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Hypercalcemia

Related to Parathyroid gland

Unrelated to parathyroid gland

Primary hyperparathyroidism

Secondary hyperparathyroidism

Tertiary hyperparathyroidism

Typical primary hyperparathyroidism

Familial hypocalciuric hypercalcemia

Malignancy

Medication induced

Nutritional

Granulomatous disease

Surgical

Para-neoplastic syndrome: Parathyroid hormone related peptide

Metaplasia: Hypercalcemia due to bone destruction

Thiazide diuretics

Lithium

Milk alkali syndrome

Vitamin D toxicity

Sarcoidosis

Immobilization

Differential diagnosis

Hypoparathyroidism				Inheritance	Gene mutation	Clinical features
Autoimmune		Autoimmune polyglandular hypoparathyroidism	Autoimmune polyendocrine syndrome type 1	Autosomal recessive	Mutation in AIRE gene	Also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Presents with a variable combination of: Failure of the parathyroid glands, adrenal cortex, gonads, pancreatic beta cells, gastric parietal cells, thyroid gland, and hepatitis. Chronic mucocutaneous candidiasis Dystrophy of dental enamel and nails, alopecia, vitiligo, and keratopathy.
Isolated		Familial Isolated hypoparathyroidism		Autosomal dominant	PTH gene	Clinical features of hypocalcemia including: Tetany (hallmark of acute hypocalcemia). Paresthesia in fingertips, toes, and perioral area. Carpopedal spasms. Circumoral numbness.
					Glial cells missing GCM2 gene	Clinical features of hypocalcemia including: Tetany (hallmark of acute hypocalcemia). Paresthesia in fingertips, toes, and perioral area. Carpopedal spasms. Circumoral numbness. Dominant negative mutation.
				Autosomal recessive	PTH gene	Clinical features of hypocalcemia including: Tetany (hallmark of acute hypocalcemia). Paresthesia in fingertips, toes, and perioral area. Carpopedal spasms. Circumoral numbness.
					Glial cells missing 2 (GCM2) gene	Clinical features of hypocalcemia including: Tetany (hallmark of acute hypocalcemia). Paresthesia in fingertips, toes, and perioral area. Carpopedal spasms. Circumoral numbness.
				X-linked	FHL1 gene (exon 4, c.C283T, p.R95W) on chromosome locus Xq26-q27	Clinical features of hypocalcemia including: Tetany (hallmark of acute hypocalcemia). Paresthesia in fingertips, toes, and perioral area. Carpopedal spasms. Circumoral numbness.
		Autosomal dominant hypercalcemia	Autosomal dominant hypocalcemia type 1	Autosomal dominant	Calcium-sensing receptor gene mutation	Calcium-sensing receptor gene activating mutation. Most common genetic form of hypoparathyroidism. Also known as familial hypercalciuric hypocalcemia. The activating mutation results in gain in function. Calcium-sensing receptor gene activating mutation can also cause mild Bartter syndrome type 5. This mutation cause the inhibition of apical potassium channel in the thick ascending limb of the loop of Henle in the kidney.
			Autosomal dominant hypocalcemia type 2	Autosomal dominant	G protein G11 (GNA11) mutation	Clinical features of hypocalcemia including: Tetany (hallmark of acute hypocalcemia). Paresthesia in fingertips, toes, and perioral area. Carpopedal spasms. Circumoral numbness.
Congenital multisystem syndromes		DiGeorge syndrome		Autosomal dominant	22q11.2 deletion.	Presents with thymus dysfunction, cardiac defects, immunodeficiency, hypocalcemia, and other clinical problems. Also known as 22q11.2DS, CATCH 22 syndrome, Cayler cardiofacial syndrome, conotruncal anomaly face syndrome (CTAF), deletion 22q11.2 syndrome, Sedlackova syndrome, Shprintzen syndrome, VCFS, velocardiofacial syndrome, and velo-cardio-facial syndrome. CATCH 22 stands for cardiac defects, abnormal facies, thymic aplasia, cleft palate, and hypocalcemia with 22q11.2 deletion.
		CHARGE syndrome		Autosomal dominant	CHD7 G744S missense mutation	Presents with coloboma, heart defects, atresia choanae, retarded growth and development, genitourinary abnormalities, and ear anomalies and/or deafness.
		Kenny-Caffey syndrome type 1		Autosomal recessive	Deletion of the TBCE gene	Presents with hypoparathyroidism due to absent parathyroid tissue, growth retardation, medullary stenosis of tubular bones.
		Kenny-Caffey syndrome type 2		Autosomal dominant	Mutation of “family with sequence similarity 111, member A″ (FAM111A) gene located on chromosome locus 11q12.1	Patients with Kenny-Caffey sundrome type 2 have same clinical features as Kenny-Caffey syndrome type 1 except for mental retardation.
		Sanjad-Sakati syndrome		Autosomal recessive	Mutation in TBCE gene.	Sanjad-Sakati syndrome in exclusively found in arabian descent population. Presents with hypoparathyroidism, intellectual disability, dysmorphism.
		Barakat syndrome		Autosomal recessive	Mutations in the GATA3 gene	Also known as hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome. Presents with primary hypoparathyroidism, nerve deafness, steroid-resistant nephrosis.
Metabolic diseases	Mitochondiral polyneuropathies	Kearns–Sayre syndrome		Mitochondrial inheritence	mtDNA deletion	Progressive external ophthalmoplegia Retinitis pigmentosa Cardiomyopathy Heart block
		Maternally inherited diabetes and deafness (MIDD)		Mitochondrial inheritence	MT‑TL1 defect	Diabetes mellitus Deafness
	Mitochondrial enzyme deficiencies	Mitochondrial trifunctional protein deficiency (MTP deficiency)		Autosomal recessive	HADHA or HADHB gene mutation	Clinical features of mitochondrial trifunctional protein deficiency occurring during infancy include: Feeding difficulties Lethargy Hypoglycemia Hypotonia Liver problems Infants with mitochondrial trifunctional protein deficiency are also at increased risk for: Serious heart problems Breathing difficulties Coma Sudden death Clinical features of mitochondrial trifunctional protein deficiency occurring after infancy include: Hypotonia Muscle pain Breakdown of muscle tissue Peripheral neuropathy
		Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHAD deficiency)		Autosomal recessive	G1528C gene mutation	Clinical features of LCHAD deficiency include: Hypoglycemia Hepatopathy Hypotonia Cardiomyopathy Retinopathy
	Heavy metal storage disorders	Hemochromatosis		Autosomal recessive	HFE gene mutation	Early symptoms of hereditary hemochromatosis are nonspecific and may include: Fatigue Joint pain Abdominal pain Decreased libido Late stage clinical features may include: Arthritis Liver disease Diabetes Heart abnormalities Skin discoloration
		Wilson's disease		Autosomal recessive	ATP7B gene mutation	Clinical features of Wilson's disease include: Initial feature Children and young adults: Liver disease Adults: Nervous system disorders and psychiatric disorders Other clinical features include: Clumsiness Tremors Difficulty walking Speech problems Impaired thinking ability Depression Anxiety Mood swings