels of parathyroid hormone, and parathyroid adenomas, plus exclusion of NEM 1/2a and HPT/TM syndrome in this family. We analyzed the description of the first diagnosis, surgical approach, postoperative histopathological results and their development process. The first patient, treated in our institute twenty years ago, has recidivated eleven years after the treatment. Her sister had had the same diagnosis, which motivated us to investigate theirs relatives. The analysis of the characteristics that run in these patients' family has contributed to facilitate their diagnosis and therapeutic treatment, including clinical and genetic orientation of this family.

Introduction: In patients with hypoparathyroidism, conventional therapy maintains parathyroid hormone (PTH)-dependent mineral metabolism homeostasis but is unable to prevent emergence of comorbidities and low quality of life. Objectives: To evaluate long-term progression of patients with hypoparathyroidism receiving conventional therapy and their quality of life compared with patients with primary hypothyroidism and healthy controls. Design and Setting: Retrospective cohort study for quality-of-life analysis and transversal cut on clinical profile. Patients with hypoparathyroidism from four public referral centers in endocrinology and bone metabolism in the metropolitan region of Rio de Janeiro. Material and Methods: Quality of life by SF-36 protocol, and clinical profile by medical record analysis. Results: 243 individuals with hypoparathyroidism (n=113), hypothyroidism (n=65), and healthy controls (n=65) included. Median time since diagnosis and duration of conventional therapy was 8 years (IQR 4–17 years). Data on type of conventional therapy (median, minimum–maximum daily dose, percentage of patients with hypoparathyroidism using each medication): calcium supplementation (2000 mg/day, 200–6000 mg/day, 95%), cholecalciferol (2000 IU/day, 200–40000 IU/day, 44%), calcitriol (0.5 μg/day, 0.25–2 μg/day, 77%), thiazides (25 mg/day, 12.5–100 mg/day, 44%). Conclusions: Conventional therapy is associated with homeostasis of serum mineral levels, but not with improved quality of life. Compared to patients with hypothyroidism, those with additional hypoparathyroidism had lower scores in six SF-36 domains. Conventional therapy successfully maintained normal calcium levels with often high doses of calcium, vitamin D, and thiazides but could not prevent low quality of life scores and comorbidities.