Morphology and Morphometry of the Deformed Cervical Vertebrae in a Mutant Knotty-Tail (knt/knt) Mouse

Mice with short and knotty tails arose as a spontaneous mutant in an ICR strain, and they have been named knotty-tail mouse (gene symbol; knt). They also have a minor anomaly of the cervical vertebrae, especially in the axis. In this study, the cervical vertebrae of knotty-tail (knt/knt) mice were investigated by morphological and morphometric examinations during the prenatal and postnatal period. From the observation of double-stained preparations of knt/knt mice, morphological changes of cervical vertebrae were confined to the vertebral arch of the axis, which was asymmetrical and hypoplastic. From the morphometric analyses, outside of the axis, minor anomalies (i. e., broadened cervical vertebrae in the transverse direction, shortened and broadened ventral tuberculum of the atlas, thickened ventral lamina of 6th cervical vertebra) were maintained in the cervical vertebrae of knt/knt mice. Morphological deformity, reflecting an adult osseous anomaly, had been already formed in the cartilaginous axis prenatally. In the papain-digested preparations of knt/knt mice, a bony invagination into the canal was detected in the axis, and the morphometric analyses on axis revealed that the growth of spinous process was apparently disturbed in comparison with that of ICR mice.     

Repairability of skeletal alterations induced by sodium valproate in rats

The present study aimed at examining postnatal repairability of sodium valproate‐induced skeletal alterations in rats. Sodium valproate (400 mg/kg) or the vehicle (distilled water) was orally administrated to pregnant Sprague‐Dawley rats from gestation days 9 to 11. Fetuses and pups were obtained on gestation day 21 and postnatal day 11, respectively, and their skeletons were stained with Alizarin red S and Alcian blue and examined. Sodium valproate‐induced costal and vertebral alterations in the fetuses included discontinued rib cartilage, fused rib, full or short supernumerary rib, bipart ossification of thoracic centrum, supernumerary lumbar vertebrae, and lumbarization. In pups, however, discontinued rib cartilage was not observed, and the incidence of a short supernumerary rib was significantly lower than that in the fetuses, suggesting that these alterations are postnatally repairable.     

Experimental studies on cervical and lumbar ribs in mouse embryos

In humans, the presence of cervical and lumbar ribs is of particular clinical significance. However, the relevance of their occurrence in the offspring of experimental animals in reproductive toxicologic studies is poorly understood. Maternal toxicity has been implicated in the etiology but conclusive evidence is lacking. The present study was undertaken to determine the incidence of supernumerary ribs (SNR) in mouse fetuses prenatally exposed to valproic acid (VPA) and retinoic acid (RA), and to compare their differential developmental susceptibility and morphological association with other axial skeletal anomalies. Single doses of valproic acid (VPA) or retinoic acid (RA) were administered to groups of mice on one of gestation days (GD) 7-12. Fetuses were collected on GD 18 and their skeletons examined for SNR. VPA treatment on GD 7 and GD 8 resulted in a high incidence of cervical and lumbar ribs, respectively. Cervical neural arch anomalies in the GD 7 group, and eight pairs of sternal ribs and seven sternebrae in the GD 8 group were observed in excess of the background SNR suggesting a direct effect of VPA on the developing mouse skeletal system. In the RA groups, GD 8-12 were susceptible for lumbar rib induction but increased incidence of cervical ribs was observed only from GD 9-12. Peak incidence of cervical ribs was found in the GD 10 and 11 groups and that of the lumbar ribs in the GD 8 and 11 groups. Although SNR incidence generally increased with increasing dose of RA, a strict dose-response relationship was lacking. Cervical arch anomalies were observed in as many embryos as those with cervical ribs, but eight pairs of sternal ribs and seven sternebrae did not correlate well with the lumbar ribs in the peak day groups. Interrupted cervical neural arches correlated well with lumbar ribs. The reduction in the frequency of presacral vertebrae from 26 to 25 in the VPA groups was limited to GD 7 (30%) and 8 (18%) groups. RA-induced reduction in presacral vertebral number extended to GD 9 and was greater in the GD 8 than in the GD 9 groups. Sternal anomalies occurred both in VPA and RA experiments and did not strictly correlate with the frequency of SNR. VPA had a narrow window of susceptibility, whereas RA effects on sternum extended from GD 9-12. The incidence of sternal anomalies generally increased with increasing dose and advancing developmental stage at which RA exposure occurred. These developmental susceptibility windows and associated malformations, when considered in the context of the ability of these drugs to induce alterations in gene expression in mouse embryos suggest that SNR are polygenic in origin and greatly influenced by environmental toxicants.     

Abnormalities of the vertebral column and ribs associated with anorectal malformations

Lumbosacral vertebral abnormalities are a common association of anorectal malformations (ARMs) and are one of the determinants of the eventual level of fecal continence that can be achieved. This study used a fetal rat model to investigate the spectrum of axial skeletal maldevelopment that may occur with ARMs. Time-mated pregnant rats received 125 mg/kg of 1% ethylenethiourea (ETU) (experimental group) or vehicle only (control). Their fetuses were examined for external malformations and prepared for staining of their skeletons using Alcian blue and Alizarin red S. ARMs developed in 67/68 (98%) of ETU-exposed fetuses, of which 28 (42%) also developed rachischisis, mainly involving the lumbosacral vertebrae. No skeletal abnormality was found in control fetuses. ETU-exposed fetuses with ARMs and rachischisis had abnormal ossification of the vertebral centrum, abnormal fusion between the neural arches of vertebrae, localized narrow or interrupted thoracic vertebral canal, a widely open vertebral canal in the lumbosacral area (rachischisis), and absence of the lower two sacral and coccygeal vertebrae. Rib abnormalities included absence of two to three floating ribs, abnormal fusion of adjacent proximal segments, and abnormal ramification, irregularity, and angulation of their distal segments. The vertebral and rib abnormalities found in ETU-exposed fetuses with ARMs but no rachischisis were much less severe. In addition to the lumbosacral anomalies that are common with ARMs, severe abnormalities of the thoracic vertebrae and their corresponding ribs may occur also. Fetuses with both ARM and rachischisis tend to have more extensive and severe vertebral and rib anomalies. These observations imply a possible common aetiology for ARMs and vertebral anomalies and are consistent with our understanding of the perceived role of the notochord in axial development.     

Spondylocostal dysostosis

Spondylocostal dysostosis is a rare condition characterized by short stature due to a short trunk, multiple morphological abnormalities of the vertebras and ribs due to malsegmentation of the axial skeleton. Radiological features include reduced number of vertebrae and ribs, hemivertebrae, fused or sagitally cleft vertebrae or multiple rib fusions. Three distict clinical entities are described. We report nine cases of this syndrome, seven were infants and presented with an abnormal shape of the thorax. Two of them had a maningocoele, and one succumbed to the CNS anomalies on the third day of life. The other two cases were two and eight years of age. Cardiac lesion was detected in one case and renal malformations in three cases. Reduction in the rib number was present in all cases, and rib fusion in seven cases. Thoracic vertebral dysegmentation was noted in all, lumbar in three and cervical in one case. This is the first large series from India. No clear single etiology was established.     

Short Rib Polydactyly Syndrome Type III: Histopathogenesis of the Skeletal Phenotype

A morphological study of the skeletal system in a case of short rib polydactyly syndrome type III (SRPS-III) documented a “bajonet” deformity of the ribs for misalignment and overlap of cartilaginous and bony ends. This deformity resulted from a ‘tandem’ change in endochondral bone formation that is, arrested orthotopic cartilage maturation and etherotopic perichondral cartilage differention and ossification. At the cartilaginous end, cartilage maturation and vascular invasion were absent. At the bony end, longitudinal bone growth occurred by a perichondral ectopic growth plate. ‘Miniature’ versions of this ‘tandem’ change were also demonstrated in the long bones of the limbs and included focally arrested orthotopic cartilage maturation at the growth plates, perichondral cartilage differentiation, and ossification within cartilage canals. Our morphological study indicates that a generalized loss of syncrony in cartilage removal and osteogenic differentiation occurs in all growth plates, albeit with varied expressivity, and represents, at tissue level, the mechanism by which the SRPS-III skeletal phenotype develops. Received July 25, 2001; accepted August 17, 2001.     

Short stature,mental retardation,craniosynostosis, Klippel-Feil syndrome,Scheuerman kyphosis,rib gaps and other distinctive skeletal and genital anomalies

A 12-year-old girl with a syndrome of short stature, mental retardation and multiple, distinctive skeletal anomalies such as craniosynostosis, hamate-capitate fusion, first rib gaps, Klippel-Feil anomaly and Scheuerman-like kyphosis is reported.     

三维CT重建对小儿寰枢椎旋转畸形的临床价值

探讨三维ＣＴ重建小儿寰枢椎旋转的临床应用价值。方法,对７例患儿进行ＣＴ扫描和三维ＣＴ重建的检查。结果：三维ＣＴ重建清楚地显示枕寰枢椎骨 解剖和立体关系。     

Crossed fused renal ectopia with segmental fusion of bilateral ureters and abdominal aortic anomalies in a patient with caudal regression syndrome.

Caudal regression syndrome consists of multiple congenital anomalies, mainly caudal segment defects. We describe a preterm baby born to a healthy mother with typical caudal regression picture, including imperforated anus with rectovesical fistula, sacral agenesis, multiple rib and vertebral anomalies, and club feet. Crossed fused renal ectopia with fused ureters resulting in urinary obstruction was managed with transureteroureterostomy and cutaneous vesicostomy. We also found a single large umbilical artery with high abdominal aortic insertion which usually presents in sirenomelia. Because of the anatomical diversity of the urinary and cardiovascular systems associated with multiple congenital anomalies, careful evaluation is mandatory.     

Thoracolumbar rachipagus parasite

A rare example of rachipagus conjoint parasitic twinning in a newborn girl is described. A lipomatous mass with an attached hind limb (with fused feet) and a rudimentary vertebral arch were found adherent to the dorsal vertebral arches of the autosite in the thoracolumbar region. There was a clear cleavage plane between the autosite and the parasite. Microscopic sections of the excised specimen showed gut only. The autosite had no other congenital anomalies except for spina bifida in the thoracolumbar region with unfolding of the underlying cord. In the absence of underlying life-threatening anomalies, surgical excision of the parasite and treatment of the associated anomalies of the autosite is known to offer gratifying results.     

Growth hormone secretion and bone histomorphometric study in thalassaemic patients with acquired skeletal dysplasia secondary to desferrioxamine

An auxological and endocrinological study was performed in 21 thalassaemic patients with growth retardation and skeletal dysplasia secondary to desferrioxamine. Bone metaphyseal proximal tibial or iliac crest biopsy was performed in six patients with severe genu valgum or non-traumatic vertebral compression. GH insufficiency/deficiency (GH deficiency: peak after stimulation test below 6 ng/ml) was found in 72% of our thalassaemic patients with skeletal dysplasia, but in only 41% of patients without skeletal dysplasia. Bone histology showed abnormal chondrocytes, alteration of staining pattern of cartilage, irregular columnar cartilage and lacunae in the cartilaginous tissue. The behaviour of bone tissue was unpredictable (presence of thick or thin osteoid layer). Bone microfractures were sometimes present. The bone microstructure showed scarce mineralization, which was evenly or irregularly distributed. The bone tissue apatitic phase was quantitatively reduced. The hardness of bone tissue was remarkably lower than that of normal bone in three out of six patients. In conclusion, iron chelation therapy in patients with acquired skeletal dysplasia seems to interfere with GH secretion. The early identification of clinical and radiological abnormalities of skeletal dysplasia is of paramount importance in preventing severe bone destruction.     

Robinow syndrome in two siblings from consanguineous parents

A Kurdish family had two children affected with Robinow syndrome. The daughter had short stature, macrocephaly, hypertelorism, hepatosplenomegaly, short forearms and marked vertebral anomalies. Her brother had hypertelorism, hypertrophied alveolar ridges, hepatosplenomegaly, short forearms, rib anomaly and ambiguous genitalia. The karyotype of the affected male sibling showed mosaicism for 45X, 46,X,dicY(q11.22), 47,X,dicY(q11.22),dicY(q11.22).     

Prenatal diagnosis of hypochondrogenesis using fetal MRI: a case report

We describe the successful prenatal diagnosis of hypochondrogenesis by MRI. Fetal MR findings were the presence of a conspicuous cartilaginous structure in the basioccipital region, ill-defined ossification of the cervical vertebral bodies, hypoplastic thorax, retarded ossification of the pubic bones, and broad, short long bones. In contrast, fetal US revealed only the presence of short long bones. MRI accurately delineated the axial skeleton in this case and is an effective clinical tool for diagnosing skeletal dysplasias in utero.     

Segmentation anomalies of vertebrae and ribs with other abnormalities of blastogenesis: syndromes or associations?

On the basis of two recently studied human fetuses and the historical records and remnant 19th century skeletons in the Museum Vrolik in Amsterdam, we have begun an analysis of an unusual form of somite dysgenesis. This disorder includes vertebral and costal segmentation defects with or without (distal) limb malformation and deformities, anogenital anomalies, unusual colonic atresia, abdominal wall and diaphragmatic defect, Central nervous system abnormality with large head, and severe neurohypotrophic lower limb deformities. This study suggests the existence of an axial vertebral/costal dysgenesis complex with apparently or nearly normal number of cervical vertebrae. There also is some overlap with lumbosacral agenesis but different from the autosomal recessive entities Jarcho-Levin syndrome or spondylocostal dysostosis. To date, no associated heart defects have been noted.     

A neonate with anorectal malformation with rare limb defects report of a case

A 2-day-old male infant, born of a non-consanguineous marriage and uneventful pregnancy was found to have anomalies of vertebral, anal, cardiac, tracheo-esophageal, radial and limb (VACTERL) association. The striking feature was the simultaneous occurrence of two rare limb defects of right upper and lower limb in the baby who also had imperforate anus and ventricular septal defect. These limb defects were-meromelia of the right upper limb (due to transverse deficiency of right humerus and absence of all the bony elements distally), and a short right lower limb due to co-existence of proximal femoral hypoplasia and fibular hemimelia. We could not trace the co-existence of these rare skeletal defects in any case with VACTERL association in the existing English literature, as was observed by us. The simultaneous occurrence of the defects involving distant anatomic sites supports the hypothesis of ‘axial mesodermal dysplasia’ in our patient, rather than ‘caudal regression syndrome’, as is popularly held in patients with anorectal malformation (ARM). Further, it points to occurrence of an early embryonic insult, probably taking place at blastogenic stage, when the developing embryo can be considered a polytopic development field. However, in absence of antenatal history suggestive of exposure to a known teratogen and a chromosomal analysis, it appears that the spectrum of anomalies in this neonate might have resulted secondary to early amniotic leak and temporary oligohydramnios.     

Mucopolysaccharidosis 6-A (Maroteaux-Lamy disease): comparison of clinical and pathologico-anatomic findings in a 27-year-old patient

The autopsy of the 27-year-old patient suffering from a severe form of mucopolysaccharidosis type VI-A (Maroteaux-Lamy) described in the article by Rampini et al. revealed the compressive cervical myelopathy (C1) to be due to a severe, slit-like deformity of the vertebral canal which was due to a massive thickening of the ligaments, dislocation of the posterior arch of the atlas and broadening of the dura. The massive, generalized disorder of the enchondral ossification involving mainly tubular bones and spine, led to short stature, arthrosis of large joints, and to an angular thoraco-lumbar kyphoscoliosis. Our patient had a massive V-shaped stenosis of the upper third of the trachea. The atrio-ventricular valves of the heart were thickened, and there was fibrosis of the endocardium. The cardiac conduction system displayed fibrosis and foam cell transformation of the fibroblasts in the bundle of His, a lesion not previously reported. Light and electron microscopic investigation showed a massive increase of mucopolysaccharides mainly in the matrix of the fibrous tissue and of the cartilage. Furthermore, the fibroblasts and chondrocytes as well as the hepatocytes and the ganglion cells of the central nervous system contained increased amounts of glycosaminoglycans.     

Morphological features of mutant rat, IS-Tlk/Kyo, fetuses with caudal vertebral anomalies

IS-Tlk/Kyo, a rat mutant strain derived from IS/Kyo strain, exhibits a kinked and/or short tail, in addition to a congenital anomaly of the lumbar vertebrae that is a hallmark of IS/Kyo rats. Homozygotes (Tlk/Tlk) of Tlk dominant gene are known to die during embryonic development. The present report deals with the morphological features of heterozygous IS-Tlk/Kyo rat fetuses in comparison with those of IS/Kyo rat fetuses. One of the morphological features was a high incidence of tail vertebral anomalies in IS-Tlk rats (81.6% versus 0% in IS/Kyo rats). Significantly low values in number of live fetuses and ossified 5th sternebra and sacral and caudal vertebrae were observed in IS-Tlk/Kyo rats compared with those in IS/Kyo rats as well as a low incidence of fetuses with ventral septal defects in IS-Tlk/Kyo (0% versus 54.4% in IS rats). These results suggest that the Tlk gene may be involved in the formation of the vertebral centra and the ventral septum when it expresses on the genetic background of the IS rat.     

A lethal osteochondrodysplasia with mesomelic brachymelia, round pelvis, and congenital hepatic fibrosis: two siblings born to consanguineous parents

We report a hitherto unknown, lethal osteochondrodysplasia in two Japanese siblings born to consanguineous parents. The skeletal abnormalities are characterised by mesomelic brachymelia with bowed forearms, a round pelvis with shortened greater sciatic notches, an ossification defect of the pubic bones, and absence of ossification centers in the cervical vertebral bodies. The associated visceral anomalies comprised periportal fibrosis and cystic dysplasia of the intrahepatic bile ducts, pancreatic ductal ectasia, a simple renal cyst, microcephaly with multifocal laminar necrosis and ectopic gray matter, dysplastic tracheobronchial cartilage, abnormal lobulation of the lung, diaphragmatic hernia, and stenotic pulmonary valve. Thrombocytopenia was present but megakaryocytes were slightly increased in the bone marrow. The patients showed various dysmorphic features including aniridia, a long palpebral fissure, prominent nasal bridge, beaked nose, flat philtrum, low-set fleshy ears, micrognathia with submucosal cleft palate, and multiple joint contractures. Received: 23 May 1997 Accepted: 27 June 1997     

小儿主动脉弓发育不良的手术及灌注技术进展

目前,小儿主动脉弓发育不良的定义存在争议,主要的评价方法有:①近弓、远弓和峡部分别＜升主动脉的60％、50％和40％、或者横弓直径＜升主动脉远端的50％、或者横弓直径＜降主动脉直径的50％;②经验法则:横弓直径(mm)＜体重(kg)+1;③Z值:不同节段的大小低于正常平均值的两个标准差以下,即Z值＜-2.小儿主动脉弓发育不良病变谱广,不同患儿解剖和生理特点差异大,且常合并各类心内畸形,小儿主动脉弓发育不良术后近远期并发症发病率、再干预率、病死率的控制仍不满意.小儿主动脉弓发育不良的治疗也存在争议,存在多种手术和灌注方法.目前较多使用的手术方法有:扩大端端吻合术,左锁骨下动脉瓣翻转术,端侧吻合术,补片扩大术等.使用较多的灌注方法有:深低温停循环技术和选择性脑灌注技术等.因此选择合理有效的手术和灌注方法,能提高主动脉弓发育不良患儿近远期的治疗效果.根据不同主动脉弓发育不良患儿的情况进行个体化治疗是现在小儿主动脉弓发育不良外科治疗的趋势.现对小儿主动脉弓发育不良的手术及灌注技术进展做一综述.