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  • Author or Editor: Michael L. DiLuna x
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Maxwell S. H. Laurans, Michael L. DiLuna, Dana Shin, Faheem Niazi, Jennifer R. Voorhees, Carol Nelson-Williams, Eric W. Johnson, Adrian M. Siegel, Gary K. Steinberg, Michel J. Berg, R. Michael Scott, Gioacchino Tedeschi, T. Peter Enevoldson, John Anson, Guy A. Rouleau, Christopher Ogilvy, Issam A. Awad, Richard P. Lifton and Murat Gunel

Object. A gene contributing to the autosomal-dominant cerebral cavernous malformation (CCM) phenotype, KRIT1 (an acronym for Krev Interaction Trapped 1), has been identified through linkage analysis and mutation screening. The authors collected blood samples from 68 patients with familial CCM and 138 patients with apparently sporadic CCM as well as from their families, in an effort to characterize the prevalence and spectrum of disease-causing sequence variants in the KRIT1 gene.

Methods. The authors used single-strand conformational polymorphism analysis to identify genomic variants in KRIT1, which were sequenced to determine the specific mutation. Among 43 Hispanic-American kindreds who immigrated to the southwestern US from northern Mexico, 31 share an identical founder mutation. This Q455X mutation is found in 18 (86%) of 21 persons with a positive family history and in 13 (59%) of 22 persons with apparently sporadic CCM. This mutation was not found among 13 persons with CCM who were recruited from Mexico. These findings establish the key role of a recent founder mutation in Hispanic persons with CCM who live in the US.

Although nearly all Hispanic families in the US in which there are multiple CCM cases linked to the CCM1 locus, only 13 of 25 non-Hispanic CCM-carrying families have displayed evidence of linkage to the CCM1 locus. Among these 13 families, the authors identified eight independent mutations in nine kindreds. They identified four additional mutations among 22 familial CCM kindreds with no linkage information, bringing the total number of independent mutations to 12. Inherited KRIT1 mutations were not detected among 103 non-Hispanic persons in whom a family history of CCM was rigorously excluded.

Conclusions. All mutations were nonsense mutations, frame-shift mutations predicting premature termination, or splicesite mutations located throughout the KRIT1 gene, suggesting that these are genetic loss-of-function mutations. These genetic findings, in conjunction with the clinical phenotype, are consistent with a two-hit model for the occurrence of CCM.

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Aaron A. Cohen-Gadol, Michael L. DiLuna and Dennis D. Spencer

✓ The authors describe a patient who experienced stereotypical episodes of dyspnea and presyncopal sensation without loss of consciousness during a 4-month period. Further evaluation established intermittent arterial O2 desaturations associated with this dyspnea. After an extensive cardiopulmonary workup was performed for presumptive diagnosis of pulmonary embolism, a brain magnetic resonance image revealed a right medial temporal lobe lesion. The patient's dyspnea was then suspected to be a symptom of a seizure. His shortness of breath and O2 desaturation resolved with administration of phenytoin. This case, to the authors' knowledge, is the first documented example of simple partial seizures presenting with episodic autonomic cardiopulmonary symptoms in the absence of other ictal behavior. This case may also illustrate one specific limbic autonomic network.

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Ozlem Guzeloglu-Kayisli, Umit A. Kayisli, Nduka M. Amankulor, Jennifer R. Voorhees, Ozgun Gokce, Michael L. Diluna, Maxwell S. H. Laurans, Guven Luleci and Murat Gunel

Object. Molecular genetic studies of cerebral cavernous malformation (CCM) have identified three loci, CCM1–3, that can lead to CCM when mutated. Examination of the CCM1 locus established KRIT1 (Krev1 Interaction Trapped gene 1) as the CCM1 gene. Despite the identification of KRIT1 as the gene mutated in CCM1, little has been learned regarding its function. The authors recently demonstrated specific KRIT1 expression in endothelial cells. Based on this result and the fact that the CCM phenotype features defects in microvasculature, we hypothesized that KRIT1 may take an active part in normal angiogenesis.

Methods. In this study, the authors investigated the spatial and temporal expression of KRIT1 during normal vessel development and maturation by examining KRIT1 protein in both in vitro and in vivo angiogenic systems with the use of postconfluent endothelial cell cultures along with placental tissues from different developmental stages.

Conclusions. The results demonstrate that KRIT1 is expressed during capillary-like tube formation in the early stages of angiogenesis in vitro. Histological examination of placental tissue, a well-established in vivo model of angiogenesis, shows KRIT1 expression in active angiogenic and vasculogenic areas of the immature placental villi. As the placenta matures, KRIT1 expression is restricted to microvascular and small arterial endothelial cells with little or no expression seen in the intima of large vessels. It can therefore be concluded that KRIT1 is expressed during early angiogenesis by endothelial cells and may play a key role in vessel formation and/or development.

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Kaya Bilguvar, Mohamad Bydon, Fatih Bayrakli, A. Gulhan Ercan-Sencicek, Yasar Bayri, Christopher Mason, Michael L. DiLuna, Margretta Seashore, Richard Bronen, Richard P. Lifton, Matthew State and Murat Gunel

Object

Greig cephalopolysyndactyly syndrome (GCPS) is one of a spectrum of overlapping clinical syndromes resulting from mutations in the gene GLI3 on chromosome 7p. Cerebral cavernous malformation (CCM) is caused by mutations in three distinct genes, including Malcavernin (CCM2), which also maps to chromosome 7p and is located 2.8 Mbp from GLI3. The authors describe a new syndrome that combines the vascular lesions characteristic of CCM with the hallmarks of GCPS, including polydactyly, hypertelorism, and developmental delay.

Methods

The authors used high-resolution array-based comparative genome hybridization (CGH) analysis to characterize the 3 million–bp deletion on chromosome 7 that accounts for this novel clinical presentation. A 4-year-old girl presented with polydactyly, hypertelorism, and developmental delay and was also found to have multiple CCMs after suffering a seizure.

Results

Genetic analysis using array-based CGH revealed a deletion affecting multiple genes in the 7p14-13 locus, the interval that includes both CCM2 and GLI3. Quantitative real-time polymerase chain reaction (RT-PCR) on genomic DNA confirmed this genomic lesion.

Conclusions

A novel syndrome, combining features of CCM and GCPS, can be added to the group of entities that result from deleterious genetic variants involving GLI3, including GCPS, acrocallosal syndrome, Pallister–Hall syndrome, and contiguous gene syndrome. The deletion responsible for this new entity can be easily detected using either array-based chromosomal analysis or quantitative RT-PCR.

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Jennifer A. Moliterno, Michael L. DiLuna, Shreya Sood, Kurt E. Roberts and Charles C. Duncan

✓ Gastric bypass surgery has become a safe and acceptable surgical weight loss treatment for individuals who suffer from morbid obesity. Patients who undergo this procedure are subject to vitamin deficiencies due to an iatrogenic malabsorptive state. Folate, a vitamin known for its role in the prevention of neural tube defects (NTDs), can be part of the deficiency spectrum resulting from this procedure. The authors describe the case of a woman who was nonadherent to multivitamin treatment after undergoing gastric bypass surgery. Her lack of understanding and appreciation of the relationship between gastric bypass surgery, folate deficiency, and NTDs may have contributed to her noncompliance with daily multivitamin consumption. As a result, her potential problems with folate absorption could have contributed to her subsequently giving birth to a child with a myelomeningocele. Thus, patient awareness and counseling along with aggressive vitamin supplementation among this particular population may help prevent the occurrence of NTDs after gastric bypass surgery.

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Andy J. Redmond, Michael L. DiLuna, Ryan Hebert, Jennifer A. Moliterno, Rani Desai, Jonathan P. S. Knisely and Veronica L. Chiang

Object

Gamma Knife surgery (GKS) improves overall survival in patients with malignant melanoma metastatic to the brain. In this study the authors investigated which patient- or treatment-specific factors influence survival of patients with melanoma brain metastases; they pay particular interest to pre- and post-GKS hemorrhage.

Methods

Demographic, treatment, and survival data on 59 patients with a total of 208 intracranial metastases who underwent GKS between 1998 and 2007 were abstracted from treatment records and from the Connecticut Tumor Registry. Multivariate analysis was used to identify factors that independently affected survival.

Results

Survival was significantly better in patients with solitary metastasis (p = 0.04), lesions without evidence of pre-GKS hemorrhage (p = 0.004), and in patients with total tumor volume treated < 4 cm3 (p = 0.02). Intratumoral bleeding occurred in 23.7% of patients pre-GKS. Intratumoral bleeding occurred at a mean of 1.8 months post-GKS at a rate of 15.2%. Unlike the marked effect of pretreatment bleeding, posttreatment bleeding did not independently affect survival. Sex, systemic control, race, metastases location, whole-brain radiation therapy, chemotherapy, history of antithrombotic medications, and cranial surgery had no independent association with survival.

Conclusions

These data corroborate previous findings that tumor burden (either as increased number or total volume of lesions) at the time of GKS is associated with diminished patient survival in those with intracerebral melanoma metastases. Patients who were noted to have hemorrhagic melanoma metastases prior to GKS appear to have a worse prognosis following GKS compared with patients with nonhemorrhagic metastases, despite similar rates of bleeding pre- and post-GKS treatment. Gamma Knife surgery itself does not appear to increase the rate of hemorrhage.

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Matthew R. Sanborn, Michael L. DiLuna, Robert G. Whitmore and Phillip B. Storm

Fractures through the ring of the C-1 vertebrae are very rare in the pediatric patient population. In this report, the authors describe the case of a widely displaced fracture of the C-1 anterior arch in a 6-year-old boy. The fracture was initially treated using a fluoroscopy-guided, transoral, closed reduction with subsequent halo vest immobilization. Although conservative management of C-1 fractures is generally adequate and efficacious in the pediatric population, mechanistic and anatomical considerations in this case were concerning for potential instability in extension, and prompted an unusual method of closed reduction followed by treatment in a halo vest.

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Brian J. McHugh, Ryan A. Grant, Alyssa B. Zupon and Michael L. DiLuna

The etiology of os odontoideum has been debated in the literature since the condition was initially described. The authors present the case of a 4-year-old girl who was found to have an os odontoideum with atlantoaxial instability after a motor vehicle collision. Imaging performed 3 years earlier demonstrated an incompletely ossified, cartilaginous, orthotopic os separated from the body of the odontoid process at the level of the secondary ossification center with a short odontoid process. This case presents the earliest imaging demonstration of the presence of a congenital orthotopic os odontoideum at the secondary ossification center. The authors review the pertinent literature and propose that the etiology of os odontoideum is multifactorial and related to the embryology and vascular supply to the odontoid process.