DNAJC21-related thrombocytopenia in a young adult female.

Bone marrow failure type 3 (BMFS3) (MIM:617052) is a subtype of inherited bone marrow failure syndromes (IBMFS) caused by homozygous pathogenic variants in DNAJC21. It was first defined in 2016, and to date, 19 patients have been reported. Here we report the first adult patient; a 20-year-old female with a novel frameshift variant in DNAJC21 presents with thrombocytopenia, dysmorphic findings, and ovarian agenesis. Our patient expands the clinical spectrum to the milder end and suggests that DNAJC21-related disorders can have relatively mild presentations. Investigation of DNAJC21 variants in both childhood and adult patients with persistent, non-progressive thrombocytopenia will allow to broaden the gene-related phenotypic and genotypic spectrum and elucidate the pathophysiology. Therefore, we encourage revisiting undiagnosed patients to offer whole exome sequencing (WES) in adulthood.

It is all in the bag: collodion bag versus HistoGel cell block method.

INTRODUCTION: We performed a comparison of cell blocks prepared with the collodion bag and HistoGel to evaluate the ease of embedding and cutting, performance with low cellularity specimens, time and cost per specimen, and value to support immunohistochemistry and molecular diagnostics. MATERIALS AND METHODS: We processed 11 fresh, unfixed effusions using both the collodion bag and the HistoGel cell block preparation methods. Six immunohistochemistry stains were tested on 2 of the body fluids. DNA was extracted and quantified, and polymerase chain reaction cycle thresholds were evaluated from cell blocks prepared from 5 of the body fluids. The comparison parameters included embedding difficulty, cutting resistance, adequacy, cell yield, cell preservation, immunohistochemistry stain quality, DNA quantity, integrity, and purity. The time and cost to prepare each specimen was compared using normalized values for preparation of specimen, cost per year, and cost per specimen. RESULTS: Each parameter was assessed for both cell block preparation methods. All 3 of the samples with moderate or poor cell yield were low-volume (5-mL) samples prepared with the HistoGel method. In contrast, the collodion bag method produced a good yield with all three 5-mL samples. DNA recovery was greater in the collodion bag method. Similar crossing threshold values in purity reactions indicated equally high-quality matrix properties for the collodion bag and HistoGel preparations. Preparation of the specimen was 10 minutes faster with the collodion bag method, and the cost for the collodion bag method was $0.24 more expensive per cell block than using the HistoGel. CONCLUSIONS: The collodion bag method produced superior cell blocks for both morphologic and molecular studies more consistently, with lower volume specimens and with less time per specimen.

Is Hemoglobin D Trait Hematologically Silent: Comparison With Healthy Controls and ß-thalassemia Carriers.

Hemoglobin D-Los Angeles, a recessively inherited hemoglobin variant, has been introduced as hematologically silent in the heterozygous state. However, as its compound heterozygosity with other hemoglobinopathies may lead to a severe clinical phenotype, with hemoglobin S being the most serious, the detection of carriers is important. To clarify the hematologic picture, we assessed erythrocyte parameters in D carriers and compared values in healthy controls and ß-thalassemia carriers. Although values in D carriers, in the absence of confounding factors, significantly differed from thalassemia carriers (P<0.05 for all), they were not similar to healthy controls. Microcytosis (absent in healthy controls) (mean corpuscular volume: 80.7 vs. 83.5 fL, P=0.038) and erythrocytosis (6 times more than in healthy controls) (red blood cell: 5.2 vs. 4.7×10/L, P=0.002) were detected, making questionable the true silence of the D trait.

Elevated serum ferritin level with cataract of spectacular morphology: Hyperferritinemia-cataract syndrome.

Hyperferritinemia-cataract syndrome, characterized by high serum ferritin concentration and cataracts in early life, remains a less-known rare disease, with fewer than 100 families reported worldwide. Though benign, high ferritin levels frequently result in misdiagnosis with iron storage disease, and patients can be exposed to unnecessary, even invasive, evaluation and treatment procedures. The presence of cataract together with isolated serum ferritin elevation should alert clinicians to consider this syndrome. We herein present a new family with hyperferritinemia-cataract syndrome to increase clinical awareness.

Detection of blaOXA-48 and clonal relationship in carbapenem resistant K. pneumoniae isolates at a tertiary care center in Western Turkey.

BACKGROUND: Klebsiella pneumoniae is an important nosocomial pathogen that can lead to high morbidity and mortality. ESBL and carbapenamase producing strains may cause epidemic situations. The aim of our study was to investigate the molecular epidemiology and clonal relationship between carbapenem resistant K. pneumoniae strains isolated from our hospital during a three month period. METHODS: Fourteen carbapenem resistant K. pneumoniae strains isolated during April 1st-June 30th 2013 were included. The identification and the antibiotic susceptibility of the strains were studied by Vitek 2 Compact (Biomerieux, France) system. The carbapenemase production of the isolates were investigated by Modified Hodge assay. The blaOXA of the strains was investigated by in house PCR. The clonal relationship between the isolates were studied by pulsed-field gel electrophoresis (PFGE) and automatized repetitive extragenic palindromic PCR (Rep-PCR, DiversiLab sistemi, Biomerieux, France) methods. RESULTS: All the K. pneumoniae isolates were carbapenem resistant; they were all susceptible to gentamycin and colistin. All of them had blaOXA-48. The genotyping analysis revealed that eight isolates were in the same cluster both by Rep-PCR (similarity border ≥95%) and PFGE (Tennover criteriae) analysis. The other isolates did not belong to any other clusters. The strains that are in the same cluster are isolated from the Anesthesiology Intensive Care Unit during a three month period. The cluster ration by both methods was 57%. CONCLUSIONS: All K. pneumoniae strains possessed blaOXA-48. The clonal spreading was particularly detected in Anesthesiology Intensive Care Unit. Molecular epidemiological monitorization of nosocomial pathogens may prevent the spread of these multidrug resistant pathogens.

Addition of oral iron to plasma transfusion in human congenital hypotransferrinemia: A 10-year observational follow-up with the effects on hematological parameters and growth.

Congenital hypotransferrinemia (OMIM 209300) is an extremely rare disorder of inherited iron metabolism. Since its description in 1961, only 16 cases have been reported. The defective gene and molecular defect causing this disorder and clinicolaboratory findings seen in the homozygous and heterozygous states have been documented in both humans and mice. However, due to the lack of follow-up studies of the described cases, the long-term prognosis remains unknown. We present a 10-year observational follow-up of a patient previously diagnosed on a molecular basis who was treated with a unique therapy of plasma transfusion fortified with oral iron, with satisfactory clinicolaboratory responses.

Fanconi Anemia: A Rarely Considered Cause of Macrocytosis During Childhood.

We describe a Turkish boy newly diagnosed with Fanconi anemia with mutation in the FANCA gene. The patient, with normal clinical phenotype and negative chromosomal breakage test result, presented with macrocytosis. No clinical or laboratory changes were observed in a follow-up period of 4 years. The diagnosis was confirmed molecularly after a prolonged and exhaustive investigation. He was found to be a compound heterozygote for 2 mutations in the FANCA gene (1 of which is novel, c.4261-2A>C). We present this experience to alert physicians that Fanconi anemia should be considered in the differential diagnosis of otherwise unexplained macrocytosis during childhood.

Maternal serum alpha-fetoprotein levels are normal in Fanconi anemia: Can it be a lack of postnatal inhibition of AFP gene resulting in the elevation?

We investigated the feasibility of using serum alpha-fetoprotein (AFP) levels as a screening test for prenatal diagnosis of Fanconi anemia (FA). Serial measurements in maternal serum were recorded. Parents, both heterozygous for FA, had declined prenatal molecular testing. The infant was born with no somatic abnormalities, and FA was confirmed by postnatal molecular analysis. Maternal serum AFP levels during each trimester of pregnancy were normal indicating that these levels cannot be used as a screening test in prenatal diagnosis. Three-year follow-up after birth showed constantly elevated serum levels in the patient from the start, suggesting a lack of postnatal inhibition on AFP gene.

Recessive congenital methemoglobinemia in immediate generations.

We report herein on our observation of recessive congenital methemoglobinemia (type I), an autosomal recessive disorder, in immediate generations (in a mother and her daughter). Molecular analysis revealed a mechanism of inheritance not reported previously, despite the high probability of occurrence in autosomal recessive disorders. This report is also the first publication describing an extremely rare mutation (Arg50Gln) causing this disorder in the Turkish population.

Harris Platelet Syndrome in Patients of Non-Indian Origin.

Inherited giant platelet disorders are a subgroup of congenital thrombocytopenias characterized by decreased platelet counts along with macroplatelets and variable bleeding symptoms. Harris platelet syndrome, a newly described rare entity, is a subtype of inherited giant platelet disorders and is characterized by mild-to-severe thrombocytopenia, macroplatelets, and no bleeding manifestations. This entity was observed incidentally in healthy blood donors from India in the early 2000s, and the reported cases to date have without exception originated from the same region of the Indian subcontinent. We herein report the occurrence of Harris platelet syndrome in patients from a different ethnogeographic origin.

"Silent" ß-thalassemia mutation (promoter nt-101 C > T) with increased hemoglobin A2.

One of the most common silent ß-thalassemia mutations is the C > T substitution at position -101 within the distal CACCC box, which leads to a mild reduction in the expression level of the ß-globin gene. Carriers of this mutation have a normal hematologic picture without microcytosis and borderline hemoglobin A2 values, and may be missed during screening. Co-occurrence of this mutation with one of the classical ß-thalassemia mutations leads to ß-thalassemia intermedia, and this is important for Mediterranean populations where ß-thalassemia is frequent. Awareness of this mutation, which may have a heterogeneous clinical presentation, is required. We herein present the unusual hematologic findings of a Turkish family carrying this mutation.

Molecular diagnosis of Fanconi anemia with next-generation sequencing in a case with subtle signs and a negative chromosomal breakage test.

Fanconi anemia (FA) is an inherited disorder characterized by malformations, marrow failure, and predisposition to cancer. Birth defects and laboratory features are characteristic and helpful in diagnosis, when present. Chromosome fragility is pathognomonic in the diagnosis. However, in some cases, there are no obvious physical anomalies or suggestive hematologic abnormalities, and inconclusive diagnostic tests have also been described. In such cases, a molecular diagnosis is required. This approach presents some advantages, especially in populations with a high incidence of FA and of consanguinity. Herein, we present a case with mild phenotypic features, inconclusive hematological findings and a negative breakage test. The diagnosis of FA was confirmed with next-generation sequencing. To our knowledge, this is the first publication of a FA patient being molecularly diagnosed utilizing this method since its introduction. Given its technical and financial features, we suggest that next-generation sequencing might be an alternative first-line diagnostic test for selected cases from particular populations.

Association of vitiligo and response in patients with metastatic malignant melanoma on temozolomide.

Vitiligo-like lesions, although rare, are believed to be a prognostic factor in malignant melanoma. While a predictive role for such lesions was shown with immunomodulatory therapies, this relation was not demonstrated with temozolomide. We present 3 patients with metastatic malignant melanoma who developed vitiligo-like skin lesions accompanying good response to treatment and prolonged survival. Onset of vitiligo-like lesions with temozolomide in metastatic malignant melanoma may predict long-term response for this treatment.

The X chromosome: does it have a role in Bloom syndrome, a genomic instability disorder?

The Bloom syndrome, caused by mutations in a single gene [BLM (15q26.1)], is a rare genomic instability syndrome. Despite its autosomal recessive transmission, it shows a male dominance, suggesting the possibility of a subgroup with X-linked recessive inheritance. In view of the latest molecular developments achieved in the other genomic instability syndromes, the potential functions of the X chromosome in maintaining genomic stability, and particularly, the first clues of Bloom syndrome development by mechanisms other than the BLM, we suggest herein that the X chromosome should be investigated in Bloom syndrome.

Oculoectodermal syndrome: report of a new case with a broad clinical spectrum.

Oculoectodermal syndrome (OMIM 600268) is rare and characterized by aplasia cutis congenita, epibulbar dermoids, and other abnormalities. We report herein on a newly recognized patient with oculoectodermal syndrome, which is the 19th reported patient with OES. The boy aged six years demonstrated a broad clinical spectrum of this condition, including aplasia cutis congenita, epibulbar dermoids, hyperkeratotic papule, mildly enlarged cisterna magna, and an enlarged fluid space in the quadrigeminal cistern, suggesting a cyst. He also manifested anomalies not reported associated with this disorder, including systematized epidermal nevus following Blaschko's lines, hypopigmented skin lesions, and mild digital anomaly.