Lumbar and radial bone mineral density in children and adolescents with X-linked hypophosphatemia: evaluation with dual X-ray absorptiometry.

OBJECTIVE: To evaluate the bone mineral status of children being treated for X-linked hypophosphatemia, including potential differences between cortical bone in the radial diaphysis and combined cortical and trabecular bone in the lumbar spine. DESIGN AND PATIENTS: Forty-four bone mineral evaluations were performed in 11 children and adolescents with X-linked hypophosphatemia. Bone mineral density (BMD) of the lumbar spine and the radial diaphysis were measured by dual X-ray absorptiometry (DXA), second metacarpal cortical thickness was measured on hand radiographs, and these results were expressed as Z-scores (standard deviations from the mean). RESULTS: For the 11 initial examinations, Z-scores (mean+/-SD) were: radial BMD, -2.73+/-1.15, lumbar BMD, +1.28+/-1.53; and cortical thickness, -2.21+/-0.95. Lumbar BMD Z-scores were significantly greater than those for radial BMD and cortical thickness. On follow-up examinations there was a mild increase in radial BMD and decrease in lumbar BMD. Although these changes were statistically significant, they were quite small and the discordance between radial and lumbar BMD was not corrected. CONCLUSIONS: Children and adolescents who are being treated for X-linked hypophosphatemia manifest a bone mineral disorder characterized by decreased BMD in the appendicular skeleton and increased BMD in the lumbar spine. Although current therapy is successful in its anti-rachitic effects, it does not correct this bone mineral disorder and additional therapeutic trials should be considered.

Previously undescribed syndrome of spondylometaphyseal dysplasia, osteocartilaginous metaplasia of long bones, and progressive osteolysis of distal phalanges.

We present the findings and clinical course of a Caucasian woman (now age 23 1/2) who has been treated since early childhood for a previously undescribed syndrome of painful osteocartilaginous metaplasia of long bone metaphyses and painful distal phalangeal osteolysis and soft tissue swelling. Despite extensive evaluations and attempts at effective treatment, the cause and pathogenesis of her unique musculoskeletal disorder remain elusive.

Torg osteolysis syndrome.

We describe a 9-year-old girl who initially presented at age 4 with evidence of arthritis in her hands, feet, and large joints. Although she had a partial response to anti-inflammatory medications and had some laboratory results consistent with inflammatory disease, radiographs showed carpal and tarsal osteolysis associated with interphalangeal joint erosions. There was also widening of the shafts of the metacarpals and metatarsals with thinning of the cortices. Based on both the clinical progression of her illness and the radiologic characteristics, this child most likely has the Torg syndrome.

Epithelial cell wedging and neural trough formation are induced planarly in Xenopus, without persistent vertical interactions with mesoderm.

In this study we investigate the induction of the cell behaviors underlying neurulation in the frog, Xenopus laevis. Although planar signals from the organizer can induce convergent extension movements of the posterior neural tissue in explants, the remaining morphogenic processes of neurulation do not appear to occur in absence of vertical interactions with the organizer (R. Keller et al. , 1992, Dev. Dyn. 193, 218-234). These processes include: (1) cell elongation perpendicular to the plane of the epithelium, forming the neural plate; (2) cell wedging, which rolls the neural plate into a trough; (3) intercalation of two layers of neural plate cells to form one layer; and (4) fusion of the neural folds. To allow planar signaling between all the inducing tissues of the involuting marginal zone and the responding prospective ectoderm, we have designed a "giant sandwich" explant. In these explants, cell elongation and wedging are induced in the superficial neural layer by planar signals without persistent vertical interactions with underlying, involuted mesoderm. A neural trough forms, and neural folds form and approach one another. However, the neural folds do not fuse with one another, and the deep cells of these explants do not undergo their normal behaviors of elongation, wedging, and intercalation between the superficial neural cells, even when planar signals are supplemented with vertical signaling until the late midgastrula (stage 11.5). Vertical interactions with mesoderm during and beyond the late gastrula stage were required for expression of these deep cell behaviors and for neural fold fusion. These explants offer a way to regulate deep and superficial cell behaviors and thus make possible the analysis of the relative roles of these behaviors in closing the neural tube.

Autosomal dominant microcephaly with normal intelligence, short palpebral fissures, and digital anomalies.

We describe a family segregating an autosomal dominant mutation producing a syndrome comprising microcephaly with normal intelligence and short palpebral fissures together with variable signs including thumb hypoplasia, shortness of the middle phalanges of the second and fifth fingers, small feet, a gap between the first and second toes, and mild syndactyly of the toes or fingers. A characteristic radiologic finding in our family is thinning of the proximal end of the first metacarpal and shortening of that metacarpal. The severity of these findings was asymmetric in our patients. This syndrome is similar to patients described by Brunner and Winter [1991: J Med Genet 28: 389-394], Feingold [1975: Synd Ident 3:16-17, 1978: Hosp Prac 13:44-49], and König et al. [1990: Dysmorphol Clin Genet 4:83-86].

The role of planar and early vertical signaling in patterning the expression of Hoxb-1 in Xenopus.

In this paper we examine the contributions of planar and vertical signaling to the patterning of gene expression in neural development and we examine the routes of this neural induction. We have examined how the expression of Xenopus homeobox gene, Hoxb-1, is regulated by instruction from the mesoderm and/or endoderm and ask whether this instruction is by the vertical or planar routes. We investigated normal expression patterns of Hoxb-1 during early Xenopus development and Hoxb-1 expression in sandwich explants of the dorsal marginal zone, which putatively allow only planar signals to pass from the mesodermal and endodermal tissue (Spemann's organizer) to the prospective neural tissue. In the latter case we found significant variability of expression. Observations during dissections suggested that variable degrees of invasion of the mesodermal-endodermal tissue at the leading edge of the mesodermal mantle might be the cause of this variability. Alternatively, differing lengths of time that the prospective neural region spends in planar contact with tissues of the lateral or ventral regions of the embryo could also contribute to this variability. Analysis of staged Keller sandwich explants, "skewered" sandwiches, in which the degree of contact with underlying, involuted mesoderm-endodermal tissues was marked, and "over-the-pole" and "giant" sandwich explants, in which the degree of planar contact with lateral or ventral tissues was normalized, suggests that both planar and vertical signals are involved in induction and patterning of Hoxb-1 expression. The shift in Hoxb-1 expression from a broad, diffuse pattern to a local, focused pattern, characteristic of the ultimate expression pattern in vivo, does not reflect variable degrees of contact with ventral or lateral tissues, but rather reflects early vertical contact with underlying mesodermal-endodermal tissues. We observed such contact at early gastrula stages (stages 10 to 10+), stages commonly assumed not to have the potential for vertical signaling. As the bottle cells first begin to form, at stage 10-, a massive rotation of the lower involuting marginal zone occurs around an internal lip ("levre interne," Nieuwkoop and Florschutz, 1950). This rotation initiates the formation of the Cleft of Brachet from the floor of the blastocoele and brings the prospective mesoderm and endoderm at the leading edge of the marginal zone into vertical apposition with the prospective neural region quite early in gastrulation. The consequence and importance of recognizing these early internal rearrangements are that it pushes backward the time at which potential vertical inductive interactions between mesoderm and neurectoderm can occur. This means that a purely planar inductive situation can cease to exist as early as the inception of bottle cell formation and that neural patterning through vertical induction starts at the very beginning of gastrulation.

Abnormal muscle MRI in a patient with systemic juvenile arthritis.

Although myositis has been described in children with systemic-onset juvenile arthritis (JA), its documentation by MRI has not been reported. We describe a 13-year-old boy with systemic-onset JA, severe myalgia, and elevated muscle enzymes, but normal muscle strength, who had an MRI consistent with myositis. Magnetic resonance imaging can identify the specific location of myositis, allowing more precise definition of a potential complication of systemic JA.

Progressive osseous heteroplasia, uncommon cause of soft tissue ossification: a case report and review of the literature.

We report a case of an uncommon, recently described disease manifesting shortly after birth, characterized by extensive soft tissue calcification with ossification, progressive osseous heteroplasia. We describe the complex histopathologic patterns present in this case, discuss the main differential diagnoses that the surgical pathologist must consider when confronted by soft tissue ossification, and review the pertinent literature. We conclude that although the morphologic patterns of ossification in progressive osseous heteroplasia are complex and the involvement is extensive, the morphology of the lesions lacks diagnostic specificity. The diagnosis must be based on a consideration of the combined clinical data and radiologic and pathologic findings. This approach alone makes it possible to exclude a number of clinicopathologic entities that manifest with so-called osteoma cutis but whose associated lesions and genetic implications are different.

Bone mineral disorders in children: evaluation with dual x-ray absorptiometry.

PURPOSE: To evaluate the utility of dual x-ray absorptiometry (DXA) in children with bone mineral disorders. MATERIALS AND METHODS: In phase 1, radial DXA was compared with single-energy photon absorptiometry (SPA) (n = 117). In phase 2, radial and lumbar bone mineral density (BMD) measured with DXA and second metacarpal cortical thickness were compared (254 examinations, 224 children). RESULTS: For radial BMD, DXA and SPA correlated well (r = .956) and SPA-equivalent values could be calculated from DXA measurements (mean residual error = 0.024 g/cm2). After controlling for age, sex, weight, and height, partial correlations were very small for lumbar BMD with radial BMD (r = .186) and lumbar BMD with cortical thickness (r = .158), and slightly better for radial BMD with cortical thickness (r = .544). Z scores also correlated poorly with no meaningful correlation for lumbar BMD with radial BMD (r = .07) CONCLUSION: In children with bone mineral disorders, radial DXA and SPA measurements correlate well. However, lumbar BMD, radial BMD, and cortical thickness correlate poorly and lumbar BMD frequently does not identify abnormality in patients with abnormal radial BMD. Lumbar BMD alone is not adequate for evaluation of bone mineral status in these patients.

Hereditary sclerosing glomerulopathy in the conorenal syndrome.

Kidney failure is recognized to occur in association with bone malformations, yet the renal disease often is incompletely characterized. In the syndrome of cone-shaped epiphyses of the phalanges and renal failure (conorenal syndrome), the kidney disease has been previously labeled "nephronophthisis" (now termed "medullary cystic disease"). We report two siblings with the conorenal syndrome in whom longitudinal clinical study has been possible and from whom kidney biopsy specimens were obtained prior to renal failure; their renal disease is incompatible with medullary cystic disease. The variable clinical course and nephropathology of this syndrome are characterized. These results call into question the association of medullary cystic disease of the kidney with other syndromes of bone dysplasia with renal failure.

Genetic heterogeneity of heart-hand syndromes.

BACKGROUND: Heart-hand syndromes compose a class of combined congenital cardiac and limb deformities. The proto-typical heart-hand disorder is Holt-Oram syndrome, which is characterized by cardiac septation defects and radial ray limb deformity. We have recently mapped the Holt-Oram syndrome gene defect to the long arm of human chromosome 12 in two families. The role of this disease locus in the pathogenesis of related conditions such as heart-hand syndrome type III (cardiac conduction disease accompanied by skeletal malformations) or familial atrial septal defects is unknown. METHODS AND RESULTS: Clinical evaluations and genetic linkage analyses were performed in five additional kindreds with Holt-Oram syndrome and also in one kindred with heart-hand syndrome type III and one kindred with familial atrial septal defect and conduction disease. Holt-Oram syndrome in all five kindreds mapped to chromosome 12q2. These studies and previous data provide odds of greater than 10(25):1 that the Holt-Oram syndrome disease gene is at chromosome 12q2. In contrast, neither the phenotypically similar disorder heart-hand syndrome type III nor the locus responsible for a familial atrial septal defect with atrioventricular block maps to chromosome 12q2. CONCLUSIONS: We demonstrate that heart-hand syndromes are genetically heterogeneous. Conditions that clinically appear to be partial phenocopies of Holt-Oram syndrome arise from distinct disease genes.

MR imaging of hip disorders.

Magnetic resonance (MR) imaging has been applied to the study of a variety of hip disorders, principally the evaluation of avascular necrosis. The authors reviewed their experience with MR imaging of a variety of pediatric and adult hip diseases. Attention to the details of the imaging technique is essential for maximizing the diagnostic potential of MR imaging in the work-up of hip disease. Specific protocols that incorporate surface coil imaging, oblique imaging planes, and alternative pulse sequences are the foundation of successful hip studies. Gradient-echo imaging is essential for evaluating cartilaginous disorders, particularly in pediatric patients. For patients to benefit from the diagnostic capabilities of MR imaging, an appreciation of the unique information it provides must be communicated to referring physicians. In addition, an awareness of the atypical and unique MR appearances of certain hip disorders is necessary for accurate interpretation.

Sequence and rate of bone marrow conversion in the femora of children as seen on MR imaging: are accepted standards accurate?

OBJECTIVE: The purpose of this study was to reassess the normal sequence and rate of marrow conversion in the femora of children as depicted on MR imaging. MATERIALS AND METHODS: We retrospectively analyzed 81 T1-weighted MR images of the femur for the appearance and distribution of hematopoietic (red) and fatty (yellow) marrow. Eighty-one children 2 days to 15 years old with no known bone marrow abnormalities were divided into four age groups. The signal intensity and homogeneity of the marrow in the proximal epiphysis, proximal metaphysis, diaphysis, distal metaphysis, distal epiphysis, and greater trochanter were compared with the signal intensity and homogeneity of surrounding muscle and fat and graded by two observers. In select cases, region-of-interest measurements of marrow, subcutaneous fat, and muscle were obtained to validate the visual grading system. RESULTS: Conversion of hematopoietic to fatty marrow in the femur followed a well-defined sequence, occurring first in the proximal and distal epiphyses, followed by the diaphysis, distal metaphysis, and then the proximal metaphysis. Although high-signal-intensity fatty marrow could be seen within the femoral diaphysis as early as 3 months of age, fatty marrow with various degrees of heterogeneity was routinely seen in this region by 12 months of age. After 5 years of age, the femoral diaphysis showed homogeneous high signal intensity. These findings are in contrast to previously published data that describe homogeneous red marrow within the femoral diaphysis during the first year of life and homogeneous yellow marrow visualized by 10 years of age. CONCLUSION: The normal age-related sequence of femoral marrow conversion we saw on MR images conforms to the sequence described in previously published reports, but this transformation, particularly in the diaphysis, occurs significantly earlier in life than has been previously reported. This discrepancy might be explained partially by the sensitivity of signal intensity in the femoral marrow to alterations in window and level settings.

Imaging of epiphyseal injuries.

There have been many advances in the diagnosis and treatment of epiphyseal injuries in the 30 years since the publication of the landmark article by Drs Robert Salter and William Harris. They are the subject of this review. The anatomic features of the physis, epiphysis, and metaphysis are presented, and histologic studies of human and experimental physeal injuries are described. The recently recognized histologic, anatomic, and imaging characteristics of bone bridging of the physis resulting in growth disturbances are reviewed. Modification in and additions to the original Salter-Harris classification system have been proposed. The role and technique of computed tomography and magnetic resonance imaging in the assessment of the initial injury and analysis of subsequent growth disturbance are discussed.