Quality of life and outcomes after rubber band ligation for haemorrhoidal disease.

PURPOSE: The main objective of this study was to assess the impact on quality of life after rubber band ligation (RBL) in patients with symptomatic grade II-III haemorrhoids who did not improve after 6 months of conservative treatment, using quality of life scores. METHODS: This was a prospective cohort observational study where patients with haemorrhoidal disease and indication for RBL were included between December 2019 and December 2020. RBL was offered as first-line treatment in this group. Patient´s quality of life was assessed by scores: HDSS (Hemorrhoidal Disease Symptom Score) and SHS (Short Health Scale).Secondary objectives were: to evaluate the rate of patients requiring one or more RBL procedures, to establish the overall success rate of RBL and to analyse complications. RESULTS: A total of 100 patients were finally included. Regarding the impact on quality of life after RBL, a significant reduction was found in the HDSS and SHS scores (p < 0.001). The main improvement was found in the first month and it was maintained until the sixth month. A high degree of satisfaction with the procedure was reported by 76% of patients. The overall success rate of banding was 89%. A 12% complication rate was detected, the most frequent complication was severe anal pain (58.3%) and self-limiting bleeding (41.7%). CONCLUSION: Rubber band ligation, as a treatment for symptomatic grade II-III haemorrhoids that do not respond to medical treatment, leads to a significant improvement in patients' symptoms and quality of life. It also has a high degree of satisfaction between patients.

Simultaneous determination of four serotonin selective reuptake inhibitors by an UPLC MS-MS method with clinical application in therapeutic drug monitoring.

An analytical method of ultra-high performance liquid chromatography coupled to tandem mass spectrometry detection was developed and validated for the simultaneous quantification in plasma of four selective serotonin reuptake inhibitor antidepressants: sertraline, escitalopram, paroxetine, fluoxetine, and its metabolite norfluoxetine. A simple protein precipitation was performed with acetonitrile containing 100 ng/mL of indomethacin, which was used as internal standard. Chromatographic separation was carried out on an Acquity BEH C18 column with isocratic elution of the mobile phase consisting of 5 mmol/L ammonium acetate with 0.1% formic acid (A) and acetonitrile (B) at a 60:40 proportion, respectively. The flow rate was 0.4 mL/min with a run time of 5 min. A positive electrospray ionization source was used for detection. The method was linear in a range of 5-800 ng/mL, with determination coefficients greater than 0.991. The accuracy ranged from 91% to 112% for intra-assay and from 89% to 112% for inter-assay. The variation coefficients ranged from 3.1% to 14.88% for intra-assay and from 3.60% to 14.74% for inter-assay precision. The method was successfully applied for the analysis of 73 samples from patients under treatment with these antidepressants; 36.9% of the samples had concentrations outside therapeutic ranges. This method can be applied for routine analysis in clinical practice, simplifying sample processing, reducing analysis time and consequently the costs associated with it.

Curso clínico y perfil neuropsicológico de un caso de trastorno neurocognitivo frontotemporal mayor variante lingüística / Clinical course and neuropsychological profile of Frontotemporal Neurocognitive Disorder Linguistic Language Variant

Resumen El trastorno neurocognitivo frontotemporal es una enfermedad neurodegenerativa que incluye manifestaciones clínicas de subtipo comportamental y lingüística. La afasia progresiva primaria (APP) es un síndrome en el que aparecen alteraciones del lenguaje que comprende tres tipos de variantes: no fluente, semántica y logopénica. Este estudio describe la evolución clínica y las características neuropsicológicas de una mujer de 63 años que presenta un deterioro progresivo del lenguaje. Se evalúan las funciones de atención, memoria, lenguaje y funciones ejecutivas. La paciente obtuvo un bajo rendimiento en memoria, velocidad de procesamiento y funciones ejecutivas. Su lenguaje se caracteriza por presentar baja fluidez, agramatismo, parafasias verbales y dificultades en denominación. Se concluye que la paciente presenta características de la APP no fluente, que varía a través del tiempo y afecta su funcionamiento; características de un curso clínico de un trastorno neurocognitivo mayor posible debido a una degeneración del lóbulo frontotemporal.

Abstract Mild cognitive impairment, frontotemporal dementia (FTD) is a neurodegenerative disease characterized by clinical manifestations of behavior and linguistic subtypes. Primary Progressive Aphasia (APP) is a syndrome in which language alterations appear that include three types of variations: Non - fluent, Semantic and Logopenic. This study describes the clinical evolution and the neurophysiological characteristics of a 63 years old woman that started with a progressive language impairment. The functions which are evaluated are attention, memory, language and executive functions. The patient obtained a low performance in memory, processing speed and executive functions. The language is characterized by low fluency, agramatism, paraphasias and denomination difficulties. It is concluded, that the patient has characteristics of APP non-fluent which varies throughout the time and it affects her performance; characteristics of a clinical course of a greater neurocognitive disorder might be due to a lobe frontotemporal degeneration.

Role of negative pressure wound therapy in the prevention of surgical site infection in colorectal surgery. / Papel de la terapia presión negativa en la prevención de infección del sitio quirúrgico en cirugía colorrectal.

BACKGROUND: Surgical site infection (SSI) is one of the most frequent complications in colorectal surgery. It is diagnosed in 10 - 20% of colorectal procedures. Negative Pressure Wound Therapy (NPWT) has shown efficacy in the treatment of chronic and traumatic wounds, wound dehiscence, flaps and grafts. The main objective of this study is to assess NPWT in the prevention of SSI in colorectal surgery. Hospital stay reduction and SSI risk factors are secondary objectives. METHODS: We present a prospective case-control study including 80 patients after a colorectal diagnosis and surgical procedure (elective and non-elective) in 2017. Forty patients were treated with prevention NPWT for one week. Forty patients were treated according to the standard postoperative surgical wound care protocol. RESULTS: No significant differences were found in demographic variables, comorbidities, surgical approach, elective or non-elective surgery, mechanical bowel preparation and surgical procedure. Three patients has SSI in the NPWT group (8%) (95%CI 0 - 17.5). Ten patients presented SSI in the control group (25%) (95%CI 12.5 - 37.5) (p=0.034); OR 0.7 (95%CI 0.006-0.964). Hospital stay in the NPWT group was 8 days versus 12 days in the non-NPWT group (p=0.22). In the multivariate analysis, mechanical bowel preparation was found to be the only risk factor for SSI (p=0.047; OR: 0.8, CI 0.45-0.93). CONCLUSIONS: NPWT is a useful SSI prevention treatment in colorectal surgery.

Genome Sequencing and Analysis Methods in Chronic Lymphocytic Leukemia.

The genomic sequencing of chronic lymphocytic leukemia (CLL) samples has provided exciting new venues for the understanding and treatment of this prevalent disease. This feat is possible thanks to high-throughput sequencing methods, such as Illumina sequencing. The interpretation of these data sources requires not only appropriate software and hardware, but also understanding the biology and technology behind the sequencing process. Here, we provide a primer to understand each step in the analysis of point mutations from whole-genome or whole-exome sequencing experiments of tumor and normal samples.

Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome.

BACKGROUND: Wiedemann-Rautenstrauch syndrome (WRS) is a form of segmental progeria presenting neonatally, characterised by growth retardation, sparse scalp hair, generalised lipodystrophy with characteristic local fatty tissue accumulations and unusual face. We aimed to understand its molecular cause. METHODS: We performed exome sequencing in two families, targeted sequencing in 10 other families and performed in silico modelling studies and transcript processing analyses to explore the structural and functional consequences of the identified variants. RESULTS: Biallelic POLR3A variants were identified in eight affected individuals and monoallelic variants of the same gene in four other individuals. In the latter, lack of genetic material precluded further analyses. Multiple variants were found to affect POLR3A transcript processing and were mostly located in deep intronic regions, making clinical suspicion fundamental to detection. While biallelic POLR3A variants have been previously reported in 4H syndrome and adolescent-onset progressive spastic ataxia, recurrent haplotypes specifically occurring in individuals with WRS were detected. All WRS-associated POLR3A amino acid changes were predicted to perturb substantially POLR3A structure/function. CONCLUSION: Biallelic mutations in POLR3A, which encodes for the largest subunit of the DNA-dependent RNA polymerase III, underlie WRS. No isolated functional sites in POLR3A explain the phenotype variability in POLR3A-related disorders. We suggest that specific combinations of compound heterozygous variants must be present to cause the WRS phenotype. Our findings expand the molecular mechanisms contributing to progeroid disorders.

The microRNA-29/PGC1α regulatory axis is critical for metabolic control of cardiac function.

Different microRNAs (miRNAs), including miR-29 family, may play a role in the development of heart failure (HF), but the underlying molecular mechanisms in HF pathogenesis remain unclear. We aimed at characterizing mice deficient in miR-29 in order to address the functional relevance of this family of miRNAs in the cardiovascular system and its contribution to heart disease. In this work, we show that mice deficient in miR-29a/b1 develop vascular remodeling and systemic hypertension, as well as HF with preserved ejection fraction (HFpEF) characterized by myocardial fibrosis, diastolic dysfunction, and pulmonary congestion, and die prematurely. We also found evidence that the absence of miR-29 triggers the up-regulation of its target, the master metabolic regulator PGC1α, which in turn generates profound alterations in mitochondrial biogenesis, leading to a pathological accumulation of small mitochondria in mutant animals that contribute to cardiac disease. Notably, we demonstrate that systemic hypertension and HFpEF caused by miR-29 deficiency can be rescued by PGC1α haploinsufficiency, which reduces cardiac mitochondrial accumulation and extends longevity of miR-29-mutant mice. In addition, PGC1α is overexpressed in hearts from patients with HF. Collectively, our findings demonstrate the in vivo role of miR-29 in cardiovascular homeostasis and unveil a novel miR-29/PGC1α regulatory circuitry of functional relevance for cell metabolism under normal and pathological conditions.

Mouse Models to Disentangle the Hallmarks of Human Aging.

Model organisms have provided fundamental evidence that aging can be delayed and longevity extended. These findings gave rise to a new era in aging research aimed at elucidating the pathways and networks controlling this complex biological process. The identification of 9 hallmarks of aging has established a framework to evaluate the relative contribution of each hallmark and the interconnections among them. In this review, we revisit these hallmarks with the information obtained exclusively through the generation of genetically modified mouse models that have a significant impact on the aging process. We discuss within each hallmark those interventions that accelerate aging or that have been successful at increasing lifespan, with the final goal of identifying the most promising antiaging avenues based on the current knowledge provided by in vivo models.

Management of Esophageal Perforation: 28-Year Experience in a Major Referral Center.

Esophageal perforation constitutes a surgical emergency. Despite its gravity, no single strategy has been described as sufficient to deal with most situations to date. The aim of this study was to assess the etiology, management, and outcome of esophageal perforation over a 28-year period, to characterize optimal treatment options in this severe disease. A retrospective clinical review of all patients treated for esophageal perforation at Ramón y Cajal Hospital between January 1987 and December 2015 was performed (n = 57). Iatrogenic injury was the most frequent cause of esophageal perforation (n = 32). Abdominal esophagus was the main location (23 patients; 40.4%). Eight patients (14%) were managed with antibiotics and parenteral nutrition. In seven patients (12.3%), an endoscopic stent was implanted. Surgical therapy was performed in 38 patients (66.7%). Morbidity and 90-day mortality rates were 61.4 and 28 per cent, respectively. Five patients were reoperated (8.8%). Median hospital stay was 23.5 days. The mortality rate was higher among patients with spontaneous and tumoral perforation (54.5 and 100%; P = 0.009), delayed diagnosis (>24 hours; P = 0.0001), and abdominal/thoracic location (37.5%; P = 0.05). No statistical differences were found between surgical and conservative/endoscopic management (31% vs 20%; P = 0.205) although hospital staying was longer in surgical group (36.30 days vs 15.63 days; P = 0.029). Esophageal perforation was associated with high morbidity and mortality rates. Global outcomes depend on etiology, site of perforation, and delay in diagnosis. An individualized approach for each patient should be chosen to prevent septic complications of this potentially fatal disease.

Matriptase-2 deficiency protects from obesity by modulating iron homeostasis.

Alterations in iron status have frequently been associated with obesity and other metabolic disorders. The hormone hepcidin stands out as a key regulator in the maintenance of iron homeostasis by controlling the main iron exporter, ferroportin. Here we demonstrate that the deficiency in the hepcidin repressor matriptase-2 (Tmprss6) protects from high-fat diet-induced obesity. Tmprss6 -/- mice show a significant decrease in body fat, improved glucose tolerance and insulin sensitivity, and are protected against hepatic steatosis. Moreover, these mice exhibit a significant increase in fat lipolysis, consistent with their dramatic reduction in adiposity. Rescue experiments that block hepcidin up-regulation and restore iron levels in Tmprss6-/- mice via anti-hemojuvelin (HJV) therapy, revert the obesity-resistant phenotype of Tmprss6-/- mice. Overall, this study describes a role for matritpase-2 and hepcidin in obesity and highlights the relevance of iron regulation in the control of adipose tissue function.

Cancer Susceptibility Models in Protease-Deficient Mice.

For decades, proteases have been associated with cancer progression due to the ability of some members of this large group of enzymes to degrade tumor cell surroundings, thereby facilitating cancer invasion and dissemination. However, the generation of mouse models deficient in proteases has revealed the existence of a great variety of functions among proteolytic enzymes in cancer biology, including important tumor-suppressive roles. Therefore, in this chapter, we describe methods to chemically induce different types of cancer (lung adenocarcinoma, hepatocellular carcinoma, oral and esophageal carcinoma, colorectal carcinoma, skin cancer, and fibrosarcoma) in genetically modified mouse models to efficiently evaluate the specific pro- or antitumoral function of proteases in cancer.

TMEFF2 shedding is regulated by oxidative stress and mediated by ADAMs and transmembrane serine proteases implicated in prostate cancer.

TMEFF2 is a type I transmembrane protein with two follistatin (FS) and one EGF-like domain over-expressed in prostate cancer; however its biological role in prostate cancer development and progression remains unclear, which may, at least in part, be explained by its proteolytic processing. The extracellular part of TMEFF2 (TMEFF2-ECD) is cleaved by ADAM17 and the membrane-retained fragment is further processed by the gamma-secretase complex. TMEFF2 shedding is increased with cell crowding, a condition associated with the tumour microenvironment, which was mediated by oxidative stress signalling, requiring jun-kinase (JNK) activation. Moreover, we have identified that TMEFF2 is also a novel substrate for other proteases implicated in prostate cancer, including two ADAMs (ADAM9 and ADAM12) and the type II transmembrane serine proteinases (TTSPs) matriptase-1 and hepsin. Whereas cleavage by ADAM9 and ADAM12 generates previously identified TMEFF2-ECD, proteolytic processing by matriptase-1 and hepsin produced TMEFF2 fragments, composed of TMEFF2-ECD or FS and/or EGF-like domains as well as novel membrane retained fragments. Differential TMEFF2 processing from a single transmembrane protein may be a general mechanism to modulate transmembrane protein levels and domains, dependent on the repertoire of ADAMs or TTSPs expressed by the target cell.

Novel LMNA mutations cause an aggressive atypical neonatal progeria without progerin accumulation.

BACKGROUND: Progeroid syndromes are genetic disorders that recapitulate some phenotypes of physiological ageing. Classical progerias, such as Hutchinson-Gilford progeria syndrome (HGPS), are generally caused by mutations in LMNA leading to accumulation of the toxic protein progerin and consequently, to nuclear envelope alterations. In this work, we describe a novel phenotypic feature of the progeria spectrum affecting three unrelated newborns and identify its genetic cause. METHODS AND RESULTS: Patients reported herein present an extremely homogeneous phenotype that somewhat recapitulates those of patients with HGPS and mandibuloacral dysplasia. However, pathological signs appear earlier, are more aggressive and present distinctive features including episodes of severe upper airway obstruction. Exome and Sanger sequencing allowed the identification of heterozygous de novo c.163G>A, p.E55K and c.164A>G, p.E55G mutations in LMNA as the alterations responsible for this disorder. Functional analyses demonstrated that fibroblasts from these patients suffer important dysfunctions in nuclear lamina, which generate profound nuclear envelope abnormalities but without progerin accumulation. These nuclear alterations found in patients' dermal fibroblasts were also induced by ectopic expression of the corresponding site-specific LMNA mutants in control human fibroblasts. CONCLUSIONS: Our results demonstrate the causal role of p.E55K and p.E55G lamin A mutations in a disorder which manifests novel phenotypic features of the progeria spectrum characterised by neonatal presentation and aggressive clinical evolution, despite being caused by lamin A/C missense mutations with effective prelamin A processing.

Comparative study between open and minimally invasive approach in the surgical management of esophageal leiomyoma.

INTRODUCTION: Leiomyomas are the most common benign tumors of the esophagus. Although classically surgical enucleation through thoracotomy or laparotomy has been widely accepted as treatment of choice, development of endoscopic and minimally invasive procedures has completely changed the surgical management of these tumors. MATERIAL AND METHODS: We performed a retrospective review of all esophageal leiomyoma operated at Hospital Universitario Ramón y Cajal (Madrid, Spain) between January 1986 and December 2014, analyzing patients' demographic data, symptomatology, tumor size and location, diagnostic tests, surgical data, complications and postoperative stay. RESULTS: Thirteen patients were found within that period, 8 men and 5 women, with a mean age of 53.62 years (range 35-70 years). Surgical enucleation was achieved in all patients. In 8 cases (61.54%) a thoracic approach was performed (4 thoracotomies and 4 thoracoscopies), and in 5 cases (38.56%) an abdominal approach was performed (3 laparotomies and 2 laparoscopies); enucleation was carried out through a minimally invasive approach in 6 patients (46.15%). There were no cases of endoscopic resection alone. Surgery mean length was 174.38 minutes (range 70-270 minutes) and median postoperative stay was 6.5 days (range 2-27 days). There was neither mortality nor cases of intraoperative complications were described. No postoperative major complications were reported; however one patient presented important pain in his right hemithorax that required management and long term follow-up by the Pain Management Unit. With a mean follow-up of 165.57 months (median 170; range 29-336 months) no recurrences were reported. CONCLUSION: Enucleation is the treatment of choice for the majority of esophageal leiomyomas. In our experience, duration of the surgical procedure through minimally invasive approach was longer than surgery through open approach; however, postoperative stay was shorter in the first group. Paradoxically, incision pain after surgery (thoracic neuralgia) was found to be higher in the minimally invasive approach group. Nevertheless, none of the results obtained in the study reached statistical significance, probably due to the small simple size.

The role of serum osteoprotegerin and receptor-activator of nuclear factor-κB ligand in metabolic bone disease of women after obesity surgery.

Metabolic bone disease may appear as a complication of obesity surgery. Because an imbalance in the osteoprotegerin and receptor-activator of nuclear factor-κB ligand system may underlie osteoporosis, we aimed to study this system in humans in the metabolic bone disease occurring after obesity surgery. In this study we included sixty women with a mean age of 47 ± 10 years studied 7 ± 2 years after bariatric surgery. The variables studied were bone mineral density, ß-isomer of C-terminal telopeptide of type I collagen cross-links (a bone resorption marker), the bone formation markers osteocalcin and N-terminal propeptide of procollagen 1, serum osteoprotegerin and receptor-activator of nuclear factor-κB ligand. Serum osteoprotegerin inversely correlated with the bone remodeling markers osteocalcin, ß-isomer of C-terminal telopeptide of type I collagen cross-links and N-terminal propeptide of procollagen 1. The osteoprotegerin and receptor-activator of nuclear factor-κB ligand ratio also correlated inversely with serum parathormone and osteocalcin. Bone mineral density at the lumbar spine was associated with age (ß = -0.235, P = 0.046), percentage of weight loss (ß = 0.421, P = 0.001) and osteoprotegerin and receptor-activator of nuclear factor-κB ligand ratio (ß = 0.259, P = 0.029) in stepwise multivariate analysis (R 2 = 0.29, F = 7.49, P < 0.001). Bone mineral density at the hip site was associated only with percentage of weight loss (ß = 0.464, P < 0.001) in stepwise multivariate regression (R 2 = 0.21, F = 15.1, P < 0.001). These data show that the osteoprotegerin and receptor-activator of nuclear factor-κB ligand system is associated with bone markers and bone mineral density at the lumbar spine after obesity surgery.

The Degradome database: expanding roles of mammalian proteases in life and disease.

Since the definition of the degradome as the complete repertoire of proteases in a given organism, the combined effort of numerous laboratories has greatly expanded our knowledge of its roles in biology and pathology. Once the genomic sequences of several important model organisms were made available, we presented the Degradome database containing the curated sets of known protease genes in human, chimpanzee, mouse and rat. Here, we describe the updated Degradome database, featuring 81 new protease genes and 7 new protease families. Notably, in this short time span, the number of known hereditary diseases caused by mutations in protease genes has increased from 77 to 119. This increase reflects the growing interest on the roles of the degradome in multiple diseases, including cancer and ageing. Finally, we have leveraged the widespread adoption of new webtools to provide interactive graphic views that show information about proteases in the global context of the degradome. The Degradome database can be accessed through its web interface at http://degradome.uniovi.es.

Functional analysis of matriptase-2 mutations and domains: insights into the molecular basis of iron-refractory iron deficiency anemia.

Mutations in the TMPRSS6 gene are associated with severe iron-refractory iron deficiency anemia resulting from an overexpression of hepcidin, the key regulator of iron homeostasis. The matriptase (MT)-2 protein (encoded by the TMPRSS6 gene) regulates hepcidin expression by cleaving hemojuvelin [HJV/hemochromatosis type 2 (HFE2)], a bone morphogenetic protein (BMP) coreceptor in the hepcidin regulatory pathway. We investigated the functional consequences of five clinically associated TMPRSS6 variants and the role of MT-2 protein domains by generating epitope-tagged mutant and domain-swapped MT-2-MT-1 (encoded by the ST14 gene) chimeric constructs and expressing them in HepG2/C3A cells. We developed a novel cell culture immunofluorescence assay to assess the effect of MT-2 on cell surface HJV expression levels, compatible with HJV cleavage. The TMPRSS6 variants Y141C, I212T, G442R, and C510S were retained intracellularly and were unable to inhibit BMP6 induction of hepcidin. The R271Q variant, although it has been associated with iron-refractory iron deficiency anemia, appears to remain functional. Analysis of the chimeric constructs showed that replacement of sperm protein, enterokinase, and agrin (SEA), low-density-lipoprotein receptor class A (LDLRA), and protease (PROT) domains from MT-2 with those from MT-1 resulted in limited cell surface localization, while the complement C1r/C1s, Uegf, Bmp1 (CUB) domain chimera retained localization at the cell surface. The SEA domain chimera was able to reduce cell surface HJV expression, while the CUB, LDLRA, and PROT domain chimeras were not. These studies suggest that the SEA and LDLRA domains of MT-2 are important for trafficking to the cell surface and that the CUB, LDLRA, and PROT domains are required for cleavage of HJV.

A critical role for murine transferrin receptor 2 in erythropoiesis during iron restriction.

Effective erythropoiesis requires an appropriate supply of iron and mechanisms regulating iron homeostasis and erythropoiesis are intrinsically linked. Iron dysregulation, typified by iron-deficiency anaemia and iron overload, is common in many clinical conditions and impacts the health of up to 30% of the world's population. The proteins transmembrane protease, serine 6 (TMPRSS6; also termed matriptase-2), HFE and transferrin receptor 2 (TFR2) play important and opposing roles in systemic iron homeostasis, by regulating expression of the iron regulatory hormone hepcidin. We have performed a systematic analysis of mice deficient in these three proteins and show that TMPRSS6 predominates over HFE and TFR2 in hepcidin regulation. The phenotype of mice lacking TMPRSS6 and TFR2 is characterized by severe anaemia and extramedullary haematopoiesis in the spleen. Stress erythropoiesis in these mice results in increased expression of the newly identified erythroid iron regulator erythroferrone, which does not appear to overcome the hepcidin overproduction mediated by loss of TMPRSS6. Extended analysis reveals that TFR2 plays an important role in erythroid cells, where it is involved in terminal erythroblast differentiation and the regulation of erythropoietin. In conclusion, we have identified an essential role for TFR2 in erythropoiesis that may provide new targets for the treatment of anaemia.

Exome sequencing identifies a novel mutation in PIK3R1 as the cause of SHORT syndrome.

BACKGROUND: SHORT syndrome is a rare autosomal dominant condition whose name is the acronym of short stature, hyperextensibility of joints, ocular depression, Rieger anomaly and teething delay (MIM 269880). Additionally, the patients usually present a low birth weight and height, lipodystrophy, delayed bone age, hernias, low body mass index and a progeroid appearance. CASE PRESENTATION: In this study, we used whole-exome sequencing approaches in two patients with clinical features of SHORT syndrome. We report the finding of a novel mutation in PIK3R1 (c.1929_1933delTGGCA; p.Asp643Aspfs*8), as well as a recurrent mutation c.1945C > T (p.Arg649Trp) in this gene. CONCLUSIONS: We found a novel frameshift mutation in PIK3R1 (c.1929_1933delTGGCA; p.Asp643Aspfs*8) which consists of a deletion right before the site of substrate recognition. As a consequence, the protein lacks the position that interacts with the phosphotyrosine residue of the substrate, resulting in the development of SHORT syndrome.