We describe a 7-year-old first-born male patient from non-consanguineous parents. The child was in good clinical health until 5 years of age, when, he presented with mucohemorrhagic diarrhea, fever, and abdominal pain, for which he was hospitalized with a suspicion of VEOIBD. Blood tests revealed anemia and elevation of inflammatory markers. The fecal calprotectin level was significantly increased.
While the upper gastrointestinal endoscopy was normal, the colonoscopy revealed diffuse colitis, without involvement of the small intestine. Standard antibiotic (ciprofloxacin and metronidazole) and steroid treatment (prednisone 1 mg/kg) were administered with transitory clinical benefit, followed by relapse of mucohemorrhagic diarrhea during steroid taper.
Full endoscopic evaluation performed in our department revealed: intensely erythematous gastric mucosa with prepyloric erosions. The colonoscopy of the mucosa of the transverse colon, the left sigmoid colon, and the rectum appeared erythematous with ulcerations covered with fibrin. The biopsy indicated esophagitis, gastritis, and intestinal chronic inflammatory process with colonic histiocytic clusters (Figure A, top panels).
The child underwent an additional course of prednisone (2 mg/kg) and began azathioprine (up to a dosage of 2.5 mg/kg), for his apparent steroid dependence, with partial clinical benefit. At the same time, during episodes of fever and diarrhea, he received several treatments with metronidazole and/or ciprofloxacin, with a transient positive response, although all fecal cultures were negative.
Given the early onset of intestinal symptoms and the clinical severity, we performed a complete immunological investigation to exclude possible underlying primary immune defects. He had a mild decrease of IgG serum levels with poor antibody responses to tetanus toxoid, Haemophilus influenzae type b (Hib) and hepatitis B. Therefore, he was started on intravenous immunoglobulin treatment at a dose of 400 mg/kg every 3 weeks.
Of note, the patient showed persistent EBV viremia ranging from 1,218 to 32,466 copies/ml and absent seroconversion (no anti-EBNA production). A repeated colonoscopy confirmed severe pancolitis (macroscopic and microscopic findings) and PCR of DNA extracts from biopsies yielded a positive result for EBV DNA. Accordingly, the patient was administered rituximab; however, he did not tolerate therapy.
His disease course remained severe, complicated by infections, including adenovirus enteritis and pneumonia (with pleural effusion). The patient exhibited refusal of food and chronic malnutrition, despite support with polymeric formula and sometimes parenteral nutrition. Humira (80–40–20 mg) was administered twice per month for 4 months with no evidence of clinical remission.
In the meantime, next-generation sequencing (NGS) revealed a de novo and novel mutation in the XIAP gene: c.565T>C p.L189P, which, SIFT and Polyphen 2, predicted to be damaging and probably damaging, respectively. Sanger sequencing confirmed the mutation in the patient and his parents (on DNA extracted both from peripheral blood and from mouth rinsing to assess the germline mutations); however, the substitution was found only in the patient.
Since the L189P is located in the BIR2 domain of XIAP, to establish if BIR2 mutation impairs protein expression, PBMCs isolated from the patient were cultured and transformed into an EBV-immortalized B-cell line, then immunoblotted for XIAP. Reduced protein expression was observed in cells from the patient compared with a healthy control (Figure B).
Afterward, we investigated the XIAP expression in different cell subsets. In accordance with our result, intracellular XIAP expression was markedly reduced in lymphocytes, granulocytes, and monocytes (Figure C). Typically, the NOD2 activation and the XIAP/RIPK2 recruitment lead to the NF-κB translocation to the nucleus after IκBα degradation. To determine the effect of this mutation on NOD2 pathway, we investigated the XIAP direct-binding protein, RIPK2, which did not reveal alterations (Figure A). In addition, we studied the IκBα degradation in patient’s EBV-immortalized B-cell line stimulated with muramyl dipeptide (MDP), a specific NOD2-activating ligand. Consistent with the data, after stimulation, IκBα degradation was absent, suggesting defective NF-κB activation (Figure B).
Since XIAP is a potent and direct caspase inhibitor and an antiapoptotic protein, we decided to investigate whether the patient’s mutation affects this function. We performed an in vitro apoptosis assay in CD4+ and CD8+ T cells from the patient’s PBMC stimulated with OKT3/CD28 or MDP for 24 h. MDP-stimulated CD4+ and CD8+ T cells had the same features of OKT3/CD28 stimulated T cells, with further propensity to apoptosis compared with a healthy control. Interestingly, analysis of the patient’s cells revealed an increased level of basal apoptosis without stimulation (Figures C,D). Our patient exhibited increased activation-induced cell death, which may reflect the alteration of NOD2 signaling and the inability of the XIAP protein to inhibit the caspases.
Considering the unresponsiveness to several different lines of therapy, and since the patient did not have any suitable related or fully allelic-matched unrelated donor, we decided to perform HLA-haploidentical HSCT (haplo-HSCT) after negative depletion of Tαβ+/CD19+ lymphocytes, using the mother as donor. This type of allograft permits CD34+ cells, committed hematopoietic progenitor cells, fully functioning donor NK and γδ+ T cells to remain in the graft. Recent studies have shown that Tαβ+/CD19+ cell depleted haplo-HSCT is a suitable option for the definitive treatment of a wide spectrum of malignant and non-malignant disorders, in the absence of an HLA-identical donor. This technique allows a rapid engraftment, low graft failure rate, and low incidence of significant aGvHD (, ). The child was included in clinical trial protocol (NCT02065869), which was approved by the ethical committee of Bambino Gesù Children’s Hospital. This treatment regimen consisted of myeloablative [myeloablative conditioning (MAC)], but reduced-toxicity conditioning, including the combination of thiotepa (8 mg/kg), treosulfan (42 g/m2 over 3 days), fludarabine (160 mg/m2 over 4 days), and anti-T-lymphocyte globulin (ATLG, Grafalon, Neovii) to prevent graft-versus-host disease (GvHD) and graft failure. One single dose of rituximab (200 mg/mq) on day −1 was employed for preventing EBV-related posttransplant lymphoproliferative disorder. The patients did not receive any post-HSCT pharmacological GvHD prophylaxis. The median time to reach neutrophil and platelet engraftment was 13 and 11 days, respectively, and he achieved a full donor chimerism. No toxicities or serious adverse events occurred.
Endoscopic evaluation 3 and 6 months after HSCT showed normal upper GI mucosa, normal colonic mucosa with regular vascular patter, a cecal pseudo-polyp (histology: no signs of GvHD, mild esophagitis, and signs of previous colonic inflammation with regeneration) (Figure A, bottom panels). At present time, the child is 1-year post-HSCT and is in very good general condition with full donor chimerism.
One year after transplant, we analyzed again the expression of XIAP by intracellular staining and western blotting (Figures A,B) again. The protein expression was restored in all leukocyte subsets and the EBV-B-cell line. Moreover, IκBα degradation was detected, suggesting a reinstated NF-κB activation (Figure C). See Figure legend. Finally, 6 months and 1 year following HSCT, we performed the apoptosis assay to evaluate the antiapoptotic capacity, which was comparable to healthy donor (Figure D).


A 41-year-old white male with no significant past medical history presented in the emergency department (ED) with chest pain. The patient was having chest discomfort for one day. On the day of presentation, he had severe 10/10 intensity, central chest pain, aggravated with lying down and relieved with sitting up. He had associated dyspnea but denied fever, cough, presyncope, syncope, or palpitations. He denied any similar history in the past. There were no known heart murmurs. There was no history of sudden cardiac death or heart disease in family. He snorted cocaine every two weeks for several years, and the last use was a night before his symptoms started. He admitted to drinking alcohol in weekends but denied tobacco smoking.
His vital signs in the ED was significant for tachycardia, heart rate 110 beats/minute. Initial BP (blood pressure) in ED was 136/83 mmHg. On exam, he had blowing, decrescendo, grade II/VI diastolic murmur heard best in the third left intercostal space, and grade III/VI holosystolic murmur on the left sternal border. He had crackles at lung base but no pedal edema or jugular venous distension on exam.
EKG showed ST elevation suggestive of anterior and inferior infarct (). Serial troponins three times were normal. Urine drug screen was positive for cocaine. Chest X-ray showed mild cardiomegaly. The patient was admitted to the telemetry unit with presumptive diagnosis of pericarditis versus cocaine-induced coronary vasospasm. Transthoracic echocardiography (TTE) was performed for the concern of diastolic murmur and pericarditis. TTE showed 6.2 cm aortic root dilatation and severe AR (aortic regurgitation) with possible aortic dissection, EF 50%, and minimal MR (mitral regurgitation) and TR (tricuspid regurgitation). The patient was transferred to the intensive care unit (ICU). The patient's systolic BP increased to the range of 150–160 mmHg. He was started on labetalol for better BP control. CT chest showed 6 cm aneurysm of the aortic root and ascending aorta and aneurysm of the aortic arch 3.6 cm, without dissection (). The patient was taken to the operating room (OR) for emergent surgical repair and aortic valve replacement. Transesophageal echocardiography (TEE) was done in the OR. TEE finding was consistent with 6.2 cm aneurysm, moderate to severe AR but no dissection (). The aortic valve was trileaflet. Emergency repair of ascending aortic aneurysm using a Hemashield graft, and aortic valve replacement using a mechanical prosthesis, with repair of the sinus of Valsalva aneurysm was performed.
Biopsy results/pathology showed the aortic valve with degenerative changes but no cystic medial degeneration. Aortic tissue comprised large vessel walls, with hemorrhage and foci of acute and chronic inflammation. This is a nonspecific finding and can be seen in hypertensive aortic aneurysm and/or dissection. Cocaine can cause profound sympathetic stimulation and hypertension that presumably causes sheer stress on the aorta's intima that a small “Nick” or tear occurs which explains the hemorrhage in the pathology.
Blood cultures were negative. ANA panel was done for the concern of vasculitis and was negative. Marfan's gene was not tested given the pathology finding, absent Marfanoid clinical features, and negative family history. Postsurgical TTE shows prosthetic aortic valve, with no evidence of aortic regurgitation. EF 50%. Minimal MR. Mild TR. Postoperatively, he was started on heparin bridge to warfarin for anticoagulation. Because the patient had borderline low EF of 50% pre- and postoperatively, the cardiologist recommended starting the patient on metoprolol, furosemide, and lisinopril. The patient was discharged to home on postoperative day number 5.


A 34-year-old female who was seven months pregnant presented in the emergency department with complaints of a headache, high blood pressure, and convulsions for one day. She was diagnosed with eclampsia, and treatment with magnesium sulfate and hydralazine was initiated. Her condition worsened on the fourth day of her admission as she became jaundiced. Her fetus was delivered, and a referral to a tertiary care hospital was made.
On examination, the patient was lying unconscious with jaundice, pallor, bruising, and pedal edema. She had a respiratory rate of 24/min, a blood pressure of 90/48 mm Hg, and a pulse of 126/min, which was regular with good volume and no radio-radial or radio-femoral delay. Systemic examination was unremarkable, including the cardiovascular, gastrointestinal, and central nervous systems. Respiratory system examination was positive for left lower lobe crepitation.
Her laboratory investigations revealed a total leukocyte count (TLC) of 26,000 cells per microliter, hemoglobin - 8.7 g/dL, platelets - 67,000 per microliter, creatinine - 5.7 mg/dL, blood urea nitrogen - 141 mg/dL, total bilirubin - 7.2 mg/dL, alanine aminotransferase - 1,655 IU/l, aspartate aminotransferase - 1,295 IU/l, albumin - 2.5 g/dL, international normalized ratio (INR) - 1.6, activated partial thromboplastin time (aPTT) of 56 seconds, and a prothrombin time (PT) of 19 seconds.
A blood culture was sent, and an intravaginal ultrasound was done, which was negative for any retained product of conception. She was put on piperacillin/tazobactam empirically. Her respiratory distress worsened over the next day; a decision was made to put her on mechanical ventilation because of acute respiratory distress syndrome (ARDS). Chest X-ray showed bilateral infiltration with a PaO2/FiO2 ratio of 237.
Over the coming days, her leukocytosis worsened with a TLC up to 46,000 per microliter, and her condition became critical with deranged renal function tests, liver functions tests, prothrombin time, and international normalized ratio (INR). Her antibiotic was changed to meropenem. On the fifth day, the patient was weaned off from the ventilator, but her sepsis did not improve. On the seventh day, her blood culture came out positive for ceftazidime-resistant Burkholderia cepacia. Though she was getting a sensitive antibiotic, her TLC kept rising with hepatic and renal failure, and she died on the ninth day of her admission with multiorgan failure.


A 75 year old lady, felt excruciating pain on her right heel cord when she half -stepped on a pavement, over-flexing her right foot in an attempt to avoid a car. She was put in a back slab by her primary care physician and referred to our hospital where she presented 24 hours after the incident. On examination, there was swelling and bruising on the back side of the heel, but no skin blistering. Her right ankle plantar flexion power was markedly diminished. No ankle plantar flexion was demonstrated upon squeeze of her right calf. A bone fragment was palpable just under the skin above the heel bump. X-rays confirmed an avulsion fracture of the heel at the insertion of the Achilles tendon Fig. (). Urgent operative treatment was the only option for this displaced (type 2) fracture of the calcaneal tuberosity, in order to restore continuity of the gastrosoleus complex and avoid skin necrosis due to pressure by the displaced fragment. The patient’s past medical history was significant only for hypertension and hyperlipidemia.
Under general anesthesia, with the patient in a prone position and using a pneumatic tourniquet, the fracture was approached through a posteromedial lazy J incision, made with the longitudinal limb at the midline between the medial border of Achilles tendon and the posteromedial border of the distal tibia. The investing fascia was incised open, to expose the Achilles tendon and the avulsed bone fragment. The hematoma around the fracture was cleared, the calcaneal fracture was reduced and the bone fragment was fixed with a cancellous screw and a suture anchor, because the shape and thinness of the avulsed fragment did not allow the placement of a second screw. Satisfactory reduction of the fracture was achieved and the wound was closed in layers. Skin closure was performed with nylon sutures. Postoperative x-rays demonstrated adequate reduction of the fracture (Fig. ).
Postoperatively, the patient was put in a plaster back slab with the foot in approximately 25 degrees of plantar flexion, so that no active ankle movement would be allowed and no stress applied on the Achilles tendon repair. Intravenous antibiotics were given for 48 hours and the patient was released from hospital 3 days post operatively, with instructions for daily subcutaneous low molecular weight heparin injections and a scheduled appointment for re-evaluation after a week.
She failed to attend her scheduled appointment, and came back in the emergency department 2 weeks post-operatively, complaining of pain at the surgical site. She reported a new fall, when trying to walk around the house 5 days after the operation, but she didn’t return to the hospital immediately. The plaster was removed and a dark necrotic lesion 4x3cm was noticed, a few cm above and laterally to the surgical incision. A new lateral x-ray was taken and failure of the reduction was noticed, as the screw along with the bone fragment had been detached. Obviously the fragmented bone part had applied pressure to the overlying skin, causing local ischemia and necrosis. The skin around this necrotic area had the clinical appearance of infection, though we were unable to determine whether it was a local or a deep infection (Fig. ).
The patient was re-admitted and taken to the operating room for a second time. Since the soft tissue coverage of the area was inadequate and in the presence of infection, no further fixation was considered. Under local anesthesia and sedation, the necrotic skin was excised to healthy tissue. The bone fragment was removed together with the screw used for the initial osteosynthesis Fig. (), but the attached part of the Achilles tendon was preserved and re-attached to the calcaneous tuberosity using two anchor sutures Fig. (). The wound was inevitably left uncovered; a full plaster cast was applied, with the leg in plantar flexion and a posterior window to allow observation of the wound on a daily basis (Fig. ).
Platelet rich plasma (PRP) treatment was commenced to improve the soft tissue condition, reduce the size of the skin deficit and hopefully induce tendon-bone healing. Platelet rich plasma is an emerging biologic tool, that has been shown in dozens of published studies to improve healing of wounds, tendons and bone. Furthermore, V.A.C. therapy was locally applied. V.A.C therapy is the controlled application of sub-atmospheric pressure to a wound, using a therapy unit to intermittently or continuously convey negative pressure to a specialized wound dressing, to help promote wound healing and increase local angiogenesis. A total of 5 sessions of PRP treatment were applied along with the V.A.C. therapy, for a total period of eight weeks. The size of the skin lesion was reduced to 2x2 cm and the depth of the deficit was less than 1 cm (Fig. ).
At this point we decided to proceed with the coverage of the remaining lesion using a small rotational flap from the lower end of the wound, combined with full thickness skin grafts taken from the lateral left thigh. Two weeks later, the flap and 90% of the grafts had survived, the Achilles tendon was at that time completely covered (Fig. ) and the patient was put on a removable dynamic brace that allowed ankle mobilization and gradual weight bearing. Finally, 12 weeks after skin excision and tendon re-attachment the skin was completely healed, the patient had restored her right ankle motion (plantarflexion of 35 degrees and dorsiflexion of 15 measured with a goniometer) and was able to perform a single heel rise (Fig. ).


A 50-year-old African American male with a past medical history of hypertension, gout, sleep apnea, and hypothyroidism was evaluated for abdominal pain, associated with unintentional 20-pound weight loss, nausea, and vomiting. He denied fever, chills, night sweats, headaches, dyspnea, skin rash, arthralgias, oral ulcers, Raynaud's phenomenon, or chest pain.
On physical exam, he was found to have bilateral parotid and submandibular gland enlargement and right eye proptosis. The patient disclosed that his brother has retroperitoneal fibrosis secondary to IgG4-RD. The initial abdominal computed tomography (CT) revealed a duodenal mass. Endoscopic retrograde cholangiopancreatography (ERCP) showed a mildly dilated common bile duct, not associated with mass or stricture. A biopsy of the intra- and infra-ampullary area demonstrated active chronic duodenitis without evidence of malignancy.
A CT of the thorax showed a confluence of elongated anterior and right paravertebral soft tissue from the midthoracic region to the diaphragmatic level, associated with mildly enlarged thoracic lymph nodes, borderline ascending aortic aneurysm, and scattered small lung nodules ().
Complete blood count and biochemical profile were remarkable for chronic anemia and hypoalbuminemia, with normal renal and hepatic function. Monoclonal protein evaluation showed elevated IgG level of 5410 mg/dL (normal: 700–1600 mg/dL), and bone marrow biopsy demonstrated plasma cell dyscrasia (plasma cell count of 6%) with no evidence of lymphoproliferative disorder. Additional laboratory results revealed positive antinuclear antibody (ANA), low complement levels, elevated total IgG and IgG4 subclass, and elevated sedimentation rate (). The QuantiFERON®-TB Gold test was negative.
He underwent excision of a submandibular gland, and the pathology revealed chronic sclerosing sialadenitis, with a large subset of inflammatory cells positively staining for IgG4 ().
Subsequently, video-assisted thoracoscopy (VATS) was performed. During the procedure, a multilobar paraspinal mass near the diaphragm was noted, with pathology showing dense fibrosclerosis with increased lymphocytic infiltrates. Although staining for IgG and IgG4 was limited by the level of background staining and areas of crush artifact within the tissue, there was an increase of IgG4 plasma cells ().
A follow-up chest CT revealed a prominent paravertebral mass. In view of this finding, the patient was started on prednisone 40 mg daily. While on prednisone, he significantly improved. A subsequent CT done 5 months later showed a decrease in the paraspinal mass (). The serum IgG4 level also decreased significantly with prednisone treatment (). Unfortunately, after prednisone was discontinued, the IgG4 level increased, and there was slight progression in thickness of the paravertebral soft tissue.
Prednisone was restarted, and rituximab therapy was planned.


A five year old boy was admitted to the pediatric emergency department in a University Hospital, on 20th September 2016, in a poor health condition with severe respiratory distress and severe weakness. The patient was a known case of failure to thrive (FTT) and had been suffering from fatigue, respiratory symptoms, weight loss, intermittent fevers, anorexia, nausea and vomiting, edema of legs and abdominal distension from one month earlier.
Clinical examination revealed an undernourished child with marked pallor, tachypnea, hepatomegaly and submandibular lymphadenopathy. The initial laboratory data is seen in .
Packed cells and platelets were infused to compensate anemia and thrombocytopenia. Microbial cultures from blood, urine and cerebrospinal flood (CSF) samples were all negative for any bacterial growths.
In the initial CXR, consolidation was seen in the right lung. Otherwise cardiac silhouette was within the normal limits and musculoskeletal structures had no pathologic findings.
The patient was referred for whole body bone scan with suspicion of malignancy and bone metastasis. Immediately after intravenous injection of 74 MBq of 99mTc-MDP, scanning was performed in 2 second intervals for 2 minutes from thoracolumbar region. Whole body blood pool images were also obtained immediately after early flow images for 5 minutes. Perfusion images were recorded in a matrix of 128×128. Multiple 750 Kilo counts spot views were recorded 2 and 3 hours later in a matrix of 256×256. All of these acquisitions were done with a dual-head E-CAM SPECT camera equipped with low energy, high resolution collimators and the SPECT images were performed with64 projections over 360°, 25 s/step, 64×64 matrix and noncircular orbit. The bone scan revealed highly increased activity in both lungs in the perfusion and blood pool phases (). Delayed images also showed highly increased activity in lung and gastric wall and the skeleton was not seen clearly (). This pattern suggested secondary calcification in the lungs and stomach. Considering hematologic findings in laboratory tests, hypercalcemia from a hematologic malignancy was the most probable diagnosis. Bone marrow aspiration was done and established the diagnosis of ALL. Lymphoblasts did not have myeloid markers and were positive for CD5 and CD7 which confirmed the diagnosis of T cell type of ALL.
Follow up blood examination showed elevated WBC count associated with presence of myelocytes, promyelocytes and band cells in the blood.
Abdominal ultrasonography revealed hepato-megaly. Both kidneys showed increased cortical echogenicity and absence of corticomedullary junction suggesting parenchymal renal disease.
Chest CT showed bilateral hyperdense centrilobular nodules with ill-defined margin suggestive of metastatic calcification throughout both lungs (). Differential diagnosis includes infectious/inflammatory process, malignancies (myeloproliferative disorders) and alveolar hemorrhage. CT bone window revealed lytic lesions involving body and posterior elements throughout the spine. Differential diagnoses for widespread lytic bone lesions were: metastasis, lymphoproliferative disorders, hyperparathyroidism (brown tumors), and infectious/inflammatory process.
Intravenous antibiotic therapy with Meropenem, Vancomycin and Co-Trimoxazole started with suspicion of pneumonia. Also treatment with furosemide and corticosteroid were done. No improvement in respiratory symptoms was noted and the patient passed away from respiratory insufficiency on Oct 11 2016. No autopsy was performed.


The first patient was a 31-year-old female, presenting for an EP study with possible pacemaker placement. The patient was able to ambulate without the use of a walker or braces. She reported the ability to walk a considerable distance before becoming fatigued. As a part of the MMD disease process, the patient was also diagnosed with central sleep apnea and used a CPAP machine at night. She denied any history of gastroesophageal reflux disease (GERD). The decision was made to proceed with the EP study under monitored anesthesia care (MAC) and convert to general anesthesia (GA) if a pacemaker needed to be placed. The patient received Ondansetron 4 mg IV, Metoclopramide 10 mg IV, and Dexamethasone 4 mg IV at the start of the procedure in order to prevent nausea, vomiting, and possible aspiration. For sedation, she was given Fentanyl 50 mcg IV, Midazolam 2 mg IV, and was started on a Propofol infusion. She tolerated the study well.
When the EP study revealed a prolonged PR interval (217 ms) and a wide QRS (125 ms), the cardiology team decided to proceed with pacemaker placement. At this time, the decision was made to convert to GA and secure the airway. The patient was given an additional bolus of Propofol (80 mg IV) and Fentanyl (50 mcg IV) and was successfully intubated using direct laryngoscopy without the use of paralytic agents. She tolerated this well and was maintained on a Propofol infusion for the duration of the procedure. On emergence from GA, the patient received Ondansetron 4 mg IV and was extubated uneventfully after she was taking adequate tidal volumes, protecting her airway, and following commands. She was discharged home the next day with no acute events.


The second patient was a 25-year-old male, the younger brother of the first patient. He presented for an EP study with possible pacemaker placement. The patient reported generalized weakness and poorer functional status than his sister, necessitating the use of assistance to ambulate. However, in contrast with his sister, this patient denied a history of sleep apnea or the use of a CPAP machine (polysomnogram was reportedly negative). He also denied any history of GERD. This patient had a similar anesthetic plan prescribed, using MAC anesthesia for an EP study and converting to GA if a pacemaker needed to be placed. For sedation, the patient received a total of 100 mcg of Fentanyl IV (in 50 mcg boluses) and 2 mg of Midazolam IV (in 1 mg boluses). He required minimal sedation for the study and was comfortable throughout. His EP study did not reveal any ECG abnormalities (PR interval 200 ms, QRS 110 ms), and there was no need for pacemaker insertion at the time. The patient emerged from sedation without incident and recovered in the post-anesthesia care unit without evidence of respiratory compromise. He was discharged home the same day with recommendations for serial ECGs every 6–12 months.


The third patient, the middle sibling of the first two patients, was a 27-year-old male presenting for an EP study with possible pacemaker placement. The patient reported generalized weakness as well but was able to ambulate without any assistance. He had a history of central sleep apnea and used a CPAP machine at night, similar to his sister, the first patient. On physical exam, it was noted that the patient had extremely poor dentition with multiple erythematous areas, suspicious for infection and/or abscess. After discussion with the electrophysiology team, it was agreed that if the patient needed pacemaker insertion, he would need to obtain dental clearance prior to placement due to high risk of device infection. However, the EP study could still proceed. The plan was to use MAC anesthesia for the study and have the patient return for a subsequent anesthetic if a pacemaker was indicated. He received Dexamethasone 4 mg IV, Famotidine 20 mg IV, Metoclopramide 10 mg IV, and Ondansetron 4 mg IV for nausea and vomiting prophylaxis. For the procedure, the patient received a total of 100 mcg of Fentanyl IV (in 50 mcg boluses) and 2 mg of Midazolam IV (in 1 mg boluses). Interestingly, during the study, the patient developed atrial fibrillation with rapid ventricular response, and heart rate as high as the 150 s. His blood pressure was stable throughout the event. The decision was made to cardiovert the patient. Propofol 30 mg IV bolus was given, and cardioversion was performed without the need for intubation. The patient subsequently returned to normal sinus rhythm. The EP study showed abnormal infranodal conduction and pacemaker placement was recommended. However, due to poor dentition and concern for tooth abscess, pacemaker placement was deferred. After satisfactory recovery from sedation and no evidence of respiratory compromise or apneic events, the patient was discharged home.


A 16-month-old Albanian girl presented at our Department with acute gastroenteritis. Fever, diarrhea, and vomiting were her main symptoms. She was dehydrated, pale, and weak. Her history of nutrition and immunization was normal for her age. A physical examination revealed reduced turgor and elasticity of skin, but no other findings. Her abdomen was at the level of her chest, soft, with minimal palpatory pain. Her liver and spleen were not palpable.
A laboratory examination found her erythrocyte sedimentation rate at level of 60 mm at the first hour, white blood cells (WBC) count 12.400, and C-reactive protein of 41 mg/L. There were 15% eosinophils of overall WBC count; glucose level of blood was 10.9 mmol/L. Glucose was positive in urine as well as acetone and proteins. Liver tests were normal.
Ascaris worm and ova were found in stool that was otherwise negative for bacteria, adenovirus, and rotavirus.
At abdominal ultrasound, we found a single, long, linear echogenic structure without acoustic shadowing containing a central, longitudinal anechoic tube with characteristic movement within the gallbladder. Edema of the gallbladder wall was suggestive of associated inflammation. There were no other findings on adjacent structures and organs (Fig. ).
After the diagnosis was established, our patient was given antihelminthic therapy with mebendazole, 100 mg twice a day for 3 days and was free of the disease at the control visit. Because of elevated markers of inflammation and acute cholecystitis at ultrasound, she was treated with antibiotics.


A 22-month-old Albanian girl presented at our Department with acute gastroenteritis. Fever, diarrhea and vomiting, dehydration, and weakness were her main symptoms. A physical examination revealed reduced turgor and elasticity of skin, but was otherwise normal.
A laboratory examination found her erythrocyte sedimentation rate at a level of 36 mm at the first hour, WBC count 18.000, and C-reactive protein of 12 mg/L. There were 10% eosinophils of overall WBC count. Other tests were normal. Ascaris worm and ova were found in stool that was otherwise negative for bacteria, adenovirus, and rotavirus. An abdominal ultrasound found features characteristic for gallbladder ascariasis without associate inflammation (Fig. )
After the diagnosis was established, she was given antihelminthic therapy with mebendazole, 100 mg twice a day for 3 days, and antibiotics due to elevated markers of inflammation. At the control examination, she was free of disease.


A 4-year-old (50-month old) Albanian girl presented at our Department with fever, diarrhea, and vomiting due to acute gastroenteritis. She was mildly dehydrated. A physical examination was otherwise normal.
A laboratory examination found her erythrocyte sedimentation rate at a level of 40 mm at the first hour, WBC count 14.000, and C-reactive protein of 18 mg/L. There were 14% eosinophils of overall WBC count. Other tests were normal. Ascaris worm and ova were found in stool. An abdominal ultrasound found features characteristic for gallbladder ascariasis without associate inflammation (Fig. ).
After the diagnosis was established, she was treated with mebendazole, 100 mg twice a day for 3 days. Due to elevated markers of inflammation an antibiotic was also given. At the control examination, she was free of disease.


A 10-year-old (130-month old) Albanian boy presented at our Department with mild fever, but numerous episodes of diarrhea and vomiting. He was severely dehydrated and weak. The admission diagnosis was acute gastroenteritis. A physical examination revealed reduced turgor and elasticity of skin and little pain during the abdominal palpation.
A laboratory examination found his erythrocyte sedimentation rate at a level of 30 mm at the first hour, WBC count 15.000, and C-reactive protein of 24 mg/L. There were 14% eosinophils of overall WBC count. Other tests were normal. Ascaris worm and ova were found in stool that was otherwise negative for bacteria, adenovirus, and rotavirus. An abdominal ultrasound found features characteristic for gallbladder ascariasis with associate inflammation.
After the diagnosis was established, he was given antihelminthic therapy with mebendazole, 100 mg twice a day for 3 days, and antibiotics due to elevated markers of inflammation and characteristic feature of cholecystitis at ultrasound examination (Fig. ).


A twenty-seven-year-old woman with no relevant medical history presented with lower back pain of one-year duration.
She denied any history of medications, smoking, hypertension, headaches, palpitations, excessive perspiration, muscle weakness, bruising easily, fatigue, hematuria, menstrual disorders, acne, or hirsutism.
Physical examination was unremarkable; specifically, no masses, lymphadenopathy, peripheral edema, hirsutism, acne, alopecia, cushingoid features, striae, or petechiae were noted. Blood pressure: 110/70 mmHg, with no orthostatic hypotension.
An ultrasound scan was performed because of the lower back pain and showed a 46 × 40-mm hypoechoic solid lesion in the left adrenal gland. A CT scan of the abdomen and pelvis was ordered, which demonstrated a 50 × 42-mm rounded, solid, homogeneous expansive lesion of distinct borders in the left adrenal gland. The lesion had a spontaneous density of 46 Hounsfield units, showing enhancement after contrast administration (Figs and ).
The patient′s complete blood count, urine analysis, blood urea nitrogen, and creatinine levels were all within normal limits.
Laboratory tests were ordered during the early follicular phase, and at 8 am fasting, the results were as follows: total testosterone: 0.9 ng/mL (normal: 0.1–0.8 ng/mL), DHEA-S: 2735.3 ng/mL (normal: 201–4142 ng/mL), androstenedione: 3.3 (normal: 0.5–2.7 ng/mL), 17 hydroxyprogesterone: 3.1 ng/mL (normal: 0.3–1.0 ng/mL), aldosterone: 11 ng/dL (normal: 1.2–16 ng/dL, plasma renin activity (PRA): 0.2 ng/mL/h (normal: 0.5–2.6 ng/mL/h), aldosterone/ARP ratio: 55, sodium: 141 mmol/L (normal: 135–145 mmol/L), potassium: 3.9 mmol/L (normal: 3.5–5.3 mmol/L), plasma cortisol: 16.2 μg/dL (normal: 5–25 μg/dL), and ACTH: <10.0 pg/mL (normal: <54 pg/mL). Other measurements were ordered, including salivary cortisol at 23:00 h: 9.3 nmol/L (normal: 0.7–5.0 nmol/L), urinary free cortisol: 73.2 μg/24 h (normal: <100.0 μg/24 h), adrenaline: 4.7 μg/24 h (normal: 0–6.2 μg/24 h), noradrenaline: 14.2 μg/24 h (normal: 11.3–74.3 μg/24 h), and vanillynmandelic acid: 3.8 mg/24 h (normal: <8.5 mg/24 h); 24–h urinary metanephrines measurement was not available in our country at the time of the patient evaluation.
Measurement of nocturnal salivary cortisol was repeated: 5.1 nmol/L (normal: 0.7–5.0 nmol/L). Overnight 1 mg dexamethasone suppression test was ordered: Plasma cortisol levels at 8 am were 16.3 μg/dL (normal <1.8 μg/dL). Endogenous hypercortisolism of adrenal origin was confirmed, associated with biochemical features consistent with elevated aldosterone/PRA ratio (primary aldosteronism not evaluated by confirmatory tests) and hyperandrogenism.
Because of tumor size and plurihormonal secretion, a decision was made to proceed with surgery, which was performed 10 months after diagnosis. A laparoscopic approach was used, but because of the large tumor size, conversion to open surgery was necessary. Left adrenalectomy was performed. No preoperative therapy was performed because there were no clinical or biochemical data suggesting catecholamine hypersecretion; however, careful intraoperative blood pressure monitoring was performed, which remained stable throughout the procedure. The patient made good progress, receiving postoperative hydrocortisone replacement 20 mg/day for 2 months.
Left adrenal gland that weighed 134 g and measured 9.9 × 7.5 × 4.9 cm, with a brownish surface. On cut section, the parenchyma was replaced by a brownish-yellowish tumor proliferation, with areas of hemorrhage and hard-elastic consistency. Histological sections revealed tumor proliferation composed of polygonal cells of large hyperchromatic bizarre nuclei with isolated intranuclear vacuoles and prominent nucleoli; abundant eosinophilic cytoplasm. Cells were arranged in nests separated by thin fibrous septae; the tumor mass was surrounded by a thick capsule. The mitotic index was low: 2–3 mitoses per 50 high-power fields. There was no evidence of vascular embolism or capsular invasion. Little residual adrenal parenchyma was observed at the periphery of the lesion. Ki-67: 3%.
Two months after surgery, hydrocortisone therapy was discontinued and hormonal laboratory measurements were performed, with normal results (Table ).
The patient made good progress, with no evidence of tumor recurrence on the follow-up computed tomography scans and laboratory tests performed annually during the last 9 years.


Arthroscopic isolated partial meniscectomy was performed in a 53-year-old female with MRI confirmed degenerative tear in the posterior horn of the medial meniscus. She manifested pain at medial side of the left knee joint, but cannot be alleviated after two weeks medication of oral NASIDS. The operation was done smoothly under subarachnoid anesthesia without using a tourniquet, and cost only 20 min. Degenerative tear in the posterior 1/3 medial meniscus but no obvious chondral lesion were found intraoperatively. The patient was slim, with the BMI of 23.7, and had no malignancy, VTEs and vascular diseases history but ipsilateral leg varicose veins, no use of anticoagulant and hormone. Also no one in her family had history regarding VTE events. As a routine procedure of thromboprophylaxis, the patient was encouraged to perform ankle pump and continuous passive motion (CPM) exercises after surgery but no use of elastic stockings, and 3200 IU low molecular weight heparin calcium(LMWHC) was injected subcutaneously at the morning of following day. Then she was allowed walking and discharged, flexion and extension of knee joint without weight bearing and straight leg-raising exercises were encouraged but long distance walking was discouraged at home.
Three weeks after surgery, she found swell at the knee joint and it extend to calf and ankle sequentially, but had not attached importance to it. On the 33th postoperative day, dyspnea, palpitation, and nausea were felt abruptly after stand up, and these symptoms had not alleviated after a rest. Soon she presented with severe dyspnea, tachycardia, and hypotension at ambulance and was transfer to emergency department. Pitting edema in the calf was found. An arterial blood gases analysis showed decreased PO2 (72 mmHg, normal 80–100 mmHg) and PCO2 (31 mmHg, normal 35–45 mmHg). Coagulation function showed elevated D-dimmer (2494 ng/ml, normal 0–243 ng/ml) and FDP (28.88μg/ml, normal 0–5 μg/ml).Electrocardiography revealed sinus tachycardia and a right ventricular strain pattern, and chest CTA showed obstruction in both pulmonary arteries (Fig. ). So she was diagnosed pulmonary embolism(PE) and was admitted into ICU, Urokinase (0.2 million units ivgtt in10 minutes, followed by 1.2 million units ivgtt for 10 h) thrombolysis was administered, enoxaparin(60 mg ih q12h) and warfarin(3.125 mg po qn) were prescribed subsequently for anticoagulation. One week later, her condition was stable and transfer to normal ward, the edema at calf also alleviated obviously. The intravenous ultrasound confirmed thrombosis of popliteal vein and small saphenous vein (Fig. ). The reexamined chest CTA revealed pulmonary arteries obstruction had dissolved. After two weeks anticoagulation of warfarin(3.125 mg po qn), the thrombosis of popliteal vein vanished and the patient discharged. Warfarin was prescribed, and regular follow up was conducted to monitor the coagulation function and residual small saphenous vein thrombosis in outpatient department.


A 5-year-old female patient was referred due to acanthosis nigricans and generalized lanugo which developed in the last two years. According to the past medical history, she was born by cesarean section after an uneventful pregnancy with a birth weight of 3500 g and length of 49 cm. She was the first child of first-degree consanguineous parents. Her developmental milestones were normal. There is no family history of any remarkable medical problems. She had a healthy sibling who did not have any dysmorphic features.
Her weight was 18.7 kg [standard deviation (SD) score -0.08], height 98.7 cm (SD score -2.6), and body mass index 19.2 kg/m2 (SD score 1.94). Severe acanthosis nigricans of the neck, axillae, the external genitalia and antecubital regions, generalized lanugo, mildly decreased subcutaneous fat, coarse face, large ears, high nasal bridge, upturned nose, abnormalities of the teeth, gingival hyperplasia, and polydactyly in her left hand were noted (). Complete blood count, liver and renal function tests, electrolytes, lipid profile, fasting and postprandial glucose levels, glycosylated hemoglobin (HbA1c), thyroid function tests, insulin-like growth factor (IGF) 1, and serum IGF binding protein-3 levels were normal, while fasting insulin was extremely high (). After an overnight fast, an oral glucose tolerance test (OGTT) (1.75 g/kg) was performed and impaired glucose tolerance was detected. Bone age was consistent with 4 years according to the Greulich-Pyle atlas. Healthy eating and lifestyle changes were recommended to the patient for impaired glucose tolerance. Clinical features and metabolic status were found to be unchanged after one year of follow-up.
After getting informed consent from the parents, DNA was extracted from peripheral leukocytes using standard methods. All exons and flanking intron regions of the INSR (NM_000208.3) were sequenced and a homozygous mutation was found: c.3529+5G>A (IVS19+5G>A) (). This impact of variant was analyzed by using Human Splicing Finder V3 and Mutation Taster and both predicted this variant to be damaging. Our literature search yielded a heterozygote variant in a case with Donohue syndrome with compound heterozygote genotype (p.Arg1027* in exon 17 and c.3529+5G>A) that was recently reported in a congress session (). There is no functional analysis data in the literature. Frequency of this variant was 4 in 121408 in EXAC database. This variant was also present in dbSNP database with rs764083259 code. DANN score is 0.8688.
Screening for the relevant mutation was performed in family members. The parents and the 3-year-old sibling were heterozygous for the same mutation ().


A 29-year-old Caucasian male who was previously fit and well was transferred to our renal unit with significant acute kidney injury (AKI).
He first presented to his local hospital with palpitations, a weeklong history of fever, myalgia, progressive generalised muscle weakness and a diarrhoeal illness. He denied any headaches or confusion. His symptoms started approximately 24 h after attending a barbeque. No one else that attended the barbeque was unwell. There was no history of foreign travel or any illicit drug abuse.
He works as an office fitter. He likes fishing regularly but has not indulged in this activity of recent. He admitted to caring for his mother’s pet, a cat, in the past 2 weeks.
On examination, he was clinically jaundiced. His temperature was 38.4°c; blood pressure (BP) 121/57 mmHg; and pulse 70 bpm. Cardiovascular, respiratory, abdominal and neurological examination was otherwise unremarkable.
Urinalysis showed presence of blood 3+ and protein 2+. Electrocardiogram only showed sinus tachycardia with no evidence to suggest pericarditis.
Initial investigations on Day 1 of admission revealed a haemoglobin level of 9.4 g/dl, white cell count 11.5 × 109/L and marked thrombocytopenia with a platelet count of 17 × 109/L. His urea was raised at 23.7 mmol/L with a creatinine level of 534 μmol/L. His potassium was 4.1 mmol/L with a bicarbonate level of 18 mmol/L. His liver function test was also deranged with an albumin of 23 g/L, bilirubin 281 μmol/L, alkaline phosphatase (ALP) 58 unit/L and alanine aminotransferase (ALT) of 212 unit/L. International normalized ratio was minimally raised at 1.2 and with a normal prothrombin time of 12.4 s. His creatine kinase was elevated at 8776 unit/L with a normal troponin level. C- reactive protein was also elevated at 200 mg/dL. Both haptoglobin and fibrinogen levels were raised at 466 mg/dL and 5.64 g/L; consistent with an infective process. The lactate dehydrogenase level was significantly raised at 1109 unit/L. C3 level was normal but C4 level was reduced at 0.06 g/L. Autoimmune markers including antinuclear antibody, anti-double-stranded DNA antibodies and antiphospholipid screen were negative.
The initial blood film at the local hospital and a repeat at our tertiary unit showed presence of schistocytes. His direct antiglobulin test screen was negative.
In light of his history of diarrhoea, acute kidney injury, and thrombocytopenia with evidence of haemolysis, a presumptive diagnosis of shiga toxin-producing Escherichia coli induced haemolytic uraemic syndrome (HUS) was made. He was given platelet transfusion and initiated on daily plasma exchange (PEX). The decision was also made to prescribe Piperacillin/Tazobactam in view of his raised inflammatory markers, pyrexia and chest x-ray suggesting a hospital-acquired pneumonia. After 12 h of antibiotic administration and PEX on Day 1, he became unwell with evidence of shock. He had further temperature spikes of 38°c, BP dropped to 60/40 mmHg and tachycardia of 150 bpm. Repeat investigations showed worsening inflammatory markers and evidence of ongoing haemolysis with marked anaemia. He required inotropic support for 4 h as he was resuscitated with fluid and blood products. He remained profoundly polyuric since admission.
Ultrasound abdomen showed normal sized kidneys and no abnormalities seen in other visceral organs. Echocardiogram was unremarkable.
On Day 3 when both blood and stool cultures were found to be negative, a probability of systemic infection was explored. Serum antibodies for brucella, bartonella, cytomegalovirus, Ebstein-Barr virus, human immunodeficiency virus and hepatitis were negative. A positive Microscopic Agglutination Test (MAT) with raised titres at 1:320 and the presence of anti-leptospira IgM by ELISA at a titre of 1:2560 confirmed the suspicion of leptospirosis on illness day 14 (admission day 7).
He continued to improve clinically. A renal biopsy was not attempted due to his presentation with profound thrombocytopenia and his renal function improved rapidly with treatment. He completed 5 days of intravenous antibiotics and 10 days of oral doxycycline. He only received 4 sessions of PEX and never required dialysis. He was discharged on Day 10 with a creatinine level of 82 μmol/L and a platelet count of 294 × 10^9/L. His liver function tests were gradually improving with a bilirubin of 264 μmol/L (peak bilirubin 705 μmol/L), ALT 148 unit/L (peak ALT 212 unit/L) and ALP 147 unit/L (peak ALP 200 unit/L).


A healthy 66-year-old man with no previous medical history was admitted to the ED for a first episode of rapid onset severe epigastric pain. It appeared at rest without associated symptoms such as dyspnea or vomiting. He reported taking non-steroidal anti-inflammatories for 1 week prior to admission for an epicondylitis. On admission, his pain had rapidly subsided and the physical examination was inconclusive: blood pressure, temperature, heart rate, and capillary filling were normal. Thoracic auscultation and abdominal palpation revealed only slight epigastric pain. ECG and troponin assay were normal as was hemoglobin, bilirubin, liver enzymes, and lipase levels. As a part of our department’s policy, a POCUS was performed essentially to rule out cholelithiasis. It was performed using a Philips CX50 with a 3.5–5 MHz abdominal probe. There were no gallstones; however, POCUS revealed a mass located between the spleen and the left kidney (Fig. and Additional file : Video 1) measuring 80 * 74 mm. The mass was vascular with a strong color Doppler signal (Fig. and Additional file : Video 2) and an intraluminal thrombus which explains why the Doppler signal does not fill all the lumen. The maximum velocity in the aneurysm was only 18 cm/s because of the large diameter. The aorta was explored from diaphragm to bifurcation. No other aneurysm was found. Small amounts of free peritoneal fluid were detected around the spleen.
Urgent computed tomography diagnosed a fissurated giant aneurysm of the splenic artery (Figs. , , ). A selective angiography (Fig. ) was then performed under general anesthesia; a complete exclusion of the aneurysm was obtained with glue/lipiodol embolization. The post-intervention course was uneventful and the patient was discharged home 3 days later. The patient has remained free from any complications of the embolization 6 months after the procedure.


We present the case of a male Caucasian infant, aged 9 months and 3 weeks, who is brought to the emergency room having 40 °C fever, vomiting associated with breast feeding, restlessness, symptoms with an onset in the last 12 h, and associated with the mother’s referral as for the protuberant fontanelle. At the time of admission, the infant was febrile 38.8 °C, pale, with perioral cyanosis, with a normal lung assessment, relative bradycardia - heart rate (HR) of 88 beats per minute (bpm), with asymmetric deep tendon reflexes more diminished on the right side, right Babinski reflex present, right hemibody motor deficit, bulging of the anterior fontanelle, and Glasgow Coma Scale of 8. He was born naturally, normal birth weight, with food diversification started at the age of 6 months, and still breast fed at the moment. The only condition in the infant’s history is a gastroesophageal reflux disease (GERD), diagnosed at the age of 2 months, for which the patient received a treatment with esomeprazole 0.5 mg/kg/qd (5 mg/qd) for the last 4 months. The GERD improved after food diversification was introduced, but some inconstant vomiting is still present. Laboratory investigations revealed the following alterations: leukopenia – white blood cells 2.6 × 109/L, 88.2% (2.293 × 109/L) neutrophils, hemoglobin 9.9 g/L, hematocrit 28.8%, mean corpuscular volume 70.6 fL, platelets 133 × 109/L, blood protein 5.74 g/dl, blood glucose 102 mg/dl, C-reactive protein 215 mg/L (references value 0–10 mg/L), and procalcitonin 10 ng/ml (references value < 0.5 ng/ml).
A chest radiography was performed and revealed an emphasized bilateral infrahilar and hilar interstitial drawing.
A cranial computerized tomograpohy (CT) scan was performed and revealed the following aspect: a diffuse cerebral edema with a wide left parietal hypodense area.
A cranial magnetic resonance imaging (MRI) was also performed and the findings were the following: a diffused swelling aspect of the cortical areas (hyposignal T1/T2 and hyperintensity on FLAIR sequences) with the disappearance of cortical sulci, and with the blurring of the cortical gray and white matter border in the left paramedian areas of the frontal, parietal, and occipital lobe. Hypersignal T2 and hyperintensity on FLAIR sequences in the fronto-parietal sulcus (bilateral) with a haematic component in magnetic susceptibility sequences. Ectasia of the small cortical cerebral veins, without cerebral lacuna images at the level of high flow cortical veins or venous sinuses. Small images with restricted diffusion spread across the bilateral supratentorial brain parenchyma. The administration of gadolinium-based contrast agent highlighted small diffused areas in the right frontal lobe white matter right, in the left frontal and parietal lobe, underlying areas of edema and at the level of the meninges, predominantly in the frontal and parietal lobes. See Figs. and .
3D Time of flight angiography TOF sequences revealed no abnormalities in the cerebral arterial circulation. The conclusion of the MRI was: the described aspect corresponds to a meningoencephalitis. See Fig. .
A transfontanelar puncture was performed, and revealed a purulent cerebrospinal fluid (CSF), a CSF on examination with 310 WBCs/mm3 (reference values 0 to 10), a glucose of 5 mg/dL (reference values 40 to 70 mg/dL), a protein of 28.35 g/L (reference values 0.15 to 0.2 g/L), and with a latex agglutination test positive for group B Streptococcus (GBS). Gram stained smear shows a high number of leukocytes, rare red blood cells, and numerous Gram positive cocci arranged in pairs or short chains that were confirmed on growth medium as Streptococcus agalactiae. The antibiogram of the bacterial isolates determined by disc diffusion method revealed the sensitivity to ampicillin, linezolid, vancomycin, teicoplanin, trimethoprim/sulfamethoxazole, ciprofloxacin, and the resistance to tetracycline and clindamycin. The treatment was initialized with cerebral depletion therapy (such as administration of intravenous solutions like mannitol), ampicillin 200 mg/kg/day, ceftriaxone 90 mg/kg/day, and vancomycin 60 mg/kg/day. After receiving the susceptibility tests result for the isolated strain, ampicillin, and vancomycin were administered. Also, dexamethasone, and antiseizure drugs were associated to the treatment. The bacteriological examination of mother’s genital secretions, breast milk, and peri-areolar skin were negative. The bacteriological examination of infant’s gastric secretion, was unfortunately performed after initiation of the treatment and was negative. His response to the therapy was slowly favorable, the survival being associated with motor (right hemiplegia), language deficits, and episodic irritability (Additional file : Flow diagram).


The patient is a 6-year-old African-American male with autoimmune enteropathy (diagnosed 12 months prior to admission, based on the following criteria: intractable diarrhea, small bowel villous atrophy, presence of circulating anti-enterocyte antibodies, and responsiveness to immunosuppressive treatment) who was hospitalized for worsening non-bloody, watery diarrhea, severe malnutrition, and hypocalcemia. Initially, he responded well to glucocorticosteroid monotherapy. However, for the 6 months prior to this admission, social issues gradually led to interruption of this therapy with recurrence of diarrhea (Figure A) and weight loss. Despite re-initiation of glucocorticoids, diarrhea persisted, so tacrolimus was added to his treatment regimen. He responded well with combination therapy, but 6 weeks prior to admission, he developed recurrent diarrhea and weight loss (despite appropriate administration of medications and consistent therapeutic tacrolimus levels). He had no other medical problems and had no relatives with gastrointestinal or immunological disease. Findings on the initial physical examination revealed a moderately malnourished (height Z = −0.56, weight Z = −2.25, BMI Z = −2.85) child with hypothermia (temperature 97.5 °F), hypotension (blood pressure 83/54 mmHg), tachycardia (pulse 103 beats per minute), dry mucus membranes, sunken orbits, temporal wasting, and a protuberant but otherwise benign abdomen. His laboratory values are shown in Figures B–E.
He was initially resuscitated with intravenous fluids. However, his diarrhea (Figure A) and metabolic acidosis (Figure E) remained while hypokalemia (Figure D) worsened. All enteral intakes were withheld and total parenteral nutrition was initiated, while intravenous solumedrol and oral tacrolimus were continued. Despite good therapeutic blood levels of tacrolimus (Figure C), the diarrhea persisted (Figure A). Pan cultures of stool, urine, and blood revealed no abnormal growth. Stool ova and parasites analysis, viral, and Clostridium difficile toxin A/B studies were negative. On hospital day 4, he developed severe hypocalcemia with tetany (contractures of the hands and lower extremities), and worsening hypokalemia and metabolic acidosis. He was transferred to the intensive care unit for a closer monitoring and given three consecutive doses of q 3-h intravenous calcium chloride (0.5 mEq elemental Ca2+/kg/dose), in addition to intravenous fluids and other electrolyte replacements. Remarkably, as his serum-ionized Ca2+ normalized, his diarrhea resolved (Figure A). In fact, after 3 days of calcium therapy, he became constipated.
With weaning of calcium supplementation, there was a recurrence of diarrhea, hypocalcemia, and metabolic acidosis. Five days after discontinuing calcium, his daily stool output increased to more than 2 L—close to that before calcium supplementation. The diarrhea resolved within 2 days of administration of oral calcium carbonate suspension (1.3 mEq elemental Ca2+/kg/day) (Figure A). Of note, he received a combination of glucocorticoid-tacrolimus (at therapeutic levels) therapy during the entire hospitalization. At discharge, the patient was prescribed vitamin D in addition to calcium supplementation to restore normal Ca2+ balance. He was also placed on an unrestricted diet. At his recent 3-month follow-up clinic visit, he had no diarrhea, and the serum calcium levels remained normal.


A 33-year-old Caucasian female presented with progressive headaches, ataxia, anosmia, diminished sense of taste, and visual field disturbances. The ophthalmology examination found papilledema. A comprehensive review of the systems and the physical examination were otherwise negative. The magnetic resonance imaging (MRI) demonstrated an irregularly shaped 6.3 X 4.8 X 4.8 cm intra-dural mass, suggestive of a meningioma arising from the olfactory groove. Intraoperatively, an origin from the olfactory groove was confirmed. Bi-coronal frontal craniotomy accomplished gross total resection of the highly-vascularized tumor (Figure ). Resection of limited extensions of the tumor through expanded olfactory tract perforations in the olfactory groove necessitated repair of the anterior cranial fossa with a pericranial graft. There were no surgical complications.
Post-operatively, the computed tomography (CT) scan demonstrated removal of the tumor and a small amount of blood in the resection cavity. At discharge, on postoperative day (POD) eight, the patient was neurologically intact to the exam and ambulated independently. She was referred to a radiation oncologist for adjuvant therapy. At her six-week postoperative visit, her previous visual symptoms and headaches had subsided. The analysis of the tumor specimen revealed a spindle cell neoplasm associated with perivascular collagen, positive signal transducer and activator of transcription 6 (stat6) expression, normal mitotic activity (four mitoses per 10 high-powered fields), and no necrosis, all of which were consistent with the World Health Organisation (WHO) grade II lesion. An HPC had not been considered in the differential prior to the surgical resection, given the location of the lesion.


Due to recurrent palpitation and tremor over at least 3 years, a 14-year-old girl was admitted to our center on 22 July 2013. She had been diagnosed with hyperthyroidism in another hospital according to her thyroid function on 15 July 2010. Methimazole was prescribed primarily, and it was changed for propylthiouracil on 29 June 2011. However, her thyroid function remained abnormal over the 3 years prior to her presentation at our department (Tables and ). All antithyroid drugs had been suspended for 5 months since 28 January 2013, and she was admitted to our center on 22 July 2013 for further checkup and diagnosis. Her thyroid function was rechecked twice during her stay in our ward. The results showed remarkable elevation of FT3 and FT4 levels with a suppressed TSH level. At both time points, the FT3 concentration exceeded 30.8 pmol/L (normal range, 3.5–6.5 pmol/L), and the FT4 concentration exceeded 154.8 pmol/L (normal range, 11.5–22.7 pmol/L). The serum TSH concentrations at the two time points were 0.013 μIU/mL and 0.006 μIU/mL (normal range, 0.55–4.78 μIU/mL). The measured levels of TSH receptor antibody (TRAb) were 40 mIU/mL and 35.36 mIU/mL (normal range, 0–1.58 mIU/mL). After administration of a small dose of 131iodine, the radioactive iodine uptake rate was 68.69% at 2 h (normal range, 4.5%–24.5%), 85.98% at 6 h (normal range, 8.7%–42%), and 69.53% at 24 h (normal range, 19%–61%). A magnetic resonance (MRI) scan taken previously in 2012 at the other hospital showed a slightly enlarged pituitary gland not occupied by a lesion.
Physical examination on admission revealed a body temperature of 37.2°C, heart rate of 120 beats per minute, respiratory rate of 18 breaths per minute, blood pressure of 110/60 mmHg (1 mmHg = 0.133 kPa), weight of 40 kg, height 1.55 m, and body mass index of 16.65 kg/m2. The patient's thyroid was moderately enlarged without murmur or a nodule. Along with the heart rate of 120 beats per minute, there was obvious accentuation of the first heart sound and tremor, but no edema or proptosis were found. No other specific findings were observed.
The patient's father was advised to undergo a check of his thyroid function and receive genetic testing to determine whether he also had THR, which is a familial disease. Thyroid function tests in our hospital revealed a FT3 concentration of 10.3 pmol/L (normal range, 3.5–6.5 pmol/L), FT4 concentration of 32.03 pmol/L (normal range, 11.5–22.7 pmol/L), and TSH concentration of 1.662 μIU/mL (normal range, 0.55–4.78 μIU/mL) for the father on 05 February 2013 (Table ). Repeated tests on 22 July 2013 showed elevated FT3 and FT4 levels with a normal serum TSH concentration (Table ).
The patient's history was not inconsistent with simple Graves’ hyperthyroidism, and her father's thyroid function indicated THR syndrome without any comorbidities. Therefore, genetic testing for mutations of the TR β gene was performed. A point mutation in the TR β gene was identified in the patient and her father (Fig. ). The 95th base C was replaced by T (C95T) on exon 10 with the codon of ACU changed to AUU, and the encoded threonine was changed to isoleucine.
Subacute thyroiditis, iatrogenic thyrotoxicosis, iodide-induced thyrotoxicosis, thyrotropin-secreting pituitary adenoma, and multinodular toxic goiter were excluded according to the patient's history, clinical manifestations, and follow-up observations.
The patient was then diagnosed with THR complicated by Graves’ disease. Methimazole 30 mg/day and propranolol 90 mg/day were started on 22 July 2013, and then, methimazole 30 mg/day and propranolol 60 mg/day were maintained from 13 August 2013. After discharge, she was followed up regularly. The patient became asymptomatic with stable thyroid function, slightly elevated FT3 and FT4 levels, and a normal TSH level (Table ).


A 2-year-old African American girl with a past medical history of extreme prematurity born at 25 weeks of gestational age and seizure disorder was transferred to our hospital with a rash for 1 day, with associated conjunctival injection and crusting around the eye. The mother reported that the girl did not want her skin to be touched, possibly secondary to pain. The mother also reported fever, decreased appetite, and decreased energy. There was no prior history of a similar rash. The patient had no rhinorrhea, cough, or congestion. Her medication history was significant for a change from levetiracetam to zonisamide for seizure control about two and a half weeks prior to presentation. Neurology had recommended the change for improved seizure control and for improved adherence since zonisamide was once-daily dosing. The patient did not have any other new medications including antibiotics within the past month prior to presentation.
On physical examination, the patient was afebrile and difficult to console. She had erythematous targetoid macules, papules, and plaques with dusky centers on her face, neck, chest, abdomen, back, bilateral upper extremities, and bilateral lower extremities involving 75% body surface area (BSA). Nikolsky sign was positive in 9% BSA upon presentation, and the rash progressed within 24 h to approximately 20% BSA Nikolsky positive. Tense bullae were noted on her face, arms, and legs with sloughing on the left upper arm at site of prior bandage. Mucosal lesions included erosions and crusting of her lips, conjunctival injection, and erythema and erosions of her labia minora (Figs and ).
Biopsies for frozen section and permanent pathology revealed full-thickness epidermal necrosis with a pauci-inflammatory infiltrate (Fig. ). Herpes simplex virus and varicella zoster virus polymerase chain reaction tests from a bulla were negative. Laboratory studies revealed significant transaminitis with alanine aminotransferase (ALT) of 891 U/L and aspartate aminotransferase (AST) of 595 U/L. Alkaline phosphatase was also elevated at 304 IU/L. Complete blood count, electrolytes, and kidney function were within normal limits. Respiratory viral panel, hepatitis A immunoglobulin M (IgM) antibody, hepatitis B core IgM antibody, hepatitis B surface antigen, and hepatitis C antibody were negative. Serum urea, bicarbonate, and glucose levels were within normal limits. The patient was admitted to the pediatric intensive care unit with the diagnosis of Stevens–Johnson syndrome/toxic epidermal necrolysis overlap. Her severity of illness scale for toxic epidermal necrolysis (SCORTEN) was one .
Zonisamide was discontinued immediately, and intravenous immunoglobulin (IVIg, 1 g/kg/day) for 3 days was administered without complications. Neurology restarted the patient on levetiracetam for her seizure disorder. Her skin improved significantly over the next 2 weeks, and at the time of discharge, only mild crusting of her lips remained with all other cutaneous lesions healed. Her transaminitis resolved during admission as well.


In February 2015, a 70-year-old female patient was referred by her medical practitioner to the Alessandria Hospital Osteonecrosis of the Jaws (ONJ) Multidisciplinary Team due to severe oral infections.
The woman reported to be affected by osteoporosis and had been receiving weekly treatment of 70 mg alendronate for 5 years. She denied any history of diabetes, severe cardiovascular disease, cancer, myeloma, head-neck radiotherapy, and facial trauma.
The patient complained of pain at the left maxilla and the right side of the mandible.
The recent dental history had started 15 months before, in November 2013, when the patient went to her dentist with the aim to restore the masticatory function compromised by a long period of neglect.
The dentist, on the basis of the clinical and radiological evaluation (), proposed the extraction of the roots of teeth 25 and 44 (ISO tooth-numbering system), root canal treatment of 27, the restoration with prosthetic crowns of the elements 27, 34, and 47, and the fabrication of a superior and an inferior partial removable prosthesis.
In March 2014, the patient came back to the dentist practice with a new panoramic radiograph (); this, according to the changed conditions (element 24 broken), varied the rehabilitation project, and the extraction of the roots of 24 and 25 were planned. An ill-defined area of radiolucency was present between the roots of 43 and 44 but no further investigations or considerations were made at that time.
The next month, the woman, with no prior antibiotic prophylaxis, underwent the extraction of the roots of 24 and 25 with local anesthesia; during the same appointment, she also underwent the extraction of the root 44, without local anesthesia because this root was extremely mobile; at the end of surgery, the dentist did neither sutured nor prescribed antibiotic therapy.
The following scheduled appointments were delayed due to the continuing pain and the lack of complete healing of the post-extractive sites.
Six months later, in October 2014, the patient still presented with recurrence of abscesses on the second and fourth quadrant, a fistula in the region of 24/25, and third-degree mobility of the lower-right cuspid (43). The dentist requested a new radiograph () that showed a wide, circular radiolucent area involving the bone distal to 43 together with less-defined alterations in the upper left quadrant.
During the follow-up in December 2014, on the basis of what had been observed in the oral cavity and on the panoramic radiograph, the practice dentist hypothesized the presence of bone sequestrum in the upper-left bicuspid region and of a cystic lesion englobing the root of 43. He prescribed amoxicillin (1 g, 1 tablet twice a day for 6 days) and chlorhexidine (0.20%) oral rinses. At the next check-up, objective and subjective symptoms were still present and the dentist proposed a surgical revision of post-extraction sites.
In February 2015, the patient decided to have a second opinion, and her medical practitioner asked for evaluation at the Osteonecrosis of Jaws (ONJ) Multidisciplinary Group at Alessandria Hospital. At clinical inspection, the upper-left premolar area showed granulating tissue with underlying apparent necrotic bone upon probing ().
In the right mandible, a hard-elastic painful swelling and a fistula distal to 43 were observed ().
Hence, on the basis of the recent dental history, a diagnosis of multifocal non-exposed MRONJ was suspected and alendronate intake was suspended. After the first visit, a computed tomography (CT) scan of the jaws, without iodine contrast, was performed and it showed that on the right side of the mandible was an osteolytic area 20 mm in diameter, extended in the region of the premolars, englobing the root of the lower-right cuspid, and containing bone fragments. This lesion determined swelling of the buccal mandibular cortical, which appeared also eroded both on the lingual and buccal side; the adjacent spongious bone and the periosteum on the buccal side appeared thickened ().
In the left maxillary, a large area of bone rarefaction and erosion extending from the area of cuspid to second premolar was observed ().
After the CT scan, the patient was referred to the University Oral Care Center in Novara, which was nearer to her hometown. Here the clinicians, confirming the diagnosis of MRONJ, prescribed amoxicillin + clavulanic acid (1 g, 1 tablet every 12 h), metronidazole (250 mg, 2 tablets every 12 h), and a 0.20% chlorhexidine oral rinse every 12 h.
The patient was proposed to undergo surgical intervention in order to remove the necrotic bone which was causing the recurrent abscesses. She was referred to a third-level center for ONJ, the Unit of Oral Pathology and Laser-assisted Oral Surgery of the University of Parma, which specialized in laser-assisted treatments of MRONJ. Here the patient accepted to undergo surgical operation with local anesthesia. The surgery consisted of the osteotomy of the right alveolar ridge of mandible and vaporization of osteonecrotic area with Er:YAG laser; extraction of 42, 43, and 34; and surgical revision of the upper-left premolar region.
Before surgery, the patient received antibiotic therapy (the previous antibiotic regimen was substituted with ciprofloxacin (500 mg, 1 tablet every 12 h) because a bacterial strain of Serratia marcescens resistant to amoxicillin plus clavulanate and metronidazole was isolated by means of cultural exam) and sessions of low-level laser therapy (LLLT) with a diode device (Giotto®, Dental Medical Technologies SRL, Lissone, Italy; parameters: 980 nm, optical fiber of 600 microns in diameter, 1 W continuous wave, 120 s, 3 times a week for 4 weeks).
In June 2015, the planned surgical intervention was performed without any intraoperative complications.
She was discharged with the indication to continue antibiotics and LLLT for 21 days until the removal of sutures and to apply chlorhexidine gel 1% on surgical wounds twice daily.
Four bone specimens collected from the mandible during surgery were subjected to histopathological examination: the one including dental elements 43 and 42 appeared macroscopically grey, of impaired consistency, and irregular surface with histopathological signs of osteonecrosis. The two bone chips collected mesially and distally near the osteolytic lesion and the one taken nearby the extractive socket of 34 consisted of normal bone.
Seven days after surgery, the patient had a perimandibular hematoma but the postsurgical wound was fully closed. Sutures were removed after 3 weeks. At this time, the patient ended the antibiotic therapy but continued the application of local antiseptics.
A 3-month follow-up consisting of oral inspection and professional dental prophylaxis was scheduled. The woman neither present exposed necrotic bone in the oral cavity nor complained of any symptoms ( and ).
During the follow-up period, it was suggested to the patient that teeth 27 and 48 be extracted. The elements were non-restorable and carried the potential risk of causing infection and triggering new foci of bone osteonecrosis.
Tooth extractions were performed in February 2016 at Parma University. Antibiotic therapy (amoxicillin + clavulanic acid, 1 g tablets, 1 tablet every 12 h; and metronidazole, 250 mg tablets, 2 tablets every 12 h) was started 3 days before the intervention and continued for 2 weeks after it. Twelve sessions of LLLT were performed before and after the intervention.
After 7 days, the patient reported mild bleeding from the mandibular socket; after 10 days, at the same site, a small mucosal dehiscence appeared. After 18 days, the dehiscence resolved with local applications of 1% chlorhexidine gel and a complete reepithelization of the extractive sockets was achieved 4 weeks after tooth extractions.
At the oral inspection carried out in October 2016, the oral mucosa showed no dehiscence ( and ) in the areas of extractions, and mandible CT scans without iodine contrast revealed no erosion of the mandibular cortical bone ( and ). The upper arch of the patient was rehabilitated with a removable partial denture with cast clasps on elements 17, 14, and 21, and the lower arch with a removable partial denture with cast claps on elements 33 and 41.


This presently 33-year-old woman of Caucasian (Austrian) origin initially presented with a childhood-onset dilated cardiomyopathy, requiring heart transplantation at the age of 17 years. Histologically, basophilic degeneration and pronounced vacuoles were present in cardiac muscle cells. During childhood, the patient also suffered from relapsing episodes of viral (Herpes simplex) and bacterial (pneumonia, tonsillitis) infections. Additionally, in her 20s, she repeatedly displayed episodes of fever and rash, which could clinically be classified as acute febrile neutrophilic dermatosis (also referred to as Sweet’s Syndrome). This autoimmune condition promptly responded to systemic treatment with corticosteroids, but invariably relapsed as soon as the steroid dosage was reduced. At the age of 21, the patient developed a progressive muscular weakness affecting all four limbs, eventually rendering her wheelchair dependent 10 years later. A detailed neurological examination at the age of 32 documented a bilateral ptosis, a proximally pronounced weakness of the lower limbs (MRC 2, pelvic girdle) with relatively preserved strength in distal leg muscles (MRC 4). Upper limbs were also, but less severely, affected (MRC 4- in the shoulder girdle and MRC 4 + in distal muscles). Routine laboratory investigations showed a mild leucocytosis (13 G/L) under steroid treatment and fluctuating CK serum levels between 80 U/L and 1000 U/L (normal < 170 U/L). Electromyography of the quadriceps femoris muscle showed a myopathic pattern. Nerve conduction studies were normal. An MRI scan of the thigh muscles and the pelvic girdle confirmed a marked generalized muscular atrophy. A subsequent histological investigation of muscle tissue (vastus lateralis muscle) was inconclusive, merely showing fatty and fibrotic degeneration. The family history was generally unremarkable. Both parents (aged 72 and 67) and two siblings (aged 42 and 37) were alive and neither reported similar symptoms. Consanguinity was explicitly denied.
In Table , clinical details of both reported patients are summarized and compared to the previously published family carrying the same mutation.


A 24-year-old female came with a history of asymmetrical enlargement of left breast for 4 months. The physical examination revealed asymmetrical enlargement of left breast with a large ill-defined lump mainly occupied in the upper inner quadrant. No skin discoloration or ulcer was seen (Fig. ). Digital mammography with tomosynthesis (Hologic Selenia Dimensions, MA, USA) demonstrated extremely dense breasts with asymmetrical enlargement of the left breast. There was a large ill-defined mass mainly occupying at upper inner quadrant. No associated architectural distortion or suspicious microcalcifications were seen. Additional ultrasonography showed an ill-defined infiltrative mixed hypoechoic and hyperechoic mass at the same area. This mass demonstrated multiple vascular structures and a large arterial feeder. There were few benign left axillary lymph nodes (Fig. ).
Breast MRI (1.5 T, Espree, Siemens) was performed. It displayed a large infiltrative mass with indistinct margin, approximated ~8.9 × 7.8 × 5.5 cm3. The mass showed isosignal intensity on T1WI and strongly hypersignal intensity on T2WI. After intravenous contrast administration, this mass demonstrated rapid arterial enhancement with mixed plateau and washout on delayed phase (types II and III kinetic curve enhancement pattern). Some areas of the mass showed washout enhancement pattern on delayed phases (type III kinetic curve pattern) but the majority of the mass showed plateau enhancement. This mass extended anteriorly close to the skin without evidence of skin invasion or skin nodules. The mass also contained few small internal hemorrhagic foci (Fig. ).
Repeated ultrasound-guided biopsy was performed. The histomorphology showed atypical vascular proliferation that was not correspondent for angiosarcoma. The CD31, CD34, FLI-1 and Factor VIII were positive, while S-100 and AE1/AE3 were negative. The immunohistochemical study supported endothelial nature, However, the entire specimen was required for accurate result.
Preoperative radiation was suggested by our multidisciplinary team. After the external beam irradiation with total dose of 60 Gy in 30 fractions was obtained, the physical examination showed markedly decreased size of the tumour. Follow up mammogram and ultrasound demonstrated an ill-defined mass with interval decreased in size and vascularity. Correspondingly, the follow up MRI showed interval decrease in size and enhancement of a 5.3 × 3.0 cm2. ill-defined infiltrative enhancing mass at left upper inner quadrant. This mass showed slow arterial enhancement with persistent enhancement on delayed phase (type I kinetic curve enhancement pattern) (Fig. ). The patient had mild erythematous skin after radiation. As a result, breast conserving surgery was suggested by our multidisciplinary team.
Ultrasound-guided skin marked wide excision was operated (Fig. ). The specimen showed area of congested reddish soft tissue mass which contained tumour foci and internal hemorrhag (Fig. ). The histological result showed proliferating endothelial cells forming small vessels and small areas of elicited aggregation of congested blood vessels. These findings were suggestive of angiomatosis of the breast. No malignant cells which indicated angiosarcoma was demonstrated (Fig. ).
Postoperatively, patient was instructed to follow up in 6 months for clinical examination and follow up mammogram with ultrasound (Fig. ). The imaging studies showed complete disappearance of the previous large ill-defined mass at left upper inner quadrant.


A female patient, 49 years old, from Nagasaki, Japan, presented since early February 2017 with skin papules on both forearms, then she developed a painful mouth ulcer with multiple neck swellings by late February. She sought the medical advice of her dentist who recommended referral to internal medicine department for hospitalisation.
Initial examination at the internal medicine department revealed a painful small ulcer at the middle of the soft palate with a pain score of 5/18 and cervical lymph node swellings. The complete blood count was normal and a biopsy showed no malignancy. The condition was diagnosed as candidiasis, and anti-fungal treatment was prescribed with an improvement of the pain score of 1/18 but healing of the ulcer was not noticed despite adherence to therapy.
By late March 2017, progression of the palatal ulcer and non-improvement of cervical lymphadenopathy indicated re-admission of the patient for further clinical assessment and laboratory investigations. A full blood count () showed normal red blood cells (RBCs) count and morphology (RBCs count: 4.4 × 106, normal: 3.8–4.9 × 106) and normal platelets count and morphology (platelets count: 274 × 103, normal: 158–348 × 103). The total leukocytic count was normal: 8.3 × 103 (3.3–8.6 × 103) but 40% of leucocytes were abnormal lymphocytes (abnormal lymphocytic count: 3.3 × 103, normal: 0). Biochemical and immunological investigations () revealed normal lactate dehydrogenase: 172 U/L (124–222 U/L), normal serum calcium (8.8-10.1 mg/dL), and negative antinuclear antibody. High level of HTLV-1 monoclonal bands was recognised by Southern blot method (>45, normal: <1 cutoff-index), also serum level of soluble interleukin-2 receptor (sIL-2R) was very high (3420 U/mL) which then raised to 5960 U/mL one month later (in asymptomatic HTLV-1 carrier it should not exceed 800 U/mL). Flow cytometry showed CD4: 77.9%, CD8: 12.3%, CD25: 72.1%, CCR4: 68.1% and TSLC1: 68.7%.
A screening upper endoscopy with narrow band imaging (NBI) showed multiple oral and pharyngeal ulcers with irregular margins, raised edges and erythematous floors ( and ), thick aryepiglottic folds (), multiple small gastric fundic gland polyps and multiple small submucosal duodenal swellings (). Biopsies were taken from the pharyngeal and duodenal lesions for tissue diagnosis.
Head and neck computerised tomography (CT) showed mild bilateral cervical and axillary lymphadenopathy with left maxillary sinus effusion. Chest CT: ground glass infiltration of the right lung upper lobe apical segment mostly inflammatory and multiple sub-pleural lung nodules about 6 mm in diameter scattered in the right lung lower lobe and left lung upper lobe with thickening of the adjacent pleura. Abdominal CT: mild free ascites and gall bladder wall thickening mostly adenomyomatosis. Liver, spleen and other abdominal organs were normal.
Whole body positron emission tomography-CT (PET-CT) revealed dense accumulation of fluorodeoxyglucose (FDG) in the pharynx, palate and tip of the tongue, lymph nodes affection including axillary, cervical, para-aortic, porta hepatis, iliac and inguinal lymph nodes, parenchymal lung nodular sub-pleural infiltration, and skin involvement including scalp, back of the neck, both upper arms, both forearms, first finger of the left hand and fifth finger of the right hand.
Histopathologic examination of pharyngeal biopsy revealed infiltration by malignant lymphoid cells with hyperchromatic enlarged nuclei and scanty cytoplasm ( and ) while immune-histochemical staining showed CD3 (+), CD4 (+) and CD8 (–) cells (–). A picture compatible with ATL. On the other hand; duodenal biopsy showed non-specific inflammatory changes with lymphocyte and plasma cell infiltration.
As laboratory investigations, imaging findings and tissue diagnosis were consistent with the aggressive subtype of smouldering ATL (leukaemic subtype), intensified chemotherapy was started using mLSG-15 protocol (VCAP-AMP-VECP) in addition to intrathecal cytarabine, methotrexate and prednisone. The patient partially improved following chemotherapy and will be scheduled for stem cell therapy.


In April 2015, a 45-year-old Chinese female presented with intermittent constipation and hematochezia and was admitted to our institution. Three months before the admission, the patient was seen in the local hospital with a chief complaint of progressive abdominal distension for the past 3 months along with a loss of appetite. Computed tomography (CT) of the liver (Fig. ) showed a tumor approximately 11.0 cm in diameter in the right lobe of the liver. The results for blood routines and liver function and coagulation tests were within normal ranges. Tumor marker determination was also normal. Doctors suspected that the liver tumor was a primary hepatic tumor, such as hepatocellular carcinoma. The patient underwent partial hepatectomy in the local hospital. However, the postoperative pathology revealed that the hepatic lesion was a moderately differentiated NET (G2). Immunohistochemistry findings included HepPar-1 (−), AFP (−), CK7 (−), CK20 (−), CK (+), CD56 (+), Ki-67 (7%), Syn (+), CgA (−/+). A subsequent colonoscopy discovered a nodule 1.4 cm in diameter, located on the anterior wall of the rectum, 4 cm above the anal verge, and histological examination confirmed the diagnosis of rectal NET (G2). These findings indicated that the liver tumor might have metastasized from the asymptomatic rectal NET. Magnetic resonance imaging was also performed for the evaluation of the rectal tumor and revealed a small mucosal tumor at the rectum; no lymph nodes were found in the pelvic cavity. Therefore, the rectal NET was staged T1N0 (data not shown). The patient attended our clinic for further treatment. Somatostatin receptor scintigraphy (SRS) showed abnormal uptake in the left ilium (Fig. ), which was considered not to be a metastasis, as indicated by multidisciplinary treatment consultations. As the tumor was located low in the rectum, 4 cm above the anal verge, abdominoperineal resection should be performed. When the patient does not consent to a radical procedure based on concerns for quality of life, TEM becomes an optimal solution.
Rigid sigmoidoscopy was used to confirm the location of the nodule, followed by TEM under general anesthesia. The patient was placed in the prone position with the lesion placed at the bottom of the operating field. The surgery was performed as previously described by Buess et al,[ using the Buess original TEM system (Richard Wolf GmbH, Knittlingen, Germany). After marking the resection area with coagulation dots using a needle cautery, ensuring a free margin area of 1 cm, the tumor was removed one at a time with a full-thickness excision. Defects in the rectal wall were irrigated and closed using running sutures with 3/0 absorbable monofilaments (Fig. ). The surgery was completed within 45 minutes with an approximate blood loss of 10 mL. After surgery, the resected specimen was pinned out on a cork board (Fig. ). No analgesic was required postoperatively. An elementary diet was initiated on the second day, and the patient was dismissed from PUMCH (Peking Union Medical College Hospital) 2 days after the surgery in good clinical condition.
The postoperative pathology revealed that the tumor, 12 mm in diameter, was located beyond the muscularis propria and had invaded adipose tissue with lymphovascular invasion (Fig. ). However, the deep and lateral surgical margins were completely tumor-free. Tumor cells showed a moderate cell proliferation index (Ki-67 8%). Immunohistochemistry studies included the following: AE1/AE3 (+), PGP9.5 (+), Syn (+), CK20 (−), CD56 (+), CgA (+), CD34 (−). The final diagnosis was rectal NET G2 (carcinoid). The patient was informed to a radical abdominoperineal resection, but she did not consent to this treatment planning. The patient was followed up regularly as an outpatient with evaluation by CT and endoscopic examination every 3 months. Two years later, the patient presented with back pain. And the SRS showed pathologic uptake in the liver, lumbar spine, and left ilium (Fig. ). Nevertheless, no local recurrence in the rectum was found using digital rectal examination.


A 40-year-old female patient visited the Department of Oral and Maxillofacial Radiology of Tehran Dental School.
She was asymptomatic and the lesion was detected incidentally at routine radiography by her dental practitioner.
Intraorally, the patient had mild bony hard swelling in the anterior region of the mandible. The overlying mucosa was normal, and there was no sign of acute dentoalveolar or mucosal infection in the mandible region. The anterior mandibular teeth were displaced without mobility. The panoramic radiograph revealed a well-defined unilocular radiolucency with corticated rim, which extended from right to left mental foramens. Because of the lesion, the roots of the left lateral mandibular incisor and canine were deviated and resorbed (Figures and ). The shadow of cervical spine was superimposed over the central part of the lesion (). Axial slice showed expansion of buccal and lingual cortical plates in the anterior mandible with perforation along the outer cortical plate at the left side (). Differential diagnosis included calcifying odontogenic cyst, central giant cell granuloma, AOT, and ameloblastoma. The lesion was completely enucleated. Microscopically, epithelial cells were arranged as spindle shaped cells in sheets and trabecular pattern and can form duct-like and rosette-like structures in a scant hyalinized stroma ().
On gross examination the lesion appears as an elliptical tissue, measuring about 3.5 × 2.7 cm in size (Figures and ). Cut section of the mass revealed multiple cystic spaces and solid area. Small calcifications foci are scattered throughout the tumor. Small islands of tumoral cells have infiltrated the fibrous capsule (). Thus, the final diagnosis was given as extrafollicular AOT.


A two-day-old female infant, born at term after uneventful pregnancy, was referred to our paediatric cardiology team to be evaluated for a light murmur. She was born by vaginal delivery; her post-natal adaptation was normal and auxometric parameters were adequate for her gestational age. No clinical signs of dysmorphism or cyanosis or dyspnea were evident; her peripheral oxygen saturation was 98% at room air and the heart rate was normal. On cardiac auscultation, a 1-2/VI murmur could be heard in the left upper sternal border; pulmonary auscultation as well as peripheral pulses were normal. Colour-Doppler echocardiography revealed the absence of the right pulmonary artery, whereas the main and left pulmonary arteries had normal size. The pulmonary valve was normal. There was no evidence of a patent ductus arteriosus (PDA) nor other cardiac defects except for a small patent foramen ovale. The size and function of both cardiac ventricles were normal and without ventricular hypertrophy. The size and origin of the coronary arteries, as well as the aortic arch, were normal. A physiological tricuspid insufficiency was noticed, with an estimated pulmonary artery pressure of 30 mmHg. These cardiovascular features were confirmed by echocardiographic examination, 1 week later. Suspecting an isolated unilateral absence of the right pulmonary artery (UARPA), we decided to carry out chest X-ray and MRI. The former showed normal pulmonary aeration with regular size of both lungs and a normal cardiac silhouette, the latter showed the absence of the right pulmonary artery, with a slightly increased lumen and size of the main and left pulmonary arteries (Fig. ). Fortunately, the right lung was shown to be perfused by some systemic collateral arteries arising principally from the right subclavian artery and from the celiac trunk. MRI also excluded other heart defects and confirmed normal cardiac function.
In the light of an isolated malformation, as our child was still asymptomatic and she had regular growth rates, no medical or surgical treatment was deemed to be needed. Nevertheless, as symptoms may occur later in life, a thorough clinical and cardiological follow up was immediately started. At present, our patient is 3 years old and remains completely asymptomatic. She is a very active child and shows no sign of fatigue. She has not had any feeding difficulties and her growth has been regular. No major pulmonary infections have been reported. During her first 3 years of life, we have thoroughly monitored her pulmonary artery pressure and the right ventricular function, which have always been normal. In the light of these findings and her clinical condition, our referral paediatric heart surgeon also recommended a wait and see attitude.


Case 1 (4 weeks): The patient was a 75-year-old woman with a history of dermatomyositis and severe lung involvement who had acute aortic native valve EFIE with HLSR in 2003 and was treated with 4 weeks of ampicillin/gentamicin (data published elsewhere) []. The relapse occurred 46 days after completing treatment; the patient presented with fever and positive blood cultures with the same strain of E. faecalis. No perivalvular complications, heart failure, or embolic events developed. She restarted ampicillin/gentamicin at the same dose, but 20 days later she developed renal failure and switched to ampicillin/ceftriaxone. Treatment was maintained for 22 days (total treatment time 6 weeks), and renal function recovered at the end of admission. She was alive and well after 1 year.


Case 2 (6 weeks): The patient was a 53-year-old man with Child B alcoholic cirrhosis who had been diagnosed with aortic native valve EFIE without HLAR in 2008. He had been treated with 6 weeks of ampicillin/gentamicin because of a periannular abscess. The patient was not initially considered a candidate for surgery owing to the high surgical risk. After a relapse 4 months after completing treatment, he was transferred to our center to be evaluated for surgery, since he had developed massive aortic insufficiency and an aorto-ventricular fistula. He developed renal failure after 3 weeks of treatment with ampicillin/gentamicin; therefore, therapy was switched to ampicillin/ceftriaxone. The patient completed 6 weeks of therapy with negative blood cultures and no fever. He underwent cardiac surgery, but died 20 days later from postsurgical multiorgan failure.


Case 3 (4 weeks): The patient was a 65-year-old man with Child C liver cirrhosis who had been diagnosed with aortic NVIE and HLR to both aminoglycosides in 2009. He was treated initially with ampicillin/ceftriaxone for 4 weeks. He experienced a first relapse 3 weeks after completing treatment, and treatment with ampicillin/ceftriaxone was maintained for 6 weeks. Twenty-four hours after the end of treatment, he again presented with fever and positive blood cultures. Treatment was started with daptomycin 10 mg/kg and ampicillin 2 g/4 h, although ampicillin was withdrawn 5 days later owing to lack of synergy in vitro according to the time-kill curves. Ten days after completing 6 weeks of daptomycin, he developed fever, and blood cultures were positive for the same strain of E. faecalis; therefore, ampicillin monotherapy was started. The patient died from heart failure a few days later owing to worsening of initial valve function and fluid overload.


Case 4 (4 weeks): The patient was a 51-year-old man who was diagnosed with Child B HCV cirrhosis and native aortic valve non-HLAR EFIE in 2010 (with severe aortic insufficiency but not heart failure) and was initially treated with ampicillin/ceftriaxone for 4 weeks. He was not considered a candidate for surgery owing to liver disease and pancytopenia. He was readmitted 6 weeks after completing treatment with fever, and blood cultures again yielded E. faecalis. As time-kill curves demonstrated a lack of synergy for ampicillin/ceftriaxone, the patient was treated with ampicillin for 6 weeks and gentamicin for 4 weeks. He remained alive after 2 years of follow-up.
The time-kill curves showing the in vitro susceptibility of the strains causing the relapse in each case are depicted in . The combination of ampicillin plus gentamicin was synergistic and reached a bactericidal effect in all the strains, except against the isolate from case 3, which presented HLR against both aminoglycosides. The double beta-lactam combination was synergistic in all cases with the exception of case 3 and showed a bactericidal effect against case 1 and case 4. The combination of daptomycin plus ampicillin only increased the in vitro activity against the isolate from case 3, which was the one treated with that combination as rescue therapy. However, synergy and bactericidal activity were not reached either in this case. No antagonism was observed with any combination against any strain.