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Mutations in the FOLR1 gene, encoding for the folate alpha receptor (FRa), represent a rare recessive genetic cause of cerebral folate deficiency (CFD), a potentially reversible neurometabolic condition. Patients typically present with developmental delay, seizures, abnormal movements, and delayed myelination. We hereby expand the phenotypic and genotypic spectrum of the disease with the report of the first two Greek siblings that were found compound heterozygous for one known FOLR1 gene mutation (p.Cys65Trp) and a mutation (p.Trp143Arg) that has not yet been reported in the literature (class 3 variant according to ASHG classification). A distinguishing feature of the older sibling is the manifestation of drug‐resistant epileptic spasms beyond infancy. These had a relatively good response to a ketogenic diet, as an additional treatment to topiramate and valproate. A further clinical improvement was observed when folinic acid was combined with the above treatment. While a response to folinic acid is well established in the disorder, the efficacy of its combination with the ketogenic diet needs further evaluation, but we suggest considering it early in the course of drug resistant epilepsy in the setting of CFD. The younger sibling was diagnosed and treated with folinic acid at an early‐symptomatic stage. Both patients had moderately low age‐related CSF 5‐methyltetrahydrofolate levels at diagnosis with the older sibling (that was already treated at base line collection) averaging 19 nmol/L (normal range: 44‐122 nmol/L) and the younger one 49 nmol/L (normal range 63‐122 nmol/L). These levels were restored to normal limits after folinic supplementation.

Background The neurodevelopmental impairment in tuberous sclerosis complex (TSC) has a multifactorial origin. Various factors have been proposed as predictors of neurological outcome such as tuber load, seizure onset, and TSC2 mutation. Cerebellar lesions have been associated with worse neuroradiological phenotype, but their contribution is not well understood. Methods A partly retrospective and partly prospective pediatric cohort study was conducted at three hospitals in Greece between 2015 and 2020. Patients aged ≤ 18 years with a confirmed TSC daignosis were included and underwent brain imaging, a semistructured interview (authorized Greek version of the tuberous sclerosis-associated neuropsychiatric disorders, or TAND, checklist), and intellectual ability assessment. Results The study populations consisted of 45 patients with TSC (22 females, 23 males; mean age 9.53 years). Twenty patients (44.4%) had cerebellar lesions. Cerebellar involvement was the most powerful predictor of tuber load (P = 0.03). Cerebellar lesions were associated with giant cell astrocytomas (SEGAs) (P = 0.01) and severe neurological outcome (P = 0.01). Even though in the univariate analysis early seizure onset, tuber load, and cerebellar involvement were associated with intellectual impairment and neurological severity, none of them was an independent predictor of cognitive outcome and neurological severity. Conclusions Cerebellar lesions are common among individuals with TSC. Cerebellar involvement correlates with supratentorial derangement and the development of SEGAs, which is suggestive of a more severe clinical and neuroradiological phenotype. Cerebellar involvement and early seizure onset were not independent predictors of either neurological severity or intellectual disability or neurobehavioral outcome; their role in TSC clinical phenotype should be further investigated.

Syringomyelia is the development of a fluid-filled cavity or syrinx within the spinal cord that can cause loss of sensation and muscle spasticity. Guillain-Barre syndrome (GBS) is a postinfection autoimmune disease, classified as an acute polyneuropathy. This report describes the emergency admission of a 6-year-old girl presenting with sudden pallor and pain in both lower limbs. The patient’s reflexes were normal, as were the results of her sonography, radiography and biochemical tests; however, spinal MRI revealed extensive compartmentalised syringomyelia extending from C2 to T3. A sensory and motor nerve conduction study revealed a demyelinating type motor polyneuropathy which, along with positive Mycoplasma pneumoniae test, was suggestive of GBS. Intravenous immunoglobulin infusion showed excellent results. In conclusion, we report a rare paediatric case of syringomyelia coexisting with GBS. It is important to bear in mind the possibility of other coexisting diseases even if MRI reveals definitive characteristics of another condition.

Nephroblastoma (Wilms tumor) is a kidney neoplasia, predominately occurring at very young age, resulting from the malignant transformation of renal stem cells. The Ras proto-oncogenes and B-Raf are members of an intracellular cascade pathway, which regulates cell growth and differentiation, and ultimately cancer development. Our objective was to determine the mutation rate and to measure the mRNA levels of the three Ras genes and of B-Raf in formalin-fixed paraffin-embedded tissue samples from 32 patients with nephroblastoma and 10 controls. No mutations were detected in the four studied genes among our Wilms tumors cases, while Ras and B-Raf expression was higher in malignant samples versus controls. Statistical analysis revealed a positive correlation of K-Ras (p

Please cite this paper as: Gourvas V, Sifakis S, Dalpa E, Soulitzis N, Koukoura O, Spandidos D. Reduced placental prolyl hydroxylase 3 mRNA expression in pregnancies affected by fetal growth restriction. BJOG 2010;117:1635–1642. Objective To investigate the role of the hypoxia-inducible factor (HIF) pathway in fetal growth restriction (FGR). Design A case–control study. Setting Research laboratory and gynaecology clinic. Sample Twenty placentas from normal pregnancies and 20 from FGR pregnancies. Methods RNA extraction, cDNA synthesis, quantitative real-time polymerase chain reaction (qRT-PCR) assay, statistical analysis. Main outcome measures mRNA expression of HIF-1α, HIF-2α and HIF-β (ARNT), along with prolyl hydroxylase domain 3 (PHD3), which leads to proteasomal degradation of HIF-α subunits. Results No statistically significant differences in the transcription levels of ARNT and HIF-2α were found between FGR and normal placentas. By contrast, PHD3 and HIF-1α mRNA were downregulated in FGR placentas. PHD3 mRNA expression was associated with gestational age at delivery (P = 0.008), birthweight centile (P = 0.029) and abnormal umbilical artery (UA) Doppler measurements (P = 0.034). Conclusions As PHD3 regulates the HIF-mediated hypoxic response in FGR, we deduce that fetal adaptation to hypoxia ranges from impaired to adequate, as observed by the gradient of PHD3 downregulation in relation to the severity of FGR.

Background Warthin's tumor is a common benign neoplasm of the salivary gland. Human Herpes Virus 8 (HHV-8) is the etiologic agent for all forms of Kaposi's sarcoma (KS), and HHV-8 DNA is present in saliva, suggesting that non-sexual transmission is associated with latent infection of the salivary gland. Objectives To provide insights into the HHV-8 cell tropism, the presence of HHV-8 was investigated in a series of Warthin's tumors of the salivary gland and corresponding adjacent normal tissue. Study design Forty-three patients with Warthin's tumors (cystadenolymphoma) were tested for the presence of HHV-8 DNA, and corresponding adjacent normal tissue samples were obtained from 15 patients. DNA was extracted from the paraffin-embedded tissues. A nested polymerase chain reaction (PCR) assay was applied, and the positive samples were confirmed by direct sequencing. Results HHV-8 DNA was detected in 19 out of 43 (44%) salivary gland tumor samples. Among the 15 cases with paired samples, 9 were HHV-8-positive for both samples, 4 were HHV-8-negative for both samples while in two cases HHV-8 was detected only in the tumor specimens. Conclusions HHV-8 is frequently detected in adenoid salivary neoplasms, suggesting a significant role of the virus in the etiopathogenesis of the disease. Larger studies are required to investigate the role of HHV-8 in the development or progression of Warthin's tumors.

article i nfo Introduction: The placental anticoagulant protein Annexin A5 (ANXA5) is a multifunctional protein that is highly expressed on the apical surfaces of syncytiotrophoblasts, and plays an important role in haemostatic regulations, maintaining blood fluidity of the placenta. The aim of this study was to investigate the expression of ANXA5 in pregnancies complicated by preeclampsia (PE). Materials and Methods: Placental tissue samples were collected from 23 pregnancies with PE and 34 normal pregnancies. ANXA5 mRNA levels were measured by quantitative Real-Time PCR (qPCR), while ANXA5 protein expression was measured by Western Blot (WB) and immunohistochemistry. Results: ANXA5 mRNA expression in PE samples was lower than 1% of its expression in normal samples (mean ± SD: 0.002 ± 0.004 vs. 0.55 ± 0.38, p b 0.001), while ANXA5 protein levels in PE samples were approximately at 65% of the average normal expression (mean ± SD: 0.53 ± 0.30 vs. 0.81 ± 0.25, p = 0.001). Immunohistochemical analysis also verified the above results, since PE placentas tended to have low labelling indexes (LIs), in contrast to controls which demonstrated high LIs (p = 0.020). Statistical analysis of the WB data revealed that ANXA5 protein expression was increased in PE smokers vs. PE non-smokers (mean ± SD: 0.64 ± 0.23 vs. 0.41 ± 0.33, p = 0.027). Conclusions: These results suggest that ANXA5 downregulation could be part of the pathophysiology of PE and the possible impairment in coagulation processes, which are seen in pregnancies that demonstrate PE. Fur- ther studies may investigate whether ANXA5 could be used as a biomarker for the early detection of PE and for the prediction of its severity.

The placenta is the organ that is responsible for providing the developing fetus with all the nutrients necessary for its growth and is also responsible for removing fetal waste. Placentation is a crucial process that includes angiogenesis. Angiogenesis involves not only the fetal circulation, but also placental and endometrial vascular changes. In this study, we review the literature regarding any impairment in the angiogenic process in placentas from pregnancies complicated by fetal growth restriction (FGR). Angiogenesis is regulated by a list of factors, also known as growth factors, such as the vascular endothelial growth factor (VEGF), the placental growth factor (PlGF) and the basic fibroblastic growth factor (bFGF), as well as the partial pressure of oxygen in the fetoplacental vessels. Other factors, such as transcriptional factors, also play a pivotal role, controlling the above-mentioned growth factors. Alterations in these pathways have been described in cases of growth-restricted fetuses. In this review, we provide an insight into these processes and identify the most crucial factors involved.

Victor Gourvas1, Efterpi Dalpa2, Nikos Vrachnis3 and Stavros Sifakis4 1Department of Pathology, General Hospital “G. Genimatas”, Thessaloniki, 2Department of Pediatrics, General Hospital “G. Papageorgiou”, Thessaloniki, 32nd Department of Obstetrics & Gynecology, Aretaieion Hospital, University of Athens, Athens, 4Department of Obstetrics & Gynecology, University Hospital of Heraklion, Crete, Greece