Non-Existent
18th December 2008, 11:45 PM
Introduction
Background
Marco Fraccaro first described achondrogenesis in 1952.1 He used the term to describe a stillborn female with severe micromelia and marked histological cartilage changes. The term was later used to characterize the most severe forms of chondrodysplasia in humans, which were invariably lethal before or shortly after birth. By the 1970s, researchers concluded that achondrogenesis was a heterogeneous group of chondrodysplasias lethal to neonates; achondrogenesis type I (Fraccaro-Houston-Harris type) and type II (Langer-Saldino type) were distinguished on the basis of radiological and histological criteria.
In 1983, a new radiological classification of achondrogenesis (types I-IV) by Whitley and Gorlin was adopted in the McKusick catalog.2 According to this classification, type I and type II have the same femoral cylinder index (CIfemur; calculated as length of femur divided by width of femur) range (1.0-2.8). Both types have crenated ilia and stellate long bones. Multiple rib fractures are characteristic of type I but not type II. Type III has nonfractured ribs, halberd ilia, mushroom-stem long bones, and a CIfemur of 2.8-4.9. Type IV has nonfractured ribs, sculpted ilia, well-developed long bones, and a CIfemur of 4.9-8.0. This radiological classification based on the CIfemur was later abandoned. Researchers suggested that achondrogenesis type III probably corresponds to type II and that type IV probably corresponds to mild type II (hypochondrogenesis).
In the late 1980s, structural mutations in collagen II were shown to cause achondrogenesis type II, which thus constitutes the severe end of the spectrum of collagen II chondrodysplasias.3 Achondrogenesis type I was subdivided further in 1988 on the basis of convincing histological criteria.4 It was subdivided into type IA, which has apparently normal cartilage matrix but inclusions in chondrocytes, and type IB, which has an abnormal cartilage matrix. Classification of type IB as a separate group has been confirmed by the discovery of its association with mutations in the diastrophic dysplasia sulfate transporter (DDST) gene, making it allelic with diastrophic dysplasia.5
Currently, 3 variants of achondrogenesis have been defined based on radiologic and histopathologic features: type IA (Houston-Harris), type IB (Parenti-Fraccaro), and type II (Langer-Saldino). Achondrogenesis IA appears to be autosomal recessive, but the mutant gene is still unknown. Type IB is caused by recessive mutations of the diastrophic dysplasia sulfate transporter gene (SLC26A2), and type II is caused by autosomal dominant mutations of the type II collagen gene (COL2A1).
Pathophysiology
A series of mutations in the DDST gene has been identified in patients with achondrogenesis type IB.5, 6 Homozygosity or compound heterozygosity for these mutations, which leads to premature stop codons or structural mutations in transmembrane domains, is associated with achondrogenesis type IB. Extracellular loops or cytoplasmic tail mutations or low messenger RNA (mRNA) levels, which cause regulatory mutation, usually result in atelosteogenesis type II or diastrophic dysplasia with less severe phenotypes. Chondrocytes and skin fibroblasts cultured from type IB patients are unable to incorporate exogenous sulfate.
Different mutations in the gene that encodes type II collagen (COL2A1) cause achondrogenesis type II as well as other type II collagenopathies (eg, spondyloepiphyseal dysplasias, hypochondrogenesis). Type II has a single base change, substituting serine for glycine in the type II procollagen gene of the alpha 1(II) chain. This disrupts the triple helix formation, leading to a paucity of type II collagen in the cartilage matrix. Epiphyseal cartilage lacks type II collagen. It is replaced by type I and type III collagens, which are not normally produced by chondrocytes. Differentiated chondrocytes do not express type II collagen. In addition to skeletal abnormalities, severe pulmonary hypoplasia, thought to be related directly to the underlying pathology in collagen expression, is associated with achondrogenesis.
Type II achondrogenesis/hypochondrogenesis (Whitley and Gorlin prototype IV) has immunohistologic findings that demonstrate apparent abnormal intracellular accumulation of type II collagen within vacuolar structures of chondrocytes. This suggests the presence of abnormal, poorly secreted type II collagen. Molecular defects of type II collagen and new dominant mutations account for the observed phenotype.
Frequency
United States
Lethal achondrogenesis types I and II are both rare. Their respective frequencies are unknown; however, the overall frequency has been estimated at 1 in 40,000 births.
Mortality/Morbidity
Achondrogenesis type I results in stillbirth more frequently than type II.
Babies with achondrogenesis type I who are not stillborn typically have a shorter gestation and survive for a shorter time than those with type II. They are also smaller with much shorter limbs, which supports the general view that type I is the more severe form.
Race
Achondrogenesis has no racial predilection.
Sex
Males and females are equally affected.
Age
Achondrogenesis is detected prenatally or at birth because of typical clinical, radiological, histological, and molecular findings.
Clinical
History
Prenatal history
Polyhydramnios
Hydrops
Breech presentation
Physical
Achondrogenesis type I
Growth - Lethal neonatal dwarfism, mean birth weight of 1200 g
Craniofacial - Disproportionately large head; soft skull; sloping forehead; convex facial plane; flat nasal bridge, occasionally associated with a deep horizontal groove; small nose, often with anteverted nostrils; long philtrum; retrognathia; increased distance between lower lip and lower edge of chin; double chin appearance (often)
Neck - Extremely short
Thorax - Short and barrel-shaped thorax, lung hypoplasia
Heart -Patent ductus arteriosus, atrial septal defect, ventricular septal defect
Abdomen - Protuberant
Limbs - Extremely short (micromelia), much shorter than type II; flipperlike appendages
Achondrogenesis type II
Growth - Lethal neonatal dwarfism, mean birth weight of 2100 g
Craniofacial - Disproportionately large head, large and prominent forehead, flat facial plane, flat nasal bridge, small nose with severely anteverted nostrils, normal philtrum (often), micrognathia
Neck - Extremely short
Thorax - Short and flared thorax, bell-shaped cage, lung hypoplasia
Abdomen - Protuberant
Limbs - Extremely short (micromelia)
Causes
Type IA is an autosomal recessive disorder with an unknown chromosomal locus. In the current International Nomenclature of Constitutional Disorders of Bone, type IA is classified under spondylodysplastic and other perinatally lethal groups of osteochondrodysplasias.
Type IB is an autosomal recessive disorder resulting from mutations of the diastrophic dysplasia sulfate transporter (DDST) gene (SLC26A2), which is located at 5q32-q33.
Type II is an autosomal dominant type II collagenopathy resulting from mutations in the COL2A1 gene, which is located at 12q13.1-q13.3.
Background
Marco Fraccaro first described achondrogenesis in 1952.1 He used the term to describe a stillborn female with severe micromelia and marked histological cartilage changes. The term was later used to characterize the most severe forms of chondrodysplasia in humans, which were invariably lethal before or shortly after birth. By the 1970s, researchers concluded that achondrogenesis was a heterogeneous group of chondrodysplasias lethal to neonates; achondrogenesis type I (Fraccaro-Houston-Harris type) and type II (Langer-Saldino type) were distinguished on the basis of radiological and histological criteria.
In 1983, a new radiological classification of achondrogenesis (types I-IV) by Whitley and Gorlin was adopted in the McKusick catalog.2 According to this classification, type I and type II have the same femoral cylinder index (CIfemur; calculated as length of femur divided by width of femur) range (1.0-2.8). Both types have crenated ilia and stellate long bones. Multiple rib fractures are characteristic of type I but not type II. Type III has nonfractured ribs, halberd ilia, mushroom-stem long bones, and a CIfemur of 2.8-4.9. Type IV has nonfractured ribs, sculpted ilia, well-developed long bones, and a CIfemur of 4.9-8.0. This radiological classification based on the CIfemur was later abandoned. Researchers suggested that achondrogenesis type III probably corresponds to type II and that type IV probably corresponds to mild type II (hypochondrogenesis).
In the late 1980s, structural mutations in collagen II were shown to cause achondrogenesis type II, which thus constitutes the severe end of the spectrum of collagen II chondrodysplasias.3 Achondrogenesis type I was subdivided further in 1988 on the basis of convincing histological criteria.4 It was subdivided into type IA, which has apparently normal cartilage matrix but inclusions in chondrocytes, and type IB, which has an abnormal cartilage matrix. Classification of type IB as a separate group has been confirmed by the discovery of its association with mutations in the diastrophic dysplasia sulfate transporter (DDST) gene, making it allelic with diastrophic dysplasia.5
Currently, 3 variants of achondrogenesis have been defined based on radiologic and histopathologic features: type IA (Houston-Harris), type IB (Parenti-Fraccaro), and type II (Langer-Saldino). Achondrogenesis IA appears to be autosomal recessive, but the mutant gene is still unknown. Type IB is caused by recessive mutations of the diastrophic dysplasia sulfate transporter gene (SLC26A2), and type II is caused by autosomal dominant mutations of the type II collagen gene (COL2A1).
Pathophysiology
A series of mutations in the DDST gene has been identified in patients with achondrogenesis type IB.5, 6 Homozygosity or compound heterozygosity for these mutations, which leads to premature stop codons or structural mutations in transmembrane domains, is associated with achondrogenesis type IB. Extracellular loops or cytoplasmic tail mutations or low messenger RNA (mRNA) levels, which cause regulatory mutation, usually result in atelosteogenesis type II or diastrophic dysplasia with less severe phenotypes. Chondrocytes and skin fibroblasts cultured from type IB patients are unable to incorporate exogenous sulfate.
Different mutations in the gene that encodes type II collagen (COL2A1) cause achondrogenesis type II as well as other type II collagenopathies (eg, spondyloepiphyseal dysplasias, hypochondrogenesis). Type II has a single base change, substituting serine for glycine in the type II procollagen gene of the alpha 1(II) chain. This disrupts the triple helix formation, leading to a paucity of type II collagen in the cartilage matrix. Epiphyseal cartilage lacks type II collagen. It is replaced by type I and type III collagens, which are not normally produced by chondrocytes. Differentiated chondrocytes do not express type II collagen. In addition to skeletal abnormalities, severe pulmonary hypoplasia, thought to be related directly to the underlying pathology in collagen expression, is associated with achondrogenesis.
Type II achondrogenesis/hypochondrogenesis (Whitley and Gorlin prototype IV) has immunohistologic findings that demonstrate apparent abnormal intracellular accumulation of type II collagen within vacuolar structures of chondrocytes. This suggests the presence of abnormal, poorly secreted type II collagen. Molecular defects of type II collagen and new dominant mutations account for the observed phenotype.
Frequency
United States
Lethal achondrogenesis types I and II are both rare. Their respective frequencies are unknown; however, the overall frequency has been estimated at 1 in 40,000 births.
Mortality/Morbidity
Achondrogenesis type I results in stillbirth more frequently than type II.
Babies with achondrogenesis type I who are not stillborn typically have a shorter gestation and survive for a shorter time than those with type II. They are also smaller with much shorter limbs, which supports the general view that type I is the more severe form.
Race
Achondrogenesis has no racial predilection.
Sex
Males and females are equally affected.
Age
Achondrogenesis is detected prenatally or at birth because of typical clinical, radiological, histological, and molecular findings.
Clinical
History
Prenatal history
Polyhydramnios
Hydrops
Breech presentation
Physical
Achondrogenesis type I
Growth - Lethal neonatal dwarfism, mean birth weight of 1200 g
Craniofacial - Disproportionately large head; soft skull; sloping forehead; convex facial plane; flat nasal bridge, occasionally associated with a deep horizontal groove; small nose, often with anteverted nostrils; long philtrum; retrognathia; increased distance between lower lip and lower edge of chin; double chin appearance (often)
Neck - Extremely short
Thorax - Short and barrel-shaped thorax, lung hypoplasia
Heart -Patent ductus arteriosus, atrial septal defect, ventricular septal defect
Abdomen - Protuberant
Limbs - Extremely short (micromelia), much shorter than type II; flipperlike appendages
Achondrogenesis type II
Growth - Lethal neonatal dwarfism, mean birth weight of 2100 g
Craniofacial - Disproportionately large head, large and prominent forehead, flat facial plane, flat nasal bridge, small nose with severely anteverted nostrils, normal philtrum (often), micrognathia
Neck - Extremely short
Thorax - Short and flared thorax, bell-shaped cage, lung hypoplasia
Abdomen - Protuberant
Limbs - Extremely short (micromelia)
Causes
Type IA is an autosomal recessive disorder with an unknown chromosomal locus. In the current International Nomenclature of Constitutional Disorders of Bone, type IA is classified under spondylodysplastic and other perinatally lethal groups of osteochondrodysplasias.
Type IB is an autosomal recessive disorder resulting from mutations of the diastrophic dysplasia sulfate transporter (DDST) gene (SLC26A2), which is located at 5q32-q33.
Type II is an autosomal dominant type II collagenopathy resulting from mutations in the COL2A1 gene, which is located at 12q13.1-q13.3.