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Achondroplasia(ACH)

MedGen UID:
1289
Concept ID:
C0001080
Congenital Abnormality
Synonyms: ACH; Achondroplastic dwarfism
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, 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.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Achondroplasia (86268005); Chondrodystrophia fetalis (86268005); Achondroplastic dwarf (86268005); Osteosclerosis congenita (86268005); Congenital osteosclerosis (86268005); Achondroplastic dwarfism (86268005)
 
Gene (location): FGFR3 (4p16.3)
OMIM®: 100800
Orphanet: ORPHA15

Definition

Achondroplasia is the most common process resulting in disproportionate small stature. Affected individuals have short arms and legs, a large head, and characteristic facial features with frontal bossing and midface retrusion (formerly known as midface hypoplasia). In infancy, hypotonia is typical, and acquisition of developmental motor milestones is often both aberrant in pattern and delayed. Intelligence and life span are usually near normal, although craniocervical junction compression increases the risk of death in infancy. [from GTR]

Additional descriptions

From GeneReviews
Achondroplasia is the most common process resulting in disproportionate small stature. Affected individuals have short arms and legs, a large head, and characteristic facial features with frontal bossing and midface retrusion (formerly known as midface hypoplasia). In infancy, hypotonia is typical, and acquisition of developmental motor milestones is often both aberrant in pattern and delayed. Intelligence and life span are usually near normal, although craniocervical junction compression increases the risk of death in infancy.  https://www.ncbi.nlm.nih.gov/books/NBK1152
From OMIM
Achondroplasia is the most frequent form of short-limb dwarfism. Affected individuals exhibit short stature caused by rhizomelic shortening of the limbs, characteristic facies with frontal bossing and midface hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, genu varum, and trident hand (summary by Bellus et al., 1995).  http://www.omim.org/entry/100800
From GHR
Achondroplasia is a form of short-limbed dwarfism. The word achondroplasia literally means "without cartilage formation." Cartilage is a tough but flexible tissue that makes up much of the skeleton during early development. However, in achondroplasia the problem is not in forming cartilage but in converting it to bone (a process called ossification), particularly in the long bones of the arms and legs. Achondroplasia is similar to another skeletal disorder called hypochondroplasia, but the features of achondroplasia tend to be more severe.All people with achondroplasia have short stature. The average height of an adult male with achondroplasia is 131 centimeters (4 feet, 4 inches), and the average height for adult females is 124 centimeters (4 feet, 1 inch). Characteristic features of achondroplasia include an average-size trunk, short arms and legs with particularly short upper arms and thighs, limited range of motion at the elbows, and an enlarged head (macrocephaly) with a prominent forehead. Fingers are typically short and the ring finger and middle finger may diverge, giving the hand a three-pronged (trident) appearance. People with achondroplasia are generally of normal intelligence.Health problems commonly associated with achondroplasia include episodes in which breathing slows or stops for short periods (apnea), obesity, and recurrent ear infections. In childhood, individuals with the condition usually develop a pronounced and permanent sway of the lower back (lordosis) and bowed legs. Some affected people also develop abnormal front-to-back curvature of the spine (kyphosis) and back pain. A potentially serious complication of achondroplasia is spinal stenosis, which is a narrowing of the spinal canal that can pinch (compress) the upper part of the spinal cord. Spinal stenosis is associated with pain, tingling, and weakness in the legs that can cause difficulty with walking. Another uncommon but serious complication of achondroplasia is hydrocephalus, which is a buildup of fluid in the brain in affected children that can lead to increased head size and related brain abnormalities.  https://ghr.nlm.nih.gov/condition/achondroplasia

Clinical features

Brachydactyly
MedGen UID:
67454
Concept ID:
C0221357
Congenital Abnormality
Congenital anomaly of abnormally short fingers or toes.
Trident hand
MedGen UID:
98430
Concept ID:
C0426874
Finding
A hand in which the fingers are of nearly equal length and deflected at the first interphalangeal joint, so as to give a forklike shape consisting of separation of the first and second as well as the third and fourth digits.
Genu varum
MedGen UID:
154257
Concept ID:
C0544755
Finding
A bending or abnormal curvature affecting a long bone of the leg.
Short femoral neck
MedGen UID:
373033
Concept ID:
C1836184
Finding
An abnormally short femoral neck (which is the process of bone, connecting the femoral head with the femoral shaft).
Flared metaphysis
MedGen UID:
337976
Concept ID:
C1850135
Finding
The presence of a splayed (i.e.,flared) metaphyseal segment of one or more long bones.
Rhizomelia
MedGen UID:
357122
Concept ID:
C1866730
Congenital Abnormality
Disproportionate shortening of the proximal segment of limbs (i.e. the femur and humerus).
Limited elbow extension
MedGen UID:
401158
Concept ID:
C1867103
Finding
Limited ability to straighten the arm at the elbow joint.
Neonatal short-limb short stature
MedGen UID:
337984
Concept ID:
C1850171
Finding
A type of short-limbed dwarfism that is manifest beginning in the neonatal period.
Rhizomelia
MedGen UID:
357122
Concept ID:
C1866730
Congenital Abnormality
Disproportionate shortening of the proximal segment of limbs (i.e. the femur and humerus).
Conductive hearing impairment
MedGen UID:
9163
Concept ID:
C0018777
Disease or Syndrome
An abnormality of vibrational conductance of sound to the inner ear leading to impairment of sensory perception of sound.
Recurrent infections of the middle ear
MedGen UID:
155436
Concept ID:
C0747085
Disease or Syndrome
Increased susceptibility to otitis media, as manifested by recurrent episodes of otitis media.
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Autosomal recessive nonsyndromic hydrocephalus is characterized by onset in utero of enlarged ventricles due to a disturbance of cerebrospinal fluid accumulation. Affected individuals may have neurologic impairment (summary by Drielsma et al., 2012). Hydrocephalus can also be caused by Arnold-Chiari malformation, atresia of foramen of Magendie, stenosis of aqueduct of Sylvius (307000), toxoplasmosis, hydranencephaly, etc. Furthermore, it develops in infancy or childhood in achondroplasia (100800) and in Hurler disease (607014). Genetic Heterogeneity of Congenital Hydrocephalus See also autosomal recessive HYC2 (615219), caused by mutation in the MPDZ gene (603785) on chromosome 9p. An X-linked form (307000) is caused by mutation in the L1CAM gene on (308840) on chromosome Xq28.
Megalencephaly
MedGen UID:
65141
Concept ID:
C0221355
Congenital Abnormality
A congenital abnormality in which the occipitofrontal circumference is greater than two standard deviations above the mean for a given age. It is associated with HYDROCEPHALUS; SUBDURAL EFFUSION; ARACHNOID CYSTS; or is part of a genetic condition (e.g., ALEXANDER DISEASE; SOTOS SYNDROME).
Brain stem compression
MedGen UID:
82849
Concept ID:
C0270680
Disease or Syndrome
No development of motor milestones
MedGen UID:
892432
Concept ID:
C4020874
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Upper airway obstruction
MedGen UID:
149266
Concept ID:
C0740852
Disease or Syndrome
Increased resistance to the passage of air in the upper airway.
Infantile muscular hypotonia
MedGen UID:
395993
Concept ID:
C1860834
Finding
Muscular hypotonia (abnormally low muscle tone) manifesting in infancy.
Recurrent infections of the middle ear
MedGen UID:
155436
Concept ID:
C0747085
Disease or Syndrome
Increased susceptibility to otitis media, as manifested by recurrent episodes of otitis media.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
A skeletal deformity characterized by an unusually prominent forehead. Causes include acromegaly, Hurler syndrome, Silver-Russell syndrome, and thalassemia major.
Brachydactyly
MedGen UID:
67454
Concept ID:
C0221357
Congenital Abnormality
Congenital anomaly of abnormally short fingers or toes.
Trident hand
MedGen UID:
98430
Concept ID:
C0426874
Finding
A hand in which the fingers are of nearly equal length and deflected at the first interphalangeal joint, so as to give a forklike shape consisting of separation of the first and second as well as the third and fourth digits.
Genu varum
MedGen UID:
154257
Concept ID:
C0544755
Finding
A bending or abnormal curvature affecting a long bone of the leg.
Lumbar hyperlordosis
MedGen UID:
263149
Concept ID:
C1184923
Finding
An abnormal accentuation of the inward curvature of the spine in the lumbar region.
Short femoral neck
MedGen UID:
373033
Concept ID:
C1836184
Finding
An abnormally short femoral neck (which is the process of bone, connecting the femoral head with the femoral shaft).
Generalized joint laxity
MedGen UID:
322888
Concept ID:
C1836308
Finding
Joint hypermobility (ability of a joint to move beyond its normal range of motion) affecting many or all joints of the body.
Flared metaphysis
MedGen UID:
337976
Concept ID:
C1850135
Finding
The presence of a splayed (i.e.,flared) metaphyseal segment of one or more long bones.
Malar flattening
MedGen UID:
347616
Concept ID:
C1858085
Anatomical Abnormality
Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.
Small foramen magnum
MedGen UID:
348813
Concept ID:
C1861217
Finding
An abnormal narrowing of the foramen magnum.
Lumbar kyphosis in infancy
MedGen UID:
354980
Concept ID:
C1863423
Finding
Rhizomelia
MedGen UID:
357122
Concept ID:
C1866730
Congenital Abnormality
Disproportionate shortening of the proximal segment of limbs (i.e. the femur and humerus).
Limited elbow extension
MedGen UID:
401158
Concept ID:
C1867103
Finding
Limited ability to straighten the arm at the elbow joint.
Limited hip extension
MedGen UID:
766282
Concept ID:
C3553368
Finding
Limitation of the extension of the hip, i.e., decreased ability to straighten the hip joint and thereby increase the angle between torso and thigh; moving the thigh or top of the pelvis backward.
Spinal stenosis with reduced interpedicular distance
MedGen UID:
867265
Concept ID:
C4021625
Finding
An abnormal narrowing of the spinal canal related to a reduction in the interpedicular distance (i.e., the distance measured between the pedicles on frontal [coronal] imaging).
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
A skeletal deformity characterized by an unusually prominent forehead. Causes include acromegaly, Hurler syndrome, Silver-Russell syndrome, and thalassemia major.
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.
Malar flattening
MedGen UID:
347616
Concept ID:
C1858085
Anatomical Abnormality
Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.
Small foramen magnum
MedGen UID:
348813
Concept ID:
C1861217
Finding
An abnormal narrowing of the foramen magnum.
Midface retrusion
MedGen UID:
767172
Concept ID:
C3554258
Posterior positions and/or vertical shortening of the infraorbital and perialar regions, or increased concavity of the face and/or reduced nasolabial angle.

Professional guidelines

PubMed

Toriello HV, Meck JM; Professional Practice and Guidelines Committee.
Genet Med 2008 Jun;10(6):457-60. doi: 10.1097/GIM.0b013e318176fabb. PMID: 18496227Free PMC Article

Recent clinical studies

Etiology

Hoover-Fong J, McGready J, Schulze K, Alade AY, Scott CI
Am J Med Genet A 2017 May;173(5):1226-1230. Epub 2017 Apr 4 doi: 10.1002/ajmg.a.38150. PMID: 28374958
Brooks JT, Ramji AF, Lyapustina TA, Yost MT, Ain MC
J Pediatr Orthop 2017 Jan;37(1):e43-e47. doi: 10.1097/BPO.0000000000000662. PMID: 26469688
Wigg K, Tofts L, Benson S, Porter M
Am J Med Genet A 2016 Nov;170(11):2882-2888. Epub 2016 Sep 8 doi: 10.1002/ajmg.a.37779. PMID: 27605460
Orhant L, Anselem O, Fradin M, Becker PH, Beugnet C, Deburgrave N, Tafuri G, Letourneur F, Goffinet F, Allach El Khattabi L, Leturcq F, Bienvenu T, Tsatsaris V, Nectoux J
Prenat Diagn 2016 May;36(5):397-406. Epub 2016 Apr 7 doi: 10.1002/pd.4790. PMID: 26850935
Brooks JT, Bernholt DL, Tran KV, Ain MC
J Pediatr Orthop 2016 Jun;36(4):349-54. doi: 10.1097/BPO.0000000000000458. PMID: 26114241

Diagnosis

Brooks JT, Ramji AF, Lyapustina TA, Yost MT, Ain MC
J Pediatr Orthop 2017 Jan;37(1):e43-e47. doi: 10.1097/BPO.0000000000000662. PMID: 26469688
Wigg K, Tofts L, Benson S, Porter M
Am J Med Genet A 2016 Nov;170(11):2882-2888. Epub 2016 Sep 8 doi: 10.1002/ajmg.a.37779. PMID: 27605460
Orhant L, Anselem O, Fradin M, Becker PH, Beugnet C, Deburgrave N, Tafuri G, Letourneur F, Goffinet F, Allach El Khattabi L, Leturcq F, Bienvenu T, Tsatsaris V, Nectoux J
Prenat Diagn 2016 May;36(5):397-406. Epub 2016 Apr 7 doi: 10.1002/pd.4790. PMID: 26850935
Ahoor MH, Amizadeh Y, Sorkhabi R
Middle East Afr J Ophthalmol 2015 Oct-Dec;22(4):522-4. doi: 10.4103/0974-9233.167819. PMID: 26692730Free PMC Article
Accogli A, Pacetti M, Fiaschi P, Pavanello M, Piatelli G, Nuzzi D, Baldi M, Tassano E, Severino MS, Allegri A, Capra V
Am J Med Genet A 2015 Mar;167A(3):646-52. doi: 10.1002/ajmg.a.36933. PMID: 25691418

Therapy

Ota S, Zhou ZQ, Romero MP, Yang G, Hurlin PJ
Hum Mol Genet 2016 Oct 1;25(19):4227-4243. Epub 2016 Aug 9 doi: 10.1093/hmg/ddw255. PMID: 27506979
Biosse Duplan M, Komla-Ebri D, Heuzé Y, Estibals V, Gaudas E, Kaci N, Benoist-Lasselin C, Zerah M, Kramer I, Kneissel M, Porta DG, Di Rocco F, Legeai-Mallet L
Hum Mol Genet 2016 Jul 15;25(14):2997-3010. Epub 2016 Jun 3 doi: 10.1093/hmg/ddw153. PMID: 27260401Free PMC Article
Balci HI, Kocaoglu M, Sen C, Eralp L, Batibay SG, Bilsel K
Bone Joint J 2015 Nov;97-B(11):1577-81. doi: 10.1302/0301-620X.97B11.36037. PMID: 26530664
Bouali H, Latrech H
Pediatr Endocrinol Rev 2015 Jun;12(4):388-95. PMID: 26182483
Song SH, Agashe MV, Huh YJ, Hwang SY, Song HR
Acta Orthop 2012 Jun;83(3):282-7. Epub 2012 Apr 11 doi: 10.3109/17453674.2012.678802. PMID: 22489887Free PMC Article

Prognosis

Mori H, Matsumoto K, Kawai N, Izawa T, Horiuchi S, Tanaka E
Am J Orthod Dentofacial Orthop 2017 Apr;151(4):793-803. doi: 10.1016/j.ajodo.2016.03.034. PMID: 28364903
White KK, Bompadre V, Goldberg MJ, Bober MB, Campbell JW, Cho TJ, Hoover-Fong J, Mackenzie W, Parnell SE, Raggio C, Rapoport DM, Spencer SA, Savarirayan R
Am J Med Genet A 2016 Jan;170A(1):42-51. Epub 2015 Sep 23 doi: 10.1002/ajmg.a.37394. PMID: 26394886
White KK, Parnell SE, Kifle Y, Blackledge M, Bompadre V
Am J Med Genet A 2016 Jan;170A(1):32-41. Epub 2015 Sep 23 doi: 10.1002/ajmg.a.37385. PMID: 26394798
Kaga A, Murotsuki J, Kamimura M, Kimura M, Saito-Hakoda A, Kanno J, Hoshi K, Kure S, Fujiwara I
Congenit Anom (Kyoto) 2015 May;55(2):116-20. doi: 10.1111/cga.12097. PMID: 25385298
Simmons K, Hashmi SS, Scheuerle A, Canfield M, Hecht JT
Birth Defects Res A Clin Mol Teratol 2014 Apr;100(4):247-9. Epub 2014 Feb 12 doi: 10.1002/bdra.23210. PMID: 24677650

Clinical prediction guides

Hoover-Fong J, McGready J, Schulze K, Alade AY, Scott CI
Am J Med Genet A 2017 May;173(5):1226-1230. Epub 2017 Apr 4 doi: 10.1002/ajmg.a.38150. PMID: 28374958
Wigg K, Tofts L, Benson S, Porter M
Am J Med Genet A 2016 Nov;170(11):2882-2888. Epub 2016 Sep 8 doi: 10.1002/ajmg.a.37779. PMID: 27605460
Atanda A Jr, Wallace M, Bober MB, Mackenzie W
J Pediatr Orthop 2016 Jul-Aug;36(5):e55-8. doi: 10.1097/BPO.0000000000000622. PMID: 27276636
White KK, Parnell SE, Kifle Y, Blackledge M, Bompadre V
Am J Med Genet A 2016 Jan;170A(1):32-41. Epub 2015 Sep 23 doi: 10.1002/ajmg.a.37385. PMID: 26394798
Khalil A, Morales-Roselló J, Morlando M, Bhide A, Papageorghiou A, Thilaganathan B
Ultrasound Obstet Gynecol 2014 Jul;44(1):69-75. doi: 10.1002/uog.13339. PMID: 24623391

Recent systematic reviews

Miccoli M, Bertelloni S, Massart F
Horm Res Paediatr 2016;86(1):27-34. Epub 2016 Jun 30 doi: 10.1159/000446958. PMID: 27355624
White KK, Bompadre V, Goldberg MJ, Bober MB, Campbell JW, Cho TJ, Hoover-Fong J, Mackenzie W, Parnell SE, Raggio C, Rapoport DM, Spencer SA, Savarirayan R
Am J Med Genet A 2016 Jan;170A(1):42-51. Epub 2015 Sep 23 doi: 10.1002/ajmg.a.37394. PMID: 26394886
Kim SJ, Pierce W, Sabharwal S
Acta Orthop 2014 Apr;85(2):181-6. doi: 10.3109/17453674.2014.899856. PMID: 24650027Free PMC Article
Schiedel F, Rödl R
Disabil Rehabil 2012;34(12):982-7. Epub 2011 Nov 23 doi: 10.3109/09638288.2011.631677. PMID: 22112021
Trotter TL, Hall JG; American Academy of Pediatrics Committee on Genetics.
Pediatrics 2005 Sep;116(3):771-83. doi: 10.1542/peds.2005-1440. PMID: 16140722

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