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Hyperparathyroidism Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Classification

Classification of hyperparathyridism
Features Primary hyperparathyroidism Secondary hyperparathyroidism Tertiary hyperparathyroidism
Pathology Hyperfunction of parathyroid cells due to hyperplasia, adenoma or carcinoma. Physiological stimulation of parathyroid in response to hypocalcaemia. Following long term physiological stimulation leading to hyperplasia.
Cause
Associations May be associated with multiple endocrine neoplasia. Usually due to chronic renal failure or other causes of Vitamin D deficiency. Seen in chronic renal failure.
Serum calcium High Low/Normal High
Serum phosphate Low/Normal High High
Management Usually surgery if symptomatic. Cincacalcet can be considered in those not fit for surgery. Treatment of underlying cause. Usually cinacalcet or surgery in those that don't respond.

Causes

Common Causes

  • Post-surgical (most common cause)[1]
  • Autoimmune (2nd most common cause)[2]
    • Polyglandular autoimmune syndrome type 1
      • Also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy or APECED), or acquired hypoparathyroidism associated with autoimmune hypothyroidism
    • Isolated autoimmune hypoparathyroidism

Less Common Causes

  • Infiltration and/or destruction of parathyroid glands
    • Metal overload
      • Iron overload
        • Hemochromatosis
        • Thalassemia (due to repeated blood transfusion)
      • Copper overload
        • Wilson's disease
      • Aluminium deposition
        • Usually seen in patients with end-stage renal disease on hemodialysis
      • Hypermagnesemia
    • Radiation-induced destruction parathyroid glands
    • Hypomagnesemia (reversible)
    • Metastatic disease
    • Granulomatous disease
      • Amyloidosis
    • Syphilis
  • Progressive systemic sclerosis
  • Neonatal cause
    • Maternal hyperparathyroidism
  • Genetic causes

Genetic Causes

  • Chromosomal defects dup(1q),del(5p),dup(8q),del(10q),del(22q)
  • Monogenic hypoparathyroidism
  • Zellweger syndrome
  • Diabetic embryopathy
  • Fetal alcohol syndrome
  • Retinoid embryopathy


  • Isolated hypoparathyroidism
    • Autosomal dominant
      • Autosomal dominant familial isolated hypoparathyroidism caused by PTH gene mutation[3]
      • Autosomal dominant familial isolated hypoparathyroidism caused by caused by glial cells missing 2 (GCM2) gene mutation - Dominant negative effect[4]
      • Autosomal dominant hypocalcemia[5]
        • Autosomal dominant hypocalcemia type 1
          • Calcium-sensing 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 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.[6][7]
        • Autosomal dominant hypocalcemia type 2
          • G protein G11 (GNA11) mutation
    • Autosomal recessive
      • Autosomal recessive familial isolated hypoparathyroidism caused by PTH gene mutation[8]
      • Autosomal recessive familial isolated hypoparathyroidism caused by glial cells missing 2 (GCM2) gene mutation[9][4]
    • X-linked
      • X-linked recessive hypoparathyroidism
        • Caused by mutation in gene variant FHL1 (exon 4, c.C283T, p.R95W) on chromosome locus Xq26-q27.[10]
  • Congenital multisystem syndromes
    • DiGeorge syndrome[11]
    • Autosomal dominant disorder
      • Presents with thymus dysfunction, cardiac diseases, immunodeficiency, hypocalcemia, and other clinical problems
      • Caused by 22q11.2 deletion
      • Also known as 22q11.2DS, autosomal dominant Opitz G/BBB syndrome, CATCH 22 Syndromes, 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, abnormal facies, thymic aplasia, cleft palate, and hypocalcemia with 22q deletion
    • CHARGE syndrome[12]
      • Autosomal dominant disorder
      • Presents with coloboma, heart defects, atresia choanae, retarded growth and development, genitourinary abnormalities, and ear anomalies and/or deafness.
      • Caused by CHD7 G744S missense mutation
    • Kenny-Caffey syndrome[13]
      • Autosomal recessive inheritence
      • Deletion of the TBCE gene responsible for encoding a protein that participates in beta-tubulin folding.
      • Presents with hypoparathyroidism due to absent parathyroid tissue, growth retardation, medullary stenosis of tubular bones)
    • Sanjad-Sakati syndrome[14]
      • Sanjad-Sakati syndrome in exclusively found in arabian descent popultion.
      • Autosomal recessive disorder
      • Mutation in TBCE gene.
      • Presents with hypoparathyroidism, intellectual disability, dysmorphism
    • Barakat syndrome[15][16]
      • Autosomal recessive inheritance
      • Mutations in the GATA3 gene
      • Also known as hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome
      • Presents with primary hypoparathyroidism, nerve deafness, steroid-resistant nephrosis
    • Kearns-Sayre syndrome[17]
      • Mitochondrial inheritence
      • Presents with mitochondrial myopathy, ophthalmoplegia, retinal degeneration, cardiac conduction defects, primary hypoparathyroidism)
    • Pearson marrow pancreas syndrome[18]
      • Mitochondrial inheritence
      • Presents with lactic acidosis, neutropenia, sideroblastic anemia, pancreatic exocrine dysfunction, and hypoparathyroidism
    • Mitochondrial encephalopathy

References

  1. ↑ Marx SJ (2000). "Hyperparathyroid and hypoparathyroid disorders". N. Engl. J. Med. 343 (25): 1863–75. doi:10.1056/NEJM200012213432508. PMID 11117980.
  2. ↑ Eisenbarth GS, Gottlieb PA (2004). "Autoimmune polyendocrine syndromes". N. Engl. J. Med. 350 (20): 2068–79. doi:10.1056/NEJMra030158. PMID 15141045.
  3. ↑ Arnold A, Horst SA, Gardella TJ, Baba H, Levine MA, Kronenberg HM (1990). "Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism". J. Clin. Invest. 86 (4): 1084–7. doi:10.1172/JCI114811. PMC 296835. PMID 2212001.
  4. ↑ 4.0 4.1 Canaff L, Zhou X, Mosesova I, Cole DE, Hendy GN (2009). "Glial cells missing-2 (GCM2) transactivates the calcium-sensing receptor gene: effect of a dominant-negative GCM2 mutant associated with autosomal dominant hypoparathyroidism". Hum. Mutat. 30 (1): 85–92. doi:10.1002/humu.20827. PMID 18712808.
  5. ↑ Roszko KL, Bi RD, Mannstadt M (2016). "Autosomal Dominant Hypocalcemia (Hypoparathyroidism) Types 1 and 2". Front Physiol. 7: 458. doi:10.3389/fphys.2016.00458. PMC 5067375. PMID 27803672.
  6. ↑ Vezzoli G, Arcidiacono T, Paloschi V, Terranegra A, Biasion R, Weber G, Mora S, Syren ML, Coviello D, Cusi D, Bianchi G, Soldati L (2006). "Autosomal dominant hypocalcemia with mild type 5 Bartter syndrome". J. Nephrol. 19 (4): 525–8. PMID 17048213.
  7. ↑ Choi KH, Shin CH, Yang SW, Cheong HI (2015). "Autosomal dominant hypocalcemia with Bartter syndrome due to a novel activating mutation of calcium sensing receptor, Y829C". Korean J Pediatr. 58 (4): 148–53. doi:10.3345/kjp.2015.58.4.148. PMC 4414630. PMID 25932037.
  8. ↑ Sunthornthepvarakul T, Churesigaew S, Ngowngarmratana S (1999). "A novel mutation of the signal peptide of the preproparathyroid hormone gene associated with autosomal recessive familial isolated hypoparathyroidism". J. Clin. Endocrinol. Metab. 84 (10): 3792–6. doi:10.1210/jcem.84.10.6070. PMID 10523031.
  9. ↑ Ding C, Buckingham B, Levine MA (2001). "Familial isolated hypoparathyroidism caused by a mutation in the gene for the transcription factor GCMB". J. Clin. Invest. 108 (8): 1215–20. doi:10.1172/JCI13180. PMC 209530. PMID 11602629.
  10. ↑ Pillar N, Pleniceanu O, Fang M, Ziv L, Lahav E, Botchan S, Cheng L, Dekel B, Shomron N (2017). "A rare variant in the FHL1 gene associated with X-linked recessive hypoparathyroidism". Hum. Genet. 136 (7): 835–845. doi:10.1007/s00439-017-1804-9. PMC 5487855. PMID 28444561.
  11. ↑ Fomin AB, Pastorino AC, Kim CA, Pereira CA, Carneiro-Sampaio M, Abe-Jacob CM (2010). "DiGeorge Syndrome: a not so rare disease". Clinics (Sao Paulo). 65 (9): 865–9. PMC 2954737. PMID 21049214.
  12. ↑ Jain S, Kim HG, Lacbawan F, Meliciani I, Wenzel W, Kurth I, Sharma J, Schoeneman M, Ten S, Layman LC, Jacobson-Dickman E (2011). "Unique phenotype in a patient with CHARGE syndrome". Int J Pediatr Endocrinol. 2011: 11. doi:10.1186/1687-9856-2011-11. PMC 3216247. PMID 21995344.
  13. ↑ Metwalley KA, Farghaly HS (2012). "Kenny-Caffey syndrome type 1 in an Egyptian girl". Indian J Endocrinol Metab. 16 (5): 827–9. doi:10.4103/2230-8210.100645. PMC 3475915. PMID 23087875.
  14. ↑ Rafique B, Al-Yaarubi S (2010). "Sanjad-Sakati Syndrome in Omani children". Oman Med J. 25 (3): 227–9. doi:10.5001/omj.2010.63. PMC 3191633. PMID 22043344.
  15. ↑ Muroya K, Hasegawa T, Ito Y, Nagai T, Isotani H, Iwata Y, Yamamoto K, Fujimoto S, Seishu S, Fukushima Y, Hasegawa Y, Ogata T (2001). "GATA3 abnormalities and the phenotypic spectrum of HDR syndrome". J. Med. Genet. 38 (6): 374–80. PMC 1734904. PMID 11389161.
  16. ↑ Van Esch H, Groenen P, Nesbit MA, Schuffenhauer S, Lichtner P, Vanderlinden G, Harding B, Beetz R, Bilous RW, Holdaway I, Shaw NJ, Fryns JP, Van de Ven W, Thakker RV, Devriendt K (2000). "GATA3 haplo-insufficiency causes human HDR syndrome". Nature. 406 (6794): 419–22. doi:10.1038/35019088. PMID 10935639.
  17. ↑ Schaefer AM, Walker M, Turnbull DM, Taylor RW (2013). "Endocrine disorders in mitochondrial disease". Mol. Cell. Endocrinol. 379 (1–2): 2–11. doi:10.1016/j.mce.2013.06.004. PMC 3820028. PMID 23769710.
  18. ↑ Seneca S, De Meirleir L, De Schepper J, Balduck N, Jochmans K, Liebaers I, Lissens W (1997). "Pearson marrow pancreas syndrome: a molecular study and clinical management". Clin. Genet. 51 (5): 338–42. PMID 9212183.
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