U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

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
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.
 
Gene (location): GNAS (20q13.32)
 
Monarch Initiative: MONDO:0012912
OMIM®: 612463
Orphanet: ORPHA79445

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
Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
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).
Enamel hypoplasia
MedGen UID:
3730
Concept ID:
C0011351
Disease or Syndrome
Developmental hypoplasia of the dental enamel.
Delayed eruption of teeth
MedGen UID:
68678
Concept ID:
C0239174
Finding
Delayed tooth eruption, which can be defined as tooth eruption more than 2 SD beyond the mean eruption age.
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
Disease or Syndrome
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.

Term Hierarchy

Professional guidelines

PubMed

Salemi P, Skalamera Olson JM, Dickson LE, Germain-Lee EL
J Clin Endocrinol Metab 2018 Jan 1;103(1):158-168. doi: 10.1210/jc.2017-00860. PMID: 29059381Free PMC Article

Recent clinical studies

Etiology

Mazoni L, Apicella M, Saponaro F, Mantovani G, Elli FM, Borsari S, Pardi E, Piaggi P, Marcocci C, Cetani F
J Clin Endocrinol Metab 2021 Jul 13;106(8):e3005-e3020. doi: 10.1210/clinem/dgab208. PMID: 33780542
Han SR, Lee YA, Shin CH, Yang SW, Lim BC, Cho TJ, Ko JM
Exp Clin Endocrinol Diabetes 2021 Feb;129(2):118-125. Epub 2019 Sep 23 doi: 10.1055/a-1001-3575. PMID: 31546270
Snanoudj S, Molin A, Colson C, Coudray N, Paulien S, Mittre H, Gérard M, Schaefer E, Goldenberg A, Bacchetta J, Odent S, Naudion S, Demeer B, Faivre L, Gruchy N, Kottler ML, Richard N
J Bone Miner Res 2020 May;35(5):913-919. Epub 2020 Jan 13 doi: 10.1002/jbmr.3948. PMID: 31886927
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
Silve C, Clauser E, Linglart A
Horm Metab Res 2012 Sep;44(10):749-58. Epub 2012 Jul 19 doi: 10.1055/s-0032-1316330. PMID: 22815067

Diagnosis

Jüppner H
J Clin Endocrinol Metab 2021 May 13;106(6):1541-1552. doi: 10.1210/clinem/dgab060. PMID: 33529330Free PMC Article
Germain-Lee EL
Curr Opin Pediatr 2019 Aug;31(4):537-549. doi: 10.1097/MOP.0000000000000783. PMID: 31145125Free PMC Article
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
Simpson C, Grove E, Houston BA
Lancet 2015 Mar 21;385(9973):1123. Epub 2014 Dec 5 doi: 10.1016/S0140-6736(14)61640-8. PMID: 25484027
Silve C, Clauser E, Linglart A
Horm Metab Res 2012 Sep;44(10):749-58. Epub 2012 Jul 19 doi: 10.1055/s-0032-1316330. PMID: 22815067

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
Mune T, Katakami H, Morita M, Noguchi S, Ushiroda Y, Matsukura S, Yasuda K, Miura K
J Clin Endocrinol Metab 1994 Mar;78(3):575-80. doi: 10.1210/jcem.78.3.8126128. PMID: 8126128
Pfeiffer RA, Santelmann R
Birth Defects Orig Artic Ser 1977;13(1):319-37. PMID: 322750
Nedok AS, Garzicic BS, Soldatovic BM
J Clin Endocrinol Metab 1968 Oct;28(10):1513-4. doi: 10.1210/jcem-28-10-1513. PMID: 5681646

Prognosis

Miyado M, Fukami M, Takada S, Terao M, Nakabayashi K, Hata K, Matsubara Y, Tanaka Y, Sasaki G, Nagasaki K, Shiina M, Ogata K, Masunaga Y, Saitsu H, Ogata T
J Am Soc Nephrol 2019 May;30(5):877-889. Epub 2019 Apr 8 doi: 10.1681/ASN.2018121268. PMID: 30962325Free PMC Article
Salemi P, Skalamera Olson JM, Dickson LE, Germain-Lee EL
J Clin Endocrinol Metab 2018 Jan 1;103(1):158-168. doi: 10.1210/jc.2017-00860. PMID: 29059381Free PMC Article
Weinstein LS, Chen M, Liu J
Ann N Y Acad Sci 2002 Jun;968:173-97. doi: 10.1111/j.1749-6632.2002.tb04335.x. PMID: 12119276
Weinstein LS, Yu S, Warner DR, Liu J
Endocr Rev 2001 Oct;22(5):675-705. doi: 10.1210/edrv.22.5.0439. PMID: 11588148
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

Clinical prediction guides

Mazoni L, Apicella M, Saponaro F, Mantovani G, Elli FM, Borsari S, Pardi E, Piaggi P, Marcocci C, Cetani F
J Clin Endocrinol Metab 2021 Jul 13;106(8):e3005-e3020. doi: 10.1210/clinem/dgab208. PMID: 33780542
Jüppner H
J Clin Endocrinol Metab 2021 May 13;106(6):1541-1552. doi: 10.1210/clinem/dgab060. PMID: 33529330Free PMC Article
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
Tafaj O, Jüppner H
J Endocrinol Invest 2017 Apr;40(4):347-356. Epub 2016 Dec 19 doi: 10.1007/s40618-016-0588-4. PMID: 27995443
Silve C, Clauser E, Linglart A
Horm Metab Res 2012 Sep;44(10):749-58. Epub 2012 Jul 19 doi: 10.1055/s-0032-1316330. PMID: 22815067

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

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Recent activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...