Achondrogenesis is a heterogeneous group of lethal chon- drodysplasias. Achondrogenesis type I (Fraccaro-Houston-Harris type) and type II (Langer-Saldino type) were distinguished on the basis of radiological and histological criteria. Achondrogenesis type I was further subdivided, on the basis of convincing histo- logical criteria, into type IA, which has apparently normal car- tilage 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 recently by the dis- covery of its association with mutations in the diastrophic dys- plasia sulfate transporter (DTDST) gene, making it allelic with diastrophic dysplasia.
GENETICS/BASIC DEFECTS
1. Type IA: an autosomal recessive disorder with an unknown chromosomal locus
2. Type IB
a. An autosomal recessive disorder
b. Resulting from mutations of the DTDST gene, which is located at 5q32-q33
3. Type II
a. Autosomal dominant type II collagenopathy
b. Resulting from mutations in the COL2A1 gene, which is located at 12q13.1-q13.3
CLINICAL FEATURES
1. Prenatal/perinatal history a. Polyhydramnios b. Hydrops
c. Breech presentation d. Perinatal death 2. Achondrogenesis type I
a. Growth
i. Lethal neonatal dwarfism ii. Mean birth weight of 1200 g b. Craniofacial features
i. Disproportionately large head ii. Soft skull
iii. Sloping forehead iv. Convex facial plane
v. Flat nasal bridge, occasionally associated with a deep horizontal groove
vi. Small nose, often with anteverted nostrils vii. Long philtrum
viii. Retrognathia
ix. Increased distance between lower lip and lower edge of chin
x. Double chin appearance c. Extremely short neck d. Thorax
i. Short and barrel-shaped thorax ii. Lung hypoplasia
e. Heart
i. Patent ductus arteriosus ii. Atrial septal defect iii. Ventricular septal defect f. Protuberant abdomen g. Limbs
i. Extremely short (micromelia), shorter than type II ii. Flipper-like appendages
3. Achondrogenesis type II a. Growth
i. Lethal neonatal dwarfism ii. Mean birth weight of 2100 g b. Craniofacial features
i. Disproportionately large head ii. Large and prominent forehead iii. Midfacial hypoplasia
a) Flat facial plane b) Flat nasal bridge
c) Small nose with severely anteverted nostrils iv. Normal philtrum
v. Micrognathia vi. Cleft palate c. Extremely short neck d. Thorax
i. Short and flared thorax ii. Bell-shaped cage iii. Lung hypoplasia e. Protuberant abdomen
f. Extremely short limbs (micromelia)
DIAGNOSTIC INVESTIGATIONS
1. Radiological features a. Variable features
b. No single obligatory feature
c. Distinction between type IA and type IB on radi- ographs not always possible
d. Degree of ossification: age dependent, and caution is needed when comparing radiographs at different ges- tational ages
e. Achondrogenesis type I
i. Skull: Varying degree of deficient cranial ossifi- cation consisting of small islands of bone in membranous calvaria
ii. Thorax and ribs
a) Short and barrel-shaped thorax
b) Thin ribs with marked expansion at costo- chondral junction, frequently with multiple fractures
iii. Spine and pelvis
a) Poorly ossified spine, ischium, and pubis b) Poorly ossified iliac bones with short medial
margins
7iv. Limbs and tubular bones
a) Extreme micromelia, with limbs much shorter than in type II
b) Prominent spike-like metaphyseal spurs c) Femur and tibia frequently presenting as
short bone segments
v. Subtype IA (Houston-Harris type) a) Poorly ossified skull
b) Thin ribs with multiple fractures c) Unossified vertebral pedicles d) Arched ilium
e) Hypoplastic but ossified ischium f) Wedged femur with metaphyseal spikes g) Short tibia and fibula with metaphyseal flare vi. Subtype IB (Fraccaro type)
a) Adequately ossified skull b) Absence of rib fractures
c) Total lack of ossification or only rudimentary calcification of the center of the vertebral bodies
d) Ossified vertebral pedicles
e) Iliac bones with ossification only in their upper part, giving a crescent-shaped, “paraglider- like” appearance on X-ray
f) Unossified ischium
g) Shortened tubular bones without recognized axis
h) Metaphyseal spurring giving the appearance of a “thorn apple” or “acanthocyte” (a descrip- tive term in hematology)
i) Trapezoid femur j) Stellate tibia k) Unossified fibula
l) Poorly ossified phalanges f. Achondrogenesis type II
i. Skull
a) Normal cranial ossification b) Relatively large calvaria ii. Thorax and ribs
a) Short and flared thorax b) Bell-shaped cage
c) Shorter ribs without fractures
iii. Spine and pelvis: relatively well-ossified iliac bones with long, crescent-shaped medial and inferior margins
iv. Limbs and tubular bones
a) Short, broad bones, usually with some dia- physeal constriction and flared, cupped metaphyseal ends
b) Metaphyseal spurs, usually smaller than type I 2. Histologic features
a. Achondrogenesis type IA i. Normal cartilage matrix
ii. Absent collagen rings around the chondrocytes iii. Vacuolated chondrocytes
iv. Presence of intrachondrocytic inclusion bodies (periodic acid-Schiff [PAS] stain positive, dia- stase resistant)
v. Extraskeletal cartilage involvement
vi. Enlarged lacunas vii. Woven bone b. Achondrogenesis type IB
i. Abnormal cartilage matrix: presence of
“demasked” coarsened collagen fibers, particu- larly dense around the chondrocytes, forming collagen rings
ii. Abnormal staining properties of cartilage a) Reduced staining with cationic dyes, such as
toluidine blue or Alcian blue, probably because of a deficiency in sulfated proteo- glycans
b) This distinguishes type IB from type IA, in which the matrix is close to normal and inclusions can be seen in chondrocytes, and from achondrogenesis type II, in which cationic dyes give a normal staining pattern c. Achondrogenesis type II
i. Cartilage
a) Slightly larger than normal
b) Grossly distorted (lobulated and mush- roomed)
ii. Markedly deficient cartilaginous matrix iii. Severe disturbance in endochondral ossification
iv. Hypercellular and hypervascular reserve cartilage with large, primitive mesenchymal (ballooned) chondrocytes with abundant clear cytoplasm (vacuoles) (“Swiss cheese-like”)
v. Overgrowth of membranous bones resulting in cupping of the epiphyseal cartilages
vi. Decreased amount and altered structure of pro- teoglycans
vii. Relatively lower content of chondroitin 4-sulfate viii. Lower molecular weight and decreased total
chondroitin sulfation ix. Absence of type II collagen
x. Increased amounts of type I and type III collagen 3. Biochemical testing
a. Lack of sulfate incorporation: cumbersome and not used for diagnostic purposes
b. Sulfate incorporation assay in cultured skin fibrob- lasts or chondrocytes: recommended in the rare instances in which the diagnosis of achondrogenesis type IB is strongly suspected but molecular genetic testing fails to detect SLC26A2 (DTDST) mutations 4. Molecular genetic studies
a. Mutation analysis of the DTDST gene, reported in:
i. Achondrogenesis type IB (the most severe form) ii. Atelosteogenesis type II (an intermediate form) iii. Diastophic dysplasia (the mildest form)
iv. Recessive multiple epiphyseal dysplasia b. Achondrogenesis type IB
i. Mutation analysis: testing of the following four most common SLC26A2 (DTDST) gene muta- tions (mutation detection rate about 60%) a) R279W
b) IVS1+2T>C (“Finnish” mutation) c) delV340
d) R178X
ii. Sequence analysis of the SLC26A2 (DTDST) coding region (mutation detection rate over 90%) a) Private mutations
b) Common mutations
c. Achondrogenesis type II: mutation analysis of the
COL2A1 geneGENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. Achondrogenesis type IA and type IB (autoso- mal recessive disorders)
a) Recurrence risk: 25%
b) Unaffected sibs of a proband: 2/3 chance of being heterozygotes
ii. Achondrogenesis type II
a) Usually caused by a new dominant muta- tion, in which case recurrence risk is not sig- nificantly increased
b) Asymptomatic carrier parent (germline mutation for a dominant mutation) may be present in the families of affected patients, in which case recurrence risk is 50%
b. Patient’s offspring: lethal entities not surviving to reproduction
2. Prenatal diagnosis a. Ultrasonography
i. Polyhydramnios ii. Fetal hydrops
iii. Disproportionally big head iv. Nuchal edema
v. Cystic hygroma vi. A narrow thorax vii. Short limbs
viii. Poor ossification of vertebral bodies and limb tubular bones (leading to difficulties in determin- ing their length)
ix. Suspect achondrogenesis type I
a) An extremely echo-poor appearance of the skeleton
b) A poorly mineralized skull c) Short limbs
d) Rib fractures b. Molecular genetic studies
i. Prenatal diagnosis of achondrogenesis type IB and type II by mutation analysis of chorionic vil- lus DNA or amniocyte DNA in the first or sec- ond trimester
ii. Achondrogenesis type IB
a) Characterize both alleles of DTDST before- hand
b) Identify the source parent of each allele c) Theoretically, analysis of sulfate incorpora-
tion in chorionic villi might be used for pre- natal diagnosis, but experience is lacking iii. Achondrogenesis type II
a) The affected fetus usually with a new domi- nant mutation of the COL2A1 gene
b) Possible presence of asymptomatic carriers in families of an affected patient
c) Prenatal diagnosis possible if the mutation has been characterized in the affected family 3. Management
a. Supportive care
b. No treatment available for the underlying lethal disorder
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Fig. 1. A neonate with achondrogenesis type I showing large head, short trunk, and extreme micromelia. Radiograph shows unossified calvarium, vertebral bodies and some pelvic bones. The remaining bones are extremely small. There are multiple rib fractures. The sagit- tal section of the femora and the humeri are similar. An extremely small ossified shaft is capped by a relatively large epiphyseal cartilage at both ends. Photomicrographs of resting cartilage with high magni- fication show many chondrocytes that contain large cytoplasmic inclusions which are within clear vacuoles (Diastase PAS stain).
Electron micrograph shows inclusion as a globular mass of electron dense material. It is within a distended cistern of rough endoplasmic reticulum.
Fig. 2. Achondrogenesis type II. As in type I, this neonate shows large head, short trunk, and micromelia. Sagittal section of the femur shows much better ossification of the shaft than type I. The cartilage lacks glis- tering appearance due to cartilage matrix deficiency. Photomicrograph of the entire cartilage shows severe deficiency of cartilage matrix. The cartilage canals are large, fibrotic, and stellate in shape. Physeal growth zone is severely retarded.
Fig. 3. Two infants with achondrogenesis type II showing milder spec- trum of manifestations, bordering the type II and spondyloepiphyseal congenita.
Fig. 4. A newborn girl with achondrogenesis type II showing large head, midfacial hypoplasia, short neck, small chest, and short limbs. The radi- ographs shows generalized shortening of the long bones of the upper and lower extremities with marked cupping (metaphyseal spurs) at the meta- physeal ends of the bones. This is most evident at the distal ends of the tibia, fibular, radius and ulna, and distal ends of the digits. Radiographs also shows short ribs without fractures and hemivertebrae involving thoracic vertebrae as well as the sacrum. Conformation-sensitive gel electrophoresis analysis indicated a sequence variation in the fragment containing exon 19 and the flanking sequences of the COL2A1 gene (Gly244Asp). Similar mutations in this area have been seen in patients diagnosed with hypochondroplasia and achondrogenesis type II.
