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Chromosomal microdeletion syndromes are frequently associated with neurological disease including epilepsy and behavioral abnormalities. Yet, for most microdeletions, neurological phenotypes are variable and the exact molecular cause of neurological disease is not yet understood. Terminal deletions in the long arm of chromosome 2 (2q37.3) are among the most common microdeletion syndromes diagnosed, and have been associated with epilepsy, autistic-like features, short stature, obesity, and brachydactyly type E (short 4th and 5th metacarpals and metatarsals). However, neither epilepsy nor any of the other clinical features are invariant in 2q37.3 deletion. To elucidate the genetic mechanisms underlying this clinical variability we report what is, to our knowledge, the first description of inherited 2q37.3 deletion (without other complex chromosomal rearrangements) in three family members and present two sporadic cases and accompanying chromosomal microarray data. The clinical features of the three familial and two sporadic cases combined with the chromosomal microarray results suggest that all of the clinical features seen in 2q37.3 deletion may be variably expressed.

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.

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. Am. J. Med. Gen. 80:207–212, 1998. © 1998 Wiley-Liss, Inc.

We present the findings and clinical course of a Caucasian woman (now age 23½) 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. Am. J. Med. Genet. 80:187–195, 1998. © 1998 Wiley-Liss, Inc.

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 Konig et al. [1990: Dysmorphol Clin Genet 4:83-86].

To evaluate the utility of dual x-ray absorptiometry (DXA) in children with bone mineral disorders.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).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)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.

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.

A 2-year-old child with a ventriculoperitoneal shunt and a shunt revision 18 months previously developed a shunt infection. A CT scan of the abdomen was performed soon after the shunt catheter was removed. A peculiar invagination in the liver was demonstrated along the same course of a recently removed intraperitoneal catheter, presumably caused by the catheter. There have been no reported cases of deformity and pseudo-fissure of the liver, which may mimic pathologic processes on ultrasound or CT, caused by a ventriculoperitoneal shunt.

Punctate epiphyses are caused by a diverse group of conditions. They may be an inherited part of certain bone dysplasias or an incidental finding occurring occasionally in various disorders. The pattern of the puncta together with other radiologic findings aid in making the correct diagnosis.

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.

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.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.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.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.

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.

We describe a “new” mild malformation of the phalanx, which we call the “angel-shaped phalanx” (ASP) because of its resemblance to the little angels used for the decoration of Christmas trees. A particular middle phalangeal type of ASPs is found in a distinct variety of multiple epiphyseal dysplasia with marked retardation of bone age and severe coxarthrosis in adult life, previously reported as “hereditary peripheral dysostosis” [Bach-man, 1967: Proc R Soc Med 60:21–22; Giedion, 1969: Fortschr Rontgenstr 110:507–524]. However, these authors overlooked the unique configuration of the middle phalanges. We renamed the condition “angel-shaped phalango-epiphyseal dysplasia (ASPED)”, which may be transmitted in an autosomal-dominant manner. Six new patients are added, bringing the total to nine patients (two families and two isolated patients). ASPs were seen in five of six children. The ASPs grew into inconspicuous brachydactyly after physeal closure (3/3). The most important additional radiological finding is late and dysplastic development of both femoral heads (5/5), leading to Pertheslike and osteoarthritic changes and severe hip pain in the early thirties (2/2 adults, having reached this age). The marked retardation of carpal bone age may lead to unnecessary clinical evaluation for endocrine disorders. Less frequent clinical manifestations of ASPED are hyperextensibility of the interphalangeal joints (7/9) and hypodontia (4/7). Other types of ASPs are observed in brachyphalangy type C, spondylo-megepiphyseal-metaphyseal dysplasia, and other conditions. The concept of mild bone abnormalities as specific markers for genetic disease, as with cone-shaped epiphyses and now evident in ASPED, may also be useful for ASPs in general. © 1993 Wiley-Liss, Inc.

Objective. To assess the effects of methotrexate (MTX) therapy on radiologic progression in juvenile rheumatoid arthritis (JRA). Methods. We evaluated serial wrist radiographs for carpal length in 23 JRA patients with bilateral wrist involvement, before and during MTX treatment. These carpal length measurements were compared with established norms for carpal length in a healthy pediatric population. Results. Both clinical responders to MTX (17 of 23 patients) and nonresponders (6 of 23) had decreasing carpal length prior to initiation of the treatment. Eleven of the 17 clinical responders had improved carpal length after a mean of 2.5 years of MTX treatment. All 6 clinical nonresponders had progressive loss of carpal length. Conclusion. MTX treatment resulted in radiologic improvement, as measured by carpal length, in the majority of children with JRA who had a clinical response to MTX.

We describe a brother and sister and an unrelated boy with congenital cerebellar hypoplasia and endosteal sclerosis. All 3 children presented with ataxia and developmental delay, and were found to have microcephaly, short stature, oligodontia, strabismus, nystagmus, and congenital hip dislocation. A previously published case is reviewed. The disorder appears to represent a newly recognized autosomal recessive syndrome.

Juvenile rheumatoid arthritis, leukemia, hypertrophic osteoarthropathy, sickle cell disease, and child abuse can all be causes of joint disease in the child's hand. The role of radiology is to diagnose disease and follow disease progression so that therapy can be modified. Because much of the child's hand is unossified cartilage, measurements, bone mineralization, and maturation are important components of the radiologic evaluation.

Measurements are useful in the radiologic evaluation of the hand. They permit an objective evaluation of subtle alterations in the relative lengths of hand bones, which may be useful in the diagnosis of many congenital malformation syndromes. Evaluation of width of the carpus can be useful in the evaluation of juvenile rheumatoid arthritis as well as many bone dysplasias. Carpal angle measures, the relative position of the distal radius and ulna, as well as cortical measures of the second metacarpal have many clinical applications.

Torg syndrome is a multicentric osteolysis syndrome of unknown etiology. We identified mutations in the MMP2 gene in a patient with Torg syndrome that resulted in complete loss of MMP2 activity. MMP2 mutations were previously identified in patients with NAO and Winchester syndrome. Our findings suggest that Torg, NAO, and Winchester syndrome are allelic disorders. Introduction: Torg, nodulosis-arthropathy-osteolysis (NAO), and Winchester syndrome are a group of autosomal recessive osteolysis syndromes with marked clinical and radiological overlap. It has been suggested that the three conditions are causally related, but molecular evidence for this assumption has been lacking. Recently, mutations in the matrix metalloproteinase 2 gene (MMP2) have been reported in patients with NAO and Winchester syndrome. Materials and Methods: We sequenced the MMP2 gene in a patient with clinical and radiographic findings of Torg syndrome. MMP2 activity was measured with gelatin zymography. Results: Two mutations in the MMP2 gene were identified in this patient. Gelatin zymography indicated complete loss of MMP2 activity. Conclusions: Torg, NAO, and Winchester syndrome are allelic disorders. The name Torg-Winchester syndrome is suggested as a common denominator for this group of disorders.

Neonatal onset multisystem inflammatory disease (NOMID), an autoinflammatory disease, is characterized by fever, chronic urticarial rash, CNS manifestations, and arthropathy. Approximately 50% of patients with NOMID have de novo missense mutations in CIAS1, which is associated with modulation of the IL-1b and apoptotic pathways. Approximately 60% of NOMID patients have prominent arthropathy, most commonly involving the knees, the cause of which remains poorly understood. To more fully describe the findings of NOMID arthropathy on MRI and radiography and to provide a better understanding of the origin of the bony lesions. We imaged 20 patients with NOMID to further investigate NOMID-associated bony lesions. Bony abnormalities were seen in the knees of 11/20 patients. The knee findings included enlarged, deformed femora and patellae in all and tibiae in the majority, without evidence of synovitis. Some patients had other joint involvement. Most had short stature and valgus or varus knee deformities. No association was noted between bony abnormalities and CIAS1 mutations. The abnormalities appeared to be the result of a mass-producing process. The resulting heterogeneously calcified masses appeared to originate in the physis and deformed the adjacent metaphysis and epiphysis. These findings suggest that the arthropathy of NOMID is the result of abnormal endochondral bone growth. Further investigation is needed to determine whether this deformity is triggered by inflammation early in development or by CIAS1 mutations causing abnormal chondrocyte apoptosis.

Background. Brachydactyly has been described on physical examination in patients with Smith–Magenis syndrome (SMS). Metacarpophalangeal pattern profile analysis (MCPPPA), a method of graphic depiction of the relative size of the bones of the hand, has been used to objectively evaluate radiographs of the hand in patients with SMS in two small series: a single case and a study of four patients. This technique has confirmed brachydactyly and has suggested conflicting MCPPPA results. Objective. The purpose of our study was to evaluate the hand by MCPPPA in a large series of patients with SMS. Patients and methods. We measured the bones of the hand and performed MCPPPA in 29 confirmed cases of SMS. Results. Our results in 29 patients demonstrated a different MCPPPA in patients with SMS than previously reported. The analysis confirmed brachydactyly and the previously described trend of more pronounced shortening of the distal bones relative to the more proximal bones, but also demonstrated a previously undescribed pattern: relative enlargement of the proximal phalanx of the thumb and middle phalanx of the fifth finger. However, statistical analysis suggested that the pattern was not highly characteristic. Conclusion. MCPPPA of 29 patients with SMS demonstrates a pattern different than previously reported, but not highly characteristic.

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.

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.

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].

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.

The Holt-Oram syndrome is an autosomal dominant condition characterized by skeletal abnormalities that are frequently accompanied by congenital cardiac defects. The cause of these disparate clinical features is unknown. To identify the chromosomal location of the Holt-Oram syndrome gene, we performed clinical and genetic studies.Two large families with the Holt-Oram syndrome were evaluated by radiography of the hands, electrocardiography, and transthoracic echocardiography. Genetic-linkage analyses were performed with polymorphic DNA loci dispersed throughout the genome to identify a locus that was inherited with the Holt-Oram syndrome in family members.A total of 19 members of Family A had Holt-Oram syndrome with mild-to-moderate skeletal deformities, including triphalangeal thumbs and carpal-bone dysmorphism. All affected members of Family A had moderate-to-severe congenital cardiac abnormalities, such as ventricular or atrial septal defects or atrioventricular-canal defects. Eighteen members of a second kindred (Family B) had Holt-Oram syndrome with moderate-to-severe skeletal deformities, including phocomelia. Twelve of the affected members had no cardiac defects; six had only atrial septal defects. Genetic analyses demonstrated linkage of the disease in each family to polymorphic loci on the long arm of chromosome 12 (combined multipoint lod score, 16.8). These data suggest odds greater than 10(16):1 that the genetic defect for Holt-Oram syndrome is present on the long arm of chromosome 12 (12q2).Mutations in a gene on chromosome 12q2 can produce a wide range of disease phenotypes characteristic of the Holt-Oram syndrome. This gene has an important role in both skeletal and cardiac development.

We present the clinical and radiological features of two children with fatigue fractures of the sacrum. Both patients were active, had no underlying bone disease and presented with insidious onset of low back pain. Plain radiography was non-contributory to the diagnosis. In both patients a focal area of increased activity was present in the lateral aspect of the sacrum on bone scintigraphy, which corresponded to linear medullary sclerosis in the sacral ala demonstrated by computed tomography. Magnetic resonance imaging in one patient revealed a linear signal void in the sacral ala on T1- and T2-weighted images. This was surrounded by diffuse low marrow signal on T1-weighted images, and increased marrow signal on T2-weighted images. Fatigue fractures of the sacrum should be considered in the differential diagnosis of low back pain in children. An awareness of their appearance on magnetic resonance imaging is important as this modality is increasingly utilised, particularly in children.

With the recent advances that have become available with imaging, we are able to gain considerable information about joint diseases. Although conventional radiography still plays a very important part in the diagnosis of joint disease, ultrasound, computed tomography, magnetic resonance imaging, and nuclear medicine studies have all enhanced our ability to evaluate joint disorders. Each of these modalities need not be used in every patient but when chosen carefully, can efficiently provide useful information both for diagnosis and management. These various modalities are also extremely useful to rule out the mimics of joint disease. Magnetic resonance has recently been shown to be useful in evaluation of dermatomyositis and of vasculitides in the brain.

Measurements are useful in the radiologic evaluation of the hand. They permit an objective evaluation of subtle alterations in the relative lengths of hand bones, which may be useful in the diagnosis of many congenital malformation syndromes. Evaluation of width of the carpus can be useful in the evaluation of juvenile rheumatoid arthritis as well as many bone dysplasias. Carpal angle measures, the relative position of the distal radius and ulna, as well as cortical measures of the second metacarpal have many clinical applications.

Juvenile rheumatoid arthritis, leukemia, hypertrophic osteoarthropathy, sickle cell disease, and child abuse can all be causes of joint disease in the child's hand. The role of radiology is to diagnose disease and follow disease progression so that therapy can be modified. Because much of the child's hand is unossified cartilage, measurements, bone mineralization, and maturation are important components of the radiologic evaluation.

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.

A 9.5-year-old girl had popliteal arterial and venous compression by a distal femoral osteochondroma. Magnetic resonance imaging demonstrated the relation of the vessels to the osteochondroma and a three-phase bone scintigram showed asymmetry of arterial perfusion and evidence of venous stasis.

Two patients with severe intrauterine growth retardation and bird-headed appearance are described. These two children had most of the clinical features of the so-called Seckel dwarfism. The radiological findings included: (1) ivory epiphyses affecting all phalanges in one patient and many phalanges in another; (2) cone-shaped epiphyses in the proximal phalanges; (3) marked disharmonic bone maturation between carpals and phalanges, between individual carpals, and from side to side; (4) alteration in the length of the hand bones, with considerable similarity of the metacarpophalangeal pattern between the two children; (5) relatively small carpals, which have an angular configuration; and (6) relatively normal or increased cortical thickness of the metacarpals.

Plain spine radiographs from 31 patients with pathologically proven intraspinal tumors were analyzed retrospectively by an experienced pediatric radiologist unfamiliar with the cases in order to evaluate the applicability and reliability of the radiographic signs commonly used for diagnosis. Interpediculate distances (IPDs) were graphed onto standard curves to assess whether graphic analysis aided in diagnosis. In this group of patients, no single radiographic criterion permitted better than 40% true-positive diagnosis. False-positive diagnoses were made in 0–10% of cases, depending on the sign employed. Use of multiple roentgen signs in conjunction achieved 55% true-positive and 3% false-positive diagnoses, while use of graphed IPDs alone achieved 57% true-positive and 11% false-positive diagnoses. Addition of graphed IPDs to visual inspection of the radiographs led to detection of 6 tumors (19%) not otherwise appreciated, but tripled the false-positive rate from 3 to 10%.

A well-nourished teen-age girl with psychogenic vomiting demonstrated clinical and radiographic findings of SMAS. Her upper gastrointestinal radiographic studies were normal a few weeks before and three years after the study in which radiographic findings of SMAS were present. Psychologic factors should be considered in SMAS when no condition involving inanition, immobility, abdominal compression, or coexisting abdominal disturbance can be identified.