Ihh and PTH1R signaling in limb mesenchyme is required for proper segmentation and subsequent formation and growth of digit bones.

Digit formation is a process, which requires the proper segmentation, formation and growth of phalangeal bones and is precisely regulated by several important factors. One such factor is Ihh, a gene linked to BDA1 and distal symphalangism in humans. In existing mouse models, mutations in Ihh have been shown to cause multiple synostosis in the digits but lead to perinatal lethality. To better study the exact biological and pathological events which occur in these fused digits, we used a more viable Prx1-Cre;Ihh(fl/fl) model in which Cre recombinase is expressed during mesenchymal condensation in the earliest limb buds at E9.5 dpc and found that mutant digits continuously fuse postnatally until phalanges are finally replaced by an unsegmented "one-stick bone". Mutant mice displayed osteocalcin-positive mature osteoblasts, but had reduced proliferation and abnormal osteogenesis. Because of the close interaction between Ihh and PTHrP during endochondral ossification, we also examined the digits of Prx1-Cre;PTH1R(fl/fl) mice, where the receptor for PTHrP was conditionally deleted. Surprisingly, we found PTH1R deletion caused symphalangism, demonstrating another novel function of PTH1R signaling in digit formation. We characterized the symphalangism process whereby initial cartilaginous fusion prevented epiphyseal growth plate formation, resulting in resorption and replacement of the remaining cartilage by bony tissue. Chondrocyte differentiation displayed abnormal directionality in both mutants. Lastly, Prx1-Cre;Ihh(fl/fl);Jansen Tg mice, in which a constitutively active PTH1R allele was introduced into Ihh mutants, were established to address the possible involvement of PTH1R signaling in Ihh mutant digits. These rescue mice failed to show significantly improved phenotype, suggesting that PTH1R signaling in chondrocytes is not sufficient to restore digit formation. Our results demonstrate that Ihh and PTH1R signaling in limb mesenchyme are both essential to regulate proper development of digit structures, although they appear to use different mechanisms.

Cervical spine synostosis: an anatomical study with emphasis on embryological and clinical aspects.

PURPOSE: The objectives were to study the anatomical features of fused vertebra in the cervical region. MATERIALS AND METHODS: The study included 363 cervical vertebras which were macroscopically observed for the fusion and their morphology was studied. RESULTS: Among our specimens, one fusion was observed between the C1 and C2 and the other was between C2 and C3. The mean anteroposterior diameter of normal atlas and axis were 42.1 +/- 0.9 mm and 46 +/- 0.5 mm respectively. The fused C1-C2 had 39 +/- 0.6 mm anteroposterior diameter. The mean lengths of anterior arch of normal atlas and body of axis were 16 +/- 0.9 mm and 23 +/- 0.7 mm respectively and the fused C1-C2 body length was 30 +/- 0.3 mm. The mean anteroposterior diameter of normal C2 and C3 vertebra were 46 +/- 0.5 mm and 47 +/- 0.8 mm respectively and of fused C2-C3 was 44 +/- 0.2 mm. The body length of C2 was 23 +/- 0.7 mm and C3 was 33 +/- 0.1 mm. The body length of fused C2-C3 was 36 +/- 0.8 mm. CONCLUSION: The present study has provided additional information on the anatomy, morphology of cervical spine synostosis with their embryological basis and clinical implications.

Congenital radioulnar synostosis in an active duty soldier: case report and literature review.

Congenital radioulnar synostosis (CRS) is a developmental deformity that interferes with pronation and supination of the upper extremity. CRS often results in functional, cosmetic, and cultural limitations. The purpose of this paper is to present a patient with CRS who is currently functioning as a generator mechanic in the U.S. Army and to review the literature for current treatment options. We know of no other individual in the U.S. Army who is on active duty status with this deformity.

Intrathoracic kidney and vertebral fusion: a model of combined misdevelopment.

We report a case of right intrathoracic kidney associated with a complex somite malformation that comprised vertebral fusion and right intrathoracic supernumerary ribs. The interpretation of this association as a disease model of nature allows us to propose a unifying hypothesis on the pathogenesis of this form of renal dystopia.

Congenital proximal radio-ulnar synostosis: clinical and anatomical features.

A new radiographic classification is proposed based on a study of 31 cases of congenital proximal radio-ulnar synostosis in which close correlation was observed between the clinical and radiographic pictures. The authors attempt to clarify some aspects of the pathogenesis of this rare disease.

Considerations about the cloverleaf skull.

The study of four cloverleaf skulls (two fetuses, one infant, and a young adult) concerns two Pfeiffer syndromes, a thanatophoric dysplasia and an isolated case. Clinical and radiologic examinations showed malformations at the level of the calvarium, the base, orbital cavities, and, sometimes, limb abnormalities. Correlations between these findings and the microradiographic analysis of nondemineralized sections elucidate this trilobular appearance of the skull. Premature temporoparietal suture closure terminates at a constricted surface of the lateral sides of the skull during the fetal life. Extension of the synostosis to coronal and frontal sutures and thickening of the occipital bone squama block lengthening of the skull. The consecutive reduction in skull volume is compensated by the maintenance of the permeability during the neonatal period of the sagittal and lambdoid sutures. Microradiographic examination shows that this anomaly may be of vascular origin and associated with abnormal osteoclastic resorption.

[Scapholunate synostoses within the framework of congenital carpal synostoses]. / Synostoses radio-scapho-lunaires dans le cadre des synostoses carpiennes congénitales.

Modality of appearance in fetal life. Racial (certain) and congenital (probable) predisposing factors. X-ray discovery of radioscapholunate fusion after minor sprain of the wrist in a young 22 year old woman otherwise without past history. Functional study of the wrist. Analysis of six similar observations reported to date.

Congenital radioulnar synostosis.

Congenital radioulnar synostosis can be severely disabling, especially if it is bilateral or if severe hyperpronation exists. Functionally, patients with severe deformity have trouble getting a cup to the mouth, using eating utensils, or accepting objects in an open palm. Of 33 patients (17 bilateral and 7 unilateral) underwent derotational osteotomy, with the majority being performed through the synostosis held with, an intramedullary wire and secondary transfixing device. There were eight complications, four involving neurovascular compromise. In bilateral cases, the best end position appears to be 10% to 15% of pronation in the dominant extremity and neutral in the other. Eighty-two percent of the patients had good or excellent results.

Cyclophosphamide-induced temporomandibular synostosis.

The study of malformations helps toward a better understanding of normal development, which is of significance to the orthodontist. Experiments in teratology have induced an extensive variety of facial abnormalities, but temporomandibular joint (TMJ) synostosis has never been previously reported. Ten pregnant female rabbits were treated with a daily injection of 50 mg. cyclophosphamide (DNA synthesis inhibitor), from day 11 to day 14, which is the period that precedes formation of the face. The control sample comprised five female rabbits. The fetuses were obtained by cesarean section on day 28 and stained with alizarin. Six of the ten treated female animals produced offspring that had TMJ synostosis. The skull with TMJ synostosis showed a retrognathic mandibular pattern in relation to the maxilla, and the bony trabeculae in the mandibular angle showed a downward orientation instead of the horizontal orientation seen in animals without synostosis. The length of the heads was significantly smaller in the treatment group than in the control group; within the treatment group, the heads with synostosis were significantly smaller than those without synostosis. It could be hypothesized that the cyclophosphamide might have affected intrinsic factors in the temporomandibular mesenchyma; an impairment in the development and function of the mandibular musculature, which is a vital factor in joint development and maintenance, might also have contributed to the genesis of the malformation. The association of immobilization and mandibular hypodevelopment seems to be in agreement with today's theories on maxillofacial growth.

A morphogenetic classification of craniofacial malformations.

A new classification of malformations of the face and cranium is proposed, based on embryologic studies and observations concerning a great number of patients seen by the authors. First of all, one should distinguish between cerebral craniofacial (with brain and/or eyes involved) and craniofacial malformations. Craniofacial malformations may be characterized by dysostosis and by synostosis. Malformations with dysostosis may be produced by transformation as well as differentiation defects. Synostosis is always caused by a differentiation defect. A new nomenclature is introduced.

[Congenital radio-ulnar synostosis of children (author's transl)]. / Les synostoses radio-cubitales congénitales chez l'enfant.

29 congenital radio-ulnar synostosis have been observed in 16 childrens. The authors review the clinical patterns of this affection: most often bilateral, it results in impossibility of pronosupination of the wrist which has but little functional consequence, if the hand is in an intermediary position. On the X-ray its almost always a superior radio-ulnar synostosis but the inferior radio-ulnar joint is abnormal and non functional. Only the children severely handicapped by a hand fixed in pronation should be operated upon. No good result can be hoped from a surgery that tries to restore pro-supination. The best surgical technique seems to be a simple horizontal osteotomy through the synostosis itself which allows a derotation of the forearm into the functional intermediary position. Severe complications can occur. Indications and technique must be very careful since this congenital abnormality is very well tolerated.

Anomalies of the craniovertebral border.

Pertinent embryology is reviewed as a background for understanding anomalies of the craniovertebral border. These anomalies constitute a variable spectrum due either to incomplete assimilation or abnormal fusion.

Clinical and experimental studies of the congenital constriction band syndrome, with an emphasis on its etiology.

The findings in fifty-nine patients with congenital constriction band syndrome and in experiments in which limb malformations resembling those of the human constriction band syndrome were successfully reproduced in rat fetuses by amniocentesis indicated that these malformations arise from excessive contraction of the uterine muscle during pregnancy, with resulting hemorrhages from the marginal blood sinuses of the digital rays. Such malformations in humans may arise during the fifth and sixth weeks counted from ovulation. It therefore was concluded that this syndrome is not hereditary but is produced by prenatal environmental factors.