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 To date, a total of 58 different variants in FLT4, 20 of which are unpublished, have been observed in 95 families with MD.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 Furthermore, the unpublished variants are presented including clinical data.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.     

First experience of the use of a generic of plerixafor in peripheral blood stem cell mobilization in multiple myeloma and lymphoma patients

Mobilization failure in patients is a major therapeutic concern which makes subsequent ASCT impossible. A new growth factor called Plerixafor (Mozobil®) developed by the pharmaceutical industry (Sanofi-aventis, France), is a chemoreceptor antagonist, CXCR4 type, which disrupts the interaction of SDFI and CXCR4, thereby enhancing the effect of G-CSF mobilization and is especially indicated for mobilization failure. Currently, there is a generic of plerixafor developed by the pharmaceutical industry (Hetero Drugs Ltd, India). The brand name of this medicine is Mozifor®. The objective of this study was to evaluate if generic plerixafor has the same efficacy and safety as originator plerixafor when used with G-CSF in the mobilization of PBSCs for autologous ASCT in multiple myeloma (MM) and lymphoma failure patients. The 32 patients received plerixafor were divided in two groups. The first group concerns the 11 consecutive patients prospectively received generic plerixafor (Mozifor®) in the period between January to July 2020. These were compared with a retrospective control cohort (second group n = 21) who had been treated between 2009 and 2019 with originator plerixafor (Mozobil®). For the Mozifor® group, the mean CD34+ was 4.54x10⁶/kg(1.56-6.79), the median time to achieve an absolute neutrophil count >0.5 G/L was 13 days (range: 8–21). The median time to self-sustained platelet count >20 G/L was 15 days (range: 8–24). For the Mozobil® group, the mean CD34+ was 3.1x10⁶/kg (0.56-8.91) (p=0.86), the median time to achieve an absolute neutrophil count >0.5 G/L was 10 days (range 7–23). The median time to self-sustained platelet count >20 G/L was 13 days (range: 7–29). Our study showed that the generic of plerixafor was practically identical to that of the originator (Mozobil®) with no significant difference (p = 0.52). This study demonstrates the safety and feasibility of mobilization PBSC with generic plerixafor in ASCT in MM and lymphoma. Although these outcomes are encouraging, prospective comparison with other traditional auto-HCT regimens used for patients with MM and lymphoma is warranted.     

COVID-19 impact on pharmacy education in Saudi Arabia: Challenges and opportunities

The first case of COVID-19 was announced at the end of year 2019, and later many cases were identified worldwide. In Saudi Arabia, the first case was announced on 2 March 2020. To prevent the spread of this pandemic disease, many precautionary actions were taken by Saudi government. One of these actions was closing public and private schools and universities and transfer the educational activities to virtual platforms. All colleges of Pharmacy in Saudi Arabia, whether the 21 public or the eight private ones, were affected by those sudden transitions and their responses varied according to their preparedness levels. Here we shared our experience in king Saud University in the curricular components of pharmacy school that includes classroom teaching, laboratory teaching, experiential training, assessment, and extracurricular activity and student support during COVID-19 compulsory lockdown. Lastly, we presented the lesson learned toward pharmacy education from COVID-19 pandemic.     

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     

The association of primary hyperparathyroidism and primary ovarian failure: a de novo t(X; 2) (q22p13) reciprocal translocation

CASE: A 40-year-old female presented with primary amenorrhoea at 17 years of age. She was tall at 98th centile for height with eunuchoidal body habitus. Her breast development was Tanner stage 3, pubic and axillary hair Tanner stage 4 with normal external genitalia. Her bone age was 13.4 years at a chronological age of 17.8 years. Gonadotrophins were elevated indicating primary ovarian failure. A diagnostic laparotomy revealed hypoplastic, infantile uterus with bilateral streak gonads. Chromosomal analysis showed a balanced reciprocal translocation 46X, t(X; 2) (q22 p13). She became pregnant by in vitro fertilization with egg donation at the age of 36 years. At 13 weeks of gestation, she presented with intractable vomiting. She had raised corrected serum calcium and parathyroid hormone concentrations consistent with the diagnosis of primary hyperparathyroidism (PHPT). She underwent parathyroidectomy at 24 weeks of gestation with removal of a large left inferior parathyroid adenoma which normalized her serum calcium. Multipoint linkage from a genome-wide screen has identified a region of suggestive linkage on chromosome 2p13.3-14 in some cases of familial isolated hyperparathyroidism (FIHP). CONCLUSION: To our knowledge, this is the first case of primary amenorrhoea due to reciprocal translocation involving chromosome 2 and the X chromosome associated with PHPT. PHPT in this case is most likely to be as a result of chromosome 2 involvement where a locus for FIHP has been identified. Identification of the gene involved on chromosome 2p13.3-14 will be of considerable interest.