Lethal skeletal dysplasia
Skeletal dysplasias are genetic diseases
that interfere with normal bone development and growth. Those that are lethal in the perinatal period restrict the growth
of long bones including the ribs. The resulting small thoracic cage causes a mechanical restriction of lung growth. This may
be lethal at birth, or death may occur in early infancy. In some cases the lungs are able to push the diaphragms down into
the abdomen permitting some lung growth. In general, the limb bones are markedly shortened and in perinatal lethal disease
are often below the 5th percentile. The diagnosis of a lethal skeletal dysplasia can be made prenatally based on
the short femur and small thorax. In some cases, a specific type of dysplasia will also be diagnosed.
The estimated frequency of lethal skeletal
dysplasias is 1.5 per 10,000 births. Another way of looking at the frequency is 9 per 1000 perinatal deaths. There is
a wide variety of phenotypes and genotypes that provide a good model of how different molecular mechanisms produce a common
lethal outcome. The osteochondrodysplasias can be grouped by a common phenotype or molecular mechanism. The most common lethal
groups are osteogenesis imperfecta, thanatophoric dysplasias, achondrogenesis and short ribbed polydactyly. Below are portions
of the 1997 International Nomenclature and Classification of the Osteochondrodysplasias (1997)
(list not available on this
In many cases, there will already be a
prenatal, or neonatal diagnosis of a lethal skeletal dysplasia made before the autopsy is begun. Rarely, the pathologist will
need to make the diagnosis of skeletal dysplasia in a very small infant with pulmonary hypoplasia. In either case, the cornerstone
of diagnosis is the radiograph. Unless diagnostic radiographs were obtained before death, post mortem radiographs are needed,
ideally anterior-posterior and lateral as a minimum. To an expert radiologist, the radiographs will usually establish the
diagnosis of a specific type of skeletal dysplasia. They will distinguish normal proportionate growth retardation from skeletal
dysplasia. The autopsy will contribute to the diagnosis by documenting other organ pathology, by describing the bone pathology,
and by obtaining any sample needed for a specific molecular diagnosis.
The chest circumference in comparison to the body weight will document the small chest, and lung to body weight ratio
will document the pulmonary hypoplasia. In some early fetuses, there may not be demonstrable pulmonary hypoplasia, and the
diagnosis of lethality relies on having the correct diagnosis of a specific skeletal dysplasia. Rarely, the lungs will be
large because of growth into the abdomen by eventration of the diaphragm. Limb lengths can be measured, but if not routine,
a lower extremity length can be obtained by subtracting the crown rump length from the crown heel. Since some skeletal dysplasias
have underlying molecular mechanisms that effect more than bone, a careful complete autopsy will document the extent and pattern
of other defects.
The gross bone pathology that can be seen at autopsy includes the width of fontanels including an open metopic (mid
forehead suture), abnormal mineralization of the skull, rib or other bone fractures, and distortions of the femur. In addition
to routine histologic samples of the bone cartilage junction of the rib, and a mid saggital section of the vertebral body,
a section of skull, and of femur can be helpful. These four types of bone development may be affected to a different degree
in different types of skeletal dysplasia. The femur is the most accessible long bone. The femur can be sampled by clipping
the acetabulum free of the pelvis. Then starting within the pelvis, the femur is dissected free of soft tissue. No external
incision is necessary. The bone may be removed at the knee or cut above the knee. A dowel can be inserted to replace the bone.
The femur can be split parallel to the diaphysis usually with a small saw. A thin strip of bone can be taken from the edge
to midpoint of the parietal skull bone without external effect (assuming permission for examination of the head). There is
a published protocol for bone sampling in cases of skeletal dysplasia.
The bone histology often relies on comparison of the stages of enchondral ossification to the normal. The chondrocytes
may fail to form columns. The columns may be too short or too few, or their alignment may loose its normal straightness. The
tabeculae may not show normal ossification of cartilage, normal thickness or normal remodeling as they enter the diaphysis.
The resting cartilage may be too vascular. Periosteal bone formation may too thick, or may form too deep a cuff around the
growth plate. The shafts of bones may show fracture callus. Individual chondrocytes may have PAS positive inclusions. Seldom
is a single feature diagnostic. In many cases, a semi-quantitative judgment requires side by side comparison with controls.
If in doubt, it is better to obtain autopsy
specimens for specialized diagnostic tests since they can not be obtained later. Skin for fibroblast culture, and rib for
chondrocyte culture, can be obtained aseptically and stored in cell culture media at room temperature. The rib is convenient
for obtaining a piece of bone and cartilage to snap freeze, and a small piece at the growth plate can be minced and fixed
in glutaraldehyde. Portions of all the bones can be held without decalcification for plastic embedding. An even simpler approach
is to send overnight fresh bone on ice to the Skeletal Dysplasia Registry: Below is a quote from the Registry:
Send autopsy evaluations, photos/x-rays (if possible
AP and Lat. x-rays of entire fetus), pertinent lab studies (ie: genetic test results), as well as tissue specimens (3-4
ribs and a femur ensures that we receive ample growth plate and cartilage samples). These specimens should be sent to
us with identification and also shipped to us overnight (Mon-Thurs.) on wet ice. We also accept whole fetus specimens
which again should also be shipped to us overnight (Mon-Thurs.) on wet ice. We do not accept Saturday deliveries.
Should we need to collect blood from the family in most cases we coordinate the blood draw with a genetic counselor or with
the referring physician's clinic
In some cases, a molecular diagnosis will
clarify doubts about the radiological diagnosis and make genetic counseling more secure. For subsequent pregnancies, a precise
molecular diagnosis may or may not be needed depending if ultrasound can make the diagnosis as early as tissue sampling. Even
if the special samples are not eventually needed for diagnosis, they may be valuable for research. Skeletal dysplasias offer
an opportunity to understand the translation of molecular defect to phenotype in a wide variety of mechanisms. The International
Skeletal Dysplasia Registry has some active protocols and can provide consent documents. The registry has consents on its website: http://www.cedars-sinai.edu/3805.html
The basic principles governing bone development, growth, modeling are beyond my ability to summarize, but there are
some simple heuristic principles that the pathologist may find helpful. First is the distinction between enchondral and membranous
bone growth. Enchondral growth starts with the condensation of a cartilage anlagen. A growth plate develops in the cartilage
which produces a linear progression of ossification. The cartilage cells proliferate, then align in columns, then balloon
and degenerate, following which the intervening matrix calcifies, and finally is replaced by bone. Bone lengthening is achieved
by this process. Membranous bone produced bone directly without a cartilage template. Bones like the cranial plate are entirely
membranous. Most long bones have a periostium of membranous bone, the growth of which increases the width of the bone. Membranous
bone extends around the zone of enchondral bone growth which accounts for the cusp at the ends of the bone seen on radiographs
of fetal bone (cusp of Ranvier). The separation of linear enchondral bone growth from expansive membranous bone growth provides
a framework for understanding how molecular mutations cause different bone morphologies. A secondary fact is that collagen
II is the main collagen of cartilage and collagen I of bone.
The second principle is that bone is a composite material in some ways analogous to a sky scraper building. The collagen
acts like the steel girders and bone matrix acts like the concrete. When the collagen is defective, the bone fractures or
crumbles. Without the ossified matrix, the bone bends.
The third is a related principle that states the forces shaping bone can be divided into hydrostatic and shear stresses.
The former can be thought of as forces that tend to compress or expand the bone and that act normal (perpendicular) to the
surface of the bone and are equal in all directions. This is equivalent to blowing up a balloon. This is the force to which
the matrix is most likely to respond (or cause). Stress forces are from asymmetric forces pulling on a bone, such as from
a muscle attachment, and tend to deform the bone. These forces can be seen as tangential to the surface and equivalent to
bending the bone. The collagenous fiber of bone will respond to the shear stress. Through molecular mechanisms, these physical
forces elicit cellular growth and secretion that guide bone morphogenesis. One hypothesis is that shear stress encourages
ossification of cartilage, and intermittent compressive dilatational stress inhibits ossification. This model was used to
explain the known shapes of the sternum.
These simplified principles may help bring some focus to the array of bone findings in lethal skeletal dsyplasias.
They may also aid reasoning when faced with unknown or novel bone findings. These principles are also related to the basics
changes with understanding of these diseases. Growth disorders of bone are osteochondraldysplasias. Malformations of bone
are named dysotoses. A dysplasia can be named for the region of the bone involved. The zone of enchondral growth is metaphyseal
dysplasia. The articular end of the cartilage is the epiphyseal dysplasia. The fetus has not developed a separate zone of
enchondral bone formation in the epiphysis. The formed shaft is diaphyseal dysplasia. Dysplasias may also be named by the
segment of limb that is shortened: rhizomelic (proximal), mesomelic (middle) and acromelic (distal). Diastrophic dysplasia
refers to twisted bone.
The gross examination
of bone in general is not as informative at the radiograph. Measurements of gross bone will be vary from those taken from
the radiograph because of minimal magnification based on distance from the plate, or in utero ultrasound which used echo changes
to define end points. There is a monograph of extensive direct measurements of fetal bone, but the book is not always available. Precise bone measurement is not usually needed diagnostically.
However the femur is measured, it usually is less than 80% of the mean for gestational age in the lethal dysplasias. This is far less than the 5th percentile.
The histologic study of bone in the skeletal dysplasias has been reviewed in detail for many, not just lethal, types. In the commonly described dysplasias, histology contributes little
to the diagnosis. Samples should still be examined since unexpected findings may occur or an unusual form of dysplasia may
not have been expected. For research studies undecalcified sections, frozen sections and electron microscopy can be undertaken,
but in most cases routine decalcified sections are adequate to understand the bone pathology. Larger bone samples can be cut
with a saw or sharp blade to improve the speed of fixation and decalcification. This may produce some fractures, but usually
an intact section can be obtained after decalcification.
Specific Lethal Skeletal Dysplasias
The two types of thanatophoric dysplasia were recognized prior to discovery of the molecular defect. Some cases show some overlap of features. Type 1 thanatophoric dysplasia has
short curved femora, and very shallow vertebral bodies. Type 2 has straight femora and taller vertebral bodies. Type 2 is
associated with the most severe Kleeblattschädel anomaly (in English clover leaf skull). The clover leaf appearance is due to bulging laterally in both temporal
areas, and a high vertical extension with a widely open metopic suture and anterior fontanel. The eyes may be proptotic. Hydrocephalus
may be present. A milder degree of clover leaf skull may be detectable in some cases of Type 1. The short bone growth in both
types is reflected histologically in a decreased thickness and cellularity of the enchondral growth plate. Type 1 shows minimal
normal ballooning of chondrocytes. Ballooning while reduced is present in Type 2.
Achondroplasia is a common non lethal autosomal dominant skeletal dysplasia. The homozygous form is lethal
and resembles thanataphoric dsyplasia, a very common lethal dwarfism. In the early 1990’s the genetic defect of achondroplasia
was discovered to be a very consistent mutation in the fibroblast growth factor 3 receptor, a protein expressed in cartilage
and brain. The same protein was mutated in hypochondroplasia.
Shortly after, there were multiple reports that thanataphoric dysplasia was due to multiple different mutations of
this same gene[9-11]. The mechanism of dysplasia in this
case appears to be failure to stimulate cartilage growth due to unresponsiveness to fibroblast growth factor 3. The two clinical
subtypes of thanatophoric dysplasia (straight versus curved femora) have different patterns of mutation with all type 2 cases
having the mutation Lys650Glu substitution . The type 2 mutation
has been shown to constitutively activate the transcription factor Stat1 which in turn induces expression of cell cycle inhibitor
p21. Interestingly in this disease of spontaneous
mutation the only known risk factor is increased parental age, including paternal age. Microscopically the pathogenesis is reflected in failure of enchondral bone formation.
The distinctions among lethal skeletal dysplasias (except osteogeneisis imperfecta) by radiology and histology is relatively
subtle, perhaps since they all have a common phenotype of failed thoracic and limb growth. Hwang and Ghadially reported a
unique globular smooth-tubule aggregate found in thanatophoric dysplasia. I did not find this organelle in the two cases I examined, but I looked prior to the report. Good radiographs,
and samples for molecular diagnosis that routinely include living fibroblast and cartilage cells are key to eventually obtaining
the correct diagnosis.
Lethal osteogenesis imperfecta.
This is a common lethal skeletal dysplasia, although the incidence of thanatophoric dysplasia is more common in some
series. The molecular basis is an abnormality in the collagen I strength of the bone resulting in bone fracture. In the radiologic-clinical
classification proposed by Sillence and co-workers, the lethal form was designated type II (Type I is mild, Type III is severe,
and Type IV is moderately severe). This spectrum of severity should parallel the severity of the weakness of the collagen
bone structure. The high frequency may be due to the vulnerability to mutation of the long collagen 1A1 and 1A2 chains. A
mutation that substitutes GLY in the repetitive Gly-X-Y triplets destabilizes the triple helix of the collagen molecule.
The defective chains are incorporated in the type 1 procollagen molecule creating weaker collagen. The original molecular
understanding of this disease was derived from the electrophoresis of hydrogen bromide digested fragments of soluble collagen
1 derived from fibroblast cultures. Usually one normal and one abnormally mobile fragment of the same chain of collagen
were found. Having one abnormal chain was sufficient to weaken the collagen structure. That finding proved that lethal osteogenesis
was usually a dominant heterozygous mutation. Since the mutation often was not present even in mosaic form in the parents,
the mutation must have been a parental germline (empirically approximately 6-7% and can be from either parent) or embryonic
mutation. Indeed the mutation can sometimes be identified in the sperm.
Identification of the mutation by PCR
of collagen 1 genes has demonstrated considerable molecular heterogeneity. I can not hope to summarize this information better
than the authors themselves. I have copied an abstract from the collaborative group. The molecular correlations are fascinating.
In the lethal variants more detailed study of the bone might show details of the molecular anatomic relationships.
“ Osteogenesis imperfecta (OI) is a generalized disorder of connective tissue characterized
by fragile bones and easy susceptibility to fracture. Most cases of OI are caused by mutations in type I collagen. We have
identified and assembled structural mutations in type I collagen genes (COL1A1 and COL1A2, encoding the proalpha1(I) and proalpha2(I)
chains, respectively) that result in OI. Quantitative defects causing type I OI were not included. Of these 832 independent
mutations, 682 result in substitution for glycine residues in the triple helical domain of the encoded protein and 150 alter
splice sites. Distinct genotype-phenotype relationships emerge for each chain. One-third of the mutations that result in glycine
substitutions in alpha1(I) are lethal, especially when the substituting residues are charged or have a branched side chain.
Substitutions in the first 200 residues are nonlethal and have variable outcome thereafter, unrelated to folding or helix
stability domains. Two exclusively lethal regions (helix positions 691-823 and 910-964) align with major ligand binding regions
(MLBRs), suggesting crucial interactions of collagen monomers or fibrils with integrins, matrix metalloproteinases (MMPs),
fibronectin, and cartilage oligomeric matrix protein (COMP). Mutations in COL1A2 are predominantly nonlethal (80%). Lethal
substitutions are located in eight regularly spaced clusters along the chain, supporting a regional model. The lethal regions
align with proteoglycan binding sites along the fibril, suggesting a role in fibril-matrix interactions. Recurrences at the
same site in alpha2(I) are generally concordant for outcome, unlike alpha1(I). Splice site mutations comprise 20% of helical
mutations identified in OI patients, and may lead to exon skipping, intron inclusion, or the activation of cryptic splice
sites. Splice site mutations in COL1A1 are rarely lethal; they often lead to frameshifts and the mild type I phenotype. In
alpha2(I), lethal exon skipping events are located in the carboxyl half of the chain. Our data on genotype-phenotype relationships
indicate that the two collagen chains play very different roles in matrix integrity and that phenotype depends on intracellular
and extracellular events”.
There are well documented cases of autosomal
recessive lethal osteogenesis imperfecta. At least one cause was found by looking at a gene the caused abnormal bone formation
in mice. The phenotype of weak collagen can occur because the defective collagen can not bind to the matrix (see quote
above). The mouse model involved defects in cartilage associated protein (CRTAP). A defect in this protein was searched for
and found in human cases of severe OI without a collagen mutation. These children had severe osteoporosis and may have been
in the spectrum of Type IIC, but this was not discussed. The mouse model and molecular techniques have proven their clinical
utility in this disease. Identifying the mutation permits diagnosis of disease in germ cells and early embryonic cells, neither
of which would express the phenotype.
Sillence and co-workers proposed sub-classification of lethal Type II into IIA, IIB, and IIC. I have autopsied only
Type IIA. The cause of the limb and rib shortening in this entity is the extensive fracturing of bones. Both the radiology
and the histology show almost continuous fractures with repair in the ribs and long bones. The histology demonstrates irregular,
thin trabeculae often with intermittent cartilaginous fracture callus. One study of bone histology correlated with the Sillence
subtypes found that IIA, IIB and III all had similar histology, but differed in degree. Their single case of type IIC
showed a lattice of trabeculae with thick cartilaginous cores. In Sillence and co-workeres paper one family with 3 siblings
with Type IIC were first cousins. That paper also noted that Types A and B vary only in severity, but that Type C also had
abnormalities of long bones and ribs, which point to marked reduction in skeletal matrix”. The direct correlation
of detailed histologic changes with specific molecular defects in OI has not been completely explored.
Demonstrating that an aborted fetus with
osteogenesis imperfecta has “lethal” disease depends on radiologic evidence of Type II. The lungs at the time
of termination may not be severely hypoplastic in the less severe sub-types. Byers and co-workers divided cases of type II
into five subgroups 1-5 based on decreasing severity. Infants in the first 2 subgroups were either stillborn or died before
24 hours. The other groups showed very variable survival from hours to months. Even in those infants able to survive for months
suffered from multiple bone fractures. Perhaps the most the pathologist can do is establish the extent of fractures and the
molecular evidence of a known lethal collagen mutation.
A surprising feature is the lack of ossification
of the skull rather than multiple fractures. This could be the result of resorbed small fractures, but it might imply an inability
to develop a degree of tension or thickness in the membranous connective tissue needed to generate membranous bone. The brain
appears to bulge over the face which often just reflects normal brain growth. There are reports of brain abnormalities, perhaps
related to susceptibility to physical trauma. Hydrocephalus has been reported in 4 infants attributed to both hemorrhage and
to occipital bone fracture. White matter injury and neuronal migration abnormalities have also been noted in OI. The
authors provided evidence for and against three hypotheses: abnormal collagen guidance of neuronal migration, physical microtrauma,
and hypoxic ischemic injury related to the perivascular microcalcifications present in some cases. The most severe abnormalities
were in a single case of OI type II2C.
Bone is not the only tissue that depends on collagen I for strength. Clinically
most evident is the blue sclera in osteogenesis imperfecta which results from thinning over the pigmented choroid layer. More
dramatic are fetuses that have weak skin and fascia resulting in rupture of the skull or separated limbs. I autopsied an infant in whom the brain delivered prior to the baby as the expulsive force of labor ruptured
the head. At the autopsy table in one case, holding the baby by one foot to measure an accurate crown heel length, the foot
separated from the leg.
In severe cases, the heart valves may
become incompetent from weak chordae tendinae. A detailed study of 2 cases demonstrated abnormal collagen and increased cellularity
of the atrio-ventricular valves using electron microscopy. This study found that the abnormalities were more severe in
the older gestation fetus 34 weeks compared to 23 and suggested this may be related to the increased proportion of collagen
I compared to collagen III in the heart (and skin) with fetal maturation. An incompetent tricuspid valve by elevating umbilical
venous pressure may lead to fetal hydrops and stillbirth. Even in non-lethal forms of osteogenesis imperfecta there may be
widening of the root of the aorta and other cardiac lesions[26, 27].
Calcification of the great vessels and
endocardium may be present. I have seen calcification of the media of the aorta in one case. A logical mechanism would be
micro-injury to the media weakened from abnormal collagen. However, calcium and phosphorus in blood from bone resorption could
play a role. An under-investigated area is the affect of the extensive fracture repair on parathyroid metabolism. One anatomic
study reported parathyroid hemorrhage in 4 infants with lethal osteogenesis that lived more than 9 days, but none in 4 who
died within 72 minutes of birth. I can only confirm its absence in infants dieing shortly after birth, but the paper also
found hypocalcemia in two infants (one with hyperphosphatemia as well). Not surprisingly the extensive bone resorption and
repair might stress parathyroid homeostatic mechanisms.
There are two major divisions, type I (Parenti-Fraccaro) and type II (Langer-Saldino). Externally type I has some resemblance
to osteogenesis imperfection with distorted short limbs. Radiographically, the limb bones are very short with cupped metaphysic
and often spiking metaphysis. This group is further divided into types IA and
IA may have rib fractures and absent mineralization of the vertebra. Type IB
appears to be similar but less severe without rib fractures and more abundant metaphyseal spiking. In the newer classifications
Type IA is groupsed with
spondylodysplastic and other lethal disorders. Type IB is grouped with diastrophic dysplasia based on mutations in the same
Type II may demonstrate the early lymphatic
obstruction sequence. Type II has a different radiologic appearance with slightly longer bones with deeply cupped metaphysis,
and more ossification of the spine. Hypochondrogenesis is part of a spectrum of less severe forms of Type II. Membranous
bone formation is not affected, and the cuff of Ranvier accounts for the deep ossified epiphyseal cups. The metaphyseal spurs
could be wrinkles in the membranous bone formation. The lack of vertebral ossification suggests that this mineralization relies
most heavily on enchondral rather than membranous bone. The decreased skull mineralization is more difficult to understand
unless it is secondary to underlying distortion of the basicranium.
Histologically type I shows a predominance of hypercellular chondrocytes without formation of columns or ballooning.
The chondrocytes may be vacuolated and in type IA have PAS positive inclusions. In Type II there is still a predominance
of disorganized chondrocytes, but they show ballooning and with a striking hypervascularity.
The distinction of types or even of identification of this class of skeletal dysplasia needs confirmation by experts
such as the International Skeletal Dysplasia Registry. An editorial by Dr. Kapur opined that despite detailed tables including
an excellent one that he provided, the distinctions between the types are “black and white” and no single feature
is reliable. The molecular bases for two of these dysplasias have been identified. Type II is analogous to osteogenesis imperfecta in that it results from a mutation
in the collagen helix, and the severity varies with the location of the mutation in the helix. In this disease the weakened
fiber is collagen type 2, rather then collagen type 1. Other mutations in collagen type 2 cause Kneist dysplasia and spondyloepiphyseal
Type IB can be caused by a mutation in
the diastrophic dysplasia sulfate transporter gene. The morphogenetic mechanism in this case was elegantly elucidated by showing
a lack decorin proteoglycan immuno-staining in the cartilage matrix. Decorin is found exclusively in the interterritorial
matrix which that area in enchondral ossification that becomes the calcified columns and eventually cartilaginous core of
bony trabeculae. The protein core can be immunologically identified in the chondrocytes, just not in the matrix. The territorial
matrix surrounding the chondrocytes shows exclusively biglycan which is preserved in this disease. Fibrocytes grow into the
area that would be interterritorial matrix. The authors conclude that the matrix is disorganized and weakened by this specific
loss of decorin production. Weakened collagen type II fibers in Type II achondrogenesis must also cause mechanical weakening
of the critical cartilage matrix, thus accounting for some overlap of the features of these diseases. Type IA has prominent PAS positive material in the chondrocyte
rER, and a similar disarrangement of enchondral ossification. The findings have been interpreted as a matrix component not
being secreted which weakens the overall matrix integrity. This concept fits well with the morphologic mechanisms in the
other two types.
I have three cases and all are type II.
Short rib polydactyly syndromes
This group is divided into four morphologic
types as well as including asphyxiating thoracic dystrophy of Jeune and Ellis-van Creveld disease.. Only Ellis-van Creveld
has a known gene basis with the majority having a mutation in EVC1 or EVC2. The first four types are neonatally lethal and
have very short ribs, sometimes polydactyly and various often overlapping visceral disorders[36-39]. Type I (Saldino-Noonan)
has torpedo shaped long bones. Type II Majewski have short oval tibia. Type III (Verma-Naumoff has a banana peel shape tibia.
Type IV (Beemer) resembles Majewski with a less short tibia and only rarely has polydacyly. In practice, there may be overlap
among the types
histological study of type III concluded that the basis is a loss of synchrony in cartilage differentiation and osteogenic
differentiation in growth plates . The broad range of nonosseous malformation suggests an origin with homeobox or transcription
factors rather than a bone specific morphogen.
This entity which means “bowed limb” encompasses Kyphomelic dysplasia as well. A bent limb usually femur
however is commonly found in many other skeletal dysplasias often with high frequency.
The “campomelic syndrome excluding kyphomelia is a cause of severe pulmonary hypoplasia. It characterized by
bent femurs and tibias, flat midface and micrognathia, hypoplastic scapula and eleven ribs. Multiple autopsy studies have
found a wide range of internal anomalies including the heart and brain[43-45]. There was distinctive hypoplasia of the tracheal
bronchial tree. Perhaps the most unusual finding was a female phenotype in genetic males. This observation led to the discovery
that the disease is caused by mutations in the transcription factors SOX9. This factor on chromosome 17 is structurally
related to the testis determining factor SRY, and is expressed in the fetal testis and skeleton. Mutations that cause a haplotype
insufficiency in SOX 9 DNA binding or function result in both the autosomal sex reversal and campomelia.
severity of this disease varies from perinatal lethal to adults with some dental disease, but no bony problems. The lethal
perinatal form is characterized by marked under-mineralization of bone, and other bony anomalies including various abnormal
femur contours and mid shaft spurs of the ulna and tibia. The features can vary between cases as to which bones are undermineralized
and in type of bony malformation for example, “chromosome like’, or campomelic femurs. As with most lethal skeletal
dysplasias, the infant’s have severe pulmonary hypoplasia. The etiology is decreased activity of tissue non-specific
alkaline phosphatase due to mutation in ALPL gene. The mutation results in increased inorganic pyrophosphate in the bone
matrix which interferes with growth of nascent hydroxyapatite crytstals. Not surprisingly the severity of the bony disease
depends on the extent of decrease of alkaline phosphatase activity. There is one interesting exception, in the nonlethal
perinatal form, the gene is inherited from the mother, and it is the combination of the maternal disease and fetal disease
that results in perinatal symptoms that resolve. The placenta has alkaline phosphatase activity, as does the maternal serum.
Perhaps in cases with just a small decrease in activity, maternal serum enzyme can substitute for placental. The link between
bone and placental phosphatase however is not clear. Since the disease can improve in some infants after birth, early reports
of successful enzyme replacement may not have been due to the therapy, but newer replacement therapies including bone
marrow transplant may be successful.
This is a very interesting lethal skeletal dysplasia since the same syndrome divides into two completely different
molecular mechanisms. One group has just skeletal manifestations including craniosynostosis, radioulnar or radiohumeral
synostosis, bowed femora, and midface hypoplasia. This group has mutations in the fibroblast growth factor receptor 2 mutation
analogous to thanatophoric dyusplasia. The other group has a mutation in the P450 oxidoreductase (POR) gene which is involved in many enzymes in the body including those involved with steroidogenesis.
Patients with the Antley-Bixler skeletal phenotype and having ambiguous genitalia and disordered steroidogenesis have this
Caffey syndrome, prenatal lethal type
Most Caffey syndrome is usually postnatal onset and self limited, but the form that develops in utero in usually fatal
with pulmonary hypolasia, and often fetal hydrops and polyhydramnios[53-56]. The prenatal disease, like the postnatal, shows
a marked cortical hyperostosis associated with loss of bone marrow space due to fibrosis. In the prenatal cases, the long
bones and ribs are shortened. There is usually hepatomegaly with increased erythropoiesis possibly due to the loss of bone
marrow space. The etiology is unknown. There have been familial cases even in the perinatal form, but it is usually sporadic.
The bone histology resembles the periosteal changes seen in prolonged PGE1 administration in neonates.
This entity is characterized by distinct epiphyseal stippling on radiographs. It is commonly divided into two very
distinct syndromes. The first is rhizomelic chondrodysplasia punctata which has deficiencies of various peroxisomal enzymes and a very poor prognosis with the majority of infants dying in the first year of life.
The typical findings are symmetric proximal limb shortening (hence rhizomelic), dysmorphic face, cataracts, ichthyosis, and
joint contractures. The severe psychomotor retardation in one autopsy was correlated with loss of white matter but normal
myelination. This type can has been diagnosed prenatally since the discovery of its biochemistry, and may frequently
result in a therapeutic abortion and perinatal autopsy. Unlike Zellweger’s
syndrome and neonatal adrenoleukodystrophy, the peroxizomes are structurally intact.
The second type, Conradi-Hünermann type or X linked dominant form, is very variable in its clinical severity. The disease is caused by
a mutation in the Emopamil Binding Protein (EBP) which causes a deficiency of postsqualene cholesterol biosynthesis, different
from that in the more common Smith-Lemli-Opitz syndrome. Improbably, many of the features are the same as in the peroxisomal
type including the punctuate epiphyseal calcifications, the rhizomelic shortening (although usually asymmetric) and ichthyosis.
This form lacks the severe pyshomotor retardation and usually has a better prognosis. However, in at least one case, there
was severe pulmonary hypoplasia and immediate perinatal death in a 28 week gestation infant. Interestingly, this type
was diagnosed prenatally in 1972 by prenatal radiography.
There are multiple other skeletal dysplasias
with chondrodysplasia punctata. Historically, one cause was the administration of coumadin during pregnancy.
Non-lethal skeletal dysplasias
There are many non-lethal dysplasias that can be seen to be manifest at birth. The International Nomenclature and Classification
lists a data column as to whether lesions are present at birth. Some of these infants may be terminated for disease, but others
may die of causes unrelated to their skeletal dysplasia. The pathologist can not be versed in all these diseases, and needs
to rely on other experts as well as researching the individual disease in the medical literature. However, the autopsy may
provide some insight into the early mechanism of these diseases.
Kinney (Linarelli) Caffey syndrome:
The example of non lethal disease is from an infant that died
at 6 weeks of age, but whose disease was evident in the perinatal period. This case was more severe than some of the reported
Kenny-Caffey cases[65, 66]. This syndrome is characterized by marked growth failure including low birth weight, transient
congenital hypoparathyroidism, and narrow thick diaphysis of long bones with small medullary cavities. There is a similar
syndrome found in the Middle East, Sanjad-Sakati syndrome. Both of these syndromes have been
mapped to mutations in the TBCE gene on chromosome 1q43-44. This gene codes for a chaperone protein required for the proper
folding of α tubulin subunits and the formation of α-β-tubulin dimmers. Studies of fibroblasts from these patients
have shown microtubular abnormalities. The case example had a micropenis that might be related to microtubular function in
the testes. The brain showed an unusual myelination pattern that may or may not have been related to microtubule axonal function.
The infant eventually died of pneumonia which again may or may not have been related to microtubular function of cilia. The
role of microtubules in parathyroid secretion is not clear.
A dysostosis involves individual bones, in this
case rib and vertebra, rather than bone development in general. Both this disease and spondylocostal dysostosis have been
called Jacho-Levin syndrome in the medical literature. Spondylocostal dysostosis has intrinsic abnormalities of the ribs and is not as severe. Spondylothoracic dysostosis
has vertebral abnormalities (fusions, hemivertebra) and fusion of the ribs at the costo-vertebral junction. The chest is described
as “crab like”. There is markedly shortened stature and the abdomen is protuberant. While the lesion is described
as lethal, there may be over 50% survival, at least as reported in one series. This disease has a higher prevalence in Puerto Rico, and genetic studies have found a likely founder mutation in the Mesp2 gene in that population. This gene in the mouse is expressed
as a stripe in the presomite mesoderm that prefigures somite formation. Knockout mice demonstrate a phenotype similar to spondylothoracic
Not really a skeletal
Larson syndrome demonstrates among other things
congenital joint dislocations. We reported a case with congenital joint dislocations that was lethal in the neonatal period
in 2 infants of the same parents. One of there infants was autopsied and demonstrated a peculiar distortion of the growth plate in which the cartlage
columns seemed to bend and sometimes narrow to nothing. The infant had mild pulmonary hypoplasia and pneumonitis. The unautopsied
sibling had a bell shaped hypoplastic chest.
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