Pseudohypoparathyroidism
| Pseudohypoparathyroidism | |
|---|---|
| Specialty | Endocrinology |
Pseudohypoparathyroidism is a rare autosomal dominant genetic condition associated primarily with resistance to the parathyroid hormone.[1] Those with the condition have a low serum calcium and high phosphate, but the parathyroid hormone level (PTH) is inappropriately high (due to the low level of calcium in the blood). Its pathogenesis has been linked to dysfunctional G proteins (in particular, Gs alpha subunit). Pseudohypoparathyroidism is a very rare disorder, with estimated prevalence between 0.3 and 1.1 cases per 100,000 population depending on geographic location.[2]
Types
[edit]Types include:
- Type 1a (OMIM 103580)
- Has a characteristic phenotypic appearance (Albright's hereditary osteodystrophy), including short fourth and fifth metacarpals and a rounded facies. It is most likely an autosomal dominant disorder.[3] It is also associated with thyroid stimulating hormone resistance. Caused by GNAS1 mutation.[4]
- Type 1b (OMIM 603233)
- Lacks the physical appearance of type 1a, but is biochemically similar.[5] It is associated with a methylation defect in the A/B exon of GNAS1, caused by STX16 disruption.[6][7]
- Type 2 (OMIM 203330)
- Also lacks the physical appearance of type 1a.[8] Since the genetic defect in type 2 is further down the signalling pathway than in type 1, there is a normal cAMP response to PTH stimulation despite the inherent abnormality in calcium regulation. The specific gene is not identified.
While biochemically similar, type 1 and 2 disease may be distinguished by the differing urinary excretion of cyclic AMP in response to exogenous PTH.[citation needed]
Some sources also refer to a "type 1c" (OMIM 612462).[9] The phenotype is the same as in type 1a, but red blood cells show normal Gs activity. As it is also caused by a GNAS mutation, it is not clear whether it should be considered an entity separate from Ia.[10]
Presentation
[edit]Patients may present with features of hypocalcaemia including carpo-pedal muscular spasms, cramping, tetany, and if the calcium deficit is severe, generalized seizures. IQ is typically mildly depressed or unaffected. Additional characteristics include short stature, obesity, developmental delay, and calcification of the basal ganglia in the deep white matter of the brain.[citation needed]
Type 1a pseudohypoparathyroidism is clinically manifest by bone resorption with blunting of the fourth and fifth knuckles of the hand, most notable when the dorsum of the hand is viewed in closed fist position. This presentation is known as 'knuckle knuckle dimple dimple' sign (Archibald's sign). This is as opposed to Turner syndrome which is characterized by blunting of only the fourth knuckle, and Down syndrome, which is associated with a hypoplastic middle phalanx.[citation needed]
Related conditions
[edit]The term pseudopseudohypoparathyroidism is used to describe a condition where the individual has the phenotypic appearance of pseudohypoparathyroidism type 1a, but is biochemically normal.
| Condition | Appearance | PTH levels | Calcitriol | Calcium | Phosphates | Imprinting | |
|---|---|---|---|---|---|---|---|
| Hypoparathyroidism | Normal | Low | Low | Low | High | Not applicable | |
| Pseudohypoparathyroidism | Type 1A | Skeletal defects | High | Low | Low | High | Gene defect from mother (GNAS1) |
| Type 1B | Normal | High | Low | Low | High | Likely a gene defect from mother (GNAS1 and STX16) however it can also be the result of an imprinting issue of (GNAS1) due to mother and father in equal measure | |
| Type 2 | Normal | High | Low | Low | High | ? | |
| Pseudopseudohypoparathyroidism | Skeletal defects | Normal | Normal | Normal[11] | Normal | gene defect from father | |
Diagnosis
[edit]Biochemical findings
[edit]- hypocalcemia
- hyperphosphatemia
- elevated parathyroid hormone (hyperparathyroidism)
- Suppressed calcitriol levels[12]
Treatment
[edit]Calcium and Calcitriol supplements, the latter with a larger dose than for treatment of hypoparathyroidism.[citation needed]
See also
[edit]References
[edit]- ^ Bastepe M (2008). "The GNAS Locus and Pseudohypoparathyroidism". Genomic Imprinting. Advances in Experimental Medicine and Biology. Vol. 626. pp. 27–40. doi:10.1007/978-0-387-77576-0_3. ISBN 978-0-387-77575-3. PMID 18372789.
- ^ Ucciferro, Peter; Anastasolpoulou, Catherine (10 August 2020). Pseudohypoparathyroidism. Treasure Island (FL): StatPearls Publishing. PMID 31613489. Retrieved 2 May 2021.
- ^ Online Mendelian Inheritance in Man (OMIM): 103580
- ^ de Nanclares GP, Fernández-Rebollo E, Santin I, et al. (June 2007). "Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright's hereditary osteodystrophy". J. Clin. Endocrinol. Metab. 92 (6): 2370–3. doi:10.1210/jc.2006-2287. PMID 17405843.
- ^ Online Mendelian Inheritance in Man (OMIM): 603233
- ^ Laspa E, Bastepe M, Jüppner H, Tsatsoulis A (December 2004). "Phenotypic and molecular genetic aspects of pseudohypoparathyroidism type Ib in a Greek kindred: evidence for enhanced uric acid excretion due to parathyroid hormone resistance". J. Clin. Endocrinol. Metab. 89 (12): 5942–7. doi:10.1210/jc.2004-0249. PMID 15579741.
- ^ Fröhlich LF, Bastepe M, Ozturk D, Abu-Zahra H, Jüppner H (June 2007). "Lack of Gnas epigenetic changes and pseudohypoparathyroidism type Ib in mice with targeted disruption of syntaxin-16". Endocrinology. 148 (6): 2925–35. doi:10.1210/en.2006-1298. PMID 17317779.
- ^ Online Mendelian Inheritance in Man (OMIM): 203330
- ^ Aldred MA (May 2006). "Genetics of pseudohypoparathyroidism types Ia and Ic". J. Pediatr. Endocrinol. Metab. 19 (Suppl 2): 635–40. doi:10.1515/jpem.2006.19.s2.635. PMID 16789628. S2CID 26538688.
- ^ Bastepe, M (2008). "The GNAS Locus and Pseudohypoparathyroidism". Genomic Imprinting. Advances in Experimental Medicine and Biology. Vol. 626. pp. 27–40. doi:10.1007/978-0-387-77576-0_3. ISBN 978-0-387-77575-3. PMID 18372789.
- ^ Shahid Hussain; Sharif Aaron Latif; Adrian Hall (1 July 2010). Rapid Review of Radiology. Manson Publishing. pp. 262–. ISBN 978-1-84076-120-7. Retrieved 30 October 2010.
- ^ Levine, Michael. "Pseudohypoparathyroidism: A Variation on the Theme of Hypoparathyroidism" (PDF). Archived from the original (PDF) on 2016-03-04. Retrieved 2014-11-10.
Further reading
[edit]- Mantovani, G; Bastepe, M; Monk, D; de Sanctis, L; Thiele, S; Usardi, A; Ahmed, SF; Bufo, R; Choplin, T; De Filippo, G; Devernois, G; Eggermann, T; Elli, FM; Freson, K; García Ramirez, A; Germain-Lee, EL; Groussin, L; Hamdy, N; Hanna, P; Hiort, O; Jüppner, H; Kamenický, P; Knight, N; Kottler, ML; Le Norcy, E; Lecumberri, B; Levine, MA; Mäkitie, O; Martin, R; Martos-Moreno, GÁ; Minagawa, M; Murray, P; Pereda, A; Pignolo, R; Rejnmark, L; Rodado, R; Rothenbuhler, A; Saraff, V; Shoemaker, AH; Shore, EM; Silve, C; Turan, S; Woods, P; Zillikens, MC; Perez de Nanclares, G; Linglart, A (August 2018). "Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement" (PDF). Nature Reviews. Endocrinology. 14 (8): 476–500. doi:10.1038/s41574-018-0042-0. PMC 6541219. PMID 29959430.