Novel SCN9A variant associated with congenital insensitivity to pain.

BACKGROUND: Congenital insensitivity to pain (CIP) is a rare autosomal recessive syndrome characterized by lack of pain perception and a wide spectrum of clinical signs such as anosmia and hyposmia. Variants in SCN9A gene are associated with CIP. We here report on a Lebanese family with three CIP patients referred for genetic investigations. METHODS AND RESULTS: Whole exome sequencing analysis revealed the presence of a novel nonsense, homozygous SCN9A pathogenic variant: SCN9A (NM_001365536.1): c.4633G > T, p.(Glu1545*) in exon 26. CONCLUSION: Our three Lebanese patients had CIP, urinary incontinence and normal olfactory function while two of them also presented with osteoporosis and osteoarthritis; this association of features has not been previously reported in the literature. We hope that this report would contribute to a better delineation of the phenotypic spectrum associated with SCN9A pathogenic variants.

Genetic markers of chronic lymphocytic leukemia: a retrospective study of 312 patients from a reference center in Lebanon.

Aim: Chronic lymphocytic leukemia (CLL) is a highly heterogenous hemopathy. Genetic stratification of CLL patients has important prognostic and therapeutic values - mainly immunoglobulin heavy chain variable region gene (IGHV) mutational status and the presence of cytogenetic abnormalities. The genetics of CLL in Lebanon is scarcely described in the literature. Patients & methods: In this work, we studied the genetic biomarkers of 312 Lebanese CLL patients. Results: Prominent IGHV genes were IGHV4-34, IGHV1-69 and IGHV3-30; and CLL #1 and #5 presented major subsets. Some similarities as well as major differences were highlighted when comparing our data with previously published data. Conclusion: The distribution of IGHV alleles in our series differed from previously described distributions, suggesting involvement of antigenic selection and regional variables in CLL pathogenesis.

CFTR mutational screening by next-generation sequencing reveals novel variants and a high carrier rate in a Middle Eastern population.

Cystic fibrosis is the most common life-limiting autosomal recessive disease in western countries with an incidence of 1:2500 in United States and 1:1000 in some European countries. Similar incidences were noted for the Middle East with variations from 1 in 2560 to 1 in 15,876 according to the degree of consanguinity. This is a preliminary systematic study that aims to assess the incidence and carrier rate of cystic fibrosis in the Middle Eastern Lebanese population; known for a high frequency of consanguinity. One hundred thirteen DNA samples were collected from neonatal blood cards obtained from newborns to healthy unrelated families with no previous history of Cystic fibrosis. Screening for Cystic Fibrosis-causing pathogenic variants was performed using next generation sequencing, and 17 different single nucleotide variants were detected, including six pathogenic and likely pathogenic. 5.5%-7% newborns were found to be carriers of a variant strongly suggestive of pathogenicity and comparable to published literature worldwide. This pilot analysis highlights the challenging interpretation of CFTR variants in a country underrepresented by large ethnic population analyses, and stresses the importance of premarital screening programs for Cystic fibrosis.

FISH analyses for 1p and 19q status on gliomas: Reporting an 8 years' experience from a tertiary care center in the Middle East.

Diffuse gliomas are the most common primary malignancies of the central nervous system (CNS). The 2016 edition of the World Health Organization (WHO) classification of CNS tumors opted to integrate current molecular data with the traditional histologic diagnosis in the definition of the disease. This integrated diagnosis offers a greater level of objectivity and helps in establishing more definitive diagnoses for tumors that may have been controversial on histology alone. The classification of gliomas may require FISH technique to identify chromosomal abnormalities. FISH is commonly used to identify 1p/19q codeletion, but many challenges are encountered in the process. In this study, we review the FISH results for 1p/19q codeletion of n = 85 diffuse glioma samples examined at a tertiary care center in the Middle East over a period of 8 years. We also conduct a literature review to study the potential role of DNA-microarray in the identification of 1p/19q deletions. Glioblastoma (GBM), WHO grade IV is the most common glioma type identified (n = 24; 29%). All oligodendrogliomas show 1p/19q codeletion (26/26) while 12.5% of GBMs have 1p/19q codeletion (3/24). Isolated 1p deletions are only identified in one case of diffuse astrocytoma, WHO grade II. Isolated 19q deletions are identified in oligoastrocytoma, anaplastic astrocytoma, and glioblastoma. FISH is the most commonly used technique to diagnose oligodendroglioma because it is a simple, effective, and accessible technique in settings with limited resources. However, the optimization process remains highly variable between laboratories. Microarray is a more objective technique that can provide more information about the genetic alterations of the tumor for better diagnosis and sub-classification of diffuse glioma types.

The Spectrum of ß-Thalassemia Mutations in the Population Migration in Lebanon: A 6-Year Retrospective Study.

ß-Thalassemia (ß-thal) is highly prevalent among the Mediterranean populations. In Lebanon, the carrier rate of the disease is estimated to be around 2.0-3.0%. In this retrospective study, we determined the spectrum of ß-thal mutations in a total of 170 individuals from a sample of 140 Lebanese, Iraqi and Syrian refugee families in Lebanon, over a period from 2012 to 2018. Twenty-eight different ß-globin gene mutations were identified. The most prevalent mutations were IVS-I-110 (G>A) (HBB: c.93-21G>A), IVS-II-1 (G>A) (HBB: c.315+1G>A), IVS-I-6 (T>C) (HBB: c.92+6T>C) and IVS-I-1 (G>A) (HBB: c.92+1G>A), accounting for the majority of mutations found in HBB mutations analysed in 250 alleles. Ten different ß-globin gene mutations that were not previously described in Lebanon were identified in our study. These mutations include the IVS-II-848 (C>A) (HBB: c.316-3C>A), codons 9/10 (+T) (HBB: c.30_31insT), codon 15 (-T) (HBB: c.46delT), -86 (C>G) (HBB: c.-136C>G), Cap +22 (G>A) (HBB: c.-29G>A), -28 (A>C) (HBB: c.-78A>C), codon 7 (GAG>TAG) (HBB: c.22G>T), codon 26 (GAG>TAG) (HBB: c.79G>T), codons 41/42 (-TTCT) (HBB: c.126_129delCTTT), and codons 82/83 (-G) (HBB: c.250delG). Of these, six mutations [codons 9/10, codon 15 (-T), -86, codon 7, codon 26, codons 82/83) were identified in Lebanese samples only; one mutation (IVS-II-848) was identified in both Lebanese and Iraqis; and three mutations (Cap +22, -28, codons 41/42) were identified in Iraqi samples only. Further studies will help better delineate the spectrum of ß-thal mutations among different ethnic groups, and provide crucial prevention strategies.

DNMT3B deficiency presenting as severe combined immune deficiency: A case report.

Immunodeficiency, Centromeric instability and Facial anomalies (ICF) syndrome is a group of rare autosomal recessive disorders. The immune disease in the ICF syndrome consists mainly of humoral immunodeficiency. T-cell dysfunction has previously been suspected to be part of the syndrome's spectrum. However, patients with ICF display, at a young age, a normal number of T cells that tend to decline throughout disease progression due to apoptosis. Biallelic mutations in the DNMT3B gene account for around 50% of ICF cases (ICF type 1). The remaining half may be linked to ZBTB24, CDCA7 or HELLS. Here we report a novel homozygous DNMT3B mutation (NM_ 006892; p.R826H) in a Lebanese family presenting in early infancy with severe combined immune deficiency (SCID). This work expands the clinical spectrum of the ICF syndrome and confirms the importance of tailoring therapeutic approaches for each patient with ICF syndrome, according to the clinical manifestations of his disease.

BACs-on-Beads™ assay, a rapid aneuploidy test, improves the diagnostic yield of conventional karyotyping.

BACs-on-Beads (BoBs™) assay is a rapid aneuploidy test (RAT) that detects numerical chromosomal aneuploidies and multiple microdeletion/microduplication syndromes. This study was conducted to appraise the usefulness of the BoB™ assay as a complementary diagnostic tool to conventional karyotyping for the rapid detection of chromosomal aneuploidies. A total of 485 prenatal (amniotic fluid and chorionic villi) and blood/products of conception samples were collected between July 2013 and August 2018, and analyzed by the BoBs™ assay and cytogenetic karyotyping and further validated by fluorescence in situ hybridization (FISH). Forty-three of 484 qualifying samples (8.9%) were identified as abnormal by the BoBs™ assay. The assay was comparable to karyotyping in the detection of common structural abnormalities (trisomy 21, trisomy 18, X, and Y), with a sensitivity of 96.0% and a specificity of 100%. BoBs™ assay detected 20 microdeletion and microduplication syndromes that were missed by karyotyping. BoBs™, however, missed 10 cases of polyploidies and chromosomal rearrangements which were identified by conventional karyotyping. Our findings suggest that BoBs™ is a reliable RAT which is suitable in combination with conventional karyotyping for the detection of common aneuploidies. The assay also improves the diagnostic yield by recognizing clinically relevant submicroscopic copy number gains and losses.

BRCA mutations in a cohort of Iraqi patients presenting to a tertiary referral center.

BACKGROUND: Unique pathogenic mutations in BRCA1 and 2 genes have been reported in different populations of patients originating from the Middle East region. Limited data are available for the Iraqi population. For many reasons a large number of Iraqi patients present to Lebanon for medical care. This is the first report of BRCA full gene sequencing conducted in a cohort of high-risk patients originating from Iraq. METHODS: This is a retrospective review of Iraqi patients diagnosed with breast or ovarian cancer referred for BRCA mutation testing at the American University of Beirut from January 2012 to October 2018. RESULTS: Of the 42 Iraqi women who underwent genetic testing at our institution, 3 BRCA pathogenic variants were found. Two mutations in BRCA1 c.224_227delAAAG and c.5431C > T and one mutation in BRCA2 c.5576_5579delTTAA were identified. Three other patients had sequence changes considered as variants of undetermined significance. CONCLUSION: In this cohort of high-risk patients, one out of the three pathogenic BRCA variants detected has not previously been reported in the Middle Eastern population. Further studies are required to delineate the spectrum of BRCA mutations in the Iraqi population.

Molecular profiling of adult acute myeloid and lymphoid leukemia in a major referral center in Lebanon: a 10-year experience report and review of the literature.

Recurrent genetic abnormalities confer distinct morphologic features and play a role in determining the clinical behavior, prognosis and adequate treatment of acute leukemia. In the MENA region, only one study targets the frequency of genetic modifications in AML, reporting a higher occurrence of acute promyelocytic leukemia in Lebanon. Determining the frequency of translocations and gene mutations in acute myeloid and lymphoid leukemia cases in an adult patients' population in Lebanon and comparing the resultant genetic profile with the published international molecular profile of adult acute leukemia. Laboratory results of adult patients diagnosed with AML or ALL presenting to AUBMC for genetic profiling between years 2006 until June 2016 were reviewed. Genetic profiling of AML cases in our CAP accredited molecular diagnostics laboratory consists of a validated lab developed RT-PCR for the detection of RUNX1/RUNX1T1, CBFB/MYH11, KMT2A/MLLT3, PML-RARA, and BCR-ABL and mutations in the FLT3 receptor, NPM1, c-kit and CEPBA genes. The ALL panel tests for the presence of BCR-ABL1, ETV6/RUNX1; KMT2A/AFF1, and TCF3-PBX1. We reviewed 580 AML and 175 ALL cases. In the AML cohort, the M:F ratio was 1.3:1 with a mean age of 50 years. t(15;17) was present in 7.6%, t(8;21) in 4.2%, inv(16) in 3.7%, t(9;22) in 2.2% and t(9;11) in 1.7% of cases. FLT3 mutation (ITD or TKD) was present in 25.2% of all cases and 30.1% of Cytogenetics-normal (CN) patients. Mutations of the NPM1 gene was present in 31.4% of AML cases and in 43.8% of CN patients. Double positive (NPM1+/FLT3+) cases accounted for 20% of NK patients. CEBPA and c-kit mutations were detected in 7.3% and 2.4% respectively. In the ALL cohort, the mean age was 37 years. B- and T-lymphoblastic leukemia constituted 84.6% and 15.4% of ALL cases and the M:F ratio was 1.2:1 and 2.86:1 respectively. B-ALL patients were positive for t(9;22) in 14.2%, t(4;11) in 5.4%, t(1;19) in 2.7% and t(12;21) in 1.4%. T-ALL patients were negative for translocations found in our ALL panel. A lower mean age was found in our adult leukemic Lebanese population as compared to the Western cases. Other interesting findings were the lower percentage of inv(16), lower incidence of TCF3-PBX1, and the mild increase in Philadelphia positivity in our AML cohort. In our ALL cohort, t(9;22) positivity was less than expected for adult lymphoblastic leukemia. Full molecular profiling by next generation sequencing is required for further classification of cases into prognostic categories. This study will be a baseline reference for future research and epidemiological data useful for transplant centers and oncologists both in Lebanon and the region.

BRCA mutation screening and patterns among high-risk Lebanese subjects.

BACKGROUND: Previous studies have suggested that the prevalence of BRCA1 and 2 mutations in the Lebanese population is low despite the observation that the median age of breast cancer diagnosis is significantly lower than European and North American populations. We aimed at reviewing the rates and patterns of BRCA1/2 mutations found in individuals referred to the medical genetics unit at the American University of Beirut. We also evaluated the performance of clinical prediction tools. METHODS: We retrospectively reviewed the cases of all individuals undergoing BRCA mutation testing from April 2011 to May 2016. To put our findings in to context, we conducted a literature review of the most recently published data from the region. RESULTS: Two-hundred eighty one individuals were referred for testing. The prevalence of mutated BRCA1 or 2 genes were 6 and 1.4% respectively. Three mutations accounted for 54% of the pathogenic mutations found. The BRCA1 c.131G > T mutation was found among 5/17 (29%) unrelated subjects with BRCA1 mutation and is unique to the Lebanese and Palestinian populations. For patients tested between 2014 and 2016, all patients positive for mutations fit the NCCN guidelines for BRCA mutation screening. The Manchester Score failed to predict pathogenic mutations. CONCLUSION: The BRCA1 c.131G > T mutation can be considered a founder mutation in the Lebanese population detected among 5/17 (29%) of individuals diagnosed with a mutation in BRCA1 and among 7/269 families in this cohort. On review of recently published data regarding the landscape of BRCA mutations in the Middle East and North Africa, each region appears to have a unique spectrum of mutations.

Acquired centromeric heteromorphism of chromosome 7 yields discordant results between fluorescent in situ hybridization and karyotype analysis in a child with severe congenital neutropenia.

Monosomy 7 is an indicator of malignant transformation in patients with different subtypes of severe congenital neutropenias (SCNs). We present the case of a 5-year-old male diagnosed with SCN. Standard karyotype and fluorescent in situ hybridization (FISH) analyses for centromere of chromosome 7 (chromosome enumeration probe 7 [CEP7]) in bone marrow samples showed disomy for chromosome 7 and a single copy of CEP7. In all cells examined, karyotype analysis of peripheral PHA-stimulated blood samples revealed disomy for chromosome 7. Our results address the issue of centromeric heteromorphism in cytogenetic analysis. Herein, we report a case where FISH using CEP7 in the bone marrow sample showed the presence of only one signal suggesting monosomy seven due to an acquired heteromorphism, whereas extensive conventional karyotyping showed disomy of chromosome 7.

Dietary Zinc Intake and Plasma Zinc Concentrations in Children with Short Stature and Failure to Thrive.

BACKGROUND: The burden of zinc deficiency on children includes an increased incidence of diarrhea, failure to thrive (FTT) and short stature. The aim of this study was to assess whether children with FTT and/or short stature have lower dietary zinc intake and plasma zinc concentrations compared to controls. METHODS: A case-control study conducted at the American University of Beirut Medical Center included 161 subjects from 1 to 10 years of age. RESULTS: Cases had a statistically significant lower energy intake (960.9 vs. 1,135.2 kcal for controls, p = 0.010), lower level of fat (30.3 vs. 36.5 g/day, p = 0.0043) and iron intake (7.4 vs. 9.1 mg/day, p = 0.034). There was no difference in zinc, copper, carbohydrate and protein intake between the 2 groups. The plasma zinc concentration did not differ between the cases and controls (97.4 vs. 98.2 µg/dl, p = 0.882). More cases had mild-to-moderate zinc deficiency when compared to controls with 10.3 vs. 3.6%, p = 0.095. CONCLUSION: Our study did not show statistically significant difference in dietary zinc intake and plasma zinc concentrations between children with FTT and/or short stature compared to healthy controls. A prospective study is planned to assess the effect of zinc supplementation on growth parameters in FTT children.

Alpha thalassemia allelic frequency in Lebanon.

BACKGROUND: Hemoglobinopathies are the most common reported monogenic disorders worldwide. It is well established that Mediterranean and Arab countries are high risk areas for thalassemia in general, and for alpha thalassemia in particular. Reports of alpha thalassemia gene mutations from the Lebanese population are limited. PROCEDURE: We investigated the spectrum of alpha thalassemia mutations in a sample of 70 unrelated Lebanese families. Six different mutations of alpha thalassemia gene were identified. RESULTS: The most prevalent mutations were the single gene deletion -α(3.7) (43%) and the non-gene deletion α2 IVS1 [-5nt] (37%). The double deletional determinant -(MED) was detected only in 14% of thalassemic chromosomes. CONCLUSION: We determined the mutational spectrum of alpha thalassemia which might be used in the future for molecular investigations of the disease in susceptible patients in our population.

Clinical and molecular analysis in families with autosomal recessive osteogenesis imperfecta identifies mutations in five genes and suggests genotype-phenotype correlations.

Autosomal recessive osteogenesis imperfecta (AR-OI) is an inherited condition which in recent years has been shown with increasing genetic and clinical heterogeneity. In this article, we performed clinical assessment and sought mutations in patients from 10 unrelated families with AR-OI, one of whom was presented with the additional features of Bruck syndrome (BS). Pathogenic changes were identified in five different genes: three families had mutations in FKBP10, three in SERPINF1, two in LEPRE1, one in CRTAP, and one in PPIB. With the exception of a FKBP10 mutation in the BS case, all changes are novel. Of note, insertion of an AluYb8 repetitive element was detected in exon 6 of SERPINF1. Since the studied patients had variable manifestations and some distinctive features, genotype/phenotype correlations are suggested.

Split daily recombinant human LH dose in hypogonadotrophic hypogonadism: a nonrandomized controlled pilot study.

This prospective controlled nonrandomized pilot study was conducted to investigate whether split daily doses of recombinant human LH (rHLH) is more efficacious than the single daily dose in supporting follicular development and ovulation in primary hypogonadotrophic hypogonadism (HH). Twenty-seven women with HH received a 150 IU fixed daily subcutaneous dose of recombinant human FSH, supplemented by 75 IU daily dose of rHLH given either as a single dose (n=9; single-dose group) or four equally divided doses (n=18; split-dose group). Ovulation was defined by three efficacy end points: at least one follicle ⩾17mm in diameter, pre-ovulatory serum oestradiol ⩾400pmol/l and a midluteal progesterone ⩾25nmol/l. Although lacking statistical significance, the proportion of women in the rHLH split-dose group who fulfilled all three end points was higher than the single-dose group (72.2% versus 55.6%). Women in the split-dose group achieved higher serum oestradiol concentrations per follicle, endometrial thickness measurements and numbers of follicles than in the single-dose group (not statistically significant). The odds ratio for ovulation rate was 2.08 (not statistically significant). There were no serious untoward side effects. Administering rHLH in split daily doses could provide superior results compared with the traditional single daily dose. We conducted this clinical study to investigate whether a split daily dose protocol of recombinant human LH (rHLH) is more efficacious than the single daily dose in supporting follicular development and ovulation in primary hypogonadotrophic hypogonadism (HH). HH is an uncommon entity that can lead to very low or undetectable serum gonadotrophin concentrations. It manifests in anovulation, amenorrhoea and subsequent infertility. Twenty-seven women with HH received a 150 IU fixed daily subcutaneous dose of recombinant human FSH, supplemented by a 75 IU daily dose of rHLH given either as a single dose (n=9; single-dose group) or four equally divided doses (n=18; split-dose group). Ovulation was defined by these three efficacy end points: at least one follicle ⩾17mm in mean diameter, pre-ovulatory serum oestradiol concentration ⩾400pmol/l and a midluteal progesterone concentration ⩾25nmol/l. The proportion of women in the rHLH split-dose group who fulfilled all three end points was higher than the single-dose group (72.2% versus 55.6%). Women in the split-dose group achieved higher serum oestradiol concentrations per follicle, endometrial thickness measurements and numbers of follicles than in the single-dose group, without statistical significance. Women who received the split-dose regimen were more likely to have ovulation than the other group. We had no serious problematic side effects. Our results suggest that administering rHLH in split daily doses could provide superior results compared to the traditional single daily dose.

A homozygous missense variant in PTPN2 with early-onset Crohn's disease, growth failure and dysmorphic features in an infant: a case report.

Crohn's disease (CD) is a chronic idiopathic inflammatory bowel condition that can affect any part of the gastrointestinal tract. Several hundred candidate loci or genes including PTPN2 have been reportedly associated with CD. A whole-exome sequencing (WES) was conducted in a 9-year-old Lebanese girl with a CD onset at 13 months and in both her asymptomatic parents. The analysis detected an extremely rare homozygous variant in PTPN2: c.359C>T, p.(Ser120Leu) in the patient, while both her parents were heterozygous. This variant, located in the protein tyrosine phosphatase (PTP) domain within a highly conserved amino acid, is classified as VUS according to the American College of Medical Genetics (ACMG) criteria. To evaluate the hypothetical functional consequences of the identified variant, a quantitative expression analysis of PTPN2 was performed in blood tissues of the patient, her parents, and two healthy controls. PTPN2 expression was not noted in the patient compared to her parents and the normal controls, suggesting a functional PTPN2 impairment caused by c.359C>T. This variant c.359C>T, p.(Ser120Leu) in PTPN2 has never been previously described in the literature. Our report suggests an association of PTPN2: c.359C>T with early-onset CD.

Analysis of ASS1 gene in ten unrelated middle eastern families with citrullinemia type 1 identifies rare and novel variants.

BACKGROUND: Citrullinemia type 1 (CTLN1) is a rare autosomal recessive disease caused by argininosuccinate synthetase (ASS) deficiency. Manifestations vary from the acute neonatal or "classic" form to a milder, late-onset, or "unconventional" form. To date, more than 93 variants in the ASS1 gene located on chromosome 9q43.11 (OMIM #215700) are reportedly responsible for CTLN1. Their incidence and distribution vary according to geographic origins and ethnicity, and a correlation, although not clearly delineated, has been established between the genotype and the phenotype of the disease. Though, in the Middle East, national descriptions of CTLN1 are still lacking. METHODS: A total of ten unrelated Middle Eastern families, five Lebanese, two Syrians, and three Iraqis with citrullinemia index cases, were included in this study. Upon informed consent, DNA was extracted from the whole blood of the index patients as well as their parents and siblings. Genetic analysis was carried out by Sanger sequencing of the ASS1 gene. RESULTS: Seven different variants were identified. Two novel variants, c.286C>A (p.(Pro96Thr), RNA not analyzed) in exon 5 and deletion c.685_688+6del(p.(Lys229Glyfs*4), RNA not analyzed) in exon 10, were found in one Lebanese and one Syrian family, respectively, and were correlated with early-onset and severe clinical presentation. Five other known variants: c.535T>C (p.(Trp179Arg), RNA not analyzed) in exon 8, c.787G>A (p.(Val263Met), RNA not analyzed) in exon 12, c.847G>A (p.(Glu283Lys), RNA not analyzed) in exon 13, c.910C>T (p.(Arg304Trp), RNA not analyzed) in exon 13, and c.1168G>A (p.(Gly390Arg), RNA not analyzed) in exon 15, were found in Lebanese, Syrian, and Iraqi families, and were associated with diverse clinical presentations. CONCLUSION: Two novel variants and five known variants were found in a total of ten unrelated Middle Eastern families.

Implementation of an intensive risk-stratified treatment protocol for children and adolescents with acute lymphoblastic leukemia in Lebanon.

With modern risk-adapted therapy, over 80% of children with acute lymphoblastic leukemia (ALL) in high-income countries (HICs) are cured. In countries with limited resources, however, therapy results for pediatric ALL are still not encouraging. We describe our experience in treating children with ALL using a risk-adapted protocol at a tertiary referral center in Lebanon. From May 2002 to August 2009, 111 consecutive patients 1-21 years of age with newly diagnosed ALL received the CCCL ALL protocol which was based on the St. Jude Children's Research Hospital Total XV Study. The median age at diagnosis was 5 years 5 months. The male to female ratio was 1.5. Forty-six patients received the intermediate-/high-risk arm and 65 received the low-risk arm. Only one patient (0.9%) died during induction therapy. Relapse occurred in 8 (7.2%) patients. Eight (7.2%) patients died, 4 of whom were in remission. The median follow-up of the patients was 38 months. The 5-year overall survival and event-free survival were and 88.5% (95% CI: 77.1-94.4) and 78.7% (95% CI: 69.8-88.4), respectively. Our results are comparable to those in HICs in spite of the limited resources and the relatively low socioeconomic status of the Lebanese population. Children treated on this protocol experienced significant toxicity necessitating expert supportive care, but benefited from improved cure rates and prolonged survival.

Fever in women may interfere with follicular development during controlled ovarian stimulation.

PURPOSE: This study aims to evaluate the effects of fever on follicular development in women undergoing controlled ovarian stimulation during in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) cycles. MATERIALS AND METHODS: This was a retrospective observational self-controlled study at a tertiary-care fertility centre. Six gonadotropin stimulation cycles characterised by poor ovarian response in which women reported the occurrence of a febrile illness, were considered for evaluation. Fever-exposed cycles were compared to the next stimulation cycle in the same women. Primary outcome measures were final number of pre-ovulatory follicles (≥ 16 mm) and final peak serum estradiol levels (pg/mL). Other outcome measures were final number of medium-sized follicles (12-15 mm), final mean estradiol serum level per follicle ≥ 12 mm (pg/mL), total days of stimulation and total gonadotropin ampoules utilised. RESULTS: Fever-exposed cycles were associated with significantly lower number of pre-ovulatory follicles (0.7 ± 0.8), significantly higher number of medium-size follicles (21.0 ± 4.5), and significantly reduced serum estradiol per follicle ≥12 mm (50.7 ± 11.7 pg/mL). They also required a significantly longer duration of ovarian stimulation (15.7 ± 3.3 days) and a significantly increased number of gonadotropin ampoules (47.2 ± 10.9). Four women had polycystic ovary syndrome and one hypothalamic hypogonadism. CONCLUSION: This preliminary report suggests a possible negative effect of fever on follicular development and ovarian estradiol production in some women undergoing controlled ovarian stimulation.

An investigational ovarian stimulation protocol increased significantly the psychological burden in women with premature ovarian failure.

OBJECTIVE: To assess the psychological impact (Hospital Anxiety and Depression Scale) of an investigational ovarian stimulation protocol in women with premature ovarian failure (POF). DESIGN: Prospective longitudinal study. POPULATION: Ten women with POF. METHODS: Women with idiopathic POF were placed on three consecutive treatment cycles consisting of gonadotropin ovarian stimulation after estrogen priming, gonadotropin-releasing hormone agonist pituitary desensitization, and corticosteroid immune suppression. RESULTS: Median anxiety and depression scores increased significantly from baseline following three consecutive treatment cycles from 4.0 (range 2.0-8.0) to 11.0 (range 10.0-14.0) (p-value 0.041) and from 1.5 (range 0-6.0) to 9.0 (range 7.0-10.0) (p-value 0.039), respectively. There were nine "probable" anxiety (90%) and three "probable" depression (30%) cases on the final treatment cycle compared with none (0%) on baseline (p-value 0.004 and 0.250, respectively). CONCLUSIONS: The use of investigational ovarian stimulation protocols in women with idiopathic POF was associated with excessive psychological strain. Women with POF should be cautioned against the potentially harmful aspect of similar treatments of unproven benefit.