Achondrogenesis

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.
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).
Epidemiology
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
See the list below:
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
See the list below:
Achondrogenesis has no racial predilection.
Sex
See the list below:
Males and females are equally affected.
Age
See the list below:
Achondrogenesis is detected prenatally or at birth because of typical clinical, radiological, histological, and
molecular findings.
Etiology
Causes
See the list below:
• 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.
Pathophysiology
• A series of mutations in the DDST gene has been identified in patients with
achondrogenesis type IB. 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 patients with type IB 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
directly related 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.
Clinical Presentation
Achondrogenesis type I
See the list below:
1. Growth - Lethal neonatal dwarfism, mean birth weight of 1200 g
2. 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)
3. Neck - Extremely short
4. Thorax - Short and barrel-shaped thorax, lung hypoplasia
5. Heart - Patent ductus arteriosus, atrial septal defect, ventricular septal defect
6. Abdomen - Protuberant
7. Limbs - Extremely short (micromelia), much shorter than type II; flipper-like
appendages
Achondrogenesis type II
See the list below:
1. Growth - Lethal neonatal dwarfism, mean birth weight of 2100 g
2. Craniofacial - Disproportionately large head, large and prominent forehead, flat
facial plane, flat nasal bridge, small nose with severely anteverted nostrils, normal
philtrum (often), micrognathia
3. Neck - Extremely short
4. Thorax - Short and flared thorax, bell-shaped cage, lung hypoplasia
5. Abdomen - Protuberant
6. Limbs - Extremely short (micromelia)
DD
Other differentials to consider include the following:
• Atelosteogenesis type II
• Fibrochondrogenesis
• Grebe dysplasia
• Homozygous achondroplasia
• Hypochondrogenesis
• Lethal osteogenesis imperfecta
• Roberts syndrome
• Schneckenbecken dysplasia
• Short rib-polydactyly syndromes
• Spondyloepiphyseal dysplasia congenita, lethal form
Work Up
Laboratory Studies
See the list below:
• Molecular studies for achondrogenesis are performed on
ethylenediaminetetraacetic acid (EDTA)–anticoagulated blood for DNA analysis.
• Mutation analysis of the DDST gene identifies the following: point mutations,
deletions leading to premature stop codons, substitutions or deletions of amino
acids within transmembrane domains, substitutions of amino acids in intracellular
or extracellular domains, and presumed mutations lying outside the coding region
but causing low mRNA levels.
• Several mutations of the DDST gene have been reported in patients with type IB
(the most severe form), patients with atelosteogenesis type II (an intermediate
form), and patients with diastrophic dysplasia (the mildest form).
• Mutation analysis can be used to ascertain carriers, particularly in consanguineous
families. However, biochemical analysis of fibroblast cultures has not been able to
distinguish heterozygotes from normal homozygotes.
• Mutation analysis of the COL2A1 gene detects a single base change that has been
observed in a patient with achondrogenesis type II in the type II procollagen gene
(ie, substitution of serine for glycine in the alpha 1 [II] chain).
Imaging Studies
Radiological features may vary, and no single feature is obligatory. Distinction between type
IA and type IB on radiographs is not always possible. Degree of ossification is age
dependent, and caution is needed when comparing radiographs at different gestational
ages.
Achondrogenesis type I (Fraccaro-Houston-Harris type)
See the list below:
• Skull - Varying degree of deficient cranial ossification consisting of small islands of bone
in membranous calvaria
• Thorax and ribs - Short and barrel-shaped thorax; thin ribs with marked expansion at
costochondral junction, frequently with multiple fractures
• Spine and pelvis - Poorly ossified spine, ischium, and pubis; poorly ossified iliac bones
with short medial margins
• Limbs and tubular bones - Extreme micromelia, with limbs much shorter than in type II;
flipper-like appendages; prominent spike-like metaphyseal spurs; femur and tibia
frequently presenting as bone segments
• Subtype IA (Houston-Harris type) - Poorly ossified skull, thin ribs with multiple fractures,
unossified vertebrae, arched ilium, hypoplastic but ossified ischium, wedged femur with
metaphyseal spikes, short tibia and fibula with metaphyseal flare, "rectangular bones"
• Subtype IB (Fraccaro type) - Adequately ossified skull, absence of rib fractures, ossified
posterior vertebral pedicles, crenated ilium, unossified ischium, trapezoid femur,
stellate tibia, unossified fibula, arms and legs shorter than in type IA
Achondrogenesis type II (Langer-Saldino type)
See the list below:
• Skull - Normal cranial ossification, relatively large calvaria
• Thorax and ribs - Short and flared thorax; bell-shaped cage with broader, shorter
ribs without fractures
• Spine and pelvis - Relatively well-ossified iliac bones with long, crescent-shaped
medial and inferior margins
• Limbs and tubular bones - Short, broad bones, usually with some diaphyseal
constriction and flared, cupped ends; metaphyseal spurs usually smaller than type
I; disproportionately long fibula; mushroom-stem bones
Treatment
Medical care
• Medical care is supportive in achondrogenesis. No treatment is available for the
underlying disorder.
• Genetic counseling
• Achondrogenesis type IA and type IB are inherited as autosomal recessive disorders. For
a couple who has an affected child, the recurrence risk is 1 in 4 (25%). This risk is
markedly higher than the recurrence risk for achondrogenesis type II, which is usually
caused by a new dominant mutation.
• In type II, asymptomatic carriers may be present in the families of affected patients. It is
important to consider the possibility of germline mosaicism in de novo dominant
conditions such as achondrogenesis II. Couples having delivered a pregnancy considered
to have a de novo dominant disorder should be counseled that the recurrence risk is
greater than the background risk, although the exact recurrence risk is uncertain. If 2 or
more siblings are affected, the recurrence risk increases further. [17]
• Genetic counseling must rely on accurate differentiation between achondrogenesis
type I and type II.
Gallery
• An infant with achondrogenesis type II. Note the disproportionately large head,
large and prominent forehead, flat facial plane, flat nasal bridge, small nose with
severely anteverted nostrils, micrognathia, extremely short neck, short and flared
thorax, protuberant abdomen, and extremely short upper extremities.
• This posteroanterior (PA) view radiograph of an infant with achondrogenesis type II
shows the relatively large calvaria with normal cranial ossification, short and flared
thorax, bell-shaped cage and shorter ribs without fractures, relatively well ossified
iliac bone with long crescent-shaped medial and inferior margins, and short
tubular bones. The sacrum, pubis, and ischium are not visible.
• Lateral view radiograph of an infant with achondrogenesis type II. Note the
relatively large head with a normal cranial ossification and enlarged fontanelles,
short ribs, absent sternal ossification, ossification only in anterior parts of the
vertebral bodies, and short and curved femora.