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Grebe syndrome(AMDG; AMD2A)

MedGen UID:: 75557
•Concept ID:: C0265260
•: Disease or Syndrome

Synonyms:	ACROMESOMELIC DYSPLASIA 2A; Acromesomelic dysplasia, Grebe type; Brazilian achondrogenesis; Chondrodysplasia, Grebe Type; Grebe dysplasia
SNOMED CT:	Grebe dysplasia (77542002); Grebe syndrome (77542002); Acromesomelic dysplasia Grebe type (77542002)
Modes of inheritance:	Autosomal recessive inheritance MedGen UID: 141025 •Concept ID: C0441748 • 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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele). Autosomal recessive inheritance (Orphanet)

Gene (location): Gene(s) directly associated with this condition or phenotype.	GDF5 (20q11.22)

Monarch Initiative:	MONDO:0008703
OMIM®:	200700
Orphanet:	ORPHA2098

Definition

Acromesomelic dysplasia-2A (AMD2A), or Grebe chondrodysplasia, is an autosomal recessive disorder characterized by severe abnormality of the limbs and limb joints. The severity of limb shortening progresses in a proximal-distal gradient, with the hands and feet being most affected. The fingers and toes lack articulation and appear as skin appendages. In contrast, axial skeletal structures and the craniofacial skeleton are not affected. Heterozygous individuals are of average stature and have mild skeletal abnormalities (summary by Thomas et al., 1997). Because Grebe syndrome exhibits increasing severity in a proximal-distal gradient, it is classified as a form of acromesomelic dysplasia (Costa et al., 1998). For discussion of the genetic heterogeneity of acromesomelic dysplasia, see AMD1 (602875). [from OMIM]

Clinical features

From HPO

Short femur

MedGen UID:: 87499
•Concept ID:: C0345375
•: Congenital Abnormality

An abnormal shortening of the femur.

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Postaxial hand polydactyly

MedGen UID:: 609221
•Concept ID:: C0431904
•: Congenital Abnormality

Supernumerary digits located at the ulnar side of the hand (that is, on the side with the fifth finger).

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Hypoplasia of the radius

MedGen UID:: 672334
•Concept ID:: C0685381
•: Congenital Abnormality

Underdevelopment of the radius.

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Short phalanx of finger

MedGen UID:: 163753
•Concept ID:: C0877165
•: Finding

Short (hypoplastic) phalanx of finger, affecting one or more phalanges.

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Pes valgus

MedGen UID:: 299028
•Concept ID:: C1578482
•: Anatomical Abnormality

An outward deviation of the foot at the talocalcaneal or subtalar joint.

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Short humerus

MedGen UID:: 316907
•Concept ID:: C1832117
•: Congenital Abnormality

Underdevelopment of the humerus.

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Fibular hypoplasia

MedGen UID:: 316909
•Concept ID:: C1832119
•: Finding

Underdevelopment of the fibula.

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Aplasia/Hypoplasia involving the metacarpal bones

MedGen UID:: 322855
•Concept ID:: C1836192
•: Finding

Aplasia or Hypoplasia affecting the metacarpal bones.

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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).

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Short tibia

MedGen UID:: 338005
•Concept ID:: C1850259
•: Finding

Underdevelopment (reduced size) of the tibia.

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Valgus hand deformity

MedGen UID:: 348042
•Concept ID:: C1860179
•: Finding

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Aplasia/Hypoplasia of metatarsal bones

MedGen UID:: 348560
•Concept ID:: C1860182
•: Finding

Absence or underdevelopment of the metatarsal bones.

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Hypoplasia of the ulna

MedGen UID:: 395934
•Concept ID:: C1860614
•: Congenital Abnormality

Underdevelopment of the ulna.

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Acromesomelia

MedGen UID:: 350410
•Concept ID:: C1864365
•: Finding

Small hands and feet.

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Patella aplasia/hypoplasia

MedGen UID:: 358246
•Concept ID:: C1868577
•: Finding

Absence or underdevelopment of the patella.

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Short digit

MedGen UID:: 893063
•Concept ID:: C4023124
•: Finding

One or more digit that appears disproportionately short compared to the hand/foot, whereby either the entire digit or a specific phalanx is shortened.

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Distal tibiofibular synostosis

MedGen UID:: 1864156
•Concept ID:: C5937398
•: Congenital Abnormality

Fusion of the distal (i.e.., located away from the trunk) part of the tibia and fibula.

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Fibular torsion

MedGen UID:: 1053443
•Concept ID:: CN378273
•: Finding

Excessively rotated (also called torsion) position of the fibula (calf bone). An increased external rotation of the fibula in the incisura tibiofibularis of more than 5 degrees may lead to an increased pressure and will negatively affect the cartilage.

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Disproportionate short-limb short stature

MedGen UID:: 342370
•Concept ID:: C1849937
•: Finding

A type of disproportionate short stature characterized by a short limbs but an average-sized trunk.

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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.

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Flexion contracture

MedGen UID:: 83069
•Concept ID:: C0333068
•: Anatomical Abnormality

A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.

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Abnormality of limbs
Abnormality of the musculoskeletal system
- Flexion contracture
Abnormality of the nervous system
- Intellectual disability
Growth abnormality
- Disproportionate short-limb short stature

Term Hierarchy

GTR
MeSH

CClinical test, RResearch test, OOMIM, GGeneReviews, VClinVar

CROGVGrebe syndrome

Acromesomelic dysplasia
- Grebe syndrome

Recent clinical studies

Diagnosis

Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5.

Martinez-Garcia M, Garcia-Canto E, Fenollar-Cortes M, Aytes AP, Trujillo-Tiebas MJ
J Bone Miner Metab 2016 Sep;34(5):599-603. Epub 2015 Aug 15 doi: 10.1007/s00774-015-0693-z. PMID: 26275437

Prenatal sonographic diagnosis of Grebe syndrome.

Cordero DR, Goldberg Y, Basel D, Kilpatrick MW, Klugman S, Tsipouras P, Gross S
J Ultrasound Med 2006 Jan;25(1):115-8; quiz 119-21. doi: 10.7863/jum.2006.25.1.115. PMID: 16371562

Grebe syndrome with bilateral fibular hemimelia and thumb duplication.

Rao N, Joseph B
Skeletal Radiol 2002 Mar;31(3):183-7. Epub 2002 Jan 23 doi: 10.1007/s00256-001-0461-0. PMID: 11935206

Grebe syndrome: clinical and radiographic findings in affected individuals and heterozygous carriers.

Costa T, Ramsby G, Cassia F, Peters KR, Soares J, Correa J, Quelce-Salgado A, Tsipouras P
Am J Med Genet 1998 Feb 17;75(5):523-9. doi: 10.1002/(sici)1096-8628(19980217)75:5<523::aid-ajmg13>3.0.co;2-m. PMID: 9489798

Antenatal diagnosis of Grebe syndrome in a twin pregnancy by ultrasound.

Kulkarni ML, Kulkarni BM, Nasser PU
Indian Pediatr 1995 Sep;32(9):1007-11. PMID: 8935268

See all (8)

Therapy

Grebe syndrome in Vietnamese sisters: not Agent Orange.

Lin AE, Wheeler PG, Smith R
Clin Genet 2001 Jan;59(1):25-7. doi: 10.1034/j.1399-0004.2001.590104.x. PMID: 11168021

See all (1)

Prognosis

Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5.

Martinez-Garcia M, Garcia-Canto E, Fenollar-Cortes M, Aytes AP, Trujillo-Tiebas MJ
J Bone Miner Metab 2016 Sep;34(5):599-603. Epub 2015 Aug 15 doi: 10.1007/s00774-015-0693-z. PMID: 26275437

Clinical and molecular analysis of Grebe acromesomelic dysplasia in an Omani family.

Al-Yahyaee SA, Al-Kindi MN, Habbal O, Kumar DS
Am J Med Genet A 2003 Aug 15;121A(1):9-14. doi: 10.1002/ajmg.a.20256. PMID: 12900894

See all (2)

Clinical prediction guides

Characterization of an acromesomelic dysplasia, Grebe type case: novel mutation affecting the recognition motif at the processing site of GDF5.

Martinez-Garcia M, Garcia-Canto E, Fenollar-Cortes M, Aytes AP, Trujillo-Tiebas MJ
J Bone Miner Metab 2016 Sep;34(5):599-603. Epub 2015 Aug 15 doi: 10.1007/s00774-015-0693-z. PMID: 26275437

Clinical and molecular analysis of Grebe acromesomelic dysplasia in an Omani family.

Al-Yahyaee SA, Al-Kindi MN, Habbal O, Kumar DS
Am J Med Genet A 2003 Aug 15;121A(1):9-14. doi: 10.1002/ajmg.a.20256. PMID: 12900894

See all (2)

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Grebe syndrome(AMDG; AMD2A)

Definition

Clinical features

Term Hierarchy

Recent clinical studies

Diagnosis

Therapy

Prognosis

Clinical prediction guides

Supplemental Content

Table of contents

Genetic Testing Registry

Clinical resources

Molecular resources

Consumer resources

Reviews

Related information

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