The goal of this observational study is to create, manage and analyze a multicenter national database of patients affected by hypoparathyroidism or pseudohypoparathyroidism, aimed at collecting and studying anamnestic, diagnostic, genetic, clinical, and therapeutic data in a relatively wide number of patients with these two rare pathologies, in Italy.

The study will include 41 specialist clinical centers of endocrinology, pediatric endocrinology, pediatrics, and endocrine surgery, located throughout the Italian territory, and to which patients refer from all the 20 regions of Italy.

Data will be collected over time, both in retrospective and prospective manners, during the 10-year duration of the study, starting from the recruiting visit (basal visit) and then during each follow-up visits patients will undergo for the control of disease at the recruiting clinical centers.

Collected data will include both the most classic traits of the pathology and the less common ones, with the final goal of refining and deepening medical knowledge in the field of these two clinical conditions affecting parathyroid function and calcium homeostasis, and, thus, to be able to define optimal clinical and therapeutic management of patients, improving their quality of life.

The main aspects this observational study aims to assess and clarify are:

1. Evaluation of prevalence and incidence of hypoparathyroidism, globally and in its different etiological forms, and of pseudohypoparathyroidism in Italy.
2. Clinical characterization of different etiological forms of hypoparathyroidism, through both cross-sectional and longitudinal analyses of collected data.
3. Clinical characterization of pseudohypoparathyroidism, through both cross-sectional and longitudinal analyses of collected data.
4. Over time collection of data on bone status and bone fragility in patients with hypoparathyroidism and pseudohypoparathyroidism, to evaluate the prevalence and incidence of fragility fractures in these patients, globally and also based on gender, age, and disease etiology.
5. Over time evaluation of response to pharmacological therapies in patients with hypoparathyroidism and pseudohypoparathyroidism The study will include two independent cohorts of female and male patients of any age, one including patients with chronic hypoparathyroidism of each etiological forms (cohort 1), and one including patients with pseudohypoparathyroidism (cohort 2). The study does not include either any control group/comparison group or healthy volunteers.

The study itself does not involve any medical intervention or drug administration. Pharmacological treatments for which data on response to therapy will be collected in the database, are those administered to patients for the control/treatment of hypoparathyroidism or pseudohypoparathyroidism, regardless of their inclusion in this observational study.

A. Background and rationale:

Hypoparathyroidism is a rare endocrine disease characterized by low levels of calcium (hypocalcemia) and high levels of phosphorus (hyperphosphatemia) in the blood, as a result of inappropriately low or completely absent levels of parathyroid hormone (PTH). Data on the global epidemiology of this disease are still incomplete, it is estimated to affect less than 1 case in 200,000 people. Even more incomplete are the national incidence data.

Hypoparathyroidism can be acquired or congenital. The most common form of hypoparathyroidism is post-surgical (about 75% of cases), following surgery in the neck region with damage and/or removal of the parathyroid glands. Among other forms of acquired hypoparathyroidism there are, in a much lower percentage, those caused by irradiation of the neck, viral infections with infiltration of the parathyroid tissue (i.e. tuberculosis), metastatic infiltrations, autoimmune diseases, chronic magnesium depletion (malabsorption, alcoholism or malnutrition).

Congenital hypoparathyroidism can be caused by germline mutations in various genes, which regulate the correct development and/or functionality of the parathyroid glands and synthesis and release of PTH, and can arise as an isolated or syndromic form, the latter in association with other endocrine and non-endocrine alterations.

The term pseudohypoparathyroidism, on the other hand, refers to a heterogeneous group of hereditary diseases characterized by resistance to PTH in target organs (proximal tubules of the kidney), which causes hypocalcemia and hyperphosphatemia in the presence of normal and even elevated PTH levels.

The real global and Italian prevalence and incidence of hypoparathyroidism and pseudohypoparathyroidism is not certain; the lack of specific national and international registries for this pathology remains a major limitation to its in-depth clinical understanding and to the optimization of the therapeutic management of patients.

Implementing and detailing as much as possible the epidemiological, clinical and therapeutic history of hypoparathyroidism, in its various etiological forms, and pseudohypoparathyroidism means not only improving the clinical management of the individual patient, but also allowing for better planning of social, political and health interventions for these pathologies and, overall, improving the quality and life expectancy of patients.

For this reason, it is extremely important to create multicenter national databases, such as the one proposed by this study, which allow to collect a relatively high number of patients affected by hypoparathyroidism or pseudohypoparathyroidism, whose cases can be, thus, carefully studied in every aspect, both retrospectively and prospectively.

A previous Italian database (HypoparaNET) [1] was established in the period March 2014-September 2015, collecting 509 cases of chronic hypoparathyroidism from 16 Italian Endocrinological Clinical Centers. However, this database collected patients' data limited exclusively to the time of inclusion in the study, not including the collection of follow-up data, and, thus, allowing only an epidemiological evaluation and a cross-sectional observational analysis of the data collected at the time of inclusion in the study.

Instead, in the present study, the investigators aim to collect data on hypoparathyroidism and pseudohypoparathyroidism cases over time, allowing not only to analyze epidemiological data and to perform a single shot analysis of collected data, but also to be able to perform longitudinal analyses of the two diseases, with particular attention to the response to therapies.

B. Main aim and specific objectives:

Main goal of this observational study is to create, manage and analyze a retro-prospective multicenter national database of patients with hypoparathyroidism or pseudohypoparathyroidism in Italy, aimed at collecting and studying anamnestic, diagnostic, genetic, clinical, and therapeutic data on these two endocrine diseases in a relatively wide number of patients.

Such a database will allow for an epidemiological evaluation of prevalence and incidence hypoparathyroidism or pseudohypoparathyroidism in Italy, and to collect case history of patients whose clinical cases will be studied in detail and followed over time up to 10 years after the recruitment in the study, in order to refine knowledge in the field of these two rare endocrine diseases.

Specific objectives of the studies are:

1. Creation of an Italian centralized multicenter database of patients with hypoparathyroidism or pseudohypoparathyroidism, through the collection of patients at 41 specialist clinical centers of endocrinology, pediatric endocrinology, pediatrics, and endocrine surgery, located throughout the Italian territory and visiting patients from all the 20 regions of Italy.
2. Collection of a relatively high number of patients with hypoparathyroidism of different etiology or with pseudohypoparathyroidism.
3. Retrospective collection of data about hypoparathyroidism or pseudohypoparathyroidism, at the time of the recruiting visit.
4. Continuous and updated prospective collection of patients' data over time, starting from the first recruiting visit up to 10 years after the recruitment in the study.
5. Evaluation of prevalence and incidence of hypoparathyroidism, globally and in its different etiological forms, and of pseudohypoparathyroidism, in Italy.
6. Clinical characterization of different etiological forms of hypoparathyroidism, through both cross-sectional and longitudinal analyses of collected data
7. Clinical characterization of pseudohypoparathyroidism, through both cross-sectional and longitudinal analyses of collected data
8. Over time collection of data on bone status and bone fragility in patients with hypoparathyroidism and pseudohypoparathyroidism, to evaluate the prevalence and incidence of fragility fractures in these patients also based on gender, age, and disease etiology
9. Over time evaluation of response to pharmacological therapies in patients with hypoparathyroidism and pseudohypoparathyroidism.

C. Study population:

The study will include two independent cohorts of female and male patients of any age, one including patients with chronic hypoparathyroidism (cohort 1), and one including patients with pseudohypoparathyroidism (cohort 2).

The study does not include either any control group/comparison group or healthy volunteers.

Based on the previous experience with the HypoparaNET database, the investigators can estimate to be able to include in the study at least 600 patients affected by hypoparathyroidism or pseudohypoparathyroidism during the 10 years of the study.

Inclusion criteria

• Cohort 1: chronic hypoparathyroidism (all etiological forms)
• Cohort 2: pseudohypoparathyroidism Exclusion criteria
• None

D. Study design and setting:

Non-profit, multicenter, national, retro-prospective, observational study, consisting in the design, creation, management and analysis of an Italian database of patients with hypoparathyroidism or pseudohypoparathyroidism.

The study will last 10 years. The enrollment of patients with hypoparathyroidism or pseudohypoparathyroidism, the inclusion in the database with retrospective collection of their clinical data, and the subsequent prospective collection of clinical follow-up data will take place throughout the duration of the study. For the retrospective collection, retrospective data on hypoparathyroidism or pseudohypoparathyroidism will be retrieved from patient's medical records, at the time of the medical visit that the patient will carry out at the Clinical Center for the evaluation of his/her disease, regardless of inclusion in this study. Prospective data relating to hypoparathyroidism or pseudohypoparathyroidism follow-up will be collected during the subsequent medical follow-up visits, scheduled for each patient as part of the clinical management of his/her clinical condition, regardless of inclusion in this study.

Being an observational study, this study itself does not involve the administration of any drug, nor the use of any medical device, nor does it involve additional medical visits, clinical analyses or care procedures in addition to those conventionally scheduled for the clinical and therapeutic management of patient affected by hypoparathyroidism or pseudohypoparathyroidism. No participant biospecimens of any type will be collected and retained to perform this study. Pharmacological treatments for which data on response to therapy will be collected in the database, are those usually administered to patients for the control/treatment of hypoparathyroidism or pseudohypoparathyroidism, regardless of their inclusion in this observational study.

All data will be collected anonymously, and they will be analyzed as aggregates. Data collected in the database will be, first, processed using descriptive statistics, such as frequency tables for categorical data, median and quartiles for quantitative data on ordinal scales and mean and standard deviation for quantitative data on metric scales. Secondly, the correlations between variables will be evaluated using the Pearson correlation index in the case of continuous variables and the chi-square test for categorical variables.

E. Data and variables:

Data collected in the database will include (if available in patient's medical records and part of the normal clinical and therapeutic management of patient regardless of inclusion in this study):

• Demographics (sex, year of birth)
• Family history of chronic hypoparathyroidism or pseudohypoparathyroidism in first-degree relatives (only for patients with a congenital form of the disease)
• History of neck irradiation, viral infections with infiltration of the parathyroid tissue (i.e. tuberculosis), metastatic infiltrations, autoimmune diseases, chronic magnesium depletion, and neck surgery as possible cause of chronic hypoparathyroidism
• Presence of comorbidities
• Age at diagnosis/onset of hypoparathyroidism or pseudohypoparathyroidism
• Genetic testing for congenital forms of hypoparathyroidism or pseudohypoparathyroidism (if performed)
• Clinical manifestations of the diseases (i.e paresthesia, cramps, tetany, chondrocalcinosis, nephrocalcinosis, nephrolithiasis, chronic renal failure, ectopic calcifications, neurocognitive and brain disorders, ocular manifestations)
• DXA and/or pQCT/HR-pQCT evaluation of bone status
• History of fragility fractures
• Biochemical measurements of parameters of parathyroid function, bone and mineral metabolism and renal function (at baseline and follow-up visits)
• Pharmacological therapies (drug, duration, posology)
• Self-evaluation of quality of life (i.e. Questionnaire SF36)
• Disease-related morbidity and mortality

Inclusion Criteria:

• Cohort 1: chronic hypoparathyroidism (all etiological forms)
• Cohort 2: pseudohypoparathyroidism

Exclusion Criteria:

• None

Two independent cohorts of female and male patients of any age, one including patients with chronic hypoparathyroidism (cohort 1), and one including patients with pseudohypoparathyroidism (cohort 2).