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Background/Objectives: In recent years, the use of smartphones has significantly increased among populations of almost every age. The aim of our work is to analyze the impact of an application (app) that follows up with the progress of a patient who underwent a thoracic surgery procedure in the first 30 days after discharge. Methods: We prospectively analyzed all the patients included in the pilot study from March 2023 to September 2023. The Care4Today™ app was downloaded and activated by the patient preoperatively. From the day of discharge, the app sent questions related to pain perception, breathing capacity, general clinical conditions, problems with surgical wound and quality of life. In the case of negative responses, clinical staff received an email with an orange (medium problem) or red (serious problem) alert. Results: Among the 96 patients who were included, 82 eventually downloaded and used the app. The mean age of the patients was 60.7 years (range 19-80), and 43 (52.4%) were female. Minimally invasive techniques (VATS or RATS) were used in 76 cases (92.7%). The mean length of in-hospital stay was 5.3 days. Malignancy was the reason for surgery in 66 cases (80.5%). The answer rate was 75.8%. A total of 698 orange alerts and 52 red alerts were sent by the app. Re-hospitalization was needed in two cases (only one case related to our surgical procedure). The app was globally judged as useful in the management of convalescence (with an average rating of 7.4 out of 10). Age was not related to the completion rate of answers. Conclusions: The use of the app Care4Today could prevent unexpected re-hospitalization and possible complications. The patients appreciated the use of this tool, and they found it useful for safer postoperative recovery. No difference according to the patients' age was found regarding the use of the app.

Background: Surgery for thymic cancers is considered the key of curative treatment. Preoperative patients' characteristics and intraoperative features might influence postoperative outcome. We aim to verify short-term outcomes and possible risk factors for complications after thymectomy., Methods: We retrospectively investigated patients undergoing surgery for thymoma or thymic carcinoma in the period between January 1, 2008, and December 31, 2021, in our department. Preoperative features, surgical technique (open, bilateral VATS, RATS), intraoperative characteristics and incidence of postoperative complications (PC) were analyzed., Results: We included in the study 138 patients. Open surgery was performed in 76 patients (55.1%), in 36 VATS (26.1%) and in 26 RATS (36.1%). Resection of one or more adjacent organs due to neoplastic infiltration was required in 25 patients. PC appeared in 25 patients (52% Clavien-Dindo grade I, 12% grade IVa). Open surgery had a higher incidence of PC (p < 0.001), longer postoperative in-hospital stay (p = 0.045) and larger neoplasm (p = 0.006). PC were significant related to pulmonary resection (p = 0.006), phrenic nerve resection (p = 0.029), resection of more than one organ (p = 0.009) and open surgery (p = 0.001), but only extended surgery of more organs was confirmed as independent prognostic factor for PC (p = 0.0013). Patients with preoperative myasthenia symptoms have a trend toward stage IVa complications (p = 0.065). No differences were observed between outcomes of VATS and RATS., Conclusions: Extended resections are related to a higher incidence of PC, while VATS and RATS guarantee a lower incidence of PC and shorter postoperative stay even in patients that require extended resections. Symptomatic myasthenia patients might have a higher risk toward more severe complications., (© 2023. The Author(s).)

Beckwith-Wiedemann Syndrome (BWS) is a pediatric overgrowth disorder involving a predisposition to embryonal tumors. Most of the tumors associated with BWS occur in the first 8-10 years of life, and the most common is Wilms tumor (WT). BWS clinical heterogeneity includes subtle overgrowth features or even silent phenotypes, and WT may be the presenting symptom of BWS. WT in BWS individuals exhibit distinct characteristics from those of sporadic WT, and the management of these patients needs a peculiar approach. The most important feature is a higher risk of developing bilateral disease at some time in the course of the illness (synchronous bilateral disease at diagnosis or metachronous recurrence after initial presentation with unilateral disease). Accordingly, neoadjuvant chemotherapy is the recommended approach also for BWS patients with unilateral WT to facilitate nephron-sparing surgical approaches. This review emphasizes the importance of early BWS recognition, particularly if a WT has already occurred, as this will result in an urgent consideration of first-line cancer therapy., Competing Interests: The authors declare no conflict of interest.

Myopericytoma is a rare tumor generally arising from skin and soft tissues of extremities, trunk, head, and neck regions, rarely from visceral sites. An intrathoracic visceral localization may carry a broad differential diagnosis including primary lung, pleura and chest wall lesions, or metastatic lesions. To date, any radiological features have been recognized and diagnosis of myopericytoma with intrathoracic localization remains still challenging. Here, we describe the case of a subpleural lesion incidentally diagnosed in an older adult affected by gastric cancer. Radiological features did not allow a differential diagnosis between a benign lesion, a primary tumor, or a metastasis. After resection, the histological examination showed histopathological features congruent with the diagnosis of myopericytoma. This unusual presentation reflects the need to share clinical, radiological, and histopathological data about this uncommon but frequently misdiagnosed disease., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

A Correction has been published | View Neurogenic tumors represent 10 to 34% of all mediastinal tumors and among them, neurofibroma originating from the vagus nerve are rare entities. We present a case of a neurofibroma with cystic degeneration originating from the left branch of the vagus nerve in a 27-year-old man without von Recklinghausen disease. A complete robotic resection of the mediastinal mass has been performed, with amputation of the vagus nerve enclosed in the mass. The postoperative course was uneventful and the patient was discharged in two days.

Mesothelioma is an aggressive disease arising from parietal pleura. Surgery is a valuable option in the frame of a multimodality treatment. Several surgical approaches have been standardized with the aim of a macroscopic complete resection; these often require homolateral diaphragm and pericardial resection and reconstruction. Extrapleural pneumonectomy (EPP) and extended pleurectomy decortication (EPD) have been recognized as radical surgical procedures. Nevertheless, both operations are technically challenging and associated with a significant rate of peri-operative morbidity and non-negligible mortality. The diaphragmatic and pericardial reconstruction technique is mandatory to avoid respiratory impairment and to reduce post-operative complications like gastric and cardiac herniation. Moreover, in the case of localized chest wall recurrence, surgery might be considered a valuable therapeutical option for highly selected and fit patients. All the technical aspects of the resection and reconstruction of the diaphragm, pericardium, and chest wall are described as well as the possible use of new minimally invasive techniques. In addition, the choice of different prosthetic materials, considering the most recent innovations in the field, are discussed.

Diamond-Blackfan anaemia (DBA) is a rare and heterogeneous disease characterised by hypoplastic anaemia, congenital anomalies and a predisposition for malignancies. The aim of this paper is to report the findings from the Italian DBA Registry, and to discuss the Registry's future challenges in tackling this disease. Our 20-year long work allowed the connection of 50 Italian Association of Paediatric Haematology and Oncology (AIEOP) centres and the recruitment of 283 cases. Almost all patients have been characterised at a molecular level (96%, 271/283), finding a causative mutation in 68% (184/271). We confirm the importance of determination of erythrocyte adenosine deaminase activity (eADA) and of ribosomal RNA assay in the diagnostic pipeline and characterisation of a remission state. Patients with mutations in large ribosomal subunit protein (RPL) genes had a significant correlation with the incidence of malformations, higher eADA levels and more severe outcomes, compared to patients with mutations in small ribosomal subunit protein (RPS) genes. Furthermore, as a consequence of our findings, particularly the incidence of malignancies and the high percentage of patients aged >18 years, we stress the importance of collaboration with adult clinicians to guarantee regular multi-specialist follow-up. In conclusion, this study highlights the importance of national registries to increase our understanding and improve management of this complex disease., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Primary familial brain calcification (PFBC) is a rare disease characterized by brain calcifications that mainly affect the basal ganglia, thalamus, and cerebellum. Among the four autosomal-dominant genes known to be associated with the disease, SLC20A2 pathogenic variants are the most common, accounting for up to 40% of PFBC dominant cases; variants include both point mutations, small insertions/deletions and intragenic deletions. Over the last 7 years, we have collected a group of 50 clinically diagnosed PFBC patients, who were screened for single nucleotide changes and small insertions/deletions in SLC20A2 by Sanger sequencing. We found seven pathogenic/likely pathogenic variants: four were previously described by our group, and three are reported here (c.303delG, c.21delG, and c.1795-1G>A). We developed and validated a synthetic Multiplex Ligation-dependent Probe Amplification (MLPA) assay for SLC20A2 deletions, covering all ten coding exons and the 5' UTR (SLC20A2-MLPA). Using this method, we screened a group of 43 PFBC-patients negative for point mutations and small insertions/deletions, and identified two novel intragenic deletions encompassing exon 6 NC&#95;000008.10:g.(42297172&#95;42302163)&#95;(423022281&#95;42317413)del, and exons 7-11 including the 3'UTR NC&#95;000008.10:g.(?&#95;42275320)&#95;(42297172&#95;42302163)del. Overall, SLC20A2 deletions may be highly underestimated PFBC cases, and we suggest MLPA should be included in the routine molecular test for PFBC diagnosis.

Myelopoiesis was evaluated in 66 pediatric patients with chronic neutropenia who were positive for anti-neutrophil antibodies (median age at diagnosis: 11 months, median neutrophil count at diagnosis: 419/μl). Other causes of neutropenia were excluded. Bone marrow morphology, clonogenic tests and/or the peripheral blood CD 34+ cell count, and apoptotic rate were evaluated in 61 patients with neutropenia lasting > 12 months or severe infections. The peripheral blood CD 34+ cell count and apoptotic rate were evaluated in five patients with shorter neutropenia. The median follow-up time was 29 months (range 7-180 months). Forty-seven patients (71.2%) had a spontaneous recovery after 7-180 months (median 29 months). The group of patients younger than 24 months at diagnosis (n = 50) had a higher probability of recovery (40/50 vs. 7/16 χ2 p<0.01) with a shorter period of neutropenia (median 26 versus 47 months, Kaplan-Meier analysis p = 0.001). The colony-forming units-granulocyte-macrophage (CFU-GM) were significantly decreased in 26/35 patients (74%) evaluated for clonogenic tests. All patients with normal CFU-GM recovered (9/9 patients); whereas, neutropenia persisted in 12/26 patients with reduced CFU-GM (46%, Pearson χ2 p = 0.02). In 36/55 (65%) patients evaluated by flow cytometry we observed reduced circulating CD34+ cells compared with controls of the same age. An increase in the circulating CD34+ cell apoptotic rate was observed in 28/55 patients (51%). Infections requiring hospitalization were observed in 9/18 (50%; Pearson χ2, p = 0.03) patients with both decreased circulating CD34+ cells and increased CD34+ apoptotic rates. In the group aged < 24 months, we observed a significant correlation between the persistence of neutropenia and decreased circulating CD34+ cells (Pearson χ2 p = 0.008). In conclusion, reduced CFU-GM and circulating hematopoietic progenitors were observed in a subgroup of children with chronic neutropenia who were positive for anti-neutrophil antibodies and had a higher incidence of severe infections and delayed spontaneous remission., Competing Interests: The authors have declared that no competing interests exist.

Objectives: A small number of patients with advanced pulmonary adenocarcinomas treated with tyrosine kinase inhibitors (TKIs) was subsequently considered eligible for surgery. Our goal was to report the clinical characteristics, pathological features and prognosis of these patients with the aim of exploring the feasibility of this strategy of care., Methods: We retrospectively reviewed the medical files of 19 patients in whom systemic treatment, including TKIs, resulted in a possible stabilization of the disease such that they were considered eligible for surgery (adjuvant surgery)., Results: Lobectomy, pneumonectomy or segmentectomy was performed in 68.4%, 26.3% and 5.3% of cases, respectively. Limited fibrotic tissues were detected intraoperatively in 8 patients who received TKIs as the sole systemic treatment. The postoperative course in the hospital was uneventful in 13 (68.4%) cases; 3 (15.8%) patients suffered major complications. The post-pneumonectomy early morbidity rate was 60%. A pathological analysis of the tumours showed that the median rate of fibrosis was 32.5% (0-100); of viable neoplastic tissue, 25.0% (0-90); and of necrosis, 12.5% (0-80%). Four tumours (21.1%) exhibited no viable tumour cells. The fibrosis ratio was higher in patients older than 60 years (P = 0.01) and in those treated with erlotinib (P = 0.03). The 3- and 5-year overall survival and disease-free survival rates were 79.5%/39.8% and 44.4%/29.6%, respectively. Pneumonectomy and <50% fibrosis or >30% viable tumour cells in the pathological specimens were factors significantly associated with lower disease-free survival., Conclusions: In a subset of highly selected patients, adjuvant lung surgery following treatment with TKI showed a large spectrum of histological changes in the pathological specimens and encouraging preliminary survival results. Pending further research, it may prove a relatively reliable and safe therapeutic choice, except when an extensive resection like a pneumonectomy is planned.

Chromosomal region 1p22 is deleted in ⩾20% of multiple myeloma (MM) patients, suggesting the presence of an unidentified tumor suppressor. Using high-resolution genomic profiling, we delimit a 58 kb minimal deleted region (MDR) on 1p22.1 encompassing two genes: ectopic viral integration site 5 (EVI5) and ribosomal protein L5 (RPL5). Low mRNA expression of EVI5 and RPL5 was associated with worse survival in diagnostic cases. Patients with 1p22 deletion had lower mRNA expression of EVI5 and RPL5, however, 1p22 deletion status is a bad predictor of RPL5 expression in some cases, suggesting that other mechanisms downregulate RPL5 expression. Interestingly, RPL5 but not EVI5 mRNA levels were significantly lower in relapsed patients responding to bortezomib and; both in newly diagnosed and relapsed patients, bortezomib treatment could overcome their bad prognosis by raising their progression-free survival to equal that of patients with high RPL5 expression. In conclusion, our genetic data restrict the MDR on 1p22 to EVI5 and RPL5 and although the role of these genes in promoting MM progression remains to be determined, we identify RPL5 mRNA expression as a biomarker for initial response to bortezomib in relapsed patients and subsequent survival benefit after long-term treatment in newly diagnosed and relapsed patients.

Background: Lobectomy for benign lung disease is renowned to be technically complex and to be subjected to an increased complication rate. The objective of this study was to evaluate whether the results obtained with video-assisted surgery (VATS) in benign disease are comparable to those obtained in oncologic surgery, where VATS has been validated., Methods: We have reviewed the files of 246 consecutive patients who underwent VATS lobectomy from January 2012 to August 2015. The cohort was divided into two groups according to pathology (benign or malignant). Outcome parameters on scrutiny were demographics, pathology, duration of air leak, drainage and hospital stay, conversion, and perioperative complication rate. Comparisons were made with the χ 2 test and Student's t test; any p value ≤0.05 was considered as significant., Results: Group 1 (36 patients) included patients who underwent lobectomy for benign disease and group 2 (210 patients) patients affected by lung cancer or pulmonary metastases. The two groups differed with reference to age (p < 0.001), history of cancer (p < 0.001), history of stroke (p = 0.05), and the presence of pleural adhesions (p = 0.03). There was no difference for duration of air leaks, chest tube drainage and hospital stay, conversion rate, and perioperative complication rate., Conclusions: We conclude that pathology did not impact on outcomes after VATS lobectomy. This study suggests that VATS is as a safe option in selected patients with benign disease requiring lobectomy, despite a more complex technical context.

Objectives: The management of pIIIA-N2 non-small-cell lung cancer (NSCLC) is still controversial. In particular, there are wide variations in overall survival (OS), suggesting the existence of subgroups among N2 patients. We aimed to evaluate the prognostic value of microscopic pN2 in NSCLC., Methods: Between 1996 and 2015, the data from all 982 pathologically stage IIIA-N2 patients who underwent surgery with curative intent for NSCLC were retrospectively reviewed. Microscopic pN2 disease was defined as a nodal metastasis ranging from 0.2 to 2 mm in size., Results: With a median follow-up of 17 months (2-101), the 5-year OS for the whole cohort was 31%. Microscopic N2 was observed in 309 (31.5%) patients. Microscopic N2 was associated with better median OS compared with macroscopic N2 [42 months (95% CI 36.85-47.15) vs 23 months (95% CI 19.7-26.29), P < 0.0001, with a corresponding 5-year OS rate of 39 and 21%, respectively]. In multivariate analysis, microscopic N2 remained a favourable independent prognostic factor [HR 0.681 (95% CI 0.481-0.967), P = 0.03]. The median OS of microscopic N2 patients who benefitted from simple follow-up was significantly better than those who underwent chemotherapy, radiation therapy or both [43 months (95% CI 24.22-61.78) vs 22 months (95% CI 17.43-26.47) vs 31 months (95% CI 27.66-34.34) vs 16 months (95% CI 14.6-17.4), P = 0.008]., Conclusion: Microscopic N2 seems to be associated with better prognosis in patients with pIIIA-N2 NSCLC and these could benefit from a simple follow-up. Prospective cohort studies are necessary to confirm these preliminary results., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Diamond-Blackfan anaemia (DBA) is an inherited disease characterized by pure erythroid aplasia that has been tagged as a 'ribosomopathy'. We report a multi-centre study focused on the analysis of rRNA processing of 53 Italian DBA patients using capillary electrophoresis analysis of rRNA maturation of the 40S and 60S ribosomal subunits. The ratio of 28S/18S rRNA was higher in patients with mutated ribosomal proteins (RPs) of the small ribosomal subunit. In contrast, patients with mutated RPs of the large ribosomal subunit (RPLs) had a lower 28S/18S ratio. The assay reported here would be amenable for development as a diagnostic tool., (© 2016 John Wiley & Sons Ltd.)

Background: Complete surgical excision is the most important long-term prognostic factor of thymomas. Although video-assisted thoracoscopic surgery (VATS) has been reported as an effective treatment to excise mediastinal thymic lesions, it has not replaced median sternotomy as the standard approach because of the lack of long-term follow-up studies. The objective of this study was to analyze and to compare the outcome of VATS extended thymectomy with the traditional open approach., Methods: This is a single center's retrospective study of 27 patients submitted to surgery for early stage thymomas between 1995 and 2007. Histologic subtype and clinicopathologic staging were classified, respectively, according to World Health Organization and Masaoka criteria. Patients with preoperative computed tomography scan evidence of clinical Masaoka stage 1 thymomas were selected for VATS thymectomy with unilateral technique., Results: All patients successfully underwent surgery: 3 with VATS and 4 with an open approach. There were no differences in time of surgery and postoperative complication between the two groups. Patients who had VATS had shorter postoperative hospital stay than patients who had open technique. After a median follow-up of 123 months, there were no postoperative recurrences., Conclusion: VATS is a safe operation and has comparable effectiveness to the open technique in terms of oncological radicality for small, early stage thymoma., (Georg Thieme Verlag KG Stuttgart · New York.)

Diamond Blackfan anemia (DBA), a syndrome primarily characterized by anemia and physical abnormalities, is one among a group of related inherited bone marrow failure syndromes (IBMFS) which share overlapping clinical features. Heterozygous mutations or single-copy deletions have been identified in 12 ribosomal protein genes in approximately 60% of DBA cases, with the genetic etiology unexplained in most remaining patients. Unlike many IBMFS, for which functional screening assays complement clinical and genetic findings, suspected DBA in the absence of typical alterations of the known genes must frequently be diagnosed after exclusion of other IBMFS. We report here a novel deletion in a child that presented such a diagnostic challenge and prompted development of a novel functional assay that can assist in the diagnosis of a significant fraction of patients with DBA. The ribosomal proteins affected in DBA are required for pre-rRNA processing, a process which can be interrogated to monitor steps in the maturation of 40S and 60S ribosomal subunits. In contrast to prior methods used to assess pre-rRNA processing, the assay reported here, based on capillary electrophoresis measurement of the maturation of rRNA in pre-60S ribosomal subunits, would be readily amenable to use in diagnostic laboratories. In addition to utility as a diagnostic tool, we applied this technique to gene discovery in DBA, resulting in the identification of RPL31 as a novel DBA gene., (© 2014 Wiley Periodicals, Inc.)

The paper presents an unusual case of single small bowel metastasis from primary lung leiomyosarcoma (PLL) presenting with abdominal pain and gastrointestinal (GI) bleeding successfully treated by surgery with radical aim.

Mutations in the hematopoietic transcription factor GATA-1 alter the proliferation/differentiation of hemopoietic progenitors. Mutations in exon 2 interfere with the synthesis of the full-length isoform of GATA-1 and lead to the production of a shortened isoform, GATA-1s. These mutations have been found in patients with Diamond-Blackfan anemia (DBA), a congenital erythroid aplasia typically caused by mutations in genes encoding ribosomal proteins. We sequenced GATA-1 in 23 patients that were negative for mutations in the most frequently mutated DBA genes. One patient showed a c.2T > C mutation in the initiation codon leading to the loss of the full-length GATA-1 isoform., (© 2014 Wiley Periodicals, Inc.)

Diamond-Blackfan anemia is an autosomal dominant disease due to mutations in nine ribosomal protein encoding genes. Because most mutations are loss of function and detected by direct sequencing of coding exons, we reasoned that part of the approximately 50% mutation negative patients may have carried a copy number variant of ribosomal protein genes. As a proof of concept, we designed a multiplex ligation-dependent probe amplification assay targeted to screen the six genes that are most frequently mutated in Diamond-Blackfan anemia patients: RPS17, RPS19, RPS26, RPL5, RPL11, and RPL35A. Using this assay we showed that deletions represent approximately 20% of all mutations. The combination of sequencing and multiplex ligation-dependent probe amplification analysis of these six genes allows the genetic characterization of approximately 65% of patients, showing that Diamond-Blackfan anemia is indisputably a ribosomopathy.

Diamond Blackfan anemia typically presents in infants and is often associated with many kinds of malformations. Severity of anemia often needs transfusional support in the first months of life. We describe here a patient with Diamond Blackfan anemia related to a RPL5 mutation. The patient had no physical abnormalities and experienced a very late onset of transfusion dependency.

Acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome is a rare condition belonging to the group of ectodermal dysplasias caused by TP63 mutations. Its clinical phenotype is similar to ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC) and limb-mammary syndrome (LMS), and differs from these disorders mainly by the absence of cleft lip and/or palate. We report on a 39-year-old patient who was found to be heterozygous for a c.401G > T (p.Gly134Val) de novo mutation of TP63. This patient had the ADULT phenotype associated with cleft palate. Our findings, rather than extend the clinical spectrum of ADULT syndrome, suggest that cleft palate can no longer be considered an element for differential diagnosis for ADULT, EEC, and LMS. Our data, added to other reports on overlapping phenotypes, support the combining of these three phenotypes into a unique entity that we propose to call "ELA syndrome," which is an acronym of ectrodactyly-ectodermal dysplasia-cleft lip and palate, limb-mammary, and ADULT syndromes., (Copyright © 2011 Wiley Periodicals, Inc.)

Diamond-Blackfan Anemia (DBA) is characterized by a defect of erythroid progenitors and, clinically, by anemia and malformations. DBA exhibits an autosomal dominant pattern of inheritance with incomplete penetrance. Currently nine genes, all encoding ribosomal proteins (RP), have been found mutated in approximately 50% of patients. Experimental evidence supports the hypothesis that DBA is primarily the result of defective ribosome synthesis. By means of a large collaboration among six centers, we report here a mutation update that includes nine genes and 220 distinct mutations, 56 of which are new. The DBA Mutation Database now includes data from 355 patients. Of those where inheritance has been examined, 125 patients carry a de novo mutation and 72 an inherited mutation. Mutagenesis may be ascribed to slippage in 65.5% of indels, whereas CpG dinucleotides are involved in 23% of transitions. Using bioinformatic tools we show that gene conversion mechanism is not common in RP genes mutagenesis, notwithstanding the abundance of RP pseudogenes. Genotype-phenotype analysis reveals that malformations are more frequently associated with mutations in RPL5 and RPL11 than in the other genes. All currently reported DBA mutations together with their functional and clinical data are included in the DBA Mutation Database., (© 2010 Wiley-Liss, Inc.)

Congenital portosystemic shunts (PSS) are rare vascular anomalies with different gross anatomy. Persistent patent ductus venosus (PDV) represents an uncommon cause of intrahepatic PSS. The diagnosis of this condition may not be obvious because of its wide spectrum of clinical manifestations, ranging from asymptomatic to life-threatening disease. We report the case of three boys with neuropsychological symptoms associated with mild fasting hyperammonemia. An oral protein load allowed the detection of a detoxication defect due to PSS related to PDV. This simple procedure can be worthwhile of attention in patients with mental retardation, behavior disturbances, and learning difficulties after exclusion of common causes of inherited hyperammonemia, namely, urea cycle disorders, organic acidemias, and fatty acid oxidation defects.

Background: Diamond-Blackfan anemia is a rare, pure red blood cell aplasia of childhood due to an intrinsic defect in erythropoietic progenitors. About 40% of patients display various malformations. Anemia is corrected by steroid treatment in more than 50% of cases; non-responders need chronic transfusions or stem cell transplantation. Defects in the RPS19 gene, encoding the ribosomal protein S19, are the main known cause of Diamond-Blackfan anemia and account for more than 25% of cases. Mutations in RPS24, RPS17, and RPL35A described in a minority of patients show that Diamond-Blackfan anemia is a disorder of ribosome biogenesis. Two new genes (RPL5, RPL11), encoding for ribosomal proteins of the large subunit, have been reported to be involved in a considerable percentage of patients., Design and Methods: In this genotype-phenotype analysis we screened the coding sequence and intron-exon boundaries of RPS14, RPS16, RPS24, RPL5, RPL11, and RPL35A in 92 Italian patients with Diamond-Blackfan anemia who were negative for RPS19 mutations., Results: About 20% of the patients screened had mutations in RPL5 or RPL11, and only 1.6% in RPS24. All but three mutations that we report here are new mutations. No mutations were found in RPS14, RPS16, or RPL35A. Remarkably, we observed a higher percentage of somatic malformations in patients with RPL5 and RPL11 mutations. A close association was evident between RPL5 mutations and craniofacial malformations, and between hand malformations and RPL11 mutations., Conclusions: Mutations in four ribosomal proteins account for around 50% of all cases of Diamond-Blackfan anemia in Italian patients. Genotype-phenotype data suggest that mutation screening should begin with RPL5 and RPL11 in patients with Diamond-Blackfan anemia with malformations.