Multisystem pathology in McLeod syndrome.

We present a comprehensive characterization of clinical, neuropathological, and multisystem features of a man with genetically confirmed McLeod neuroacanthocytosis syndrome, including video and autopsy findings. A 61-year-old man presented with a movement disorder and behavioral change. Examination showed dystonic choreiform movements in all four limbs, reduced deep-tendon reflexes, and wide-based gait. He had oromandibular dyskinesia causing severe dysphagia. Elevated serum creatinine kinase (CK) was first noted in his thirties, but investigations, including muscle biopsy at that time, were inconclusive. Brain magnetic resonance imaging showed white matter volume loss, atrophic basal ganglia, and chronic small vessel ischemia. Despite raised CK, electromyography did not show myopathic changes. Exome gene panel testing was negative, but targeted genetic analysis revealed a hemizygous pathogenic variant in the XK gene c.895C > T p.(Gln299Ter), consistent with a diagnosis of McLeod syndrome. The patient died of sepsis, and autopsy showed astrocytic gliosis and atrophy of the basal ganglia, diffuse iron deposition in the putamen, and mild Alzheimer's pathology. Muscle pathology was indicative of mild chronic neurogenic atrophy without overt myopathic features. He had non-specific cardiomyopathy and splenomegaly. McLeod syndrome is an ultra-rare neurodegenerative disorder caused by X-linked recessive mutations in the XK gene. Diagnosis has management implications since patients are at risk of severe transfusion reactions and cardiac complications. When a clinical diagnosis is suspected, candidate genes should be interrogated rather than solely relying on exome panels.

Complex spinal fixation of a cervical vertebra Brown tumour: report of an unusual case.

Brown tumours affecting the cervical spine are a rare but recognised complication of renal failure-related secondary hyperparathyroidism. We present a case of a 26 year-old female with radiculopathy who was managed successfully with 360° cervical spine fixation and parathyroidectomy.

AL amyloidosis presenting with limb girdle myopathy.

An elderly Caucasian man presented with a 10-month history of proximal myopathy and dysphagia. His serum creatine kinase (CK) was elevated at 877 U/L (normal 40-320) and electromyography confirmed a myopathic process. Blood and urine tests suggested myeloma; bone marrow examination showed 30% plasma cells and stained positive for amyloid. The muscle biopsy was initially reported as normal but in the light of the bone marrow report, the biopsy specimen was stained for amyloid, which was positive. We diagnosed systemic amyloidosis causing a myopathy and have started treatment for myeloma.

Identification of Prdm genes in human corneal endothelium.

Corneal endothelial cells (CECs) are essential for maintaining corneal stromal hydration and ensuring its transparency, which is necessary for normal vision. Dysfunction of CECs leads to stromal decompensation, loss of transparency and corneal blindness. Corneal endothelium has low proliferative potential compared to surface epithelial cells leading to poor regeneration of CEC following injury. Additionally, the tissue exhibits age related decline in endothelial cell density with re-organisation of the cell layer, but no regeneration. The mechanisms which control proliferation and differentiation of neural crest derived CEC progenitors are yet to be clearly elucidated. Prdm (Positive regulatory domain) family of transcriptional regulators and chromatin modifiers are important for driving differentiation of a variety of cellular types. Many Prdm proteins are expressed in specific precursor cell populations and are necessary for their progression to a fully differentiated phenotype. In the present work, we sought to identify members of the Prdm gene family which are specifically expressed in human (h) CECs with a view to begin addressing their potential roles in CEC biology, focussing especially on Prdm 4 and 5 genes. By performing semi-quantitative reverse transcription coupled to PCR amplification we found that in addition to Prdm4 and Prdm5, Prdm2 and Prdm10 genes are expressed in hCECs. We further found that cultured primary hCECs or immortalised HCEC-12 cells express all of the Prdm genes found in CECs, but also express additional Prdm transcripts. This difference is most pronounced between Prdm gene expression patterns of CECs isolated from healthy human corneas and immortalised HCEC-12 cells. We further investigated Prdm 4 and Prdm 5 protein expression in cultured primary hCECs and HCEC-12 cells as well as in a human cadaveric whole cornea. Both Prdm 4 and Prdm 5 are expressed in human corneal endothelium, primary hCECs and in HCECs-12 cells, characterised by expression of the Na+/K+-ATPase. We observed that both proteins exhibit cytosolic (intracellular, but non-nuclear and distinct from extracellular fluid) as well as nuclear localisation within the endothelial layer, with Prdm 5 being more concentrated in the nuclei of the endothelial cells than Prdm 4. Thus, our work identifies novel Prdm genes specifically expressed in corneal endothelial cells which may be important in the control of CEC differentiation and proliferation.

Germinoma of the medulla oblongata - A case report.

We describe a case of primary intracranial medulla oblongata germinoma in a 23-year-old female who presented with deteriorating balance and mobility. Imaging demonstrated an exophytic lesion arising from the dorsal medulla oblongata and extending into the fourth ventricle. The tissue sample was obtained via suboccipital craniotomy and a diagnosis of a primary medullary germinoma was made. The patient underwent whole craniospinal axis radiotherapy and remains well and recurrence-free at 1-year follow up.

Rosette-forming glioneuronal tumor with dissemination throughout the ventricular system: a case report.

A 33-year-old female was found to have a rosette-forming glioneuronal tumor (RGNT) occurring within the fourth ventricle with multifocal extension to the third and lateral ventricles. She presented with headaches, blurred vision, nausea, and intermittent dizziness. A brain magnetic resonance imaging (MRI) scan showed hydrocephalus and multifocal nodules throughout the ventricular system with the largest mass occupying the fourth ventricle. An endoscopic third ventriculostomy and biopsy were performed. Histological examination demonstrated a glioneuronal neoplasm with the characteristic features of RGNT. While the histopathological features of our case are well in accord with those reported in the literature, the multifocal intraventricular growth pattern has only been described twice before. Moreover, RGNT of the fourth ventricle with dissemination throughout the supratentorial ventricles has only been described once before. Long-term studies are required to assess the best treatment modalities and clinical behavior of this extremely rare disseminated RGNT entity.

Atypical Presentation of Low-Grade Small Lymphocytic Lymphoma of the Lacrimal Sac.

Lymphoma of the lacrimal sac is uncommon and usually presents as a lacrimal sac mass, against a background of known systemic lymphoma. This study presents the case of a 70-year-old man with small lymphocytic lymphoma of the lacrimal sac and widespread systemic involvement presenting as common canalicular obstruction without a palpable mass or systemic symptoms.

Giant intracranial hemangioma in a neonate.

In this report we detail the case of an infant presenting with a giant intracranial congenital hemangioma and describe the clinical features and surgical management. Congenital hemangiomas are benign vascular tumors that typically present as skin lesions in neonates and infants. On rare occasions they present as intracranial tumors. The possibility that these tumors may undergo spontaneous regression poses a treatment dilemma.

Glioblastomas with oligodendroglial component have the same clinical phenotype as classical glioblastomas.

INTRODUCTION: Glioblastomas are the commonest primary brain tumour and are considered one of the most heterogeneous tumour types. The introduction of a glioblastoma with oligodendroglial component (GBM + O) in the latest WHO Classification of Tumours of the Central Nervous System (1) was to help with this. There has been conflicting evidence as to whether this tumour conferred a better prognosis than classical glioblastoma (GBM). The aim of this study was to study the clinical phenotype of these GBM + O tumours and compare it to the classical GBM. MATERIALS AND METHODS: All patients with histological evidence of a glioblastoma between 1st January 2007 and 31st January 2011 were identified from the Neuropathology Database. Clinical and radiological details were obtained for all patients. The overall survival of patients who were treated with chemoradiotherapy was obtained and the GBM + O cohort compared to the classical GBM cohort. RESULTS: Three hundred and ninety-six patients with newly diagnosed glioblastomas were identified: 294 (74.2%) had classical GBM and 102 (25.6%) had GBM + O. The two cohorts presented at a similar age (61.1 years GBM + O vs. 63.2 years GBM; P = 0.09) and were matched for sex and side of the tumour. GBM + O were more likely to be located in the frontal lobes (38.2% for GBM + O vs. 27.2% for GBM: P = 0.04). In the group that was treated with chemoradiotherapy the overall survival was similar (median survival GBM + O 361 days vs. 379 days GBM; Log Rank 0.61, P = 0.43). CONCLUSION: The presence of an oligodendroglial component does not confer any improvement in survival and has a similar clinical phenotype to classical GBMs.

A review of solitary fibrous tumours of the orbit and ocular adnexa.

Solitary fibrous tumour (SFT) is an uncommon spindle cell tumour of mesenchymal origin characterised by NAB2-STAT6 gene fusion. Although it was first described in the pleura, it can occur in connective tissue in any part of the body, but rarely presents in the orbit and ocular adnexa. SFT, which is part of the same disease spectrum as other fibroblastic tumours such as giant cell angiofibroma, haemangiopericytoma and fibrous histiocytoma, usually presents as a painless, slow-growing mass in any age group and generally follows a benign course, with a good prognosis after complete excision. However, malignant forms rarely occur. Even for benign tumours a more aggressive clinical behaviour is possible, with relentless infiltrative local growth, frequent recurrence following surgery, and malignant transformation with the potential for metastatic spread. Careful long-term follow-up is essential. The published literature on SFTs of the orbit and ocular adnexa is reviewed, and the aetiology, clinical presentation, epidemiology, radiological features, histopathology, immunohistochemistry, risk stratification, clinical management, and prognosis are discussed, reflecting on our own experience.

A rare presentation of rapidly progressing myopathy in an adolescent.

We present a case of severe juvenile dermatomyositis with limited response to steroids in an adolescent who developed symptoms within hours after receiving Pfizer BNT162b2 coronavirus disease 2019 vaccine. The patient presented with severe weakness of proximal muscles, dyspnoea, and tachycardia. His muscle enzymes were raised, and he was diagnosed with severe juvenile dermatomyositis following magnetic resonance imaging and muscle biopsy. His management was challenging, requiring multidisciplinary input, and difficult decisions with regard to the appropriate immunomodulatory treatments. The patient had to undergo escalating immunosuppressive treatments before he began to recover clinically and biochemically. To our knowledge, this is the first case in an adolescent although a few cases of similar presentations following coronavirus disease 2019 vaccination have been reported in adults. Elucidating the potential relationship of the vaccine with this severe myopathy in an adolescent is important for global vaccination policies, but avoiding the conflation of association with causation is also crucial in the context of the pandemic.

Doxycycline attenuates and delays toxicity of the oculopharyngeal muscular dystrophy mutation in transgenic mice.

The muscular dystrophies are a heterogeneous group of disorders for which there are currently no cures. Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset, progressive disease that generally presents in the fifth or sixth decade with dysphagia, ptosis and proximal limb weakness. OPMD is caused by the abnormal expansion of a (GCG)n trinucleotide repeat in the coding region of the poly-(A) binding protein nuclear 1 (PABPN1) gene. In unaffected individuals, (GCG)6 codes for the first six alanines in a homopolymeric stretch of ten alanines. In most individuals with OPMD this (GCG)6 repeat is expanded to (GCG)8-13, leading to a stretch of 12-17 alanines in mutant PABPN1. PABPN1 with an expanded polyalanine tract forms aggregates consisting of tubular filaments within the nuclei of skeletal muscle fibers. We have developed a transgenic mouse model of OPMD that manifests progressive muscle weakness accompanied by intranuclear aggregates and TUNEL-stained nuclei in skeletal muscle fibers. The onset and severity of these abnormalities were substantially delayed and attenuated by doxycycline treatment, which may exert its therapeutic effect by reducing aggregates and by distinct antiapoptotic properties. Doxycycline may represent a safe and feasible therapeutic for this disease.

Sinus pericranii: an overview and literature review of a rare cranial venous anomaly (a review of the existing literature with case examples).

Sinus pericranii is a rare vascular abnormality characterised by abnormal connections between the intra- and extracranial venous systems and is usually found in children. In most instances, a sinus pericranii presents as a soft scalp swelling that appears with the patient in the recumbent position and disappears in the erect position. We review two cases of sinus pericranii presented in adulthood and treated surgically with good outcomes. We have performed a search of the English literature using the PubMed database and reviewed the published cases to date to present an overview of this pathological entity.

The Role of Sural Nerve Biopsy in the Diagnosis of Vasculitis.

OBJECTIVE: The diagnostic yield of sural nerve biopsy (SNB) in vasculitis is uncertain. Our aim was to document relevant characteristics of patients undergoing SNB in the investigation of vasculitis; determine the diagnostic yield; relate positive biopsy findings to patient demographic, laboratory, and clinical variables; and to calculate the rate of surgical complications. METHODS: Patients with suspected vasculitis that underwent SNB as part of diagnostic evaluation at academic medical centers in Sweden and the United Kingdom were identified by searching local pathology databases and clinic registers. A structured review of medical case records and pathology reports was conducted. Histological findings were categorized as definite, probable, or no vasculitis in accordance with the 2015 Brighton Collaboration reinterpretation and update of the Peripheral Nerve Society guidelines for vasculitic neuropathy. Definite and probable findings were considered positive for vasculitis. RESULTS: Ninety-one patients that underwent SNB were identified (45% female). Forty (44%) patients showed histological evidence of vasculitis: 14 definite and 26 probable. A concomitant muscle biopsy conducted in 10 patients did not contribute to the diagnostic yield. Positive antineutrophil cytoplasmic antibody test, organ involvement other than the nervous system, and a longer biopsy sample were associated with a positive biopsy. The reported surgical complication rate was 15%. CONCLUSION: SNB of sufficient length is a useful procedure to confirm a diagnosis of vasculitis.

Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy.

Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift variants do not increase the propensity of hnRNPA2 protein to fibrillize. Rather, the frameshift variants have reduced affinity for the nuclear import receptor karyopherin ß2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with HNRNPA2B1 to include an early-onset form of OPMD caused by frameshift variants that alter its nucleocytoplasmic transport dynamics.

Neurenteric cyst of the anterior cranial fossa: case report and literature review.

Intracranial neurenteric cysts are rare congenital lesions that typically occur in the posterior fossa. We report a case of a 70-year-old gentleman presenting with gait disturbance, found to have a neurenteric cyst primarily arising from and expanding the sella turcica. A review of the literature revealed 27 reports of supratentorial neurenteric cysts. Clinical presentation, radiological characteristics, treatment, prognosis and embryological origin are discussed. Intracranial neurenteric cysts should be included in the differential with any well-demarcated cystic lesion without enhancement on magnetic resonance imaging (MRI). Complete surgical excision is the treatment of choice, with good prognosis.

Paravertebral cervical chordoma--a case report.

Chordomas constitute <5% of vertebral column tumours and a third of these arise in the upper cervical spine and tend to be clival - usually midline, with occasional eccentric extension. We report a case of cervical chordoma presenting as a lateral neck mass and discuss its origin, diagnosis and management.

Mascara-induced nasolacrimal duct obstruction.

A 35-year-old woman underwent left external dacryocystorhinostomy (DCR) following a recent bout of left acute dacryocystitis. She had a right DCR 14 years earlier. Her relatively young age of presentation prompted suspicion of secondary nasolacrimal duct obstruction and, although the left lacrimal sac appeared macroscopically normal peroperatively, a lacrimal sac biopsy was taken. Histopathology revealed florid chronic inflammation, with abundant granular brown pigment and polarisable crystals suggestive of an exogenous material in the lacrimal sac mucosa compatible with mascara. After initial improvement, her epiphora has recurred 1-year postoperatively, but her ocular discharge has resolved. Mascara-induced conjunctival pigmentation is well established. However, there are very few published reports of nasolacrimal duct obstruction due to mascara. Since cosmetic application of mascara and kohl eyeliner is widespread, patients and practitioners should be aware of their potential to migrate into the lacrimal apparatus and cause chronic inflammation with secondary nasolacrimal duct obstruction.

BRAF V600E Mutant Lung Adenocarcinoma Presenting With a Skull Base Metastasis and Pituitary Adenoma Collision Tumour.

We report an unusual initial presentation for metastatic lung adenocarcinoma (LAC) with progressive loss of vision, a rare molecular phenotype and rapid visual response to surgical resection. A 60-year-old female presented with rapid and progressive visual loss over four weeks. Contrast-enhanced CT and MRI scans showed an enhancing lobulated mass in the base of skull infiltrating into the sella turcica. The patient underwent transnasal endoscopic debulking of the mass with rapid improvement in her vision. Histology showed a collision tumour with a pituitary adenoma and a microacinar metastatic adenocarcinoma. Staging CT of the chest, abdomen and pelvis showed a T4 N2 M1 right LAC. Molecular profiling of the metastasis confirmed an activating mutation involving codon 600 of BRAF gene (BRAF V600E). The patient was treated with combination chemotherapy but rapidly deteriorated and unfortunately died due to progressive disease. Efforts to access BRAF/MEK inhibitors for off-label use were unsuccessful. We believe our patient would have benefited from a BRAF/MEK inhibitor. This case illustrates the very unusual presentation of metastatic LAC with visual loss secondary to a collision tumour containing a pituitary adenoma and metastatic adenocarcinoma.