A 59-year-old male with a pertinent medical history of dyslipidemia recently treated with rosuvastatin presented to the emergency department (ED) with the chief complaint of fever for the last three weeks. The fever was high grade in intensity, ranging from 100.5°F to 102.2°F, gradual in onset, intermittent in nature, and progressively worsening. It was associated with fatigue, chills, and diaphoresis. On reviewing other systems he further mentioned an unintentional weight loss of 10 pounds during the last three months. He denied any nausea, abdominal pain, tenderness, diarrhea, constipation, drug abuse history, chest pain, shortness of breath, cough, palpitations, night sweats, weakness, muscle aches, joint pain, or any other complaints. He had no recent travel history outside the US over the last one year. The only medical disease he had was hypercholesterolemia for which has was started on 10 mg rosuvastatin tablet six months ago but was advised by his primary care doctor to stop it a month ago due to mild transaminitis on lab work as an outpatient. He had no previous surgical history and the family history was not pertinent.
On arrival at the ED, the patient was febrile with a temperature of 101°F and tachycardia with a heart rate of 121 beats per min; all other vital signs were within normal limits. On physical examination, he was anicteric, had no abdominal palpable mass or tenderness with normal bowel sounds. The rest of the physical examination was also unremarkable. On investigation, his blood work was within normal range except for an increase in the levels of the liver enzyme with alanine aminotransferase (ALT) at 187 U/L (n=0-41 U/L) and aspartate aminotransferase (AST) at 152 U/L (n=0-41 U/L). Complete blood count (CBC) with differential and serum electrolytes were also normal. There were no abnormalities in bilirubin and alkaline phosphatase. The chest X-ray was unremarkable. The initial CT scan of the abdomen showed mild splenomegaly, a small amount of pelvic ascites, and a fatty liver. The patient was admitted with suspicion of sepsis from an unknown cause. The symptoms of the patient, hepatic-steatosis with an increase in both ALT and AST suggested hepatocellular damage, most likely hepatitis (Table ).
Cultures of his blood and urine were done on admission and initial management with intravenous fluids followed by a dose of ceftriaxone 1000 mg along with Tylenol 650 mg was started in ED. The patient remained stable during his inpatient stay with the exception of daily spikes in temperature as high as 103.1°F around early evening. The urine and blood cultures later came back negative for any microbial growth. The investigation continued with a toxicological profile, acute hepatitis panel for hepatitis A, B, and C viruses antigens and antibodies, serum acetaminophen level, urine copper and serum ceruloplasmin, as well as an antinuclear antibodies (ANA) test with an autoimmune profile, and all the results came out negative. The patient’s serum inflammatory markers were high, including ferritin 2888 ng/mL (n=30-400 ng/mL) along with transaminitis and he was continuously spiking high-grade fever daily afternoon with progressive fatigue during his seven-day hospital course. After seven days of investigation and evaluation by infectious disease and heme-oncologist, he has declared as a case of fever of unknown origin, and a bone marrow biopsy was scheduled to rule out hemophagocytic lymphohistiocytosis (HLH). On day eight in the hospital, a CBC was performed with peripheral smear and flow cytometry, revealing atypical lymphocytosis with no evidence of clonality. Later on the same day, the serology for CMV came out positive with the polymerase chain reaction (PCR) showing a value of 1692 with CMV PCR log of 3.23 (normal <0.00 Log IU/ml) indicating a disseminated cytomegalovirus infection (Table ). Given that all other causes of hepatitis were excluded, it was safely concluded that the patient had an acute CMV hepatitis.
The decision to treat this acute viral hepatitis with antiviral therapy was made due to its severe course. Treatment was started with valganciclovir 900 mg intravenously twice a day in the hospital and upon discharge shifting it to oral 900 mg every 12 hours for a total of 14 days. The patient symptomatically improved and became fully functional thereafter.


The patient is a 60-year-old African American male with multiple medical issues presenting with chest pressure, dyspnea on exertion, and progressive bilateral lower extremity edema. Evaluation and work-up of this patient revealed the presence of a supracristal VSD with severe pulmonary hypertension and both right and left ventricular dysfunction with a left ventricular ejection fraction (LVEF) of 35%-40%. Interdisciplinary discussions determined that the patient was not a candidate for a minimally invasive repair of his VSD. The patient was scheduled for open surgical repair by a team consisting of both an adult and a pediatric congenital cardiac surgeon.
The patient was brought to the operating room and a pre-induction radial arterial line placement was performed. After uneventful induction, intubation and central venous line placement, transesophageal echocardiography (TEE) was placed. The TEE revealed the VSD seen best in midesophageal long axis (MELAX) view. Left to right flow through the VSD occurred throughout the cardiac cycle. AI with an eccentric jet directed towards the basal anterior ventricular septum was seen but without evidence of AV leaflet prolapse. In short axis the AV was trileaflet with normal leaflet excursion, possible asymmetric leaflet size (smaller left coronary cusp). Sinus of valsalva was normal and nonaneurysmal.
Midline sternotomy was performed. The patient was heparinized, pericardium was opened and suspended. Aortic cannulation followed by tricaval cannulation (patient had a persistent left superior vena cava) occurred without complications. Cardiopulmonary bypass (CPB) was initiated and cardioplegia was administered antegrade as well as via the coronary ostia after performing an aortotomy. An incision was made in the pulmonary artery to locate and inspect the VSD; after failing to locate the VSD, the aortotomy was extended to reveal the sub-valvular septum and the VSD. After thorough direct visualization and evaluation of the VSD, bovine pericardium was used to repair the defect. Inspection of the AV revealed relatively normal leaflets with fenestrations at the left and right coronary cusp commissures; resuspension of the commissures was performed. After cross clamp release and de-airing maneuvers, initiation of CPB wean and TEE was again performed. The TEE revealed significant severe, central AI. No residual defect was seen at the site of the supracristal VSD. The decision was made to return to CPB and replace the AV with a 25 mm Medtronic Mosaic® tissue valve (Medtronic, Minneapolis, MN, USA). De-airing maneuvers were performed again and the aortic cross clamp was removed in advance of a slow wean off CPB. TEE revealed well-seated bioprosthetic AV, no perivalvular leak, or significant regurgitation. There was significant continued left ventricle (LV) dysfunction and right ventricle (RV) dilation and dysfunction. Intra-aortic balloon pump (IABP) was placed via the right femoral artery under TEE guidance and the patient was started on inhaled nitric oxide at 40 ppm in addition to IV infusions of epinephrine and norepinephrine to support contractility and systemic vascular resistance (SVR). LVEF and SVR improved; TEE exam revealed decreased RV dilation and improved LVEF from pre-IABP function. The patient was successfully weaned from CPB, and at conclusion of surgery the patient was transported to the ICU. While in the ICU, the patient was noted to have progressively increased chest tube output; decision was made to take the patient back to the operating room for re-exploration and any other indicated procedures. The source of bleeding was located and controlled; the patient returned to the ICU post-operatively.
The figures displayed are a sample of the views obtained during intraoperative TEE. Images obtained during AV repair/replacement are often not challenging to obtain and are simply to assess if AI is improved, unchanged, or worse. However, in the setting of a supracristal VSD, this TEE exam was notably more challenging.
Figures - highlight the defects prior to repair. These images are abnormally challenging to obtain due to the complexity of AI in the setting of a supracristal VSD. These images are obtained to guide the surgical plan. Figure highlights the improved aortic sufficiency following repair.


A 23-year-old male patient was hospitalized for hypokalemia since 2 years. Two years earlier, the patient had hypokalemia due to severe diarrhea after eating unclean food. No fatigue, numbness of limbs, palpitation, or chest tightness was noted. Serum potassium was 2.77 mmol/L during a routine physical examination. The patient developed normally and is unmarried. There was no history of similar disease in the family. Consanguineous marriage was denied. After admission, a physical examination was performed: blood pressure, 110/70 mmHg. The results of electrolytes at admission showed that the levels of serum potassium and serum magnesium were 2.84 mmol/L and 0.77 mmol/L, respectively. Blood gas analysis showed mild metabolic alkalosis.


A 41-year-old male patient was hospitalized due to elevated blood sugar levels that persisted for half a year. The patient suffered from hypokalemia for 8 years (blood potassium 2.5–2.9 mmol/L). The patient suffered from occasional feebleness and aching in both the lower limbs, which improved after potassium supplementation. There was no history of similar disease in the family. Consanguineous marriage was seen in his parents. After admission, a physical examination was conducted: blood pressure, 108/68 mmHg. The results of electrolytes at admission showed that the levels of serum potassium and serum magnesium were 2.39 mmol/L and 0.56 mmol/L, respectively. Blood gas analysis showed metabolic alkalosis.


A 37-year-old female patient was hospitalized for reduplicated twitching limbs for 10 years and syncope on 3 occasions. Ten years earlier, the patient suffered from limb twitching without obvious induction, which was accompanied by numbness and the twitching of both hands. Over the last 10 years, recurrent syncope occurred on three occasions. This was accompanied by sweating, a loss of consciousness, and urine incontinence. The symptoms lasted for several minutes and improved spontaneously, mostly after fatigue. In many emergency cases, the patient's serum potassium level was 2.5–3.0 mmol/L. The 24-hour urinary calcium excretion quantitative value was 2.57 mmol, which was lower than the normal reference value. In addition, the oral hydrochlorothiazide diuretic test (HCT test) was performed in this patient as described by Colussi et al. []. The results showed that the maximum difference of chlorine excretion rate before and after HCT test was 2.1%, indicating that there was dysfunction of distal renal tubules. Moreover, the patient was diagnosed with hyperthyroidism and failed to adhere to medication. Her deceased grandfather suffered from limb numbness and was not examined for blood potassium. Her mother suffered from limb numbness and low blood potassium levels (the specific situation is unknown), but her symptoms improved after oral potassium chloride. The elderly brothers and sisters were assessed for blood potassium which was normal on 3 occasions. One elderly sister died, the cause of death being unclear. A cousin displayed numbness of the limbs with blood potassium levels of 2.81 mmol/L. One son had no obvious numbness in his limbs, and his blood potassium was normal. A family tree is shown in . Following admission, a physical examination was performed: blood pressure, 126/80 mmHg. The results of electrolytes at admission showed that the levels of serum potassium and serum magnesium were 3.29 mmol/L and 0.79 mmol/L, respectively. Blood gas analysis showed metabolic alkalosis.
There were no abnormal blood lipids in the 3 patients including blood coagulation factors. Liver and kidney function were normal. Amongst the patients, case 2 had diabetes mellitus. The results of blood potassium, magnesium, calcium, 24-hour urine potassium, and blood gas analysis are detailed in . All 3 patients had hypokalemia, renal potassium loss, and metabolic alkalosis. Thyroid function, adrenal cortex hormones, and aldosterone were normal. Renin levels increased in all 3 cases. In addition, no obvious abnormalities in adrenal CT and pituitary MRI were observed in the 3 patients.
High-throughput second-generation sequencing and bioinformatics analysis of the 36 hypokalemia-related genes were performed to identify possible mutation sites. Direct sequencing was used to verify the patients and their parents (). In case 1, two compound heterozygous mutations in the SCL12A3 gene were identified. One originated from the father (p. T60M), and the other originated from the mother (p. L858H). Case 2 had a homozygous mutation (p.N359K) from the parents. Case 3 had two genetic mutations from the mother, including the P.T60M mutation in the SCL12A3 and P.W391R mutation in the CLCNKB gene. These are known as Bartter syndrome type III and classic Bartter syndrome mutations.


A 20-year-old man presented with asymptomatic skin lesions of three months duration. The lesions began in the biceps area. Subsequently, they spread proximally and distally from the location, eventually extending to the central chest and the distal ventral wrist.
The patient’s past medical history was significant for hypoplastic heart syndrome, for which he had surgery at age nine years. The patient was taking ASA, lisinopril, and metoprolol for several years. He had no history of vaccinations, travel, or recent infection.
Cutaneous examination revealed small individual and confluent papules in a linear pattern on the right upper extremity extending from the wrist to the mid-right central chest (Figures -).
Microscopic examination of the lesions showed a superficial infiltrate of lymphocytes and histiocytes in a linear, band-like, distribution in the papillary dermis with extension along the eccrine sweat glands. Spongiosis and necrotic keratinocytes were present in the overlying epidermis. A periodic acid-Schiff stain was negative for hyphae.
Correlation of the history, clinical presentation, and pathology established a diagnosis of BLAISE with features of both lichen striatus and blaschkitis. Treatment options discussed with the patient include observation and topical corticosteroids. The patient elected to apply high potency betamethasone dipropionate 0.05% twice daily. A near-complete resolution of his skin lesions was observed after two weeks of treatment (Figures -).


A 66-year-old gentleman was admitted with progressive shortness of breath and bilateral lower extremity edema. His past medical history was remarkable for congenital hydrocephalus with a ventriculo-peritoneal (VP) shunt, chronic right lower extremity lymphedema from orthopedic surgery, atrial flutter and heart failure with reduced ejection fraction with reportedly poor medication compliance.
Over the previous four years, the patient had multiple hospital admissions for shortness of breath and atypical chest pain. In 2016, he was diagnosed with typical counterclockwise atrial flutter. In 2017, he once again presented with shortness of breath but this time he had atrial fibrillation and underwent electrical cardioversion, with atrial flutter recurrence in 2018 requiring atrial flutter ablation. At that time, worsening left ventricular function was noted with progressive right ventricular dilation and varying degrees of tricuspid regurgitation. Investigation into anatomic and secondary causes of presentation was inconclusive.
During the current admission, the patient was hemodynamically stable but tachycardic (100 bpm) and saturating well at room air. Physical examination was significant for jugular venous distension to mid neck with positive hepatojugular reflux and bilateral crackles with +4 pitting lower extremity edema up to bilateral thighs. BNP (Brain natriuretic peptide) was elevated (665 pg/mL; Ref: </=100 pg/mL), but troponin was negative. ECG showed sinus tachycardia, non-specific intraventricular conduction delay and epsilon waves in leads V2-V6 (Figure ).
An initial limited TTE showed left ventricular ejection fraction (LVEF) of 40% with mild diffuse hypokinesis, marked dilation of the right atrium (RA) and RV with decreased RV systolic function (TAPSE (tricuspid annular plane systolic excursion) 1.1 cm and TDI (tissue doppler imaging) 5 cm/s). In addition, from the inflow view the posterior leaflet showed limited motion while the anterior leaflet was not well seen (Figure ), leading to significant tricuspid regurgitation (Figure ) without evidence of pulmonary hypertension.
Since not all echocardiographic findings were congruent, particularly with the epsilon wave on ECG, a cardiac MRI was obtained. The MRI showed marked dilation of the RA and moderately dilated RV (RV end diastolic volume 143.6 ml/m2; normal 50-105 ml/m2) with decreased RV ejection fraction (37.5%). The RV/LV volume ratio was 2:1. No RV wall dyskinesia, aneurysm or fat deposition was seen. There was severe tricuspid regurgitation (Figure ). No late gadolinium enhancement was noted on phase sensitive inversion sequence. There were no other findings that would indicate ARVC on MRI. Since the patient had diarrhea and some facial flushing, we considered carcinoid syndrome as a differential diagnosis but the urinary 5-Hydroxyindoleacetic acid (5-HIAA) level was negative.
The patient improved with intravenous diuresis. A dedicated TTE was then repeated using nonstandard imaging planes and for the first time, the point of coaptation and resultant tricuspid regurgitation was found within the mid RV cavity. In addition, the septal tricuspid leaflet was tethered and apically displaced (26mm from the mitral counterpart). The origin of the anterior leaflet was normally located but the point of coaptation was also apically displaced (20 mm into the main RV chamber) (Figure ). Severe regurgitation was seen with flow reversal into the hepatic veins.
Based on these imaging findings, we arrived at a diagnosis of a variant of Ebstein’s anomaly. The patient underwent right heart catheterization for hemodynamic assessment, which was significant for raised right sided pressures (mean right atrial pressure 19 mmHg, right ventricular pressure 34/15 mmHg, pulmonary artery pressure 35/25 mmHg with mean of 28 mmHg), pulmonary capillary wedge pressure (21 mmHg) and decreased cardiac index (1.78 L/min/m2). The patient was discharged after optimization of fluid status with appropriate medical therapy for heart failure and close follow-up in clinic, with plan for surgical evaluation by an adult-congenital cardiac surgeon.


We report a case of a 22-year-old female patient with a history of left leg pain for 1 month when she fell and sustained a supracondylar fracture at the distal femur. She underwent a surgical treatment by open reduction and internal fixation with a distal femoral locking plate and screws. Follow-up radiographic imaging revealed proper bony and implant alignments (). However, abnormal osteolytic lesions were retrospectively detected at the fracture site. Few months later, she experienced a progressive enlarged mass prominent at the medial aspect of the left knee with severe night pain that brought her to visit her physician again (). A magnetic resonance imaging (MRI) scan was performed, and a cortical bone destructive lesion with soft tissue mass at the distal femur was detected as hypointense signal intensity (SI) on T1-weighted, hyperintense SI on T2-weighted, and STIR sequence along with radiating heterogenous enhancement (). The patient was then referred to King Chulalongkorn Memorial Hospital with a diagnosis of a progressive enlarging tumor at the left distal femur. An incisional biopsy was done, and the result indicated that the patient had conventional high-grade osteosarcoma. There were no distant metastases from the Computed Tomography (CT) scan of the chest or Technitium-99m bone scintography. Three courses of cisplatin and doxorubicin were given to her as the neoadjuvant chemotherapy, and the MRI was repeated. The results were satisfactory.
Treatment options were discussed with the patient. The patient opted for the standard rotationplasty type A-1 according to the Winkelmann Classification [] as her definitive treatment. The operation was scheduled at Surin Hospital which was nearby her hometown. The plan of resection was made based on the repeated MRI after neoadjuvant chemotherapy. The skin incision was designed into a rhomboid shape with the apex at the level of the proximal bone cut and the distal arms meeting at the level of the distal cut. The two oblong arms of the skin incision met posteriorly both proximally and distally. The posterior cuts were then joined by a single vertical posterior incision (). Femoral vessels, sciatic nerve, and common peroneal nerve were identified and protected (). Circumferential soft tissue along with the tumor was en bloc resected aiming for an adequate margin. Temporary Kirschner wire fixations were inserted above the femur and below the tibia to propose the resection level as guidance for the orientation (Figures and ). The distal limb was externally rotated to 180 degrees and reattached to the femur while preventing vascular kinging during the turn (). The locking compression plate and screws were fixed on the posterolateral femur and anteromedial tibia, and soft tissue was sutured layer by layer. Postoperative imaging yielded satisfactory results, and the wound healed uneventfully (). The patient was able to move her ankle as a knee and external prosthetic fitting was made. Adjuvant chemotherapy was given after a free margin with good tumor necrosis which was achieved from pathological study. At her 3-year follow-up visit, she is alive and doing well. She has a stable size of lung nodules. She can walk with the external prosthesis, limping slightly. Her new knee could move as expected, and she was satisfied with the result of the treatment (). Furthermore, she just recently gave birth.


An 11-year-old boy was admitted to a suburban general hospital due to blunt abdominal trauma (caused by a bicycle handlebar) and was transferred to our department five hours after the initial injury due to worsening abdominal pain. On arrival, the patient showed right upper quadrant and epigastric abdominal pain with cutaneous swelling, and was alert and afebrile, with a pulse rate of 110/min. Laboratory tests showed an increased WBC count (20.35 × 10 e3/uL - N-91 % with a reference range of 4.0–10.0 e3/uL). Abdominal US was negative, but due to his worsening overall condition, the patient underwent a contrast-enhanced CT scan that showed a suspected duodenal perforation in the II portion of the duodenum, with free air in the retroperitoneum and free fluid in the peritoneal space, wall thickening, and duodenal haematoma (a and b). The patient immediately underwent an exploratory laparotomy that showed a diffuse haematoma of the second portion of the duodenum, with a laceration of the peritoneal attachment and a perforation of the anterior surface of the duodenum near the junction of the 2nd and 3rd duodenal tract, which opened into the peritoneum with biliary leakage (II type laceration – AAST-OIS) []. Following a careful Kocker manoeuvre to examine the entire 2nd and 3rd portion of the duodenum, the perforation was repaired with a single stitch suture and omental patch; duodenal bulb, biliary tree and pancreas were intact. Two drains were left in the peritoneum, the first close to the perforation and the second in the pelvis. A percutaneous central catheter was also inserted through the right internal jugular vein. The patient was admitted to the ward in good condition and with TPN. 48 h later, biliary fluid began to appear in the drain, with no abdominal sign of peritonitis, nor worsening of the patient’s overall condition. A new contrast-enhanced CT scan showed a small amount leakage in the I-II portion of the duodenum, and conservative treatment was started. The amount of fluid increased over the following 24 h, reaching a volume of around 800 mL/day. On the suspicion of a failure of the previous suture, the patient underwent an endoscopy to insert a biliary drain. The test showed a new perforation in the duodenal bulb, and a guidewire was introduced (). The subsequent laparotomy showed a single perforation on the anterior wall of the duodenal bulb (II type laceration – AAST-OIS), immediately after the pylorus (), while the previous perforation was perfectly closed, as seen at the previous endoscopy. The perforation was repaired with a single stitch suture and omental patch, and a new drain was left in place. After 48 h in ICU, the patient was readmitted to the ward in good condition and on TPN. After three days without any biliary leakage from the drain, the patient began presenting with biliary vomiting. X-ray showed an intestinal obstruction, prompting a new laparotomy which showed an ileal obstruction due to peritoneal adhesion. The post-operative period was uneventful, and the drain was removed on the 5th post-operative day. He was gradually returned to oral feeding and was discharged on the 10th post-operative day in a good condition. At three months’ follow up, the patient is completely recovered.


A 28-year-old Sudanese woman with a bachelor’s degree in English literature was diagnosed with JHF during her childhood, her parents are cousins of the second degree. She has two sisters, one of whom shares the same diagnosis. The patient’s initial presentation was in the form of a facial papular skin rash. She was 1.5 years of age and living with her parents in her home country of Sudan at the time. At the age of five years, she developed skin nodules and gingival hypertrophy, a skin biopsy was taken and showed a periodic acid-Schiff (PAS) positive myxoid background with scattered spindle cells, confirming the diagnosis of JHF. By her late teenage years, disease progression continued, and bilateral knee and elbow stiffness started emerging.
Upon attending the genetics clinic in Hamad General Hospital (HMC), Doha, Qatar at 20 years of age, she had joint stiffness, multiple masses on her hands and typical skin features. She underwent multiple excision biopsy procedures for the various subcutaneous swelling in her back and was following with the endocrine and gastrointestinal clinics for short stature, vitamin-D deficiency, chronic diarrhea and malabsorption. She was 34 kg in weight and 150 cm in height. DNA testing confirmed the diagnosis of JHF by detection of large homozygous deletions of exons 15 and 16 in the ANTXR2 gene.
In December 2016, the patient had her first encounter with the Plastic Surgery team. She presented with multiple small hard nodules over the forehead, nose, ears and big toe. Patient received local triamcinolone acetonide injections for numerous bilateral hand nodules at that time, and excision of other facial lesions. At one-year follow-up post-surgical removal, no recurrence of the facial lesions was noted. Patient also noted a significant decrease in pain, size, and softening of her hand skin lesions.
In December 2017, two new lesions at the back, each measuring around (8 x 8 x 7 cm), respectively, were excised (Figure ). Histopathology was again consistent with JHF. Post-operative course was smooth, and no recurrence was detected.
In February 2019, the left shoulder subcutaneous mass was increasing in size and the patient had a return of numerous, previously injected hand growths. The lesions were innumerable and local injections would cause significant pain. Hence, a trial of 40 mg oral prednisolone was attempted for one week and then half of the dose over two weeks, followed by a quarter of the original dose over another two weeks. Patient reported a noticeable improvement in pain, the size of lesions and joint stiffness while she was on oral corticosteroid therapy.
In May 2020, patient underwent excision of the enlarging left shoulder swelling (15 x 8 x 8 cm) with overlying skin necrosis and multiple bilateral ear and chin swellings. Grossly, lesions contained thick mucinous slough (Figure ). She was satisfied with the outcome and no reappearance was detected at three months post operation.
In August 2020, patient follow-up showed no recurrence of the previously excised lesions in the shoulders and back. Hand nodules that were treated by local and systemic corticosteroid showed only partial and temporary improvement. She was operated to remove some of the remaining painful hand lesions to improve her function and relieve the pain (Figure ).


A 49-year-old Japanese man had splenic infarction with unknown cause 2 years ago. He had continued to take warfarin as anticoagulant therapy, but stopped taking the medication as self-judgment several months ago. He had no classical arteriosclerosis factors (hypertension, dyslipidemia, diabetes mellitus, and smoking status). He had sudden-onset rest chest dorsalgia and was transported to our hospital. Immediately after arrival, his pain temporarily improved. On initial examination, his blood pressure was 130/83 mmHg, pulse rate 110 beats/min, respiratory rate 30 cycles/min, and oxygen saturation 100% on room air. His physical examination showed a regular heart rhythm and no murmur, normal respiratory sounds in both lungs, and no edema in his lower extremities. On initial laboratory test, his high-sensitivity troponin I level was 1453.1 pg/mL (normal range: 0.0–26.2), creatinine kinase (CK) 261 U/L (59–248), CK-MB 26 U/L (0–6), platelets 31.5 × 104 /μL (15.8–34.8 × 104), fibrinogen 237 mg/dL (190–390), and D-dimer 1.7 μg/ml (0–0.9). Initial electrocardiography showed normal sinus rhythm and no ST-T change. Transthoracic echocardiography revealed normal wall motion and no asynergy. Contrast computed tomography (CT) showed a small PE and no aortic dissection (Fig. a, b). However, he complained of chest pain again following CT. Emergent coronary angiography (CAG) showed no severe stenosis in the right coronary artery and left circumflex artery, but a large thrombus with Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow from the proximal to mid portion of the left anterior descending (LAD) artery (Fig. a-c). A 7-Fr guiding catheter was advanced through the left radial artery to the left coronary artery ostium, and a guidewire was advanced to the distal LAD artery. Near-infrared spectroscopy–intravascular ultrasonography (NIRS–IVUS) showed a large amount of thrombus from the proximal to the mid LAD artery, and the max lipid core burden index (LCBI) was 81 (Fig. d). Thrombectomy was performed using a 7-Fr aspiration catheter (Fig. a) and intracoronary thrombolysis by urokinase 60,000 U. Angiography and NIRS–IVUS revealed decreased thrombus in the LAD artery (Fig. b-c). The procedure was completed at this time because additional angioplasty with or without stent was at high risk of slow-flow phenomenon. In the pathological findings, the collected thrombus using an aspiration catheter had many fibrin precipitates. We suspected paradoxical embolism because the ultrasonography revealed a DVT in the bilateral lower leg, but contrast CT and transesophageal echocardiography showed no right-to-left short circuit including a patent foramen ovale, atrial septal defect, and ventricular septal defect, and pulmonary arteriovenous fistula. Further examination of coagulation abnormality revealed hyperhomocysteinemia (total homocysteine level: 140.8 nmol/mL [6.3–18.9], vitamin B12: 121 pg/mL [180–914], folate: 2.3 ng/mL [> 4.0], protein C activity: 111% [70–140], and free protein S: 131.7% [60–150]). Therefore, he was diagnosed with ACS complicated with PE and DVT simultaneously induced by hyperhomocysteinemia. He continued antithrombotic therapy using aspirin, warfarin (his international normalized ratio was controlled from 2 to 3), and heparin (1.5–2.5 times the reference value activated partial thromboplastin time) for 1 week. Peak CK was 347 U/L, and NIRS–IVUS and optical coherence tomography (OCT) revealed decreased thrombus and no significant residual organic stenosis in the LAD artery following 1 week of antithrombotic therapy (Fig. a). He was discharged from our hospital continuing antithrombotic therapy with aspirin and warfarin. Follow-up CAG and OCT after 9 months revealed complete thrombus disappearance in the LAD artery (Fig. a). His total homocysteine level had decreased to 85.1 nmol/mL by the dietary therapy. He had no cardiovascular event or major bleeding for 1 year.


A 39-year-old male firefighter presented to the emergency department with left ankle pain and inability to bear weight after falling from a 1-meter jump height while playing basketball. He reported landing on the dorsum of his left foot with the ankle in the plantar flexion position. Clinically, there was moderate ankle swelling in the medial aspect with a limited range of motion of the ankle joint. His X-rays were unremarkable. He was diagnosed with an ankle sprain and was managed with rest, ice, elevation, compression, and analgesia. Five days later, he presented to the orthopedic clinic with the same complaints. On examination, he had localized swelling just anterior to the medial malleolus. Upon palpation, there was a slightly tender cord-like structure that moved back and forth with gentle plantar and dorsiflexion of the ankle (Figure ; Video ). Traumatic dislocation of the TPT was suspected, and an urgent MRI was performed. The MRI revealed a significant thickening of the TPT, tenosynovitis of the adjacent flexor digitorum longus, a possible tear of the flexor retinaculum, and a partial tear of the superficial deltoid ligament (Figures -). The patient was offered surgery on the next elective list.
Operative procedure
The patient was placed in supine position, and to facilitate external rotation of the left leg, a bolster was placed under the contralateral hip. A 6-cm longitudinal incision was made along the anterior aspect of the medial malleolus (Figure ). The retinaculum was found intact; however, its anterior continuity with the periosteum was avulsed as one layer from the underlying bare bone. After incising the retinaculum, the tendon was found subperiosteally anterior to the medial malleolus. Intra-operatively, the retromalleolar groove was found to be shallow compared with the size of the tendon (Figure ), trials of relocation of the unstable tendon were attempted, and the posterior tibialis tendon was irreducible in the groove. Therefore, to deepen the groove, a longitudinal osteotomy at the edge of the groove was performed using a small, thin osteotome. The fibrocartilage surface of the groove floor was preserved while the shell of bone was levered as a flap with the osteotome to expose the underlying cancellous bone. A curette was used to remove a small amount of the cancellous bone to make a gutter. The flap was then over-reduced to make a concavity. This last step was performed by tapping on the side of a rounded bone tamp that was placed in the groove over a piece of gauze. The TPT was reduced in the groove and found to be stable (Figure ), and the retinaculum was repaired with non-absorbable sutures (Figure ). A couple of sutures were passed through the posterior edge of the medial malleolus. Care was taken to avoid over-tightening the retinaculum so that the tendon was freely mobile with a smooth gliding motion. A layered closure was performed, and a short back slab was applied.
Postoperative management
The patient was permitted to touch-down on the back slab using a pair of crutches for six weeks. After the back slab was removed, ankle motion was started and progressive weight-bearing was allowed. The patient had regular follow-up visits for 12 months.
Outcome
After three months, the patient had no pain or swelling in the ankle. He was able to bear full weight, and he had a full ankle range of motion. He was allowed to play sports after six months. At 12 months, he was asymptomatic and was back to his pre-injury level of activity.


An 82-year-old woman with hypertension was hospitalized because of fever (39 °C). The abdomen was tender, without signs of peritonitis. Blood tests revealed an increased white blood cell count of 15,790/μl, C-reactive protein 24.52 mg/dL, hemoglobin 8.2 mg/dL, carcinoembryonic antigen 8.9 mg/dL, and CA19-9 level 22.4 mg/dL. Computed tomography (CT) revealed a 10 cm in diameter liver abscess and inflammation of the colon (). Lower gastrointestinal endoscopy revealed a type 2 tumor in the transverse colon. Pathology revealed well-differentiated adenocarcinoma. The endoscope was passable, but the tract was becoming narrower (). The patient required early surgery and we performed preoperative examination in parallel with treatment of the liver abscess. Furthermore, it was necessary to improve her general condition for the operation.
At diagnosis of the liver abscess, tazobactam/piperacillin (TAZ/PIPC) antibiotics were started empirically. Klebsiella pneumoniae was detected in the admission blood culture, and we confirmed it to be susceptible to TAZ/PIPC.
We considered performing percutaneous transhepatic abscess drainage (PTAD), but decided against this initially because it was deemed to be less effective to drain due to the presence of a septum in the abscess []. However, approximately 2 weeks after admission, the inflammatory response was elevated again and fever also was observed. A CT scan showed that the liver abscess was slightly enlarged without shrinkage. PTAD was performed because antibiotic treatment alone was not sufficient to cure the liver abscess (). A white viscous pus discharge was observed, and K. pneumoniae was detected in the blood and discharge cultures. After drainage, the fever resolved and the inflammatory response improved markedly.
TAZ/PIPC was administered for a total of 28 days. The abscess drainage tube showed a very small amount of drainage with improvement in inflammation and the patient's general condition. Contrast studies were done at 12 days after insertion and the tube was removed after confirmation of abscess resolution. Approximately 4 weeks after the start of treatment, the patient underwent standby surgery for transverse colon cancer (hepatic flexure; ), consisting of laparoscopic converted to open right hemi-colectomy (D3). Operative time was 195 min and estimated blood loss was minimal. The procedure was converted due to strong adhesion of the tumor to the duodenum.
The patient progressed well postoperatively, except for a minor postoperative wound infection, and was discharged approximately 20 days postoperatively.
No cancer/hepatic abscess recurrence was noted at followup approximately 1 year postoperatively. The case has been reported in line with the SCARE criteria [].


On December 2017, a 50-year-old Caucasian woman, previously in good health, developed cutaneous erythematosus papular lesions both on the palmar and dorsal surface of hands and fissuring of the distal fingers, in the absence of other symptoms. She consulted a dermatologist who prescribed topical steroids. Three months later, Raynaud's phenomenon and dryness of the skin appeared. She consulted a rheumatologist who, after laboratory examinations showing antinuclear antibody (ANA) positivity, made the diagnosis of undifferentiated connective tissue disease (UCTD) and prescribed prednisone 25 mg daily with progressive tapering until 12.5 mg daily, with partial improvement. Two months later, she developed arthritis of hands and wrists, alopecia, and worsening of the skin lesions. She consulted another rheumatologist who added hydroxychloroquine 400 mg daily without any improvement. Instead, asthenia, muscle weakness, and pain appeared. For this reason, the rheumatologist prescribed cyclosporine 160 mg daily; hydroxychloroquine was stopped because of the onset of vertigo, which disappeared with drug suspension, while prednisone 12.5 mg daily was continued. On October 2018, because of further worsening of asthenia and myalgia and the onset of mild dyspnea, high-resolution computed tomography (HRCT) of the chest was performed, and it showed initial signs of ILD.
Then, the patient was referred to our attention and she was admitted to our rheumatology ward.
Concerning the medical history, she did not report comorbidities, pregnancies, or miscarriages. She had smoked for ten years, but she was not smoking anymore. She was in menopause from the age of 45. Her family history was unremarkable. At the physical examination, she was afebrile, normotensive, and breathing and cardiac rates were, respectively, 16 times/min and 90 beats/min. Cardiac and abdominal examinations were normal; pulmonary examination showed fine bilateral basal crackles. There were papular erythematosus lesions on both the palmar and dorsal surface of her hands and extensor surface of elbows and concomitant fissuring of the distal fingers (). Musculoskeletal examination did not evidence joint tenderness/swelling or deformity, but it revealed a reduction of muscle strength at the four limbs. Laboratory tests showed a mild normochromic, normocytic anemia, a slight increase of aspartate aminotransferase (AST) (52 U/L; normal range <40 U/L) and of lactate dehydrogenase (LDH) (688 U/L; normal range <400 U/L), a modest polyclonal hypergammaglobulinemia, and an increase of C reactive protein (CRP) (10 mg/L; normal range <5 mg/L), while white blood count, platelets, creatinine, electrolytes, erythrocyte sedimentation rate (ESR), uric acid, alanine aminotransferase (ALT), creatine phosphokinase, and urinalysis were normal. Screening for hepatitis B and C virus was negative, while the QuantiFERON-TB Gold test was indeterminate.
A skin right hand biopsy revealed the presence of interface dermatitis, with perivascular inflammatory infiltrate prevalently at the dermoepidermal junction and injury of the basal cells keratinocytes, as it can be observed either in systemic lupus erythematosus (SLE) or in DM [].
Electromyography (EMG) of the upper limbs evidenced signs of median neuropathy in the right hand and no other pathological sign.
Muscle magnetic resonance (MRI) of the lower limbs showed diffuse and symmetric oedema of all the muscles of the thigh without fatty degeneration ().
Chest HRCT confirmed the presence of bilateral apical pleural thickening and various subpleural, paramediastinal, and basal areas of reticular thickening associated with ground glass lesions. There was no pleural effusion or linfoadenopathy. Spirometry with diffusing capacity for carbon monoxide (DLco) evidenced signs of a disventilatory obstructive syndrome with severe DLco reduction (53% of the predicted value). Echocardiogram was normal.
A nailfold capillaroscopy revealed different alterations such as a disordered loops architecture, capillary enlargement with some megacapillaries, microhaemorrhages, and neoangiogenesis, suggestive of a “scleroderma-like pattern” ().
Indirect immunofluorescence (IIF) for ANA showed a cytoplasmic pattern at a titer of 1 : 160; rheumatoid factor, anti-SSA (Ro), anti-SSB (La), anti-Sm, anti-RNP, anti-Jo1, anti-SCL-70, anti-ds DNA, C3, C4, and anti-citrullinated peptide antibody (ACPA) were normal, while a myositis panel immunoblotting test evidenced anti-MDA5 positivity (53 AU; normal range <10).
Therefore, the patient was discharged with a diagnosis of anti-MDA5 DM and ILD. Prescribed therapy was mycophenolate mofetil 2 gm daily and prednisone 25 mg daily associated with a weekly bisphosphonate tablet and a prophylactic therapy for Mycobacterium tuberculosis.
At the follow-up visit, two months later, the patient reported worsening of fatigue, weakness, and dyspnea. Her laboratory exams showed an increase of inflammatory indexes (ESR 50; normal range <30; CRP 15 mg/L; normal range <5 mg/L), while a spirometry evidenced a further DLco reduction (42% of the predicted value).
After consultation with the respiratory physician, we decided to discontinue mycophenolate and start a second-line therapy with RTX 1000 mg on two occasions 2 weeks apart. Prednisone was continued with progressive tapering to 12.5 mg daily.
Patient was re-evaluated two months later. She reported a marked improvement of fatigue, muscle weakness, and dyspnea. At physical examination, the skin lesions had improved. Laboratory tests showed a reduction of ESR and CRP values (ESR 30; normal range <30; CRP 5; normal range <5 mg/L). DLco parameters were significantly ameliorated (from 42% to 56% of the predicted value). Therefore, it was possible to reduce prednisone dosage from 12.5 mg to 10 mg daily.
The patient is currently under follow-up in our unit.


An 82-year-old man was referred for an abnormal shadow detected 4 months previously on computed tomography (CT) in a regular follow-up after bilateral clear cell renal cell carcinoma. He underwent left nephrectomy 14 years ago and right partial nephrectomy 5 years ago. At that time, he stated that he had a prolonged cough for several months. He had a smoking history of a half pack-year for 20 years. His father had gastric cancer, his mother had thyroid cancer, and his son had a brain tumor. He was a merchant and had no exposure history to asbestos. He had a bird mamelliha.
Chest CT showed a 14-mm nodular shadow on the apex of the right upper lobe of the lung with no lymphadenopathy or pleural effusion. PET/CT (positron emission tomography-computed tomography) revealed abnormal accumulation in 2 nodules of the upper lobe of the right lung and ipsilateral hilar- and mediastinal lymph nodes (Fig. ). Abdominal CT and brain MRI (magnetic resonance imaging) were negative for metastasis. Laboratory examinations showed elevated levels of serum progastrin-releasing peptide [ProGRP; 115 pg/mL (normal range: 0–70.9 pg/mL)] and soluble IL-2 receptor [S.IL-2R; 992 U/mL (normal range: 122–496 U/mL)], and a slightly elevated level of squamous cell carcinoma antigen [SCC; 2.7 ng/mL (normal range: 0–2.5 ng/mL)]. Serum levels of carcinoembryonic antigen (CEA) and cytokeratin-19 fragments (CYFRA) were within normal limits. Lung metastasis from renal cancer or primary lung cancer was clinically suspected and the patient underwent partial resection of the upper lobe of the right lung via video-assisted thoracotomy.
A gross examination revealed a solid tumor with an irregular border, measuring 25 × 12 × 10 mm with a white cut surface (Fig. ). Paraffin sections showed that the tumor was composed of sheets of monomorphic small round cells with necrosis, which was not consistent with typical clear cell renal cell carcinoma (Fig. ). There was no obvious or abrupt squamous differentiation or tube formation. Tumor cells had round- to oval-shaped nuclei with distinct nucleoli and a scanty cytoplasm. Mitotic figures (27/20 HPF) were clearly observed. There was lymphatic invasion and two intrapulmonary metastases of 2 and 1 mm in size. These intrapulmonary metastases were detected in the sub-pleura 8 mm from the main tumor. Primary and intrapulmonary metastatic lesions both extended into the soft tissue of bronchial vascular bundles and the structure of the pulmonary artery was maintained inside the tumor (Fig. ). There was no pleural invasion, pleural dissemination, or venous infiltration. The surgical margin was negative. We initially suspected small cell carcinoma; however, immunohistochemistry was less typical (Fig. ) because tumor cells were focally positive for neuron-specific enolase (NSE) and chromogranin A and negative for CD56 and synaptophysin. Although we searched for lymphoma, tumor cells were only focally positive for B-cell lymphoma-2 (BCL-2) and negative for other lymphocytic markers (leukocytic common antigen (LCA), CD3, CD5, terminal deoxynucleotidyl transferase (TdT), CD10, CD20, CD79a, and cyclin D1). Due to the focal positivity of BCL-2, we suspected synovial sarcoma as a differential diagnosis and attempted to exclude other diseases, but were unable to reach a final diagnosis based on general immunohistochemistry alone. Tumor cells were positive for epithelial membrane antigen (EMA) and vimentin and focally positive for CD99, HHF-35, desmin, calponin, and Sal-like protein 4 (SALL4). They were negative for AE1/AE3, cytokeratin 7 (CK7), cytokeratin 20 (CK20), cytokeratin 5/6 (CK5/6), CAM5.2, thyroid transcription factor 1 (TTF-1), tumor protein p63 (p63), p40, myoblast determination protein 1 (MyoD1), caldesmon, glypican 3 (GPC3), placental alkaline phosphatase (PLAP), calretinin, S-100, CD117 [c-kit], Melan A, HMB-45, Wilm’s tumor suppressor gene 1 (WT-1), paired box gene 8 (PAX8), and D2–40. EBER in situ hybridization was also negative. Our differential diagnoses for these small round cell tumors were small cell carcinoma, germ cell tumor, soft tissue sarcoma (synovial sarcoma, extra-skeletal Ewing’s sarcoma, Ewing-like sarcoma [CIC rearrangement sarcoma, and sarcoma with BCOR genetic alterations], and malignant glomus tumor), and NUT carcinoma.
We subsequently performed NUT immunohistochemistry (rabbit monoclonal, C52B1, × 100, TRSpH9, Cell Signaling) using AutostainerLink48, which showed diffusely positive tumor nuclei with a speckled pattern. FISH and RNA sequencing (RNA-Seq) revealed the presence of the BRD4-NUT fusion gene (Fig. ). These results led to the final diagnosis of primary pulmonary NUT midline carcinoma with the BRD4-NUT fusion (pT3NxM0).


A 64-year-old man was referred to our emergency department from a local hospital. He fell down from a 3-m stepladder while pruning branches of a tree. Brain computed tomographic (CT) scan revealed acute epidural hematoma in both frontal convexities (), and he underwent craniotomy at the local hospital. On follow-up brain CT, an orbital roof fracture with a displaced bony fragment and hemorrhage was noticed in the left superior extraconal space. Thereafter, he was transferred to our department ().
Upon examination, movement of the extraocular muscles was normal. He did not complain of diplopia or decreased sensation of the face. He also did not have nasal stuffiness. Exophthalmometry revealed the same findings for both eyes (18 mm/18 mm). Facial CT scan before the second operation revealed a displaced orbital roof fracture segment ().
Under general anesthesia, craniotomy was performed and the epidural hematoma was evacuated. The displaced bony fragment was removed from the left anterior cranial fossa, and the anterior skull base was reconstructed with a titanium mesh plate (Optimus neuroplate, 3D Mesh 50×50 mm; Osteonic, Seoul, Korea) ().


A 56-year-old married woman was referred to the Cancer Rehabilitation Center (Ce.Ri.On) in Florence for BC-related follow-up management. In particular, the patient had an increased breast swelling for several years causing tension and pain especially on the left side of the thorax. The survivor was included in the Ce.Ri.On waiting list for a possible rehabilitation program, and then randomly recruited to initiate an adapted PA (APA) intervention. In September 2018, on the basis that there was no medical contraindication, the Ce.Ri.On rehabilitation physician recommended the woman’s participation in a well-planned and structured PA pathway consisting of two cycles of eight-week APA followed by eight-week adapted fitness (AF) in order to reduce breast swelling and pain, and to improve shoulder movement. Tracing the clinical history, in November 2014 mammogram findings showed a suspicious lump on the upper quadrant of the left breast in the asymptomatic patient without family history of cancer. Ultrasound-guided core biopsy revealed an invasive mammary carcinoma. Next month, nipple-sparing mastectomy and axillary lymph node dissection was performed, and immediate tissue expander (i.e., Allergan 300 SV) reconstruction was also executed. The histopathologic report was an infiltrating ductal carcinoma grade 3. Subsequently, owing to early nipple necrosis postoperatively, 10 sessions of hyperbaric oxygen therapy were administered. Moreover, the patient received BC adjuvant treatment such as four chemotherapy cycles, two radiotherapy sessions and hormone therapy (i.e., letrozole) for about five years. In December 2015, capsulectomy with tissue expander removal and prosthesis (i.e., Allergan 280 MM) insertion were performed. Concurrently, contralateral prophylactic mastectomy for calcifications followed by immediate reconstruction with permanent prosthesis was also carried out. In September 2016, a postoperative persistent seroma developed, requiring percutaneous drainage every two/three weeks. The diagnosis of seroma formation was also confirmed by magnetic resonance imaging. In March 2017, in order to solve this clinical sequela, further bilateral capsulectomy, implant removal and replacement by more voluminous prosthesis (i.e., Allergan 375 MF) were performed. However, a month later, seroma reappeared in the left side. In fact, copious amounts of fluid (i.e., 180–200 mL) were frequently aspirated. Cytology and histology of accumulated fluid showed negative results. In August 2017, the seroma localized to the left side had not improved. In particular, the patient was physically active and referred a worsening of symptoms after swimming. The seroma was aspirated once again, and the cytological examination of the fluid showed no sign of bacterial growth. Then, from September 2017 to February 2018, lymphatic drainage was prescribed three days per week. Afterwards it was suspended because the ultrasound confirmed the persistence of seroma between the implant and the capsule (thickness 1 cm). Noteworthy, all treatments were suspended because the seroma, although not solved, remained stable in absence of minimal effort. Finally, the patient was referred to an adapted exercise specialist (D.M.) in September 2018 and executed a structured PA pathway. Physical assessment and two cycles of eight-week APA program were carried out at the Ce.Ri.On center between October 2018 and January 2019. After APA ending, an AF protocol was properly continued outside the Ce.Ri.On from February 2019 to March 2019. To date, in order to maintain the benefits achieved by following a structured PA pathway, the subject continues the AF activity. At baseline, during and after ending the structured PA intervention, the woman underwent a functional test battery to assess the upper limb mobility through active ROM test and muscle length test [,,]. Active ROM test was executed with the subject standing by goniometry taking into account the extension (range 0–45°), flexion (range 0–180°), external rotation (range 0–90°), and abduction (range 0–180°) [,]. Muscle length test was performed with the subject in a supine position by elevating the arm and measuring the distance (cm) from the lateral epicondyle to the surface, with a smaller distance from the surface corresponding to a greater upper limb mobility []. Moreover, for assessing lumbar and hamstring ROM, a sit and reach test was used [,,]. To perform this test, the subject sits with legs extended as straight as possible and then flexes the hip joints and vertebral column trying to touch the toes in dorsiflexion with the fingertips of both hands simultaneously. A meter rule is placed between the legs with 0 cm located at the heel line to measure the distance from toes to hands []. Indirect assessment of pectoralis minor muscle (PMm) length test was also applied by setting the subject in supine position and measuring the distance between treatment table and acromion. In particular, a forward shoulder/scapular posture is frequently related to a tight PMm []. In addition, the subject filled in the Short Form-12 (SF-12) questionnaire and the numerical rating scale (NRS) to evaluate health-related QoL and to assess back and shoulder pain intensity, respectively [,,]. The SF-12 questionnaire consists of a physical component score and a mental component score. For both components, higher scores indicate a greater QoL []. The NRS evaluates pain intensity on a 0–10 scale (0 = no pain, 10 = worst imaginable pain) []. A signed informed consent form was obtained from the participant in accordance with the Declaration of Helsinki.


A 25-year-old healthy Japanese primigravida was referred by a maternity hospital. The fetus was suspected to have either CCD or congenital intestinal atresia (CIA) based on the fetal ultrasonographic findings of polyhydramnios and dilated bowel loops. After fetal heart monitoring detected frequent severe variable decelerations, a male infant was delivered by cesarean section at 29 weeks of gestation. Birth weight was 1434 g; Apgar scores were 7 and 8 at 1 and 5 minutes, respectively. He was the first child of non-consanguineous healthy parents. Admission to the neonatal intensive care unit was required by very low birth weight and suspected CCD. The newborn's abdomen was distended, and watery diarrhea lacking meconium passed soon after delivery. The stool had a high concentration of Cl (147 mmol/L; reference value, <90 mmol/L).(Holmberg, Perheentupa, & Launiala, ) Serum electrolytes on admission were Na, 139 mmol/L; K, 4.0 mmol/L; and Cl, 101 mmol/L. Results of venous blood gas analysis were pH, 7.363; pCO2, 35.6 mmHg; HCO3−, 19.7 mmol/L; and base excess, −4.4 mmol/L. Urinary electrolyte values were Na, 38 mmol/L; K, 4.0 mmol/L; and Cl, 37 mmol/L. Abdominal radiography ruled out intestinal obstruction. On the second day of life, he was diagnosed with CCD based on frequent watery diarrhea beginning soon after birth and high fecal chloride (Konishi et al., ; Wedenoja et al., ). Intravenous and oral replacement therapy with NaCl and KCl was administered. With treatment, serum electrolytes were maintained largely within the normal range (Table ), and general condition was good. Ninety days after birth, weighing 3168 g, he was discharged home.
We screened all coding exons of SLC26A3 (NCBI ref: NM_000111) including exon-intron boundaries by direct sequencing. Genetic analysis detected compound heterozygosity of SLC26A3; the 2 relevant mutations were c.382G>A, p.G128S and c.2063-1g>t. The c.2063-1g>t mutation also was present in the mother's DNA, but c.382G>A, p.G128S was absent from both parents’ samples (Figure ). Confounding paternity issues were ruled out by the presence of the rare nonpathogenic variant c.735+29del t in both the patient and his father (Figure ). Further, the common variant c.1299G>A (rs3735605) was identified in both patient and parents (Figure ), and the ABO blood groups of the patient, mother, and father respectively were types B, B, and O. Therefore, c.382G>A, p.G128S most likely represents a de novo mutation of SLC26A3.


At the time of our first encounter, our patient was a 25-year-old primigravida female at 22 + 4 weeks of gestational age. Pregnancy had been largely unremarkable aside from concerning findings noted on antenatal anatomy scans. The ultrasounds had revealed a fetus with bilateral enlarged and echogenic kidneys, multiple cysts within the renal parenchyma, anhydramnios, and a non-visualized bladder (Figure ). Integrated prenatal screening had been performed, and reported as a negative screen for Trisomy 21 and Trisomy 18. A three-generation family history was obtained. Our patient was of German and Scottish descent, and her partner was of Irish and English descent, with no known consanguinity. The family history was negative for any other known congenital anomalies and was otherwise unremarkable.
Due to overall poor prognosis for the fetus, and likely incompatibility with life, therapeutic termination of pregnancy was initiated with the induction of labor. Following the delivery of a male stillborn fetus at 22 + 5 weeks of gestational age, external examination and autopsy were performed. Upon examination, the male fetus had evidence of facies consistent with Potter sequence. A high-arched palate was identified, as was maxillary hypoplasia, and there was no evidence of any orofacial clefting. There were severe elbow contractures, and elbow pterygia were present bilaterally. There was post-axial polydactyly of the left hand (six digits), as well as full cutaneous syndactyly between digits two and three, and four and five. There was partial syndactyly of the right hand between digits three and four. There was no polydactyly or syndactyly of the toes. Bilateral clubfeet could not be excluded, with positional changes being considered as well. Skin examination was in keeping with the gestational age of the fetus and was otherwise unremarkable. Aside from the maxillary hypoplasia and aforementioned syndactyly, no other classic features of the EEC spectrum were identified (Figure ).
Autopsy confirmed the presence of pulmonary hypoplasia, in the presence of bilaterally enlarged kidneys with multicystic renal cortical dysplasia. The right kidney weighed 8 g, and the left weighed 5 g, with a combined weight of 13 g (the combined age-related norm was listed as 4.77 ± 1.39 g on autopsy report). The cysts were disorganized, variable in shape and size, and were as large as 0.5 cm in diameter. They were lined by simple cuboidal epithelium and many had collars of smooth muscle. The ureters and bladder were clearly identified with no obvious abnormalities (Figure ). The testes were both intra-abdominal and consistent with the gestational age of the stillborn fetus.
Skeletal survey was performed and was negative for any obvious skeletal congenital anomalies beyond the post-axial polydactyly of the left hand.
Differential diagnosis at the time, based on the above findings, was quite broad. Considerations included triploidy, microdeletion and microduplication syndromes, and single-gene disorders including ciliopathies, and other congenital anomalies of the kidneys and urinary tract (CAKUT). QF-PCR testing was performed in the stillborn fetus and was consistent with a normal disomic complement of chromosomes 13, 18, and 21 in a male fetus. Chromosomal microarray results were also consistent with a normal male fetus.
A whole-exome trio (XomeDx) was submitted clinically. The exonic regions and flanking splice junctions of the genome were sequenced by massively parallel (NextGen) sequencing on an Illumina sequencing system with a minimum of 100 bp paired-end reads. The reads were aligned to the human genome build GRCh37/UCSC hg19 and analyzed for sequence variants using Xome Analyzer. This identified a de novo heterozygous pathogenic variant in exon 5 of the TP63 gene: p.His247Arg: c.740A>G (NM_003722.4).
This particular missense variant has been reported in several individuals affected with EEC (Clements et al., ; Hyder et al., ; Polla et al., ; Rinne et al., ), including two siblings affected by severe ectrodactyly and mild ectodermal dysplasia, without clefting (Sorasio, Biamino, Garelli, Ferrero, & Silengo, ). Associated GU anomalies have also been described, including bilateral hydronephrosis (Hyder et al., ), congenital absence of the right kidney with left hydronephrosis in one individual, and mild vesicoureteric reflux in another (Clements et al., ).


An 86-year-old female initially presented to our clinic with complaint of intermittent left arm pain and left fingers paresthesia in dermatomal distribution and left lower extremity pain for one year. The patient’s medical history was significant for Brooke-Spiegler syndrome with multiple scalp lesions resected throughout her life and parotid basal cell adenoma. No changes to the scalp lesions were noted. The patient had no neurological deficits on physical exam.
CT of the cervical spine demonstrated lytic lesion of C7 vertebral body. MRI of the cervical spine showed 4.7 x 4.9 cm destructive heterogeneous soft tissue mass involving C7 vertebral body, pedicle and spinous process with extension into left C67, C7T1 neuroforamina, left C7 epidural space and left paravertebral/prevertebral space (Figure ). The left C7 and C8 nerve root compression was consistent with patient’s left arm radicular symptoms. The etiology of the left leg pain was unknown.
Needle biopsy of the lesion (Figure ) was consistent with skin adnexal neoplasm in the spectrum of cylindroma/spiradenoma.
Though no malignant features were detected on histologic examination (Figure ), the unusual location of the lesion and local invasion of neural structures raised concern for malignant transformation of existing cylindromas. No genetic analysis was done. The patient was subsequently lost to follow up.


A 72-year-old female with a past medical history of hypertension, hyperlipidemia, and type 2 diabetes was admitted to our department with the chief complaint of shortness of breath since a week. Symptoms were present at rest as well as with exertion. The patient also complained of increase in abdominal girth and bloating over the last two months. One month prior to presentation, she was seen by a gynecologist for vaginal bleeding. Ultrasonography of the abdomen and pelvis was performed, which showed a pelvic mass. The patient missed the follow-up appointment with the gynecologist. The patient denied any joint pain, peripheral edema, or history of liver or cardiovascular disease. On respiratory examination, there was right-sided dullness with absent breath sounds, and abdominal examination revealed shifting dullness on percussion. Chest X-ray (Figure ) on admission showed a large right-sided pleural effusion.
Pulmonology service was consulted, and thoracentesis was performed, during which 1,500 cc of amber color fluid was obtained. Pleural fluid analysis was performed, as shown in Table .
Meigs' syndrome was suspected because of presentation as well as lab workup. A right PleurX® catheter (Becton, Dickinson and Company, Franklin Lakes, NJ, USA) was placed on pulmonology recommendations. However, on day 3 of admission, the patient’s cancer antigen 125 (CA 125) level was 3,653. A CT scan demonstrated pelvic mass along with pleural effusion and ascites (Figure ).
Ovarian malignancy was suspected, and the patient was transferred to a tertiary care hospital for further workup. An exploratory laparotomy was performed, which showed high-grade ovarian serous carcinoma, with the greatest dimension being 17.5 cm with architectural features suggestive of solid endometrial-like transitional variant after total hysterectomy and bilateral salpingo-oophorectomy. The postoperative course was uneventful, and the PleurX® catheter was removed on the third postoperative day. Postoperative diagnoses were ovarian malignancy, secondary malignancy of the omentum, and pelvic peritoneum and pelvic lymph nodes.
After surgery, the pleural effusion and ascites resolved. The patient is scheduled to receive six courses of carboplatin and taxols.


Male, 58-year-old, seller, referring nail dystrophy in all the quirodactyls () and first on the halux (, ), bilaterally, two years ago. He also presented pallor on mucous membranes, periorbital edema (), more exuberant on the right eye, skin of yellowish and fragile tonality, xeroderma, fissures in palms and plants, asthenia and dizziness with reports of falls. Laboratory investigation showed Hb = 10,7 g/dL, TSH > 50 μU/mL, T4L = 0.65 ng/dL (0.54–1.48 ng/dL), T3 < 0.25 ng/dL, the patient was diagnosed as primary hypothyroidism and received the prescription of levothyroxine. A significant improvement of the symptoms and of the skin was achieved after the first month of treatment ().


A 71-year-old Caucasian male presented to our emergency department complaining of shortness of breath, dry cough, generalized malaise, and myalgias/arthralgias for one-week duration. His history was significant for hypertension, a previous inguinal hernia repair, and hemorrhoidectomy. Upon initial presentation, he was febrile (Tmax of 38.6C) and had a leukocyte count within normal limits. Chest X-ray (CXR) imaging revealed bilateral patchy peripheral infiltrates indicative of pneumonia (). A nasal swab upon presentation to the ER returned positive for COVID-19. Within 48 hours of admission, the patient's respiratory function continued to decline, and repeat CXR after ET placement showed progressive lung parenchymal consolidation ().
On the eleventh day of admission, the patient desaturated <65% due to ET cuff rupture requiring replacement. This prompted BMV, afterward, substantial abdominal distention was noted. Initial imaging with a CXR showed intraperitoneal free air, with a follow-up abdominal CT scan confirming massive free air in the abdomen (). Surgical staffs were consulted, and the decision was made to bring the patient to the OR. Exploratory laparotomy was performed, identifying a 4 × 4cm anterior gastric perforation along lesser curvature.


A 42-year-old never married man was bitten in his left hand in 2004 by a friend during an argument. Details are summarized in Table , case 11. The bite was cared for and documented by an employee of a surgical outpatient clinic. There was a gaping bleeding wound which was not sutured. Although the patient acknowledged the presence of an HIV infection of the aggressor, no PEP was recommended. The HIV–ELISA–screening test performed by a general practitioner 7 days after the incident was negative. Ninety days later (97 days after the bite incident), a HIV–ELISA antibody–screening test was positive and confirmed by Western blot. However, the patient did not show up again because of depression and alcohol problems. Nineteen months after the bite incident, he presented at Charité, the University Hospital of Berlin with thoracical herpes zoster. HIV-1 infection was confirmed by Western blot (CD4 cell count 415/µl, viral load 132,000 HIV RNA copies/ml). He imperturbably denied any further potential risk factors for acquiring HIV during the past 12 months prior to the bite until 97 days after the bite when the first test turned out to be positive. He did not remember any signs and symptoms of acute retroviral syndrome.
The bite victim and the aggressor were interviewed about the circumstances of the bite incident. Both denied having had any sexual activities with each other or having shared any devices bearing the risk of potential HIV transmission and agreed to perform comparative virus nucleic acid sequencing. The sequences of the viruses showed close relatedness. Both viruses belonged to HIV-1 group M subtype B. Based on the usual mutation rate, the date when the viruses might have had a common ancestor virus was calculated. Considering a usual mutation rate of 1–3 × 10−3 nucleotide substitutions per site per year [, ], both strains were calculated to have had a common ancestor virus about 42 months prior to the blood withdrawal. The bite occurred 27 months prior to blood examination. Of note, the aggressor suffered from an advanced immunodeficiency with high viral load (Table , case 11) which can be associated with a higher mutation rate []. Based on the inherent variability of the mutation rate, we considered that the calculated date fitted well into the factual time of the bite event.


A 47-year-old man was admitted to the Department of Urology of the Fifth Affiliated Hospital of Zunyi Medical College with space-occupying lesions in the kidney and liver during a regular medical examination in August 2016. The patient complained of mild, intermittent, right upper quadrant discomfort for 2 months. Moreover, the patient had a history of chronic hepatitis B for 20 years. Physical examination showed that the liver edge was palpable 3 cm below the right costal margin and that there was mild tenderness. There was no yellowing of the skin or mucosa and no liver palms. The complete blood count and serum biochemistry data on admission were as follows: hemoglobin, 136 g/l (normal range, 120∼160 g/l); white blood cell, 4.2 × 109/l (normal range, 4.0–10 × 109/l); platelets, 154 × 109/l (normal range, 100∼300 × 109/l); alpha-fetoprotein (AFP), 35.49 ng/ml (normal range, 0∼7 ng/m); glucose (fasting) 5.0 mmol/l (normal range, 3.9∼6.1 mmol/l); normal protein/albumin 42.6 g/l (normal range, 40∼55 g/l) and 25.0 g/l (normal range, 20∼40 g/l); a normal bilirubin 8.0 μmol/l (normal range, 0∼23 μmol/l). His liver enzymes were within the normal range (ALT 21 units/l, AST 16 units/l). The hepatitis virus test showed positivity for hepatitis B surface antigen (HBsAg), but he was negative for HCV. The enhanced computed tomography (CT) scan revealed a mildly enhanced tumor measuring approximately 3 × 4 × 5 cm3 in the right lobe of the liver and an obviously enhanced mass measuring approximately 2 × 3 × 3 cm3 in the inferior pole of the left kidney, and no mass lesions were found on the bilateral adrenal glands (Fig. ). Enlargement of the lymph nodes was not found in the abdominal cavity or retroperitoneum.
The clinical presumptive diagnoses were RCCC (T1N0M0) and HCC (T2N0M0). The patient subsequently underwent nephron-sparing surgery (NSS) of the left kidney and radical partial excision of segments Vand VI of the right liver lobe by laparoscopic surgery. The IHC findings of the PCCCL (Fig. ) were as follows: hepatocyte (+), AFP (+), CEA (-), and HBsAg (+). The pathological findings of the renal tumor revealed Fuhrman grade II RCCC (Fig. ), and the PCCCL was stage B according to the Barcelona Clinic Liver Cancer (BCLC) staging system. The immunohistochemistry results of the kidney tumor were as follows: CD10 (+), CK7 (-), EMA (+), and vimentin (+). Based on the radiological imaging and pathological results, neither regional lymph node nor distant lymph node metastasis was found, and the TNM (tumor-node-metastasis) classification was T1N0M0 for RCCC and T2aN0M0 for PCCCL. TACE was performed in the segmental artery 2 weeks after tumor resection. One month after the operation, the patient started adjuvant therapy with sorafenib (400 mg twice per day orally), and the re-examination of serum AFP showed a level of 5.22 ng/m.
Unfortunately, a follow-up CT image revealed a 1.9 × 2.0 × 2.0 cm3 mass on the right adrenal gland 2 months postoperatively (Fig. A). His serum AFP was 13.27 ng/ml, and the patient underwent radiofrequency ablation (RFA) for right adrenal metastasis. The patients postoperative course was uneventful, and he was discharged after 14 days. He was followed up regularly with clinical examinations and tumor marker tests (including those for AFP, CEA, CA-199, and CA125) every 3 months. No local recurrence or distant metastasis was found on the follow-up abdominal CT scans, which were acquired every 3 months for 2 years.


A 48-year-old female with past medical history of failure to thrive requiring percutaneous endoscopic gastrostomy (PEG) tube placement presented to the emergency department (ED) with PEG tube dislodgement. Her PEG tube was initially placed in 2009, with surgical replacements in 2012 and 2018. Examination revealed a soft, nontender, non-distended abdomen with an open gastrostomy tract. ED course included placement of a new gastrostomy tube into the existing tract and confirmatory gastrografin radiography ().


We present the case of a 26-year-old Asian gentleman who presented to the Accident & Emergency (AnE) with three-week history of pain in the right foot. The pain was present all the time and there were no aggravating or relieving factors. He had no previous medical problems. There was no history of tobacco or alcohol use, and he was a car mechanic by profession. There was no history of trauma. He had no allergies and did not have any pets. There was no history of recent travel. Physical examination, vitals and an X-ray of right foot were normal and the patient was discharged home on simple analgesia. No blood tests were done on his first presentation.
A referral to physiotherapy was made as well. He, however, represented a week later with similar symptoms. His D-dimers were elevated, however, right leg venous Doppler was negative for a deep vein thrombosis (DVT).
He presented to AnE for the third time and in addition to the foot pain, he now reported tingling sensations in his hands and weight loss of 1 stone in last three weeks. His general practitioner (GP) was suspecting a rheumatological problem and had already requested a computed tomography of chest/abdomen/pelvis (CT CAP) and a magnetic resonance imaging (MRI) of the right foot for him.
He was admitted to the hospital on this occasion. On examination his chest was clear with a central trachea and normal vesicular breathing. There was no clubbing and there were no palpable lymph nodes. Heart sounds were normal. Abdomen was soft, non-tender with a palpable liver edge 2 cm below the costal margin. Neurological exam revealed good power and tone in all limbs with no focal motor or sensory deficit. There were no cerebellar signs and he had a normal gait.
His blood eosinophils were raised at 1.1 with deranged liver function tests (LFTs). A chest X-ray on admission was normal.
He was referred to the Neurology team for his symptoms of pain and paraesthesias. A diagnosis of multiple sclerosis was ruled out by a normal MRI head and spine. A lumbar puncture (LP) was performed and cerebrospinal fluid (CSF) showed raised protein (1.24), normal opening pressure and no oligo-clonal bands with normal differential counts. Neurology team further advised nerve conduction studies (NCS) which showed “subacute demyelinating length dependent sensorimotor polyneuropathy with substantial axonal loss in the distal lower limbs”. Neurology suspected a diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP), however, duration of his symptoms was short and inconsistent with this diagnosis. He received five days of IV immunoglobulins with little improvement. Neurology advice was to consider a course of methylprednisolone. He was booked in for outpatient neurology follow-up.
MRI (Figure ) of his right foot showed stress fracture of fifth metatarsal and focal oedema in anterior aspect of calcaneum. Orthopedic team was called upon. They asked for an MRI of left foot which showed multiple stress-related focal changes/stress fractures in first, second, fourth and fifth metatarsals (Figure ). They advised “off loader boots” on both feet and mobilization as tolerated. Outpatient follow-up was arranged.
Rheumatology team reviewed him and advised that he most likely has marble bone disease. They advised outpatient rheumatology follow-up post discharge.
He was referred to hematology in view of young age, weight loss and an enlarged liver. After reviewing the case hematology team conducted a bone marrow biopsy which was normal.
His liver was imaged with an ultrasound in view of deranged LFTs and palpable liver and was noted to be “enlarged in size and hypoechoic”. An acute liver screen to look for viral, autoimmune, haemochromatosis and fatty liver disease was carried out and was negative.
The CT-CAP (Figure ) done for unexplained weight loss was reported as having “multilobar bilateral patchy subtle ground glass pulmonary opacification (GGO)”.
This prompted the involvement of the respiratory team. The respiratory team advised lung function testing (PFTs) (Table ) that showed a restrictive defect with reduced TLCO.
T-Spot was negative. In view of the eosinophilia, GGO changes on CT and lung function test findings, a bronchoscopy with transbronchial lung biopsy (TBBx) was done and bronchoalveolar lavage (BAL) samples were taken for microbiology, cytology and histopathology. A differential count revealed mononuclear cells 60%, lymphocytes 35%, neutrophils 4%, and eosinophils 1%. Aura-mine, fungal and viral cultures were negative. Trans-bronchial lung biopsy showed “non-necrotising granulomatous inflammation” (Figure ).
A number of differentials were considered before finally treating the patient as sarcoidosis. His bloods since his first presentation through to his follow-up are tabulated below (Tables , ) along with a list of other investigations and how they were used to rule out the considered differentials.
The biopsy results in conjunction with eosinophilia, high urinary calcium, restrictive lung disease on PFTs and high proteins on LP were consistent with a diagnosis of sarcoidosis.
He was started on oral prednisolone 50 mg by the respiratory team and discharged home with a planned multidisciplinary follow-up to ensure comprehensive care.
He has since been reviewed in the respiratory, rheumatology, neurology and orthopedic clinics. He reports his symptoms have shown significant improvement. His repeat MRI of feet (Figures , ) two months after his discharge showed that his stress fractures had improved. He also had a repeat CT thorax, three months after discharge which showed resolution of GGO. He remains under respiratory follow-up and continues to do well.


A 59-year-old female patient with no significant past medical history presented to the emergency room with a history of fever, headache, drowsiness, and body pains for one week. Suspecting viral encephalitis, acyclovir was initiated. The patient had one episode of generalized tonic-clonic seizures (GTCS) post-admission. Magnetic resonance imaging (MRI) of the brain ruled out a cerebrovascular accident. CSF analysis did not show features of meningoencephalitis. Serum sodium was 122 meq/mol. Hyponatremia was suspected as the cause of the GTCS, and the patient was started on 3% normal saline. The patient recovered, and a Glasgow Coma Scale score of 15 was noted. However, six hours later, she became drowsy and went into respiratory failure with a partial pressure of carbon dioxide (PaCO2) of 55, prompting non-invasive ventilatory support. The patient had one more episode of GTCS. On examination following that episode, she had altered sensorium, disorientation, confusion, and faciobrachial dystonic seizures (FBDS), hinting at autoimmune encephalitis. A serum autoimmune panel was ordered, which came back negative. Three anti-epileptic drugs, namely, sodium valproate, phenytoin, and levetiracetam, were started. However, the patient continued to have recurrent complex partial seizures. She developed hyperthermia, tachycardia, and hypertension, indicating autonomic dysfunction. Infectious causes, including herpes simplex, chikungunya, cytomegalovirus, and dengue were ruled out. Procalcitonin was normal. The autonomic dysfunction was treated with nitroglycerine and dexmedetomidine infusion. Despite this, the patient had continuous faciobrachial dystonia and cataplexy. Methylprednisolone, 1 g/day, was started. Paraneoplastic causes were ruled out through CT scans and tumor markers. The patient required ventilator support because of recurrent status epilepticus and autonomic instability. As she continued to have recurrent seizures despite steroids, intravenous immunoglobulins were initiated. The patient had persistent seizures on the ventilator with four antiepileptic drugs (levetiracetam, phenytoin, sodium valproate, clonazepam), and propofol infusion of 1.5 mg/kg/hr. A diagnosis of super-refractory status epilepticus was made because of persistent seizures after 24 hrs of propofol infusion. Repeat MRI of the brain showed medial temporal lobe hyperintensity. Thiopentone, 3 mg/kg/hr, was started for burst suppression and the dosage was increased to a maximum of 6 mg/kg/hr. Midazolam, 2 mg/hr, was continued, along with thiopentone, and an intermittent bolus of thiopentone was given.
After three days of thiopentone infusion, the EEG showed a generalized, reduced spike pattern. The thiopentone dose was reduced and eventually stopped, but she continued to have faciobrachial dystonia. Suspecting N-methyl-D-aspartate (NMDA)-receptor encephalitis, magnesium sulfate, 1 g/hr, and ketamine infusion, 1.5 mg/kg/hr, were started and were continued for one week. The FBDS persisted, prompting the initiation of second-line immunotherapy with rituximab, 625 mg (at 375 mg/m2) with serial CD19 and CD20 antibody monitoring.
The patient improved neurologically with reduced spikes on EEG. Eventually, two weeks down the line, the patient was discharged without any neurological or cognitive abnormality.
The investigations and timeline of events during the hospital stay are depicted in Tables -, respectively.


A 38-year-old woman, smoker (2 cigarettes a day), was referred to the oral medicine service at the Andres Bello University, for having “white spots” in her mouth. Her medical history revealed that the patient suffers from insulin resistance, for which she takes metformin, otherwise, her medical history is unremarkable.
Upon intraoral examination, multiple non-removable, painless white plaques of variable size and thickness where observed in the attached gingiva, with no involvement of the free marginal gingivae and alveolar mucosa (Fig. A). Also, a similar white plaque widespread across the hard palate sparing the free marginal gingival was noticed (Fig. B). On the dorsal side of the tongue, the filiform papillae were elongated, thickened and whiter than normal, which gave the impression as if the tongue had a white coat covering it (Fig. C). No other alterations were observed.
By further questioning, the patient comments that she has never noticed anything out of the ordinary in her mouth, but she does have thick yellowish focal plaques in both of her soles (Fig. ). No similar lesions were present in other parts of her body, including the palms of her hands. The patient also explains that her father and grandmother have similar lesions on palms and soles.
Based on these findings and under the suspicion of a genodermatoses (), an incisional biopsy of the lesions in the hard palate and attached gingivae was performed. Histopathologically, both specimens revealed a hyperplastic and hyperorthokeratinized stratified squamous epithelium with basal hyperplasia containing multiple normal mitosis (Fig. A). The spinous, granular and corneum stratum showed dispersed basophilic keratohyalin granules (Fig. B). At higher magnification, the keratinocytes contained paranuclear bodies, seen as round eosinophilic condensation that indented the nuclei, giving it a coma or “Pac-man” shape (Fig. C). The connective tissue underneath was of normal appearance, demonstrating a dense collagenized chorion, containing multiple fibroblasts, hyperemic capillaries and the presence of chronic inflammatory cells.
Upon these clinical and histopathological findings, the final diagnosis was rendered as focal palmoplantar and gingival keratosis disorder. The patient was referred to dermatology for further investigations.


The patient is a 24-year-old African-American female with a past medical history of tuberous sclerosis, gestational hypertension, stable renal angiomyolipoma, and recent pneumothorax, most recently three months prior to admission. She presented with a four-week history of productive cough. The cough was described as occurring intermittently throughout the day, productive of light-yellow colored sputum, and being associated with rhinorrhea and sinus congestion. She reported her uncle as a sick contact, who was being treated for an upper respiratory infection at the time she developed symptoms. The patient endorsed shortness of breath with mild exertion. The patient also complained of increased urinary frequency and dysuria that had started three days prior to admission; however, she denied any complaints of headaches, fever, chest pain, weakness, changes in vision, nausea, vomiting, or changes in bowel habits. The patient admitted to actively smoking tobacco and smokes approximately five cigarettes daily.
On presentation to the emergency department, the patient was not in respiratory distress. Her vital signs showed a blood pressure of 148/77 mmHg, heart rate of 74 beats per minute, temperature of 98.3 degrees Fahrenheit, and oxygen saturation of 97% on room air. The patient’s physical examination was significant for absent breath sounds in the right basilar and anterior-mid lung field compared to the left with no wheezes or rales. Her examination was otherwise benign. Her laboratory studies are shown in Table .
She was evaluated further with a chest X-ray (Figure ), computed tomography (CT) of the chest, abdomen, and pelvis (Figure ), which was compared to her CT chest from her visit three months prior to her current admission (Figure ), and magnetic resonance image (MRI) of the abdomen (Figure ). The summary of imaging impressions is given in Table .
The patient was determined to have developed a recurrent spontaneous pneumothorax as a result of her cough. She received a dose of albuterol-ipratropium nebulizer therapy and a one-time 500 mg oral dose of levofloxacin followed by a chest tube placement. The patient’s pneumothorax ultimately resolved. Upon removal of the chest tube three days later, the patient was discharged to her home in stable condition, with advice to follow-up regularly with the medical team in the outpatient clinic.


The patient was a 30-year-old woman who was admitted to our institution due to a 3-week history of intermittent vaginal bleeding. She had a medical history of hypertension for 2 years and regular menses (gravida 0 para 0). On admission, her blood pressure was 149/86 mmHg, her heart rate was 125 beats/min, and her temperature was 38.1 °C. A physical examination revealed moderate pitting edema in both lower limbs. A routine blood test performed in a nearby hospital 4 days before admission showed leukocytosis, severe anemia and thrombocytopenia (Table ). Laboratory investigations in our hospital revealed the following: C-reactive protein (CRP): > 200 mg/L; hyperplastic anemia (41 g/L); blood urea nitrogen: 39.21 mmol/L; creatinine: 624 μmol/L (7.06 mg/dL); hypoalbuminemia (25.4 g/L); alkaline phosphatase (ALP): 332 U/L; gamma glutamyltransferase: 501 U/L; uric acid: 968 μmol/L; transaminase: normal; fibrinogen: 750 mg/dL; activated partial thromboplastin time (APTT): 70.3 s; plasma correcting test: 37.3 s of immediate APTT and 48.5 s of incubated APTT; autoantibodies [antinuclear antibody, rheumatoid factor, anti-double-stranded DNA antibody, anticardiolipin antibody, anti-neutrophil cytoplasmic antibody, anti-glomerular basement membrane antibody, etc.]: negative; immunoglobulin (IgA, IgG, and IgM): normal; β2 microglobulin: > 8 mg/L (1.00–3.00); M protein: negative; complement 3 and 4: decreased; direct antiglobulin test (DAT): 3+; and procalcitonin: 43.63 ng/ml. Broken red blood cells were not observed on the blood smear. The blood culture, G/GM test and viral detection (Epstein-Barr virus, cytomegalovirus, parvovirus B-19, epidemic hemorrhagic fever, HIV, etc.) test were negative. The urinary sediment examination showed the following: urinary protein: 1+; occult blood: 2+, and hematuria: 56/μl. The 24-h urinary protein level was not checked because of oliguria. Ultrasound scans of the urinary and gynecological systems were normal. Plain computed tomography revealed a small amount of polyserositis and lymphadenopathy in multiple nodes but no evidence of malignant solid tumors or signs of infection. Bone marrow aspiration showed bone marrow hyperplasia, and immunohistochemistry was normal. 18FDG-positron emission tomography/computed tomography revealed that glucose analog 2-(18F)fluoro-2-deoxy-D-glucose activity was increased in the mediastinal, paraaortic, bilateral neck, bilateral axillary, and bilateral inguinal lymph nodes (SUVmax: 5.2). The largest node measured approximately 2.7 cmx1.2 cm, and hepatosplenomegaly with increased FDG activity was observed in the spleen (SUVmax: 5.2).
On admission, the patient was treated with the following: 1) oral Diane-35 (ethinylestradiol cyproterone), 1 tablet q 8 h in the first week and 1 tablet qd in weeks 2–4; 2) regular hemodialysis, three times a week; 3) intravenous anti-infection with meropenem (0.5 q 12 h on day 2) and moxifloxacin (0.4 qd on day 2 and replaced with linezolid on day 7); and 4) blood transfusion as needed (RBC: 800 ml; plasma: 200 ml (total)). After the above treatment, her condition did not improve, with an intractable decrease in hemoglobin and platelets, and her CRP level continued to be above 200 mg/L (Fig. ).
The data described above (no evidence of a solid tumor, negative etiologic test and ineffective antibiotic therapy, and no evidence of hemolysis that favored TTP and HUS) indicated a differential diagnosis. Considering her positive DAT and APTT correction test, the latter indicated the presence of a coagulation factor inhibitor in the blood; therefore, we concluded that the autoimmune mechanism was involved in her pathogenesis. Therefore, intravenous methylprednisolone (60 mg qd) was given on day 13. Fortunately, her temperature decreased to normal on day 14, and improvements in laboratory tests were found (i.e., CRP and APTT decreased to normal levels); however, anemia and thrombocytopenia improved relatively slowly. Though severe thrombocytopenia (14 × 109/L) was observed on day 14, lymph node biopsy was performed on the basis of platelet transfusion on day 15. The results showed atrophic germinal centers and obvious proliferation of endothelial vessels in the T-zone. The histological findings were in accordance with the hyaline-vascular (HV) type of CD (Fig. ). During this period, glucocorticoid therapy alone resulted in a progressive improvement in anemia and thrombocytopenia. Further laboratory tests showed mild to moderate increases in interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) (9.5 pg/ml and 231.47 pg/ml, respectively), normal levels of IgG4 and negative HHV-8 PCR. Based on these findings, her clinicopathological findings met both Iwaki’s and Masaki’s diagnostic criteria for TAFRO syndrome.
Due to persistent thrombocytopenia and concerns about the risk of bleeding, renal biopsy was not performed until day 40. Histopathology showed 17 glomeruli, 7 of which were ischemic sclerosis. The mesangial cells and matrixes of the remainder of the glomeruli showed slightly diffuse proliferation and local aggravated endothelial cell proliferation. The basement membrane was thickened heterogeneously, and some of the glomerular basement membrane was ischemic and shrunken. Vacuole and granular degeneration was observed in renal tubular epithelial cells, with expansion of the lumen and diffuse atrophy. The arteriole had an “onion skin” appearance, with a thickened wall and narrowed lumen. Immunofluorescence staining showed that immunoglobulin (IgM++) was deposited in clumps or granules along the mesangial area and capillary wall. Electron microscopy did not reveal any electron-dense deposits but showed widening of the loose layer in the glomerular basement membrane with the accumulation of cell debris. Based on these findings, the patient was diagnosed with thrombotic microangiopathy (TMA)-like renal lesions with subacute renal tubular interstitial nephropathy (Fig. ). Her urine output increased gradually (approximately 1000 ml/d), and the dialysis interval was prolonged. However, her platelet level decreased again on day 48. On day 50, she accepted intravenous tocilizumab (TCZ, anti-IL-6 receptor monoclonal antibody, from Roche) (8 mg/kg qw in the first month and then once a month). She stopped dialysis on day 65. During the 13-month follow-up, her laboratory tests, including routine blood tests, ALP, CRP and APTT, were all normal, but her creatine level did not decrease to normal levels (249 μmol/L 6 months after admission).