Primary oral manifestation of Langerhans cell histiocytosis refractory to conventional therapy but susceptible to BRAF-specific treatment: a case report and review of the literature.

Langerhans cell histiocytosis (LCH) is a diagnostic and therapeutic challenge. We report on a rare case of its primary oral manifestation that was treated successfully with the BRAF-specific agent, vemurafenib, after insufficient standard LCH treatment. This case underlines the importance of proper diagnosis and the evaluation of targeted therapy as a valuable tool in LCH treatment. Furthermore, the close collaboration of surgeons, oncologists, and dentists is mandatory to ensure adequate treatment, restore the stomatognathic system in debilitating post-treatment situations, improve quality of life, and ensure effective disease control in infants and young patients.

Lymphatic malformation with acquired Horner syndrome in an infant.

An infant presented with right upper eyelid ptosis and was subsequently diagnosed with acquired Horner syndrome. Further evaluation revealed a right-sided cervicothoracic lymphatic malformation. At 13 weeks of age, the child underwent percutaneous intracystic sclerotherapy with a mixture of sodium tetradecyl sulphate and ethanol. Twenty-one weeks after initial treatment, ophthalmic examination showed complete resolution of the blepharoptosis and pupillary miosis. Percutaneous sclerotherapy not only effectively treated the space-occupying lymphatic malformation but also reversed the Horner syndrome that was presumably induced by neural tension (more likely) or compression.

Potential Risks to Stable Long-term Outcome of Allogeneic Hematopoietic Stem Cell Transplantation for Children With Cerebral X-linked Adrenoleukodystrophy.

Importance: Allogeneic hematopoietic stem cell transplantation is the standard intervention for childhood cerebral X-linked adrenoleukodystrophy. However, the pretransplant conditions, demyelination patterns, complications, and neurological outcomes of this therapy are not well characterized. Objectives: To identify the risks to stable neurocognitive survival after hematopoietic stem cell transplantation and to describe subgroups of patients with distinct clinical long-term outcomes. Design, Setting, and Participants: This case series analyzed the treatment and outcome of a cohort of 36 boys who underwent hematopoietic stem cell transplantation at Charité Universitätsmedizin Berlin, Germany, between January 1, 1997, and October 31, 2014. Case analysis was performed from January 1, 2016, through November 30, 2017. During this retrospective review, the adrenoleukodystrophy-disability rating score and the neurological function score were used. Demyelinating lesions in the brain were quantified by the Loes score. Main Outcomes and Measures: Overall survival, survival without major functional disabilities, and event-free survival were analyzed. Patients' clinical symptoms, demyelination patterns, and stem cell source were stratified. Results: Of the 36 boys who underwent hematopoietic stem cell transplantation, the median (range) age was 7.2 (4.2-15.4) years; 18 were presymptomatic and 18 were symptomatic. Twenty-seven patients (75%) were alive at a median (interquartile range [IQR]) follow-up of 108 (40-157) months. Sixteen of 18 presymptomatic patients (89%) survived, and 13 (72%) had an event-free survival with a median (IQR) survival time of 49 (37-115) months. Among the symptomatic patients, 11 of 18 (61%) survived, but only 1 was an event-free survival (6%) (median [IQR] time, 9 [3-22] months). Of the 9 patients who received a bone marrow transplant from a matched family donor, all survived. Among the 36 patients, 6 disease-related deaths (17%) and 3 transplant-related deaths (8%) occurred. Deaths from disease progression (n = 6) occurred only in patients with demyelination patterns other than parieto-occipital. In total, 18 patients (50%) displayed limited parieto-occipital (Loes score <9) or frontal (Loes score <4) demyelination before transplant (favorable). None of these patients died of progressive disease or developed major functional disabilities, 15 of them were characterized by stable neuroimaging after the transplant, and event-free survival was 77% (95% CI, 60%-100%). In contrast, the other 18 patients with more extended parieto-occipital demyelination (n = 6), frontal involvement (n = 4), or other demyelination patterns (n = 8) progressed (unfavorable): 13 patients developed epilepsy and 10 developed major functional disabilities, and their event-free survival was 0%. This newly defined neuroimaging assessment correlated best with neurocognitive deterioration after transplant (hazard ratio, 16.7; 95% CI, 4.7-59.6). Conclusions and Relevance: All patients with favorable neuroimaging who received matched bone marrow remained stable after transplant, while some of the other patients developed major functional disabilities. Newborn screening for the disease and regular neuroimaging are recommended, and patients who lack a matched bone marrow donor may need to find new therapeutic options.

Lymphatic malformation with acquired Horner syndrome in an infant.

An infantpresented with right upper eyelid ptosis and was subsequently diagnosed with acquired Horner syndrome. Further evaluation revealed a right-sided cervicothoracic lymphatic malformation. At 13 weeks of age, the child underwent percutaneous intracystic sclerotherapy with a mixture of sodium tetradecyl sulphate and ethanol. Twenty-one weeks after initial treatment, ophthalmic examination showed complete resolution of the blepharoptosis and pupillary miosis. Percutaneous sclerotherapy not only effectively treated the space-occupying lymphatic malformation but also reversed the Horner syndrome that was presumably induced by neural tension (more likely) or compression.

An overlapping phenotype of Osteogenesis imperfecta and Ehlers-Danlos syndrome due to a heterozygous mutation in COL1A1 and biallelic missense variants in TNXB identified by whole exome sequencing.

Osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS) are variable genetic disorders that overlap in different ways [Cole 1993; Grahame 1999]. Here, we describe a boy presenting with severe muscular hypotonia, multiple fractures, and joint hyperflexibility, features that are compatible with mild OI and hypermobility type EDS, respectively. By whole exome sequencing, we identified both a COL1A1 mutation (c.4006-1G > A) inherited from the patient's mildly affected mother and biallelic missense variants in TNXB (p.Val1213Ile, p.Gly2592Ser). Analysis of cDNA showed that the COL1A1 splice site mutation led to intron retention causing a frameshift (p.Phe1336Valfs*72). Type 1 collagen secretion by the patient's skin fibroblasts was reduced. Immunostaining of a muscle biopsy obtained from the patient revealed a clear reduction of tenascin-X in the extracellular matrix compared to a healthy control. These findings imply that the combination of the COL1A1 mutation with the TNXB variants might cause the patient's unique phenotype.

Stented endoscopic third ventriculostomy­indications and results.

OBJECTIVE: In patients with risk of reclosure of a performed opening in the floor of the third ventricle, a stented endoscopic third ventriculostomy (sETV) was performed to maintain continuous cerebrospinal fluid (CSF) diversion in patients with occlusive hydrocephalus. A retrospective analysis of a patient series is presented. METHODS: A cohort of nine patients (median age 12 years and 9 months; range 1 month to 25 years and 9 months) was studied retrospectively. Etiology of hydrocephalus was aqueduct stenosis due to tumorous occlusion and tumorous infiltration of the third ventricular floor in seven of nine patients. For two patients with simple aqueductal stenosis, a sETV was performed because of young age of 1 month in one and because of previous ETV failure in the other. RESULTS: Correct placement of the implanted stent was demonstrated in all treated patients. There was no operative morbidity after the performed sETV. Resolution or improvement of symptoms was achieved in eight of nine patients (88.9%), and failure to control clinical symptoms was observed in one patient (11.1%), who needed subsequent shunt insertion. Decreased ventricular dimensions were seen after the sETV procedure. The median fronto-occipital horn ratio (FOHR) decreased from 0.46 (range 0.43-0.58) to 0.45 (range 0.37 to 0.59) after a median of 3 months and to a median of 0.40 (range 0.30 to 0.50) after 17 months. The median fronto-occipital horn width ratio FOHWR decreased from 0.31 (range 0.22 to 0.52) to 0.28 (range 0.14 to 0.52, p = 0.06) after a median of 3 months and to a median of 0.21 (range 0.09 to 0.36, p < 0.05). CONCLUSION: sETV is a feasible and safe alternative procedure which when performed with an appropriate trajectory allows treatment of occlusive hydrocephalus with altered anatomy of the third ventricular floor. sETV has been demonstrated to resolve or improve clinical and radiological signs of disturbed CSF circulation.

Endoscopic and Microsurgical Treatment of Sylvian Fissure Arachnoid Cysts-Clinical and Radiological Outcome.

OBJECTIVE: A Sylvian fissure arachnoid cyst (SAC) is a well-recognized location for an intracranial arachnoid cyst in the pediatric population. For those cysts, which can rupture and be accompanied by a subdural hygroma or hematoma, several treatment modalities have been reported. We report clinical and radiological outcome of fenestration of these cysts by either endoscopy or microsurgery. METHODS: A retrospective review of the database of operative procedures revealed 24 procedures (20 endoscopic and 4 microsurgical procedures) to fenestrate a SAC at university hospitals in Berlin, Germany and Tokyo, Japan. RESULTS: With the applied technique, a reduction of SAC volume of more than 10% was achieved in 83.3% of all patients. The median volume of SACs (n = 24) was significantly reduced from 83.5 mL (range 21-509 mL) preoperatively to 45.5 mL (range 8.4-261 mL; P < 0.01) after 3.5 months and to 29.0 mL (range 0-266 mL; P < 0.01) after 15 months. In children (n = 8) with a ruptured SAC the combined extraaxial volume of a SAC and accompanying hygroma/hematoma was reduced from 166 mL (range 111-291 mL) before surgery to 127 mL (range 87-329 mL) after 2 months and to 77 mL (range 25-140 mL; P < 0.05) after 11 months. Acute clinical symptoms were generally resolved postoperatively; headaches were resolved or improved in 75%. A significant association of resolution or improvement of headaches and volume reduction was demonstrated. CONCLUSIONS: The study demonstrated efficacy in a predominantly endoscopically treated patient cohort with Sylvian fissure arachnoid cysts, as indicated by improvement of clinical symptoms and diminished radiological SAC volume after treatment.

Interstitial 12p deletion involving more than 40 genes in a patient with postnatal microcephaly, psychomotor delay, optic nerve atrophy, and facial dysmorphism.

Interstitial deletions of chromosome 12p are rare, and the phenotype spectrum is therefore still unknown. The thirteen patients reported so far suffer from developmental delay, optic nerve hypoplasia, micropenis, hypoplastic hair and skin, oligodontia, brachydactyly, and arterial hypertension. We report a de novo 12p12.2-p11.22 deletion of 9.2 Mb detected by array CGH analysis in a boy with global developmental delay, muscular hypotonia, postnatal microcephaly, facial dysmorphism including small ears, epicanthus, broad nasal bridge and hypoplastic nostrils. In addition, the patient had optic nerve atrophy, inverted nipples, micropenis, and a hemangioma. The deleted region encompasses more than 40 reference genes. We compare phenotype and deletion extent of our index patient to that of previous reports and thereby contribute to the understanding of interstitial 12p deletion phenotypes. Knowledge of the pattern of this deletion phenotype will help clinicians to diagnose this abnormality in their patients and to counsel the parents accordingly. Further descriptions may be able to contribute to the clarification.

Endoscopic neurosurgery in preterm and term newborn infants--a feasibility report.

OBJECTIVE: Neuroendoscopic procedures became essential in neurosurgical treatment of disturbed cerebrospinal fluid dynamics. While a vast number of papers report on the neuroendoscopic experience for adults and children, no series so far reported on techniques and indications for neonate infants. We present our experience for the feasibility of neuroendoscopic procedures in preterm and term newborn infants. METHODS: All preterm and term infants who underwent an endoscopic neurosurgical intervention prior to the 28th day after the previously estimated date of delivery were identified by retrospective review. Surgical procedures and techniques, complications, and further follow-up data are reported. RESULTS: During the study period, 14 infants (median age at surgery, 36+(2)/7 weeks of gestation) underwent 20 endoscopic procedures. The performed procedures included endoscopic septostomy (n = 3), endoscopic shunt placement for multiloculated hydrocephalus (n = 4), endoscopic transaqueductal stenting for isolated fourth ventricle (n = 3), and endoscopic lavage for ventriculitis (n = 4) or for intraventricular hemorrhage (n = 6). No severe complications were seen, while two patients necessitating unexpected interventions during further follow-up (10 %). CONCLUSIONS: Despite the fragility of preterm and term newborn infants, neuroendoscopic procedures may play an important role in the treatment of disturbed cerebrospinal fluid (CSF) dynamics also in this patient population. The neuroendoscopic approach may be curative in conditions like isolated lateral ventricle, may facilitate simplified and effective CSF diversion in multiloculated hydrocephalus or isolated fourth ventricle, and may be beneficial in the course of ventriculitis and intraventricular hemorrhage. Further studies must verify our experience with a bigger cohort of patients and on a multicenter basis.

First case report of a peripheral T-cell lymphoma, not otherwise specified, of the central nervous system in a child.

We report on the first pediatric patient with a localized primary peripheral T-cell lymphoma, not otherwise specified, of the central nervous system (CNS). The solid lesion that was enhanced in magnetic resonance images of the left precentral region was totally resected. The histopathology revealed a peripheral T-cell lymphoma, not otherwise specified. Staging procedures showed that the lesion was confined to the CNS. Without any further therapy, the patient still remains in complete remission 6 years after diagnosis. Thus, we conclude that a peripheral T-cell lymphoma, not otherwise specified, of the CNS can occur in children. In the case presented here, complete resection sufficed.

Endoscopic treatment of isolated fourth ventricle: clinical and radiological outcome.

BACKGROUND: Treatment of an isolated fourth ventricle should be considered when clinical symptoms or a significant mass effect occur. OBJECTIVE: To report clinical and radiographic outcomes after endoscopic transaqueductal or transcisternal stent placement into the fourth ventricle. METHODS: In 19 patients (age, 34th week of gestation-20 years; median age, 17.5 months), 22 endoscopic procedures were performed. Either an aqueductoplasty or, in cases with a supratentorially extended fourth ventricular component, an interventricular fenestration was performed. In all patients, a stent connected to the cerebrospinal fluid--diverting shunt was placed through the fenestration. Surgical complications and radiological and clinical outcomes are reported. RESULTS: All 19 patients had a mean follow-up of 26.9 ± 18.2 months. No persisting neurological complications were observed; 27.3% of patients experienced complete resolution of presenting symptoms, whereas 68.3% demonstrated partial resolution. Symptoms with short duration (< 4 weeks) resolved completely, whereas long-standing symptoms partially improved. Short-term shunt complications (n = 2; insufficient catheter placement and subdural hygroma) and a need for long-term stent revisions (n = 3; stent retraction and shunt revision for other causes) were observed. The mean fourth ventricular volume was reduced after surgery (44.2 ± 25.8 to 23.1 ± 21.9 mL; P < .01). Pontine diameter increased from 0.9 ± 0.3 to 1.2 ± 0.3 cm (P < .01) after surgery. Both effects were still demonstrated on later radiological follow-up of 24.4 ± 14.2 months (fourth ventricular size, 24.7 ± 28.1 mL; P < .01; pontine diameter, 1.3 ± 0.3 cm; P < .01). CONCLUSION: The clinical and radiological outcomes after endoscopic aqueductoplasty and interventriculostomy in children with an isolated fourth ventricle indicate that this procedure is feasible, effective, and safe.

Suspected chronic myocarditis at cardiac MR: diagnostic accuracy and association with immunohistologically detected inflammation and viral persistence.

PURPOSE: To retrospectively compare the diagnostic accuracy of three cardiac magnetic resonance (MR) imaging approaches for the detection of histologic and immunohistologic criteria (reference standard) proved myocardial inflammation in patients clinically suspected of having chronic myocarditis (CMC). MATERIALS AND METHODS: Cardiac MR imaging was performed in 83 consecutive patients (55 male, 28 female; mean age, 44.8 years +/- 17.7 [standard deviation]) clinically suspected of having CMC, after written informed consent was obtained according to guidelines of the local ethics committee, which approved the study. T2-weighted triple-inversion-recovery imaging to calculate the edema ratio (ER), T1-weighted imaging before and after contrast agent administration to calculate the myocardial global relative enhancement (gRE), and inversion-recovery gradient-echo imaging to evaluate areas of late gadolinium enhancement (LE) were performed. The MR results were correlated with the endomyocardial biopsy (EMB) findings to detect intramyocardial inflammation and cardiotropic viral genomes analyzed at polymerase chain reaction assay. For statistical analyses, receiver operating characteristic analysis and the Wilcoxon test for unpaired data were used because the Kolomogorov-Smirnov test revealed a distribution of data that was different from normality. RESULTS: Intramyocardial inflammation and cardiotropic viral persistence were confirmed at immunohistologic analysis in 48 and 49 of the 83 patients, respectively. The sensitivity, specificity, and diagnostic accuracy of the MR parameters, as compared with the immunohistologic detection of inflammation, were, respectively, 62%, 86%, and 72% for gRE; 67%, 69%, and 68% for ER; and 27%, 80%, and 49% for LE. Cardiac MR-derived gRE, ER, and LE were not associated with polymerase chain reaction proof of viral genomes. CONCLUSION: In patients clinically suspected of having CMC, increased gRE and ER indicating inflammation were common findings that could be confirmed at immunohistologic analysis, whereas LE had low sensitivity and accuracy. Cardiac MR imaging may be helpful in detecting intramyocardial inflammation noninvasively, but it fails to depict viral persistence.

[CT-Guided brachytherapy. A novel percutaneous technique for interstitial ablation of liver metastases]. / CT-gesteuerte Brachytherapie. Eine neue perkutane Technik zur interstitiellen Ablation von Lebermetastasen.

PURPOSE: To assess safety and efficacy of CT-guided brachytherapy of liver malignancies. PATIENTS AND METHODS: 21 patients with 21 liver malignancies (19 metastases, two primary liver tumors) were treated with interstitial CT-guided brachytherapy applying a (192)Ir source. In all patients, the use of image-guided thermal tumor ablation such as by radiofrequency or laser-induced thermotherapy (LITT) was impeded either by tumor size > or = 5 cm in seven, adjacent portal or hepatic vein in ten, or adjacent bile duct bifurcation in four patients. Dosimetry was performed using three-dimensional CT data sets acquired after CT-guided positioning of the brachytherapy catheters. RESULTS: The mean tumor diameter was 4.6 cm (2.5-11 cm). The mean minimal tumor dose inside the tumor margin amounted to 17 Gy (12-20 Gy). The proportion of the liver parenchyma exposed to > 5 Gy was 18% (5-39%) of total liver parenchyma minus tumor volume. Nausea and vomiting were observed in six patients after brachytherapy (28%). One patient demonstrated obstructive jaundice due to tumor edema after irradiation of a metastasis adjacent to the bile duct bifurcation. We commonly encountered asymptomatic increases of liver enzymes. Local control rates after 6 and 12 months were 87% and 70%, respectively. CONCLUSION: CT-guided brachytherapy is safe and effective. This technique displays broader indications compared to image-guided thermal ablation by radiofrequency or LITT with respect to tumor size or localization.

CT-guided interstitial brachytherapy of liver malignancies alone or in combination with thermal ablation: phase I-II results of a novel technique.

PURPOSE: To assess the safety and efficacy of CT-guided brachytherapy alone or in combination with laser-induced thermotherapy (LITT) in patients with liver malignancies. METHODS AND MATERIALS: Thirty-seven patients presented with 36 liver metastases and two primary liver carcinomas. Twenty-one patients were treated with CT-guided high-dose-rate brachytherapy alone using a 192Ir source. Sixteen patients received brachytherapy directly after MRI-guided LITT. The indications for brachytherapy alone were a tumor size >5 cm, adjacent central bile duct or adjacent major vessels causing unfavorable cooling effects for thermal ablation, and technical failures of LITT. The dosimetry for brachytherapy was performed using three-dimensional CT data acquired after percutaneous applicator positioning. On average, a minimal dose of 17 Gy inside the tumor margin was applied (range, 10-20 Gy). RESULTS: The mean tumor size was 4.6 cm (range, 2.5-11 cm). The mean liver volume receiving > or =5 Gy was 16% (range, 2-40%) of the total liver. Severe complications were recorded in 2 patients (5%). One patient developed acute liver failure possibly related to accidental continuation of oral capecitabine treatment. Another patient demonstrated obstructive jaundice owing to tumor edema after irradiation of a metastasis adjacent to the bile duct bifurcation. A commonly encountered moderate increase of liver enzymes was greatest in patients with combined treatment. The local control rate after 6 months was 73% and 87% for combined treatment and brachytherapy alone, respectively. CONCLUSION: CT-guided brachytherapy using three-dimensional CT data for dosimetry is safe and effective alone or in combination with LITT. Brachytherapy as a stand-alone treatment displayed genuine advantages over thermal tumor ablation.