FLT4/VEGFR3 and Milroy Disease: Novel Mutations,a Review of Published Variants and Database Update

Milroy disease (MD) is an autosomal dominantly inherited primary lymphedema. In 1998, the gene locus for MD was mapped to 5q35.3 and variants in the VEGFR3 (FLT4) gene, encoding vascular endothelial growth factor receptor 3 (VEGFR3), were identified as being responsible for the majority of MD cases. Several reports have since been published detailing pathogenic FLT4 mutations. To date, a total of 58 different variants in FLT4, 20 of which are unpublished, have been observed in 95 families with MD. A review of published mutations is presented in this update. Furthermore, the unpublished variants are presented including clinical data. Comparison of clinical features in patients and their families with the same mutations reveals incomplete penetrance and variable expression, making genotype–phenotype correlations difficult. Most mutations are missense, but a few deletions and one splicing variant have also been reported. Several animal models have confirmed the role of VEGFR3 in lymphangiogenesis and studies show mutant VEGFR3 receptors are not phosphorylated. Here, an MD patient with the same p.Ile1053Phe change as seen in the Chy mouse is presented for the first time. This finding confirms that this mouse lineage is an excellent model for MD. All the data reviewed here has been submitted to a database based on the Leiden Open (source) Variation Database (LOVD) and is accessible online at www.lovd.nl/flt4.     

Visceral basidiobolomycosis: An overlooked infection in immunocompetent children

Visceral basidiobolomycosis is an unusual fungal infection of viscera caused by saprophyte Basidiobolus ranarum. It is very rare in healthy children and poses a diagnostic challenge due to the non-specific clinical presentation and the absence of predisposing factors. We report a case of gastrointestinal basidiobolomycosis in a 4-year-old healthy girl who presented with a short history of abdominal pain, bleeding per rectum, fever, and weight loss. The diagnosis was based on high eosinophilic count, classical histopathology findings of fungal hyphae (the Splendore-Hoeppli phenomenon), and positive fungal culture from a tissue biopsy. Fungal infection was successfully eradicated with a combined approach of surgical resection of the infected tissue and a well-monitored course of antifungal therapy. The atypical clinical presentation, diagnostic techniques, and the role of surgery in the management of a rare and lethal fungal disease in an immunocompetent child are discussed.Key words: Basidiobolomycosis, child, fungal infection, gastrointestinal, immunocompetent     

Prevalence and causes of blindness and diabetic retinopathy in Southern Saudi Arabia

Objectives:

To determine the prevalence and causes of blindness and diabetic retinopathy (DR) in Jazan district, Southern Saudi Arabia.

Methods:

Using the standardized Rapid Assessment for Avoidable Blindness (RAAB) and DR cross-sectional methodology, 3800 subjects were randomly selected from the population of ≥50 years of age in Jazan, Saudi Arabia between November 2011 and January 2012. Participants underwent screening comprised of interview, random blood glucose test, and ophthalmic assessment including visual acuity (VA) and fundus examination. Among participants with VA <6/18 in either eye, the cause(s) of visual impairment was determined. Participants were classified as diabetic if they had previous diagnoses of diabetes, or random blood glucose >200 mg/dl. Diabetic participants were assessed for DR using dilated fundus examination. All data were recorded using the RAAB + DR standardized forms.

Results:

The prevalence of bilateral blindness <3/60 was 3.3% (95% confidence interval [CI]: 2.74 - 3.90). Cataract was the leading cause of blindness (58.6%); followed by posterior segment diseases (20%), which included DR (7; 3.3%). The prevalence of diabetes mellitus (DM) was 22.4%, (95% CI: 21.09 - 23.79), among them; 27.8% had DR. The prevalence of sight-threatening DR was 5.7%.

Conclusion:

The prevalence of DM and the corresponding proportion of DR in this region is lower than that reported in other regions of Saudi Arabia. However, the prevalence of blindness not related to DR is relatively higher than the other studies.The Kingdom of Saudi (KSA) ranks seventh in the global burden of diabetes mellitus (DM), with an estimated prevalence of 23.5% for age groups 20-79 years.1 Ocular complications are quite common among diabetic patients. It is well established that within 15 years of diabetes approximately 2% of diabetics may turn legally blind, and approximately 10% may develop severe visual impairment. Diabetic retinopathy (DR) is one of the serious potential complications. It occurs in approximately 77% of the type 2 diabetics within 10 years of the diabetes onset, and almost in all type 1 diabetics.2 A global review of diabetic retinopathy reported that on average, 34.6% of all diabetic patients have some forms of DR.3 Recent studies in KSA have reported a high prevalence of DR among diabetics in different regions of the country. A recent population based study in Taif,4 in the Western region of KSA reported that 33% of all diabetics have some form of DR; while another hospital based study in the Madinah region reported the same estimate at 36%.5 With this high burden of the disease, the Saudi Ministry of Health (MoH) in collaboration with the Saudi National Prevention of Blindness Committee (NPBC) commissioned more studies to determine the magnitude of the problem in other regions of the vast country. Thus, a population-based survey was conducted to estimate both prevalence and pattern of DR, in addition to the magnitude and causes of blindness and visual impairment in the Jazan district, in the Southwestern region of KSA. Jazan covers an area of 11,670 Km², and has a population of 1,533,496 inhabitants. It lies to the Southwest coast of the Red Sea and is bordered by Yemen to the south. The study adopted the Rapid Assessment for Avoidable Blindness and Diabetic Retinopathy (RAAB+DR) technique, which is a survey methodology developed by the International Centre for Eye Health, London School of Hygiene and Tropical Medicine (ICEH-LSHTM), London, United Kingdom.6 The RAAB+DR is a simple and cost effective cross-sectional community-based survey of persons 50 years and older, that focuses primarily on the prevalence of avoidable blindness. It estimates the prevalence of blindness and visual impairment, their causes, and magnitude of DR in a specific geographical area, usually at the district, or province level. The RAAB+DR methodology has concrete proven reliability and validity.4,7     

Significance of serum levels of vitamin D and some related minerals in breast cancer patients

Vitamin D and calcium are involved in a wide range of proliferation, apoptosis and cell signaling activities in the body. Suboptimal concentrations may lead to cancer development. The role of phosphate in cancer metabolism is particularly relevant in breast cancer while, magnesium deficiency favors DNA mutations leading to carcinogenesis. Objectives: To determine serum levels of vitamin D, calcium, phosphorus, magnesium, and parathormone in female breast cancer patients and to assess their association with some prognostic factors in breast cancer. Design and methods: This study is done on 98 newly diagnosed female breast cancer patients and 49 age matched apparently healthy female volunteers as controls. Serum samples from all patients and controls were subjected to 25-OH Vit D, calcium, phosphorus, magnesium, and parathormone measurements. Results: In the breast cancer group, the median serum levels of 25-OH Vit D were 15 ng/ml, while it was 21 ng/ml in the control group. Levels of 25-OH Vit D and other tested minerals were significantly lower while calcium:magnesium (Ca:Mg) ratio, and calcium:phosphorus (Ca:P) ratio were significantly higher in the breast cancer group. Significant negative correlation was detected between phosphorus and calcium, ionized calcium , calcium magnesium ratio, and calcium phosphorus ratio. Conclusion: It is not only the deficient levels of Vit D and other related minerals, but the combination of the abnormal levels of all the studied parameters that might contribute to the development of cancer. Further studies with larger number of patient are needed.