Absent Ossification Research Articles

Narrative Review on the Role of Imaging in DDH.

Developmental dysplasia of hip (DDH) represents a spectrum from acetabular dysplasia to fixed dislocation, giving disability through premature osteoarthritis. Most DDH cases continue to present without any known risk factors such as breech presentation, female sex, and family history. Incidence and population-based outcomes of DDH are difficult to reliably establish due to many DDH definitions and classifications using different types of examinations. This review takes a historical perspective on the role of imaging in DDH. Pelvic radiographs (X-Ray) were amongst the first medical images identifying DDH, but these have a limited role in infancy due to absent ossification. In the 1980s, ultrasound led to a large expansion in infant DDH screening. Unfortunately, even for well-trained users, DDH indices on ultrasound generally lack reproducibility, and have led to overdiagnosis of mild DDH. CT and MRI more thoroughly evaluate the 3D hip deformity in DDH, but are costly, less available and involve radiation dose and/or anaesthesia. Recently 3D ultrasound has been used to characterize the 3D deformity of DDH more fully, with improved inter-observer reliability, particularly amongst novice users. 3D ultrasound is also well suited to automated image analysis, but high-resolution 3D probes are costly and not widely available. Combining the latest handheld portable ultrasound probes and artificial intelligence analysis could lead to an inexpensive tool permitting practical mass population screening for DDH. Overall, our understanding of DDH is heavily influenced by the imaging tools used to visualize it and changing quickly with modern technology.

Delayed sternal ossification in congenital heart disease: incidence using computed tomography.

While congenital heart disease (CHD) is known to be associated with sternal abnormalities, its association with absent sternal ossification is less well known. The literature is sparse and based on radiographs. To quantify delayed sternal ossification in CHD using computed tomography (CT). An imaging database search identified children with complex CHD and controls younger than 3years of age who underwent chest CT from 2010 to 2019. Records were reviewed for demographics, CHD type and other pertinent history. Images were reviewed for manubrial or sternal segment ossification. Controls consisted of children undergoing chest CT for noncardiac reasons. Statistical analyses were conducted using a significance threshold of 0.05. Fifty-nine children had complex CHD (mean age: 9.4months); 36 (61.0%) had cyanotic CHD. There were 189 controls (mean age: 17.9months). Delayed sternal ossification was present in 7 children (11.9%) in the study group; 6 had cyanotic heart disease (85.7%). Patterns of ossification included manubrium only; manubrium and first sternal segment; first and second sternal segments; and manubrium, first segment and hypoplastic second segment. Three controls (1.6%) had sternal ossification delay, all with manubrial ossification only. Delayed sternal ossification was more prevalent in the study group than in the controls (P=0.002). Compared to the controls, a higher incidence of delayed sternal ossification was seen in children with cyanotic CHD (P<0.001) but not acyanotic CHD (P=0.37). Delayed sternal ossification occurs in children with CHD, particularly cyanotic forms, and requires no additional work-up.

Maternal exposure to nanosized titanium dioxide suppresses embryonic development in mice.

Although nanoscale titanium dioxide (nano-TiO2) has been extensively used in industrial food applications and daily products for pregnant women, infants, and children, its potential toxicity on fetal development has been rarely studied. The main objective of this investigation was to establish the effects of maternal exposure of nano-TiO2 on developing embryos. Female imprinting control region mice were orally administered nano-TiO2 from gestational day 0 to 17. Our findings showed that Ti concentrations in maternal serum, placenta, and fetus were increased in nano-TiO2-exposed mice when compared to controls, which resulted in reductions in the contents of calcium and zinc in maternal serum, placenta, and fetus, maternal weight gain, placental weight, fetal weight, number of live fetuses, and fetal crown–rump length as well as cauda length, and caused an increase in the number of both dead fetuses and resorptions. Furthermore, maternal nano-TiO2 exposure inhibited development of the fetal skeleton, suggesting a significant absence of cartilage, reduced or absent ossification, and an increase in the number of fetuses with dysplasia, including exencephaly, spina bifida, coiled tail, scoliosis, rib absence, and sternum absence. These findings indicated that nano-TiO2 can cross the blood–fetal barrier and placental barrier, thereby delaying the development of fetal mice and inducing skeletal malformation. These factors may be associated with reductions in both calcium and zinc in maternal serum and the fetus, and both the placenta and embryos may be major targets of developmental toxicity following maternal exposure to nano-TiO2 during the prenatal period. Therefore, the application of nano-TiO2 should be carried out with caution.

Micro-computed tomography assessment of vertebral column defects in retinoic acid-induced rat model of myelomeningocele.

Myelomeningocele (MMC) is a common congenital malformation and the most severe form of spina bifida characterized by the protrusion of spinal cord and meninges through the spinal defect. Our objective was to improve the assessment of congenital vertebral defects in animal models of MMC using three-dimensional high resolution micro-computed tomography (micro-CT) imaging and quantitative digital analyses methods. Lumbosacral MMC was induced in fetal rats by exposure of pregnant mothers at embryonic day 10 (E10) to all-trans retinoic acid, and rats were examined at term (embryonic day 22). The axial skeleton was examined in an MMC model for the first time using ex vivo micro-CT at 10 μm voxel resolution to allow high resolution two-dimensional and three-dimensional characterization of anomalies in lumbosacral vertebrae, and quantitative assessment of distances between dorsal vertebral arches in lumbosacral regions in MMC rats, compared with normal controls. We observed, in detail, skeletal defects in lumbosacral vertebra of MMC rats, including in the morphology of individual dorsal vertebral arches. Use of high resolution micro-CT has also enabled us to identify the delayed (nonfused) or absent ossification in vertebral bodies, increased fusion of adjacent lateral vertebral elements, and quantify the extent of dorsal arch widening. Distances between dorsal vertebral arches showed statistically significant increases from L5 through S4 in MMC rats, compared with normal controls. High-resolution micro-CT combined with digital quantification methods is a powerful technique ideally suited for precise assessment of complex congenital skeletal abnormalities such as examined in this rodent model of MMC.

Apaf1 apoptotic function critically limits Sonic hedgehog signaling during craniofacial development

Apaf1 is an evolutionarily conserved component of the apoptosome. In mammals, the apoptosome assembles when cytochrome c is released from mitochondria, binding Apaf1 in an ATP-dependent manner and activating caspase 9 to execute apoptosis. Here we identify and characterize a novel mouse mutant, yautja, and find it results from a leucine-to-proline substitution in the winged-helix domain of Apaf1. We show that this allele of Apaf1 is unique, as the yautja mutant Apaf1 protein is stable, yet does not possess apoptotic function in cell culture or in vivo assays. Mutant embryos die perinatally with defects in craniofacial and nervous system development, as well as reduced levels of apoptosis. We further investigated the defects in craniofacial development in the yautja mutation and found altered Sonic hedgehog (Shh) signaling between the prechordal plate and the frontonasal ectoderm, leading to increased mesenchymal proliferation in the face and delayed or absent ossification of the skull base. Taken together, our data highlight the time-sensitive link between Shh signaling and the regulation of apoptosis function in craniofacial development to sculpt the face. We propose that decreased apoptosis in the developing nervous system allows Shh-producing cells to persist and direct a lateral outgrowth of the upper jaw, resulting in the craniofacial defects we see. Finally, the novel yautja Apaf1 allele offers the first in vivo understanding of a stable Apaf1 protein that lacks a function, which should make a useful tool with which to explore the regulation of programmed cell death in mammals.

Yunis-Varón Syndrome Is Caused by Mutations in FIG4, Encoding a Phosphoinositide Phosphatase

Yunis-Varón syndrome (YVS) is an autosomal-recessive disorder with cleidocranial dysplasia, digital anomalies, and severe neurological involvement. Enlarged vacuoles are found in neurons, muscle, and cartilage. By whole-exome sequencing, we identified frameshift and missense mutations of FIG4 in affected individuals from three unrelated families. FIG4 encodes a phosphoinositide phosphatase required for regulation of PI(3,5)P(2) levels, and thus endosomal trafficking and autophagy. In a functional assay, both missense substitutions failed to correct the vacuolar phenotype of Fig4-null mouse fibroblasts. Homozygous Fig4-null mice exhibit features of YVS, including neurodegeneration and enlarged vacuoles in neurons. We demonstrate that Fig4-null mice also have small skeletons with reduced trabecular bone volume and cortical thickness and that cultured osteoblasts accumulate large vacuoles. Our findings demonstrate that homozygosity or compound heterozygosity for null mutations of FIG4 is responsible for YVS, the most severe known human phenotype caused by defective phosphoinositide metabolism. In contrast, in Charcot-Marie-Tooth disease type 4J (also caused by FIG4 mutations), one of the FIG4 alleles is hypomorphic and disease is limited to the peripheral nervous system. This genotype-phenotype correlation demonstrates that absence of FIG4 activity leads to central nervous system dysfunction and extensive skeletal anomalies. Our results describe a role for PI(3,5)P(2) signaling in skeletal development and maintenance.

Severe neurologic manifestations from cervical spine instability in spondylo‐megaepiphyseal‐metaphyseal dysplasia

Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD; OMIM 613330) is a dysostosis/dysplasia caused by recessive mutations in the homeobox-containing gene, NKX3-2 (formerly known as BAPX1). Because of the rarity of the condition, its diagnostic features and natural course are not well known. We describe clinical and radiographic findings in six patients (five of which with homozygous mutations in the NKX3-2 gene) and highlight the unusual and severe changes in the cervical spine and the neurologic complications. In individuals with SMMD, the trunk and the neck are short, while the limbs, fingers and toes are disproportionately long. Radiographs show a severe ossification delay of the vertebral bodies with sagittal and coronal clefts, missing ossification of the pubic bones, large round "balloon-like" epiphyses of the long bones, and presence of multiple pseudoepiphyses at all metacarpals and phalanges. Reduced or absent ossification of the cervical vertebrae leads to cervical instability with anterior or posterior kinking of the cervical spine (swan neck-like deformity, kyknodysostosis). As a result of the cervical spine instability or deformation, five of six patients in our series suffered cervical cord injury that manifested clinically as limb spasticity. Although the number of individuals observed is small, the high incidence of cervical spine deformation in SMMD is unique among skeletal dysplasias. Early diagnosis of SMMD by recognition of the radiographic pattern might prevent of the neurologic complications via prophylactic cervical spine stabilization.

Ambiguous genitalia, microcephaly, seizures, bone malformations, and early death: A distinct MCA/MR syndrome

We report on two siblings with hypotonia, ambiguous genitalia, microcephaly, ptosis, microretrognathia, thin lips, seizures, absent ossification of pubic rami, and brain abnormalities at the MRI. The two siblings died at 5 and 8 months, respectively. Molecular analysis indicated that SOX9, ARX, and DHCR7 genes were normal. Comparative genomic hybridization (CGH)-array analysis performed on the younger boy indicated two notable deletions, one on paternally inherited chromosome 4, and one on maternally inherited chromosome 5. The same deletions were found in a normal sister. Differential diagnoses and the possibility of a hitherto unreported syndrome are discussed.

An unclassifiable short rib‐polydactyly syndrome with acromesomelic hypomineralization and campomelia in siblings

The short rib-polydactyly (SRP) group are lethal skeletal dysplasias with an autosomal recessive inheritance pattern that can be distinguished on radiological and histological grounds. We report on two consecutive pregnancies complicated by a SRP syndrome with acromesomelic hypomineralization and campomelia that cannot be definitely categorized, yet possesses features of this group of conditions. The skeletal changes observed in both cases included markedly shortened ribs, shortened humeri and femora, limb bowing, absent ossification of the radii, ulnae, tibiae and fibulae, as well as the bony elements of the hands and feet, hypoplastic scapulae and peritoneal calcifications. In one case, the pancreas was abnormal in shape, without a tail and the spleen was not identified. Ectopic splenic tissue and intestinal malrotation were identified and were suggestive of a laterality disorder. Whether these two cases should be considered an atypical form of SRP cannot be completely resolved at this present time and will need to wait on further progress in molecular testing.

Molecular prenatal diagnosis in 2 pregnancies at risk for spondyloepiphyseal dysplasia congenita

BackgroundSpondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominant skeletal dysplasia characterized by short stature, abnormal epiphyses, and flattened vertebral bodies. Secondary prevention of SEDC can be achieved by prenatal diagnosis. Reports of antenatally-diagnosed SEDC fetuses have been very rare and molecular prenatal diagnosis even rarer. We previously reported a familial G504S mutation in the type II collagen (COL2A1) gene resulting in SEDC. In this study, molecular prenatal diagnosis was performed to 2 couples in this family with pregnancies at risk for SEDC. MethodsAmniotic fluid was sampled by amniocentesis under ultrasound guidance at 19+3 and 18+6 weeks' gestation, respectively. Karyotype and molecular genetic analysis were performed on cultured amniotic fluid cells. Maternal cell contamination was excluded by short tandem repeat (STR) analysis. Direct DNA sequencing and DHPLC were conducted to detect the potential mutation in exon 23 of COL2A1 gene. Both women underwent serial sonograms because they insisted that the molecular diagnosis should be confirmed by another method, although they had been informed that mutation analysis is predictive of the disease. ResultsKaryotype of both fetuses was normal and molecular genetic analysis revealed that fetus 1 carried a G504S mutation in exon 23, while fetus 2 was normal. In case 1, femur length of the fetus was markedly below the 5th centile at 23 weeks' gestation, which confirms the accuracy of molecular diagnosis. A medical termination was carried out at 27+5 weeks' gestation and a male fetus with a relatively large head and short limbs was delivered. The fetal radiograph demonstrated a number of features, including generalised platyspondyly, absent ossification of the vertebral bodies in the cervical region and significant shortening of the long bones. The diagnosis of SEDC was thus confirmed clinically. Ultrasound monitoring of fetus 2 showed that its femur length was normal for gestational age at repeated scans, which was consistent with the molecular diagnosis. ConclusionsMolecular analysis allows early and accurate prenatal diagnosis for SEDC once mutation is known in a family. However, considering the poor genotype/phenotype correlation in many cases of SEDC, the combination of ultrasound as well as molecular genetic approach might be needed.

Expanding spectrum of congenital disorder of glycosylation Ig (CDG‐Ig): Sibs with a unique skeletal dysplasia, hypogammaglobulinemia, cardiomyopathy, genital malformations, and early lethality

In this report, we describe a brother and sister who presented at birth with short-limb skeletal dysplasia, polyhydramnios, prematurity, and generalized edema. Dysmorphic features included broad nose, thick ears, thin lips, micrognathia, inverted nipples, ulnar deviation at the wrists, spatulate fingers, fifth finger camptodactyly, nail hypoplasia, and talipes equinovarus. Other features included short stature, microcephaly, psychomotor retardation, B-cell lymphopenic hypogammaglobulinemia, sensorineural deafness, retinal detachment and blindness, intestinal malrotation with poor gastrointestinal motility, persistent hyponatremia, intermittent hypoglycemia, and thrombocytopenia. Cardiac anomalies included PDA, VSD, hypertrophic cardiomyopathy, and arrhythmias. The brother had a small penis with hypospadias, hypoplastic scrotum, and non-palpable testes. Skeletal findings included absent ossification of cervical vertebral bodies, pubic bones, knee epiphyses, and tali. Both sibs died before age 2 years, one of overwhelming sepsis and the other of cardiorespiratory failure associated with her cardiomyopathy. Metabolic studies showed a type 1 pattern of abnormal serum transferrin glycosylation. Fibroblasts synthesized truncated LLOs, primarily Man(7)GlcNAc(2), suggestive of CDG-Ig. Both sibs were compound heterozygotes for a novel 301 G > A (G101R) mutation and a previously described 437 G > A (R146Q) mutation in ALG12. Congenital disorders of glycosylation should be considered for children with undiagnosed multi-system disease including neurodevelopmental delay, skeletal dysplasia, immune deficiency, male genital hypoplasia, and cardiomyopathy.

Coxa Vara

Coxa vara can be a progressive deformity in children with skeletal dysplasia. Preoperative anteroposterior pelvic radiographs of 30 children with spondyloepiphyseal dysplasia congenita and spondyloepimetaphyseal dysplasia were used to test the reliability of a new radiographic measure of coxa vara, the Hilgenreiner-trochanteric angle. An additional 10 patients (20 hips) with coxa vara deformities needing valgus-producing proximal femoral osteotomies also were reviewed. Interobserver reliability with plain radiographs was 0.929 for the left side and 0.914 for the right side using interclass correlation coefficients. Intraobserver reliability also was high, with an interclass correlation coefficient of 0.875. Twelve hips corrected by osteotomy had adequate ossification to measure the Hilgenreiner-epiphyseal angle, head-shaft angle, and Hilgenreiner-trochanteric angle. Only one of these hips had a recurrence. The results were good in all of the other ossified hips. Eight hips had limited ossification; only two of these hips maintained acceptable alignment. Six hips had less postoperative correction and progressive deformity at the final followup. We present a novel measurement technique to determine the degree of coxa vara deformity in children with delayed or absent ossification of the capital femoral epiphysis.

Diaphanospondylodysostosis (DSD): Confirmation of a recessive disorder with abnormal vertebral ossification and nephroblastomatosis

We report on four patients from three families, with similar radiological findings: absent (or severely delayed) ossification of vertebral bodies and associated anomalies. The babies were stillborn or died soon after birth of respiratory insufficiency. Two patients are sibs (female and male) born to first cousin Malian parents. The two others were non-consanguineous. This perinatally lethal entity comprises short neck, short wide thorax, and normally shaped limbs. Associated, inconstant anomalies are myelomeningocele, cystic kidneys with nephrogenic rests (in the sibs), and cleft palate. Radiologically, the hallmarks are absence of ossification of the vertebral bodies and sacrum, abnormal position of the vertebral pedicles, which are lamellar and angulated, ribbon-like ribs reduced in number, narrow pelvis, upward widening of the iliac wings, and unusual tilt of the ischiopubic rami, contrasting with the normal appendicular skeleton. Maroteaux briefly described one of the patients in the 2002 edition of "Maladies osseuses de l'enfant" and three sibs with similar renal and radiological findings were reported in 2003 in this Journal. Combined with the latter cases, these four new patients allow delineation of a specific lethal AR syndrome with ossification defect of the axial skeleton and renal dysplasia. We propose to name this entity diaphanospondylodysostosis.

Two billion years of actin. Meeting on cytoskeletal dynamics: from cell biology to developmental disease.

This meeting began with personal retrospective presentations from two of the founding fathers of European cytoskeletal research—V. Small (Vienna, Austria) and U. Lindberg (Stockholm, Sweden)—to commemorate the thirtieth anniversary of the first definitive publication to establish the existence of an actin cytoskeleton in non‐muscle cells (Lazarides & Weber, 1974). ### Ancient cytoskeletons Whereas other meetings often feature an occasional talk on the prokaryotic cytoskeleton, this meeting devoted a whole session to several aspects of our present knowledge of these ancient systems. This was well received and served as a useful reminder that the cytoskeleton is not just the domain of eukaryotic cell biologists. J. Errington (Oxford, UK) introduced the topic of the bacterial cytoskeleton and reviewed earlier studies that showed the filamentous nature of the ancient bacterial actin proteins MreB and Mbl (MreB‐like). As he pointed out, although we have known about actin filaments for 30 years, they have almost certainly existed for more than two billion years. Many early studies on bacterial cell shape indicated that the cell wall alone conveyed the information that was required for morphology. However, the finding that some of the genes that had been identified in mutational cell‐shape screens encoded protein products that resided in the cytosol meant that this idea had to be revisited. Errington and colleagues are now investigating the functions of the Mbl protein, which is one of three MreB homologues in Bacillus subtilis . They have used fluorescence recovery after photobleaching (FRAP), which is a technically demanding technique in an organism as small as a bacterium, to show that the helical Mbl cables are dynamic structures in vivo (Fig 1). The kinetics of recovery indicate that this is achieved through turnover from unbleached parts of the cell. These studies also imply that the organization of the cables is not likely to be …

Embryo/fetal toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in rats and rabbits.

The purpose of this study was to evaluate the effects of lasofoxifene, a selective estrogen receptor modulator (SERM), on rat and rabbit fetal development. Lasofoxifene was administered orally to rats (1, 10, 100 mg/kg) between gestation days (GD) 6-17, and in rabbits (0.1, 1, 3 mg/kg) between GD 6-18. Maternal body weight and food consumption were monitored throughout pregnancy. Fetuses were delivered by Cesarean section on GD 21 in rats, and GD 28 in rabbits, to evaluate fetal viability, weight, and morphology. Drug concentrations in maternal plasma were measured in a separate cohort of animals at several time points commencing on GD 17 (rats) and 18 (rabbits). On GD 18 (rat) and GD 19 (rabbit) drug concentrations were measured in maternal plasma and in fetal tissue 2 hr post dosing to determine the fetal to maternal drug ratio. In rats, there were dose-related declines in maternal weight gain and food consumption. Post implantation loss was significantly increased at dosages of 10 and 100 mg/kg, and the number of viable fetuses was decreased at 100 mg/kg. The placental weights increased, whereas fetal weights decreased in a dose-dependent manner. Lasofoxifene-related teratologic findings were noted at 10 and 100 mg/kg and included imperforate anus with hypoplastic tails, dilatation of the ureters and renal pelvis, misaligned sternebrae, hypoflexion of hindpaw, wavy ribs, and absent ossification of sternebrae. In rabbits, neither maternal weight gain nor food consumption were affected during treatment. Between GD 26-28, there was a dose-dependent increased incidence of red discharge beneath the cages. At 1 and 3 mg/kg, resorptions and post-implantation loss increased. There were no significant external or visceral effects, but 3 mg/kg there was an increased incidence of supernumerary ribs. Although the maternal plasma Cmax and AUC(0-24) were dose-dependent, the exposures in the rat were many orders of magnitude greater than in the rabbit even for the same 1 mg/kg dose. The single time point fetal/maternal drug ratio was higher in the rat (1.3-0.78) than in the rabbit (0.21-0.16). In general, both maternal and fetal effects of lasofoxifene were similar to those reported with other SERMs. Although the incidence or severity of these effects was, in some instances, greater in the rat than in the rabbit, the doses and the resultant maternal and fetal exposures were many orders of magnitude higher in the rat, suggesting the rabbit to be more sensitive to the toxicological effects of lasofoxifene.

Musculoskeletal Ultrasound in Pediatric Trauma

The radiologic evaluation of musculoskeletal injuries in young children is difficult due to the absent ossification of several secondary ossification centers, which therefore cannot be seen directly on plain radiographs. When relying on conventional radiographs, even severe cartilaginous or soft tissue injuries cannot be visualized, as there is no possibility to differentiate them from bruises or sprains. It is the aim of this review to present clinically relevant applications of ultrasound imaging in pediatric musculoskeletal trauma. Currently used ultrasound techniques for evaluation of typical pediatric fractures or joint dislocations, techniques for differentiation between stable and unstable intraarticular fractures, the use of sonography for monitoring reduced bone length in long bones after fracture, sonographic guidelines for evaluation of tendon injuries or lesions, and sonographic imaging techniques in arthritis and osteomyelitis are described. Musculoskeletal sonography—despite its inability to view through intact cortical bone and its accuracy being dependent on skill and experience of the investigator—provides important information about soft tissue, bony or cartilaginous injuries in children.

A newly recognized autosomal recessive syndrome with abnormal vertebral ossification, rib abnormalities, and nephrogenic rests

We describe three cases of a severe malformation syndrome in siblings of both sexes. The characteristic features observed were absent intrauterine ossification of an apparently normal cartilaginous spinal column; rib abnormalities, with unossified segments and posterior gaps; thoracic hypoplasia; and multiple intralobar nephrogenic rests in the kidneys. This syndrome can be identified in early pregnancy by ultrasound scans due to the lack of ossification of the thoraco-lumbar spine and its association with increased nuchal translucency thickness. We suggest that this is a newly recognized autosomal recessive syndrome.

"Missing" sternal ossification center: potential mimicker of disease in young children.

To evaluate the frequency of "missing" sternal ossification center (asynchronous non-ossification) in young children. Lateral chest radiographs obtained in 229 children (mean age, 3.7 years) were retrospectively evaluated for sternal ossification. Four superior sternal segments were considered normal if they were ossified to a similar degree. A segment was considered asynchronous if decreased ossification, as compared with the remaining sternal segments, was demonstrated or if ossification was absent. Asynchronous ossification of inferior sternal segment 5 was recorded separately. Logistic regression analysis was applied to determine if there was a statistically significant relationship (P <.05) between age or sex and pattern of sternal ossification (normal vs asynchronous). Of the 916 superior four sternal segments (four segments in each of 229 patients) evaluated, 32 (3.5%) showed asynchronously decreased or absent ossification. Locations of these 32 segments follow: segment 1, two (0.2%) instances; segment 2, 14 (1.5%) instances; segment 3, two (0.2%) instances; and segment 4, 14 (1.5%) instances. Inferior segment 5 was not ossified in 73 (31.9%) patients. There was a statistically significant relationship between decreased age and increased likelihood of occurrence of asynchronous ossification of one of the sternal ossification centers 1-4 (P >.003) and of occurrence of asynchronous ossification at sternal segment 2 (P <.018). Missing sternal ossification centers occur most commonly at segments 2 and 4. Such asynchronous non-ossifications become less common in older children.

?Baby rattle? pelvis dysplasia

We report an apparently previously undescribed lethal skeletal dysplasia, clinically resembling achondrogenesis, but with distinct radiologic and chondro-osseous morphologic features. These comprise bifid distal ends of the long bones of the limbs, absent vertebral body ossification, a unique "baby rattle" pelvic configuration with tall and broad ilia, absent endochondral ossification, regions of mesenchymal cells within the resting cartilage, and abnormal mesenchymal ossification.

A new lethal chondrodysplasia with platyspondyly, long bone angulation and mixed bone density

A fetus diagnosed by sonography at 20 weeks' gestation had multiple skeletal abnormalities. The main features were absent ossification of the skull and cervical and upper thoracic vertebral bodies; short, angulated femora, tibiae, radii and ulnae but normal humeri; platyspondyly; trident-shaped acetabular roofs; sclerotic bands on the iliac wings and scapulae; clavicular hooks; and overall, mixed bone density. We suggest that this is a new chondrodysplasia which, since the parents are first cousins, could follow autosomal recessive inheritance.