Stephen Done

Mutations in CSPP1 Cause Primary Cilia Abnormalities and Joubert Syndrome with or without Jeune Asphyxiating Thoracic Dystrophy

Joubert syndrome (JBTS) is a recessive ciliopathy in which a subset of affected individuals also have the skeletal dysplasia Jeune asphyxiating thoracic dystrophy (JATD). Here, we have identified biallelic truncating CSPP1 (centrosome and spindle pole associated protein 1) mutations in 19 JBTS-affected individuals, four of whom also have features of JATD. CSPP1 mutations explain ∼5% of JBTS in our cohort, and despite truncating mutations in all affected individuals, the range of phenotypic severity is broad. Morpholino knockdown of cspp1 in zebrafish caused phenotypes reported in other zebrafish models of JBTS (curved body shape, pronephric cysts, and cerebellar abnormalities) and reduced ciliary localization of Arl13b, further supporting loss of CSPP1 function as a cause of JBTS. Fibroblasts from affected individuals with CSPP1 mutations showed reduced numbers of primary cilia and/or short primary cilia, as well as reduced axonemal localization of ciliary proteins ARL13B and adenylyl cyclase III. In summary, CSPP1 mutations are a major cause of the Joubert-Jeune phenotype in humans; however, the mechanism by which these mutations lead to both JBTS and JATD remains unknown.

Copper Deficiency Presenting as Metabolic Bone Disease in Extremely Low Birth Weight, Short-Gut Infants

Copper deficiency can cause bone lesions in infants, which might be confused with child abuse. Two extremely low birth weight preterm infants had complicated medical courses requiring prolonged parenteral nutrition for short-gut syndrome, which led to the development of cholestasis. Both had spent their entire lives in the hospital. They had been on prolonged ventilator support for chronic lung disease. They developed signs of copper deficiency between 5 and 6 months of age, initially raising child abuse concerns. Musculoskeletal discomfort led to the recognition of radiographic findings of metabolic bone disease. Included were osteoporosis, metaphyseal changes, and physeal disruptions. Copper levels were low; both low copper parenteral nutrition and gut losses from refeeding diarrhea likely contributed to their deficiency. Therapeutic supplementation with copper corrected their deficits and clinical and radiologic findings. The information from these cases, in particular, their radiologic findings, indicate the need to monitor copper status in at-risk premature infants. These findings may aid prevention and earlier recognition of copper deficiency. Their specific radiologic and clinical findings should aid differentiation of such children from abused infants.

Tumorlike Conditions of the Pleura

Tumorlike conditions of the pleura are rare, but diagnosis is facilitated by recognizing certain imaging patterns and interpreting them in the clinical context. A tumorlike condition of the pleura is any nonneoplastic lesion of the pleura itself, or within the pleural space, that resembles a tumor. An approach to diagnosis of the tumorlike conditions of the pleura is provided, and these conditions are grouped into focal or diffuse conditions, with an emphasis on specific imaging features. Focal tumorlike conditions of the pleura include pleural plaque, thoracic splenosis, thoracic endometriosis causing catamenial pneumothorax, and pseudotumor caused by pleural effusion. Thoracic splenosis should be considered in a patient who has a healed left lower rib fracture, an absent spleen, and left lower pleural nodules. Thoracic endometriosis with catamenial pneumothorax should be considered in a woman of childbearing age who presents with right scapular pain and recurrent pneumothorax occurring at or around the onset of menses. Extrapleural hematoma is a nonpleural mimic of pleural tumor and shares some imaging features with focal tumorlike conditions of the pleura, despite residing in the extrapleural space. Diffuse tumorlike conditions of the pleura include diffuse pleural thickening and rare conditions such as Erdheim-Chester disease and diffuse pulmonary lymphangiomatosis. Erdheim-Chester disease should be considered when diffuse pleural thickening occurs with a perirenal soft-tissue halo or distal femoral sclerosis. Diffuse pulmonary lymphangiomatosis should be considered when findings include diffuse pleural thickening, interlobular septal and peribronchovascular interstitial thickening, and mediastinal fat infiltration limited to the thorax and when these findings persist despite diuretic therapy.

The etiology and significance of fractures in infants and young children: a critical multidisciplinary review.

This paper addresses significant misconceptions regarding the etiology of fractures in infants and young children in cases of suspected child abuse. This consensus statement, supported by the Child Abuse Committee and endorsed by the Board of Directors of the Society for Pediatric Radiology, synthesizes the relevant scientific data distinguishing clinical, radiologic and laboratory findings of metabolic disease from findings in abusive injury. This paper discusses medically established epidemiology and etiologies of childhood fractures in infants and young children. The authors also review the body of evidence on the role of vitamin D in bone health and the relationship between vitamin D and fractures. Finally, the authors discuss how courts should properly assess, use, and limit medical evidence and medical opinion testimony in criminal and civil child abuse cases to accomplish optimal care and protection of the children in these cases.

Ellis–van Creveld syndrome: its history

The story of Ellis–van Creveld syndrome is one of serendipity. By chance, Simon van Creveld and Richard Ellis purportedly met on a train and combined their independently encountered patients with short stature, dental anomalies and polydactyly into one landmark publication in 1940. They included a patient used in work published previously by Rustin McIntosh without naming McIntosh as a coauthor. This patient was followed radiologically by Caffey for nearly two decades. In 1964, Victor McKusick felt compelled to investigate a brief report in an obscure pharmaceutical journal on an unusual geographic cluster of short-statured Amish patients in Pennsylvania. This review highlights the lives of the individuals involved in the discovery of Ellis–van Creveld syndrome in their historic context.

EXT2-positive multiple hereditary osteochondromas with some features suggestive of metachondromatosis

Metachondromatosis (MC) and hereditary multiple osteochondromas (HMO) are thought to be distinct disorders, each with characteristic x-ray and clinical features. Radiographic differences are the current mainstay of differential diagnosis. Both disorders are autosomal dominant, but the majority of patients with HMO have mutations in EXT-1 or EXT 2 genes. The genetic defect in MC is unknown, although recent studies indicate a possible identifiable mutation. The cancer risk in HMO is thought to be greater than in MC, although the small number of cases make such conjecture imprecise. The purpose of this report is to review existing literature and examine whether radiographic findings in HMO and MC can be reliable as a stand-alone means of differential diagnosis. Three members of a multi-generational family with an autosomal dominant exostosis syndrome were studied by clinical examination and complete skeletal survey. The roentgenographic characteristics of all osteochondromas were analyzed. The father underwent gene sequencing for EXT-1 and EXT-2, which revealed a novel EXT-2 mutation. Typical radiographic and clinical findings of both HMO and MC were seen throughout the family as well as in individuals. These family study findings contradict many of the long-standing clinical and x-ray diagnostic criteria for differentiating MC from HMO. The phenotypic crossover between the two conditions in this family, and results of genetic analysis, suggest that in the absence of a definitive genetic diagnosis, radiographic and clinical diagnosis of past and future cases HMO and MC may not be as reliable as previously assumed.

Osteopetrorickets: infantile malignant osteopetrosis paradoxically complicated by rickets

This 6-month-old girl presented with intermittent esotropia and a bulging fontanelle. CT head demonstrated significant thickening of the calvaria and facial bones. Subsequent radiographic skeletal survey revealed diffuse sclerotic bones with obliteration of the marrow cavity with a bonein-bone appearance in the small bones of the hands and feet, consistent with osteopetrosis. Additional findings included diffuse metaphyseal cupping and fraying, widening of the physes, and periosteal new bone formation along the long bones (Figs. 1 and 2). Radiographic features along with clinical and biochemical findings were consistent with superimposed rickets. Rickets is a paradoxical complication of infantile osteopetrosis resulting from inability of osteoclasts to maintain a normal calcium-phosphorus balance, despite markedly positive total body calcium. Bone marrow transplantation is the therapy of choice for osteopetrosis; however, the clinical response to bone marrow transplantation is inadequate if there is underlying rickets. Hence, it is important to detect and successfully treat rickets in these patients prior to bone marrow transplantation [1, 2].

Three-dimensional computed tomography skull reconstructions as an aid to child abuse evaluations

Objectives Skull fractures can be difficult to recognize on radiographs and axial computed tomography (CT) bone windows. Missed findings may delay abuse diagnosis. The role of three-dimensional (3-D) reconstructions in child abuse evaluations was retrospectively evaluated. Methods Twelve exemplary cases between August 2006 and July 2009 are described. All, except 2 medical-legal cases, were clinical abuse consultations. With the use of a 1-to-3 scale, ease and accuracy of interpretation of findings between plain films, bone windows, and 3-D CT images were independently assessed by 2 radiologists. Results In 7 cases, skull fractures were missed on initial review of skull films and/or bone windows. Three children sustained additional abusive injury before 3-D CT reconstructions demonstrated subtle skull fractures, though imaged, were missed on initial readings. Three children with initially unrecognized fractures had timely 3-D reconstructions confirming fractures, allowing protective intervention before additional injury. An unrecognized ping-pong fracture was discovered on 3-D reconstructions with an inflicted subdural hemorrhage, defining the injury as an impact. Two 3-Ds demonstrated communication of biparietal fractures along the sagittal suture. This changed interpretation to single, rather than 2 separate, concerning impacts. Three potential skull fractures were found to represent large sutural bones. In all cases, ease and accuracy of interpretation scores were highest for 3-D CT. Conclusions Without increasing patient radiation exposure, 3-D CT reconstructions may reveal previously unrecognized skull fractures, potentially allowing abuse diagnosis before additional injury. They may clarify normal skull variants and affirm accidental injury causes. We now routinely include 3-D reconstructions on cranial CTs for children younger than 3 years.

Pseudoachondroplasia and the seven Ovitz siblings who survived Auschwitz

This historical report focuses on the first clinical description of pseudoachondroplasia and its radiographic findings. Only half a century ago, pseudoachondroplasia was recognized as a genetic disorder with a distinct but variable phenotype of short stature, normal facial features, and progressive joint problems starting in adolescence. Radiologically, the disease is particularly intriguing because the patients appear normal at birth. The patients develop the typical gait disturbances when they begin to walk. Radiographs show the characteristic anterior tongue-shaped lumbar vertebral body changes that develop after the first year of life. This account presents the most well-known group of individuals affected by pseudoachondroplasia, the Ovitz family, who narrowly escaped death in the concentration camp of Auschwitz in 1944 because of SS physician Dr. Josef Mengele’s fascination with dwarfs. It was not until 1995 that the underlying genetic defect in the COMP gene was identified on chromosome 19.

Fetal diagnosis of spondylocostal dysplasia: Limits of conventional fetal ultrasound & MRI in diagnosing anomalies.

We present a case of postnatally recognized spondylocostal dysplasia that was prenatally misdiagnosed as fetal thoracolumbar kyphoscoliosis secondary to spinal fusion anomalies. Neither two-dimensional ultrasound nor MRI identified the rib anomalies, nor did they allow for correct identification of the more compromised lung. Spondylocostal and spondylothoracic dysostoses involve rib deformities and distortion of the bony thorax that lead to pulmonary compromise. Correct prenatal diagnosis might not be made with standard fetal imaging. Three-dimensional ultrasound should be pursued (when available) upon recognition of a thoracic scoliosis to fully assess rib development.