The 46-year-old female patient was diagnosed with relapsing-remitting MS in 2005. She started on interferon-beta 1a in 2005 presenting a stable disease course in the following years. In 2010, severe idiopathic pulmonary arterial hypertension (IPAH) and one-vessel coronary artery disease were diagnosed after progressive exertional dyspnea, dizziness, marked restricted physical performance and mild stenocardia since 10 months, characterizing heart failure stage III of classification of the New York Heart Association (NYHA). Echocardiography showed right ventricular hypertrophy, moderate reduction of left ventricular and severe reduction of right ventricular function, paradox septum deviation and severe tricuspid valve insufficiency with an estimated systolic pressure of 90 mmHg (Table ). Routine echocardiography 12 months before was without abnormal results. Combined left and right heart catheterization demonstrated one-vessel coronary artery disease and severe pre-capillary pulmonary hypertension with a mean pulmonary arterial pressure of 66 mmHg (normal: 10–20 mmHg), left ventricular end-diastolic pressure of 12 mmHg (normal: 3–12 mmHg), cardiac index of 1.5 L/min/m2 (normal: 2.5-4.0 L/min/m2) and pulmonary vascular resistance of 14.1 wood units (normal: 0.25-1.6 wood units). The initial level of N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP) presented with an increase up to 207 pmol/L (normal: ≤17 pmol/L). One week after placing a drug eluding stent in the left main coronary artery (LMCA) control echocardiography revealed an unchanged severe pulmonary hypertension with near normalized left ventricular function. Diagnosis of severe IPAH was established by exclusion of other causes of pulmonary hypertension according to the diagnostic criteria reported by Galie et al. []. Compression of the LMCA by an enlarged pulmonary artery was excluded by CT-angiography of the pulmonary arteries. The patient started on the endothelin receptor antagonist ambrisentan and phosphodiesterase inhibitor tadalafil. By this treatment, the patient reported an improvement of physical performance, no more dizziness and stenocardia as well as a stable disease course corresponding to heart failure of stage NYHA II. In further evaluations, mild right ventricular hypertrophy and insufficiency, mild tricuspid valve insufficiency, decrease of right ventricular-systolic pressure in echocardiography, normal lung function, mild impairment in diffusion capacity of carbon monoxide and mild hypocapnia was detectable in the following years (Table ).
In 2013, she demonstrated with significant clinical disease activity of MS with two relapses and MRI activity with three gadolinium-enhancing lesions and an Expanded Disability Status Scale (EDSS) of 4.0. Because of positive JC-virus serology, fingolimod was selected as second line treatment. Before first dose application, extensive cardio-pulmonary testing demonstrated stable cardiovascular parameters as described above (Table ). The baseline electrocardiogram (ECG) showed a sinus rhythm with a right bundle branch block. During first dose, heart rate (HR) decreased at maximum by 13 bpm at 4 hours and reached baseline HR 6 hours after initial fingolimod administration. 12 lead ECG as well as Holter ECG did not demonstrate any significant abnormalities (Table ). Blood pressure (BP) in lying and tilted up position presented within normal range during the whole 6 hours monitoring (Table ). The patient did not complain any findings in the first 6 hours after fingolimod application. Cardio-pulmonary testing one week, one, three and nine months after first dose application demonstrated stable parameters in ECG, BP, echocardiography, body plethysmography and blood gas analysis (Table ). Especially relevant parameters of right ventricular and pulmonary circulation including right ventricular hypertrophy, right ventricular end-systolic pressure (RVESP), right-ventricular ejection fraction and tricuspid annular plane systolic excursion (TAPSE) kept stable on fingolimod treatment (Table ). Detailed testing of the autonomic nervous system demonstrated no change of the efferent sympathetic regulation and left ventricular function after orthostatic stress before, 2 hours, 4 hours, and 6 hours after fingolimod first dose application as well as in three and nine month follow up (Table ). Maximal heart rate variability measured by expiration/inspiration quotient (E/I) during deep metronomic breathing showed a decrease to 1.06, which stabilized over time back to 1.09 (Table ) []. There were no additional cardiac or pulmonary symptoms than known before fingolimod treatment.


A 41 year-old Caucasian woman with a history of Ehlers-Danlos type III syndrome, migraine headaches, and sciatica received a lumber 4/lumbar 5 translaminar epidural steroid injection from a contaminated compounded steroid lot (06292012@26) on August 31, 2012 []. Seventeen days after her injection, she developed headaches, nausea and vomiting and was diagnosed with sinusitis and migraines. Thirty-seven days after injection she received a notification letter of exposure from the compounding facility and presented to her local emergency department. She underwent a lumbar puncture (LP) showing pleocytosis (Table ). Given these results and otherwise negative workup for alternative etiologies, and in the context of the ongoing contaminated steroid outbreak, she was treated with liposomal amphotericin B (5 mg/kg daily) and voriconazole (5 mg/kg IV q12h) for presumptive fungal meningitis. Repeat lumbar puncture (LP) performed one week after initiation of therapy showed no increase in pleocytosis (Table ). She was discharged from the outside facility three days later on oral voriconazole, though medication initiation was delayed due to medication supply issues.
She presented to this hospital three days after discharge with fevers, worsening headache and vomiting. She also had developed new left face, hand and foot numbness. Neurological exam revealed diminished light touch and temperature sensation in the region of the left cranial trigeminal nerve, mandibular division, left hand and the dorsal aspect of left foot, as well as 4/5 strength on left foot dorsiflexion. Brain magnetic resonance imaging (MRI) on October 21 showed evidence of acute infarct at the right pons with the suggestion of a prominent vessel in the right perimesencephalic cistern suspicious for a mycotic aneurysm and evidence of diffuse vasculopathy of the vertebrobasilar arteries, (Figure ). A computed tomography (CT) angiography showed a 4.1 mm aneurysm at the right superior cerebellar artery in the right perimesencephalic cistern (Figure A). Repeat LP showed stable pleocytosis (Table ). She was restarted on liposomal amphotericin B (7.5 mg/kg daily) and intravenous voriconazole (6 mg/kg q12h).
One week later, repeat brain MRI with gadolinium showed evidence on gradient echo sequences of subarachnoid signal changes consistent with either blood or inflammation in the prepontine cistern, bilateral occipital horns, and right hemispheric subarachnoid space. The aneurysm appeared stable in size, though more irregular. In consultation with Neurosurgery, the risks of operation given the location, size and friable appearance of the aneurysm outweighed the potential benefits of surgical intervention. She had a MRI lumbar spine due to new onset urinary retention during her hospitalization (November 13th) which showed evidence of arachnoiditis affecting intrathecal and bilateral dorsal extradural components. The patient underwent a repeat LP on November 9th, now 10 weeks after initial contaminated steroid injection, which indicated persistent pleocytosis (Table ). The voriconazole level, 5 days after reinitiation of 6 mg/kg intravenous therapy was less than 1 mcg/mL and dosing was increased to 9 mg/kg dosing despite presence of hallucinations on the lower nontherapeutic dose begun at this second hospitalization on October 21st.Prior to discharge repeat CT angiography showed slight decrease in aneurysm size to 3.8 mm and no subarachnoid hemorrhage (not shown). Three months into therapy the right superior cerebral artery aneurysm was diminished but not resolved in February, 2013 (Figure B).
Microbiological studies resulted in negative fungal cerebrospinal fluid (CSF) cultures on October 8, 15, 21 and Novemberz 9 at the hospital clinical laboratory. CSF PCR was also negative for fungal and Exserohilum species detection at Centers for Disease Control and Prevention (CDC) []. Archival CSF from the three October and single November LPs held in the state lab were retrospectively evaluated for (1,3)-β-D-glucan (BDG), with results showing levels greater than 500 pg/mL (positive >80 pg/mL).She received a total of 32 weeks of antifungal treatment, initially with 14 weeks of combined voriconazole and liposomal amphotericin B, followed by 8 weeks of voriconazole alone due to renal insufficiency from liposomal amphotericin B, followed by 4 weeks of combined therapy and ending with 6 weeks of liposomal amphotericin B alone which was discontinued secondary to renal dysfunction, nausea, emesis and myalgias. She completed 26 weeks of voriconazole and 24 weeks of liposomal amphotericin B. Magnetic resonance angiography (MRA) was performed at the end of antifungal therapy, which showed resolution of the aneurysm. Her symptoms resolved forty weeks after onset. MRA was performed at the end of antifungal therapy, which showed resolution of the aneurysm. An August, 2013 CTA performed 3 months after discontinuation of all antifungal therapy did not show any recurrence of aneurysm (Figure ). More than a year after onset of symptoms and 6 months off therapy she remains well and is considered a “cure”.


A 33 year-old woman with a history of primary infertility
was referred to Royan Infertility centre,
Tehran, Iran. Evaluation of her partner confirmed
azospermia, which led to testicular sperm extraction
(TESE) and diagnosis of male factor infertility.
The woman then underwent an IVF trial.
The first in vitro fertilization (IVF) cycle was started
using a GnRH-a long protocol (GnRH-a combined
with Gonal F). Follicle number and growth
were monitored by transvaginal ultrasound scans.
Oocyte retrieval was performed transvaginally
and nineteen oocytes were obtained. Nine oocytes
were fertilized using intracytoplasmic sperm injection
(ICSI). Ultimately three embryos at the
four-cell stage, AB grade, were transferred into
the uterine cavity and the remaining embryos were
cryopreserved. An ultrasound scan was performed
32 days after embryo transfer and a gestational sac
with a regular fetal heart rate was seen.
Two months later the next ultrasound evaluation
at 15 weeks gestation revealed a fetus with two
weeks’ growth retardation, severe reduction of amniotic
fluid, and a 29 mm cervical canal length was
recorded. Meanwhile, due to male sperm analysis
results which demonstrated azospermia and a history
of two mentally retarded children from the
man’s previous marriage, the woman underwent
amniocentesis for chromosomal evaluation and a
normal 46xx fetus was recorded.
At 27 weeks of gestation, she was referred to the
hospital with chief complaints of high blood pressure (180/110 mmHg), edema of the lower extremities
(++), proteinuria (++) and sudden weight
gain. She was diagnosed with severe preeclampsia
and fetal growth retardation was noted. She received
routine therapies (magnesium sulfate and
antihypertensive medications including Methyldopa,
Hydralazine and Labetalol) and with respect
to anticipation of preterm delivery, four doses of
betamethasone were given to enhance fetal lung
maturity.
Finally, the patient underwent an elective cesarean
delivery at 27 weeks’ gestation and a 580 g female
infant with Apgar scores three and five at one and
five minutes, was born. The infant was admitted to
the Neonatal Intensive Care Unit and underwent
intubation and mechanical ventilation for poor respiratory
effort. Then she was prescribed one dose
of Survanta for lung maturity improvement and after
24 hours, the respirator was separated. She was
administered Ampicillin and Amikacin but due to
leukocytosis and positive C-reactive protein (CRP)
on day three, Vancomycin and Cefotaxime were
replaced. She also received 400 mg/kg intravenous
immunoglobulin (IVIG) daily for three consecutive
days and the results of complete blood count
(CBC) and CRP tests were maintained within the
normal ranges.
The echocardiogram on day three revealed evidence
of patent ductus arteriosus (PDA), which resulted
in an occasional drop in heart rate. With administration
of oral Ibuprofen, improvement was
achieved as observed in the next echo. The cranial
ultrasound scan was normal in the first week of life
and no evidence of intraventricular haemorrhage
(IVH) or other pathology was found. Ophthalmologic
examination at the age of one month did
not show evidence of retinopathy of prematurity
(ROP).
Three months after birth, the infant was discharged
healthy. All examinations of the neonate were recorded
as normal without any complications such
as ROP or IVH. The infant was in complete physical
and mental health, weighing 7800 g and all
developmental skills were age-appropriate after a
one-year follow-up.


A 6-year-old female patient presented to the Paediatrics Clinic with abdominal pain. Her routine blood count and biochemical tests were normal. The abdominal ultrasonography (USG) has noted an approximately 16 × 29 mm anechoic cyst adjacent to the gall bladder (). The choledochus and the intrahepatic bile ducts were normal. Based on the prediagnoses of cystic duct cyst and choledochal cyst, the patient underwent a MRCP imaging using the 3 Tesla MRI. The MRCP image revealed a fusiform dilatation in the cystic duct. The cystic duct normally joined the choledochus. The choledochus and the intrahepatic bile ducts were observed to be normal (). No abnormal junctions were observed between the biliary and the pancreatic ducts. The patient was not operated and she is followed up through USG.


A 69-year-old female was admitted to the General Hospital of Chengdu Military Region of PLA (Chengdu, China) due to swelling, nodules, ulcers and pain in the right leg. Six months previously, the patient had been impaled by a bamboo pole on the tibialis anterior of the right leg. This was followed by the gradual emergence of skin redness, suppuration and ulceration. Anti-infective medications at local clinics resulted in no clinical improvement. Three months prior to admission, the patient was noted to have a fasting blood glucose level of 18.0 mmol/l. Insulin treatment was administered and a scab formed on the wound in the leg. Approximately one month following this, several painless and erythematous subcutaneous nodules appeared on the patient’s lower right leg. Several of the nodules ulcerated and a mixture of blood and pus was exuded. There was no itching reported. The patient was diagnosed with diabetes and diabetic foot, and was given treatments for anti-infection, insulin, blood circulation activation and debridement for half a month. The blood glucose level returned to normal. When the patient was discharged, the swelling on the right leg had disappeared, although the nodules persisted and the sores had formed a crust. One month prior to admission, the number of nodules on the right leg gradually increased. There was seropurulent discharge from some of the lesions. At admission, three irregularly-shaped, dark red papules (with an approximate diameter of 1.5 cm) emerged near the right knee.
Inspection of the lower extremities revealed multiple, painless, purple-brown colored, circular and clearly delineated nodular lesions, 2×2 cm in size, which were localized to the lower right leg and foot (). Crimson liquid was exuding from certain lesions and some crusts had formed. Laboratory investigations revealed that the blood glucose level was normal. No abnormalities in the biochemical and urine tests were identified. Examination of autoantibodies also revealed no abnormalities and the X-rays of the chest were unremarkable. A plain film of the right leg revealed a small area of shadow in the soft tissue area, which was considered as a foreign material. Gross pathological changes in the bones and joints were not identified. Magnetic resonance angiography (MRA) of the lower extremity vasculature revealed that stenosis was present in the peroneal artery of the lower right leg. An ultrasound scan of the lower extremity vasculature demonstrated extensive thrombosis involving the right calf muscle veins. A skin biopsy revealed signs consistent with a suppurative inflammation process in the skin, with a large number of inflammatory cells (mainly small lymphocytes) present.
The diagnosis of sporotrichosis and diabetes (with deep vein thrombosis) was considered. Pus was collected from the draining lesions. Fungal tests under direct microscopic examination and fungal cultures were repeatedly negative. Pus cultured on a common medium for 48 h revealed no bacterial growth. Ziehl-Neelsen staining of purulent material obtained from a draining lesion revealed the presence of multiple acid-fast bacilli (). Cultures of the pus on Sabouraud medium at 28°C for five days yielded a rapidly growing, nontuberculous mycobacterium. Direct microscopic examination following Ziehl-Neelsen staining was positive for acid-fast bacilli (). This bacterium grew well on blood, MacConkey, Sabouraud and nutrient agars at 28°C on day five. A biofilm was formed when the pus was cultured in nutrient broth for three days at 28°C. Thus, a diagnosis of ‘RGM growth’ was made.
The identification of this RGM isolate was further confirmed by DNA sequence analysis of 16S rDNA (corresponding to E. coli positions 27 to 1492 bp) using qPCR primers 27F (5′-AGAGTTTGATCCTGGCTCAG-3′) and 1492R (5′-GGYTACCTTGTTACGACTT-3′). The results revealed a sequence similarity of 100% with M. abscessus (GenBank accession no. NR_074427.1) and 99% with M. chelonae (GenBank accession no. AM884326.1). A citrate utilization test was then carried out and the result was negative. The pathogenic bacterium was ultimately identified as M. abscessus. Treatment was initiated with intravenous sulfamethoxazole 800 mg twice daily and imipenem 1 g twice daily in combination with debridement. One week later the condition of the patient was significantly improved with exudate cessation and diminishing cutaneous lesions ().
Following the identification of the microorganism as M. abscessus and susceptibility testing, the patient was discharged on sulfamethoxazole 800 mg twice daily by oral administration for an additional three months. Upon several follow-up visits within one year, the patient maintained a range of healthy blood sugar levels and the cutaneous lesions were gradually eliminated.


A 45-year-old female presented to the Daegu Catholic University Hospital (Daegu, Korea) with a mass in the right breast that had been present for the previous two months. The patient had previously suffered no serious illnesses and had no known family history of malignancy, including breast cancer. The patients’s mother was known to have diabetes, but there was no known family history of MEN1.
Upon physical examination, a fixed, firm mass, 2 cm in diameter, was palpated without tenderness in the right breast. There was no clinical evidence of regional lymphadenopathy. Mammography revealed a spiculate hyperdense lesion in the upper portion of the right breast (). Ultrasonography (USG) revealed an irregularly-shaped hypoechoic lesion in the right breast in accordance with the finding of the mammography (). The patient underwent an ultrasound-guided core needle biopsy, which revealed the features of an invasive ductal carcinoma. Radiological studies, including computed tomography (CT) of the chest, magnetic resonance imaging (MRI) of the breast and positron emission tomography-CT (PET-CT) of the torso were conducted for pre-operative evaluation of the right breast cancer. PET-CT showed metabolically active lesions in the right breast, the anterior mediastinum, the peripancreatic area of the upper abdomen and the left adrenal gland, which corresponded to the lesions observed on the CT scan (). In addition, the left thyroid gland and the endometrium of the uterus showed mild FDG uptake on the PET-CT, and a suspicious metastatic nodule of the lung was observed on the CT scan. The findings of an additional abdominopelvic CT scan indicated a neuroendocrine tumor of the pancreas, paraganglioma, a left adrenal adenoma, gallstones and uterine subserosal myoma.
Concomitantly, laboratory examinations revealed hypercalcemia (11.8 mg/dl; normal range, 8.2–10.2 mg/dl), hypophosphatemia (2.0 mg/dl; normal range, 2.5–4.5 mg/dl) and an increased intact parathyroid hormone (iPTH) level of 340.8 pg/ml (normal range, 12–72 pg/ml). The workup for the suspected MEN syndrome revealed an increased basal plasma level of insulin-like growth factor-1 (430 ng/ml; normal range, 124–290 ng/ml), prolactin (43.9 ng/ml; normal range, 3–25 ng/ml) and calcitonin (286.3 pg/ml; normal range, <10 pg/ml), and an increased 24-h urinary free cortisol level (563.5 μg/24 h; normal range, 55.5–286.0). Basal plasma levels of other hormones, including growth hormone, thyroid stimulating hormone, adrenocorticotrophic hormone, gonadotrophic hormone, cortisol, aldosterone, plasma rennin activity, gastrin, insulin and urinary catecholamines, were all within normal limits.
MRI brain scans showed a tumor of 1.4×0.9 cm in size at the posterior aspect of the adenohypophysis, which was indicative of a pituitary macroadenoma. USG of the neck revealed relatively well-defined hypoechoic nodules in the bilateral thyroid lobes. Fine-needle aspiration cytology for nodules at the inferior pole of the bilateral thyroid lobes showed a few atypical epithelial cells of suspected parathyroid origin.
The patient underwent multiple pancreatic mass enucleation, left adrenalectomy, cholecystectomy and hysterectomy. The pathological diagnosis was of calcitonin-producing pancreatic endocrine carcinoma for the pancreatic mass, adrenal cortical adenoma for the adrenal mass, cholelithiasis and uterine leiomyoma with adenomyosis, respectively. A month later, a right breast lumpectomy with right axillary lymph node dissection, total thyroidectomy, parathyroidectomy, extended thymectomy and wedge resection of the lung were performed simultaneously. The pathological diagnosis of the resected breast was of an invasive ductal carcinoma associated with ductal carcinoma in situ demonstrating estrogen receptor (ER)-positive, progesterone receptor-positive and HER2/neu proliferation-negative breast cancer, and metastatic carcinoma was detected in the right axillary lymph nodes (). The pathological diagnosis of nodules in the thyroid gland, parathyroid gland, anterior mediastinal mass and lung nodule were bilateral papillary thyroid carcinomas, not medullary carcinoma, and parathyroid adenomas, a thymic carcinoid tumor and lung hamatoma, respectively. Subsequent to the surgery, the serum calcium levels and the iPTH decreased to within the normal range. The suspicious pituitary adenoma remained untreated and has not since changed in size in 2 years of follow-up examinations. Following the surgery, the patient received adjuvant chemotherapy with 4 cycles of Adriamycin and cyclophosphamide, followed by 4 cycles of docetaxel and then radiation therapy to the right chest and axilla. The patient is currently undergoing anti-estrogen therapy using tamoxifen, and has exhibited no evidence of local tumor recurrence or distant metastases in the 2 years since the surgery.
Given the clinical impression of combined MEN1 and MEN2A based on the clinical manifestations of the patient, confirmatory genetic testing for the MEN1, as well as the RET gene was performed. Also, BRCA1 and BRCA2 genetic testing was performed to determine the association between gene mutations and the development of other tumors, including breast cancer.
Once informed consent had been obtained, peripheral blood samples were collected from the patient. Genomic DNA was extracted from blood using a commercial kit (Wizard Genomic DNA Purification kit; Promega, Madison, WI, USA). Polymerase chain reaction and mutational analyses of the genes were performed as previously described (–). All coding exons for the MEN1 gene, and exons 10, 11, 13, 14, 15 and 16 of the RET proto-oncogene were analyzed by direct sequencing. The 22 exons and the exon-intron boundaries of the BRCA1 gene and the 26 exons and the exon-intron boundaries of the BRCA2 gene were analyzed by direct sequencing. DNA sequencing was performed on the pretreated PCR product using an automated direct sequence analyzer (ABI PRISM 3100 Genetic Analyzer; Applied Biosystems, Foster City, CA, USA).
The MEN1 gene germline mutational analysis revealed a 5-bp duplication in exon 3, namely, c.196_200dupAGCCC, which resulted in a frameshift mutation of the MEN1 gene. This mutation is one of the known germ-line mutations of the MEN1 gene in MEN1 patients (). In addition, a polymorphism of the MEN1 gene was detected at codon 423 in exon 10 of the MEN1 gene, with substitution of a cytidine to a thymidine (C423T), which did not cause a change of amino acid. Mutation analysis for the RET, BRCA1 and BRCA2 genes showed a polymorphism of the RET and BRCA1 genes, but no significant mutation was detected in this patient.


In 1998, a 20-year-old male was admitted to the General Hospital of Tianjin Medical University (Tianjin, China) with symptoms of dizziness, unsteadiness and nausea for three weeks, as well as vomiting for one week. Magnetic resonance imaging (MRI) revealed a mass in the cerebellar vermis and surgery was performed to excise the tumor. The pathological examination identified a hemangioblastoma. Three years later, the patient was readmitted to hospital due to dizziness lasting for one week. An MRI examination showed recurrence of the hemangioblastoma in the cerebellum and the patient underwent surgery to resect the tumor. In April 2012, the patient was readmitted to hospital for the third time due to jaundice. An enhanced computed tomography (CT) scan of the abdomen revealed multiple RCCs in the kidneys, and a nodule with a rich blood supply in the pancreatic head. In addition, numerous cysts were identified throughout the pancreas (). These observations were confirmed by magnetic resonance cholangiopancreatography, which revealed that the nodule in the pancreatic head was ~2.9×2.2 cm in size and possibly a NET. Due to the size and location of the tumor, the bile duct in the pancreas was compressed and the upper parts of the common bile and hepatic ducts were dilated. Since it was not possible to excise the RCCs, the patient also refused surgery to resect the pancreatic head mass. A metallic stent was placed at the stenosis site of the common bile duct, which alleviated the jaundice ( and ). Nine months later, the patient returned to the hospital with a fever, abdominal pain and jaundice. An enhanced abdominal CT was performed, which revealed no change in the size of the pancreatic head mass. The patient’s symptoms were relieved following anti-inflammatory therapy for one week. However, the patient continued to suffer the same symptoms every two months, and gradually, anti-inflammatory therapy failed to alleviate the symptoms. Radiography tests revealed complete blockage of the stent and thus, percutaneous transhepatic cholangiography (PTCD) surgery was performed.
Genomic DNA was extracted from the peripheral blood leukocytes and polymerase chain reaction was performed. Direct sequencing revealed a known mutation of a base pair change at nucleotide 473 in exon 3 (T473T/C) of the VHL gene, resulting in the amino acid change Leu158Pro.
There was a recorded family history of VHL disease, with the patient’s mother, grandmother, two uncles and three aunts also suffering from the disease. Additionally, one uncle had succumbed to RCC and five other individuals in the family had succumbed to cerebral hemangioblastomas.


A 62-year-old female was admitted to San Bortolo Hospital, Vicenza, Italy, in September 2011, with fever and abdominal pain lasting for several weeks. The patient’s and family history were unremarkable. Physical examination revealed only slight discomfort on palpation of the epigastric area. Liver and spleen were regular in size.
White blood count (WBC) was 11.7 × 103/μL, 60% lymphocytes, and liver function tests (LFT) were abnormal (AST 333 IU/mL, ALT 433 IU/mL [normal value <37], GGT 296 IU/mL [n.v. <33], alkaline phosphatase (ALP) 221 IU/L [normal range 30–105], bilirubin 1.0 mg/dL [n.v. <1.3]), some inflammatory indices were raised (C-reactive Protein 3.65 mg/L [n.r 0.00–0.50], ferritin 1442 ng/mL [n.r. 10–160 ], lactate dehydrogenase 1098 U/L [n.r. 200–420], creatine phosphokinase 24 U/L [n.r. <200 ] procalcitonin 0.54 ng/mL [n.v.<0.5], with normal erythrocyte sedimentation rate (ESR) 27 mm/h [n.r. 2–45]).
Chest X-Ray was negative. An abdominal ultrasound (US) (Aplio XG Model SSA-790A, Toshiba, Tokyo, Japan), showed a complete thrombosis of the left portal branch, confirmed by a contrast-enhanced ultrasound (SonoVue, Bracco, the Netherlands) and a computed tomography (CT) scan (see , Panel 1a). No other lesions were found in the abdomen. A hematologic evaluation ruled out myeloproliferative and lymphoproliferative disorders; although a bone-marrow biopsy was not considered, an immune-phenotypic analysis of the peripheral white blood cells and red blood cells resulted in normal range and did not find cellular clones with GPI-linked molecules deficit (in order to exclude paroxysmal nocturnal hemoglobinuria). Inherited and acquired risk factors for thrombosis were ruled out (See ). The patient was a mild smoker (5 cigarettes/day) and was not on hormones; neoplastic markers (Carcinoembryonic [CEA] and carbohydrate antigen [Ca] 19.9 and 15.3, alpha-fetoprotein [AFP]) were all negative. Antibodies against the main hepatotropic viruses (HAV, HBV, HCV, HEV) were negative while HCMV serology suggested primary infection (IgM 10.86 mg/dL [negative <1], IgG 12.8 mg/dL [negative<11]). HCMV DNA (real-time PCR, Real Time Alert QPCR, Elitech Group Nanogen, Milan, Italy) was positive at 3434 copies/ml (sensitivity cutoff: >1111). Thus, acute HCMV hepatitis complicated with portal vein thrombosis was hypothesized.
The patient was treated with i.v. gancyclovir (5 mg/Kg/bid) and low molecular weight heparin (sodium enoxaparin 4.000 U.I. bid) for 15 days. On discharge, HCMV DNA was undetectable. An abdominal US performed before discharge showed thrombus organization (retraction and hyperechoic clot) (see , Panels 1b and 1c). The patient continued oral anticoagulant treatment (Warfarin 5 mg/day with INR check every 2–3 days in the first two weeks) for 21 months after discharge until her abdominal US showed an almost complete re-canalization of the left portal branch. A prolonged follow-up (40 months) including clinical interview, abdominal ultrasound, blood and LFT resulted normal.


A 20-year-old Caucasian woman was admitted to Maggiore Hospital in Crema, Italy, in November 2011, for gastric pain and headache lasting three days. A US scan of the upper abdomen (Esaote myLab25, Esaote, Genova, Italy) showed portal thrombosis of the intra-hepatic right and left branches, splenomegaly and free fluid in the perihepatic area and in the Douglas pouch. Chest X-Ray was negative. Biochemical examination revealed abnormal liver function tests: (AST 162 IU/ml, ALT 243 IU/mL, GGT 167 IU/mL, ALP 402 IU/L) and increased inflammatory indices (Lactate dehydrogenase 747 U/L, C-reactive Protein 1.5 mg/L); ESR was normal at 23 mm/h.
The patient received anticoagulant therapy (continuous infusion of unfractionated heparin, 18 UI/Kg/h). An abdominal CT confirmed portal thrombosis involving the left and the right intra-hepatic branches and the superior and inferior mesenteric veins. A 3 cm long thrombus was identified at the beginning of the splenic vein, which was still patent. The patient was transferred to the Intensive Care (ICU) of San Matteo Hospital, Pavia, Unit where blood tests confirmed abnormal liver enzymes with normal white blood cells (WBC: 4100/mm3, 63% of lymphocytes). At ICU admission, a new CT scan confirmed the thrombosis (see , Panel 1d) and showed also pericardial and bilateral pleural effusions.
Thrombophilic conditions were ruled out by specific tests (See ). The patient did not smoke and was not on hormones.
Lymphocyte immunophenotyping was consistent with acute viral illness (CD4/CD8 0.5, CD4: 31.1%, CD8: 57.8%). Serology revealed acute HCMV infection: IgM anti CMV (ELISA): 11.8 (negative < 0.9, positive > 1.1), IgG avidity test (ELISA): 18%, (low < 35, high >50). HCMV DNA (real-time PCR) was positive 100 copies/ml (cut-off ≥100 copies). Serology for HIV, HCV, HBV, S.typhi, Yersinia spp, Hantavirus, Listeria spp, Leptospira spp, Borrelia spp and HSV-8 were negative. Neoplastic markers (CEA, Ca 19.9 and Ca15.3, AFP) were all negative.
She was treated with anticoagulants (unfractionated heparin followed by enoxaparin 100 UI/Kg), with progressive regression of the thrombosis and disappearance of the fluid collections. A US scan one month after discharge showed further regression of PVT.


A 72-year-old male presented to the Ojiya General Hospital (Ojiya, Japan) with right knee pain of 3 months in duration, with no history of previous trauma. This patient had a history of colon cancer that had been resected 2 years prior to presentation. There was no recurrence or metastasis. Initial workup roentgenograms, which were performed at the Nagaoka Red Cross Hospital (Nagaoka, Japan) showed a ground glass appearance and a well-defined lucency with sclerotic margins in the right femur and tibia. Although these features are consistent with polyostotic FD, an ill-defined osteolytic lesion, 4×3 cm in size, was superimposed on the changes of FD in the inferior part of the femur (). Magnetic resonance imaging (MRI) showed the extraosseous extent of the tumor from the lesion in the distal part of the femur (). The lesion was intensively enhanced by injection of gadopentetate dimeglumine (), which is suggestive of malignant transformation of FD. The patient did not show cutaneous pigmentation, endocrine disturbances, or soft tissue lesions, as can be seen in McCune-Albright and Mazabraud’s syndromes. No other members of the family had a history of bone tumor. Blood chemistry data showed that the alkaline phosphatase and C-reactive protein levels were elevated to 960 IU/l (normal level, 120–325 IU/l) and 7.39 mg/dl (normal level, <0.3 mg/dl), respectively. Other values, including those of serum calcium (9.4 mg/dl; normal level, 8.7–11.0 mg/dl), phosphorus (4.2 mg/dl; normal level, 2.6–4.4mg/dl), aspartate aminotransferase (24 U/l; normal level, 12–34 U/l), alanine aminotransferase (12 U/l; normal level, 7–36 U/l) and total bilirubin (0.7 mg/dl; normal level, 0.2–1.2 mg/dl), were within acceptable limits. Open biopsy revealed an osteosarcoma with an adjacent area of FD. The patient was referred to the Niigata Cancer Center Hospital (Niigata, Japan) for further treatment of this lesion. Since a pathological fracture through the lesion of the distal femur (see ) had become evident after admission to our hospital, the patient underwent thigh amputation.
Gross specimen analysis showed that in the distal femur, the tumor had destroyed part of the cortex and had extended to the surrounding soft tissue. Microscopic examination of this area showed highly pleomorphic, spindle-shaped tumor cells, producing various forms of osteoid (). The tumor was densely cellular with a high mitotic rate, including atypical figures. The histological features of this area confirmed the diagnosis of osteosarcoma. The adjacent intramedullary part of the tumor in the femur and the tibia showed a solid yellow-white appearance. Microscopic examination of these lesions showed features consistent with FD; small trabeculae of woven bone of various sizes and shapes, scattered within a fibrous tissue without evidence of osteoblastic activity (). Thus, the case was diagnosed as secondary osteosarcoma arising in pre-existing FD.
Chromosomal analysis by G-banded karyotyping showed 44,X,-Y, add()(p11), add()(p15), der()add()(p15)t(1;11)(q21;q23),add()(q11), -13, der(22)t(12;22)(q11;p12) in nine out of 10 metaphases from the osteosarcoma lesion. RT-PCR analysis for Gsα mutations, which was performed as previously described (), demonstrated the presence of a Gsα mutation at the Arg 201 codon in both the primary tumor cells and secondary osteosarcoma cells ().
In terms of systemic treatment, adjuvant chemotherapy was not administrated to the patient due to advanced age. At 4 years of clinical follow-up, the patient was well without local recurrence or metastatic disease.


A 23-year-old lady reported to the Department of Oral Medicine & Radiology, Sri Ramachandra University and Research Institute, with a complaint of swelling in the right side of the face for the past 6 months. She had incidentally noticed the swelling which remained of the same size for 3 months, after which it became more bulging. Over the last 3 months she experienced intermittent pricking type of pain. Medical history was unremarkable. Clinical examination revealed a diffuse swelling in the right mandibular body region measuring about 2 × 2 cm in dimension, which was warm, tender, and soft in consistency. The swelling was mobile in the horizontal direction and showed restricted mobility in the vertical plane. Overlying skin was pinchable (). On clenching the swelling became more prominent. Intraoral examination revealed no abnormality. A clinical diagnosis of buccal node lymphadenitis and a differential diagnosis of soft tissue abscess, masseteric hypertrophy, accessory parotid tumor, and lymphovascular tumor were considered and the necessary diagnostic workup was done.
Routine hematological investigations were within normal limits. Posteroanterior view of mandible showed no pathology; ultrasonography showed a 2.2 × 0.6 cm mixed echoic lesion within the right side masseter muscle with a speck of calcification (). Left masseter appeared normal. Colour Doppler ultrasound showed dilated vascular channels with good flow (Figures and ). There were no interarterial/venous communications. MRI showed a small well defined T2 mixed hypo and hyperintense mass signal, space occupying lesion (SOL), along the anteroinferior aspect of the right masseter, measuring 2.1 × 2.5 × 1.8 cm in dimension in the axial view () and fat suppressed T2 coronal view ().
Under general anesthesia, preauricular skin incision was made, dissecting lateral to the parotid gland, and skin flaps were raised. Within the masseter a small bulging mass, measuring about 2 × 2.5 cm in dimension, was evident. The branches of the facial nerve were preserved. The external carotid artery was looped and proximal vascular control was achieved; small feeding vessels were individually ligated and blood loss during the procedure was minimal. The mass was completely removed with a margin of normal surrounding muscle to prevent recurrence. Primary closure was done. Postsurgically she was prescribed with antibiotics and analgesics for 5 days. There was mild postoperative facial edema, which subsided within twenty days with no evidence of pain and significant cosmetic problem. Histological examination revealed fibrofatty tissue and fragments of muscle with several thick walled and thin walled vessels with occasional nerves. There were also areas of hemorrhage and congestion, suggestive of a venous hemangioma (). After a 3-year followup patient was asymptomatic and ultrasonography revealed no evidence of lesion ().


A 54-year-old woman presented to her personal physician and complained the pain on her right breast. She underwent a breast surgery in our hospital. The patient and her family’s medical histories were unremarkable.
The patient was 157 cm tall and weighed 53 kg. Physical examination of the right breast (area C) revealed an elastic hard mass measuring 2.5 cm × 2.5 cm. Margins were distinct, with relatively good mobility and a tumor-nipple distance of 3.2 cm. No axillary or cervical lymph nodes were palpable. Hematological and biochemical blood test results were normal. The levels of tumor markers, such as carcinoembryonic antigen, carbohydrate antigen 15-3, and National Cancer Center-Stomach-439, were within normal limits.
Mammography revealed an indistinct margined hyper dense mass in the right outer portion, which was assessed as Breast Imaging-Reporting and Data System category 4C (: MLO view, : CC view). Breast ultrasonography (US) revealed complex cystic lesion, and the tumor was large with 2.5 cm diameter (). Complex cystic lesion on US with blood content on fine-needle aspiration (FNA) cytology revealed malignant cells. Preoperative magnetic resonance imaging (MRI) findings and a T2 weight image revealed an early enhancement image with no intraductal spread (). No distant metastases was identified on computed tomography or bone scan. The tumor stage was T2N0M0. Breast-conserving surgery and sentinel lymph node biopsy were performed.
The results exposed two sentinel lymph nodes and no malignant cell. The tumor measured 2.0 cm in diameter and contained a central cystic area (,). Histopathological examination showed low papillary growth in the cystic cavity surface, which was covered by adenocarcinomatous components associated with some squamous metaplasia. Most of the lesions comprising the cyst wall were a mixture of irregular bundles of spindle-shaped tumor cells and fibrous connective tissue proliferation. The tumor was diagnosed as spindle cell ().
Immunostaining of spindle-shaped tumor cells showed positive results for cytokeratin (AE1/AE3) and vimentin (,), partially positive results for s-100, and negative results for desmin and α-actin. The final histopathological diagnosis was spindle cell carcinoma. Histological grade from malignancy was grade III. Lymphatic invasion was negative, whereas blood vessel invasion was positive. Lymph node metastasis was negative, and p-stage I was diagnosed. Estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 (HER2), which showed negative results by biochemical tests, were called triple negative type in subtype classification. The postoperative course was uneventful. The patient received six courses of FEC-100 chemotherapy. Radiotherapy included simultaneous integrated boost enforced 60 Gy (2 Gy/day) to the residual breast tissue. After 24 months of postoperation, no recurrence has been detected.


A 72-year-old Japanese woman was referred to our institution for treatment of congestive heart failure with dyspnea on exertion. At 57 years of age she had experienced Stanford type A acute aortic dissection and underwent replacement of the ascending aorta under deep hypothermia and retrograde cerebral perfusion using a 30-mm vascular prosthesis without malperfusion. At 66 years of age she was diagnosed with severe aortic valve stenosis with a narrow aortic annulus and underwent aortic valve replacement with a mechanical valve (ATS Open Pivot® AP™ 18 mm; ATS Medical Inc., Minneapolis, MN, USA) accompanied by enlargement of the aortic annulus (Nicks procedure
[]). To enlarge the aortic annulus, a glutaraldehyde-fixed equine pericardial patch was used to form the aortic root from the ascending aortic vascular prosthesis to the non-coronary cusp of the aortic valve. The patient had received warfarin therapy for atrial fibrillation after aortic valve replacement. Six years after the aortic valve replacement with aortic annulus enlargement, she presented with congestive heart failure.
Chest x-ray showed cardiomegaly with pleural effusion and pulmonary congestion. Computed tomography (CT) revealed a huge mass consistent with pseudoaneurysm in front of the right atrium and aortic root (Figure
). Magnetic resonance angiography showed a pseudoaneurysm with blood flow from the aortic root near the sinotubular junction (Figure
). Echocardiography revealed a pseudoaneurysm with continuous flow from the aortic root, moderate tricuspid regurgitation, and moderate mitral regurgitation. Peak velocity in the aortic mechanical valve was 2.7 m/sec (peak pressure gradient: 27 mmHg), with normal ejection fraction and no left ventricular dilatation. No inflammatory or infectious response was noted.
These findings suggested that the patient’s congestive heart failure was caused by cardiac compression from the pseudoaneurysm.
Repeat median sternotomy risked cardiac injury or rupture of the pseudoaneurysm. Therefore, we attempted median sternotomy under cardiopulmonary bypass with moderate hypothermia. Additionally, an aortic occlusion balloon was inserted into the ascending aorta through the right femoral artery to prevent bleeding from the pseudoaneurysm. After systemic heparinization, cardiopulmonary bypass was established with an arterial cannula to the left femoral and right axillary arteries and a venous cannula to the right atrium through the left femoral vein. We then performed a repeat median sternotomy with the patient under moderate hypothermia of 28°C. Because of dense adhesions around the superior vena cava and ascending aorta caused by the pseudoaneurysm, lysis of adhesions and clamping of the ascending aorta were not possible. After circulatory arrest, we excised the pseudoaneurysm. We identified a longitudinal tear in the equine pericardial patch near the ascending aortic vascular prosthesis and an intact suture line (Figure
). The ascending aorta was balloon-occluded and circulation was quickly reestablished. Excision of the pseudoaneurysm with mural thrombus created a defect in the right atrial wall. We removed the equine pericardial patch around the tear and performed patch repair of the aortic root using a double-layered patch consisting of an inner bovine pericardial patch layer and an outer Hemashield patch layer (Hemashield Double Velour Fabric; MAQUET Holding B.V. & Co. KG, Rastatt, Germany) with a felt-reinforced suture line. We then performed tricuspid annuloplasty and repair of the right atrial wall using an equine pericardial patch.
After the patient was weaned uneventfully from cardiopulmonary bypass, transesophageal echocardiography showed an improvement in mitral valve regurgitation from moderate to mild. The patient was extubated 20 hours after surgery and discharged on postoperative day 20 with improving congestive heart failure. A year after the operation, no pseudoaneurysm-related change was detected.


A 30-year-old woman from Saudi-Arabia was admitted to our department of internal medicine with the strong suspicion of first manifestation of acute myeloid leukemia. Laboratory testing showed mild anemia and thrombocytopenia with normal leukocyte count. The differential blood cell count, however, showed 47% leukemic blasts. A bone marrow biopsy was performed immediately. With approximately 90% blasts the diagnosis of acute myeloid leukemia (AML) was confirmed. Flow cytometry showed an expression of CD34, HLA-DR, CD38 and cyMPO. A cross-lineage of CD56 was found, which correlates with a poor prognosis []. Cytogenetics and molecular analysis of the bone marrow cells revealed an ETV6-gen deletion in 12p13. According to the hematologic protocol intensive induction chemotherapy with HAM (high-dose Ara-C and Mitoxantron) was immediately initiated.
On day 8 after admission (2 days after the first cycle of chemotherapy was finished) the patient developed neutropenic fever up to a temperature of 39.4°C. The first laboratory testing showed a decrease in leukocytes down to 0.4 G/l with a C-reactive protein (CRP) less than 0.1 mg/dl. Escherichia coli with an extended-spectrum beta-lactamase (ESBL) was isolated from initially taken blood cultures, whereas all other clinical and diagnostic examinations (x-ray of the chest, urine, echocardiography and ultrasonography) were normal. Empirical broad-spectrum antibiotics was immediately initiated with Piperacillin/Tazobactam and switched to Meropenem after microbiologic testing confirmed ESBL sepsis. On that first day of fever, the patient told us, that she fell in the bathroom hurting her right knee two days before (day 6 after admission). There was no apparent injury on her leg. On further clinical examination, besides fever, her vital signs were always normal. In the course of the next 2 days neutrophils dropped below 0.1 G/l and CRP levels soared to a peak of 29.9 mg/dl. Highest procalcitonin level (PCT) measured was 1.7 ng/ml. Three days after the patient suffered from the minor injury to her lateral thigh, she suddenly presented a small hematoma with only little pain (day 9 after admission). There were no signs of superinfection of the hematoma explaining the clinical and laboratory signs of this unclear systemic infection. On that day, the patient was first presented to the surgical department. Within the next two days, the hematoma rapidly changed to a big untypical necrosis of the skin (day 11 after admission, see Figure ). Therefore, the patient was again presented to the surgical department. The patient was still in a good general condition with only little pain. A CT scan was initiated and showed entrapped air under the site of necrosis. Although the skin manifestation was not typical for a necrotizing soft tissue lesion, we considered the possibility of an untypical case of NF during severe neutropenia. Therefore, a surgical exploration was performed immediately (see Figure ). Macroscopically, subcutaneous tissue, fascia and muscle showed the typical characteristics of necrotizing fasciitis with grey necrotic tissue, facial edema, vessel thrombosis and non-contacting muscle. Intraoperative, there was only minimal resistance dissecting the subcutaneous fascia off the deep fascia, which is commonly described as positive “finger test” []. The histological findings showed facial necrosis, vasculitis, thrombosis and suppuration of the veins and arteries coursing through the fascia. But, there were no signs of disease-causing bacteria or infiltration of polymorphonuclear leukocytes in the deep dermis and fascia as expected. First microbiological testing did not find any bacteria. The initial histopathological report could not confirm the typical picture of necrotizing fasciitis (see Figure ). In the further course of time, intensive care medicine was needed. After confirmation of adequate morphologic blast clearance in the bone marrow supportive treatment with granulocyte colony stimulating factor (G-CSF) was added on day 18 (after start of chemotherapy). Neutrophils eventually recovered on day 23 (>500/μl). After beginning to recover, histopathological analyses of additional specimen of surgical resections showed the expected typical pathological findings like inflammatory cells and bacteria. Furthermore, microbiological testing confirmed ESBL infection. A multiplicity of operations with extended debridement was performed in order to eradicate the infection using negative pressure wound therapy. After successful eradication the skin defect involved the complete lateral thigh including nearly the whole circumference of the lower leg. In the further course of time, the immense skin defects had to be prepared for further reconstructive surgery. Reconstructive surgery with mesh graft harvest was complicated by the limited residual skin available on the lower extremity and the delay on wound healing of the harvest sites. Due to unfavorable cytogenetics and the complicated course of treatment our patient was assigned to undergo allogeneic stem cell transplantation in first remission. But, the transplantation was only possible with wounds totally closed. It took another six surgical interventions and nearly eight months to finally close all wounds (see Figure ). After further recovery the patient underwent allogeneic stem cell transplantation as planned. Today, she is doing well and there is no evidence of disease.


A 6-year-old male child reported in the Department of
Pedodontics, Dr ZA Dental college, AMU, Aligarh with
the chief complaint of loosening of teeth, bleeding and
swollen gums. The child had small stature (Fig. 1), cachetic,
and mildly lethargic. All sensory and motor responses are
with in normal limit.
Laboratory testing revealed total bilirubin of 0.5 mg/dl
(normal 0.2-1.3), alkaline phosphatase 1277 (normal 250),
SGOT 67 (normal 13), SGPT 46 (normal 14), a prothrombin
time of 13 seconds (normal 12.6-15.2) and serum albumin
level of 4.2 gm/dl (normal 3.5-4.8). Bone marrow iron was
nil, suggest for iron deficiency anemia. Because the child
appeared malnourished, a vitamin deficiency was suspected,
but serum folate, vitamin A, vitamin B12, and vitamin D
levels were within normal limits. The patient had a normal
serum glucose level, and urine osmolality was markedly low
at 4 mOsm/k (normal 300-900). Skin of scalp showed
seborrheic dermatitis. All vital signs of the patient were in
between normal limits. No abnormality in patient’s
respiratory and blood vascular system were observed.
Thyroid function test was normal; thyromegaly was seen
but no feature of hypothyroidism. Hepatomegaly with no
other organ dysfunction was too there.
Intraoral examination revealed poor oral hygiene, soft
and erythmatous gingiva, bleeding on probing, multiple
missing teeth, generalized tooth mobility and periodontal
pocket with halitosis. Submandibular lymphadenopathy was
present.
For radiographic examination panoramic view was
taken. This showed multiple radiolucent lesions in maxilla and mandible with generalize alveolar bone loss, providing
the radiographic image of ‘floating teeth’ (Fig. 2). Computed
tomography of head shows multiple sharply marginated
radiolucent lesions involving the calvaria, mainly parital
bone associated with small extra-axial soft tissue component
(Figs 3 to 8). Tomography of face revealed lytic lesion
involving alveolus of mandible associated with minimal soft
tissue component with tooth appearing to be floating inside
with lytic lesion involving alveolus of maxilla and mandible.
All these features were suggestive of a case of histiocytosis.
Skin biopsy of the patient showed Langerhans’ cell
histiocytosis with marked CD1a and S-100. Mandible biopsy
showed larged number of histiocytes (CD-68 and S-100
positive), which is too suggestive for Langerhans cell
histiocytosis. Electron microscopy showed the presence of
Birbeck granules (Figs 9A and B). Bone marrow biopsy
showed large number of histiocytes (CD-68 and S-100
positive) mixed with neutrophlic and lymphocytes. Overall
it was a clear case of Langerhans cell histiocytosis involving
both mandible and maxilla along with skull too.


A 6-month-old Tunisian girl presented with severe heart failure. Findings on physical examination were: weight, 6kg (−1, 3 standard deviation); length, 64cm (+0.2 standard deviation); heart rate, 120 beats/minute; and blood pressure, 100/60mmHg. There was no cardiac murmur. Electrocardiography (ECG) findings were left ventricular hypertrophy, abnormal Q waves in leads I, AVL, V5, and V6. In chest roentgen, her cardiothoracic index was 62%. Transthoracic echocardiography (TTE) showed a dilated and hypokinetic left ventricle with an ejection fraction (EF) of 35% and mild mitral regurgitation (Figure ). Her right coronary artery (RCA) was dilated. The origin of her left coronary artery (LCA) was not seen making anomalous origin of her LCA strongly suspect. No associated cardiac anomalies were noted. The baby underwent cineaortography which showed an enlarged RCA arising from her aorta (Ao) and a retrograde filling of her LCA through collaterals from her RCA (Figure ). ECG-gated CT-angiography, subsequently confirmed the diagnosis when revealing a RCA arising from her Ao with anomalous origin of her LCA emerging from her PA (Figures and ). Consequently, she underwent an uncomplicated aortic reimplantation of her left main coronary artery. No perioperative or postoperative complication occurred and she was discharged 10 days after surgery. She was on full dose of angiotensin-converting enzyme inhibitors and beta blockers.
She was still alive 6 months after surgery with a good functional status and normal growth. Echocardiographies performed during follow up found an improvement in systolic function with an EF of 45% with persisting mild mitral insufficiency.


The patient, a 72-year-old woman, had a clinical history of immune-mediated thrombocytopenia. During routine laboratory analysis, an unexpected increase of white blood count (WBC) was found and a CML was suspected. The laboratory data showed a WBC count of 39.2 × 103/mcL, with 60% of neutrophils, 21% of lymphocytes, 10% of monocytes, 2% of eosinophils, 2% of basophils, 4% of myelocytes, and 1% of metamyelocytes. Hemoglobin concentration of 13.5 g/dL was within the normal range, while the platelet count was low (101 × 103/mcL). Cytogenetic analysis on bone marrow and RT-PCR on peripheral blood were carried out. Conventional cytogenetic analysis was performed on unstimulated 24- and 48-hour bone marrow cultures. Cells were cultured and processed by standard methods [] and chromosomes were stained by QFQ-banding. The analysis was performed according to the Italian and European Acquired Cytogenetics and the ESMO (European Society of Medical Oncology) clinical practice guidelines [–]. FISH analysis using BCR/ABL1 t(9;22) Triple-Color and Dual-Fusion probe and Sub-Telomere 9qter probe (Kreatech Diagnostics Vlierweg 20, 1032 LG Amsterdam, The Netherlands) was done following the manufacturer procedures. Karyotype result was described according to the ISCN 2013 []. Reverse-transcription quantitative polymerase chain reaction (RT-PCR) for chimeric BCR-ABL1 transcript on peripheral blood was performed with Philadelphia p210 Q-PCR Alert kit (Nanogen Inc., San Diego, CA, USA), based on TaqMan technology. RNA extraction and RT-PCR were performed following the insert kit instructions (Nanogen Inc., San Diego, CA, USA). The measurement of the cDNA of P210 was normalized to the cDNA of ABL1 gene. Conventional cytogenetic analysis on bone marrow showed on 22 metaphases a reciprocal translocation involving the long arm of chromosomes 12 and 22, t(12;22), without the involvement of chromosome 9 (). The presence of a cryptic BCR/ABL1 fusion transcript was detected by RT-PCR and subsequently by interphase FISH analyses on bone marrow. Quantitative RT-PCR analysis for BCR/ABL1 on peripheral blood revealed the major chimeric transcript, with a BCR-ABL1(P210)/ABL1 ratio of 14.95% (International Scale). FISH analysis with BCR/ABL1 t(9;22) Triple-Color and Dual-Fusion probe was performed to characterize the t(12;22) translocation and to detect the localization of the fusion gene. The probe set is a mixture of ASS-ABL1 probe labeled in red and of BCR probe with the proximal BCR region labeled in blue and the distal one in green. FISH on 200 metaphases and nuclei showed the following: (i) one purple (blue/red) fusion signal representing the fusion gene (BCR/ABL1) on der(22), (ii) one green signal of 3′ BCR sequences on chromosome 12 involved in translocation t(12;22), (iii) a green/blue signal on normal chromosome 22, and (iv) a red signal on normal chromosome 9 (Figures and ). The reciprocal fusion ABL1/BCR signal was not detected. FISH analysis on 200 nuclei and metaphases using the subtelomeric 9qter probe was performed to further investigate the involvement of chromosome 9 in the complex rearrangement: it showed a normal signal pattern. In summary, FISH disclosed the deletion of the 5′ ABL1 sequences, including the ASS gene, on der(9), and allowed to map the breakpoint of t(12;22) within the sequences distal to BCR gene. The BCR probe gave a splitted signal on der(22) and on der(12), respectively. The ISCN karyotype was 46,XX,der(9)del(9)(q34q34)ins(22;9)(q11.2;q34q34),der(12)t(12;22)(q13;q11.2),der(22)ins(22;9)t(12;22)[22]. All these results were consistent with the CML diagnosis and the patient started the treatment with Imatinib mesylate (Glivec). After three months of therapy, the WBC count was 5.1 × 103/mcL, with 49.7% of neutrophils, 37.8% of lymphocytes, 7.6% of monocytes, 4.3% of eosinophils, 0.6% of basophils, the hemoglobin concentration was 12.4 g/dL, and platelets count was 211 × 103/mcL. The molecular cytogenetic followup by interphase FISH with BCR/ABL1 probe on 200 nuclei, after 4 and 6 months of therapy, showed a normal signal pattern, while the chromosome analysis at six months revealed a new abnormal clone detected in the 5% (2 out of 5 metaphases and 10 out of 200 interphase nuclei analyzed by FISH with chromosomes 8 and 9 centromeric probes) of the sample with trisomies 8 and 9 (48,XX,+8,+9).


A 9-year-old boy came to dental office in morning session, had slipped and fallen at a playground previous evening. His two front teeth were avulsed and stored in a polyethylene bag. The patient’s medical history was noncontributory. On examination, the patient did not show any signs or symptoms of neurological or extraoral injury. Intraoral examination revealed mixed dentition with missing permanent maxillary right central and lateral incisors (). He showed incisal overjet of 3.5 mm and end-to-end molar relationships. Oral hygiene was fair. No other oral injury was detected clinically. Adjacent teeth elicited positive response to vitality test. Examination of the avulsed tooth revealed that the crowns were intact and that the roots of incisors had wide apical foramina (). Preoperative radiograph revealed no other hard-tissue injury (). On examination of avulsed teeth necrotic dried remnants of periodontal tissue were present over the roots. The avulsed teeth had been kept dry for about 16 hours.
The available treatment options were explained to the parents and it was decided to replant the avulsed incisors. The roots of the avulsed teeth were scraped gently to remove the necrotic periodontal tissue and access cavities prepared through crowns of avulsed teeth. Thorough biomechanical preparation was done with hand K-files (Dentsply, Maillefer, Ballaigues, Switzerland) and 2.5% sodium hypochlorite solution and normal saline solution were used as root canal irrigants. Roots were dried with absorbent points and obturated with gutta-percha points (Dentsply, Maillefer, Ballaigues, Switzerland) and zinc oxide eugenol-based sealer. Root end cavities of around 3 mm were prepared and restored with intermediate restorative material (IRM, Dentsply). After initial setting of IRM, teeth were placed in tetracycline solution for around 20 minutes.
Following local anesthesia with 2% lidocaine containing 1:20,000 epinephrine (Xylocaine; AstraZeneca Pharma Ind Ltd, Bangaluru, India) sockets were explored gently for the presence of tooth or alveolar bone fragments. Fresh bleeding was established in the alveolar sockets, teeth were replanted and splinted to the adjacent teeth with acid etch resin and wire splint. A 7-day course of systemic penicillin and analgesic were prescribed; antitetanus booster was given to prevent any systemic complication. Another radiograph was obtained to confirm proper positioning of the replanted incisors (). Splint was removed after 14 days. The patient was seen again at 2 weeks, 6 weeks () and 12 weeks after replantation and then followed half-yearly. At the time of writing, the patient had been followed for 2 years ( and ). Esthetic correction of teeth was done with direct composite resin. Full coverage crowns with affected incisors and periodic pulp vitality testing with adjacent unaffected teeth was advised. The replanted incisors developed mild replacement root resorption. Nevertheless, they remained functional and were esthetically acceptable. The patient and his parent were informed about ankylosis or replacement resorption as the patient grew. Long-term treatment might need sacrifice of teeth and prosthodontic replacement.


A thirty-six year-old male presented to the emergency department with a one-month history of increasing left neck mass accompanied by pain, severe shortness of breath, and eight kilograms of unintentional weight loss. He had spent several months in Ethiopia prior to presenting to our centre, where the working diagnosis for his neck mass was lymphocytic thyroiditis, based on several FNA biopsies. As a result, propylthiouracil (PTU) and propranolol were prescribed. His past medical, family and social histories were all unremarkable for malignant risk factors. Upon presentation, he was found to be euthyroid (TSH = 0.42 mU/L, Free T3 = 4.3 pmol/L, and Free T4 = 22.7 pmol/L). His thyroid indices prior to starting PTU were unavailable and thus, we can only assume that he was in a hyperthyroid state prior to administration of PTU.
CT scans revealed a mass arising from the thyroid measuring 8 × 9 × 12 cm, which stretched from the hyoid bone to the level of the innominate vein. The neck mass was situated just left of midline within level VI. Along with invasion of the esophagus, left thyroid and arytenoid cartilages, the tumor completely effaced both the left internal carotid and internal jugular vessels (Figure ). The trachea was significantly displaced to the right with the narrowest luminal segment measuring 7 mm. In addition to the extensive lymph node involvement from level IA to the supraclavicular fossa, upper mediastinal lymphadenopathy with innumerable pulmonary metastases up to 2.1 cm was noted. Following the biopsy and in light of the imaging, the tumor was staged T4b, N1b, M1 [].
In order to secure this precarious airway, an awake intubation in the operating room was successfully carried out. This was followed by an open biopsy of the neck mass. Endoscopy was not pursued given the significant esophageal obstruction. After careful review by the multidisciplinary Head and Neck Oncology team, it was felt that based on the significant invasion of neighbouring structures, the tumor was surgically unresectable. Moreover, a tracheostomy was considered unreasonable given the impressive superimposition of the tumor on the trachea. Chemotherapy and radiotherapy were considered less desirable options since the patient was now requiring aggressive ventilator and hemodynamic supports.
Given the few alternatives, a family meeting was held and as per the patient and his family’s wishes, a trial of extubation was attempted. It was agreed upon that it would not be beneficial to the patient to reintubate, should the airway deteriorate post extubation. Despite his extubation to heliox and the use of epinephrine nebulizers, he became increasingly stridulous and hypoxic. As per his previous wishes, the patient was provided comfort measures and he passed shortly after.


In 2012, a 4-year old Caucasian girl, on holiday with her parents, was brought to University Hospital Rijeka emergency department with abdominal cramps, vomiting and bloody diarrhea that had started 24 hours before her admission. Gastroenterocolitis was initially suspected, but as the abdominal pain intensified, an explorative laparotomy was performed on the third day of disease to exclude perforated appendicitis, which the surgeon eventually did not confirm. On the first postoperative day she appeared confused, dyspnoic, hypotensive, pale, oliguric and her laboratory findings were: hemoglobin (Hb) 60 g/L, hematocrit (Hct) 19%, platelet count 43×10
9/L, white blood cell (WBC) count 17×10
9/L, urea 16.6 mmol/L, creatinine 308 μmol/L, creatine kinase 971 U/L, aspartate aminotransferase (AST) 317 U/L, alanine transaminase (ALT) 276 U/L, C-reactive protein (CRP) 175.2 mg/L, lactate dehydrogenase (LDH) 3856 U/L, albumins 19 g/L, complement component 3 (C3) 0.5 g/L, complement component 4 (C4) 0.08 g/L, degree of
in vivo hemolysis 50 mg/L, pH 7.265, pCO
2 3.64 kPa, pO
2 9.2 kPa, HCO
3 12 mmol/l, SBE -13.1 mmol/L. She was immediately admitted to intensive care where she was analgosedated with 6 mg of midazolam and 200 mcg of fentanyl, intubated with an uncuffed orotracheal tubus and invasive mechanical ventilation was started. During the first week of disease she received multiple transfusions of packed red blood cells, fresh frozen plasma and platelets as continuous adrenergic and diuretic support was established with 5–8 mcg/kg/min of dopamine and 50 mg/24 h of furosemide, respectively. After additional laboratory tests, typical HUS caused by reaction to
E. coli toxin was diagnosed. By the end of the first week of disease her medical condition had not improved and she became anuric, accompanied by combined metabolic and respiratory acidosis, pulmonary edema, bilateral pleural and pericardial effusions, ascites and persistent anemia and thrombocytopenia. Continuous veno-venous hemodiafiltration (CVVHDF) as well as plasmapheresis were indicated. Access was established via an intravascular catheter placed through the right internal jugular vein guided by ultrasound. CVVHDF was performed for 12 days. Characteristics of dialysis included a dialyzer membrane surface area of 0.8 m
2, solution containing bicarbonate (multiBic 2 mmol/L potassium solution for haemofiltration; Fresenius Medical Care Deutschland GmbH) and a blood flow rate of 3–6 ml/kg/min. The system was anticoagulated with 100 IU/kg of unfractionated heparin each day. An additional blood flow rate for ultrafiltration was 0.5–2 ml/kg/h. The renal replacement therapy was only stopped for 3 hours a day in order to carry out plasmapheresis which was also initiated on the 8th day of disease. This lasted for 10 days, for 2 hours each day and 40 ml/kg of fresh frozen plasma was used per day. During this period continuous analgosedation with 0.15 mg/kg/h midazolam and 0.075 mg/kg/h morphine, as well as invasive mechanical ventilation were maintained. Continuous adrenergic support was stopped after the 6th day of disease. After 12 days of renal placement therapy, diuresis started to improve while serum creatinine and urea started to decrease. Despite the polyuria during the initial phase of recovery of renal function, because of the still significant fluid retention, we established negative fluid balance by continuous infusion of furosemid. Renal function had completely recovered by the 25th day of disease (
). We have reason to believe that the blood levels of creatinine and urea at the time that the CVVHDF was started were falsely lower because of hemodilution caused by the body’s extreme retention of extracellular water.
During the course of plasmapheresis a marked recovery of the platelet count and hemoglobin level was noticed, as well as a significant decline of LDH levels and the degree of
in vivo hemolysis. After termination of plasmapheresis, an additional time was needed for restoration of platelets and normal erythrocytes to optimal levels because of their biological cell cycle. We were restrictive throughout in the transfusion of packed red cells, aiming for a target hemoglobin level of 70–80 g/L.
The most striking laboratory finding during the first two weeks of disease was extreme leukocytosis which persisted during the second week of disease; the highest WBC count was 94×10
9/L. As no other signs of systemic bacterial infection or invasive mycosis were noticed, we believe that leukocytosis was provoked by the systemic inflammatory response to toxemia. We observed the gradual decrease in the WBC count after the initiation of plasmapheresis and its subsequent normalization by the end of the third week of disease. This trend was correlated with the values of LDH plasma levels (
).
Bilateral pleural effusions needed evacuation by thoracocentesis on two occasions, on the 8th and 13th day of disease. A CT scan of the thorax performed on teh 15th day of disease revealed a massive left-sided hemothorax complicated by compressive and obstructive atelectasis of the left lung (
). The hemothorax had to be surgically drained on the 16th day of disease. During the second week of disease we confirmed acute respiratory distress syndrome (ARDS) according to PaO
2 to FiO
2 ratio and evidence of hepatization of the lungs on serial ultrasound scans. Because of the pulmonary manifestations of the disease, a protective ventilation strategy using was employed. We mostly used airway pressure release ventilation (APRV) and biphasic positive airway pressure (BIPAP) modes on a Dräger Evita XL mechanical ventilator and frequently applied lung recruitment with the positive end-expiratory pressure (PEEP) technique monitored by ultrasound. Respiratory function completely recovered by the end of the third week of disease without apparent permanent damage and the girl was successfully extubated on the 24th day of disease.
We ceased the analgosedation on the 12th day of disease in order to evaluate the neurological status of the girl. She appeared comatose, estimated as GCS 4 (E2V1M1) on the Glasgow Coma Scale with flaccid tetraparesis, rotatory nystagmus and symmetrical mydriatic pupils with slow response to light stimulation. An MRI scan of the brain recorded on the 12th day of disease revealed areas of raised signal in the pons, bilaterally in lateral parts of the thalamus (
), as well as in the right external capsule and the left internal capsule. These findings were analogous with lesions already described in literature believed to be the result of microvascular damage
. Analgosedation was reinstated and afterwards periodically discontinued every few days for approximately 6 hours in order to examine the girl’s clinical neurological status. After the 18th day her level of consciousness and neurological status started to gradually improve and we decided to definitively cease analgosedation 7 days later. No permanent neurological damage was recorded.
We were concerned by severe gastric retention, absent or silent peristalsis and constipation with episodical soft and rare stools during the second week of disease. An MRI of the abdomen performed on the 12th day of disease showed an edematous intestinal wall and distension of the jejunum, ileum and colon ascendens with several air fluid levels (
). Laboratory findings displayed elevated serum transaminases, total and direct bilirubin and amylase as well as hypoalbuminemia. After prodromal gastroenterocolitis, paralytic ileus obviously evolved and was persistent throughout the second and third week of disease. Therefore, all necessary fluid, macronutrients and micronutrients were completely delivered parenterally via a central venous catheter from the start of disease. In combination with already initiated parenteral nutrition, we carefully started enteral feeding by the end of the second week of disease. As no signs of intraabdominal compartment syndrome, perforation or peritonitis were registered, we wanted to reestablish gastrointestinal function conservatively. Therefore, we applied continuous infusion of 6–10 mg/24h of metoclopramid and intermittent rectal suppositories of 2.5–5 mg of bisacodyl for the next two weeks. We also progressively increased the contribution of the enteral input as soon as peristalsis started to improve. Bowel function slowly recovered by the beginning of the fourth week of disease.
As the patient and her family had been on holiday at the time of admission, an in-person follow up was not possible. However, the authors made contact with the family in 2013 and the parents reported that their daughter was perfectly healthy and without apparent consequences.


An 84-year-old man presented in the emergency room with urinary retention. Ultrasound revealed an enlarged prostate, suggestive for benign prostatic hyperplasia. The patient was treated with a Millin retropubic prostatectomy. Macroscopical examination showed prostatic tissue with firm to rubbery, white, circumscribed nodules.
Microscopic examination revealed a well-delineated nodular lesion with normal surrounding prostatic tissue (). The lesion consisted of loosely arranged, bland spindle cells in a myxoid to collagenous stroma (). Prominent vessels were present with marked hyalinization of the wall in some of them (). Mitotic figures were absent. Morphologically, these features were suggestive for CAF.
Immunohistochemical analysis revealed strong positivity for alfa-sma, desmin, caldesmon, CD34, and progesteron receptor (PR) (). CD31, ALK1, Myogenin, and estrogen receptor (ER) were negative.
Interphase dual-colour fluorescence in situ hybridization (FISH) was performed on 4 μm formalin-fixed, paraffin embedded tumour sections, by a cohybridization of Spectrum Orange-labelled RB1/13q14 probe (LSI RB1-SO; Vysis Inc., Downers Grove, IL, USA) and a reference Spectrum Green-labelled chromosome X centromere probe (CEPX-SG, Vysis Inc.), as previously described []. The number of differentially labeled hybridization signals representing investigated gene and reference centromere X chromosomal regions were individually recorded for 100 nonoverlapped interphase nuclei, using a Zeiss microscope (Axioplan 2, Jena, Germany) equipped with the appropriate filters and CYTOVISION software. A cut-off of 30% was established for a positive result.
By FISH, 48% of nuclei demonstrated the monoallelic RB1/13q14 loci loss (), as indicated by the presence of only one red signal in reference to chromosome X probe (green signal).


A 50-year-old male was treated with ipilimumab (3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of 4 administrations) for stage four disease 5 years after his primary diagnosis, resulting in disease stabilization. Two years later, reinduction of ipilimumab (3 mg/kg administered intravenously over 90 min every 3 weeks for a total of four administrations) was offered because of progression. A year later a new solitary right MBM () was treated with SRS (1 fraction of 20 Gray (Gy)) with response over 6 months (). Treatment with the BRAF inhibitor dabrafenib was initiated at a dose of 150 mg twice daily for progression with extracranial disease that had a positive BRAF mutation.
Ten months later the brain lesion progressed (), accompanied by increasing headache and confusion without any other disease progression. RNB was suspected and treatment with methylprednisolone (32 mg, bid) and valproic acid (500 mg, bid) was initiated. Symptoms and perilesional oedema persisted at two months after the initiation of corticotherapy (). A neurosurgical resection confirmed the diagnosis of RNB (Figures and –). Eighteen months later the patient remains in complete remission on dabrafenib treatment.


A 29-year-old man with stage four BRAF V600E positive disease had a solitary MBM in the left frontal lobe () treated with surgery. Four months later, two new left frontal brain metastases had WBRT (30 Gy, 10 fractions) with a SRT boost (45 Gy in 10 fractions) ( shows the first lesion at that time). Two months later ipilimumab was initiated (3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of four administrations). Four months later, a recurrent left frontal and new parietal lobe brain metastasis were treated with SRS (18 Gy in one fraction) (). Seven months later he developed headaches. Histology of the left frontal lobe metastases showed RNB (). At last follow-up six months later he then had progression.


A 62-year-old man with unknown primary wild type BRAF metastatic melanoma had symptoms with three MBMs in the left temporal lobe, precentral gyrus, and frontal lobe treated with SRT (40 Gy in 8 fractions) [, ]. Three months later progressive extracranial disease was treated with ipilimumab (3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of four administrations). Six months later he presented with seizures and dysarthria, which were caused by an increase in the temporal lesion. Neurosurgical histology showed RNB. One month later he developed a right hemiparesis due to an increase in size of the lesion localized in the left precentral gyrus. Histology showed RNB. Six months later, sixteen months after the initial SRT, he re-presented with a worsening right hemiparesis due to a recurrence of the left precentral gyrus lesion. Histology revealed RNB. The patient died postoperatively from pulmonary embolus.


Two years after a BRAF wild type primary diagnosis, a 72-year-old man had a lung and three brain metastases in right frontoparietal, left parietal lobe, and left cerebellar hemisphere locations treated with WBRT (30 Gy in 10 fractions) with simultaneous integrated boost (45 Gy in 10 fractions) in a RCT. Three months later, ipilimumab was initiated (3 mg/kg or 10 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of four administrations) to treat progressing extracranial disease. Fourteen months after RT he developed a headache and gait disturbance, with MRI showing enlargement of the right frontoparietal lesion. Neurosurgical resection showed RNB ().


A 67-year-old Caucasian woman with typical symptoms of angina pectoris was referred to the cardiological department of our hospital for further diagnostic evaluation. She noted progressive episodes of gnawing chest pain during the last weeks.At admission, the electrocardiogram (ECG) showed sinus rhythm with ST-decreases in I and AVF. Laboratory examination revealed a troponin I level of 2.3 ng/ml (normal range <0.5 ng/ml). A chest radiograph showed a normal heart configuration without pulmonary congestion, infiltration, effusion or pneumothorax. Transthoracic (TTE) and transesophageal echocardiography (TEE) demonstrated a normal left ventricular ejection fraction and no pericardial effusions. The heart valves appeared unremarkable. However, a slight tricuspid valve regurgitation with a small mobile nodular tumor mass at the anterior leaflet was seen (Figure , Panels A and B). Subsequent invasive coronary angiography revealed significant stenosis of all three main coronary arteries (left main, left circumflex and right coronary artery).The patient was taken to the operating theatre, where a median sternotomy was performed and cardiopulmonary bypass was installed via aorto-bicaval cannulation with normothermia. After opening of the right atrium, a soft friable gelatinous tumor was successfully excised (Figure , Panel C). Afterwards, the left internal mammary artery was anastomosed to the left anterior descending (LAD), and two single saphenous vein graphs were anastomosed to the ramus circumflex (RCX) and the right coronary artery (RCA). Patient’s recovery was uneventful. Histological examination of the resected tissue revealed a papillary fibroelastoma with complex branching papillary fronds and characteristic three-layered pattern of papillary fibroelastoma (Figure , Panel D).


A 64-year old Japanese woman who presented with edema around her fingers and forearm followed by rapid development of skin sclerosis was diagnosed with systemic sclerosis. She was anti-topoisomerase I (Scl-70) antibody positive and had 35mmHg of estimated right ventricular pressure, as shown by echocardiography in 2006. She was prescribed prednisolone at 7.5mg/day. She was negative for both hepatitis B surface antigen (HBs Ag) and hepatitis C virus antibody (HCV Ab). In 2007, dyspnea at exertion and severe Raynaud’s phenomenon were confirmed. The findings of a chest computed tomography scan showed bilateral pulmonary fibrotic lesion and an elevated KL-6 level of 4360U/mL; she was diagnosed with pulmonary fibrosis. In addition, echocardiography results showed an elevation of her estimated right ventricular pressure to 50mmHg; she was therefore clinically diagnosed with pulmonary arterial hypertension (World Health Organization, WHO, functional class III) associated with connective tissue disease-derived pulmonary fibrosis.After bosentan treatment was initiated in May 2008 at 125mg/day, dyspnea at exertion improved and her 6-minute walking distance was increased by 40m from 332m; however, the results of blood tests indicated liver function abnormalities: increased levels of alanine aminotransferase (ALT; 4.5 times the normal upper limit), alkaline phosphatase (ALP; 3.2 times the normal upper limit), and gamma-glutamyltransferase (GGT; 6.4 times the normal upper limit; Figure ). No other additional drugs were administered during the 2 months before and after the bosentan administration. An ultrasound examination of her liver revealed no morphologic abnormality. The abnormal levels revealed in the liver function tests were normalized soon after the discontinuation of bosentan; however, dyspnea at exertion gradually deteriorated, and therefore bosentan 62.5mg/day and ursodeoxycholic acid 300mg/day were started simultaneously from February 2009. The results of her liver function tests did not show any abnormalities even after 2 years of the combination therapy, and the dose of both ursodeoxycholic acid and bosentan were increased to 600mg/day and 125mg/day, respectively from March 2011. No abnormal levels were found in the results of her liver function tests during 31 months of follow-up after the dose elevation of bosentan. Bosentan improved her estimated right ventricular pressure to 35mmHg, subjective symptoms from WHO functional class III to II, and Raynaud’s phenomenon after bosentan retreatment, and she is currently receiving bosentan as an out-patient.


A 69-year-old Japanese woman who presented severe Raynaud’s phenomenon, hardening of the skin on her fingers and joint pain was diagnosed with systemic sclerosis. She was anti-centromere antibody and anti-mitochondria antibody positive. Echocardiography results showed 30mmHg of estimated right ventricular pressure in 2008. Betamethasone 0.25mg/day was introduced to control her joint pain. Raynaud’s phenomenon and dyspnea at exertion started to deteriorate from April 2011. Imaging findings did not show any abnormality in her lung field but echocardiography indicated an elevation of her estimated right ventricular pressure to 45mmHg, and we thus clinically diagnosed pulmonary arterial hypertension associated with connective tissue disease (WHO functional class III).Bosentan 125mg/day was started from July 2011, and this resulted in the improvement of breathlessness at exertion; however, after 3 weeks the results of her liver function tests revealed abnormal levels: elevation of ALT (1.9 times the normal upper limit), ALP (2.5 times the normal upper limit), and GGT (3.9 times the normal upper limit; Figure ). No additional drugs were administered during the 2 months before the bosentan administration, and an ultrasound examination of her liver showed no morphologic abnormality at this time point. She was negative for both HBs Ag and HCV Ab. Bosentan was reduced to 62.5mg/day and ursodeoxycholic acid was introduced simultaneously at 300mg/day. Her liver function abnormalities normalized soon after the initiation of the combination therapy. Ursodeoxycholic acid was increased to 600mg/day and bosentan was increased to the initial dose of 125mg/day from October 2011. No abnormalities in her liver function were seen during 24 months of follow-up. Bosentan improved her estimated right ventricular pressure to 30mmHg and her subjective symptoms from WHO functional class III to II after the introduction of bosentan.


The proband is a boy and he is the only child born from a 36 year old father and a 27 year old mother. The parents were healthy and unrelated; paternal family history was negative for genetic diseases, while in the maternal family, eight members were affected by retinitis pigmentosa with an autosomal dominant pattern of transmission. Prenatal ultrasonographic evaluation gave normal results in fetal growth and morphology. No prenatal invasive genetic test was performed.
The child was born by natural delivery after a 40 week gestation plus 5 days. Birth weight was 3420 g (25°- 50° centile for gestational age), length at birth was 52 cm, (between 50°- 75° centile), occipito-frontal circumference (OCF) was 35.5 cm (50°- 75° centile), APGAR score was 9/10. In neonatal period, the child presented hyperpyrexia (blood, urine and cerebrospinal fluid microbiological analyses were all negative) and greater than 10% weight loss, which regressed with adequate nutrition. Episodes of bronchospasm and tirage, repeated episodes of cyanosis and desaturation resolved spontaneously shortly before discharge (at one month of age). During childhood his height growth was at the lower limit. He did not show any major malformation, besides submucous cleft palate. Brain MRI scan did not show any structural anomalies.
He had mild myopia and his hearing was normal. He did not show any significant medical complications.
At the age of 12 years and 1 month his weight was 41.6 kg (25°-50° percentile), his height was 134.2 cm (<3° percentile) and his OFC was 53 cm (50° percentile). His Body Mass Index (BMI) was 23 (75°-90° percentile). Facial dysmorphic features included long face, high nasal bridge, short and smooth philtrum, micrognathia. He had small hands and nasal speech.
Endocrinological analysis (IGF-1 dosage and growth hormone stimulation test with arginine) showed results consistent with isolated growth hormone (GH) deficiency. A further brain MRI scan, carried out when he was twelve, revealed a small pituitary gland. GH treatment has been advised and the patient has just started this therapy.
Written informed consent was obtained from the parents for publication of this case report and any accompanying images.
At birth, karyotype on peripheral blood lymphocytes was requested because of mild hypotonia and minor dysmorphic features.
Conventional cytogenetic analysis revealed an interstitial deletion on chromosome 11 from bands 11q13.5 to 11q21 (Figure A). The parents’ karyotypes were both normal and the analysis was extended to 100 metaphases to rule out 11q deletion mosaicism. At the age of twelve, a comparative genomic hybridization array (Array-CGH) was performed using a CGH + SNP 4 × 180 K microarray kit (Agilent Technologies). The microarray contained 110,172 probes with a median probe spacing of 25.3 Kb (5 KB in International Standards for Cytogenomic Arrays Consortium, ISCA) and 59,647 SNP (UCSC hg19, ). Array-CGH was performed according to the manufacturer’s instructions (Agilent Technologies) and allowed the identification of a more distal deletion of 17,2 Mb in size: from 11q14.3 to 11q22.3 (from nt 92,434,272 to nt 109,584,301)(555 probes with median Log2ratio value of −1.04). In the same region, 337 SNP probes showed a single allele (Figure B,C). No additional pathogenetic Copy Number Variations (CNVs) were detected. The molecular karyotype, defined following the International System of Chromosome Nomenclature 2013, was: arr 11q14.3q22.3(92,434,272-109,584,301)x1.
At 1 month of age, the proband’s neurological examination showed no major dysfunctions; clinical observation according to Prechtl´s Method on the Qualitative Assessment of General Movements [] showed a pattern characterized by Poor Repertoire. His motor milestones were not significantly delayed: control of the head at 4 months, sitting without support at 8 months, hands and knees crawling at 11 months, standing with assistance at 13 months, walking alone at 24 months.
Parents reported vocalization, babbling and the first word “mamma” being uttered at one year of age. “Mamma” remained the only word used to name everything word until 19 months of age. After a period of hospitalization following an accidental fall which caused clavicle fracture and a second spell in hospital due to gastroenteritis, the child presented an arrest in speech and psychomotor competencies. These aspects were inscribed in a global regression of communicational and relational capacities.
Speech development between 20 and 36 months was characterized by: aphonia, amimia, pseudo- articulatory movements, reduced opening of the labial rima. Moreover, the child showed a poor communicative intent even at a non verbal level.
At 3 years he was a clumsy, passive and withdrawn child, not interested in playing. Therefore, at 3 years of age a psychomotor treatment with attention to relational aspects was introduced twice a week.
During the first year of rehabilitation, the proband reduced his more passive traits becoming more and more purposeful, actively responsive and assertive. Communicative intention emerged together with the increasing awareness of his speech difficulties.
There was a large discrepancy between the verbal comprehension (discrete) and expressive skills: he used gestures associated with vocalization to indicate, to formulate questions, to express disappointment or excitement. Then, speech therapy sessions began twice a week at the age of 4.
The proband showed a deficit of phonetic and non-phonetic phonation. Later, rhinolalia and rhinophonia, and a deficit in coordination and in phonological memory were observed. Consequently, a double diagnosis of specific expressive language disorder and of childhood apraxia of speech was formulated.
At 5 years, after one year of speech therapy, he achieved a quite complete phonetic repertoire, vocabulary increase with risk threshold for semantic errors, and emerging narrative skills. While he showed an adequate lexical comprehension, morphosyntactic comprehension was delayed of one year and communication was supported by mimics and gestures. At the same time, he developed social skills, showing more relational and playing capacities with peers and adults.
At age 6, verbal speech was sufficiently intelligible despite the persistence of hypotonic and uncoordinated glosso-velo-pharyngeal muscles.
His cognitive development, as measured by WIPPSI Scale, was in the lower limits of the normal range, with a discrepancy between verbal (VIQ) and performance (PIQ) scores (VIQ =85; PIQ =96; Full Scale IQ = 89) [].
At the age of 8, the proband presented an impairment in the ability of naming objects and in lexical retrieval with the help of phonemic cues. On using the Italian version of the Peabody Picture Vocabulary Test [], comprehension was almost adequate (Language quotient = 82).
Morphosyntactic comprehension using the Rustioni Metz test [] showed a delay of about 2 years. The verbal short term memory span was 3 (inadequate).
Moreover, learning difficulties in the presence of a cognitive development at the lower limit of the normal range emerged. In particular, reading comprehension, measured using the MT battery of tests [], was inadequate (correct answers: 6/10), in the absence of dyslexia and dysorthography, as measured with the Dyslexia and Orthographic coding test []. Therefore, the logopedic rehabilitation continued until the child was 9 years old, with the aim to improve oral and written language comprehension. In the meantime, his writing and reading abilities supported him in planning the phonological string in speech.
Afterwards, counselling to parents and teachers, together with neuropsychiatric follow up continued until today with longitudinal controls (twelve years). We considered highly important to support parents and teachers in finding a harmonious global development which could take into account not only the educational aspects, but also the emotional and relational sides.
We were able to observe a global improvement in cognitive abilities (as illustrated in Figure D, where WISC III at 9 and 11 years of age are compared) [].
Currently the child shows good skills at school in the application of the learned mechanisms, but he has more difficulties when logic skills and problem solving abilities are required. However, he is able to evaluate his work and adopt compensatory strategies in order to overcome his difficulties. He is competitive with his schoolmates, comparing their tests results and scores. He shows a good personal and social independence and participates in curricular and extracurricular activities with peers.