Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency.

BACKGROUND: Autosomal recessive (AR) complete IRF8 deficiency is a rare severe inborn error of immunity underlying an absence of blood myeloid mononuclear cells, intracerebral calcifications, and multiple infections. Only three unrelated patients have been reported. MATERIALS AND METHODS: We studied an Argentinian child with multiple infectious diseases and severe pulmonary alveolar proteinosis (PAP). We performed whole-exome sequencing (WES) and characterized his condition by genetic, immunological, and clinical means. RESULTS: The patient was born and lived in Argentina. He had a history of viral pulmonary diseases, disseminated disease due to bacillus Calmette-Guérin (BCG), PAP, and cerebral calcifications. He died at the age of 10 months from refractory PAP. WES identified two compound heterozygous variants in IRF8: c.55del and p.R111*. In an overexpression system, the p.R111* cDNA was loss-of-expression, whereas the c.55del cDNA yielded a protein with a slightly lower molecular weight than the wild-type protein. The mutagenesis of methionine residues downstream from c.55del revealed a re-initiation of translation. However, both variants were loss-of-function in a luciferase assay, suggesting that the patient had AR complete IRF8 deficiency. The patient had no blood monocytes or dendritic cells, associated with neutrophilia, and normal counts of NK and other lymphoid cell subsets. CONCLUSION: We describe the fourth patient with AR complete IRF8 deficiency. This diagnosis should be considered in children with PAP, which is probably due to the defective development or function of alveolar macrophages.

Hyperparathyroidism and cerebral calcifications:a case report.

The evidence of hyperparathyroidism associated with cerebral calcifications is rare. We report a case with primary hyperparathyroidism (PHPT) and cerebral calcifications. A 63-year-old female patient with a history of hypertension presented to the neurology department due to bradykinesia and declining memory for one year.   Cranial CT and magnetic resonance imaging (MRI) scan revealed symmetrical calcifications in the basal ganglia, dentate nucleus of the cerebellum and in the gray and white matter junction. In the literature review, a total of 6 patients with PHPT had cerebral calcifications. Parathyroidectomy may provide a significant remission of cerebral calcifications in a patient with PHPT.

Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function.

The tRNA synthetases catalyze the first step of protein synthesis and have increasingly been studied for their nuclear and extra-cellular ex-translational activities. Human genetic conditions such as Charcot-Marie-Tooth have been attributed to dominant gain-of-function mutations in some tRNA synthetases. Unlike dominantly inherited gain-of-function mutations, recessive loss-of-function mutations can potentially elucidate ex-translational activities. We present here five individuals from four families with a multi-system disease associated with bi-allelic mutations in FARSB that encodes the beta chain of the alpha2beta2 phenylalanine-tRNA synthetase (FARS). Collectively, the mutant alleles encompass a 5'-splice junction non-coding variant (SJV) and six missense variants, one of which is shared by unrelated individuals. The clinical condition is characterized by interstitial lung disease, cerebral aneurysms and brain calcifications, and cirrhosis. For the SJV, we confirmed exon skipping leading to a frameshift associated with noncatalytic activity. While the bi-allelic combination of the SJV with a p.Arg305Gln missense mutation in two individuals led to severe disease, cells from neither the asymptomatic heterozygous carriers nor the compound heterozygous affected individual had any defect in protein synthesis. These results support a disease mechanism independent of tRNA synthetase activities in protein translation and suggest that this FARS activity is essential for normal function in multiple organs.

A patient with extensive cerebral calcification due to pseudohypoparathyroidism: a case report.

BACKGROUND: Pseudohypoparathyroidism(PHP) is a heterogeneous group of disorders due to impaired activation of c AMP dependant pathways following binding of parathyroid hormone (PTH) to its receptor. In PHP end organ resistance to PTH results in hypocalcaemia, hyperphosphataemia and high PTH levels. CASE PRESENTATION: A 59 year old male presented with a history of progressive impairment of speech and unsteadiness of gait for 1 week and acute onset altered behavior for 1 day and one episode of generalized seizure. His muscle power was grade four according to MRC (medical research council) scale in all limbs and Chovstek's and Trousseau's signs were positive. Urgent non contrast computed tomography scan of the brain revealed extensive bilateral cerebral and cerebellar calcifications. A markedly low ionized calcium level of 0.5 mmol/l, an elevated phosphate level of 9.5 mg/dl (reference range: 2.7-4.5 mg/dl) and an elevated intact PTH of 76.3 pg/l were noted. His renal functions were normal. His hypocalcemia was accentuated by the presence of hypomagnesaemia. His 25 hydroxy vitamin D level was only marginally low which could not account for severe hypocalcaemia. A diagnosis of pseudohypoparathyroidism without phenotypic defects, was made due to hypocalcaemia and increased parathyroid hormone levels with cerebral calcifications. The patient was treated initially with parenteral calcium which was later converted to oral calcium supplements. His coexisting Vitamin D deficiency was corrected with 1αcholecalciferol escalating doses. His hypomagnesaemia was corrected with magnesium sulphate parenteral infusions initially and later with oral preparations. With treatment there was a significant clinical and biochemical response. CONCLUSION: Pseudohypoparathyroidism can present for the first time in elderly resulting in extensive cerebral calcifications. Identification and early correction of the deficit will result in both symptomatic and biochemical response.

Novel mutations in SLC16A2 associated with a less severe phenotype of MCT8 deficiency.

Mutations in the thyroid hormone transporter MCT8 cause severe intellectual and motor disability and abnormal serum thyroid function tests, a syndrome known as MCT8 deficiency (or: Allan-Herndon-Dudley syndrome, AHDS). Although the majority of patients are unable to sit or walk independently and do not develop any speech, some are able to walk and talk in simple sentences. Here, we report on two cases with such a less severe clinical phenotype and consequent gross delay in diagnosis. Genetic analyses revealed two novel hemizygous mutations in the SLC16A2 gene resulting in a p.Thr239Pro and a p.Leu543Pro substitution in the MCT8 protein. In vitro studies in transiently transfected COS-1 and JEG-3 cells, and ex vivo studies in patient-derived fibroblasts revealed substantial residual uptake capacity of both mutant proteins (Leu543Pro > Thr239Pro), providing an explanation for the less severe clinical phenotype. Both mutations impair MCT8 protein stability and interfere with proper subcellular trafficking. In one of the patients calcifications were observed in the basal ganglia at the age of 29 years; an abnormal neuroradiological feature at this age that has been linked to untreated (congenital) hypothyroidism and neural cretinism. Our studies extend on previous work by identifying two novel pathogenic mutations in SLC16A2 gene resulting in a mild clinical phenotype.

Imaging Feature of Leukoencephalopathy with Calcifications and Cysts (Labrune Syndrome).

Labrune syndrome is an uncommon central nervous system disorder characterized by leukoencephalopathy, cerebral calcifications, and cysts on brain imaging. The basic pathology is microangiopathy resulting from a mutation in the SNORD118 gene. Radiological imaging is the hallmark of the disease.

Cerebral Calcifications as a Result of Primary Hyperparathyroidism: A Report of a Rare Case.

Primary hyperparathyroidism (PHPT) is an extremely uncommon cause of cerebral calcification. A male patient, aged 45, was admitted to the neurosurgery clinic with a closed traumatic brain injury, namely a concussion, resulting in symptoms of headache and loss of balance. A CT scan was conducted, which detected bilateral calcifications on the basal ganglia and the tentorium. The blood tests revealed increased levels of serum calcium, phosphate, and parathyroid hormone (PTH), while vitamin D levels were within the normal range. The patient received symptomatic therapy for the cerebral concussion and was referred for further diagnostic procedures. Based on these exams, it was determined that the patient had a parathyroid adenoma, which was responsible for PHPT characterised by increased levels of calcium, phosphate, and PTH. The patient subsequently underwent a successful parathyroidectomy. Half a year following the surgical procedure, the patient remained free of any indications of neurological conditions, and the levels of PTH and calcium in their body were within the expected range. Whenever trying to identify the cause of cerebral calcification, it is important to explore several possible diagnoses. A possible cause that should be taken into account is PHTP.

Exudative retinopathy, cerebral calcifications, duodenal atresia, preaxial polydactyly, micropenis, microcephaly and short stature: a new syndrome?

The association of Coats disease with intrauterine growth retardation, intracranial calcification, leukodystrophy, brain cysts, osteopenia, and gastrointestinal bleeding defines Coats plus syndrome caused by mutations in the CTC1 gene, encoding conserved telomere maintenance component 1. Here, we report on a child with exudative retinopathy, cerebral calcifications, duodenal atresia, preaxial polydactyly, micropenis, microcephaly, and short stature, in whom no mutations in CTC1 were found. Our patient shares some features seen in other diseases associated with telomere shortening including Hoyeraal-Hreidarsson and Revesz syndromes. We therefore measured telomere length by Flow-Fish which was normal. The association of duodenal atresia and microcephaly also suggested a diagnosis of Feingold syndrome. However, direct sequencing of MYCN was normal, and we did not detect any hemizygous deletion of the miR-17∼92 polycistronic miRNA cluster. To our knowledge, the phenotype we report on has not been described previously, leading us to speculate that this condition may represent a new syndrome.

Leukoencephalopathy, calcifications, and cysts: Labrune syndrome.

Labrune syndrome is an extremely rare disorder characterized by a radiological triad of leukoencephalopathy, cerebral calcifications, and cysts. The condition is the result of an autosomal mutation in the SNORD118 gene, a non-protein encoding gene that mediates rRNA synthesis. The mutation results selectively in cerebral microangiopathy through an unknown mechanism. Radiological imaging is central to diagnosing the condition, but, because the condition is so rare, there is no standard treatment paradigm. We describe the longitudinal progression of a case of Labrune syndrome, including the radiological diagnosis and imaging and surgical management.

Labrune Syndrome: A Rare Leukodystrophy.

Labrune syndrome is a rare neurological disorder, with less than 100 reported cases since its identification. This disorder causes progressive cerebral degeneration. This case report describes a 21-year-old male patient who presented with tonic-clonic seizures. Upon examination, he was found to have symmetrical dense calcifications in the bilateral basal ganglia, thalami, and dentate nuclei, as well as in the white matter of both hemispheres, accompanied by cysts. MRI brain revealed confluent areas of T2/FLAIR hyperintensities involving the deep periventricular white matter in both cerebral hemispheres with sparing of subcortical U-fibres and two cysts in the left frontal and right posterior temporal region. No serologic evidence of a parasitic infection was found. Treatment was directed at addressing symptoms, and surgery was not required as the cysts were not causing a mass effect. The condition is the result of an autosomal mutation in the SNORD118 gene, a non-protein encoding gene that mediates rRNA synthesis.

Diffuse Calcinosis from Total Thyroidectomy and Secondary Hypocalcaemia.

Hypoparathyroidism is a rare endocrine disorder and its main cause is cervical surgery such as thyroidectomy. The incidence of hypoparathyroidism after total thyroidectomy varies, and is reported to be between 0.3 and 6.3%. In terms of brain imaging, hypoparathyroidism can cause calcification mainly of the basal ganglia, with other areas rarely affected. Concerning extracerebral calcification, few studies have investigated the prevalence of visceral calcifications. We describe a case of a woman with secondary hypocalcaemia who presented with a transient ischaemic attack (TIA) and the investigation revealed an extensive calcinosis of the brain and the vascular structures responsible for the event. LEARNING POINTS: Iatrogenic hypoparathyroidism with hypocalcaemia is an important complication of total thyroidectomy. Hypocalcaemia manifestations can vary from asymptomatic to life-threatening conditions.Hypoparathyroidism (with hypocalcaemia) can cause cerebral calcification mainly of basal ganglia, with other areas of the brain rarely affected.Extracerebral calcifications are under-studied.

Labrune Syndrome: A Very Rare Association of Leukoencephalopathy, Cerebral Calcifications, and Cysts.

Leukoencephalopathy, cerebral calcifications, and cysts (LCC) form a very rare association which is named as "Labrune syndrome" after Labrune who reported the first case in 1996. To the best of our knowledge only eight to 10 cases have been reported in literature to date. We report a case of a 26-year-old male with onset of neurological symptoms in late adolescence (at 19 years of age) and presented with complains of continued seizures for 7 years, giddiness with imbalance, and slowly progressive motor symptoms. MRI brain revealed multiple calcifications in bilateral basal ganglia, cerebral white matter, multiple cystic lesions in the supratentorial white matter, and abnormal diffused bilateral white matter T2 hyperintensity suggesting leukoencephalopathy. Histopathological evaluation revealed prominent congested blood vessels suggestive of angiomatous changes and cystic areas suggestive of secondary gliosis.

Could Fahr's Syndrome Have More Than One Simultaneous Etiology?

Fahr's syndrome is a rare, genetically dominant, inherited, neurological disorder characterized by abnormal deposits of calcium in the basal ganglia and the cerebral cortex. Symptoms include motor dysfunction, dementia, headache, spastic paralysis, abnormal ocular findings and seizures. Hypoparathyroidism is the most common endocrine disorder related to this syndrome, however, there are other metabolic, infectious and genetic causes. This is a case report of a Fahr's syndrome patient presenting a three-month history of self-limited partial epileptic seizures. His cranial CT had bilateral symmetrical calcifications of the basal ganglia, subcortical tissue and dentate nucleus whereas his laboratory findings were compatible with hypoparathyroidism.

Adult-onset leukoencephalopathy, cerebral calcifications, and cysts: An 8-year neuroimaging follow-up of disease progression and histopathological correlation.

Leukoencephalopathy, cerebral calcifications, and cysts (LCC) is an extremely rare neurological disease, also known as Labrune syndrome. The disease more commonly affects children and young adults and the characteristic triple imaging findings are leukoencephalopathy, calcifications and multiple cysts, presenting with a variety of supra- and infratentorial symptoms but lacking for extra-neurological manifestations. Coats plus syndrome and cerebroretinal microangiopathy with calcifications and cysts (CRMCC) share similar neurological findings with LCC, but additionally involves other extra-neurological organs. Tumoral excision is usually required due to mass effect to the eloquent brain of multiple growing cysts or hemorrhages, but the outcome of surgery varies. Here we demonstrate an 8-year neuroimaging study of a rare adult-onset case of LCC with gradual headache, hemiparesis, hand tremors, unstable gait, and seizure attacks despite several times of tumoral excision. Neuroimaging revealed multiple microbleeds and microcalcification in the leukoencephalopathic areas, with increasing calcifications, recurrent previously excised cysts and new cyst formation in the longitudinal neuroimaging follow-ups within the eight years. We believe that LCC involves microangiopathy, which causes blood-brain barrier disruption, myelin serum collection and subsequent growing cysts and dystrophic calcification formation. We provide histopathological correlation in the illustration. Due to the underlying pathomechanism and long-term recurrence nature, patients with a combination of cysts and calcifications on CT scan should be follow up carefully and postoperative recurrence after years may occur.

Aicardi-Goutières Syndrome: Brief Case Report.

The case of a term newborn diagnosed with Aicardi-Goutières syndrome, a rare encephalopathy in our environment, with Mendelian inheritance pattern, characterized by a set of nonspecific neurological symptoms associated with typical findings of intracerebral calcifications. The case is presented with diagnostic imaging, in addition to elevated levels of interferon alpha and cerebrospinal fluid lymphocytosis.

A 55-year-old female with leukoencephalopathy with cerebral calcifications and cysts: Case report and radiopathologic description.

Adult-onset leukoencephalopathies with increased cerebral volume can present a potentially challenging diagnosis for the pathologist. We present the case of a patient with a rare adult-onset disease called Leukoencephalopathy with cerebral Calcifications and Cysts (LCC). A 55-year-old woman with a history of morning headaches, mild memory loss, diabetes, and hypertension presented to the emergency department with acute onset altered mental status. CT scan revealed multiple small hypodense lesions in the white matter with calcifications in the bilateral cerebral hemispheres, basal ganglia, pons, and cerebellar hemispheres. MRI showed multiple complex/hemorrhagic cystic lesions with partial enhancement in addition to calcifications bilaterally in the frontotemporal white matter, pons, and cerebellar hemispheres, and diffuse white matter signal abnormality. The differential diagnosis included chronic infection, chronic thromboembolic disease, and neoplasm. The biopsy revealed extensive geode-like mineralization as well as smaller calcifications (calcospherites) with associated sclerosis, Rosenthal fibers, angiomatous proliferation of blood vessels with thrombosis and microbleeds. We discuss the differential diagnosis, radiologic and detailed histologic features of LCC.

Mutiple keratocystic odontogenic tumors (KCOT) in a patient with Gorlin syndrome: a case report with late presentation and absence of skin manifestations.

BACKGROUND: Gorlin syndrome is a rare autosomal dominant syndrome characterized by multiple basal cell carcinomas, keratocystic odontogenic tumors (KOT) and falx cerebral calcifications, which occur due to mutation in PTCH gene. CASE PRESENTATION: A 36 year old Asian patient presented with jaw swelling and pain. Radiographic examination revealed six cysts in maxilla and mandible which were excised and histologically were compatable with keratocystic odontogenic tumors. CT scan also revealed falx cerebral calcification which led to the diagnosis of Gorlin syndrome confirmed on genetic testing. There was no evidence of basal cell carcinoma and other manifestations of Gorlin syndrome were absent. CONCLUSIONS: Multiple KCOT are hallmark of Gorlin syndrome and should always leads to its suspicion even in the absence of other manifestations and late presentation. Moreover, keratocystic odontogenic tumors have a particularly higher risk of recurrence and patients with Gorlin syndrome are prone to develop additional keratocystic odontogenic tumors from basal cells of oral epithelium. Therefore we suggest a stepwise approach to manage such patients which include a preoperative biopsy to establish a definitive diagnosis and complete removal of all keratocystic odontogenic tumors to prevent recurrence followed by close clinical follow up and early removal of any newly developed or recurrent cyst. Additionally thorough clinical examination is necessary to rule out the possibility of Gorlin syndrome in any patient with keratocystic odontogenic tumors as there are only subtle differences in histology of those cysts with a syndromic association and clinical features of Gorlin syndrome are markedly variable. Hence late occurrence of keratocystic odontogenic tumors and absence of skin manifestations like basal cell carcinoma should not preclude a diagnosis of Gorlin syndrome.

Leukoencephalopathy with cerebral calcification and cysts: Cases report and literature review.

BACKGROUND: Leukoencephalopathy with calcifications and cysts (LCC) is a rare disease in which parenchymal cysts and calcifications within a widespread leukoencephalopathy can cause a broad spectrum of neurological symptoms. We present cases with adult LCC and discuss previously described entities in relevant literature. CASE PRESENTATION: Two cases of adult-onset LCC confirmed by clinical presentations, typical neuroimaging and neuropathological findings are reported. LITERATURE REVIEW: A detailed search of all relevant reports published in the English language between 1996 and 2015 via PubMed (http://www.ncbi.nlm.nih.gov/pubmed) was performed, with "Leukoencephalopathy", "cerebral calcifications" and "cysts" as keywords. Including the current cases, we summarized the clinical presentations, neuroimaging features, biopsy features, and genetic features of 38 LCC patients. CONCLUSION: Our findings suggested that LCC could be diagnosed by clinical presentations, neuroimaging and gene detection, and biopsy might not be necessary. Therefore, we propose a diagnostic flow chart for neuroimaging in leukoencephalopathy, cerebral calcifications and cysts.

Leukoencephalopathy, cerebral calcifications, and cysts in two sisters.

BACKGROUND: The triad of leukoencephalopathy with cerebral calcifications and cysts is a rare syndrome consisting of these three radiographic findings first described by Labrune et al. in 1996. The inheritance pattern and genetic mutation responsible for this syndrome (if any) have not been determined. PATIENT DESCRIPTION: We report the occurrence of this syndrome in siblings. Two sisters presented with leukoencephalopathy, cerebral calcifications, and cysts approximately 10 years apart, one at 18 years with longstanding epilepsy and the other at 25 years with postpartum stroke-like signs. In both individuals, computed tomography revealed calcifications in the basal ganglia and subcortical white matter as well as supratentorial cysts. Magnetic resonance imaging demonstrated diffuse white matter increased T2 signal and bilateral supratentorial cysts with enhancing walls. Both patients underwent biopsy, one an open biopsy and the other a stereotactic biopsy, with sections of the resected tissue revealing gliosis with Rosenthal fibers, myelin loss, and calcifications, plus in the larger sample cystic spaces and thick-walled abnormal blood vessels with hemosiderin deposition in the adjacent tissues. CONCLUSION: In these siblings, the triad of radiological findings, histopathologic findings, and lack of extraneurological findings on physical examination suggest an occurrence of familial leukoencephalopathy, cerebral calcifications, and cysts with probable autosomal recessive inheritance.