Silvana Maria Lovisolo

Autoimmune manifestations in SCID due to IL7R mutations: Omenn syndrome and cytopenias

B+NK+SCID (severe combined immunodeficiency) due to IL7Rα deficiency represents approximately 10% of American SCID cases. To better understand the spectrum of autoimmune disorders associated with IL7Rα deficiency, we describe two unrelated IL7Rα-deficient female SCID infants whose clinical picture was dominated by autoimmune manifestations: one with intrauterine Omenn syndrome (OS) and another with persistent thrombocytopenic purpura since 4months of age. The OS baby harbored a homozygous p.C118Y mutation in IL7R. She presented dense eosinophilic infiltrates in several organs, including pancarditis, which may have contributed to her death (on the 2nd day of life). B cells were observed in lymph nodes, spleen, bone marrow and thymus. The second patient harbored compound heterozygous p.C118Y and p.I121NfsX8 mutations. She underwent a successful unrelated cord blood transplant. In conclusion, early OS can be observed in patients with IL7R mutations, and autoimmune cytopenias could also complicate the clinical course of SCID babies with this type of defect.

Fatal pancreatic pseudocyst co-infected by Raoultella planticola: an emerging pathogen

Raoultella planticola is an aerobic Gram-negative bacterium belonging to the Enterobacteriaceae family. Initially identified in the 1980s, its pathogenic potential was further recognized when the first case of bacteremia was reported. Since then, only a few infections caused by this pathogen have been described. Although considered an opportunistic agent, fatal outcomes are associated with the infection by this pathogen, since it is more prevalent among the patients with immunodeficiency. The authors report the case of a middle-aged man diagnosed with end-stage renal disease and alcoholic pancreatitis, who was admitted to the emergency department with septic shock. Physical examination disclosed peritoneal irritation and a laparotomy was undertaken. Purulent peritonitis was found as well as a retroperitoneal abscess, which was drained. The postoperative period was troublesome, and the patient died. The autopsy showed a ruptured, infected pancreatic cyst and purulent peritonitis, among other findings. The culture of the peritoneal fluid and two blood sample sets were positive for R. planticola. The authors call attention to the importance of this emerging pathogen associated with severe gastrointestinal infections.

Congenital hyperinsulinism in Brazilian neonates: a study of histology, KATP channel genes, and proliferation of β cells.

Congenital hyperinsulinism (CHI) is a rare pancreatic β-cell disease of neonates, characterized by inappropriate insulin secretion with severe persistent hypoglycemia, with regard to which many questions remain to be answered, despite the important acquisition of its molecular mechanisms in the last decade. The aim of this study was to examine pancreatic histology, β-cell proliferation (immunohistochemistry with double staining for Ki-67/insulin), and β-cell adenosine triphosphate-sensitive potassium channels genes from 11 Brazilian patients with severe medically unresponsive CHI who underwent pancreatectomy. Pancreatic histology and β-cell proliferation in CHI patients were compared to pancreatic samples from 19 age-matched controls. Ten cases were classified as diffuse form (D-CHI) and 1 as focal form (F-CHI). β-cell nucleomegaly and abundant cytoplasm were absent in controls and were observed only in D-CHI patients. The Ki-67 labeling index (Ki-67-LI) was used to differentiate the adenomatous areas of the F-CHI case (10.15%) from the “loose cluster of islets” found in 2 D-CHI samples (2.29% and 2.43%) and 1 control (1.54%) sample. The Ki-67-LI was higher in the F-CHI adenomatous areas, but D-CHI patients also had significantly greater Ki-67-LI (mean value = 2.41%) than age-matched controls (mean value = 1.87%) (P = 0.009). In this 1st genetic study of CHI patients in Brazil, no mutations or new polymorphisms were found in the 33–37 exons of the ABCC8 gene (SUR1) or in the entire exon of the KCNJ11 gene (Kir 6.2) in 4 of 4 patients evaluated. On the other hand, enhanced β-cell proliferation seems to be a constant feature in CHI patients, both in diffuse and focal forms.

Budd–Chiari Syndrome: an unnoticed diagnosis

Budd–Chiari syndrome (BCS) encompasses a group of disorders caused by the obstruction to the hepatic venous outflow at the level of the small or large hepatic veins, the inferior vena cava, or any combination thereof. Clinical manifestation of the subacute form is characterized by supramesocolic abdominal discomfort, abdominal distension, fever, and lower limbs edema. Imaging work-up with hepatic Doppler ultrasound and abdominal computed tomography (CT) enables the diagnosis in the majority of cases. Treatment comprises long-term anticoagulation associated with measures that attempt to re-establish the flow in the thrombosed vessel (thrombolysis or angioplasty) or through the venous blood flow bypasses (transjugular intrahepatic portosystemic shunt or surgical bypass); however, the outcome is often dismal. The authors report the case of a 37-year-old woman presenting a 2-month history of dyspeptic complaints and abdominal distention. Fever was present at the beginning of symptoms. The laboratory work-up disclosed mild hepatic dysfunction, and the ultrasound showed evidence of chronic liver disease. Despite a thorough etiologic investigation, diagnosis was missed and, therefore, management could not be directed towards the physiopathogenetic process. The outcome was characterized by portal hypertension and esophageal varices bleeding. The patient died and the autopsy findings were characteristic of BCS, although an abdominal CT, close to death, had showed signs consistent with this diagnosis. The authors highlight the importance of knowledge of this entity, the diagnostic methods, and the multidisciplinary approach. BCS should be considered whenever investigating etiology for chronic or acute hepatopathy.

Septic pelvic thrombophlebitis of unknown origin: an ever threatening entity

Septic pelvic thrombophlebitis (SPT) is a rare and severe entity, which may occur after abortion, delivery, gynecological diseases, or surgeries. Diagnosis is challenging when no risk factor is clearly present, since clinically, symptoms are non-specific. Nowadays, with the aid of imaging methods, diagnosis has become more achievable, but the treatment still bears some uncertainties. The authors present a fatal case of SPT in a young woman who sought medical care already presenting signs of septic shock, referring fever and non-characteristic abdominal pain. The patient evolved rapidly to multiple organ failure and respiratory distress, which was also due to septic pulmonary embolism. The autopsy confirmed the computed tomographic findings of a right ovarian vein septic thrombophlebitis and multiple septic pulmonary embolization foci. The patient did not present any of the recognized risk factors; neither did she present signs of pelvic inflammatory disease on admission or at autopsy. However, an intrauterine device was present. The authors call attention to this entity in the differential diagnosis of a woman with fever and abdominal pain, as well as for an empiric broad-spectrum antibiotic regimen in these cases.

GLUT1 expression in pediatric adrenocortical tumors: a promising candidate to predict clinical behavior

Background Discrimination between benign and malignant tumors is a challenging process in pediatric adrenocortical tumors. New insights in the metabolic profile of pediatric adrenocortical tumors may contribute to this distinction, predict prognosis, as well as identify new molecular targets for therapy. The aim of this work is to characterize the expression of the metabolism-related proteins MCT1, MCT2, MCT4, CD147, CD44, GLUT1 and CAIX in a series of pediatric adrenocortical tumors. Methods A total of 50 pediatric patients presenting adrenocortical tumors, including 41 clinically benign and 9 clinically malignant tumors, were included. Protein expression was evaluated using immunohistochemistry in samples arranged in tissue microarrays. Results The immunohistochemical analysis showed a significant increase in plasma membrane expression of GLUT1 in malignant lesions, when compared to benign lesions (p=0.004), being the expression of this protein associated with shorter overall and disease-free survival (p=0.004 and p=0.001, respectively). Although significant differences were not observed for proteins other than GLUT1, MCT1, MCT4 and CD147 were highly expressed in pediatric adrenocortical neoplasias (around 90%). Conclusion GLUT1 expression was differentially expressed in pediatric adrenocortical tumors, with higher expression in clinically malignant tumors, and associated with shorter survival, suggesting a metabolic remodeling towards a hyperglycolytic phenotype in this malignancy.BACKGROUND Discrimination between benign and malignant tumors is a challenging process in pediatric adrenocortical tumors. New insights in the metabolic profile of pediatric adrenocortical tumors may contribute to this distinction, predict prognosis, as well as identify new molecular targets for therapy. The aim of this work is to characterize the expression of the metabolism-related proteins MCT1, MCT2, MCT4, CD147, CD44, GLUT1 and CAIX in a series of pediatric adrenocortical tumors. METHODS A total of 50 pediatric patients presenting adrenocortical tumors, including 41 clinically benign and 9 clinically malignant tumors, were included. Protein expression was evaluated using immunohistochemistry in samples arranged in tissue microarrays. RESULTS The immunohistochemical analysis showed a significant increase in plasma membrane expression of GLUT1 in malignant lesions, when compared to benign lesions (p=0.004), being the expression of this protein associated with shorter overall and disease-free survival (p=0.004 and p=0.001, respectively). Although significant differences were not observed for proteins other than GLUT1, MCT1, MCT4 and CD147 were highly expressed in pediatric adrenocortical neoplasias (around 90%). CONCLUSION GLUT1 expression was differentially expressed in pediatric adrenocortical tumors, with higher expression in clinically malignant tumors, and associated with shorter survival, suggesting a metabolic remodeling towards a hyperglycolytic phenotype in this malignancy.

Bone marrow necrosis and fat embolism syndrome: a dreadful complication of hemoglobin sickle cell disease

Sickle cell disease encompasses a wide range of genotypic presentation with particular clinical features. The entity affects millions of people, particularly those whose ancestors came from sub-Saharan Africa and other countries in the Western Hemisphere, Saudi Arabia, and India. Currently, the high frequency of S and C genes reflects natural selection through the protection of heterozygotes against severe malaria, the high frequency of consanguineous marriages, improvement of some public health policies and the nutritional standards in the poorer countries where newborns are now living long enough to present for diagnosis and management. Although there is a high burden of the disease, in many countries, the new-born sickle cell screening test is being performed and is rendering an early diagnosis; however, it is still difficult for sickle cell patients to find proper treatment and adequate follow-up. Moreover, in many countries, patients are neither aware of their diagnosis nor the care they should receive to prevent complications; also, they do not receive adequate genetic counseling. Hemoglobin SC (HbSC) disease is the most frequent double sickle cell heterozygosis found in Brazil. The clinical course tends to be more benign with fewer hospitalizations compared with double homozygotic SS patients. However, HbSC patients may present severe complications with a fatal outcome. We report the case of a 36-year-old man who presented to the emergency care facility with symptoms consistent with the diagnosis of sickling crisis. The outcome was unfavorable and death occurred just hours after admission. The autopsy revealed a generalized vaso-occlusive crisis by sickled red cells, bone marrow necrosis, and fat embolism syndrome.

Severe pulmonary hypertension due to combined pulmonary fibrosis and emphysema: another cause of death among smokers

In 2005, the combined pulmonary fibrosis and emphysema (CPFE) was first defined as a distinct entity, which comprised centrilobular or paraseptal emphysema in the upper pulmonary lobes, and fibrosis in the lower lobes accompanied by reduced diffused capacity of the lungs for carbon monoxide (DLCO). Recently, the fibrosis associated with the connective tissue disease was also included in the diagnosis of CPFE, although the exposure to tobacco, coal, welding, agrochemical compounds, and tire manufacturing are the most frequent causative agents. This entity characteristically presents reduced DLCO with preserved lung volumes and severe pulmonary hypertension, which is not observed in emphysema and fibrosis alone. We present the case of a 63-year-old woman with a history of heavy tobacco smoking abuse, who developed progressive dyspnea, severe pulmonary hypertension, and cor pulmonale over a 2-year period. She attended the emergency facility several times complaining of worsening dyspnea that was treated as decompensate chronic obstructive pulmonary disease (COPD). The imaging examination showed paraseptal emphysema in the upper pulmonary lobes and fibrosis in the middle and lower lobes. The echo Doppler cardiogram revealed the dilation of the right cardiac chambers and pulmonary hypertension, which was confirmed by pulmonary trunk artery pressure measurement by catheterization. During this period, she was progressively restricted to the minimal activities of daily life and dependent on caregivers. She was brought to the hospital neurologically obtunded, presenting anasarca, and respiratory failure, which led her to death. The autopsy showed signs of pulmonary hypertension and findings of fibrosis and emphysema in the histological examination of the lungs. The authors highlight the importance of the recognition of this entity in case of COPD associated with severe pulmonary hypertension of unknown cause.

Gonococcal endocarditis: an ever-present threat

The incidence of severe complications of the Neisseria gonorrhoeae infection has presented variations over recent decades since the advent of penicillin. Gonococcal endocarditis (GE) still remains an ever-present threat afflicting the society’s poor and sexually active young population. This entity frequently requires surgical intervention and usually exhibits a poor outcome. The interval between the onset of symptoms and the diagnosis does not usually exceed 4 weeks. One of the characteristics of GE is a proclivity for aortic valve involvement with large vegetation and valve ring abscess formation. The authors report the case of a young man with a 2-week history of fever, malaise, weakness, and progressive heart failure symptoms, who had no previous history of genital complaints or cardiopathy. The physical examination was consistent with acute aortic insufficiency, which was most probably of an infectious origin. The echocardiogram showed thickened aortic cusps and valve insufficiency. After hospital admission, the patient’s clinical status worsened rapidly and he died on the second day. The autopsy findings disclosed aortic valve destruction with vegetation and a ring abscess besides signs of septic shock, such as diffuse alveolar damage, acute tubular necrosis, and zone 3 hepatocellular necrosis. The blood culture isolated N. gonorrhoeae resistant to penicillin and ciprofloxacin. The authors call attention to the pathogen of this particular infectious endocarditis, and the need for early diagnosis and evaluation by a cardiac surgery team.

Recurrence of alveolar capillary dysplasia with misalignment of pulmonary veins in two consecutive siblings

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, developmental lung disorder, which has been increasingly reported. This entity usually presents as neonatal persistent pulmonary hypertension that is unresponsive to treatment, and is known to be uniformly fatal. Recent discoveries in the genetic field, and intensive treatments, may change the natural course of this disease, permitting easier diagnosis and giving new hope for the dismal prognosis. The authors present two cases of siblings, with two years of difference, from different fathers - one of them was a first-degree and the other a second-degree cousin of the mother. Both patients were full-term babies born apparently without malformations and were sent to the nursery. Both siblings near 35 hours of age presented severe respiratory failure due to pulmonary hypertension. The outcome was fatal in both cases and at autopsy ACD/MPV was diagnosed. The authors call attention to this entity in the differential diagnosis of acute respiratory distress in early life.