Exploring the diagnostic utility of genome sequencing for fetal congenital heart defects.

OBJECTIVE: The diagnostic yield for congenital heart defects (CHD) with routine genetic testing is around 10%-20% when considering pathogenic CNVs or aneuploidies as positive findings. This is a pilot study to investigate the utility of genome sequencing (GS) for prenatal diagnosis of CHD. METHODS: Genome sequencing (GS, 30X) was performed on 13 trios with CHD for which karyotyping and/or chromosomal microarray results were non-diagnostic. RESULTS: Trio GS provided a diagnosis for 4/13 (30.8%) fetuses with complex CHDs and other structural anomalies. Findings included pathogenic or likely pathogenic variants in DNAH5, COL4A1, PTPN11, and KRAS. Of the nine cases without a genetic etiology by GS, we had outcome follow-up data on eight. For five of them (60%), the parents chose to keep the pregnancy. A balanced translocation [46,XX,t(14; 22)(q32.33; q13.31)mat] was detected in a trio with biallelic DNAH5 mutations, which together explained the recurrent fetal situs inversus and dextrocardia that was presumably due to de novo Phelan-McDermid syndrome. A secondary finding of a BRCA2 variant and carrier status of HBB, USH2A, HBA1/HBA2 were detected in the cohort. CONCLUSIONS: GS expands the diagnostic scope of mutation types over conventional testing, revealing the genetic etiology for fetal heart anomalies. Patients without a known genetic abnormality indicated by GS likely opted to keep pregnancy especially if the heart defect could be surgically repaired. We provide evidence to support the application of GS for fetuses with CHD.

Patterns of middle-ear cholesteatoma and implications for surgical approach.

OBJECTIVES: Understanding the pattern of middle-ear cholesteatoma becomes pertinent with the rise of endoscopic surgery as surgeons decide on the optimal approach to visualise and extirpate disease. With modifications to the Telmesani attic-tympanum-mastoid staging system, this study aimed to evaluate the commonest patterns of middle-ear cholesteatoma and their implications for surgical approach. METHODS: A retrospective study was conducted in a single tertiary institution in Singapore. All patients undergoing cholesteatoma surgery between January 2012 and June 2015 were included. Staging of cholesteatoma was based on clinical assessment corroborated by radiological findings. RESULTS: Out of the 55 ears included, 98.2 per cent had cholesteatoma involving the attic. The disease extended into the mastoid antrum and beyond in 43 cases (78.2 per cent). The facial recess and/or sinus tympanum was affected in 26 cases (47.3 per cent). CONCLUSION: The majority of cholesteatoma cases present with extensive attic disease and significant mastoid involvement. In these cases, endoscopes may be best suited to adjunctive rather than exclusive use in surgery.

MR Imaging Criteria for the Detection of Nasopharyngeal Carcinoma: Discrimination of Early-Stage Primary Tumors from Benign Hyperplasia.

BACKGROUND AND PURPOSE: MR imaging can detect nasopharyngeal carcinoma that is hidden from endoscopic view, but for accurate detection carcinoma confined within the nasopharynx (stage T1) must be distinguished from benign hyperplasia of the nasopharynx. This study aimed to document the MR imaging features of stage T1 nasopharyngeal carcinoma and to attempt to identify features distinguishing it from benign hyperplasia. MATERIALS AND METHODS: MR images of 189 patients with nasopharyngeal carcinoma confined to the nasopharynx and those of 144 patients with benign hyperplasia were reviewed and compared in this retrospective study. The center, volume, size asymmetry (maximum percentage difference in area between the right and left nasopharyngeal halves), signal intensity asymmetry, deep mucosal white line (greater contrast enhancement along the deep tumor margin), and absence/distortion of the adenoidal septa were evaluated. Differences were assessed with logistic regression and the χ2 test. RESULTS: The nasopharyngeal carcinoma center was lateral, central, or diffuse in 134/189 (70.9%), 25/189 (13.2%), and 30/189 (15.9%) cases, respectively. Nasopharyngeal carcinomas involving the walls showed that a deep mucosal white line was present in 180/183 (98.4%), with a focal loss of this line in 153/180 (85%) cases. Adenoidal septa were absent or distorted in 111/111 (100%) nasopharyngeal carcinomas involving the adenoid. Compared with benign hyperplasia, nasopharyngeal carcinoma had a significantly greater volume, size asymmetry, signal asymmetry, focal loss of the deep mucosal white line, and absence/distortion of the adenoidal septa (P < .001). Although size asymmetry was the most accurate criterion (89.5%) for nasopharyngeal carcinoma detection, use of this parameter alone would have missed 11.9% of early-stage T1 nasopharyngeal carcinomas. CONCLUSIONS: MR imaging features can help distinguish stage T1 nasopharyngeal carcinoma from benign hyperplasia in most cases.

Skull base osteomyelitis secondary to malignant otitis externa mimicking advanced nasopharyngeal cancer: MR imaging features at initial presentation.

PURPOSE: Skull base osteomyelitis (SBOM) is an inflammatory process which often arises from malignant otitis externa (MOE); the diffuse skull base and adjacent soft tissue involvement may be mistaken at initial imaging for advanced nasopharyngeal carcinoma (NPC), especially if there is no prior knowledge of MOE, direct spread from the sphenoid sinus or in atypical presentations of MOE. This study aims to evaluate imaging features on MR that may differentiate SBOM from NPC. MATERIALS AND METHODS: The MR examinations of 26 patients diagnosed with SBOM between January 1996 and January 2013 were retrospectively reviewed. Comparison was also made with the MR images of 22 consecutive patients with newly diagnosed advanced T3 and T4 NPC between July 2011 and August 2012. Imaging features in both conditions were compared, including the presence of a nasopharyngeal bulge, nasopharyngeal mucosal irregularity, lateral extension, architectural distortion (or lack thereof), increased T2 signal and enhancement patterns. RESULTS: The most prevalent findings in SBOM were lateral extension, increased T2 signal in adjacent soft tissues, lack of architectural distortion and enhancement greater than or equal to mucosa. The combination of these 4 findings was found to best differentiate SBOM from advanced NPC, and found to be statistically significant (p<0.001). CONCLUSION: We suggest that the combination of lateral extension, increased T2 signal, lack of architectural distortion and enhancement greater than or equal to mucosa is helpful in differentiating SBOM from advanced NPC.

Sinonasal angioleiomyoma.

BACKGROUND: Angioleiomyoma of the nasal cavity is an extremely rare benign neoplasm. It usually occurs in the lower extremities. Up to date, only few cases of angioleiomyoma have been reported. First case of angioleiomyoma of nasal cavity was reported in 1966. We report a rare case of angioleiomyoma arising from the right maxillary sinus. CASE REPORT: A 43-year-old lady presented with recurrent epistaxis and right nasal obstruction for two months duration. Clinical examination revealed a huge right nasal mass obstructing the right nasal cavity. The tumour was excised completely via endoscopic endonasal surgical approach. Histopathological examination confirmed the tumour is sinonasal angioleiomyoma. Postoperatively, she recovered well without any recurrence after a year of followup. CONCLUSION: This tumour has an excellent prognosis and recurrence is extremely rare if excised completely.

Do we need transbronchial lung biopsy if we have bronchoalveolar lavage Xpert® MTB/RIF?

BACKGROUND: Studies evaluating the role of transbronchial lung biopsy (TBLB) in diagnosing pulmonary tuberculosis (PTB) date back decades and have shaped current practice. However, with the recent advent of bronchoalveolar lavage (BAL) Xpert® MTB/RIF, it is time to re-evaluate the role of TBLB. OBJECTIVE: To assess the impact of BAL and TBLB with the addition of BAL Xpert on diagnostic PTB yields and time to treatment initiation in sputum-scarce or acid-fast bacilli (AFB) smear-negative PTB patients. METHODS: We retrospectively reviewed all sputum-scarce or AFB smear-negative patients who underwent both BAL and TBLB for suspected PTB between March 2011 and October 2013. Xpert was performed on all BAL specimens. RESULTS: Of 158 patients included in our analysis, 44 were culture-proven PTB. Ninety-four per cent of the patients had AFB smear-negative BAL samples. The sensitivity and specificity of Xpert in AFB smear-negative BAL samples were respectively 60% and 98%. The addition of BAL Xpert expedited the institution of PTB treatment while having diagnostic yields comparable to those of conventional BAL with TBLB. CONCLUSIONS: The use of BAL Xpert may obviate the need for TBLB in increasing the diagnostic yield of PTB in sputum-scarce or AFB smear-negative patients.

Delineation of clinical features in Wiedemann-Steiner syndrome caused by KMT2A mutations.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant congenital anomaly syndrome characterized by hairy elbows, dysmorphic facial appearances (hypertelorism, thick eyebrows, downslanted and vertically narrow palpebral fissures), pre- and post-natal growth deficiency, and psychomotor delay. WSS is caused by heterozygous mutations in KMT2A (also known as MLL), a gene encoding a histone methyltransferase. Here, we identify six novel KMT2A mutations in six WSS patients, with four mutations occurring de novo. Interestingly, some of the patients were initially diagnosed with atypical Kabuki syndrome, which is caused by mutations in KMT2D or KDM6A, genes also involved in histone methylation. KMT2A mutations and clinical features are summarized in our six patients together with eight previously reported patients. Furthermore, clinical comparison of the two syndromes is discussed in detail.

Superior cervical ganglion mimicking retropharyngeal adenopathy in head and neck cancer patients: MRI features with anatomic, histologic, and surgical correlation.

INTRODUCTION: To describe the unique MRI findings of superior cervical ganglia (SCG) that may help differentiate them from retropharyngeal lymph nodes (RPLNs). METHODS: A retrospective review of post-treatment NPC patients from 1999 to 2012 identified three patients previously irradiated for NPC that were suspected of having recurrent nodal disease in retropharyngeal lymph nodes during surveillance MRI. Subsequent surgical exploration revealed enlarged SCG only; no retropharyngeal nodal disease was found. A cadaveric head specimen was also imaged with a 3T MRI before and after dissection. In addition, SCG were also harvested from three cadaveric specimens and subjected to histologic analysis. RESULTS: The SCG were found at the level of the C2 vertebral body, medial to the ICA. They were ovoid on axial images and fusiform and elongated with tapered margins in the coronal plane. T2-weighted (T2W) signal was hyperintense. No central elevated T1-weighted (T1W) signal was seen within the ganglia in non-fat-saturated sequences to suggest the presence of a fatty hilum. Enhancement after gadolinium was present. A central "black dot" was seen on axial T2W and post-contrast images in two of the three SCG demonstrated. Histology showed the central black line was comprised of venules and interlacing neurites within the central portion of the ganglion. CONCLUSIONS: The SCG can be mistaken for enlarged RPLNs in post-treatment NPC patients. However, there are features which can help differentiate them from RPLNs, preventing unnecessary therapy. These imaging findings have not been previously described.

Diagnosing features of Jacobson's nerve schwannoma.

Jacobson's nerve schwannoma is a rare middle ear tumour presenting as a mass along the cochlear promontory. It can be differentiated from other masses along the promontory based on clinical findings, and computed tomography and magnetic resonance imaging features. For small-sized masses, it is possible to differentiate the various middle ear schwannomas from one another. We present the case of a 40-year-old woman with a ten-year history of left hearing loss who was diagnosed with Jacobson's nerve schwannoma.

Kimura's Disease: Diagnostic Challenge and Treatment Modalities.

CASE REPORT: Five cases of Kimura's disease had been treated in our centre from year 2003 to 2010. All cases were presented with head and neck mass with cervical lymphadenopathy. Surgical excision was performed for all cases. Definite diagnosis was made by histopathological examination of the resected specimens. One out of five cases developed tumour recurrence four years after resection. CONCLUSION: Surgical excision is our choice of treatment because the outcome is immediate and definite tissue diagnosis is feasible after resection. Oral corticosteroid could be considered as an option in advanced disease. However, tumour recurrence is common after cessation of steroid therapy.

Genotype and clinical care correlations in craniosynostosis: findings from a cohort of 630 Australian and New Zealand patients.

Craniosynostosis is one of the most common craniofacial disorders encountered in clinical genetics practice, with an overall incidence of 1 in 2,500. Between 30% and 70% of syndromic craniosynostoses are caused by mutations in hotspots in the fibroblast growth factor receptor (FGFR) genes or in the TWIST1 gene with the difference in detection rates likely to be related to different study populations within craniofacial centers. Here we present results from molecular testing of an Australia and New Zealand cohort of 630 individuals with a diagnosis of craniosynostosis. Data were obtained by Sanger sequencing of FGFR1, FGFR2, and FGFR3 hotspot exons and the TWIST1 gene, as well as copy number detection of TWIST1. Of the 630 probands, there were 231 who had one of 80 distinct mutations (36%). Among the 80 mutations, 17 novel sequence variants were detected in three of the four genes screened. In addition to the proband cohort there were 96 individuals who underwent predictive or prenatal testing as part of family studies. Dysmorphic features consistent with the known FGFR1-3/TWIST1-associated syndromes were predictive for mutation detection. We also show a statistically significant association between splice site mutations in FGFR2 and a clinical diagnosis of Pfeiffer syndrome, more severe clinical phenotypes associated with FGFR2 exon 10 versus exon 8 mutations, and more frequent surgical procedures in the presence of a pathogenic mutation. Targeting gene hot spot areas for mutation analysis is a useful strategy to maximize the success of molecular diagnosis for individuals with craniosynostosis.

Primary lacrimal sac lymphoma with recurrence: a case report.

Primary lacrimal sac lymphoma is rare. The common clinical features are epiphora and medial canthal swelling which mimic nasolacrimal duct obstruction. Histological examination is therefore important to avoid delay in diagnosis and treatment. We report a case of primary lacrimal sac lymphoma in a 72-year-old female who developed a metachronous tumour at the hard palate one year after excision of the lacrimal sac tumour.

Biallelic DICER1 mutations occur in Wilms tumours.

DICER1 is an endoribonuclease central to the generation of microRNAs (miRNAs) and short interfering RNAs (siRNAs). Germline mutations in DICER1 have been associated with a pleiotropic tumour predisposition syndrome and Wilms tumour (WT) is a rare manifestation of this syndrome. Three WTs, each in a child with a deleterious germline DICER1 mutation, were screened for somatic DICER1 mutations and were found to bear specific mutations in either the RNase IIIa (n = 1) or the RNase IIIb domain (n = 2). In the two latter cases, we demonstrate that the germline and somatic DICER1 mutations were in trans, suggesting that the two-hit hypothesis of tumour formation applies for these examples of WT. Among 191 apparently sporadic WTs, we identified five different missense or deletion somatic DICER1 mutations (2.6%) in four individual WTs; one tumour had two very likely deleterious somatic mutations in trans in the RNase IIIb domain (c.5438A>G and c.5452G>A). In vitro studies of two somatic single-base substitutions (c.5429A>G and c.5438A>G) demonstrated exon 25 skipping from the transcript, a phenomenon not previously reported in DICER1. Further we show that DICER1 transcripts lacking exon 25 can be translated in vitro. This study has demonstrated that a subset of WTs exhibits two 'hits' in DICER1, suggesting that these mutations could be key events in the pathogenesis of these tumours.

Nasolacrimal relapse of nasopharyngeal carcinoma.

OBJECTIVES: To describe three rare cases of nasolacrimal relapse of nasopharyngeal carcinoma, and to discuss the route of tumour spread from nasopharynx to lacrimal system as well as the relevant computed tomography findings. CASE REPORT: We report three cases of nasolacrimal relapse in patients with previously treated nasopharyngeal carcinoma. The common initial presentations in these cases were epiphora and medial canthal swelling. The tumour spread from the nasopharynx to the lacrimal sac along the lateral nasal wall and nasolacrimal canal. Computed tomography demonstrated nasolacrimal canal invasion and osteomeatal complex obliteration by the tumour. Distant metastasis was detected in two cases. CONCLUSION: More targeted radiotherapy should be delivered to prevent under-treatment of nasopharyngeal carcinoma. Nasolacrimal relapse of nasopharyngeal carcinoma is an advanced disease with a poor prognosis.

Multiple symmetrical lipomatosis: case report and literature review.

OBJECTIVE: To discuss the pathophysiology and various treatment methods of multiple symmetrical lipomatosis. CASE REPORT: We report a case of multiple symmetrical lipomatosis in a middle-aged man. He presented to us with an extensive, disfiguring neck mass. Clinical examination and computed tomography suggested a lipomatous mass without compression of vital neck structures. The proximity of the lipomatous mass to the carotid sheaths attracted our interest. We performed surgical excision in this case, because of the deep infiltrative behaviour of the lipoma. The benefits and drawbacks of liposuction and surgical excision of extensive neck lipomatosis are discussed. CONCLUSION: Surgical excision and liposuction are complementary treatments in the management of multiple symmetrical lipomatosis. Patients should be aware of the limitations of both surgical options, and the risk of lipoma recurrence, before surgery. The decision on the mode of surgery relies upon the disease extent, the patient's expectations and the surgeon's experience.

Head and neck cancer: possible causes for delay in diagnosis and treatment.

OBJECTIVE: To explore the possible causes for delay in diagnosis and treatment of head and neck cancer at Sarawak General Hospital (SGH). STUDY DESIGN: This is a prospective study of time interval between onset of symptom, first medical consultation, first specialist clinic consultation, diagnosis and treatment of head and neck cancer in otorhinolaryngology head and neck (ORL-HNS) and dental clinics at Sarawak General Hospital. Forty-two consecutive cases diagnosed to have cancer between July to December 2006 were studied. RESULTS: Mean interval between onset of symptom and medical consultation was 3.8 months, mean interval between first medical consultation to ORL-HNS or dental clinic referral was 8.4 weeks, mean duration between first ORL-HNS or dental specialist consultation to histopathological diagnosis was 18.8 days while duration between diagnosis to definite treatment was 26.9 days. CONCLUSION: Most cases were diagnosed at advanced stage. Patient delay was the main problem. There was significant delay by frontier health workers in identifying sinister symptoms of malignancy. Timing for diagnosis and treatment after specialist referral were comparable with other published studies.

Imaging characteristics of schwannoma of the cervical sympathetic chain: a review of 12 cases.

BACKGROUND AND PURPOSE: SCSCs are rare. This study reviews our experience with CT and MR imaging of SCSCs. MATERIALS AND METHODS: We retrospectively reviewed the CT and MR imaging studies as well as clinical data of 12 patients (6 men, 6 women; mean age, 41 years; range, 27-55 years) with surgicopathologic evidence of SCSC, referred to our institution between January 1999 to October 2008. Images were evaluated with respect to the location, number, morphology, attenuation/signal intensity, enhancement characteristics, and patterns of mass effect of the schwannomas. RESULTS: The schwannomas were solitary, well-circumscribed, and medial to the carotid sheath. Seven were hypoattenuated to skeletal muscle on CT with poor postcontrast enhancement, 4 were isoattenuated, and a single lesion showed intense heterogeneous enhancement. At MR imaging, they were heterogeneously bright on T2WI with intense inhomogeneous postgadolinium enhancement. The ICA was displaced anteriorly in 9 patients with a component of lateral displacement in 8 of these patients. The ICA was in a neutral position in 2 patients and posterolaterally displaced in 1 patient. A single patient demonstrated separation of the ICA and IJV. There was splaying of the carotid bifurcation in 4 patients. CONCLUSIONS: We present the patterns of mass effect and the spectrum of CT and MR imaging characteristics of SCSC, including certain observations that are infrequently described in the published literature.

CT features of parotid gland oncocytomas: a study of 10 cases and literature review.

Oncocytomas of the salivary glands are rare benign epithelial tumors which occur most commonly in the parotid gland. The aim of our study was to characterize the clinical-radiologic-pathologic spectrum of parotid oncocytomas in a series of 10 cases seen in our institution between January 2003 and November 2008. The CT features of parotid oncocytomas in the largest imaging series of this rare but important benign lesion include a well-defined enhancing tumor with a "deformable" appearance when large, and a non-enhancing curvilinear cleft or cystic component. These CT findings are potentially helpful in distinguishing these benign lesions from other parotid tumors in clinical scenarios that preclude surgical resection or when biopsy results are non-diagnostic. Further studies are advocated to validate the specificity and positive predictive value of these imaging features.

Kimura's disease: imaging patterns on computed tomography.

AIM: To define the role of computed tomography (CT) in identifying and classifying the imaging patterns of diagnostic value in Kimura's disease of the head and neck. METHODS: A retrospective study was undertaken comprising 13 patients with histopathological evidence of Kimura's disease. The patients' clinical and pathological records were reviewed against a detailed analysis of their CT images performed from the base of the skull to the arch of the aorta. RESULTS: Both well-defined, nodular masses, as well as ill-defined plaque-like infiltrative masses were seen in the subcutaneous tissue of the head and neck region. All patients had lesions adjacent to the major salivary glands. The parotid gland was affected in 10 of the 13 cases and the submandibular gland was affected in the rest. Contrast enhancement was variable. More than half of the cases had associated lymphadenopathy. Some of them showed atrophy of the skin and subcutaneous fat overlying the subcutaneous masses. Blood eosinophilia was a consistent feature in all the cases. CONCLUSION: The patterns of distribution, morphology, and enhancement of the lesions in Kimura's disease that can be demonstrated at CT, enables a confident, non-invasive diagnosis of this condition, in an appropriate clinical context.