Targeted high-throughput sequencing for genetic diagnostics of hemophagocytic lymphohistiocytosis

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rapid-onset, potentially fatal hyperinflammatory syndrome. A prompt molecular diagnosis is crucial for appropriate clinical management. Here, we validated and prospectively evaluated a targeted high-throughput sequencing approach for HLH diagnostics. Methods: A high-throughput sequencing strategy of 12 genes linked to HLH was validated in 13 patients with previously identified HLH-associated mutations and prospectively evaluated in 58 HLH patients. Moreover, 2504 healthy individuals from the 1000 Genomes project were analyzed in silico for variants in the same genes. Results: Analyses revealed a mutation detection sensitivity of 97.3 %, an average coverage per gene of 98.0 %, and adequate coverage over 98.6 % of sites previously reported as mutated in these genes. In the prospective cohort, we achieved a diagnosis in 22 out of 58 patients (38 %). Genetically undiagnosed HLH patients had a later age at onset and manifested higher frequencies of known secondary HLH triggers. Rare, putatively pathogenic monoallelic variants were identified in nine patients. However, such monoallelic variants were not enriched compared with healthy individuals. Conclusions: We have established a comprehensive high-throughput platform for genetic screening of patients with HLH. Almost all cases with reduced natural killer cell function received a diagnosis, but the majority of the prospective cases remain genetically unexplained, highlighting genetic heterogeneity and environmental impact within HLH. Moreover, in silico analyses of the genetic variation affecting HLH-related genes in the general population suggest caution with respect to interpreting causality between monoallelic mutations and HLH. A complete understanding of the genetic susceptibility to HLH thus requires further in-depth investigations, including genome sequencing and detailed immunological characterization.Peer reviewe

Management of peripheral facial nerve palsy

Peripheral facial nerve palsy (FNP) may (secondary FNP) or may not have a detectable cause (Bell’s palsy). Three quarters of peripheral FNP are primary and one quarter secondary. The most prevalent causes of secondary FNP are systemic viral infections, trauma, surgery, diabetes, local infections, tumor, immunological disorders, or drugs. The diagnosis of FNP relies upon the presence of typical symptoms and signs, blood chemical investigations, cerebro-spinal-fluid-investigations, X-ray of the scull and mastoid, cerebral MRI, or nerve conduction studies. Bell’s palsy may be diagnosed after exclusion of all secondary causes, but causes of secondary FNP and Bell’s palsy may coexist. Treatment of secondary FNP is based on the therapy of the underlying disorder. Treatment of Bell’s palsy is controversial due to the lack of large, randomized, controlled, prospective studies. There are indications that steroids or antiviral agents are beneficial but also studies, which show no beneficial effect. Additional measures include eye protection, physiotherapy, acupuncture, botulinum toxin, or possibly surgery. Prognosis of Bell’s palsy is fair with complete recovery in about 80% of the cases, 15% experience some kind of permanent nerve damage and 5% remain with severe sequelae

Nutritional rickets and vitamin D deficiency in infants, children and adolescents

PubMed ID: 20526242Nutritional rickets continues to be a public health problem in many countries despite the presence of cheap and effective means of preventing the disease. Deficiency of vitamin D is associated with rickets in growing children and osteomalacia in adults. Vitamin D deficiency is attributed to a variety of causes including diet, atmospheric pollution, religious pratices that restrict sunlight exposure (clothing), geographic latitude and altitude, season, and time of the day. The clinical findings of rickets can vary among stages of the disease. It is recommended that healthy infants, children and adolescents take at least 400 IU vitamin D per day to prevent rickets and vitamin D deficiency. Pediatricians and other healthcare professionals should try to ensure that children and adolescents receive daily vitamin D requirements appropriate for their risk factors, traditions, and customs. Additionally, it is important to use every opportunity to ensure that effective preventive strategies are put in practice

Case report of two siblings with familal ovarian dysgenesis

Two sisters were admitted separately at different times (ages 15 and 12 years, respectively) to our unit because of amenorrhea, lack of secondary sex characteristics, and short stature. No evidence of other congenital anomalies was found. Laboratory studies indicated hypergonadotropic hypogonadism. Peripheral blood samples revealed normal 46,XX karyotype for both patients. No gonads were visualized by ultrasonography. The two cases underline the need to take familial ovarian dysgenesis into consideration in female patients with short stature, lack of secondary sex characteristics, normal karyotypes, and similar sibling histories

A comparison of multiple daily insulin therapy with continuous subcutaneous insulin infusion therapy in adolescents with type 1 diabetes mellitus: A single-center experience from Turkey

PubMed ID: 19694201Aim: To compare the long-term outcomes of continuous subcutaneous insulin infusion (CSII) pump therapy with the clinical and metabolic parameters recorded during multiple daily insulin (MDI) therapy. Patients and Methods: CSII pump was used by volunteer adolescents, who had a duration of diabetes mellitus (DM) longer than one year, regularly attended periodic examinations for the last year, measured and recorded blood glucose levels on average 3 to 4 times a day, and did not achieve the preferred metabolic control even though the use of MDI therapy. Carbohydrate counting and flexible MDI therapy was taught to these patients before CSII pump implantation. The metabolic and clinical parameters of the patients for the post-CSII pump period were compared with the data of flexible and non-flexible MDI periods. Results: The mean CSII pump implantation age of the 17 adolescents enrolled in the study was 15.53 ± 1.8 years, duration of DM 6.77 ± 4.05 years, flexible MDI injection duration 0.70 ± 0.20 years, and duration of CSII pump use 2.07 ± 1.12 years. A decrease was detected in HbA1c levels of the patients with transition to CSII pump compared to flexible and non-flexible MDI injection periods; however, this decrease was not statistically significant (7.71%, 8.21%, and 8.71%, respectively, p = 0.105). No statistically significant difference was detected in frequency of hypoglycemia, lipid profiles, total daily insulin requirement, and BMI SDS values of the patients when data of the post-CSII pump state were compared with that of flexible and non-flexible MDI therapy groups. Conclusion: In adolescents, it was found that CSII pump therapy is efficient and safe without any increased risk for weight gain and hypoglycemia compared to flexible and non-flexible MDI injection periods. The present study also demonstrated that flexible MDI injection therapy might be efficiently and safely used in patients who cannot receive CSII pump therapy due to social and/or financial factors. © Freund Publishing House Ltd

Acquired hemophilia A and the knowledge/awareness level of Turkish hematology fellows: On behalf of the Turkish Hematology Association, Acquired Hemophilia Working Group

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