Genotype-phenotype correlation and treatment effects in young patients with GNAO1-associated disorders.

BACKGROUND: Patients carrying pathogenic variants in GNAO1 often present with early-onset central hypotonia and global developmental delay, with or without epilepsy. As the disorder progresses, a complex hypertonic and hyperkinetic movement disorder is a common phenotype. A genotype-phenotype correlation has not yet been described and there are no evidence-based therapeutic recommendations. METHODS: To improve understanding of the clinical course and pathophysiology of this ultra-rare disorder, we built up a registry for GNAO1 patients in Germany. In this retrospective, multicentre cohort study, we collected detailed clinical data, treatment effects and genetic data for 25 affected patients. RESULTS: The main clinical features were symptom onset within the first months of life, with central hypotonia or seizures. Within the first year of life, nearly all patients developed a movement disorder comprising dystonia (84%) and choreoathetosis (52%). Twelve (48%) patients suffered life-threatening hyperkinetic crises. Fifteen (60%) patients had epilepsy with poor treatment response. Two patients showed an atypical phenotype and seven novel pathogenic variants in GNAO1 were identified. Nine (38%) patients were treated with bilateral deep brain stimulation of the globus pallidus internus. Deep brain stimulation reduced hyperkinetic symptoms and prevented further hyperkinetic crises. The in silico prediction programmes did not predict the phenotype by the genotype. CONCLUSION: The broad clinical spectrum and genetic findings expand the phenotypical spectrum of GNAO1-associated disorder and therefore disprove the assumption that there are only two main phenotypes. No specific overall genotype-phenotype correlation was identified. We highlight deep brain stimulation as a useful treatment option in this disorder.

Scoring Algorithm-Based Genomic Testing in Dystonia: A Prospective Validation Study.

BACKGROUND: Despite the established value of genomic testing strategies, practice guidelines for their use do not exist in many indications. OBJECTIVES: We sought to validate a recently introduced scoring algorithm for dystonia, predicting the diagnostic utility of whole-exome sequencing (WES) based on individual phenotypic aspects (age-at-onset, body distribution, presenting comorbidity). METHODS: We prospectively enrolled a set of 209 dystonia-affected families and obtained summary scores (0-5 points) according to the algorithm. Singleton (N = 146), duo (N = 11), and trio (N = 52) WES data were generated to identify genetic diagnoses. RESULTS: Diagnostic yield was highest (51%) among individuals with a summary score of 5, corresponding to a manifestation of early-onset segmental or generalized dystonia with coexisting non-movement disorder-related neurological symptoms. Sensitivity and specificity at the previously suggested threshold for implementation of WES (3 points) was 96% and 52%, with area under the curve of 0.81. CONCLUSIONS: The algorithm is a useful predictive tool and could be integrated into dystonia routine diagnostic protocols. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Spasmodic Abdominal Pain and Other Gastrointestinal Symptoms in Pontocerebellar Hypoplasia Type 2.

INTRODUCTION: Pontocerebellar hypoplasia type 2 (PCH2) is a rare neurodevelopmental disease with a high disease burden. Besides neurological symptoms, somatic symptoms, such as gastroesophageal reflux (GERD) and failure to thrive, are major contributors to this burden. METHODS: We report three patients with genetically confirmed PCH2A and significant gastrointestinal (GI) symptoms. RESULTS: Apart from impaired swallowing and GERD, which are frequently reported in patients with PCH2, all three patients suffered from episodes of spasmodic abdominal pain and restlessness. In one severely affected patient, lack of intestinal alkaline phosphatase (IAP) is demonstrated. CONCLUSION: GI symptoms are common in PCH2. We draw attention to episodes of spasmodic abdominal pain seriously, aggravating the condition of the patients, especially their movement disorder, and discuss the role of IAP.

Cerebral Autoregulation and Neurovascular Coupling after Craniospinal Irradiation in Long-Term Survivors of Malignant Pediatric Brain Tumors of the Posterior Fossa.

INTRODUCTION: Long-term survivors of craniospinal irradiation have an increased risk for stroke which increases with radiation dose and follow-up time. Radiotherapy induces structural changes of the cerebral vasculature, affecting both, large, and small vessels. It is unknown how these structural changes affect functional mechanisms of cerebral blood flow regulation such as cerebral autoregulation and neurovascular coupling. METHODS: Using the transcranial Doppler, we compared dynamic cerebral autoregulation and neurovascular coupling of 12 patients after long-term survival of craniospinal irradiation due to a malignant pediatric brain tumor of the posterior fossa and 12 age- and sex-matched healthy patients. Mean arterial blood pressure and cerebral blood flow velocities in the middle and posterior cerebral artery were recorded at rest during normal breathing to assess cerebral autoregulation (transfer function parameters phase and gain, as well as the correlation coefficient indices Mx, Sx, and Dx), and during 10 cycles of a visual task to assess neurovascular coupling (parameters time delay, natural frequency, gain, attenuation, and rate time). RESULTS: Parameters of cerebral autoregulation showed a consistent trend toward reduced cerebral autoregulation in patients that did not reach statistical significance. Neurovascular coupling was not altered after craniospinal irradiation. CONCLUSION: In this pilot study, we demonstrated a trend toward reduced cerebral autoregulation, and no alteration of neurovascular coupling after irradiation in long-term survivors of malignant pediatric brain tumors of the posterior fossa.

Cystic Encephalomalacia following Vasculopathy and Vasospasm of Proximal Intracranial Arteries Due to Pneumococcal Meningitis in a Infant.

Despite the availability of modern antibiotics, pneumococcal meningitis in both children and adults remains a severe disease-one known to frequently cause grave complications and residual disability. Although the appearance of arterial vasospasms in bacterial meningitis systematically has been investigated and reported on for adult patients, such research is lacking when it comes to infants. We report on a 4-week-old infant who, 6 days after onset of pneumococcal meningitis, suffered severe neurological deterioration with treatment-resistant seizures and coma. Generalized cortical and subcortical edema developed in conjunction with diminished cerebral blood flow, as depicted in magnetic resonance angiography and serial Doppler-sonographic examinations. The ischemia resulted in extensive cystic encephalomalacia. We propose that the degree of variation in cerebral blood flow in the acute phase was the result of an extensive arterial vasculopathy involving vasospasms. Awareness of this complication and prospective serial Doppler-sonographic examinations may improve our understanding of the connection between brain edema and vasculopathy. At present, however, no effective treatment appears available.

Neurovascular coupling in pregnancy and the risk of preeclampsia.

BACKGROUND AND PURPOSE: This study investigated whether a short testing of neurovascular coupling during midterm pregnancy could identify women at risk for subsequent preeclampsia. METHODS: Transcranial Doppler sonography of the posterior cerebral artery during a brief visual stimulation was analyzed in 68 women at midterm pregnancy, the primary clinical end point was preeclampsia. RESULTS: Women with bilateral notching of the uterine arteries showed an exaggerated visually evoked blood flow increase and longer time-to-peak. Neurovascular coupling was not significantly associated with the occurrence of preeclampsia. CONCLUSIONS: Neurovascular coupling was altered in women with impaired uteroplacentar vasoregulation but not a significant predictor of preeclampsia.

Impaired induction of long-term potentiation-like plasticity in patients with high-functioning autism and Asperger syndrome.

AIM: We aimed to investigate the induction of long-term potentiation (LTP)-like plasticity by paired associative stimulation (PAS) in patients with high-functioning autism and Asperger syndrome (HFA/AS). METHOD: PAS with an interstimulus interval between electrical and transcranial magnetic stimulation of 25 ms (PAS(25)) was performed in patients with HFA/AS (n=9; eight males, one female; mean age 17 y 11 mo, SD 4 y 5 mo) and in typically developing age-matched volunteers (n=9; five males, four females; mean age 22 y 4 mo, SD 5 y 2 mo). The amplitude of motor-evoked potentials was measured before PAS(25), immediately after stimulation, and 30 minutes and 60 minutes later. A PAS protocol adapted to individual N20 latency (PAS(N20+2)) was performed in six additional patients with HFA/AS. Short-interval intracortical inhibition was measured using paired-pulse stimulation. RESULTS: In contrast to the typically developing participants, the patients with HFA/AS did not show a significant increase in motor-evoked potentials after PAS(25). This finding could also be demonstrated after adaptation for N20 latency. Short-interval intracortical inhibition of patients with HFA/AS was normal compared with the comparison group and did not correlate with PAS effect. INTERPRETATION: Our results show a significant impairment of LTP-like plasticity induced by PAS in individuals with HFA/AS compared with typically developing participants. This finding is in accordance with results from animal studies as well as human studies. Impaired LTP-like plasticity in patients with HFA/AS points towards reduced excitatory synaptic connectivity and deficits in sensory-motor integration in these patients.

Efficacy, Tolerability, and Retention of Antiseizure Medications in PRRT2-Associated Infantile Epilepsy.

Background and Objectives: Pathogenic variants in PRRT2, encoding for the proline-rich transmembrane protein 2, were identified as the main cause of self-limiting sporadic and familial infantile epilepsy. Reported data on treatment response to antiseizure medications (ASMs) in defined monogenic epilepsies are limited. The aim of this study was to evaluate the treatment response of ASMs in children with monogenic PRRT2-associated infantile epilepsy. Methods: A multicenter, retrospective, cross-sectional cohort study was conducted according to the Strengthening the Reporting of Observational Studies in Epidemiology criteria. Inclusion criteria were occurrence of infantile seizures and genetic diagnosis of likely pathogenic/pathogenic PRRT2 variants. Results: Treatment response data from 52 individuals with PRRT2-associated infantile epilepsy with a total of 79 treatments (defined as each use of an ASM in an individual) were analyzed. Ninety-six percent (50/52) of all individuals received ASMs. Levetiracetam (LEV), oxcarbazepine (OXC), valproate (VPA), and phenobarbital (PB) were most frequently administered. Sodium channel blockers were used in 22 individuals and resulted in seizure freedom in all but 1 child, who showed a reduction of more than 50% in seizure frequency. By contrast, treatment with LEV was associated with worsening of seizure activity in 2/25 (8%) treatments and no effect in 10/25 (40%) of treatments. LEV was rated significantly less effective also compared with VPA and PB. The retention rate for LEV was significantly lower compared with all aforementioned ASMs. No severe adverse events were reported, and no discontinuation of treatment was reported because of side effects. Discussion: In conclusion, a favorable effect of most ASMs, especially sodium channel blockers such as carbamezepine and OXC, was observed, whereas the efficacy and the retention rate of LEV was lower in PRRT2-associated childhood epilepsy. Tolerability in these young children was good for all ASMs reported in the cohort. Classification of Evidence: This study provides Class IV evidence that in individuals with PRRT2-associated infantile epilepsy, sodium channel blockers are associated with reduced seizure frequency but levetiracetam is not.

BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas.

The molecular pathogenesis of pediatric astrocytomas is still poorly understood. To further understand the genetic abnormalities associated with these tumors, we performed a genome-wide analysis of DNA copy number aberrations in pediatric low-grade astrocytomas by using array-based comparative genomic hybridization. Duplication of the BRAF protooncogene was the most frequent genomic aberration, and tumors with BRAF duplication showed significantly increased mRNA levels of BRAF and a downstream target, CCND1, as compared with tumors without duplication. Furthermore, denaturing HPLC showed that activating BRAF mutations were detected in some of the tumors without BRAF duplication. Similarly, a marked proportion of low-grade astrocytomas from adult patients also had BRAF duplication. Both the stable silencing of BRAF through shRNA lentiviral transduction and pharmacological inhibition of MEK1/2, the immediate downstream phosphorylation target of BRAF, blocked the proliferation and arrested the growth of cultured tumor cells derived from low-grade gliomas. Our findings implicate aberrant activation of the MAPK pathway due to gene duplication or mutation of BRAF as a molecular mechanism of pathogenesis in low-grade astrocytomas and suggest inhibition of the MAPK pathway as a potential treatment.

Oncogenic FAM131B-BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma.

Activation of the MAPK signaling pathway has been shown to be a unifying molecular feature in pilocytic astrocytoma (PA). Genetically, tandem duplications at chromosome 7q34 resulting in KIAA1549-BRAF fusion genes constitute the most common mechanism identified to date. To elucidate alternative mechanisms of aberrant MAPK activation in PA, we screened 125 primary tumors for RAF fusion genes and mutations in KRAS, NRAS, HRAS, PTPN11, BRAF and RAF1. Using microarray-based comparative genomic hybridization (aCGH), we identified in three cases an interstitial deletion of ~2.5 Mb as a novel recurrent mechanism forming BRAF gene fusions with FAM131B, a currently uncharacterized gene on chromosome 7q34. This deletion removes the BRAF N-terminal inhibitory domains, giving a constitutively active BRAF kinase. Functional characterization of the novel FAM131B-BRAF fusion demonstrated constitutive MEK phosphorylation potential and transforming activity in vitro. In addition, our study confirmed previously reported BRAF and RAF1 fusion variants in 72% (90/125) of PA. Mutations in BRAF (8/125), KRAS (2/125) and NF1 (4/125) and the rare RAF1 gene fusions (2/125) were mutually exclusive with BRAF rearrangements, with the exception of two cases in our series that concomitantly harbored more than one hit in the MAPK pathway. In summary, our findings further underline the fundamental role of RAF kinase fusion products as a tumor-specific marker and an ideally suited drug target for PA.

Dystonia as a prominent presenting feature in developmental and epileptic encephalopathies: A case series.

INTRODUCTION: Although there has been increasing recognition of the occurrence of non-epileptic involuntary movements in developmental and epileptic encephalopathies (DEEs), the spectrum of dystonic presentations associated with these conditions remains poorly described. We sought to expand the catalogue of dystonia-predominant phenotypes in monogenic DEEs, building on the recently introduced concept of an epilepsy-movement disorder spectrum. METHODS: Cases were identified from a whole-exome-sequenced cohort of 45 pediatric index patients with complex dystonia (67% sequenced as parent-child trios). Review of molecular findings in DEE-associated genes was performed. For five individuals with identified DEE-causing variants, detailed information about presenting phenotypic features and the natural history of disease was obtained. RESULTS: De-novo pathogenic and likely pathogenic missense variants in GABRA1, GABBR2, GNAO1, and FOXG1 gave rise to infantile-onset persistent and paroxysmal dystonic manifestations, beginning in the limb or truncal musculature and progressing gradually to a generalized state. Coexisting, less prominent movement-disorder symptoms were observed and included myoclonic, ballistic, and stereotypic abnormal movements as well as choreoathetosis. Dystonia dominated over epileptic neurodevelopmental comorbidities in all four subjects and represented the primary indication for molecular genetic analysis. We also report the unusual case of an adult female patient with dystonia, tremor, and mild learning disability who was found to harbor a pathogenic frameshift variant in MECP2. CONCLUSIONS: Dystonia can be a leading clinical manifestation in different DEEs. A monogenic basis of disease should be considered on the association of dystonia and developmental delay-epilepsy presentations, justifying a molecular screening for variants in DEE-associated genes.

Stable high frequency background EEG activity distinguishes epileptic from healthy brain regions.

High-frequency oscillations are markers of epileptic tissue. Recently, different patterns of EEG background activity were described from which high-frequency oscillations occur: high-frequency oscillations with continuously oscillating background were found to be primarily physiological, those from quiet background were linked to epileptic tissue. It is unclear, whether these interactions remain stable over several days and during different sleep-wake stages. High-frequency oscillation patterns (oscillatory vs. quiet background) were analysed in 23 patients implanted with depth and subdural grid electrodes. Pattern scoring was performed on every channel in 10 s intervals in three separate day- and night-time EEG segments. An entropy value, measuring variability of patterns per channel, was calculated. A low entropy value indicated a stable occurrence of the same pattern in one channel, whereas a high value indicated pattern instability. Differences in pattern distribution and entropy were analysed for 143 280 10 s intervals with allocated patterns from inside and outside the seizure onset zone, different electrode types and brain regions. We found a strong association between high-frequency oscillations out of quiet background activity, and channels of the seizure onset zone (35.2% inside versus 9.7% outside the seizure onset zone, P < 0.001), no association was found for high-frequency oscillations from continuous oscillatory background (P = 0.563). The type of background activity remained stable over the same brain region over several days and was independent of sleep stage and recording technique. Stability of background activity was significantly higher in channels of the seizure onset zone (entropy mean value 0.56 ± 0.39 versus 0.64 ± 0.41; P < 0.001). This was especially true for the presumed epileptic high-frequency oscillations out of quiet background (0.57 ± 0.39 inside versus 0.72 ± 0.37 outside the seizure onset zone; P < 0.001). In contrast, presumed physiological high-frequency oscillations from continuous oscillatory backgrounds were significantly more stable outside the seizure onset zone (0.72 ± 0.45 versus 0.48 ± 0.53; P < 0.001). The overall low entropy values suggest that interactions between high-frequency oscillations and background activity are a stable phenomenon specific to the function of brain regions. High-frequency oscillations occurring from a quiet background are strongly linked to the seizure onset zone whereas high-frequency oscillations from an oscillatory background are not. Pattern stability suggests distinct underlying mechanisms. Analysing short time segments of high-frequency oscillations and background activity could help distinguishing epileptic from physiologically active brain regions.

The Phenotypic Spectrum of PRRT2-Associated Paroxysmal Neurologic Disorders in Childhood.

Pathogenic variants in PRRT2, encoding the proline-rich transmembrane protein 2, have been associated with an evolving spectrum of paroxysmal neurologic disorders. Based on a cohort of children with PRRT2-related infantile epilepsy, this study aimed at delineating the broad clinical spectrum of PRRT2-associated phenotypes in these children and their relatives. Only a few recent larger cohort studies are on record and findings from single reports were not confirmed so far. We collected detailed genetic and phenotypic data of 40 previously unreported patients from 36 families. All patients had benign infantile epilepsy and harbored pathogenic variants in PRRT2 (core cohort). Clinical data of 62 family members were included, comprising a cohort of 102 individuals (extended cohort) with PRRT2-associated neurological disease. Additional phenotypes in the cohort of patients with benign sporadic and familial infantile epilepsy consist of movement disorders with paroxysmal kinesigenic dyskinesia in six patients, infantile-onset movement disorders in 2 of 40 individuals, and episodic ataxia after mild head trauma in one girl with bi-allelic variants in PRRT2. The same girl displayed a focal cortical dysplasia upon brain imaging. Familial hemiplegic migraine and migraine with aura were reported in nine families. A single individual developed epilepsy with continuous spikes and waves during sleep. In addition to known variants, we report the novel variant c.843G>T, p.(Trp281Cys) that co-segregated with benign infantile epilepsy and migraine in one family. Our study highlights the variability of clinical presentations of patients harboring pathogenic PRRT2 variants and expands the associated phenotypic spectrum.

Preeclampsia postpartum: Impairment of cerebral autoregulation and reversible cerebral hyperperfusion.

OBJECTIVES: Preeclampsia is a pregnancy-related hypertensive disorder with endothelial dysfunction. Impaired cerebral autoregulation may lead to symptomatic cerebral hyperperfusion, which sometimes manifests not until after delivery. This study investigated, whether cerebral autoregulation was altered after delivery in healthy and preeclamptic women, and whether this associated with cerebral hyperperfusion. STUDY DESIGN: In a prospective study, 35 preeclamptic and 35 healthy women were examined with transcranial Doppler within 10 days postpartum and 6 months later. Continuous arterial blood pressure and cerebral blood flow velocities (CBFV) in the middle (MCA) and posterior cerebral arteries (PCA) were recorded at rest. MAIN OUTCOME MEASURES: Dynamic cerebral autoregulation was assessed upon regular breathing at 0.1 Hz via transfer function phase and gain between arterial blood pressure and CBFV oscillations. RESULTS: In preeclamptic women, phase was reduced after delivery in both, MCA and PCA. During the postpartum period, CBFV of the MCA, but not PCA, correlated with higher arterial blood pressure and poorer dynamic cerebral autoregulation. In healthy women with only moderately altered cerebral autoregulation, CBFV remained in the normal range. At both measurements, arterial blood pressure was higher in preeclamptic compared to healthy women. CONCLUSIONS: Women with preeclampsia had poorer cerebral autoregulation and an increased risk of transient cerebral hyperperfusion after delivery.

No long-term impairment of cerebral autoregulation after preeclampsia.

INTRODUCTION: Preeclampsia is a pregnancy-related hypertensive disorder with strongly impaired cerebral autoregulation in the acute stage. A history of preeclampsia is an independent cardiovascular and cerebrovascular risk factor. It is unclear whether impaired cerebral autoregulation persists after preeclampsia and thus contributes to the known increased cerebrovascular morbidity. METHODS: Using transcranial Doppler, we compared cerebral hemodynamics and dynamic cerebral autoregulation of 25 women with a history of severe preeclampsia and 25 healthy mothers, on average 2-3 years postpartum. Mean arterial blood pressure (MAP) and cerebral blood flow velocities (CBFV) in the middle and posterior cerebral artery were recorded at rest, dynamic cerebral autoregulation was assessed via transfer function phase and gain between oscillations of CBFV and MAP during regular breathing at 0.1 Hz. RESULTS: MAP and body mass index were higher in former preeclamptic women compared with healthy mothers (p-value <0.001 and 0.006, respectively). CBFV in the middle cerebral artery was slightly increased in former preeclamptic women compared with healthy mothers (p-value 0.004), intima-media thickness (IMT) of the common carotid artery was higher by trend (p-value 0.065). Dynamic cerebral autoregulation was not impaired in women with a history of preeclampsia, phase even tended to be higher than in healthy mothers. CONCLUSION: Dynamic cerebral autoregulation is not persistently impaired in women after severe preeclampsia. Long-term cerebrovascular changes rather result from a higher incidence of cerebrovascular risk factors in women with a history of preeclampsia.

Recurrent extracranial carotid artery vasospasms: report of 2 cases.

BACKGROUND AND PURPOSE: Spontaneous vasospasms of the submandibular internal carotid arteries are rarely observed. They are a highly dynamic process, recur frequently, and can be detected by serial ultrasound examinations. SUMMARY OF CASES: We present 2 cases of recurrent extracranial vasospasms of the internal carotid artery as a cause of stroke. In both cases, arterial dissection was initially suspected, but no intramural hematoma was detected on magnetic resonance imaging. Duplex sonography demonstrated recurrent high-grade stenoses of both internal carotid arteries that resolved spontaneously within hours to days. The vasospasms were treated with calcium antagonists and in 1 patient with oral corticoids. CONCLUSIONS: Extracranial vasospasms as a cause of stroke might be underestimated. Vasospasms of the internal carotid arteries should be considered in patients with recurring ischemic events in the absence of any other explanation. Antiphlogistic treatment in combination with calcium antagonists might be effective to reduce the frequency of vasospasms.

Dynamic cerebral autoregulation in pregnancy and the risk of preeclampsia.

Preeclampsia may affect severely the cerebral circulation leading to impairment of cerebral autoregulation, edema, and ischemia. It is not known whether impaired autoregulation occurs before the clinical onset of preeclampsia, and whether this can predict the occurrence of preeclampsia. Seventy-two women at 25 to 28 weeks of gestation were studied. Control values were derived from 26 nonpregnant women. Dynamic properties of cerebral autoregulation (DCA) were measured in the middle and posterior cerebral artery using transcranial Doppler and transfer function analysis (phase and gain) of respiratory-induced 0.1 Hz hemodynamic oscillations. Uterine artery ultrasound was performed to search for a notch sign as an early marker of general endothelial dysfunction. All women were followed up until 6 weeks after delivery for the occurrence of preeclampsia. The autoregulation parameter gain did not differ between pregnant and nonpregnant women. Phase was slightly but significantly higher in pregnant women, indicating better DCA. Women with a notch sign did not show altered DCA. A history of preeclampsia during a previous pregnancy was associated with lower phase in middle cerebral artery and posterior cerebral artery (P<0.05 each). During follow-up, 9 women developed preeclampsia. None of the DCA parameters were associated with the occurrence of preeclampsia. In conclusion, DCA is well preserved during late midterm pregnancy, even in women with disturbed uterine blood flow. Yet, pregnant women with preeclampsia in a previous pregnancy seem to have poorer DCA. Although limited in statistical power, this study does not support DCA as a strong early risk marker of preeclampsia.

Occurrence of a germinoma 22 years after resection of a mature cerebral teratoma.

We present the rare case of a 31-year-old man who developed a germinoma 22 years after resection of a mature teratoma of the pineal region. The initial stereotactic biopsy showed a granulomatous inflammation, but no malignant cells. The correct diagnosis could only be confirmed in a second cerebral biopsy, allowing for proper treatment with radiation therapy. The need to consider metachronous germinoma in this setting is discussed.