Characterization of Patients With Non-surgical Hypoparathyroidism and Pseudohypoparathyroidism
Characterization of Patients With Non-surgical Hypoparathyroidism and Pseudohypoparathyroidism
Hypoparathyroidism (hypoPT) and pseudohypoparathyroidism (Ps-hypoPT) are rare diseases,
 characterized by low levels of parathyroid hormone [PTH] and plasma calcium or high plasma
 PTH and low plasma calcium, respectively. A recently study by the investigators' group,
 identified 123 living persons with idiopathic hypoPT and 62 living persons with Ps-hypoPT,
 only few of these have been genetic tested.

 The aim of the study is to perform a detailed clinical and genetic characterization of Danish
 patients with idiopathic hypoPT and Ps-hypoPT. Patients will be examined by questionnaires,
 biochemistry, scans, bone biopsies and genetic tests. Furthermore the investigators aim to
 perform family tracing for the hereditary forms. The prevalence of magnesium depletion will
 be assessed as well.

 In addition to providing new information on symptoms, co-morbidity, and prognosis for this
 group of patients, the investigators presume that the study may improve their understanding
 on calcium homeostasis and bone metabolism in general.
Background:

 Hypoparathyroidism (HypoPT) is a group of rare clinical disorders characterized by
 hypocalcaemia and hyperphosphatemia with inappropriate low levels of parathyroid hormone
 (PTH). Due to the lack of PTH, the renal production of 1α,25-dihydroxycholecalciferol
 (1,25(OH)2D) is reduced. Most often, HypoPT is caused by accidental removal of the
 parathyroid glands during neck surgery (postsurgical hypoPT). However, in rare in-stances
 HypoPT is caused by autoimmune disorders with immune mediated destruction of the parathyroid
 glands, or a variety of genetic mutations, including the CATCH-22 (DiGeorge) Syndrome,
 familial isolated HypoPT or an activating mutation in the gene encoding the calcium-sensing
 receptor (CaSR), termed autosomal dominant hypocalcaemia (ADH).

 The CaSR is not only found in the parathyroid glands, but is also expressed by other tissue
 including the renal tubules. Low plasma levels of ionised calcium (Ca2+) are registered by
 the calcium sensing receptors (CaSR) located e.g. in the cell membranes of the parathyroids
 and in the renal tubules. Low levels of Ca2+ increases the release of PTH from the
 parathyroids, which normalises plasma Ca2+ and decrease P-phosphate. Lack of PTH decreases
 the renal synthesis of 1,25-dihydroxycholecalciferol, witch in combination with low PTH
 decreases bone turnover. Although, large-scale meta-analysis of genome wide association data
 incorporating 150 candidate genes did not link the CaSR to bone mineral density or
 osteoporotic fracture risk, no specific data are available on whether BMD in patients with an
 activating mutation in their CaSR gene (ADH patients) differs from the general population.
 The largest case series of patients with ADH so far reported included 25 patients and did not
 report BMD within this group.

 Calcium is of importance to many physiological processes, including cardiovascular
 functioning. The CaSR has been suggested to be of importance in the regulation of blood
 pressure and a Batter's like phenotype has been reported in patients with ADH. Although the
 recent study by the investigators' group did not show an increased cardiovascular morbidity
 in patients with postsurgical hypoPT, no data are available on blood pressure regulation or
 indices of atherosclerosis in patients with idiopathic hypoPT.

 PseudoHypoPT is due to PTH resistance in the target organs, causing hypocalcemia with
 inappropriate high PTH concentrations. The phenotype in type 1 is known as Albrights's
 hereditary osteodystrophy, (AOH) (maternal 2 of 8 allele). Pseudo-pseudoHypoPT is
 characterized by AOH, but without the typical biochemical findings (pater-nal allele).
 PseudoHypoPT type 2 has typical biochemical changes but no characteristic phenotype.
 Discrepant results have been reported on effects on bone mineral density (BMD), as some
 studies has shown a decreased BMD (hyperparathyroid bone disease), whereas other studies have
 shown that BMD actually may be increased.

 Untreated, hypoPT is characterized by an increased neuromuscular irritability including
 weakness, muscle cramps, paraesthesias of the lips, tongue, fingers and feet, loss of memory,
 headaches and uncontrollable cramping muscle movements of the wrists and feet (carpopedal
 spasm). Other symptoms may be spasm of the facial muscles (Chovstek´s Sign) and the
 contraction of the muscle produced by ischemia (Trousseaus Sign).

 In long standing congenital cases there may be cataract and malformations of the teeth's. Due
 to high blood phosphorous levels intracranial calcifications (basal ganglia) may be seen by
 X-ray. Renal stones and renal failure may develop either because of the disease or its
 treatment. Studies have shown that postsurgical hy-poPT is associated with a reduced quality
 of life (QoL).

 Aim:

 The aim of the project is to perform a detailed clinical and genetic characterization of
 Danish patients with idiopathic hypoparathyroidism, including pseudohypoparathyroidism.
 Patients will be examined as detailed in the section on methods, and genetic tests will be
 performed in patients who have not been tested previously. Furthermore the investigators aim
 to perform family tracing for the hereditary forms.

 Design:

 A cross-sectional descriptive study on patients with idiopathic hypoparathyroidism, autosomal
 dominant hypocalcaemia and pseudohypoparathyroidism, including family tracing for inherited
 forms.

 Materials and methods:

 Study subjects:

 All patients with non-surgical hypoPT in Denmark will be invited by letter to participate in
 the study. Patients who accept participation will undergo a detailed examination in terms of:

 -  Questionnaire/ interviews:

 -  Quality of life: To study the participants health related quality of life the WHO's 5
 Well-Being Index, the Physical Activity Scale (PAS), and the SF-36v2 will be used in a
 Danish version.

 -  Biochemistry incl. genetics

 -  24hours urine:

 -  Cardiovascular indices: Blood pressure is measured in sitting position twice after
 minimum 5 minutes of rest. The presence of atherosclerosis is assessed by tonometry
 measuring pulse wave velocity and central aortic pressure using the SphygmoCor System.

 -  Muscle function- and postural stability: Isometric maximum voluntary muscle strength on
 the dominant hand side is measured using a dynamometer connected to a computer (Good
 Strength TM, Meititur Ldt, Finland) (25;26). Muscle strength is assessed at knee and
 elbow flexion and extension. Similarly, grip strength on the dominant hand is measured.
 Balance function is assessed by measuring the dynamic stability on a stadiometer
 (Meititur Ltd, Finland). Two smaller physical tests are also performed, "Repeated chair
 stand test" and "Timed Up and Go-test".

 -  Osteodensitometry: Bone mineral content (BMC) and areal bone mineral density (aBMD) is
 assessed by Dual-Energy X-ray absorptiometry" (DXA) using a Hologic Discovery scanner.
 Measurements are performed at the lumbar spine (L1-L4), hip region, forearm, and the
 whole body. Furthermore, body composition (lean and fat-tissue mass) will be determined
 by DXA. Volumetric total, cortical, and trabecular bone mineral density (vBMD) at the
 lumbar spine (L1+L2) and at the hip are assessed using quantitative computer tomography
 (QCT) (Mid-ways Software Inc., Austin Texas, USA). Bone microarchitecture is assessed by
 high resolution peripheral quantitative computer tomography (HRpQCT)-scans of the right
 forearm and tibia using an XtremeCT scanner (Scan-co Medical).

 -  Bone biopsies: a bone biopsy will be obtained from the iliac crest for histomorphometric
 analyses. Prior to the biopsy, intravital tetracycline double marking will be performed.

 -  Family tracing: Investigations on first degree relatives will be performed in patients
 with known inherited forms of hypoPT as well as in patients with hypoPT of unknown
 origin. At first, family members will have plasma levels of calcium and PTH measured. If
 results show signs of hypoPT, the relatives will be examined as the index persons
 themselves (as detailed in this protocol).

 Statistics:

 Differences between study groups are assessed using Fisher's Exact Test for categorical
 variables and a two-sample t-test or Mann-Whitney U-test for continuous variables, as
 appropriate. Sample size calculation are as detailed in the section on hypothesis.

 Ethical considerations:

 The general protocol has been approved by the Central Denmark Region Committees on Biomedical
 Research Ethics.

 Perspective:

 HypoPT is a rare disease and only few data are available on this group of patients. In
 addition to providing new information on symptoms, co-morbidity, and prognosis for this group
 of patients, the investigators presume that the study may improve their understanding on
 mechanisms of importance to calcium homeostasis and bone metabolism in general.
Inclusion Criteria:

 -  Diagnosed with either:

 Idiopathic hypoparathyroidism, pseudohypoparathyroidism or autosomal dominant hypocalcaemia

 -  Participants must be able to read and understand Danish

 Exclusion Criteria:

 -  None