Two novel heterozygous exonic deletions lead to Chanarin-Dorfman syndrome in a patient with congenital ichthyosis, sensorineural hearing loss, and liver dysfunction.

Chanarin-Dorfman syndrome is an autosomal recessively inherited disorder characterized by ichthyosis, sensorineural hearing loss, and hepatic dysfunction. We report on a 60-year-old female of Venezuelan descent who presented with congenital ichthyosis, progressive sensorineural hearing loss, and liver cirrhosis. We identify a heterozygous copy number deletion involving exon 1 and another heterozygous deletion involving exon 3 of the ABHD5 gene. Exon 2 is preserved. Both deletions were confirmed with RT-PCR. RNAseq from peripheral blood shows a reduction of ABHD5 expression overall and an absence of exon 3 expression, confirming the deleterious effects of the identified deletions. We present exonic deletions as a potentially common type of ABHD5 variation.

H4C5 missense variant leads to a neurodevelopmental phenotype overlapping with Angelman syndrome.

Recurrent de novo missense variants in H4 histone genes have recently been associated with a novel neurodevelopmental syndrome that is characterized by intellectual disability and developmental delay as well as more variable findings that include short stature, microcephaly, and facial dysmorphisms. A 4-year-old male with autism, developmental delay, microcephaly, and a happy demeanor underwent evaluation through the Undiagnosed Disease Network. He was clinically suspected to have Angelman syndrome; however, molecular testing was negative. Genome sequencing identified the H4 histone gene variant H4C5 NM_003545.4: c.295T>C, p.Tyr99His, which parental testing confirmed to be de novo. The variant met criteria for a likely pathogenic classification and is one of the seven known disease-causing missense variants in H4C5. A comparison of our proband's findings to the initial description of the H4-associated neurodevelopmental syndrome demonstrates that his phenotype closely matches the spectrum of those reported among the 29 affected individuals. As such, this report corroborates the delineation of neurodevelopmental syndrome caused by de novo missense H4 gene variants. Moreover, it suggests that cases of clinically suspected Angelman syndrome without molecular confirmation should undergo exome or genome sequencing, as novel neurodevelopmental syndromes with phenotypes overlapping with Angelman continue to be discovered.

Keratin 19 demonstration of canal of Hering loss in primary biliary cirrhosis: "minimal change PBC"?

UNLABELLED: Liver biopsy is important for diagnosing primary biliary cirrhosis (PBC). Prior investigations suggest that immunostaining for biliary keratin 19 (K19) may show the earliest changes suspicious for PBC, namely, loss of the canals of Hering (CoH). We aimed to study the clinical outcomes of patients whose biopsy specimens appeared histologically near normal or with minimal inflammatory changes, but in which K19 staining revealed widespread periportal CoH loss, a finding we termed "minimal change PBC." Ten patients were identified prospectively as having nearly normal or mildly inflamed biopsy specimens without diagnostic or suggestive histologic features of PBC, but with near complete CoH loss; six had available follow-up clinical data, one had follow-up biopsy. Controls for clinical and/or K19 analysis included six normal livers and biopsy specimens from 10 patients with confirmed early PBC, 10 with early stage chronic hepatitis C (CHC), and nine with resolving, self-limited hepatitis (RSLH). Staining for K19 in normal controls, livers with "minimal change" PBC, CHC, and RSLH showed 9.2 ± 6.0, 0.44 ± 0.37 (P < 0.0001), 5.7 ± 4.6 (n.s.), 4.1 ± 2.1 (P < 0.02) CoH per portal tract, respectively. Patients with available clinical follow up, compared to patients with diagnostic early-stage PBC biopsies, showed identical treatment responses to ursodeoxycholic acid, similar rates and types of nonhepatic autoimmune diseases, and/or subsequent development of autoimmune hepatitis overlap syndrome. CONCLUSION: We suggest that CoH loss demonstrated by K19 immunostaining is an early feature in PBC. Clinical findings in the years following biopsy, including response to ursodeoxycholic acid, show identical changes to patients with biopsy confirmed PBC. We suggest that this "minimal change" feature may support a clinical diagnosis of PBC even in the absence of characteristic, granulomatous, duct destructive lesions.

Adult hepatoblastoma: making the challenging distinction from hepatocellular carcinoma.

Hepatoblastoma is an exceptionally rare malignancy in adults with just over 70 non-pediatric cases reported in literature. Recounted is a case of a 49-year-old female who presented with acute right upper quadrant abdominal pain, elevated serum alpha fetoprotein and a large liver mass on imaging. Hepatectomy was performed under clinical suspicion of hepatocellular carcinoma. Immunomorphologic characteristics of the tumor proved consistent with hepatoblastoma of mixed epithelial and mesenchymal type. Hepatocellular carcinoma remains to be the primary differential diagnosis for adult hepatoblastoma, however, distinguishing between these two neoplasms requires close histomorphologic assessment and immunohistochemical profiling as clinical, radiologic and gross pathologic findings typically overlap. Making this distinction is highly crucial in the timely initiation of surgical and chemotherapeutic interventions for this inherently aggressive and rapidly fatal disease.

Non-alcoholic fatty liver disease: the pathologist's perspective.

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of diseases characterized by fatty accumulation in hepatocytes, ranging from steatosis, non-alcoholic steatohepatitis, to cirrhosis. While histopathological evaluation of liver biopsies plays a central role in the diagnosis of NAFLD, limitations such as the problem of interobserver variability still exist and active research is underway to improve the diagnostic utility of liver biopsies. In this article, we provide a comprehensive overview of the histopathological features of NAFLD, the current grading and staging systems, and discuss the present and future roles of liver biopsies in the diagnosis and prognostication of NAFLD.

Biopsy sampling of breast lesions: comparison of core needle- and vacuum-assisted breast biopsies.

Needle biopsy is now the initial investigation of choice for the pre-operative diagnosis of breast lesions. This includes core needle biopsy (CNB) and vacuum-assisted biopsy (VAB) with or without radiologic assistance. The performance indices of both of these biopsy techniques were evaluated. In a large cohort of patients with breast lesions including 464 cases (285 CNB and 179 VAB), with confirmed outcomes, the diagnostic accuracy was compared using parameters including quantitation of the sampling based on the total number of cores taken, cores containing breast parenchyma, and cores with lesion; and non-epithelial changes including necrosis and calcification. CNB showed a 99% PPV, 94% NPV, 96% sensitivity, and 99% specificity, whereas VAB demonstrated a 100% PPV, 100% NPV, 100% sensitivity, and 100% specificity. The correct diagnosis in CNB was proportional to the number of cores extracted, whereas accuracy of VAB was independent of the total number of cores taken. There was a positive correlation between the presence of calcification and malignancy in CNB, but not detected under VAB. CNB and VAB were equally efficient in palpable lesions, in detecting necrosis, and calcification. Large calcification was found to be associated with malignancy in both CNB and VAB. In non-palpable lesions, VAB was more effective in the detection of calcification. The diagnostic accuracy of VAB appeared to be independent of number of cores sampled, whereas CNB required a minimum of 3-4 cores to achieve high diagnostic accuracy.

Involvement of α- and ß-catenins and E-cadherin in the development of mammary phyllodes tumours.

AIMS: Phyllodes tumours (PT) are rare but clinically important fibroepithelial tumours of the breast. ß-Catenin, a key component in Wnt signalling, has been shown to be important in the development of PT. It also functions as a component of the cadherin complex, which may therefore be implicated in PT pathogenesis. By assessing stromal α-catenin, ß-catenin and E-cadherin expression in 158 PT cases using immunohistochemistry and examining associations with clinicopathological features, we aimed to determine the role of these proteins in PT pathogenesis. METHODS AND RESULTS: Cytoplasmic ß-catenin correlated with α-catenin expression. A significantly higher expression of both markers was observed in borderline than in benign PT (P = 0.003 and <0.001, respectively), but a lower level was found in malignant PT. Cytoplasmic E-cadherin expression was significantly higher in borderline and malignant than in benign PT (P = 0.001 and 0.012, respectively), but was not correlated with other markers. Both E-cadherin and α-catenin showed stronger correlations with histological parameters than ß-catenin. α-Catenin showed a significant correlation with recurrence (P = 0.005 and 0.016, respectively). CONCLUSION: α- and ß-catenins may be important in the early stages of PT development, while E-cadherin may be required for malignant development. The correlation of α-catenin expression with tumour recurrence may be relevant in predicting PT behaviour.

Multiple Mitochondrial Dysfunction Syndrome Type 3: A Likely Pathogenic Homozygous Variant Affecting a Patient of Cuban Descent and Literature Review.

Multiple mitochondrial dysfunction syndrome type 3 (MMDS3) is a rare mitochondrial leukoencephalopathy caused by biallelic pathogenic variants in IBA57. Here, we describe a homozygous variant in IBA57, (NM_001010867.2): c.310G>T (p.Gly104Cys), in a 2-month-old infant of Cuban descent who presented with a one-month history of progressive hypotonia, weakness, and episodes of upgaze deviation. This is the first report of a patient homozygous for this variant and the first report of MMDS3 in a patient of Hispanic descent described to our knowledge. Using in silico tools, we found that the variant resides in a putative mutational hotspot located in the neighborhood of a key active ligand required for iron-sulfur cluster coordination. In addition, while previous case reports/series have reported the variable phenotypic features of the disease, the incidence of these features across the literature has not been well described. In order to construct a clearer global picture of the typical presentation of MMDS3, we reviewed 52 cases across the literature with respect to their clinical, biochemical, genotypic, and neuroradiographic features.

E-cadherin expression in the epithelial components of mammary phyllodes tumors.

Phyllodes tumors are rare but clinically important fibroepithelial tumors of the breast. Both epithelial and stromal components actively interact with each other to participate in phyllodes tumor development. Accumulated evidence suggests that the Wnt signaling pathway is important in this stromal-epithelial interaction. Given that Wnt signaling also affects E-cadherin-dependent cellular adhesion and alteration of E-cadherin is common in epithelial cancers, it is possible that alteration of E-cadherin occurs also in the epithelial components of phyllodes tumor. We assessed epithelial E-cadherin expression in 155 phyllodes tumor cases, including 92 benign (59%), 42 borderline (27%), and 21 malignant phyllodes tumor (14%), by immunohistochemistry. Its expression was correlated with clinicopathologic features and phyllodes tumor recurrence. Significant correlations of both membranous and cytoplasmic E-cadherin expression were found with stromal cellularity (P = .009 and .013, respectively), overgrowth (P = .005 and .009, respectively), and mitotic counts (P = .023 and .029, respectively) but not tumor grade, margin, and nuclear atypia. Interestingly, a significantly higher level of cytoplasmic epithelial E-cadherin expression was found in those tumors with recurrence (score, 278.79±40.91 versus 250.00±63.46) and shorter specific disease-free survival (172.24±12.63 versus 207.24±19.71 months). Further multivariate analysis showed epithelial E-cadherin expression as an independent prognostic factor for phyllodes tumor-specific survival (P<.001 for cytoplasmic staining and .001 for membranous staining). In conclusion, we have demonstrated an association of epithelial E-cadherin expression with stromal histologic features and disease recurrence in phyllodes tumor. These findings provide further evidence of the importance of stromal-epithelial interactions in phyllodes tumors and highlight the potential value of epithelial components in prognostication.

Relationship between columnar cell changes and low-grade carcinoma in situ of the breast--a cytogenetic study.

Columnar cell lesions of the breast include columnar cell changes without atypia and columnar cell changes with atypia. The latter frequently coexist and share molecular changes with low-grade carcinoma in situ and invasive carcinoma, suggesting that columnar cell changes may be precursors to progression of low-grade advanced lesions. In this study, we assessed chromosomal aberrations at 16q, hallmark for low-grade lesions, in columnar cell changes with or without atypia and their adjacent carcinoma in situ by fluorescent in situ hybridization using 3 region-specific probes spanning the entire chromosomal arm. The results were correlated with the histomorphological features of the corresponding lesions. Forty-four percent of low-grade carcinoma in situ and 31% of high-grade carcinoma in situ were associated with columnar cell changes with atypia, suggesting a link between columnar cell changes with atypia and low-grade carcinoma in situ. For the genetic aberrations, heterozygous deletion of 16q was present in 56% of low-grade carcinoma in situ but only in 19% of high-grade carcinoma in situ. Conversely, aneuploidy was found mostly in high-grade carcinoma in situ (88%). Twenty percent of columnar cell changes with atypia but none of the columnar cell changes without atypia showed heterozygous deletion of 16q. Interestingly, the same changes in 16q were observed in the columnar cell changes and their associated low-grade carcinoma in situ lesions. These findings demonstrated a genetic commonality between columnar cell changes with atypia and low-grade carcinoma in situ and substantiated the precursor role of columnar cell changes with atypia for low-grade carcinoma in situ but not high-grade carcinoma in situ of the breast.

Fine needle aspiration cytology of the breast: the nonmalignant categories.

Currently, accurate diagnosis of breast lesions depends on a triple assessment approach comprising clinical, imaging and pathologic examinations. Fine needle aspiration cytology (FNAC) is widely adopted for the pathologic assessment because of its accurracy and ease of use. While much has been written about the atypical and maliganant categories of FNAC diagnosis, little covers the non-malignanat category which represents a sheer number in all FNAC cases. Moreover, any false-negative diagnosis of the non-malignant cases may lead to missed diagnosis of cancer. This paper aims to discuss the issues of smear adequacy, the cytologic features of benign breast lesions and the dilemma of a false-negative aspirate. Much has been suggested about the smear adequacy criterion, including quantifying epithelial clusters, whereas others advocate basing adequacy on qualitative quantum of using noncellular features of FNAC. Various benign lesions could be easily diagnosed at FNAC; however, they have cytologic features overlapped with malignant lesions. False negativity of FNAC does occur; this could be caused by either "true" false-negative cases attributed to suboptimal sampling technique, poor localization of the mass or nonpalpable lesions or "false" false-negative cases due to interpretational errors. Though false-positive cases are less commonly found, they will also be discussed briefly.