Structural rearrangements as a recurrent pathogenic mechanism for SETBP1 haploinsufficiency.

Chromosomal structural rearrangements consist of anomalies in genomic architecture that may or may not be associated with genetic material gain and loss. Evaluating the precise breakpoint is crucial from a diagnostic point of view, highlighting possible gene disruption and addressing to appropriate genotype-phenotype association. Structural rearrangements can either occur randomly within the genome or present with a recurrence, mainly due to peculiar genomic features of the surrounding regions. We report about three non-related individuals, harboring chromosomal structural rearrangements interrupting SETBP1, leading to gene haploinsufficiency. Two out of them resulted negative to Chromosomal Microarray Analysis (CMA), being the rearrangement balanced at a microarray resolution. The third one, presenting with a complex three-chromosome rearrangement, had been previously diagnosed with SETBP1 haploinsufficiency due to a partial gene deletion at one of the chromosomal breakpoints. We thoroughly characterized the rearrangements by means of Optical Genome Mapping (OGM) and Whole Genome Sequencing (WGS), providing details about the involved sequences and the underlying mechanisms. We propose structural variants as a recurrent event in SETBP1 haploinsufficiency, which may be overlooked by laboratory routine genomic analyses (CMA and Whole Exome Sequencing) or only partially determined when associated with genomic losses at breakpoints. We finally introduce a possible role of SETBP1 in a Noonan-like phenotype.

Intractable diarrhea in infancy and molecular analysis: We are beyond the tip of the iceberg.

BACKGROUND: Intractable diarrhea (ID) could be defined as a syndrome of severe chronic diarrhea associated with malnutrition not easily resolved by conventional management. AIMS: To provide an overview on etiology and management of ID patients in Italy in the last 12 years. METHODS: The members of Italian Society for Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) enrolled all ID patients seen between January 1, 2011 and December 31, 2022. RESULTS: 69 children were enrolled (49 M, 20 F; median age at ID onset 9.5 days) from 7 tertiary care pediatric centers. Overall 62 patients had genetic diseases; 3 had infantile Inflammatory Bowel Disease and 1 autoimmune enteropathy in absence of genetic mutations; 2 undefined ID. Defects of intestinal immune-related homeostasis caused ID in 29 patients (42 %). CONCLUSION: ID is a rare but challenging problem, although the potential for diagnosis has improved over time. In particular, molecular analysis allowed to identity genetic defects in 90 % of patients and to detect new genetic mutations responsible for ID. Due to both the challenging diagnosis and the treatment for many of these diseases, the close relationship between immune system and digestive tract should require a close collaboration between pediatric immunologists and gastroenterologists, to optimize epidemiologic surveillance and management of ID.

Treatment of fever and associated symptoms in the emergency department: which drug to choose?

OBJECTIVE: Fever is a frequent cause of admission to the Emergency Department (ED) worldwide. Although it can be caused by a wide range of conditions, the most effective treatment based on its etiology is still undetermined. PATIENTS AND METHODS: This prospective, single-center, observational study enrolled adult patients who accessed the ED for fever. Physicians were free to administer paracetamol 1,000 mg (P), the combination paracetamol 500 mg/ibuprofen 150 mg (PI) or Ibuprofen 600 mg (I). The primary endpoint was both 1-degree and 1-point reduction in body temperature for all associated symptoms on the Numerical Rating Scale (NRS) after 1 hour (T1). The secondary endpoint was the reduction of at least 2 points on the NRS after two hours (T2). Adverse events, the need for rescue therapy, and the response based on the underlying etiology (bacterial, viral, or immune/neoplastic) were also evaluated. RESULTS: 324 patients (170 males, mean age 71±6 years) were enrolled: 187 had bacterial, 80 viral, and 57 neoplastic/inflammatory fever. Fever was treated with Paracetamol 1,000 mg (P) in 189 patients and with Paracetamol/Ibuprofen 500/150 mg (PI) in 135 subjects, while none of the patients were primarily treated with I. Based on the fever etiology P was administered to 113 patients with bacterial fever (59.8%), 48 patients with viral fever (25.4%), and 28 subjects with neoplastic/inflammatory fever (14.8%). PI was administered to 74 patients with bacterial fever (54.8%), 32 patients with viral fever (23.7%), and 29 subjects with neoplastic/inflammatory fever (21.5%). The primary endpoint was achieved by 126 patients, 70 of them (37.0%) were treated with P and 56 (41.5%) with PI (p=0.418). The secondary endpoint was achieved by 295 patients, 171 (90.5%) of them treated with P and 124 (91.9%) treated with PI (p=0.669). No significant differences were found between groups treated with P and PI concerning rescue therapy (15 vs. 6 patients; p=0.893). Interestingly, PI was more effective than P in patients with bacterial fever at T1 (P 33.6% vs. PI 48.6%; p=0.040), while efficacy of P and PI was similar at T2 for all kind of fever. CONCLUSIONS: Paracetamol 1,000 mg represents the first choice for the treatment of fever in the ED, followed by Paracetamol/Ibuprofen 500/150 mg. Interestingly, Paracetamol/Ibuprofen combination resulted in being more effective in patients with bacterial fever one hour after its administration.

A pediatric case of TEK-Related malformations and marfanoid habitus: an incidental finding or a feature?

Vascular malformations encompass a wide range of complex vascular lesions. Due to the extreme variability of clinical presentation, classification and their related syndromes presents a challenge. Here we describe a case of a boy presenting with Marfanoid habitus, cutaneous vascular malformations, and severe acute anemia due to ileal venous malformations. Although a panel of genetic markers for the Marfan phenotype was negative, we identified a de novo mutation in the TEK gene in the patient. This case supports expansion of the phenotypic spectrum of TEK-related vascular malformations.

Unimolecular and water reactions of oxygenated and unsaturated Criegee intermediates under atmospheric conditions.

Ozonolysis of unsaturated hydrocarbons (VOCs) is one of the main oxidation processes in the atmosphere. The stabilized Criegee intermediates (SCI) formed are highly reactive oxygenated species that potentially influence the HOx, NOx and SOx cycles, and affect aerosol formation by yielding low-volatility oxygenated compounds. The current knowledge spans mostly SCI formed from primary emitted VOCs, but little is known about the reactivity of oxygenated SCI. In this work we present a theoretical kinetic study of a large number of unsaturated and oxygenated SCI, covering CC, OH, OR, OOH, OOOH, COOH, COOR, and ONO2 functionalities at various stereo- and site-specific substitutions relative to the SCI carbonyl oxide moiety. Several novel reaction types are covered, the most important of which are fast intramolecular insertion reactions in OH, OOH and COOH groups, or secondary ozonide formation with a COOH group, forming cyclic oxygenated species; these reaction classes are reminiscent of the analogous bimolecular reactions. The reaction with H2O molecules was likewise studied, finding that these cyclisation reactions can be catalysed, with predicted rate coefficients nearing the collision limit. The theoretical data is used to extend the structure-activity relationships (SARs) proposed by Vereecken et al. (2017), predicting the dominant unimolecular reaction class and rate, and the rates for reaction with H2O and (H2O)2. The SARs cover over 300 SCI categories with over 40 substituent categories. The validation of these SARs is discussed, and an outlook is given for further improvement. The generally short lifetime of oxygenated SCI suggests that ozonolysis of secondary, oxygenated VOCs is unlikely to yield ambient concentrations of SCI exceeding 104 cm-3 but will contribute strongly to the in situ formation of oxygenated VOCs.

Congenital heart defects in the recurrent 2q13 deletion syndrome.

The recurrent 2q13 deletion syndrome is a rare genetic disorder associated with developmental delay, cardiac and urogenital malformations, and minor facial anomalies. Congenital heart defects (CHDs) are the most frequent malformations associated with del2q13. Experimental studies in zebrafish suggest that two genes mapping within the 2q13 critical region (FBLN7 and TMEM87B) could confer susceptibility to congenital heart defects in affected individuals. We reviewed the cardiac characteristics in four patients with 2q13 deletion admitted to our hospitals, and in published patients. Two of our patients had congenital heart defects, consisting in partial anomalous pulmonary venous connection, ostium secundum atrial septal defect ostium secundum, and small muscular ventricular septal defect in one of them, and aortic valve insufficiency with partial fusion of two commissures (incomplete bicuspid aortic valve) and mitral valve insufficiency due to trivial mitral valve prolapse in the other. The anatomic types of CHD in del2q13 syndrome are highly variable and distributed widely, including laterality defects, complex atrioventricular septal defect, septal anomalies, and cardiomyopathies. Cardiac evaluation should be part of the clinical workup at diagnosis of 2q13 deletion.

Prevalence of copy number variants (CNVs) and rhGH treatment efficacy in an Italian cohort of children born small for gestational age (SGA) with persistent short stature associated with a complex clinical phenotype.

PURPOSE: Multiple factors influence intrauterine growth and lead to low birth sizes. The impact of genetic alterations on both pre- and post-natal growth is still largely unknown. The aim of this study was to investigate the prevalence of CNVs in an Italian cohort of SGA children with persistent short stature and complex clinical phenotype. rhGH treatment efficacy was evaluated according to the different genotypes. SUBJECTS AND METHODS: Twenty-four SGA children (10F/14M) with persistent short stature associated with dysmorphic features and/or developmental delay underwent CNV evaluation. RESULTS: CNVs were present in 14/24 (58%) SGA children. Six patients had a microdeletion involving the following regions: 3q24q25.1, 8p21.2p12, 15q26, 19q13.11, 20q11.21q12, 22q11.2. In three females, the same microdeletion involving 17p13.3 region was identified. In two different patients, two microduplications involving 10q21.3 and Xp11.3 region were observed. A further female patient showed both an 11q12.1 and an Xq27.1 microduplication, inherited from her mother and from her father, respectively. In a boy, the presence of a 12p13.33 microdeletion and a 19q13.43 microduplication was found. GH treatment efficacy, expressed by height gain and height velocity in the first 12 months of therapy, was similar in subjects with and without CNVs. CONCLUSIONS: These results show that pathogenic CNVs are common in SGA children with short stature associated with additional clinical features. Interestingly, the involvement of 17p13.3 region occurs with a relative high frequency, suggesting that genes located in this region could play a key role in pre- and post-natal growth. rhGH therapy has similar efficacy in the short term whether CNVs are present or not.

Mutación c.3037G>A en el gen FBN1 asociado a síndrome de Marfan variante neonatal / Mutation c.3037G>A in the FBN1 gene associated with neonatal Marfan syndrome variant

Resumen: El síndrome de Marfan ([SM], OMIM 154700) es un trastorno del tejido conectivo que exhibe un patrón de herencia autosómico dominante, cuyas características clínicas pueden afectar de forma variable múltiples sistemas u órganos. Es causado por mutaciones en el gen FBN1 (OMIM 134797) localizado en 15q21.1. El SM neonatal es una variedad infrecuente de la entidad asociado con mutaciones en el cambio de sentido entre los exones 23-33 y mutaciones truncadas, exhibe un fenotipo más severo y alto porcentaje de mortalidad en los primeros años de vida. Se presenta el caso de adolescente masculino con SM neonatal y mutaciones en el cambio de sentido (c.3037G>A; p.Gly225Arg) en el exón 24 del gen FBN1. Ante estos hallazgos se estudió la variación fenotípica interfamiliar, la evaluación médica interdisciplinaria precoz necesaria para el manejo de las posibles complicaciones, así como el oportuno asesoramiento genético familiar.

Abstract: Marfan syndrome ([MS], OMIM 154700) is a connective tissue disorder that exhibits an autosomal dominant pattern of inheritance, whose clinical characteristics can affect multiple systems or organs in a variable way. It is caused by mutations in the FBN1 gene (OMIM 134797) located at 15q21.1. Neonatal MS is an uncommon variety of the entity associated with missense mutation between exons 23-33 and truncating mutations, exhibits a more severe phenotype and high percentage of mortality in the first years of life. The case of male adolescent with neonatal MS and missense mutation (c.3037G> A; p.Gly225Arg) in exon 24 of the FBN1 gene is presented. Given these findings, interfamilial phenotype variation, the early interdisciplinary medical evaluation necessary for the management of possible complications, as well as the appropriate family genetic counseling were studied.

Ubiquitous atmospheric production of organic acids mediated by cloud droplets.

Atmospheric acidity is increasingly determined by carbon dioxide and organic acids1-3. Among the latter, formic acid facilitates the nucleation of cloud droplets4 and contributes to the acidity of clouds and rainwater1,5. At present, chemistry-climate models greatly underestimate the atmospheric burden of formic acid, because key processes related to its sources and sinks remain poorly understood2,6-9. Here we present atmospheric chamber experiments that show that formaldehyde is efficiently converted to gaseous formic acid via a multiphase pathway that involves its hydrated form, methanediol. In warm cloud droplets, methanediol undergoes fast outgassing but slow dehydration. Using a chemistry-climate model, we estimate that the gas-phase oxidation of methanediol produces up to four times more formic acid than all other known chemical sources combined. Our findings reconcile model predictions and measurements of formic acid abundance. The additional formic acid burden increases atmospheric acidity by reducing the pH of clouds and rainwater by up to 0.3. The diol mechanism presented here probably applies to other aldehydes and may help to explain the high atmospheric levels of other organic acids that affect aerosol growth and cloud evolution.

Theoretical and experimental study of peroxy and alkoxy radicals in the NO3-initiated oxidation of isoprene.

The initial stages of the nitrate radical (NO3) initiated oxidation of isoprene, in particular the fate of the peroxy (RO2) and alkoxy (RO) radicals, are examined by an extensive set of quantum chemical and theoretical kinetic calculations. It is shown that the oxidation mechanism is highly complex, and bears similarities to its OH-initiated oxidation mechanism as studied intensively over the last decade. The nascent nitrated RO2 radicals can interconvert by successive O2 addition/elimination reactions, and potentially have access to a wide range of unimolecular reactions with rate coefficients as high as 35 s-1; the contribution of this chemistry could not be ascertained experimentally. The chemistry of the alkoxy radicals derived from these peroxy radicals is affected by the nitrate moiety, and can lead to the formation of nitrated epoxy peroxy radicals in competition with isomerisation and decomposition channels that terminate the organic radical chain by NO2 elimination. The theoretical predictions are implemented in the FZJ-NO3-isoprene mechanism for NO3-initiated atmospheric oxidation of isoprene. The model predictions are compared against peroxy radical (RO2) and methyl vinyl ketone (MVK) measurements in a set of experiments on the isoprene + NO3 reaction system performed in the SAPHIR environmental chamber (IsopNO3 campaign). It is shown that the formation of NO2 from the peroxy radicals can prevent a large fraction of the peroxy radicals from being measured by the laser-induced fluorescence (ROxLIF) technique that relies on a quantitative conversion of peroxy radicals to hydroxyl radicals. Accounting for the relative conversion efficiency of RO2 species in the experiments, the agreement between observations and the theory-based FZJ-NO3-isoprene model predictions improves significantly. In addition, MVK formation in the NO3-initiated oxidation was found to be suppressed by the epoxidation of the unsaturated RO radical intermediates, allowing the model-predicted MVK concentrations to be in good agreement with the measurements. The FZJ-NO3-isoprene mechanism is compared against the MCM v3.3.1 and Wennberg et al. (2018) mechanisms.

Experimental and theoretical study on the impact of a nitrate group on the chemistry of alkoxy radicals.

The chemistry of nitrated alkoxy radicals, and its impact on RO2 measurements using the laser induced fluorescence (LIF) technique, is examined by a combined theoretical and experimental study. Quantum chemical and theoretical kinetic calculations show that the decomposition of ß-nitrate-alkoxy radicals is much slower than ß-OH-substituted alkoxy radicals, and that the spontaneous fragmentation of the α-nitrate-alkyl radical product to a carbonyl product + NO2 prevents other ß-substituents from efficiently reducing the energy barrier. The systematic series of calculations is summarized as an update to the structure-activity relationship (SAR) by Vereecken and Peeters (2009), and shows increasing decomposition rates with higher degrees of substitution, as in the series ethene to 2,3-dimethyl-butene, and dominant H-migration for sufficiently large alkoxy radicals such as those formed from 1-pentene or longer alkenes. The slow decomposition allows other reactions to become competitive, including epoxidation in unsaturated nitrate-alkoxy radicals; the decomposition SAR is likewise updated for ß-epoxy substituents. A set of experiments investigating the NO3-initiated oxidation of ethene, propene, cis-2-butene, 2,3-dimethyl-butene, 1-pentene, and trans-2-hexene, were performed in the atmospheric simulation chamber SAPHIR with measurements of HO2 and RO2 radicals performed with a LIF instrument. Comparisons between modelled and measured HO2 radicals in all experiments, performed in excess of carbon monoxide to avoid OH radical chemistry, suggest that the reaction of HO2 with ß-nitrate alkylperoxy radicals has a channel forming OH and an alkoxy radical in yields of 15-65%, compatible with earlier literature data on nitrated isoprene and α-pinene radicals. Model concentrations of RO2 radicals when including the results of the theoretical calculations described here, agreed within 10% with the measured RO2 radicals for all species investigated when the alkene oxidation is dominated by NO3 radicals. The formation of NO2 in the decomposition of ß-nitrate alkoxy radicals prevents detection of the parent RO2 radical in a LIF instrument, as it relies on formation of HO2. The implications for measurements of RO2 in ambient and experimental conditions, such as for the NO3-dominated chemistry during nighttime, is discussed. The current results appear in disagreement with an earlier indirect experimental study by Yeh et al. on pentadecene.

[Mutation c.3037G>A in the FBN1 gene associated with neonatal Marfan syndrome variant]. / Mutación c.3037G>A en el gen FBN1 asociado a síndrome de Marfan variante neonatal.

Marfan syndrome ([MS], OMIM 154700) is a connective tissue disorder that exhibits an autosomal dominant pattern of inheritance, whose clinical characteristics can affect multiple systems or organs in a variable way. It is caused by mutations in the FBN1 gene (OMIM 134797) located at 15q21.1. Neonatal MS is an uncommon variety of the entity associated with missense mutation between exons 23-33 and truncating mutations, exhibits a more severe phenotype and high percentage of mortality in the first years of life. The case of male adolescent with neonatal MS and missense mutation (c.3037G> A; p.Gly225Arg) in exon 24 of the FBN1 gene is presented. Given these findings, interfamilial phenotype variation, the early interdisciplinary medical evaluation necessary for the management of possible complications, as well as the appropriate family genetic counseling were studied.

El síndrome de Marfan ([SM], OMIM 154700) es un trastorno del tejido conectivo que exhibe un patrón de herencia autosómico dominante, cuyas características clínicas pueden afectar de forma variable múltiples sistemas u órganos. Es causado por mutaciones en el gen FBN1 (OMIM 134797) localizado en 15q21.1. El SM neonatal es una variedad infrecuente de la entidad asociado con mutaciones en el cambio de sentido entre los exones 23-33 y mutaciones truncadas, exhibe un fenotipo más severo y alto porcentaje de mortalidad en los primeros años de vida. Se presenta el caso de adolescente masculino con SM neonatal y mutaciones en el cambio de sentido (c.3037G>A; p.Gly225Arg) en el exón 24 del gen FBN1. Ante estos hallazgos se estudió la variación fenotípica interfamiliar, la evaluación médica interdisciplinaria precoz necesaria para el manejo de las posibles complicaciones, así como el oportuno asesoramiento genético familiar.

Immunofluorescence mapping, electron microscopy and genetics in the diagnosis and sub-classification of inherited epidermolysis bullosa: a single-centre retrospective comparative study of 87 cases with long-term follow-up.

BACKGROUND: Epidermolysis bullosa (EB) comprises a heterogeneous group of skin fragility disorders, classified in four major types based on skin cleavage level, i.e. EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), Kindler EB, and in more than 30 subtypes defined by the combination of laboratory and clinical data, including disease course. OBJECTIVES: Our aims were to address whether, in the age of genomics, electron microscopy (TEM) has still a role in diagnosing EB, and whether the genotype per se may be sufficient to sub-classify EB. METHODS: A thoroughly characterized single-centre EB case series was retrospectively evaluated to compare the power of TEM with immunofluorescence mapping (IFM) in establishing the EB type, and the ability of TEM, IFM and genetics to predict selected EB subtypes, i.e. severe dominant EBS (DEBS), severe JEB, severe recessive DEB (RDEB) and DEB self-improving, using genetic and final diagnosis, respectively, as gold standard. RESULTS: The series consisted of 87 patients, including 44 newborns, with a median follow-up of 54 months. Ninety-five mutations were identified in EB-associated genes, including 25 novel variants. Both IFM and TEM were diagnostic in about all cases of JEB (21/21 for both) and DEB (43/44 for IFM, 44/44 for TEM). TEM sensitivity was superior to IFM for EBS (19/20 vs. 16/19). As to EB subtyping, IFM performed better than genetics in identifying severe JEB cases due to laminin-332 defect (14/14 vs. 10/14) and severe RDEB (eight/nine vs. seven/nine). Genetics had no role in self-improving DEB diagnosis; it almost equalled TEM in predicting severe DEBS (eight/nine vs. nine/nine) and enabled to discriminate dominant from recessive non-severe DEB phenotypes and to identify special subtypes, e.g. DEBS with KLHL24 mutations. CONCLUSIONS: Transmission electron microscopy remains relevant to the diagnosis of EBS. IFM and genetics are essential and complementary tools in the vast majority of EB cases.

Diagnostic accuracy and economic impact of three work-up strategies identifying risk groups in endometrial cancer, fully incorporating sentinel lymph node algorithm.

BACKGROUND: According to the European Society for Medical Oncology/ European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology (ESMO/ESGO/ESTRO) Consensus Conference, the role of preoperative risk groups (RGs) in endometrial cancer (EC) is to direct surgical nodal staging. We compared diagnostic accuracy and economic impact of three work-up strategies to identify RGs. METHODS: A retrospective multicentre study including patients with early-stage EC. The three different work-up strategies were as follows:-Mondovì Hospital: transvaginal ultrasonography, pelvic magnetic resonance imaging (MRI); frozen section examination of the uterus in case of imaging discordance. High-risk patients underwent abdominal computed tomography.-Gemelli Hospital: transvaginal ultrasonography, MRI, One-Step Nucleic Acid Amplification (OSNA) of sentinel lymph node (SLN); frozen section examination of the uterus in case of imaging discordance.-Negrar Hospital: positron emission tomography (PET), frozen section examination of the uterus and of SLN. For statistical purposes patients were assigned, preoperatively and postoperatively, to two groups: group A (high-risk) and group B (not high-risk). RESULTS: Three hundred eighty-five patients were included (93 Mondovì, 215 Gemelli, 77 Negrar). Endometrial biopsy errors led to 47.3% misclassifications. Test accuracy of Mondovì, Gemelli and Negrar strategies was 0.83 (95%CI 0.734-0.901), 0.95 (95%CI 0.909-0.975) and 0.94 (95%CI 0.866-0.985), respectively. Preoperative work-up mean cost per patient in group A was €514.5 at Mondovì, €868.5 at Gemelli, and €1212.8 at Negrar hospital (p-value < 0.001), while in group B was €378.8 at Mondovì, €941.2 at Gemelli, and €1848.4 at Negrar hospital (p-value < 0.001). CONCLUSIONS: In our study, work-up strategies with more relevant economic impact showed a better diagnostic accuracy. Upcoming guidelines should specify recommendations about the gold standard work-up strategy, including the role of SLN.

Caspofungin PK in critically ill patients after the first and fourth doses: suggestions for therapeutic drug monitoring?

We describe caspofungin pharmacokinetics (PK) after the first and fourth doses in 20 critically ill septic patients. Monte Carlo simulation was used to analyze the probability of target attainment (PTA) (AUC/MIC > 865) for Candida spp. Caspofungin concentrations were analyzed by HPLC in plasma and urine. A great variability in PK parameters was observed after both doses. Patients were divided in two groups according to their AUC values (AUC ≤ 75 mg h/L cut-off). In the low-AUC group Cmax, Cmin and AUC were lower, while Vd and Cl were higher than in the high-AUC group (p < 0.05, both at day 1 and 4). The mean 24-h urinary recovery of the drug was 8 ± 6.3% (day1) and 9.8 ± 6.3 (day4). Monte Carlo simulation analysis (0.03-1 mg/L MIC-range) showed that PTA was guaranteed only for MICs ≤ 0.03 mg/L in the low-AUC group, and for MICs ≤ 0.06 mg/L in the high-AUC group. No group had a PTA ≥ 90% for 0.125 mg/L MIC (the epidemiological cut-off). Mortality was higher in low-AUC group (p < 0.01). In our 'real-world' population, no clinical data can predict which patient will have lower, suboptimal caspofungin exposure, therefore we suggest TDM to optimize caspofungin therapy and reduce the risk of selecting resistances (CEAVC, 32366/2015; OSS.15.114, NCT03798600).

Correction to: Structural modeling of a novel TERC variant in a patient with aplastic anemia and short telomeres.

The original version of this article contained a mistake in the affiliation of E. Bellacchio. Correct affiliation is presented here.

Intrafamiliar clinical variability of circumferential skin creases Kunze type caused by a novel heterozygous mutation of N-terminal TUBB gene.

Circumferential skin creases Kunze type (CSC-KT; OMIM 156610, 616734) is a rare disorder characterized by folding of excess skin, which leads to ringed creases, known as Michelin Tire Baby Syndrome (MTBS). CSC-KT patients also exhibit facial dysmorphism, growth retardation, intellectual disability (ID) and multiple congenital malformations. Recently, 2 heterozygous mutations in TUBB gene and 4 mutations (both homozygous and heterozygous) in MAPRE2 gene were identified in 3 and 4 CSC-KT patients, respectively. In the 3 TUBB gene-related CSC-KT patients, all mutations fall in the N-terminal gene domain and were de novo. Mutations in the C-terminal of TUBB gene have been associated to microcephaly and structural brain malformation, in the absence of CSC-KT features. We report a 9-year-old boy with a diagnosis of CSC-KT based on MTBS, facial dysmorphism, microcephaly, severe ID, cortical atrophy and corpus callosum hypoplasia. Sanger sequencing identified a novel heterozygous c.218T>C (p.Met73Thr) mutation in the N-terminal of TUBB gene, that was inherited from the mother affected by isolated MTBS. This is the first report of inherited TUBB gene-related CSC-KT resulting from a novel heterozygous mutation in the N-terminal domain. Present data support the role of TUBB mutations in CSC-KT and definitely includes CSC-KT syndrome within the tubulinopathies.