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Geleophysic dysplasia 1(GPHYSD1)

MedGen UID:
479777
Concept ID:
C3278147
Disease or Syndrome
Synonyms: Geleophysic dwarfism; GPHYSD1
 
Gene (location): ADAMTSL2 (9q34.2)
 
Monarch Initiative: MONDO:0009269
OMIM®: 231050

Disease characteristics

Excerpted from the GeneReview: Geleophysic Dysplasia
Geleophysic dysplasia, a progressive condition resembling a lysosomal storage disorder, is characterized by short stature, short hands and feet, progressive joint limitation and contractures, distinctive facial features, progressive cardiac valvular disease, and thickened skin. Intellect is normal. The characteristic clinical findings are likely to be present in the first year of life. Cardiac, airway, and pulmonary involvement result in death before age five years in approximately 33% of individuals. [from GeneReviews]
Authors:
Pauline Marzin  |  Valérie Cormier-Daire   view full author information

Additional description

From OMIM
Geleophysic dysplasia-1 (GPHYSD1) is an autosomal recessive disorder characterized by severe short stature, short hands and feet, joint limitations, and skin thickening. Radiologic features include delayed bone age, cone-shaped epiphyses, shortened long tubular bones, and ovoid vertebral bodies. Affected individuals have characteristic facial features including a 'happy' face with full cheeks, shortened nose, hypertelorism, long and flat philtrum, and thin upper lip. Other distinctive features include progressive cardiac valvular thickening often leading to an early death, toe walking, tracheal stenosis, respiratory insufficiency, and lysosomal-like storage vacuoles in various tissues (summary by Le Goff et al., 2011). Genetic Heterogeneity of Geleophysic Dysplasia Geleophysic dysplasia-2 (GPHYSD2; 614185) is an autosomal dominant form of the disorder caused by heterozygous mutation in the FBN1 gene (134797) on chromosome 15q21.1. Acromicric dysplasia (102370) and the autosomal dominant form of Weill-Marchesani syndrome (608328) are allelic to geleophysic dysplasia-2 and share overlapping skeletal and joint features. Geleophysic dysplasia-3 (GPHYSD3; 617809) is caused by heterozygous mutation in the LTBP3 gene (602090) on chromosome 11q13.  http://www.omim.org/entry/231050

Clinical features

From HPO
Coxa valga
MedGen UID:
116080
Concept ID:
C0239137
Finding
Coxa valga is a deformity of the hip in which the angle between the femoral shaft and the femoral neck is increased compared to age-adjusted values (about 150 degrees in newborns gradually reducing to 120-130 degrees in adults).
Short palm
MedGen UID:
334684
Concept ID:
C1843108
Finding
Short palm.
Short foot
MedGen UID:
376415
Concept ID:
C1848673
Finding
A measured foot length that is more than 2 SD below the mean for a newborn of 27 - 41 weeks gestation, or foot that is less than the 3rd centile for individuals from birth to 16 years of age (objective). Alternatively, a foot that appears disproportionately short (subjective).
Short metacarpals with rounded proximal ends
MedGen UID:
383920
Concept ID:
C1856471
Finding
Aortic valve stenosis
MedGen UID:
1621
Concept ID:
C0003507
Pathologic Function
The presence of a stenosis (narrowing) of the aortic valve.
Congestive heart failure
MedGen UID:
9169
Concept ID:
C0018802
Disease or Syndrome
The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.
Mitral stenosis
MedGen UID:
44466
Concept ID:
C0026269
Disease or Syndrome
An abnormal narrowing of the orifice of the mitral valve.
Tricuspid stenosis
MedGen UID:
21678
Concept ID:
C0040963
Disease or Syndrome
A narrowing of the orifice of the tricuspid valve of the heart.
Pulmonary arterial hypertension
MedGen UID:
425404
Concept ID:
C2973725
Disease or Syndrome
Pulmonary hypertension is defined mean pulmonary artery pressure of 25mmHg or more and pulmonary capillary wedge pressure of 15mmHg or less when measured by right heart catheterisation at rest and in a supine position.
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).
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Thickened helices
MedGen UID:
325240
Concept ID:
C1837732
Finding
Increased thickness of the helix of the ear.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
High pitched voice
MedGen UID:
66836
Concept ID:
C0241703
Finding
An abnormal increase in the pitch (frequency) of the voice.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Osteopenia
MedGen UID:
18222
Concept ID:
C0029453
Disease or Syndrome
Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5.
Joint contracture of the hand
MedGen UID:
56382
Concept ID:
C0158113
Finding
Contractures of one ore more joints of the hands meaning chronic loss of joint motion due to structural changes in non-bony tissue.
Joint stiffness
MedGen UID:
56403
Concept ID:
C0162298
Sign or Symptom
Joint stiffness is a perceived sensation of tightness in a joint or joints when attempting to move them after a period of inactivity. Joint stiffness typically subsides over time.
Wrist flexion contracture
MedGen UID:
592338
Concept ID:
C0409345
Acquired Abnormality
A chronic loss of wrist joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevent normal movement of the joints of the wrist.
Camptodactyly of finger
MedGen UID:
98041
Concept ID:
C0409348
Finding
The distal interphalangeal joint and/or the proximal interphalangeal joint of the fingers cannot be extended to 180 degrees by either active or passive extension.
Delayed skeletal maturation
MedGen UID:
108148
Concept ID:
C0541764
Finding
A decreased rate of skeletal maturation. Delayed skeletal maturation can be diagnosed on the basis of an estimation of the bone age from radiographs of specific bones in the human body.
Hypoplasia of the capital femoral epiphysis
MedGen UID:
374176
Concept ID:
C1839254
Finding
Underdevelopment of the proximal epiphysis of the femur.
Platyspondyly
MedGen UID:
335010
Concept ID:
C1844704
Finding
A flattened vertebral body shape with reduced distance between the vertebral endplates.
J-shaped sella turcica
MedGen UID:
381480
Concept ID:
C1854718
Finding
A deformity of the sella turcica whereby the sella extends further anterior than normal such that the anterior clinoid process appears to overhang it, giving the appearance of the letter J on imaging of the skull.
Short long bone
MedGen UID:
344385
Concept ID:
C1854912
Finding
One or more abnormally short long bone.
Ovoid vertebral bodies
MedGen UID:
344549
Concept ID:
C1855665
Finding
When viewed in lateral radiographs, vertebral bodies have a roughly rectangular configuration. This term applies if the vertebral body appears rounded or oval.
Cone-shaped epiphysis
MedGen UID:
351282
Concept ID:
C1865037
Finding
Cone-shaped epiphyses (also known as coned epiphyses) are epiphyses that invaginate into cupped metaphyses. That is, the epiphysis has a cone-shaped distal extension resulting from increased growth of the central portion of the epiphysis relative to its periphery.
Pectus excavatum
MedGen UID:
781174
Concept ID:
C2051831
Finding
A defect of the chest wall characterized by a depression of the sternum, giving the chest ("pectus") a caved-in ("excavatum") appearance.
Irregular capital femoral epiphysis
MedGen UID:
866530
Concept ID:
C4020825
Anatomical Abnormality
Irregular surface of the normally relatively smooth capital femoral epiphysis.
Tracheal stenosis
MedGen UID:
21227
Concept ID:
C0040583
Disease or Syndrome
Narrowing of the lumen of the trachea.
Laryngotracheal stenosis
MedGen UID:
812610
Concept ID:
C3806280
Finding
Wide mouth
MedGen UID:
44238
Concept ID:
C0024433
Congenital Abnormality
Distance between the oral commissures more than 2 SD above the mean. Alternatively, an apparently increased width of the oral aperture (subjective).
Round face
MedGen UID:
116087
Concept ID:
C0239479
Finding
The facial appearance is more circular than usual as viewed from the front.
Upslanted palpebral fissure
MedGen UID:
98390
Concept ID:
C0423109
Finding
The palpebral fissure inclination is more than two standard deviations above the mean for age (objective); or, the inclination of the palpebral fissure is greater than typical for age.
Smooth philtrum
MedGen UID:
222980
Concept ID:
C1142533
Finding
Flat skin surface, with no ridge formation in the central region of the upper lip between the nasal base and upper vermilion border.
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Wide nasal bridge
MedGen UID:
341441
Concept ID:
C1849367
Finding
Increased breadth of the nasal bridge (and with it, the nasal root).
Short nose
MedGen UID:
343052
Concept ID:
C1854114
Finding
Distance from nasion to subnasale more than two standard deviations below the mean, or alternatively, an apparently decreased length from the nasal root to the nasal tip.
Long philtrum
MedGen UID:
351278
Concept ID:
C1865014
Finding
Distance between nasal base and midline upper lip vermilion border more than 2 SD above the mean. Alternatively, an apparently increased distance between nasal base and midline upper lip vermilion border.
Thin upper lip vermilion
MedGen UID:
355352
Concept ID:
C1865017
Finding
Height of the vermilion of the upper lip in the midline more than 2 SD below the mean. Alternatively, an apparently reduced height of the vermilion of the upper lip in the frontal view (subjective).
Narrow palpebral fissure
MedGen UID:
382506
Concept ID:
C2675021
Finding
Reduction in the vertical distance between the upper and lower eyelids.
Thickened skin
MedGen UID:
66024
Concept ID:
C0241165
Finding
Laminar thickening of skin.
Small nail
MedGen UID:
537942
Concept ID:
C0263523
Finding
A nail that is diminished in length and width, i.e., underdeveloped nail.
Lack of skin elasticity
MedGen UID:
892876
Concept ID:
C4021998
Finding

Professional guidelines

PubMed

Nguyen DB, Khirani S, Griffon L, Baujat G, Michot C, Marzin P, Rondeau S, Luscan R, Couloigner V, Pejin Z, Zerah M, Cormier-Daire V, Fauroux B
Am J Med Genet A 2021 Jul;185(7):2108-2118. Epub 2021 Apr 28 doi: 10.1002/ajmg.a.62236. PMID: 33908178
Marzin P, Thierry B, Dancasius A, Cavau A, Michot C, Rondeau S, Baujat G, Phan G, Bonnière M, Le Bourgeois M, Khraiche D, Pejin Z, Bonnet D, Delacourt C, Cormier-Daire V
Genet Med 2021 Feb;23(2):331-340. Epub 2020 Oct 21 doi: 10.1038/s41436-020-00994-x. PMID: 33082559
Allali S, Le Goff C, Pressac-Diebold I, Pfennig G, Mahaut C, Dagoneau N, Alanay Y, Brady AF, Crow YJ, Devriendt K, Drouin-Garraud V, Flori E, Geneviève D, Hennekam RC, Hurst J, Krakow D, Le Merrer M, Lichtenbelt KD, Lynch SA, Lyonnet S, MacDermot K, Mansour S, Megarbané A, Santos HG, Splitt M, Superti-Furga A, Unger S, Williams D, Munnich A, Cormier-Daire V
J Med Genet 2011 Jun;48(6):417-21. Epub 2011 Mar 17 doi: 10.1136/jmg.2010.087544. PMID: 21415077Free PMC Article

Recent clinical studies

Etiology

Marzin P, Thierry B, Dancasius A, Cavau A, Michot C, Rondeau S, Baujat G, Phan G, Bonnière M, Le Bourgeois M, Khraiche D, Pejin Z, Bonnet D, Delacourt C, Cormier-Daire V
Genet Med 2021 Feb;23(2):331-340. Epub 2020 Oct 21 doi: 10.1038/s41436-020-00994-x. PMID: 33082559
McInerney-Leo AM, Le Goff C, Leo PJ, Kenna TJ, Keith P, Harris JE, Steer R, Bole-Feysot C, Nitschke P, Kielty C, Brown MA, Zankl A, Duncan EL, Cormier-Daire V
J Med Genet 2016 Jul;53(7):457-64. Epub 2016 Apr 11 doi: 10.1136/jmedgenet-2015-103647. PMID: 27068007
Banka S, Cain SA, Carim S, Daly SB, Urquhart JE, Erdem G, Harris J, Bottomley M, Donnai D, Kerr B, Kingston H, Superti-Furga A, Unger S, Ennis H, Worthington J, Herrick AL, Merry CL, Yue WW, Kielty CM, Newman WG
Ann Rheum Dis 2015 Jun;74(6):1249-56. Epub 2014 Jan 17 doi: 10.1136/annrheumdis-2013-204309. PMID: 24442880
Klein C, Le Goff C, Topouchian V, Odent S, Violas P, Glorion C, Cormier-Daire V
Am J Med Genet A 2014 Feb;164A(2):331-7. Epub 2013 Dec 11 doi: 10.1002/ajmg.a.36139. PMID: 24339047
Le Goff C, Cormier-Daire V
Am J Med Genet C Semin Med Genet 2012 Aug 15;160C(3):145-53. Epub 2012 Jul 12 doi: 10.1002/ajmg.c.31337. PMID: 22791552

Diagnosis

Quitter F, Flury M, Waldmueller S, Schubert T, Koehler K, Huebner A
J Pediatr Endocrinol Metab 2022 Nov 25;35(11):1443-1447. Epub 2022 Aug 9 doi: 10.1515/jpem-2022-0287. PMID: 35942587
Wang T, Yang Y, Dong Q, Zhu H, Liu Y
Mol Genet Genomic Med 2020 Jul;8(7):e1282. Epub 2020 May 14 doi: 10.1002/mgg3.1282. PMID: 32406602Free PMC Article
Klein C, Le Goff C, Topouchian V, Odent S, Violas P, Glorion C, Cormier-Daire V
Am J Med Genet A 2014 Feb;164A(2):331-7. Epub 2013 Dec 11 doi: 10.1002/ajmg.a.36139. PMID: 24339047
Buluc L, Selek O, Aranay Y
Orthopedics 2012 Oct;35(10):e1553-5. doi: 10.3928/01477447-20120919-29. PMID: 23027497
Le Goff C, Cormier-Daire V
Pediatr Endocrinol Rev 2009 Mar;6(3):418-23. PMID: 19396027

Therapy

Li D, Dong H, Zheng H, Song J, Li X, Jin Y, Liu Y, Yang Y
Eur J Med Genet 2017 Dec;60(12):685-689. Epub 2017 Sep 14 doi: 10.1016/j.ejmg.2017.09.003. PMID: 28917829
Lee T, Takeshima Y, Okizuka Y, Hamahira K, Kusunoki N, Awano H, Yagi M, Sakai N, Matsuo M, Iijima K
Gene 2013 Jan 10;512(2):456-9. Epub 2012 Nov 2 doi: 10.1016/j.gene.2012.10.060. PMID: 23124041

Prognosis

Marzin P, Thierry B, Dancasius A, Cavau A, Michot C, Rondeau S, Baujat G, Phan G, Bonnière M, Le Bourgeois M, Khraiche D, Pejin Z, Bonnet D, Delacourt C, Cormier-Daire V
Genet Med 2021 Feb;23(2):331-340. Epub 2020 Oct 21 doi: 10.1038/s41436-020-00994-x. PMID: 33082559
Zhang A, Berardinelli SJ, Leonhard-Melief C, Vasudevan D, Liu TW, Taibi A, Giannone S, Apte SS, Holdener BC, Haltiwanger RS
J Biol Chem 2020 Nov 13;295(46):15742-15753. Epub 2020 Sep 10 doi: 10.1074/jbc.RA120.014557. PMID: 32913123Free PMC Article
Hasegawa K, Numakura C, Tanaka H, Furujo M, Kubo T, Higuchi Y, Yamashita M, Tsukahara H
J Pediatr Endocrinol Metab 2017 Jan 1;30(1):117-121. doi: 10.1515/jpem-2016-0258. PMID: 27935852
Klein C, Le Goff C, Topouchian V, Odent S, Violas P, Glorion C, Cormier-Daire V
Am J Med Genet A 2014 Feb;164A(2):331-7. Epub 2013 Dec 11 doi: 10.1002/ajmg.a.36139. PMID: 24339047
Pontz BF, Stöss H, Henschke F, Freisinger P, Karbowski A, Spranger J
Am J Med Genet 1996 May 3;63(1):50-4. doi: 10.1002/(SICI)1096-8628(19960503)63:1<50::AID-AJMG11>3.0.CO;2-T. PMID: 8723086

Clinical prediction guides

Camarena V, Williams MM, Morales AA, Zafeer MF, Kilic OV, Kamiar A, Abad C, Rasmussen MA, Briski LM, Peart L, Bademci G, Barbouth DS, Smithson S, Wang G, Shehadeh LA, Walz K, Tekin M
JCI Insight 2024 Feb 1;9(5) doi: 10.1172/jci.insight.174417. PMID: 38300707Free PMC Article
Zhang A, Berardinelli SJ, Leonhard-Melief C, Vasudevan D, Liu TW, Taibi A, Giannone S, Apte SS, Holdener BC, Haltiwanger RS
J Biol Chem 2020 Nov 13;295(46):15742-15753. Epub 2020 Sep 10 doi: 10.1074/jbc.RA120.014557. PMID: 32913123Free PMC Article
Hubmacher D, Taye N, Balic Z, Thacker S, Adams SM, Birk DE, Schweitzer R, Apte SS
Matrix Biol 2019 Sep;82:38-53. Epub 2019 Feb 7 doi: 10.1016/j.matbio.2019.02.001. PMID: 30738849Free PMC Article
Le Goff C, Cormier-Daire V
Am J Med Genet C Semin Med Genet 2012 Aug 15;160C(3):145-53. Epub 2012 Jul 12 doi: 10.1002/ajmg.c.31337. PMID: 22791552
Le Goff C, Morice-Picard F, Dagoneau N, Wang LW, Perrot C, Crow YJ, Bauer F, Flori E, Prost-Squarcioni C, Krakow D, Ge G, Greenspan DS, Bonnet D, Le Merrer M, Munnich A, Apte SS, Cormier-Daire V
Nat Genet 2008 Sep;40(9):1119-23. doi: 10.1038/ng.199. PMID: 18677313Free PMC Article

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