A new syndrome of congenital generalized osteosclerosis and bilateral polymicrogyria.

We report a 29-week male fetus with healthy consanguineous parents. He showed a severe sclerosing bone disorder affecting all skeletal elements, resulting in insufficient modeling, generalized densification, and fragility of the skeleton. This skeletal dysplasia was associated with an abnormal craniofacial development (hypertelorism, severe microretrognathia, cleft palate, absent epiglottis, reduced number, and mineralization of teeth buds) and abnormal terminal phalanges. Neuropathologic examination showed bilateral fronto-parietal cerebral polymicrogyria. This syndrome appears to represent a new variant of congenital sclerotic bone disorder of unknown origin. Autosomal recessive inheritance is possible.

Neuropathology of Raine syndrome.

We present three cases of Raine syndrome occurring in siblings of consanguineous parents. Raine syndrome is characterised by generalised osteosclerosis with craniofacial anomalies and intracranial calcifications. So far, only nine cases have been reported, and no evaluation of the distribution and extent of the cerebral mineralisations, as well as their impact on the surrounding tissue, has been undertaken yet. In our cases, calcifications were unevenly distributed throughout the central nervous system, not associated with neuronal loss or dystrophic events and appeared mostly as single calcospherites within the neuropil with occasional confluent deposits at advanced gestational age. There was intense perifocal microgliosis around single immature calcospherites, as well as mild astrogliosis around and within the confluent lesions, in which occasional macrophages could be found. Rarely, mineralisations occurred in blood-vessel walls, mainly affecting basal ganglia. Preferential sites of calcification were parietal and occipital periventricular white matter and corpus callosum, while frontal lobes were mildly affected. The cortex, temporal lobes as well as internal capsule, brain stem, cerebellum, leptomeninges, pituitary gland and choroid plexus were devoid of mineralisations. The subcortical grey matter was moderately involved in the putamen and pallidum, mildly in the caudate nucleus and subependymal germ cell matrix and not at all in the thalamus, Ammon's horn, amygdala and substantia nigra. The distribution of mineral deposits was thus inversely correlated to regional blood circulation and capillary density, with calcifications being concentrated in more sparsely perfused areas but lacking in highly vascularised tissue. This inverse relationship between mineralisation and regional blood flow was reflected in the varying distribution of calcospherites in grey and white matter as well as in the white matter of different lobes.

Novel mutations of the cathepsin K gene in patients with pycnodysostosis and their characterization.

Pycnodysostosis is a rare autosomal recessive skeletal dysplasia characterized by short stature, osteosclerosis, acroosteolysis, bone fragility, and skull deformities. Recently, mutations in the gene encoding cathepsin K (CK), a lysosomal cysteine protease localized exclusively in osteoclasts, were found to be responsible for this disease. We analyzed genomic DNA from four unrelated Japanese patients with this disorder and identified three different mutations of their CK genes: a previously reported missense mutation (A277 V), a novel single base deletion mutation (531 del T) causing a frame shift from codon 142 that results in a premature termination codon, and a novel missense mutation (L9P) in the signal peptide region. To investigate whether the L9P mutation disrupts signal peptide function and decreases protein synthesis, mutant and wild-type CK complementary DNAs driven by the cytomegalovirus promoter were transfected into COS-7 cells, and their gene products were detected by immunohistochemistry and Western blotting. Expression of the mutant protein was markedly reduced, suggesting decreased mature CK production in this patient, which may have been due to dysfunction of the signal peptide. These results provide evidence that a structural change in the signal peptide of the CK protein was involved in the pathogenesis of pycnodysostosis.

Osteopathia striata--a case report.

Osteopathia striata is an unusual skeletal condition that can affect the bones of the skull quite markedly and result in dental problems that have rarely been discussed in the literature. The characteristic features exhibited by the patient in this case report were dense maxillary and mandibular bone, a high forehead with frontal bossing, a broad nasal bridge, prominent zygomatic arches and thickened angles of the mandible. The mouth opening was limited as a result of sclerosis of the mastoid process, and right lateral excursion of the mandible was reduced, probably because of a deformity of the left condyle.

Trichodentoosseous (TDO) syndrome: case report and literature review.

Trichodentoosseous (TDO) syndrome is an autosomal dominant condition characterized by dysplastic nails, curly hair, bone sclerosis of the long bones and calvarium, taurodontism, and enamel hypoplasia that occurs with hypomaturation/hypocalcification defects. To date, nine previous case reports of TDO in the dental literature have shown that while taurodontism and enamel defects are consistently present in TDO, the changes in the nails, hair, and bones may be variably expressed and occasionally not noted. Because of this, a few previous cases of TDO syndrome had been diagnosed simply as amelogenesis imperfecta. This case report highlights the typical clinical findings, diagnostic problems, and the clues to diagnosing this interesting condition. Clinical management of TDO is centered on preventing dental abscesses with stainless steel crowns and improving appearance with esthetic restorations.

CT of the temporal bone in a patient with osteopathia striata and cranial sclerosis.

The authors present a case of congenital dysplasia affecting the long bones, skull, and other systems in a 7-year-old girl, with special attention to CT of the temporal bone, which showed abnormal ossicle fixation, a narrowed Eustachian canal, thickened sclerotic bone, and a small mastoid antrum and middle ear cavity. CT of the temporal bone can help one distinguish the etiologies of hearing loss associated with this disorder.

New distinct lethal osteosclerotic bone dysplasia (Raine syndrome).

We report a third case of a rare neonatal lethal sclerotic bone disorder with distinct craniofacial anomalies and striking radiographic and hitherto undescribed histopathologic features. The remarkable similarity between our patient and 2 recently reported infants suggests strongly a distinct entity. We propose the term Raine syndrome as a convenient identification of this disorder.

Congenitally osteosclerotic (os/os) rabbits are not cured by bone marrow transplantation from normal littermates.

The osteopetrotic (os) rabbit is a lethal mutation of autosomal recessive inheritance characterized by hypocalcemia, hypophosphatemia, fibrosis of marrow spaces, and ultrastructural abnormalities in both osteoclasts and osteoblasts. Procedures involving the transplantation of cells from normal hemopoietic tissues, which are sources of osteoclast precursors, are known to cure osteopetrosis in several mutations including some children. We tested the ability of transplanted bone marrow and/or spleen from normal littermates to reverse the skeletal sclerosis in os rabbits. Treatment of 15 neonatal mutants consisted of immunosuppression by whole-body irradiation followed by transplantation of normal bone marrow and/or spleen cell suspensions. This treatment failed to prolong life span or to cure osteopetrosis judged radiographically and histologically for up to 3 weeks posttreatment, the longest time of survival. These data indicate that transplantation of stem cells from multiple hemopoietic tissues, procedures known to cure osteopetrosis in other mutations, is not effective in the os rabbit. These results support the hypothesis that the skeletal microenvironment is not capable of supporting the development and function of normal osteoclasts in this mutation.