Georg Eich

Recessively inherited multiple epiphyseal dysplasia with normal stature, club foot, and double layered patella caused by a DTDST mutation

We have observed over 25 different mutations in the diastrophic dysplasia sulphate transporter gene (DTDST) in association with the recessive disorders achondrogenesis 1B, atelosteogenesis 2, and diastrophic dysplasia. The c862t (R279W) transition is the most common mutation in non-Finnish patients, but in these disorders it is usually combined with otherDTDST mutations. We had not seen a case of homozygosity for c862t (R279W) until we analysed DNA from a 36 year old male with tall-normal stature (180 cm) who asked for genetic counselling for suspected multiple epiphyseal dysplasia. He was treated for club foot and hip dysplasia at birth. Skeletal changes consistent with multiple epiphyseal dysplasia, with the peculiar finding of a double layered patella, were recognised during childhood. Cleft palate, swelling of the ear pinna, and hitch hiker thumb were absent. He was found to be homozygous, and both healthy parents heterozygous, for the R279W mutation in DTDST, and his fibroblasts showed a sulphate incorporation defect typical of DTDST disorders. Counselling was given for a recessive disorder, thereby considerably reducing the probability of affected offspring.  Multiple epiphyseal dysplasia is more frequently caused by dominant mutations in the COMP (EDM1, McKusick 132400) and COL9A2 genes (EDM2, McKusick 600204). A few other patients and families with features similar to our proband have been described previously and considered to have autosomal recessive MED (EDM4, McKusick 226900). This observation confirms the existence of this entity and assigns it to the phenotypic spectrum associated with mutations at theDTDST locus.

Fibrous tumours in children: imaging features of a heterogeneous group of disorders

Background. Fibrous tumours are predominantly soft tissue lesions which are relatively frequent in childhood but are little known. Imaging is often used in the evaluation of these tumours but their characteristics, particularly on US or MRI, have not been studied systematically. Objectives. To provide an overview of the clinical and imaging features of the different disorders, and to correlate them with the currently used classification schemes. Material and methods. Twenty-five patients with fibrous tumours were evaluated retrospectively. Clinical histories were studied for the histopathological diagnosis, age, signs and symptoms at presentation, mode of therapy and follow-up where available. Imaging findings were analysed for the following variables: number, location, size, margin and architecture of soft tissue and/or visceral lesions and the presence and pattern of osseous involvement. Comparison with the available literature was performed. Results. The following tumour types were encountered: desmoid fibromatosis (n = 9), myofibromatosis (n = 7), fibromatosis colli (n = 2), congenital-infantile fibrosarcoma (n = 2), adult-type fibrosarcoma (n = 2), fibrous hamartoma of infancy (n = 1), angiofibroma (n = 1) and hyaline fibromatosis (n = 1). Conclusions. While some tumours were non-specific in their clinical and radiological manifestation, others such as myofibromatosis, fibromatosis colli, fibrous hamartoma of infancy and angiofibroma exhibited a characteristic pattern which allowed a diagnosis to be made even without histology.

Juvenile chronic arthritis: imaging of the knees and hips before and after intraarticular steroid injection.

Intraarticular steroid therapy in juvenile chronic arthritis (JCA) is performed because of high local efficacy with few side effects. Imaging is used for initial evaluation and for monitoring of treatment response. The aim of this study was to compare imaging findings in diseased hips and knees before and after therapy. A prospective study was performed on 10 patients (15 joints) scheduled for intraarticular therapy. Pretherapeutic assessment included clinical work-up, radiographs, ultrasound (US), and magnetic resonance imaging (MRI) of affected joints. Following therapy, clinical and sonographic examinations were performed at 1 week and 1 month. MRI was repeated at 1 month. MRI and US demonstrated pannus formation and effusion, but differentiation was less distinct on US. Popliteal cysts and lymph nodes were visible in both modalities. MRI additionally revealed articular cartilage loss and subchondral cysts, not shown by US. Epiphyseal overgrowth and osteopenia were best seen radiographically. At present MRI is the best tool to assess the inflammatory changes of the joints in JCA. Initial staging of the joints may be done with plain films and MRI. US is useful to assess effusion and pannus and may be used to monitor treatment response.

Late intrauterine Cytomegalovirus infection: Clinical and neuroimaging findings

Fetal Cytomegalovirus (CMV) infection in early pregnancy usually results in severe neurological handicap and sensorineural hearing loss with typical neuroradiological findings of calcification, migrational anomalies, disturbed myelination, and cerebellar hypoplasia. Infections acquired in late pregnancy have less prominent signs, such as microcephaly, hearing deficits, and minor neurological handicap. We report 7 children who presented with a similar clinical complex of signs: microcephaly, sensorineural hearing impairment, behavior problems with hyperactivity, reduced apprehension for pain in 5 of the 7, ataxia in 3, and hypotonia with clumsiness in 3 others. All manifested mild to severe developmental problems. Cranial CT revealed calcification in 4 of 6 patients. MRI in all 7 children showed patchy to confluent nonprogressive dysmyelination. Only 2 children had acute neonatal signs of congenital CMV infection. We assume that these children acquired CMV infection in the third trimester of gestation, leading to microcephaly, hearing loss, and neurological and developmental problems with typical neuroradiological signs.

RMRP gene sequence analysis confirms a cartilage-hair hypoplasia variant with only skeletal manifestations and reveals a high density of single-nucleotide polymorphisms.

Mutations in the RMRP gene that codes for an RNA subunit of the MRP RNAse complex are the cause of cartilage‐hair hypoplasia (CHH; MIM 250250). We tested the hypothesis that recessive metaphyseal dysplasia without hypotrichosis (M1M 250460), a disorder presenting with short stature and metaphyseal dysplasia similar to CHH, but lacking hair anomalies, immunodeficiency and other extra skeletal features, might be allelic to CHH. We identified four mutation‐carrying alleles segregating with the skeletal phenotype in two unrelated boys and their parents. One allele carried the common Finnish mutation +70A → G; the remaining three carried +195C → T, +238C → T, and dupAAGCTGAGGACG at −2. Sequencing 120 alleles from a control group revealed an unusually high density of single‐nucleotide polymorphisms in and around the RMRP gene: the biological significance of this finding is unclear.

Heterogeneity in Schwartz-Jampel chondrodystrophic myotonia

Abstract The Schwartz-Jampel syndrome (SJS; chondrodystrophic myotonia; McK 255800) is a recessively inherited condition defined by myotonia, short stature, and bone dysplasia. Genetic linkage between SJS and chromosomal region 1q36-34 has been observed in several families, but the gene has not yet been identified. We studied the clinical and radiological features in 81 patients from the literature and 5 own patients trying to identify distinct subgroups. In addition, we tested genetic linkage to the SJS locus on chromosome 1 in one family with two affected sibs. We found that a group of patients have mild skeletal changes which may be secondary consequences of myotonia, while another group of patients appear to have primary bone dysplasia with myotonia. Within this latter group, there are differences in age of manifestation, clinical course and pattern of bone changes. We tentatively isolate three different types of SJS: type 1A, usually recognized in childhood, with moderate bone dysplasia, corresponding to the original descriptions of Schwartz, Jampel and Aberfeld; type 1B, similar to type 1A but recognizable at birth, with more pronounced bone dysplasia resembling Kniest dysplasia; and type 2, manifest at birth, with increased mortality and bone dysplasia resembling Pyle disease. Genetic analysis of the family with two sibs affected by SJS type␣2 showed evidence against linkage to chromosome 1p36-34. Conclusions SJS is clinically and radiologically heterogeneous. The causes of heterogeneity are not known yet but are likely to include both different mutations at the SJS locus on chromosome 1 and the presence of a second SJS locus. A tentative clinico-radiological classification can be useful for the characterization of patients and the development of genotype-phenotype correlations.

Infantile systemic hyalinosis in siblings: clinical report, biochemical and ultrastructural findings, and review of the literature.

A boy presented at age 3.5 months with joint contractures, restlessness, and pain on handling. His skin was thickened and there were livid-red macular lesions over bony prominences. Infantile systemic hyalinosis (ISH) was diagnosed, a presumably autosomal recessive, progressive, and painful disorder of as yet unknown pathogenesis. Observation over three years confirmed the diagnosis as typical changes, such as nodules on both ears, pearly papules in the perinasal folds and on the neck, fleshy nodules in the perianal region, and gingival hypertrophy, developed. Skin lesions and painful joint contractures progressed in spite of intense physiotherapy, and at age 3, the child had marked motor disability. The central nervous system (CNS) appeared to be intact and the infant showed normal mental development. Radiologic findings included marked generalized osteopenia, osteolytic erosions in the metaphyses of the long bones, and cortical thinning. Electron microscopy of two skin biopsies demonstrated deposition of floccular amorphous substance that was abundant around, and appeared to originate from, small blood vessels in the dermis, partially interfering with collagen fiber formation. Lysosomal inclusions were not seen. Serum acid hyaluronidase activity was within the normal range, and the synthesis of hyaluronic acid and proteoglycans in cultured skin fibroblasts was similar to that of control cells. A younger sister presented at age two months with painful joint contractures and discrete livid-red macules over both malleoli, and showed a similar progression of the disorder over the first year of life. The diagnosis of ISH should be considered in infants and children presenting with painful joint contractures and skin lesions. The pathogenesis of this disabling and disfiguring disorder remains unclear. Our data confirm probable autosomal recessive inheritance, and do not support lysosomal storage, hyaluronidase deficiency, or a primary collagen disorder, but indicate that the amorphous material accumulating in the skin and articular soft tissues may originate from the blood circulation.

Extraosseous Langerhans Cell Histiocytosis in Children

Langerhans cell histiocytosis, a rare disease that occurs mainly in children, may produce a broad range of manifestations, from a single osseous lesion to multiple lesions involving more than one organ or system. The clinical course varies widely in relation to the patients age. Multisystem disease may demonstrate especially aggressive behavior in very young children, with the outcome depending largely on the stage of disease and the degree of related organ dysfunction at the time of diagnosis. Extraosseous manifestations are less commonly seen than osseous ones and may be more difficult to identify. To accurately detect extraosseous Langerhans cell histiocytosis at an early stage, radiologists must recognize the significance of individual clinical and laboratory findings as well as the relevance of imaging features for the differential diagnosis. The pattern and severity of pulmonary, thymic, hepatobiliary, splenic, gastrointestinal, neurologic, mucocutaneous, soft-tissue (head and neck), and salivary involvement in Langerhans cell histiocytosis generally are well depicted with conventional radiography, ultrasonography, computed tomography, and magnetic resonance imaging. However, the imaging features are not pathognomonic, and a biopsy usually is necessary to establish a definitive diagnosis.

Schwartz-Jampel syndrome type 2 and stüve-wiedemann syndrome : A case for lumping

Recent studies demonstrated the existence of a genetically distinct, usually lethal form of the Schwartz-Jampel syndrome (SJS) of myotonia and skeletal dysplasia, which we called SJS type 2. This disorder is reminiscent of another rare condition, the Stüve-Wiedemann syndrome (SWS), which comprises campomelia at birth with skeletal dysplasia, contractures, and early death. To test for possible nosologic identity between these disorders, we reviewed the literature and obtained a follow-up of the only two surviving patients, one with SJS type 2 at age 10 years and another with SWS at age 7 years. Patients reported as having either neonatal SJS or SWS presented a combination of a severe, prenatal-onset neuromuscular disorder (with congenital joint contractures, respiratory and feeding difficulties, tendency to hyperthermia, and frequent death in infancy) with a distinct campomelic-metaphyseal skeletal dysplasia. The similarity of the clinical and radiographic findings is so extensive that these disorders appear to be a single entity. The follow-up observation of an identical and unique pattern of progressive bone dysplasia in the two patients (one with SJS type 2, one with SWS) surviving beyond infancy adds to the evidence in favor of identity. The hypothesis that SWS and SJS type 2 are the same disorder should be testable by molecular methods.

Extra-osseous involvement of Langerhans' cell histiocytosis in children

The predominant clinical and radiological features of Langerhans’ cell histiocytosis (LCH) in children are due to osseous involvement. Extra-osseous disease is far less common, occurring in association with bone disease or in isolation; nearly all anatomical sites may be affected and in very various combinations. The following article is based on a multicentre review of 31 children with extra-osseous LCH. The objective is to summarise the diverse possibilities of organ involvement. The radiological manifestations using different imaging modalities are rarely pathognomonic on their own. Nevertheless, familiarity with the imaging findings, especially in children with systemic disease, may be essential for early diagnosis.