Differences in peripheral neuropathy in xeroderma pigmentosum complementation groups A and D as evaluated by nerve conduction studies.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare autosomal recessive genetic disorder with defective DNA nucleotide excision repair and associated with a high frequency of skin cancer. Approximately 25% of patients develop progressive neurological degeneration. Complementation groups XP-A and XP-D are most frequently associated with neurological disorders. DESIGN/METHODS: This is a retrospective review of patients with XP who were evaluated at NIH from 1986 to 2015 and had nerve conduction studies (NCS). In the complementation groups with peripheral neuropathy, further comparisons of the NCS were made with audiological, brain imaging, neuropsychological assessments that were also performed on most of the patients. Limited neuropathology of XP-A and XP-D patients were examined.. RESULTS: The 33 patients had NCS: XP-A (9 patients), XP-C (7 patients), XP-D (10 patients), XP-E (1 patient), XP-V (4 patients), and XP-unknown (2 patients). Peripheral neuropathy based on nerve conduction studies was documented only in two complementation groups: 78% (7/9) of XP-A patients had a sensorimotor neuropathy while 50% (5/10) of XP-D patients had a sensory neuropathy only. Analysis of sural sensory nerve amplitude in both complementation groups XP-A and XP-D correlated with sensorineural hearing loss (SNHL), MRI/CT severity, and Full-scale Intelligence Quotient (IQ). Analysis of fibular motor nerve amplitude in complementation XP-A correlated with SNHL and MRI/CT severity. Limited follow-up studies showed gradual loss of NCS responses compared to an earlier and more rapid progression of the hearing loss. CONCLUSIONS: Despite similar brain imaging and audiological findings patients, XP-A and XP-D complementation groups differ in the type of neuropathy, sensorimotor versus sensory alone. A few cases suggest that sensorineural hearing loss may precede abnormal NCS in XP and therefore serve as valuable clinical indicators of XP patients that will later develop peripheral neuropathy.

Early-onset stroke and vasculopathy associated with mutations in ADA2.

BACKGROUND: We observed a syndrome of intermittent fevers, early-onset lacunar strokes and other neurovascular manifestations, livedoid rash, hepatosplenomegaly, and systemic vasculopathy in three unrelated patients. We suspected a genetic cause because the disorder presented in early childhood. METHODS: We performed whole-exome sequencing in the initial three patients and their unaffected parents and candidate-gene sequencing in three patients with a similar phenotype, as well as two young siblings with polyarteritis nodosa and one patient with small-vessel vasculitis. Enzyme assays, immunoblotting, immunohistochemical testing, flow cytometry, and cytokine profiling were performed on samples from the patients. To study protein function, we used morpholino-mediated knockdowns in zebrafish and short hairpin RNA knockdowns in U937 cells cultured with human dermal endothelial cells. RESULTS: All nine patients carried recessively inherited mutations in CECR1 (cat eye syndrome chromosome region, candidate 1), encoding adenosine deaminase 2 (ADA2), that were predicted to be deleterious; these mutations were rare or absent in healthy controls. Six patients were compound heterozygous for eight CECR1 mutations, whereas the three patients with polyarteritis nodosa or small-vessel vasculitis were homozygous for the p.Gly47Arg mutation. Patients had a marked reduction in the levels of ADA2 and ADA2-specific enzyme activity in the blood. Skin, liver, and brain biopsies revealed vasculopathic changes characterized by compromised endothelial integrity, endothelial cellular activation, and inflammation. Knockdown of a zebrafish ADA2 homologue caused intracranial hemorrhages and neutropenia - phenotypes that were prevented by coinjection with nonmutated (but not with mutated) human CECR1. Monocytes from patients induced damage in cocultured endothelial-cell layers. CONCLUSIONS: Loss-of-function mutations in CECR1 were associated with a spectrum of vascular and inflammatory phenotypes, ranging from early-onset recurrent stroke to systemic vasculopathy or vasculitis. (Funded by the National Institutes of Health Intramural Research Programs and others.).

Predicting clinical outcomes in chordoma patients receiving immunotherapy: a comparison between volumetric segmentation and RECIST.

BACKGROUND: The Response Evaluation Criteria in Solid Tumors (RECIST) are the current standard for evaluating disease progression or therapy response in patients with solid tumors. RECIST 1.1 calls for axial, longest-diameter (or perpendicular short axis of lymph nodes) measurements of a maximum of five tumors, which limits clinicians' ability to adequately measure disease burden, especially in patients with irregularly shaped tumors. This is especially problematic in chordoma, a disease for which RECIST does not always adequately capture disease burden because chordoma tumors are typically irregularly shaped and slow-growing. Furthermore, primary chordoma tumors tend to be adjacent to vital structures in the skull or sacrum that, when compressed, lead to significant clinical consequences. METHODS: Volumetric segmentation is a newer technology that allows tumor burden to be measured in three dimensions on either MR or CT. Here, we compared the ability of RECIST measurements and tumor volumes to predict clinical outcomes in a cohort of 21 chordoma patients receiving immunotherapy. RESULTS: There was a significant difference in radiologic time to progression Kaplan-Meier curves between clinical outcome groups using volumetric segmentation (P = 0.012) but not RECIST (P = 0.38). In several cases, changes in volume were earlier and more sensitive reflections of clinical status. CONCLUSION: RECIST is a useful evaluation method when obvious changes are occurring in patients with chordoma. However, in many cases, RECIST does not detect small changes, and volumetric assessment was capable of detecting changes and predicting clinical outcome earlier than RECIST. Although this study was small and retrospective, we believe our results warrant further research in this area.

Resources Required for Semi-Automatic Volumetric Measurements in Metastatic Chordoma: Is Potentially Improved Tumor Burden Assessment Worth the Time Burden?

The Response Evaluation Criteria in Solid Tumors (RECIST) is the current standard for assessing therapy response in patients with malignant solid tumors; however, volumetric assessments are thought to be more representative of actual tumor size and hence superior in predicting patient outcomes. We segmented all primary and metastatic lesions in 21 chordoma patients for comparison to RECIST. Primary tumors were segmented on MR and validated by a neuroradiologist. Metastatic lesions were segmented on CT and validated by a general radiologist. We estimated times for a research assistant to segment all primary and metastatic chordoma lesions using semi-automated volumetric segmentation tools available within our PACS (v12.0, Carestream, Rochester, NY), as well as time required for radiologists to validate the segmentations. We also report success rates of semi-automatic segmentation in metastatic lesions on CT and time required to export data. Furthermore, we discuss the feasibility of volumetric segmentation workflow in research and clinical settings. The research assistant spent approximately 65 h segmenting 435 lesions in 21 patients. This resulted in 1349 total segmentations (average 2.89 min per lesion) and over 13,000 data points. Combined time for the neuroradiologist and general radiologist to validate segmentations was 45.7 min per patient. Exportation time for all patients totaled only 6 h, providing time-saving opportunities for data managers and oncologists. Perhaps cost-neutral resource reallocation can help acquire volumes paralleling our example workflow. Our results will provide researchers with benchmark resources required for volumetric assessments within PACS and help prepare institutions for future volumetric assessment criteria.

Preoperative Imaging Features are Associated with Surgical Complications Following Carotid Body Tumor Resection.

BACKGROUND: Surgical resection remains the treatment of choice for carotid body tumors (CBTs). Although perioperative complications such as carotid artery injury and neurological deficits occur infrequently, they can be devastating. The aim of this study was to evaluate whether clinical factors or preoperative imaging findings can accurately predict perioperative complications. METHODS: Twenty CBTs were resected from 19 patients. Preoperative computed tomography (CT) and magnetic resonance imaging (MRI) of the neck were used to measure the degree of circumferential involvement of the CBT to the internal carotid artery (ICA), carotid artery narrowing, tumor length, tumor volume, and the distance from the tip of the C2 dens to the superior aspect of the CBT (dens-CBT). Operative reports and Shamblin classification (I-III) of each tumor were independently reviewed. Preoperative imaging features were compared to perioperative cranial nerve injury (CNI), rates of carotid artery injury, and major carotid artery repairs, as well as Shamblin classifications≥II. RESULTS: CNI was associated with a high-lying CBT (dens-CBT=1.8 vs. 2.9 cm, p<0.01). All four patients with CNI had a dens-CBT of <3 cm. Neither tumor length and tumor volume nor the involvement of the ICA (≥180° as measured by CT or MRI) was associated with CNI, carotid artery injury, major carotid artery repair, or Shamblin II or III classification. No carotid artery narrowing was observed in any of the cases. CONCLUSIONS: Preoperative measurement of the dens-CBT is helpful in identifying CBTs at risk for CNI after surgical resection.

Early responses to adenoviral-mediated transfer of the aquaporin-1 cDNA for radiation-induced salivary hypofunction.

No conventional therapy exists for salivary hypofunction in surviving head and neck cancer patients with Radiation Therapy Oncology Group late grade 2-3 toxicity. We conducted a phase I clinical trial to test the safety and biologic efficacy of serotype 5, adenoviral-mediated aquaporin-1 cDNA transfer to a single previously irradiated parotid gland in 11 subjects using an open label, single-dose, dose-escalation design (AdhAQP1 vector; four dose tiers from 4.8 × 10(7) to 5.8 × 10(9) vector particles per gland). Treated subjects were followed at scheduled intervals. Multiple safety parameters were measured and biologic efficacy was evaluated with measurements of parotid salivary flow rate. Symptoms were assessed with a visual analog scale. All subjects tolerated vector delivery and study procedures well over the 42-d study period reported. No deaths, serious adverse events, or dose-limiting toxicities occurred. Generally, few adverse events occurred, and all were considered mild or moderate. No consistent changes were found in any clinical chemistry and hematology parameters measured. Objective responses were seen in six subjects, all at doses <5.8 × 10(9) vector particles per gland. Five of these six subjects also experienced subjective improvement in xerostomia. AdhAQP1 vector delivery to a single parotid gland was safe and transfer of the hAQP1 cDNA increased parotid flow and relieved symptoms in a subset of subjects.

Phase II trial of pirfenidone in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas.

BACKGROUND: Pirfenidone, an oral anti-inflammatory, antifibrotic agent with activity in idiopathic pulmonary fibrosis, may mediate anti-tumor activity in neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PN) by inhibition of fibroblast proliferation and collagen synthesis. The primary objective of this open label, single arm phase II trial was to evaluate the activity of pirfenidone in children and young adults with inoperable PN. PROCEDURE: Patients (3-21 years) with NF1-related progressive PN received pirfenidone at the previously determined optimal dose (500 mg/m(2) orally, q8h) on a continuous dosing schedule (one cycle = 28 days). Volumetric MRI analysis was used to assess response. Progression was defined as ≥ 20% PN volume increase compared to baseline. Pirfenidone would be considered active if it doubled the median time to progression (TTP) compared to the TTP on the placebo arm of a phase II trial with the farnesyltransferase inhibitor tipifarnib, which used near identical eligibility criteria. Toxicities, objective response rate, and quality of life (QOL) also were evaluated. RESULTS: Thirty-six patients were enrolled and tolerated pirfenidone well with intermittent nausea and vomiting as the most frequent toxicities. A dose reduction was required in only three patients. The median TTP for pirfenidone was 13.2 months compared to 10.6 months for the placebo control group from the tipifarnib trial (two-tailed P = 0.92; one-tailed P = 0.46). No objective responses were observed. CONCLUSIONS: Pirfenidone was well tolerated, but did not demonstrate activity as defined in this trial and does not warrant further evaluation in children with NF1 and progressive PN.

Multifocal dysembryoplastic neuroepithelial tumours associated with refractory epilepsy.

Dysembryoplastic neuroepithelial tumours (DNET) are a common cause of tumour-associated epilepsy, and are usually located in the temporal lobes. We present a case of multifocal DNETs in both infra- and supra-tentorial locations, in a 23-year-old man with a coincident Type I Chiari malformation, presenting with medically refractory focal seizures. The extensive anatomical distribution of the lesions suggests a genetic component in their tumourigenesis.

Molecular imaging of pediatric brain tumors: comparison of tumor metabolism using ¹8F-FDG-PET and MRSI.

Magnetic resonance spectroscopic imaging (MRSI) and (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) are non-invasive imaging techniques routinely used to evaluate tumor malignancy in adults with brain tumors. We compared the metabolic activity of pediatric brain tumors using FDG-PET and MRSI. Children (n = 37) diagnosed with a primary brain tumor underwent FDG-PET and MRSI within two weeks of each other. Tumor metabolism was classified as inactive, active or highly active using the maximum choline:N-acetyl-asparate (Cho:NAA) on MRSI and the highest tumor uptake on FDG-PET. A voxel-wise comparison was used to evaluate the area with the greatest abnormal metabolism. Agreement between methods was assessed using the percent agreement and the kappa statistic (κ). Pediatric brain tumors were metabolically heterogeneous on FDG-PET and MRSI studies. Active tumor metabolism was observed more frequently using MRSI compared to FDG-PET, and agreement in tumor classification was weak (κ = 0.16, p = 0.12), with 42 % agreement (95 % CI = 25-61 %). Voxel-wise comparison for identifying the area of greatest metabolic activity showed overlap in the majority (62 %) of studies, though exact agreement between techniques was low (29.4 %, 95 % CI = 15.1-47.5 %). These results indicate that FDG-PET and MRSI detect similar but not always identical regions of tumor activity, and there is little agreement in the degree of tumor metabolic activity between the two techniques.

Lack of mutations in the gene coding for the hGR (NR3C1) in a pediatric patient with ACTH-secreting pituitary adenoma, absence of stigmata of Cushing's syndrome and unusual histologic features.

BACKGROUND: Rare cases of human glucocorticoid receptor (hGRalpha) (NR3C1) gene mutations have been described in the gemline or somatic state in Cushing's disease (CD). AIM: We describe a pediatric patient with CD with clinical evidence of partial glucocorticoid resistance (GR) due to the relative absence of stigmata of Cushing's syndrome (CS). CASE DESCRIPTION: A 14-year-old boy with slow growth and hypertension, but no other signs of CS was admitted for CD evaluation. Urinary free cortisol levels (UFC) were consistently 2-3-fold the upper normal range. Pituitary magnetic resonance imaging (MRI) revealed a 3x4 mm hypoenhancing lesion in the right side of the pituitary gland anteriorly (microadenoma). A graded dexamethasone suppression test indicated that the patient had partial GR. Histology confirmed an adrenocorticotrophin (ACTH)-producing pituitary adenoma. We hypothesized that a NR3C1 mutation was present. Sequencing of the entire coding region of the gene produced normal results in both peripheral and tumor DNA. CONCLUSION: We present the case of a pediatric patient with an ACTH-producing tumor but little evidence of CS. No mutations in the coding sequence of NR3C1 were detected. We conclude that low level somatic mosaicism for NR3C1 mutations or a mutation in another molecule participating in hGRalpha-signaling may account for this case.

Recurrent left atrial myxomas in Carney complex: a genetic cause of multiple strokes that can be prevented.

BACKGROUND: Intracardiac myxomas in Carney complex are significant causes of cardiovascular morbidity and mortality through embolic stroke and heart failure. The genetic, clinical, and laboratory characteristics of Carney complex-related strokes from atrial myxomas have not been described. The regulatory subunit (R1A) of the protein kinase gene (PRKAR1A) is mutated in >60% of patients with Carney complex. METHODS: We studied patients with strokes and cardiac myxomas that were hospitalized in our institution and elsewhere; a total of 7 patients with 16 recurrent atrial myxomas and >14 episodes of strokes were identified. RESULTS: Neurologic deficits were reported; in 1 patient, an aneurysm developed at the site of a previous stroke. All patients were females, were also diagnosed with Cushing syndrome, and all had additional tumors or other Carney complex manifestations. Other than gender, although there was a trend for patients being overweight and hypertensive, no other risk factors were identified. A total of 5 patients (71%) had a PRKAR1A mutation; all mutations (c418_419delCA, c.340delG/p.Val113fsX15, c.353_365del13/p.Ile118fsX6, c.491_492delTG/p.Val164fsX4, and c.177+1G>A) were located in exons 3 to 5 and introns 2 to 3, and all led to a non-sense PRKAR1A mRNA. CONCLUSIONS: Female patients with Carney complex appear to be at a high risk for recurrent atrial myxomas that lead to multiple strokes. Early identification of a female patient with Carney complex is of paramount importance for the early diagnosis of atrial myxomas and the prevention of strokes.

Neonatal diagnosis and treatment of Menkes disease.

BACKGROUND: Menkes disease is a fatal neurodegenerative disorder of infancy caused by diverse mutations in a copper-transport gene, ATP7A. Early treatment with copper injections may prevent death and illness, but presymptomatic detection is hindered by the inadequate sensitivity and specificity of diagnostic tests. Exploiting the deficiency of a copper enzyme, dopamine-beta-hydroxylase, we prospectively evaluated the diagnostic usefulness of plasma neurochemical levels, assessed the clinical effect of early detection, and investigated the molecular bases for treatment outcomes. METHODS: Between May 1997 and July 2005, we measured plasma dopamine, norepinephrine, dihydroxyphenylacetic acid, and dihydroxyphenylglycol in 81 infants at risk. In 12 newborns who met the eligibility criteria and began copper-replacement therapy within 22 days after birth, we tracked survival and neurodevelopment longitudinally for 1.5 to 8 years. We characterized ATP7A mutations using yeast complementation, reverse-transcriptase-polymerase-chain-reaction analysis, and immunohistochemical analysis. RESULTS: Of 81 infants at risk, 46 had abnormal neurochemical findings indicating low dopamine-beta-hydroxylase activity. On the basis of longitudinal follow-up, patients were classified as affected or unaffected by Menkes disease, and the neurochemical profiles were shown to have high sensitivity and specificity for detecting disease. Among 12 newborns with positive screening tests who were treated early with copper, survival at a median follow-up of 4.6 years was 92%, as compared with 13% at a median follow-up of 1.8 years for a historical control group of 15 late-diagnosis and late-treatment patients. Two of the 12 patients had normal neurodevelopment and brain myelination; 1 of these patients had a mutation that complemented a Saccharomyces cerevisiae copper-transport mutation, indicating partial ATPase activity, and the other had a mutation that allowed some correct ATP7A splicing. CONCLUSIONS: Neonatal diagnosis of Menkes disease by plasma neurochemical measurements and early treatment with copper may improve clinical outcomes. Affected newborns who have mutations that do not completely abrogate ATP7A function may be especially responsive to early copper treatment. (ClinicalTrials.gov number, NCT00001262.)

Pituitary Imaging Abnormalities and Related Endocrine Disorders in Erdheim-Chester Disease.

PURPOSE: We examined abnormal pituitary imaging (API) and associated endocrine dysfunction in subjects with ECD. METHODS: A cross-sectional descriptive examination of a natural history cohort study diagnosed with ECD was conducted at a clinical research center. Subjects underwent baseline endocrine tests of anterior and posterior pituitary function and dedicated pituitary gland MRI scans. We determined the frequency of various pituitary imaging abnormalities in ECD and assessed its relationships with age, sex, body mass index (BMI), BRAF V600E status, high sensitivity C-reactive protein (hsCRP), erythrocyte sedimentation rate (ESR), pituitary hormone deficits and number, diabetes insipidus (DI), and panhypopituitarism. RESULTS: Our cohort included 61 subjects with ECD [age (SD): 54.3 (10.9) y, 46 males/15 females]. API was present in 47.5% (29/61) of ECD subjects. Loss of the posterior pituitary bright spot (36.1%) followed by thickened pituitary stalk (24.6%), abnormal enhancement (18.0%), and pituitary atrophy (14.8%) were the most common abnormalities. DI and panhypopituitarism were more frequent in subjects with API without differences in age, sex distribution, hsCRP, ESR, and BRAF V600E status compared to normal pituitary imaging. CONCLUSIONS: We noted a high burden of API and endocrinopathies in ECD. API was highly associated with the presence of panhypopituitarism and DI. Therefore, a thorough assessment of hypothalamic-pituitary integrity should be considered in subjects with ECD.

A change in pituitary magnetic resonance imaging protocol detects ACTH-secreting tumours in patients with previously negative results.

OBJECTIVE: While detection of pituitary tumours with magnetic resonance imaging (MRI) may reduce diagnostic costs and improve surgical outcomes for patients with Cushing's disease, the optimal T1-weighted spin-echo (SE) MRI protocol remains unknown. We hypothesized that specific MR scanning parameters influence detection of corticotropinomas. DESIGN AND PATIENTS: Between December 1997 and November 2004, 21 of 84 consecutive patients with Cushing's disease had a falsely negative initial pituitary MRI study and a lesion identified subsequently at the National Institutes of Health Clinical Center. This study retrospectively reviewed and compared technical parameters used for the two pituitary T1-weighted SE MRIs in 18 patients with available scans. MEASUREMENTS: Repetition time (TR)/echo times (TE), field of view (FOV), matrix size, magnetic field strength, slice thickness, use of gadolinium contrast and the time interval between studies were recorded. RESULTS: The MRI interscan interval was 5.4 +/- 1.1 months. All scans used gadolinium, matrix sizes were similar and nearly all had 3-mm thick slices. Parameters that differed between the NIH- and externally performed scans were: TR (400 ms vs. 492 +/- 19 ms, P = 0.0002); TE (10.3 +/- 0.5 vs. 17.2 +/- 1.2 ms, P = 0.0003); FOV (12 x 12 cm vs.17 +/- 0.6 x 18 +/- 0.7 cm, P < 0.0001). Immunohistochemistry of tumours resected at transsphenoidal surgery confirmed all to be corticotropinomas. CONCLUSIONS: Not all 'T1-weighted SE' scans are equally accurate. MRI technique, particularly FOV and TR/TE value, influences results. We recommend that endocrinologists consider pituitary MRI parameters when interpreting the results.

Reversible posterior encephalopathy syndrome associated with micronodular adrenocortical disease and Cushing syndrome.

We report a 6-year-old girl with ACTH-independent Cushing syndrome secondary to bilateral adrenal hyperplasia; she presented with hypertension and seizures, and magnetic resonance imaging shows changes consistent with posterior reversible encephalopathy syndrome.

An unusual presentation of pediatric Cushing disease: recurrent corticotropinoma of the posterior pituitary lobe.

Cushing's syndrome (CS) is rare in childhood and adolescence and its diagnosis and work up are often challenging. We report the case of a 15-year-old girl with a recurrent corticotrophin (ACTH)-secreting adenoma, located in the posterior lobe of the pituitary gland. At the age of 11, she presented with classic CS symptoms; biochemical investigation was compatible with ACTH-dependent Cushing disease, although pituitary gland imaging did not show any tumor. Following transsphenoidal surgery (TSS), histopathological analysis identified an ACTH-secreting pituitary microadenoma arising from the posterior gland. The patient went into remission but 4 years later she presented with recurrent CS; this time, pituitary gland imaging showed a microadenoma located in the posterior lobe, which was resected after TSS. Posterior lobe pituitary adenomas are very rare and often hard to diagnose and treat; this is the first case of such a tumor causing recurrent Cushing's disease in a child.

Clinical findings in families with chordoma with and without T gene duplications and in patients with sporadic chordoma reported to the Surveillance, Epidemiology, and End Results program.

OBJECTIVE: To gain insight into the role of germline genetics in the development of chordoma, the authors evaluated data from 2 sets of patients with familial chordoma, those with and without a germline duplication of the T gene (T-dup+ vs T-dup-), which was previously identified as a susceptibility mechanism in some families. The authors then compared the patients with familial tumors to patients with sporadic chordoma in the US general population reported to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program through 2015. METHODS: Evaluation of family members included review of personal and family medical history, physical and neurological examination, and pre- and postcontrast MRI of the skull base and spine. Sixteen patients from 6 white families with chordoma had a chordoma diagnosis at family referral. Screening MR images of 35 relatives revealed clival lesions in 6, 4 of which were excised and confirmed to be chordoma. Thus, data were available for 20 patients with histologically confirmed familial chordoma. There were 1759 patients with histologically confirmed chordoma in SEER whose race was known. RESULTS: The median age at chordoma diagnosis differed across the groups: it was lowest in T-dup+ familial patients (26.8 years, range 5.3-68.4 years); intermediate in T-dup- patients (46.2 years, range 11.8-60.1 years); and highest in SEER patients (57 years, range 0-98 years). There was a marked preponderance of skull base tumors in patients with familial chordoma (93% in T-dup+ and 83% in T-dup-) versus 38% in the SEER program (37% in white, 53% in black, and 48.5% in Asian/Pacific Islander/American Indian/Alaska Native patients). Furthermore, 29% of white and 16%-17% of nonwhite SEER patients had mobile-spine chordoma, versus no patients in the familial group. Several T-dup+ familial chordoma patients had putative second/multiple primary chordomas. CONCLUSIONS: The occurrence of young age at diagnosis, skull base presentation, or multiple primary chordomas should encourage careful review of family history for patients diagnosed with chordoma as well as screening of at-risk family members by MRI for early detection of chordoma. Furthermore, given genetic predisposition in some patients with familial chordoma, identification of a specific mutation in a family will permit surveillance to be limited to mutation carriers-and consideration should be given for imaging the entire neuraxis in any chordoma patient presenting at an early age or with a blood relative with chordoma. Finally, future studies should explore racial differences in age at diagnosis and presenting site in chordoma.