Search

Biallelic pathogenic variants in CDC45are associated with Meier-Gorlin syndrome with craniosynostosis (MGORS type 7), which also includes short stature and absent/hypoplastic patellae. Identified variants act through a hypomorphic loss of function mechanism, to reduce CDC45 activity and impact DNA replication initiation. In addition to missense and premature termination variants, several pathogenic synonymous variants have been identified, most of which cause increased exon skipping of exon 4, which encodes an essential part of the RecJ-orthologue’s DHH domain. Here we have identified a second cohort of families segregating CDC45variants, where patients have craniosynostosis and a reduction in height, alongside common facial dysmorphisms, including thin eyebrows, consistent with MGORS7. Skipping of exon 15 is a consequence of two different variants, including a shared synonymous variant that is enriched in individuals of East Asian ancestry, while other variants in trans are predicted to alter key intramolecular interactions in α/β domain II, or cause retention of an intron within the 3ʹUTR. Our cohort and functional data confirm exon skipping is a relatively common pathogenic mechanism in CDC45, and highlights the need for alternative splicing events, such as exon skipping, to be especially considered for variants initially predicted to be less likely to cause the phenotype, particularly synonymous variants.

AbstractLittle research explores the experiences of slut shaming of sexual minorities. This qualitative study explored the phenomenon of slut shaming among men in the LGBTQIA + communities. Semi-structured interviews (n = 9) were used to gain an understanding of each participant’s experience. Finding revealed eight themes: (a) intersectional variations, (b) community and context, (c) nuances within LGBTQIA + experience, (d) modality of slut shaming, (e) perceived utility, (f) a tool of conformity, (g) responses, and (h) combatting and coping with slut shaming. Implications for supportive and affirmative mental health practices are included to aid in effectively supporting LGBTQIA + clients and providing affirmative services.

BRAT1biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17).

Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder.

KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20.

The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11(c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families.

Pathogenic variants of FIG4generate enlarged lysosomes and neurological and developmental disorders. To identify additional genes regulating lysosomal volume, we carried out a genome-wide activation screen to detect suppression of enlarged lysosomes in FIG4−/−cells.

Hereditary lung diseases can affect the airways, parenchyma and vasculature of the lung. Such diseases comprehend simple monogenic disorders such as Kartagener syndrome and α1-antitrypsin deficiency, in which mutations of critical genes are sufficient to induce well128;defined disease phenotypes. A major comprehension of the genetic basis of pulmonary diseases has produced new investigations into their underlying pathophysiology and contributed sometimes to clarify on more frequent sporadic forms. The presence of these structural abnormalities of the respiratory tract can be fatal, so that the identification of causative genes has allowed prenatal diagnosis for many diseases giving a greater hope of survival thanks to a more adequate and prompt management.

Junctophilin-3 belongs to a triprotein junctional complex implicated in the regulation of neuronal excitability and involved in the formation of junctional membrane structures between voltage-gated ion channels and endoplasmic (ryanodine) reticular receptors. A monoallelic trinucleotide repeat expansion located within the junctophilin-3 gene (JPH3) has been implicated in a rare autosomal dominant (AD) late-onset (and progressive) disorder clinically resembling Huntington disease (HD), and known as HD-like 2 (HDL2; MIM# 606438). Although the exact molecular mechanisms underlying HDL2 has not yet been fully elucidated, toxic gain-of-function of the aberrant transcript (containing the trinucleotide repeat) and loss of expression of (full-length) junctophilin-3 have both been implicated in HDL2 pathophysiology. In this study, we identified by whole exome sequencing (WES) a JPH3homozygous truncating variant [NM_020655.4: c.17405dup; p.(Val581Argfs*137)]. in a female individual affected with genetically undetermined neurodevelopmental anomalies (including delayed motor milestones, abnormal social communication, language difficulties and borderline cognitive impairment) and paroxysmal attacks of dystonia since her early infancy. Our study expands the JPH3-associated mutational spectrum and clinical phenotypes, implicating the loss of Junctophilin-3 in heterogeneous neurodevelopmental phenotypes and early-onset paroxysmal movement disorders.

Most families with genetic epilepsy with febrile seizures plus show a mutation in the sodium channel alpha 1 subunit gene, however, but there is much phenotypic heterogeneity and focal epilepsy remains relatively rare. Here, we report a family with electroclinical features indicative of temporal‐parietal‐occipital carrefour epilepsy with common occurrence of post‐ictal migraine. We studied a four‐generation family including nine affected subjects by means of EEG and MRI. Genetic testing was performed by targeted re‐sequencing (gene panel). In most patients, seizure semiology included cognitive, autonomic, and emotional symptoms, eventually evolving towards sensory visual phenomena. Focal sensory vestibular seizures and changes in body perception were also reported in some cases. Post‐ictal migraine was common, occurring in five out of the six (83%) epilepsy patients. A missense mutation (c.1130 G>A; p.R377Q) affecting the S5‐S6 segment (pore region) of the sodium channel alpha 1 subunit was identified in all affected and four unaffected subjects. Temporal‐parietal‐occipital carrefour epilepsy is part of the genetic epilepsy with febrile seizures plus spectrum. The electroclinical features in this family support the involvement of a genetically impaired neural network. High prevalence of post‐ictal migraine suggests the role of posterior brain areas in the clinical expression of this gene defect.

BackgroundPathogenic variants of GNB5encoding the β5subunit of the guanine nucleotide-binding protein cause IDDCA syndrome, an autosomal recessive neurodevelopmental disorder associated with cognitive disability and cardiac arrhythmia, particularly severe bradycardia.MethodsWe used echocardiography and telemetric ECG recordings to investigate consequences of Gnb5loss in mouse.ResultsWe delineated a key role of Gnb5in heart sinus conduction and showed that Gnb5-inhibitory signalling is essential for parasympathetic control of heart rate (HR) and maintenance of the sympathovagal balance. Gnb5−/−mice were smaller and had a smaller heart than Gnb5+/+and Gnb5+/−, but exhibited better cardiac function. Lower autonomic nervous system modulation through diminished parasympathetic control and greater sympathetic regulation resulted in a higher baseline HR in Gnb5−/−mice. In contrast, Gnb5−/−mice exhibited profound bradycardia on treatment with carbachol, while sympathetic modulation of the cardiac stimulation was not altered. Concordantly, transcriptome study pinpointed altered expression of genes involved in cardiac muscle contractility in atria and ventricles of knocked-out mice. Homozygous Gnb5loss resulted in significantly higher frequencies of sinus arrhythmias. Moreover, we described 13 affected individuals, increasing the IDDCA cohort to 44 patients.ConclusionsOur data demonstrate that loss of negative regulation of the inhibitory G-protein signalling causes HR perturbations in Gnb5−/−mice, an effect mainly driven by impaired parasympathetic activity. We anticipate that unravelling the mechanism of Gnb5signalling in the autonomic control of the heart will pave the way for future drug screening.

Benign familial infantile epilepsy (BFIE) is the most genetically heterogeneous phenotype among early‐onset familial infantile epilepsies. It has an autosomal dominant inheritance pattern with incomplete penetrance. Although PRRT2is the most mutated gene detected in families with BFIE, other mutations in KCNQ2, SCN2A, and GABRA6genes have also been described. To date, KCNQ3 mutations have been detected in only four patients with BFIE. Here, we describe the clinical pattern and course of an additional individual with BFIE associated with a novel missense heterozygous KCNQ3c.1850G>C variant inherited by his unaffected father. The incidence of KCNQ3mutations among BFIE patients is reported to be low in the literature, however, whether this is underestimated is unclear as not all current epilepsy gene panels include KCNQ3.

Histamine is a chemical mediator, released predominantly by tissue mast cells, circulating basophils, and neurons, which are activated in response to various immunological and non-immunological stimuli. Histamine has to bind to specific receptors to exert its physiological and pathophysiological functions. Endogenous histamine is the main mediator of the immediate allergic response, which moreover, performs other multiple functions, including regulation of gastric secretion, neurotransmission in the central nervous system, and immunomodulatory activity. The involvement of histamine in various disorders and the importance of receptors in the clinical features have relevant implications in clinical practice. Anti-H1 antihistamines contrast the histamine-dependent effects, mainly concerning nasal symptoms and cutaneous itching and wheal. Antihistamines are among the most prescribed drugs in pediatric care. This review updates the practical use of antihistamines in children and adolescents.

Major Facilitator Superfamily Domain containing 2a (MFSD2A) is an essential endothelial lipid transporter at the blood-brain barrier. Biallelic variants affecting function in MFSD2Acause autosomal recessive primary microcephaly 15 (MCPH15, OMIM# 616486). We sought to expand our knowledge of the phenotypic spectrum of MCPH15 and demonstrate the underlying mechanism of inactivation of the MFSD2A transporter. We carried out detailed analysis of the clinical and neuroradiological features of a series of 27 MCPH15 cases, including eight new individuals from seven unrelated families. Genetic investigation was performed through exome sequencing (ES). Structural insights on the human Mfsd2a model and in-vitro biochemical assays were used to investigate the functional impact of the identified variants. All patients had primary microcephaly and severe developmental delay. Brain MRI showed variable degrees of white matter reduction, ventricular enlargement, callosal hypodysgenesis, and pontine and vermian hypoplasia. ES led to the identification of six novel biallelic MFSD2Avariants (NG_053084.1, NM_032793.5: c.556+1G>A, c.748G>T; p.(Val250Phe), c.750_753del; p.(Cys251SerfsTer3), c.977G>A; p.(Arg326His), c.1386_1435del; p.(Gln462HisfsTer17), and c.1478C>T; p.(Pro493Leu)) and two recurrent variants (NM_032793.5: c.593C>T; p.(Thr198Met) and c.476C>T; p.(Thr159Met)). All these variants and the previously reported NM_032793.5: c.490C>A; p.(Pro164Thr) resulted in either reduced MFSD2A expression and/or transport activity. Our study further delineates the phenotypic spectrum of MCPH15, refining its clinical and neuroradiological characterization and supporting that MFSD2Adeficiency causes early prenatal brain developmental disruption. We also show that poor MFSD2A expression despite normal transporter activity is a relevant pathomechanism in MCPH15.

Mowat‐Wilson syndrome is a genetic disorder associated with a variable phenotype including peculiar facial features associated with intellectual disability, epilepsy, language impairment, and multiple congenital anomalies caused by heterozygous mutation of the ZEB2gene. The ZEB2 protein is a complex transcription factor that encompasses multiple functional domains that interact with the regulatory regions of target genes including those involved in brain development. Recently, it has been documented that ZEB2regulates the differentiation of interneuron progenitors migrating from the medial ganglionic eminence to cortical layers by repression of the Nkx2‐1homeobox transcription factor. It has therefore been suggested that the deficit in ZEB2may induce an imbalance of neuronal inhibition/excitation leading to epileptic seizures. Given the phenotypic variability of Mowat‐Wilson syndrome, to date, a distinctive genotype‐phenotype correlation has not been delineated. Here, we report a patient with a severe phenotype of Mowat‐Wilson syndrome, associated with a novel heterozygous de novoframe‐shift variant in the ZEB2gene, as well as an additional novel heterozygous missense variant in the SCN1Agene, the mutation of which is known to affect NaV1.1‐mediated sodium current in GABAergic interneurons. We hypothesize that the severe neurological phenotype of our patient may be influenced by the coexistence of both genetic mutations. [Published with video sequence]

Although mutations in the filaggrin (FLG) gene have been reported to predispose patients with atopic dermatitis (AD) skin infection susceptibility, to date, the data reported in the literature are still controversial.

To provide a complete, exhaustive summary of current literature relevant to food protein–induced enterocolitis syndrome (FPIES).

Respiratory Syncytial Virus (RSV), an enveloped, non-segmented, negative-sense RNA virus of the Paramyxoviridae family, is the most common respiratory pathogen in infants and young children worldwide, also leading to lower respiratory tract infections during infancy and subsequent development of recurrent wheezing and asthma in childhood. Despite many years of research, we still lack reliable biomarkers of the disease activity as well as effective vaccines and therapeutic strategies. Recent studies have directed attention toward High Mobility Group Box-1 (HMGB1), a 30 kDa nuclear and cytosolic ubiquitous protein, belonging to the alarmins family and promoting an immediate activation of the innate immune response, as a biomarker potentially able to elucidate the link between the RSV and chronic airway dysfunction. Herein, we aimed to summarize what is known on RSV-HMGB1 link, also describing recent findings coming from our experimental studies.

The growing interest in the new role of vitamin D, particularly as an immunomodulatory factor, has spurred basic research and the development of clinical trials to better understand the influence of supplementation on various diseases. Vitamin D is an important nutrient factor in human health due to its role in calcium metabolism regulation, cellular growth, differentiation and its fundamental discovered activity in immune functions. It has influenced different diseases, particularly inflammatory and autoimmune diseases, through immune response regulation, modulating innate and adaptive immunity. The aim of this review was to explore the role of vitamin D in the main respiratory diseases in children such as asthma, chronic rhinosinusitis, cystic fibrosis and recurrent respiratory infections.

Biomarkers of clinical and therapeutic outcome in acromegaly are needed. Polymorphisms or epigenetic changes of detoxification genes, such as those coding for the aryl hydrocarbon receptor (AHR) and the glutathione-S-transferase-P1 (GSTP1), could have a role in GH secreting pituitary tumors’ pathophysiology and clinical expression. In this study, we assessed the contribution of GSTP1gene promoter methylation status, per se or in combination with the occurrence of the AHRgene rs2066853 variant, on clinical features and response to somatostatin analogs (SSA) treatment in acromegaly patients. This is an observational, retrospective study, carried out in the Endocrine Unit of an Italian University Hospital. We enrolled 77 wild-type AIPgene acromegaly patients, who have been screened for germline AHRrs2066853 variant and GSTP1gene promoter methylation. Clinical and biochemical parameters were compared after patients’ stratification according to GSTP1methylation status and the presence of AHRrs2066853. We also evaluated the response to SSA treatment in 71 cases. 17 patients carried the AHRrs2066853 variant and 26 had methylated GSTP1(GSTP1-methyl) gene promoter. GSTP1-methyl patients showed a higher prevalence of diabetes mellitus (p= 0.01), colonic polyps (p= 0.05), and were more resistant to SSA (p= 0.02) as compared to GSTP1unmethylated patients (GSTP1-unmethyl). Patients GSTP1-unmethyl and AHRwild-type were the most sensitive to SSA treatment, while those with both GSTP1-methyl and AHRrs2066853 variant were all resistant to SSA (p= 0.01). In acromegaly, GSTP1gene methylation associates with resistance to SSA treatment, especially in patients carrying also the AHRrs2066853 variant, and with increased prevalence of colonic polyps and diabetes mellitus.

Late-onset ataxia is common, often idiopathic, and can result from cerebellar, proprioceptive, or vestibular impairment; when in combination, it is also termed cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). We used non-parametric linkage analysis and genome sequencing to identify a biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 (RFC1) gene as the cause of familial CANVAS and a frequent cause of late-onset ataxia, particularly if sensory neuronopathy and bilateral vestibular areflexia coexist. The expansion, which occurs in the poly(A) tail of an AluSx3 element and differs in both size and nucleotide sequence from the reference (AAAAG)11allele, does not affect RFC1expression in patient peripheral and brain tissue, suggesting no overt loss of function. These data, along with an expansion carrier frequency of 0.7% in Europeans, implies that biallelic AAGGG expansion in RFC1is a frequent cause of late-onset ataxia.

Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort.

De novomutations in the GRIN1gene have been recently reported as the molecular cause of a broad‐spectrum early‐onset neurological phenotype. Here, we describe a five‐year‐old girl with an early‐onset epileptic encephalopathy associated with an infantile hyperkinetic movement disorder and oculomotor abnormalities. Whole‐exome sequencing identified a novel p.Met641Leu de novovariant in the GRIN1gene as the cause of the phenotype. In silicoanalysis suggested that the p.Met641Leu variant would alter the gating property of the ion channel, with the involved methionine residue facing towards the ion pore. Long‐term systematic video‐EEG allowed us to report on the electroclinical history and, specifically, on the semiology of the hyperkinetic movement disorder and oculomotor abnormalities resembling oculogyric crises in our patient. Our findings and a review of the recent literature reinforce the notion of GRIN1‐encephalopathy as a recognizable neurological phenotype that should be suspected in early‐onset epilepsy associated with hyperkinetic movement disorders. [Published with video sequence onwww.epilepticdisorders.com]

The rapid development in the last 10-15 years of microarray technologies, such as oligonucleotide array Comparative Genomic Hybridization (CGH) and Single Nucleotide Polymorphisms (SNP) genotyping array, has improved the identification of fine chromosomal structural variants, ranging in length from kilobases (kb) to megabases (Mb), as an important cause of genetic differences among healthy individuals and also as disease-susceptibility and/or disease-causing factors. Structural genomic variations due to unbalanced chromosomal rearrangements are known as Copy-Number Variants(CNVs) and these include variably sized deletions, duplications, triplications and translocations. CNVs can significantly contribute to human diseases and rearrangements in several dosagesensitive genes have been identified as an important causative mechanism in the molecular aetiology of Charcot-Marie-Tooth (CMT) disease and of several CMT-related disorders, a group of inherited neuropathies with a broad range of clinical phenotypes, inheritance patterns and causative genes. Duplications or deletions of the dosage-sensitive gene PMP22mapped to chromosome 17p12 represent the most frequent causes of CMT type 1A and Hereditary Neuropathy with liability to Pressure Palsies (HNPP), respectively. Additionally, CNVs have been identified in patients with other CMT types (e.g.,CMT1X, CMT1B, CMT4D) and different hereditary poly- (e.g.,giant axonal neuropathy) and focal- (e.g.,hereditary neuralgic amyotrophy) neuropathies, supporting the notion of hereditary peripheral nerve diseases as possible genomic disorders and making crucial the identification of fine chromosomal rearrangements in the molecular assessment of such patients. Notably, the application of advanced computational tools in the analysis of Next-Generation Sequencing (NGS) data has emerged in recent years as a powerful technique for identifying a genome-wide scale complex structural variants (e.g.,as the ones resulted from balanced rearrangements) and also smaller pathogenic (intragenic) CNVs that often remain beyond the detection limit of most conventional genomic microarray analyses; in the context of inherited neuropathies where more than 70 disease-causing genes have been identified to date, NGS and particularly Whole-Genome Sequencing (WGS) hold the potential to reduce the number of genomic assays required per patient to reach a diagnosis, analyzing with a single test all the Single Nucleotide Variants (SNVs) and CNVs in the genes possibly implicated in this heterogeneous group of disorders.

BackgroundDespite decades that have passed since its discovery, accurate biomarkers of respiratory syncytial virus (RSV) disease activity and effective therapeutic strategies are still lacking. The high-mobility group box type 1 (HMGB1) protein has been proposed as a possible link between RSV and immune system, but only limited information is currently available to support this hypothesis.MethodsExpression of HMGB1 gene and protein was analyzed by quantitative PCR, enzyme-linked immunosorbent assay (ELISA), western blot, immunocytochemistry, and confocal microscopy in immortalized and primary human bronchial epithelial cells, as well as in rat pup lungs. The role of HMGB1 in RSV infection was explored using glycyrrhizin, a selective HMGB1 inhibitor.ResultsRSV infection strongly induced HMGB1 expression both in vitro and in vivo. Glycyrrhizin dose-dependently inhibited HMGB1 upregulation in both RSV-infected immortalized and primary human bronchial epithelial cells, and this effect was associated with significant reduction of viral replication.ConclusionOur data suggest that HMGB1 expression increases during RSV replication. This seems to have a critical pathogenic role as its selective inhibition virtually modified the infection. These observations provide further insight into the pathophysiology of RSV infection and uncover a potential biomarker and therapeutic target for the most common respiratory infection of infancy.

The monitoring of asthma is based mainly on clinical history, physical examination, and lung function test evaluation. To improve knowledge of the disease, new biomarkers of airway inflammation, including high mobility group box-1 (HMGB1), are being developed.

Mutations in proline-rich transmembrane protein 2 (PRRT2) are associated with a range of paroxysmal neurological disorders. PRRT2 predominantly localizes to the pre-synaptic terminals and is believed to regulate neurotransmitter release. However, the mechanism of action is unclear. Here, we use reconstituted single vesicle and bulk fusion assays, combined with live cell imaging of single exocytotic events in PC12 cells and biophysical analysis, to delineate the physiological role of PRRT2. We report that PRRT2 selectively blocks the transSNARE complex assembly and thus negatively regulates synaptic vesicle priming. This inhibition is actualized via weak interactions of the N-terminal proline-rich domain with the synaptic SNARE proteins. Furthermore, we demonstrate that paroxysmal dyskinesia-associated mutations in PRRT2disrupt this SNARE-modulatory function and with efficiencies corresponding to the severity of the disease phenotype. Our findings provide insights into the molecular mechanisms through which loss-of-function mutations in PRRT2result in paroxysmal neurological disorders.

Specific immunotherapy (SIT) is the only treatment able to not only act on the symptoms of allergy but also act on the causes. At present, SIT may be administered in two forms: subcutaneous (SCIT) and sublingual immunotherapy (SLIT). SCIT represents the standard modality of treatment while SLIT has recently been introduced into clinical practice and today represents an accepted alternative to SCIT. The main advantages of SIT that are lacking with drug treatment are long-lasting clinical effects and alteration of the natural course of the disease. This prevents the new onset of asthma in patients with allergic rhinitis and the onset of new sensitizations. The mechanism of action of both routes is similar; they modify peripheral and mucosal Th2-responses into a prevalent Th1-polarization with subsequent reduction of the allergic inflammatory reaction. Both have long-term effects for years after they have been discontinued, although for SLIT these evidences are insufficient To date several guidelines have defined indications, contraindications, side-effects, and clinical aspect for SCIT and SLIT. New forms of immunotherapy, allergen products and approaches to food allergy and atopic eczema represents the future of SIT.

Background Genetic factors have an important role in atopic dermatitis (AD) predisposition. Toll like receptor (TLR) are important mediators between environment and immune system. There are incosnsitent studies about TLSR polymorphisms in AD. Objective This study examined whether single nucleotide polimorphisms (SNPs) in the genes for TLR2 and TLR4 could be associated with the AD phenotypes and with its clinical severity in a large group of Italian children. Methods 187 children with Ad and 150 healthy children were recruited. AD severity was assessed by SCORAD. TLR2 (A-16934T and R753Q polymorphisms) and TLR4 (D299G and T399I SNPs) were genotyped by PCR-RFLP. Results The frequency of the R753Q was significantly higher in AD children (16.0%) compared with controls (6.0%, P=0.004; OR2.99,95%CI 1.39–6.41; RR 1.46,95%CI 1.14–1.69). AD patients a significantly different frequency of the D299G SNP (14.9%) in comparison with the controls (6.6%, P = 0.01; OR 2.46, 95%CI 1.17–5.17; RR 2.24; 95%CI 1.15–4.45). Conclusion Children with AD may have a distinct genotype and the TLR-2 R753Q SNP was prevalent in a subset of patients with AD characterized by a more severe clinical picture.