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Pseudopseudohypoparathyroidism(PPHP)

MedGen UID:
10995
Concept ID:
C0033835
Disease or Syndrome
Synonyms: Albright hereditary osteodystrophy without multiple hormone resistance; PPHP
SNOMED CT: Pseudopseudohypoparathyroidism (237659007)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM
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.
 
Gene (location): GNAS (20q13.32)
 
Monarch Initiative: MONDO:0012912
OMIM®: 612463

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
Patients with pseudopseudohypoparathyroidism do not show resistance to parathyroid hormone (PTH; 168450) or other hormones, as is the case with PHP1A (103580), but do manifest the constellation of clinical features referred to as Albright hereditary osteodystrophy (AHO), which includes short stature, obesity, round facies, subcutaneous ossifications, brachydactyly, and other skeletal anomalies. Some patients have mental retardation (Kinard et al., 1979; Fitch, 1982; Mantovani and Spada, 2006). PPHP occurs only after paternal inheritance of the molecular defect, whereas PHP1A occurs only after maternal inheritance of the molecular defect (see Inheritance and Pathogenesis below). This is an example of imprinting, with differential gene expression depending on the parent of origin of the allele (Davies and Hughes, 1993; Wilson et al., 1994). For a general phenotypic description, classification, and a discussion of molecular genetics of pseudohypoparathyroidism, see PHP1A (103580).  http://www.omim.org/entry/612463

Clinical features

From HPO
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.
Short metatarsal
MedGen UID:
341358
Concept ID:
C1849020
Finding
Diminished length of a metatarsal bone, with resultant proximal displacement of the associated toe.
Obesity
MedGen UID:
18127
Concept ID:
C0028754
Disease or Syndrome
Accumulation of substantial excess body fat.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Cognitive impairment
MedGen UID:
90932
Concept ID:
C0338656
Mental or Behavioral Dysfunction
Diminished mental function.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
A broad category of disorders characterized by an impairment to the intelligence an individual possesses. These impairments can result from trauma, birth, or disease and are not restricted to any particular age group.
Enamel hypoplasia
MedGen UID:
3730
Concept ID:
C0011351
Disease or Syndrome
A form of amelogenesis imperfecta characterised by incomplete formation of the dental enamel and transmitted as an X-linked or autosomal dominant trait.
Osteoporosis
MedGen UID:
14535
Concept ID:
C0029456
Disease or Syndrome
Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility. According to the WHO criteria, osteoporosis is defined as a BMD that lies 2.5 standard deviations or more below the average value for young healthy adults (a T-score below -2.5 SD).
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 neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
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.
Short metatarsal
MedGen UID:
341358
Concept ID:
C1849020
Finding
Diminished length of a metatarsal bone, with resultant proximal displacement of the associated toe.
Enamel hypoplasia
MedGen UID:
3730
Concept ID:
C0011351
Disease or Syndrome
A form of amelogenesis imperfecta characterised by incomplete formation of the dental enamel and transmitted as an X-linked or autosomal dominant trait.
Delayed eruption of teeth
MedGen UID:
68678
Concept ID:
C0239174
Finding
Round face
MedGen UID:
116087
Concept ID:
C0239479
Finding
The facial appearance is more circular than usual as viewed from the front.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Full cheeks
MedGen UID:
355661
Concept ID:
C1866231
Finding
Increased prominence or roundness of soft tissues between zygomata and mandible.
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.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Acquired Abnormality
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.

Term Hierarchy

Recent clinical studies

Etiology

Schneller-Pavelescu L, Vergara de Caso E, Pastor-Tomás N, Gutiérrez Agulló M, Ruiz Pérez L, Betlloch Mas I
Pediatr Dermatol 2019 May;36(3):355-359. Epub 2019 Feb 27 doi: 10.1111/pde.13769. PMID: 30809832
Elli FM, Bordogna P, de Sanctis L, Giachero F, Verrua E, Segni M, Mazzanti L, Boldrin V, Toromanovic A, Spada A, Mantovani G
J Bone Miner Res 2016 Jun;31(6):1215-24. Epub 2016 Feb 9 doi: 10.1002/jbmr.2785. PMID: 26763073
Wu YL, Hwang DY, Hsiao HP, Ting WH, Huang CY, Tsai WY, Chen HC, Chao MC, Lo FS, Tsai JD, Yang S, Shih SL, Lin SP, Lin CL, Lee YJ
PLoS One 2014;9(3):e90640. Epub 2014 Mar 20 doi: 10.1371/journal.pone.0090640. PMID: 24651309Free PMC Article
Cho SY, Yoon YA, Ki CS, Huh HJ, Yoo HW, Lee BH, Kim GH, Yoo JH, Kim SY, Kim SJ, Sohn YB, Park SW, Huh R, Chang MS, Lee J, Kwun Y, Maeng SH, Jin DK
Exp Clin Endocrinol Diabetes 2013 Oct;121(9):539-45. Epub 2013 Oct 14 doi: 10.1055/s-0033-1349867. PMID: 24127307
Van Dop C, Wang H, Mulaikal RM, Tolo VT, Rosenbaum AE
Pediatr Radiol 1988;18(5):429-31. doi: 10.1007/BF02388057. PMID: 3174285

Diagnosis

Schneller-Pavelescu L, Vergara de Caso E, Pastor-Tomás N, Gutiérrez Agulló M, Ruiz Pérez L, Betlloch Mas I
Pediatr Dermatol 2019 May;36(3):355-359. Epub 2019 Feb 27 doi: 10.1111/pde.13769. PMID: 30809832
Benvenuto P, Attarian A
J Pediatr 2018 May;196:321. Epub 2018 Feb 21 doi: 10.1016/j.jpeds.2017.12.083. PMID: 29429567
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Exp Clin Endocrinol Diabetes 2013 Oct;121(9):539-45. Epub 2013 Oct 14 doi: 10.1055/s-0033-1349867. PMID: 24127307
Rahmat N, Venables P
BMJ Case Rep 2013 Jun 24;2013 doi: 10.1136/bcr-2013-010116. PMID: 23814007Free PMC Article

Therapy

Arrigoni P, Minen A
JBJS Case Connect 2019 Apr-Jun;9(2):e0287. doi: 10.2106/JBJS.CC.18.00287. PMID: 31085937
Elli FM, Bordogna P, de Sanctis L, Giachero F, Verrua E, Segni M, Mazzanti L, Boldrin V, Toromanovic A, Spada A, Mantovani G
J Bone Miner Res 2016 Jun;31(6):1215-24. Epub 2016 Feb 9 doi: 10.1002/jbmr.2785. PMID: 26763073
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J Endocrinol Invest 1993 Oct;16(9):709-13. doi: 10.1007/BF03348916. PMID: 8282968
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Arch Dis Child 1991 Apr;66(4):533-5. doi: 10.1136/adc.66.4.533. PMID: 2031618Free PMC Article
Chopra IJ, Nugent CA
Am J Med Sci 1970 Sep;260(3):171-83. doi: 10.1097/00000441-197009000-00005. PMID: 5480625

Prognosis

Truelove A, Mulay A, Prapa M, Casey RT, Adler AI, Offiah AC, Poole KES, Trotman J, Al Hasso N, Park SM
Am J Med Genet A 2019 Jul;179(7):1330-1337. Epub 2019 May 1 doi: 10.1002/ajmg.a.61163. PMID: 31041856
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
Ward S, Sugo E, Verge CF, Wargon O
Australas J Dermatol 2011 May;52(2):127-31. Epub 2011 Jan 12 doi: 10.1111/j.1440-0960.2010.00722.x. PMID: 21605097
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Davids MS, Crawford E, Weremowicz S, Morton CC, Copeland NG, Gilbert DJ, Jenkins NA, Phelan MC, Comb MJ, Melnick MB
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Clinical prediction guides

Iwase T, Yoshida M, Hashizume Y, Yazawa I, Takahashi S, Ando T, Ikeda T, Nokura K
Neuropathology 2019 Feb;39(1):39-46. Epub 2018 Nov 14 doi: 10.1111/neup.12518. PMID: 30430658
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Bone 2015 Feb;71:53-7. Epub 2014 Oct 18 doi: 10.1016/j.bone.2014.10.006. PMID: 25464124Free PMC Article
Jin HY, Lee BH, Choi JH, Kim GH, Kim JK, Lee JH, Yu J, Yoo JH, Ko CW, Lim HH, Chung HR, Yoo HW
Clin Endocrinol (Oxf) 2011 Aug;75(2):207-13. doi: 10.1111/j.1365-2265.2011.04026.x. PMID: 21521295
Long DN, McGuire S, Levine MA, Weinstein LS, Germain-Lee EL
J Clin Endocrinol Metab 2007 Mar;92(3):1073-9. Epub 2006 Dec 12 doi: 10.1210/jc.2006-1497. PMID: 17164301
Davids MS, Crawford E, Weremowicz S, Morton CC, Copeland NG, Gilbert DJ, Jenkins NA, Phelan MC, Comb MJ, Melnick MB
Genomics 2001 Sep;77(1-2):2-4. doi: 10.1006/geno.2001.6605. PMID: 11543625

Recent systematic reviews

Batla A, Tai XY, Schottlaender L, Erro R, Balint B, Bhatia KP
Parkinsonism Relat Disord 2017 Apr;37:1-10. Epub 2016 Dec 27 doi: 10.1016/j.parkreldis.2016.12.024. PMID: 28162874

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