Cartilage Hypoplasia Research Articles

The Roles of RNA Polymerase I and III Subunits Polr1c and Polr1d in Craniofacial Development and in Zebrafish Models of Treacher Collins Syndrome.

Ribosome biogenesis is a global process required for growth and proliferation of all cells, yet perturbation of ribosome biogenesis during human development often leads to tissue-specific defects termed ribosomopathies. Transcription of the ribosomal RNAs (rRNAs) by RNA polymerases (Pol) I and III, is considered a rate limiting step of ribosome biogenesis and mutations in the genes coding for RNA Pol I and III subunits, POLR1C and POLR1D cause Treacher Collins syndrome, a rare congenital craniofacial disorder. Our understanding of the functions of individual RNA polymerase subunits, however, remains poor. We discovered that polr1c and polr1d are dynamically expressed during zebrafish embryonic development, particularly in craniofacial tissues. Consistent with this pattern of activity, polr1c and polr1d homozygous mutant zebrafish exhibit cartilage hypoplasia and cranioskeletal anomalies characteristic of humans with Treacher Collins syndrome. Mechanistically, we discovered that polr1c and polr1d loss-of-function results in deficient ribosome biogenesis, Tp53-dependent neuroepithelial cell death and a deficiency of migrating neural crest cells, which are the primary progenitors of the craniofacial skeleton. More importantly, we show that genetic inhibition of tp53 can suppress neuroepithelial cell death and ameliorate the skeletal anomalies in polr1c and polr1d mutants, providing a potential avenue to prevent the pathogenesis of Treacher Collins syndrome. Our work therefore has uncovered tissue-specific roles for polr1c and polr1d in rRNA transcription, ribosome biogenesis, and neural crest and craniofacial development during embryogenesis. Furthermore, we have established polr1c and polr1d mutant zebrafish as models of Treacher Collins syndrome together with a unifying mechanism underlying its pathogenesis and possible prevention.

Imaging Findings of Pneumothorax Caused by Bronchial Cartilage Hypoplasia in a Dog

A 10-year-old, castrated poodle dog presented with a cough for 2 weeks, and the cough initially developed since very young age. On radiographs, pneumothorax was noticed by characteristics of radiolucent area without pulmonary markings along the thoracic wall and diaphragm, retracted lung lobes from the thoracic wall and severely decreased volume of the left cranial lung lobe with disconnected bronchus. Computed tomography (CT) findings identified several pulmonary air-filled cysts and collapsed lung with abnormal shape and non-tapered end of bronchus, bronchioles at the accessory lobe and left cranial lobe. Also, pneumothorax, pneumomediastinum and subcutaneous emphysema were found. Imaging diagnosis was the spontaneous pneumothorax caused by ruptured emphysematous bullae associated with congenital bronchial cartilage abnormality or bronchial tree malformation. On surgery, hypoplasia of the left cranial lobe, right middle lobe, and accessory lobe with a bulla where air was leaking was identified. The accessory lobe was partially resected and bronchial cartilage hypoplasia was confirmed by histopathologic examination.

Isolated Congenital Hypoplasia of Nasal Lower Lateral Cartilages and Its Correction with Helical Rim and Conchal Cartilage Composite Grafts

Isolated congenital absence of the alar cartilages and nasal septum is rarely reported. We report here an example for the phenotype of carbamazepine embryopathy with lower lateral cartilage hypoplasia and our surgical approach to solve the nasal problems. This unusual presentation and the literature surrounding infant nasal surgery are discussed.

IMAGING DIAGNOSIS—CONGENITAL LOBAR EMPHYSEMA IN A DOG

A 14-week-old female West Highland White Terrier developed acute dyspnea. Radiographically there was an enlarged, hyperlucent caudal portion of the left cranial lung lobe and a diffuse, severe interstitial-to-alveolar pattern in the remaining lung lobes that was accentuated caudodorsally. Computed tomography confirmed the presence of the emphysematous lobe and further showed it to have focal lobar bronchial collapse. Lung lobe resection was performed, and the diagnosis was congenital lobar emphysema secondary to bronchial cartilage hypoplasia.

Myosin‐X is required for cranial neural crest cell migration in Xenopus laevis

Myosin-X (MyoX) belongs to a large family of unconventional, nonmuscle, actin-dependent motor proteins. We show that MyoX is predominantly expressed in cranial neural crest (CNC) cells in embryos of Xenopus laevis and is required for head and jaw cartilage development. Knockdown of MyoX expression using antisense morpholino oligonucleotides resulted in retarded migration of CNC cells into the pharyngeal arches, leading to subsequent hypoplasia of cartilage and inhibited outgrowth of the CNC-derived trigeminal nerve. In vitro migration assays on fibronectin using explanted CNC cells showed significant inhibition of filopodia formation, cell attachment, spreading and migration, accompanied by disruption of the actin cytoskeleton. These data support the conclusion that MyoX has an essential function in CNC migration in the vertebrate embryo.

17β-Estradiol inhibits chondrogenesis in the skull development of zebrafish embryos

17β-Estradiol (E2) plays important roles in the development and differentiation of the gonad and central nervous systems, but little is known regarding the effects of exogenous E2 on chondrogenesis in skeletal development. In the present study, we found that treatment with E2 1–5 days post-fertilization (dpf) at concentrations above 1.5 × 10 −5 M increased the mortality rate in zebrafish embryos. Morphological analysis showed that treatment with E2 1–5 dpf caused abnormal cartilage formation in a dose-dependent manner at concentrations above 5 × 10 −6 M. E2 1–5 dpf at 1.5 × 10 −5 M caused defects of the ethmoid plate, parallel cleft of the trabecular cartilage, and hypoplasia of Meckel's cartilage and the ceratohyal cartilage. The sensitivity of embryos to E2 depended on the developmental stage. In early chondrogenesis (1–2 dpf), the embryos were highly sensitive to E2, leading to hypoplasia of the cartilage. In situ hybridization studies showed that expression levels of patched1 ( ptc1) and patched2 ( ptc2) receptor mRNAs were markedly decreased by exposure to 2 × 10 −5 M E2 1–2 dpf. However, the expression levels of sonic hedgehog ( shh) and tiggywinkle hedgehog ( twhh) mRNAs were constant in the E2-treated embryos. In addition, the estrogen receptor antagonist ICI 182,780 did not completely abolish the effects of E2, suggesting that E2 may not inhibit chondrogenesis through its nuclear estrogen receptor. These results suggest that exposure to exogenous E2 possibly inhibits chondrogenesis via inhibition of the hedgehog (Hh) signal transduction system.

Congenital Lobar Emphysema and Tension Pneumothorax in a Dog

Congenital lobar emphysema (CLE) and tension pneumothorax (TPT) are rarely reported in dogs. A case of CLE of the right middle lung lobe predisposing to air trapping, alveolar hyperinflation, and pleural rupture resulting in fatal spontaneous TPT in a 6-month-old mixed breed dog is described. The unique alteration of "bloat line" was observed in this case in addition to compressive atelectasis of all other lung lobes and lack of negative pressure within the thoracic cavity, signifying markedly elevated intrathoracic pressure. Bronchial cartilage hypoplasia and bronchiectasis were confirmed microscopically, which likely led to abnormal dynamic collapse of bronchi during expiration, consequentially leading to increased intrapulmonary pressure, bullous emphysema, and pleural rupture resulting in TPT. TPT consequent to CLE may therefore be considered one of the potential causes of sudden death in young dogs without overt clinical illness.

Various Applications of Chondrocutaneous Composite Grafts in Secondary Cleft Lip Nose Patients

Composite chondrocutaneous grafts were applied to 12 patients in various forms to repair the columellar deficit, to form the nasal tubercle and nostril sill in cleft lip nose patients. Cleft lip-nose deformity patients with alar cartilage hypoplasia, obtuse angulation of the medial and lateral crura and the resulting plica vestibularis, internal nasal valve problems associated with the weakness of upper lateral cartilages are included in this study and composite conchal cartilage grafts are utilized to achieve a symmetrical and functional result.

Hallermann‐Streiff syndrome associated with small cerebellum, endocrinopathy and increased chromosomal breakage

Hallermann‐Streiff syndrome (HSS) is a rare clinic entity of unknown aetiology. Further clinical and metabolic‐genetic evaluations are indicated. A 2‐mo‐old female baby presented with ocular abnormalities and severe failure to thrive since birth. The clinical features were compatible with the diagnosis of HSS. Further imaging, metabolic and cytogenetic examinations were performed. Features characteristic of HSS were dyscephaly with mandibular and nasal cartilage hypoplasia, microphthalmia, bilateral cataracts with congenital glaucoma, natal teeth and proportionate dwarfism. Rare anomalies such as choanal atresia and small cerebellum, very low insulin‐like growth factor I level, hypothyroidism, generalized organic aciduria were also noticed. An increased chromosomal breakage rate is suggestive of the existence of some DNA repair defects in HSS patients. Conclusion: The associated anomalies in this patient may broaden the clinical spectrum of HSS. Underlying conditions of organic aciduria, growth factor deficiency and impaired DNA repair are likely to contribute to the progeria‐like facies, congenital cataracts and growth failure.

Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization.

In humans, SOX9 heterozygous mutations cause the severe skeletal dysmorphology syndrome campomelic dysplasia. Except for clinical descriptions, little is known about the pathogenesis of this disease. We have generated heterozygous Sox9 mutant mice that phenocopy most of the skeletal abnormalities of this syndrome. The Sox9(+/-) mice died perinatally with cleft palate, as well as hypoplasia and bending of many skeletal structures derived from cartilage precursors. In embryonic day (E)14.5 heterozygous embryos, bending of radius, ulna, and tibia cartilages was already prominent. In E12.5 heterozygotes, all skeletal elements visualized by using Alcian blue were smaller. In addition, the overall levels of Col2a1 RNA at E10.5 and E12.5 were lower than in wild-type embryos. We propose that the skeletal abnormalities observed at later embryonic stages were caused by delayed or defective precartilaginous condensations. Furthermore, in E18.5 embryos and in newborn heterozygotes, premature mineralization occurred in many bones, including vertebrae and some craniofacial bones. Because Sox9 is not expressed in the mineralized portion of the growth plate, this premature mineralization is very likely the consequence of allele insufficiency existing in cells of the growth plate that express Sox9. Because the hypertrophic zone of the heterozygous Sox9 mutants was larger than that of wild-type mice, we propose that Sox9 also has a role in regulating the transition to hypertrophic chondrocytes in the growth plate. Despite the severe hypoplasia of cartilages, the overall organization and cellular composition of the growth plate were otherwise normal. Our results suggest the hypothesis that two critical steps of the chondrocyte differentiation pathway are sensitive to Sox9 dosage. First, an early step presumably at the stage of mesenchymal condensation of cartilage primordia, and second, a later step preceding the transition of chondrocytes into hypertrophic chondrocytes.

Down's syndrome: altered chondrogenesis in fetal rib.

Down's syndrome (DS), a human genetic abnormality usually caused by an extra chromosome 21, presents a wide range of major and minor anomalies, the most significant of which are mental retardation and congenital heart defects. The anomalous phenotype also includes short stature and neck, thin calvaria, and cartilage hypoplasia. The genesis of these skeletal features is unknown. Histopathologic sections of fetal cartilage from skull, vertebra, rib, and femur were studied in 16 fetuses with DS (17-22 wk old) and 13 control non-DS fetuses (19-22 wk old) with other pathologies not directly affecting skeletal growth. Rib growth cartilage morphology showed a previously unreported structural anomaly in DS, an increase in the hypertrophic portion with a concomitant decrease in proliferative and resting zones. The hypertrophic chondrocytic zone was markedly increased in DS compared with non-DS (149 +/- 68 microm versus 36 +/- 20 microm, and 26 +/- 12 versus 7 +/- 3 expressed in percent of the total length; p < 0.0001), whereas the proliferative zone (114 +/- 58 microm versus 165 +/- 43 microm, 20 +/- 10 versus 33 +/- 4 in percent of the total length; p < 0.001) and the resting zone (53 +/- 4 versus 59 +/- 6 in %, p < 0.009) were decreased. These features were not found in the femoral epiphyseal growth plate or in cartilage from vertebra and skull. Our results demonstrate an imbalance toward the hypertrophic phenotype. This abnormality, found in DS fetuses 17-22 wk old, may represent an early manifestation of an abnormal growth cartilage maturation pattern, which manifests postnatally in long bones, leading to diminished growth rates.

Pediatric intrathoracic large airway obstruction

We describe seven patients who had intrathoracic airway obstruction resulting in severe respiratory distress. The patients were a four month old with bronchial cartilage hypoplasia presenting as congenital lobar emphysema; a one month old with segmental bronchomalacia; a one month old with tracheal bronchus; a two day old and a seven month old with aneurysmal distension of the pulmonary arteries secondary to tetralogy of Fallot, with absent pulmonary valve and atrioventricular canal with pulmonary poststenotic dilatation, respectively; a three year old with double aortic arch forming a vascular ring; and a three month old with tracheomalacia from tracheoesophageal fistula. The patients had various associated congenital defects, and all of them required one or more surgical procedures to repair the defects and relieve the airway obstruction. Five patients received endotracheal intubation with mechanical ventilation on their first admission, and three of them died postoperatively. The diagnostic workup to delineate the anatomic factors causing the obstruction, as well as to determine the therapeutic medical and surgical strategies to relieve it, are described. We conclude that the course of illness in most pediatric patients with intrathoracic airway obstruction is complex, is associated with high morbidity and mortality, and entails extensive multidisciplinary diagnostic and therapeutic efforts.