Deranged Calciotropic Hormonal Activity

Parathyroid Hormone Excess or Deficiency

Primary hyperparathyroidism, Multiple endocrine neoplasia (MEN)

Primary hyperparathyroidism is due to increased intrinsic activity of the parathyroid gland, altering the secretion of parathyroid hormone (PTH), in the absence of a known or recognized stimulus affecting calcium homeostasis.

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Familial isolated primary hyperparathyroidism (FIHP)

Familial isolated primary hyperparathyroidism (FIHP) is characterized by primary hyperparathyroidism not associated with other features. FIHP is essentially a diagnosis of exclusion.

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Familial hypocalciuric hypercalcemia

Familial hypocalciuric hypercalcemia (HHC) is a benign condition associated with hypercalcemia, low urinary calcium excretion (assessed via a calcium/creatinine clearance ratio), normal to minimally elevated PTH levels, and hypermagnesemia.

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Hypoparathyroidism in Complex Disorders (APS1, APS2)

Autoimmune polyendocrinopathy syndrome type 1 (APS1, also referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome, APECED, OMIM phenotype number #240300) is a complex disorder usually inherited as an autosomal recessive trait, although an autosomal pattern of inheritance has been described in one kindred.

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Mitochondrial Diseases

Mitochondrial diseases are a group of diseases caused by impairment of the respiratory chain. The prevalence is approximately 1–2/10.000. These disorders are subdivided in two groups: the disorders due to defects in mtDNA (mitochondrial DNA) and due to defects in nuclear DNA.

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Abnormal Parathyroid Hormone Receptor Signaling

Gsa Abnormalities

The term pseudohypoparathyroidism encompasses several rare related metabolic disorders characterized by features of functional hypoparathyroidism (hypocalcemia, hyperphosphatemia) but with high serum PTH levels.

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Acrodysostosis 2 (ACRDYS2)

Acrodysostosis is a rare skeletal dysplasia, which includes two forms, Acrodysostosis 1 (ACRDYS1) and ACRDYS2, with similar clinical characteristics, such as severe brachydactyly, facial dysostosis and nasal hypoplasia, and different mutations (see also ACRDYS1). ACRDYS2 is caused by heterozygous mutation in the PDE4D gene, encoding cAMP-specific phospho-diesterase 4D.

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McCune-Albright syndrome (MAS)

McCune-Albright syndrome (MAS) is rare disease caused by an early embryonic postzygotic somatic activating mutations in the GNAS1 gene, encoding the cAMP pathway-associated G-protein, Gsα.

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Eiken familial skeletal dysplasia

Eiken syndrome is a rare familial skeletal dysplasia, caused by homozygous mutation in the PTH/PTHrP receptor (PTHR1) gene. This disease is characterized by multiple epiphyseal dysplasia, with extremely retarded ossification (principally of the epiphyses, pelvis, hands and feet), as well as by abnormal modeling of the bones in hands and feet, abnormal persistence of cartilage in the pelvis and mild growth retardation.

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Chondrodysplasia Blomstrand type (BOCD)

Chondrodysplasia Blomstrand type (BOCD) is a rare autosomal recessive disorder, caused by homozygous or compound heterozygous inactivating mutations in the parathyroid hormone receptor-1 gene. The estimated prevalence is <1/1.000.000. Until now, few cases have been reported in the literature.

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Disorders of Vitamin D Metabolism & Action

Vitamin D hydroxylation-deficient rickets type 1A (VDDR1A)

Vitamin D hydroxylation-deficient rickets type 1A (VDDR1A) is a rare autosomal recessive disorder caused by mutations in the CYP27B1 gene, resulting in 1α-hydroxylase enzyme deficiency.

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Vitamin D-dependent rickets type 2A (VDDR2A)

Vitamin D-dependent rickets type 2A (VDDR2A) is an autosomal recessive disorder caused by mutation in the gene encoding the vitamin D receptor (VDR). Signalling via this receptor regulates gene expression in 1,25 OHvitamin D3-responsive cells.

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Disorders of Phosphate Homeostasis

Autosomal dominant hypophosphatemic rickets (ADHR)

Autosomal dominant hypophosphatemic rickets (ADHR) is a rare genetic disorder of phosphate homeostasis, caused by heterozygous point mutations at amino acid residues 176 or 179 in fibroblast growth factor 23 (FGF23).

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Osteoglophonic dysplasia (OGD)

Osteoglophonic dysplasia (OGD) is a very rare skeletal disease caused by activating mutations in a highly conserved domain in the gene encoding fibroblast growth factor receptor-1 (FGFR1). The name “osteoglophonic” was derived from the Greek word meaning a “hollowed-out” appearance of bone. 

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Autosomal recessive hypophosphatemic rickets type 2 (ARHR2)

Autosomal recessive hypophosphatemic rickets (ARHR) is an extremely rare disease, characterized by hypophosphatemia resulting from renal phosphate wasting (See also ARHR1).

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Hypophosphatemic rickets with hyperparathyroidism (HRH)

Hypophosphatemic rickets with hyperparathyroidism (HRH) is a form of hypophosphatemic rickets with marked parathyroid hyperplasia. It has been demonstrate that HRH is caused by a mutation that results in increased levels of circulating α-Klotho. It has been described a de novo translocation with a breakpoint adjacent to α-Klotho.

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Hypophosphatemia nephrolithiasis osteoporosis type 1 (NPHLOP1)

Hypophosphatemia nephrolithiasis osteoporosis type 1 (NPHLOP1) is caused by heterozygous mutation in the SLC34A1 gene. The gene encodes the protein for the type 2a sodium–phosphate cotransporter (NPT2a), which resides in the apical membrane of renal proximal tubular cells.

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Hyperphosphatemic Familial Tumoral Calcinosis (HFTC) / Hyperostosis Hyperphosphatemia Syndrome (HHS)

Familial tumoral calcinosis (FTC) is a rare disease characterized by hyperphosphatemia due to hypophosphaturia and by ectopic calcifications, in cutaneous and subcutaneous tissues, especially around large joints (hip, elbow or shoulder). 

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Normophosphatemic familial tumoral calcinosis (NFTC)

Normophosphatemic familial tumoral calcinosis (NFTC) is an autosomal recessive disorder characterized by calcium deposition in skin and mucosae, unremitting pain and life-threatening skin infections. It can be caused by mutation in the gene encoding the sterile alpha motif domain-containing-9 protein (SAMD9).

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Hereditary hyperparathyroidism jaw-tumor syndrome (HPT-JT)

Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare, autosomal-dominant disease, secondary to germline-inactivating mutations of the tumor suppressor gene CDC73 (prevalence unknown). 

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Neonatal severe hyperparathyroidism (NSHPT)

Neonatal severe hypoparathyroidism is a rare autosomal recessive disorder of calcium homeostasis. NSHPT occurs in the first 6 months of life, but is often discovered in the first few weeks postnatally. Homozygous CASR germline pathogenic variants are classically associated with NSHPT.

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Hypoparathyroidism in Complex Disorders (HDR, KSC1/2, HRD, GCLEB)

They include developmental disorders with hypoparathyroidism as a common feature, in which cytogenetic alterations, such as microdeletion 22q11.2 responsible for DiGeorge syndrome, and mutations of PTH, GCM2 and CaSR have been excluded.

Hypoparathyroidism in Complex Disorders - DiGeorge Syndrome

DiGeorge Syndrome (OMIM phenotype number #188400) is the most frequent form of hypoparathyroidism associated with multiorgan impairment due to abnormalities in transcription factors, autoimmune dysregulation or mitochondrial alterations.

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Isolated Hypoparathyroidism

Autosomal dominant hypocalcemia with hypercalciuria, also referred to as autosomal dominant hypercalciuric hypocalcemia or hypocalcemic hypercalciuria or familial hypocalcemia, is an inherited disorder of calcium metabolism, transmitted with a autosomal dominant pattern of inheritance.

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Acrodysostosis 1 (ACRDYS1)

Acrodysostosis comprises a heterogeneous group of rare skeletal dysplasia that share characteristic features, such as severe brachydactyly, facial dysostosis and nasal hypoplasia.

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Progressive osseous heteroplasia (POH)

Progressive osseous heteroplasia (POH) is a very rare genetic disease characterized by progressive ectopic ossification. This disease is generally caused by a mutation resulting in loss of function of the Gs-alpha isoform of the GNAS gene on the paternal allele.

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Metaphyseal chondrodysplasia Jansen type (JMC)

Metaphyseal chondrodysplasia Jansen type (JMC) is a rare autosomal dominant skeletal disease caused by mutations in the PTH/PTHrP receptor (PTH1R) gene.

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Multiple enchondromatosis, Ollier type

Enchondromatosis is a rare heterogeneous skeletal disease characterized by multiple enchondromas, and it includes several different subtypes of which Ollier disease and Maffucci syndrome are most common. Enchondromas are benign hyaline cartilage forming tumors in the medulla of metaphyseal bone. Ollier disease (also known as dyschondroplasia, multiple cartilaginous enchondromatosis, en- chondromatosis Spranger type I) is characterized by multiple enchondromatosis with an asymmetric distribution.

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Vitamin D hydroxylation-deficient rickets type 1B (VDDR1B)

Vitamin D hydroxylation-deficient rickets type 1B (VDDR1B) is due to a defect in vitamin D 25-hydroxylation, and is caused by mutation in the CYP2R1 gene. The synthesis of bioactive vitamin D requires hydroxylation at the 1 α and 25 positions by cytochrome P450 enzymes in the kidney and liver, respectively.

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Vitamin D-dependent rickets type 2B (VDDR2B)

Vitamin D-dependent rickets type 2B (VDDR2B) is an unusual form of Vitamin D-dependent rickets due to abnormal expression of a hormone response element binding protein that interferes with the normal function of the VDR, without mutations in the VDR coding region.

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X-linked, dominant, hypophosphatemic rickets (XLHR)

X-linked, dominant, hypophosphatemic rickets (XLHR) is a genetic disorder caused by inactivating mutations in the PHEX gene (phosphate-regulating gene with homologies to endopeptidase on the X chromosome). XLHR, first described by Albright in 1937, is the most frequent form of hypophosphatemic rickets, with a prevalence of 1/20.000. The disease affects both sexes.

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Autosomal recessive hypophosphatemic rickets type 1 (ARHR1)

Hypoparathyroidism is an uncommon endocrine-deficiency disorder characterized by low serum calcium levels, elevated serum phosphorus levels, and absent or inappropriately low levels of parathyroid hormone (PTH).

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Generalized arterial calcification of infancy (GACI)

Generalized arterial calcification of infancy (GACI) is caused, in most cases, by homozygous or compound heterozygous inactivating mutation in the ENPP1 gene, resulting in reduced plasma inorganic pyrophosphate levels.

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Hereditary hypophosphatemic rickets with hypercalciuria (HHRH)

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder, caused by homozygous or compound heterozygous mutation in the SLC34A3 gene. SLC34A3 gene encodes the sodium (Na+)-dependent phosphate cotransporter 2c (NaPi-IIc). NaPi-IIc, with NaPi-IIa encoded by SLC34A1, reabsorb most of filtered phosphate in the renal proximal tubule.

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Hypophosphatemia nephrolithiasis osteoporosis type 2 (NPHLOP2)

Hypophosphatemia nephrolithiasis osteoporosis type 2 (NPHLOP2) is caused by heterozygous mutation in the SLC9A3R1 or NHERF1 gene. NHERF1, the sodium-hydrogen exchanger regulatory factor 1, binds to the main renal phosphate transporter NPT2a and to the parathyroid hormone (PTH) receptor.

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