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Achondrogenesis type II(ACG2)

MedGen UID:
66315
Concept ID:
C0220685
Congenital Abnormality
Synonyms: ACG2; Achondrogenesis, Langer-Saldino type; Chondrogenesis imperfecta
SNOMED CT: Achondrogenesis, type II (254061001); Langer-Saldino dysplasia (254061001); Langer-Saldino achondrogenesis (254061001)
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): COL2A1 (12q13.11)
 
Monarch Initiative: MONDO:0008702
OMIM®: 200610
Orphanet: ORPHA93296

Definition

Achondrogenesis type II (ACG2) is characterized by severe micromelic dwarfism with small chest and prominent abdomen, incomplete ossification of the vertebral bodies, and disorganization of the costochondral junction. ACG2 is an autosomal dominant trait occurring mostly as new mutations. However, somatic and germline mosaicism have been reported (summary by Comstock et al., 2010). [from OMIM]

Additional descriptions

From MedlinePlus Genetics
Achondrogenesis is a group of severe disorders that affect cartilage and bone development. These conditions are characterized by a small body, short limbs, and other skeletal abnormalities. As a result of serious health problems, infants with achondrogenesis usually die before birth, are stillborn, or die soon after birth from respiratory failure. However, some infants have lived for a short time with intensive medical support.

Researchers have described at least three forms of achondrogenesis, designated as type 1A, type 1B, and type 2. The types are distinguished by their signs and symptoms, inheritance pattern, and genetic cause. However, types 1A and 1B are often hard to tell apart without genetic testing.

Achondrogenesis type 1A, which is also called the Houston-Harris type, is the least well understood of the three forms. Affected infants have extremely short limbs, a narrow chest, short ribs that fracture easily, and a lack of normal bone formation (ossification) in the skull, spine, and pelvis.

Achondrogenesis type 1B, also known as the Parenti-Fraccaro type, is characterized by extremely short limbs, a narrow chest, and a prominent, rounded abdomen. The fingers and toes are short and the feet may turn inward and upward (clubfeet). Affected infants frequently have a soft out-pouching around the belly-button (an umbilical hernia) or near the groin (an inguinal hernia).

Infants with achondrogenesis type 2, which is sometimes called the Langer-Saldino type, have short arms and legs, a narrow chest with short ribs, and underdeveloped lungs. This condition is also associated with a lack of ossification in the spine and pelvis. Distinctive facial features include a prominent forehead, a small chin, and, in some cases, an opening in the roof of the mouth (a cleft palate). The abdomen is enlarged, and affected infants often have a condition called hydrops fetalis, in which excess fluid builds up in the body before birth.  https://medlineplus.gov/genetics/condition/achondrogenesis
From MedlinePlus Genetics
Hypochondrogenesis is a rare, severe disorder of bone growth. This condition is characterized by a small body, short limbs, and abnormal bone formation (ossification) in the spine and pelvis.

Affected infants have short arms and legs, a small chest with short ribs, and underdeveloped lungs. Bones in the skull develop normally, but the bones of the spine (vertebrae) and pelvis do not harden (ossify) properly. The face appears flat and oval-shaped, with widely spaced eyes, a small chin, and, in some cases, an opening in the roof of the mouth called a cleft palate. Individuals with hypochondrogenesis have an enlarged abdomen and may have a condition called hydrops fetalis in which excess fluid builds up in the body before birth.

As a result of these serious health problems, some affected fetuses do not survive to term. Infants born with hypochondrogenesis usually die at birth or shortly thereafter from respiratory failure. Babies who live past the newborn period are usually reclassified as having spondyloepiphyseal dysplasia congenita, a related but milder disorder that similarly affects bone development.  https://medlineplus.gov/genetics/condition/hypochondrogenesis

Clinical features

From HPO
Short tubular bones of the hand
MedGen UID:
871307
Concept ID:
C4025795
Finding
Decreased length of the tubular bones of the hand, that is, the phalanges and metacarpals.
Abnormal foot morphology
MedGen UID:
1762829
Concept ID:
C5399834
Anatomical Abnormality
An abnormality of the skeleton of foot.
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.
Protuberant abdomen
MedGen UID:
340750
Concept ID:
C1854928
Finding
A thrusting or bulging out of the abdomen.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Brachycephaly
MedGen UID:
113165
Concept ID:
C0221356
Congenital Abnormality
An abnormality of skull shape characterized by a decreased anterior-posterior diameter. That is, a cephalic index greater than 81%. Alternatively, an apparently shortened anteroposterior dimension (length) of the head compared to width.
Barrel-shaped chest
MedGen UID:
120497
Concept ID:
C0264172
Finding
A rounded, bulging chest that resembles the shape of a barrel. That is, there is an increased anteroposterior diameter and usually some degree of kyphosis.
Short ribs
MedGen UID:
98094
Concept ID:
C0426817
Finding
Reduced rib length.
Microretrognathia
MedGen UID:
326907
Concept ID:
C1839546
Finding
A form of developmental hypoplasia of the mandible in which the mandible is mislocalised posteriorly.
Disproportionate short-trunk short stature
MedGen UID:
337580
Concept ID:
C1846435
Finding
A type of disproportionate short stature characterized by a short trunk but a average-sized limbs.
Short long bone
MedGen UID:
344385
Concept ID:
C1854912
Finding
One or more abnormally short long bone.
Absent vertebral body mineralization
MedGen UID:
349746
Concept ID:
C1860191
Finding
A lack of bone mineralization of the vertebral bodies.
Hypoplastic iliac wing
MedGen UID:
351279
Concept ID:
C1865027
Anatomical Abnormality
Underdevelopment of the ilium ala.
Horizontal ribs
MedGen UID:
812840
Concept ID:
C3806510
Finding
A horizontal (flat) conformation of the ribs, the long curved bones that form the rib cage and normally progressively oblique (slanted) from ribs 1 through 9, then less slanted through rib 12.
Broad long bones
MedGen UID:
867270
Concept ID:
C4021630
Finding
Increased cross-section (diameter) of the long bones. Note that widening may primarily affect specific regions of long bones (e.g., diaphysis or metaphysis), but this should be coded separately.
Edema
MedGen UID:
4451
Concept ID:
C0013604
Pathologic Function
An abnormal accumulation of fluid beneath the skin, or in one or more cavities of the body.
Cystic hygroma
MedGen UID:
60195
Concept ID:
C0206620
Neoplastic Process
A cystic lymphatic lesion of the neck.
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.
Cleft palate
MedGen UID:
756015
Concept ID:
C2981150
Congenital Abnormality
Cleft palate is a developmental defect of the palate resulting from a failure of fusion of the palatine processes and manifesting as a separation of the roof of the mouth (soft and hard palate).
Polyhydramnios
MedGen UID:
6936
Concept ID:
C0020224
Pathologic Function
The presence of excess amniotic fluid in the uterus during pregnancy.
Hydrops fetalis
MedGen UID:
6947
Concept ID:
C0020305
Disease or Syndrome
The abnormal accumulation of fluid in two or more fetal compartments, including ascites, pleural effusion, pericardial effusion, and skin edema.
Abnormally large globe
MedGen UID:
344595
Concept ID:
C1855852
Finding
Diffusely large eye (with megalocornea) without glaucoma.

Professional guidelines

PubMed

Drury S, Williams H, Trump N, Boustred C; GOSGene, Lench N, Scott RH, Chitty LS
Prenat Diagn 2015 Oct;35(10):1010-7. Epub 2015 Sep 11 doi: 10.1002/pd.4675. PMID: 26275891

Recent clinical studies

Etiology

Lee HS, Doh JW, Kim CJ, Chi JG
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J Biol Chem 1998 Feb 20;273(8):4761-8. doi: 10.1074/jbc.273.8.4761. PMID: 9468540
Tiller GE, Polumbo PA, Weis MA, Bogaert R, Lachman RS, Cohn DH, Rimoin DL, Eyre DR
Nat Genet 1995 Sep;11(1):87-9. doi: 10.1038/ng0995-87. PMID: 7550321
Borochowitz Z, Lachman R, Adomian GE, Spear G, Jones K, Rimoin DL
J Pediatr 1988 Jan;112(1):23-31. doi: 10.1016/s0022-3476(88)80113-6. PMID: 3275766
Whitley CB, Gorlin RJ
Radiology 1983 Sep;148(3):693-8. doi: 10.1148/radiology.148.3.6878687. PMID: 6878687

Diagnosis

Bruni V, Spoleti CB, La Barbera A, Dattilo V, Colao E, Votino C, Bellacchio E, Perrotti N, Giglio S, Iuliano R
Genes (Basel) 2021 Sep 10;12(9) doi: 10.3390/genes12091395. PMID: 34573377Free PMC Article
Barat-Houari M, Sarrabay G, Gatinois V, Fabre A, Dumont B, Genevieve D, Touitou I
Hum Mutat 2016 Jan;37(1):7-15. Epub 2015 Oct 21 doi: 10.1002/humu.22915. PMID: 26443184
Kodandapani S, Ramkumar V
JNMA J Nepal Med Assoc 2009 Apr-Jun;48(174):155-7. PMID: 20387359
Borochowitz Z, Lachman R, Adomian GE, Spear G, Jones K, Rimoin DL
J Pediatr 1988 Jan;112(1):23-31. doi: 10.1016/s0022-3476(88)80113-6. PMID: 3275766
Andersen PE Jr
Br J Radiol 1981 Jan;54(637):61-5. doi: 10.1259/0007-1285-54-637-61. PMID: 7192589

Prognosis

Bruni V, Spoleti CB, La Barbera A, Dattilo V, Colao E, Votino C, Bellacchio E, Perrotti N, Giglio S, Iuliano R
Genes (Basel) 2021 Sep 10;12(9) doi: 10.3390/genes12091395. PMID: 34573377Free PMC Article
Connor JM, Connor RA, Sweet EM, Gibson AA, Patrick WJ, McNay MB, Redford DH
Am J Med Genet 1985 Oct;22(2):243-53. doi: 10.1002/ajmg.1320220205. PMID: 3901754

Clinical prediction guides

Bruni V, Spoleti CB, La Barbera A, Dattilo V, Colao E, Votino C, Bellacchio E, Perrotti N, Giglio S, Iuliano R
Genes (Basel) 2021 Sep 10;12(9) doi: 10.3390/genes12091395. PMID: 34573377Free PMC Article
Faivre L, Le Merrer M, Douvier S, Laurent N, Thauvin-Robinet C, Rousseau T, Vereecke I, Sagot P, Delezoide AL, Coucke P, Mortier G
Am J Med Genet A 2004 Apr 30;126A(3):308-12. doi: 10.1002/ajmg.a.20597. PMID: 15054848
Tiller GE, Polumbo PA, Weis MA, Bogaert R, Lachman RS, Cohn DH, Rimoin DL, Eyre DR
Nat Genet 1995 Sep;11(1):87-9. doi: 10.1038/ng0995-87. PMID: 7550321
Borochowitz Z, Lachman R, Adomian GE, Spear G, Jones K, Rimoin DL
J Pediatr 1988 Jan;112(1):23-31. doi: 10.1016/s0022-3476(88)80113-6. PMID: 3275766
Horton WA, Machado MA, Chou JW, Campbell D
Pediatr Res 1987 Sep;22(3):324-9. doi: 10.1203/00006450-198709000-00017. PMID: 3309860

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