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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[1]. 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[1]. Another way of looking at the frequency is 9 per 1000 perinatal deaths[1]. 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)[2]

(list not available on this web site) 

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[3].

            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[4].

            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 of terminology.

Nomenclature 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[5]. 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[1]. 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[6]. 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

 

Thanatophoric Dysplasia:

 

            The two types of thanatophoric dysplasia were recognized prior to discovery of the molecular defect[7]. 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 Kleeblattschdel 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[8]. 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 [12]. The type 2 mutation has been shown to constitutively activate the transcription factor Stat1 which in turn induces expression of cell cycle inhibitor p21[13]. Interestingly in this disease of spontaneous mutation the only known risk factor is increased parental age, including paternal age[14]. 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[15]. 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.

 

Examples

           

 

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)[16]. 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[17]. 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[18]. 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”[19]. 

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[20]. 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[21]. 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[22]. 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 “modelling [sic] abnormalities of long bones and ribs, which point to marked reduction in skeletal matrix”[21]. 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[18]. 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[23]. White matter injury and neuronal migration abnormalities have also been noted in OI[24]. 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[25]. 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[28]. 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.

 

Examples

 

Achondrogenesis-hypochondrogenesis

 

            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 IB[29]. Type 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 gene.

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[30]. 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[31]. The chondrocytes may be vacuolated and in type IA have PAS positive inclusions[32]. 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[33].  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 dysplasia.

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[34]. 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[35]. This concept fits well with the morphologic mechanisms in the other two types.

 

Examples

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[40]

 One histological study of type III concluded that the basis is a loss of synchrony in cartilage differentiation and osteogenic differentiation in growth plates [41]. The broad range of nonosseous malformation suggests an origin with homeobox or transcription factors rather than a bone specific morphogen.

 

Examples

 

Campomelic dysplasia

 

            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[42].  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[46]. 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.

 

Examples

 

Hypophosphatasia

 

    The 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[47]. 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[48]. The etiology is decreased activity of tissue non-specific alkaline phosphatase due to mutation in ALPL gene[49]. The mutation results in increased inorganic pyrophosphate in the bone matrix which interferes with growth of nascent hydroxyapatite crytstals[50]. Not surprisingly the severity of the bony disease depends on the extent of decrease of alkaline phosphatase activity[49]. 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[51], but newer replacement therapies including bone marrow transplant may be successful.

Example

             

Antley-Bixler syndrome

 

            This is a very interesting lethal skeletal dysplasia since the same syndrome divides into two completely different molecular mechanisms[52]. 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 mutation.

 

Example

 

 

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[53]. The bone histology resembles the periosteal changes seen in prolonged PGE1 administration in neonates[57].

 

Example

 

Chondrodysplasia punctata

 

            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[58]. 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[59]. This type can has been diagnosed prenatally since the discovery of its biochemistry[60], 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-Hnermann 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[61]. 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[62]. Interestingly, this type was diagnosed prenatally in 1972 by prenatal radiography[63].

There are multiple other skeletal dysplasias with chondrodysplasia punctata. Historically, one cause was the administration of coumadin during pregnancy[64].

 

Example

 

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[67]. 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.

 

Spondylothoracic Dysostosis

 

            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[68]. 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[69]. 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 dysostosis.

 

Not really a skeletal dysplasia

 

            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[70]. 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.

 

Case example

 

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