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Pseudohypoparathyroidism type 1B(PHP1B)

MedGen UID:
350343
Concept ID:
C1864100
Disease or Syndrome
Synonyms: PHP IB; PHP1B; Pseudohypoparathyroidism Ib (PHP-Ib); Pseudohypoparathyroidism Type IB
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Not genetically inherited
MedGen UID:
988794
Concept ID:
CN307044
Finding
Source: Orphanet
clinical entity without genetic inheritance.
 
Genes (locations): GNAS (20q13.32); GNAS-AS1 (20q13.32); STX16 (20q13.32)
 
Monarch Initiative: MONDO:0011301
OMIM®: 603233
Orphanet: ORPHA94089

Disease characteristics

Excerpted from the GeneReview: Disorders of GNAS Inactivation
Disorders of GNAS inactivation include the phenotypes pseudohypoparathyroidism Ia, Ib, and Ic (PHP-Ia, -Ib, -Ic), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). PHP-Ia and PHP-Ic are characterized by: End-organ resistance to endocrine hormones including parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), gonadotropins (LH and FSH), growth hormone-releasing hormone (GHRH), and CNS neurotransmitters (leading to obesity and variable degrees of intellectual disability and developmental delay); and The Albright hereditary osteodystrophy (AHO) phenotype (short stature, round facies, and subcutaneous ossifications) and brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb). Although PHP-Ib is characterized principally by PTH resistance, some individuals also have partial TSH resistance and mild features of AHO (e.g., brachydactyly). PPHP, a more limited form of PHP-Ia, is characterized by various manifestations of the AHO phenotype without the hormone resistance or obesity. POH and OC are even more restricted variants of PPHP: POH consists of dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia. OC consists of extra-skeletal ossification that is limited to the dermis and subcutaneous tissues. [from GeneReviews]
Authors:
Chad R Haldeman-Englert  |  Anna CE Hurst  |  Michael A Levine   view full author information

Additional description

From OMIM
Pseudohypoparathyroidism refers to a heterogeneous group of disorders characterized by resistance to parathyroid hormone (PTH; 168450). Pseudohypoparathyroidism type Ib is characterized clinically by isolated renal PTH resistance manifest as hypocalcemia, hyperphosphatemia, and increased serum PTH. Biochemical studies show a decreased response of urinary cAMP to exogenous PTH, but normal Gs activity in erythrocytes because the defect is restricted to renal tubule cells. In contrast to the findings in PHP Ia, patients with PHP Ib usually lack the physical characteristics of Albright hereditary osteodystrophy (AHO) and typically show no other endocrine abnormalities, although resistance to thyroid-stimulating hormone (TSH; 188540) has been reported in PHP Ib (Levine et al., 1983, Heinsimer et al., 1984). However, patients with PHP Ib may rarely show some features of AHO (Mariot et al., 2008). For a general phenotypic description, classification, and a discussion of molecular genetics of pseudohypoparathyroidism, see PHP1A (103580).  http://www.omim.org/entry/603233

Clinical features

From HPO
Low urinary cyclic AMP response to PTH administration
MedGen UID:
350345
Concept ID:
C1864105
Finding
Brachydactyly
MedGen UID:
67454
Concept ID:
C0221357
Congenital Abnormality
Digits that appear disproportionately short compared to the hand/foot. The word brachydactyly is used here to describe a series distinct patterns of shortened digits (brachydactyly types A-E). This is the sense used here.
Short metacarpal
MedGen UID:
323064
Concept ID:
C1837084
Anatomical Abnormality
Diminished length of one or more metacarpal bones in relation to the others of the same hand or to the contralateral metacarpal.
Obesity
MedGen UID:
18127
Concept ID:
C0028754
Disease or Syndrome
Accumulation of substantial excess body fat.
Hypocalcemia
MedGen UID:
5705
Concept ID:
C0020598
Disease or Syndrome
An abnormally decreased calcium concentration in the blood.
Hyperphosphatemia
MedGen UID:
39326
Concept ID:
C0085681
Disease or Syndrome
An abnormally increased phosphate concentration in the blood.
Elevated circulating parathyroid hormone level
MedGen UID:
167805
Concept ID:
C0857973
Finding
An abnormal increased concentration of parathyroid hormone.
Pseudohypoparathyroidism
MedGen UID:
46178
Concept ID:
C0033806
Disease or Syndrome
Disorders of GNAS inactivation include the phenotypes pseudohypoparathyroidism Ia, Ib, and Ic (PHP-Ia, -Ib, -Ic), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). PHP-Ia and PHP-Ic are characterized by: End-organ resistance to endocrine hormones including parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), gonadotropins (LH and FSH), growth hormone-releasing hormone (GHRH), and CNS neurotransmitters (leading to obesity and variable degrees of intellectual disability and developmental delay); and The Albright hereditary osteodystrophy (AHO) phenotype (short stature, round facies, and subcutaneous ossifications) and brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb). Although PHP-Ib is characterized principally by PTH resistance, some individuals also have partial TSH resistance and mild features of AHO (e.g., brachydactyly). PPHP, a more limited form of PHP-Ia, is characterized by various manifestations of the AHO phenotype without the hormone resistance or obesity. POH and OC are even more restricted variants of PPHP: POH consists of dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia. OC consists of extra-skeletal ossification that is limited to the dermis and subcutaneous tissues.

Professional guidelines

PubMed

Mantovani G, Bastepe M, Monk D, de Sanctis L, Thiele S, Ahmed SF, Bufo R, Choplin T, De Filippo G, Devernois G, Eggermann T, Elli FM, Garcia Ramirez A, Germain-Lee EL, Groussin L, Hamdy NAT, Hanna P, Hiort O, Jüppner H, Kamenický P, Knight N, 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
Horm Res Paediatr 2020;93(3):182-196. Epub 2020 Aug 5 doi: 10.1159/000508985. PMID: 32756064Free PMC Article
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
Nat Rev Endocrinol 2018 Aug;14(8):476-500. doi: 10.1038/s41574-018-0042-0. PMID: 29959430Free PMC Article
Mantovani G
J Clin Endocrinol Metab 2011 Oct;96(10):3020-30. Epub 2011 Aug 3 doi: 10.1210/jc.2011-1048. PMID: 21816789

Recent clinical studies

Etiology

Urakawa T, Sano S, Kawashima S, Nakamura A, Shima H, Ohta M, Yamada Y, Nishida A, Narusawa H, Ohtsu Y, Matsubara K, Dateki S, Maruo Y, Fukami M, Ogata T, Kagami M
Eur J Endocrinol 2023 Dec 6;189(6):590-600. doi: 10.1093/ejendo/lvad163. PMID: 38039118
Danzig J, Li D, Jan de Beur S, Levine MA
J Clin Endocrinol Metab 2021 Oct 21;106(11):e4603-e4620. doi: 10.1210/clinem/dgab460. PMID: 34157100Free PMC Article
Ramalho E Silva JD, da Rocha GFMA, Oliveira MJM
Arch Endocrinol Metab 2021 Nov 1;65(1):112-116. Epub 2020 Dec 15 doi: 10.20945/2359-3997000000316. PMID: 33320452Free PMC Article
Vlachopapadopoulou EA, Anagnostou E, Dikaiakou E, Hanna P, Tsolia M, Michalacos S, Linglart A, Karavanaki K
J Pediatr Endocrinol Metab 2020 Nov 26;33(11):1475-1479. doi: 10.1515/jpem-2020-0192. PMID: 33027051
Dixit A, Chandler KE, Lever M, Poole RL, Bullman H, Mughal MZ, Steggall M, Suri M
J Clin Endocrinol Metab 2013 Jan;98(1):E103-8. Epub 2012 Nov 8 doi: 10.1210/jc.2012-2639. PMID: 23144470

Diagnosis

Urakawa T, Sano S, Kawashima S, Nakamura A, Shima H, Ohta M, Yamada Y, Nishida A, Narusawa H, Ohtsu Y, Matsubara K, Dateki S, Maruo Y, Fukami M, Ogata T, Kagami M
Eur J Endocrinol 2023 Dec 6;189(6):590-600. doi: 10.1093/ejendo/lvad163. PMID: 38039118
Keidai Y, Iwasaki Y, Iwasaki K, Honjo S, Bastepe M, Hamasaki A
J Clin Endocrinol Metab 2022 Feb 17;107(3):e947-e954. doi: 10.1210/clinem/dgab801. PMID: 34741517Free PMC Article
Ramalho E Silva JD, da Rocha GFMA, Oliveira MJM
Arch Endocrinol Metab 2021 Nov 1;65(1):112-116. Epub 2020 Dec 15 doi: 10.20945/2359-3997000000316. PMID: 33320452Free PMC Article
Goto M, Yamamoto Y, Ishii M, Nakamura A, Sano S, Kagami M, Fukami M, Saito R, Araki S, Kubo K, Kawagoe R, Kawada Y, Kusuhara K
Pediatr Int 2016 Nov;58(11):1229-1231. doi: 10.1111/ped.13096. PMID: 27882740
Bakker B, Sonneveld LJ, Woltering MC, Bikker H, Kant SG
J Clin Endocrinol Metab 2015 Nov;100(11):3963-6. Epub 2015 Sep 14 doi: 10.1210/jc.2015-2260. PMID: 26367199

Therapy

Goel NJ, Meyers LL, Frangos M
J Assist Reprod Genet 2018 Jun;35(6):975-979. Epub 2018 Feb 7 doi: 10.1007/s10815-018-1129-1. PMID: 29417303Free PMC Article
Poradosu S, Bravenboer B, Takatani R, Jüppner H
BMJ Case Rep 2016 May 11;2016 doi: 10.1136/bcr-2016-214673. PMID: 27170606Free PMC Article
Srivastava T, Krudys J, Mardis NJ, Sebestyen-VanSickle J, Alon US
Pediatr Nephrol 2016 May;31(5):795-800. Epub 2015 Dec 1 doi: 10.1007/s00467-015-3271-7. PMID: 26628282
Neary NM, El-Maouche D, Hopkins R, Libutti SK, Moses AM, Weinstein LS
J Clin Endocrinol Metab 2012 Sep;97(9):3025-30. Epub 2012 Jun 26 doi: 10.1210/jc.2012-1655. PMID: 22736772Free PMC Article
Amor DJ, Halliday J
Hum Reprod 2008 Dec;23(12):2826-34. Epub 2008 Aug 14 doi: 10.1093/humrep/den310. PMID: 18703582

Prognosis

Danzig J, Li D, Jan de Beur S, Levine MA
J Clin Endocrinol Metab 2021 Oct 21;106(11):e4603-e4620. doi: 10.1210/clinem/dgab460. PMID: 34157100Free PMC Article
Ramalho E Silva JD, da Rocha GFMA, Oliveira MJM
Arch Endocrinol Metab 2021 Nov 1;65(1):112-116. Epub 2020 Dec 15 doi: 10.20945/2359-3997000000316. PMID: 33320452Free PMC Article
Goel NJ, Meyers LL, Frangos M
J Assist Reprod Genet 2018 Jun;35(6):975-979. Epub 2018 Feb 7 doi: 10.1007/s10815-018-1129-1. PMID: 29417303Free PMC Article
Chu X, Zhu Y, Wang O, Nie M, Quan T, Xue Y, Wang W, Jiang Y, Li M, Xia W, Xing X
J Bone Miner Res 2018 Apr;33(4):743-752. Epub 2018 Jan 3 doi: 10.1002/jbmr.3360. PMID: 29240265
Garcia C, Correia CR, Lopes L
Paediatr Int Child Health 2018 Nov;38(4):281-284. Epub 2017 Jun 26 doi: 10.1080/20469047.2017.1341730. PMID: 28648114

Clinical prediction guides

Urakawa T, Sano S, Kawashima S, Nakamura A, Shima H, Ohta M, Yamada Y, Nishida A, Narusawa H, Ohtsu Y, Matsubara K, Dateki S, Maruo Y, Fukami M, Ogata T, Kagami M
Eur J Endocrinol 2023 Dec 6;189(6):590-600. doi: 10.1093/ejendo/lvad163. PMID: 38039118
Kawashima S, Yuno A, Sano S, Nakamura A, Ishiwata K, Kawasaki T, Hosomichi K, Nakabayashi K, Akutsu H, Saitsu H, Fukami M, Usui T, Ogata T, Kagami M
J Bone Miner Res 2022 Oct;37(10):1850-1859. Epub 2022 Aug 17 doi: 10.1002/jbmr.4652. PMID: 35859320
Tayeh MK, DeVaul J, LeSueur K, Yang C, Bedoyan JK, Thomas P, Hannibal MC, Innis JW
Am J Med Genet A 2022 Jul;188(7):2209-2216. Epub 2022 Apr 1 doi: 10.1002/ajmg.a.62752. PMID: 35365979Free PMC Article
Ramalho E Silva JD, da Rocha GFMA, Oliveira MJM
Arch Endocrinol Metab 2021 Nov 1;65(1):112-116. Epub 2020 Dec 15 doi: 10.20945/2359-3997000000316. PMID: 33320452Free PMC Article
Goto M, Yamamoto Y, Ishii M, Nakamura A, Sano S, Kagami M, Fukami M, Saito R, Araki S, Kubo K, Kawagoe R, Kawada Y, Kusuhara K
Pediatr Int 2016 Nov;58(11):1229-1231. doi: 10.1111/ped.13096. PMID: 27882740

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