Publications by authors named "Ilana Koren"

16 Publications

  • Page 1 of 1

Successful delivery in 17,20-lyase Deficiency.

J Clin Endocrinol Metab 2021 Apr 7. Epub 2021 Apr 7.

Reproductive Endocrinology, Ob/Gyn, Rappaport Faculty of Medicine, Technion, Israel.

Objective: To study and describe the achievement of successful pregnancy and delivery in a patient with 17,20-lyase deficiency.

Design: Controlled ovarian stimulation (COS) and In Vitro fertilization (IVF), cryopreservation of embryos and frozen-thawed embryo transfer (ET).

Setting: IVF clinic.

Patient: A 24 years old, infertile patient with 17,20-lase deficiency.

Interventions: Controlled ovarian stimulation, follicular aspiration- egg retrieval, IVF, embryo cryopreservation, thawed ET.

Main Outcome Measures: Clinical pregnancy, successful delivery.

Results: Isolated 17,20-lyase deficiency is caused by mutations in the CYP17A1 gene (coding for cytochrome P450c17), POR (coding for cytochrome P450 oxidoreductase) and CYB5A (coding for microsomal cytochrome b5) genes. A 24 yo patient with 17,20-lyase deficiency had undergone IVF with gonadotropin releasing hormone agonist (GnRHa) protocol, prednisone, and gonadotropins. After human chorionic gonadotropin (hCG) trigger 37 oocytes were retrieved, 25 ova fertilized, and 17 embryos cryopreserved. After menstrual bleeding, the endometrium was stimulated with oral estradiol, under progesterone suppression with long acting GnRHa and prednisone. When endometrial width of 8.5 mm was reached, vaginal progesterone was added, while gradually decreasing prednisone. On the fourth day of progesterone supplement, two thawed embryos were transferred. After 11 days of human menopausal gonadotropin (hMG), estradiol concentration moderately increased, but progesterone levels remained high, therefore, no fresh ET was performed. Twelve days after thawed ET, hCG was positive, and seven days later, an intrauterine gestational sac was detected, but the pregnancy ended in missed abortion. After two months, another frozen-thawed embryo transfer (FET) was performed, generating a normal gestation, which ended in successful delivery.

Conclusion: Pregnancy can be achieved in patients with 17,20-lyase deficiency, by IVF, freezing all embrya, and ET in a subsequent cycle, while suppressing endogenous ovarian progesterone with a GnRHa and adrenal suppression with high dose glucocorticoids.
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April 2021

Primary Ovarian Insufficiency Nationwide Incidence Rate and Etiology Among Israeli Adolescents.

J Adolesc Health 2020 05 25;66(5):603-609. Epub 2020 Jan 25.

Pediatric Endocrinology and Diabetes Unit, Dana-Dwek Children Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Purpose: The aim of the study was to estimate the current incidence and the distribution of etiologies of primary ovarian insufficiency (POI) in a nationwide study. The prevalence of POI in young adult women has recently increased, but the data cited for adolescents are more than three decades old.

Methods: Data regarding females aged <21 years diagnosed with POI during the years 2000-2016 were collected from all the pediatric endocrinology units in Israel. POI was defined by at least 4 months of amenorrhea in association with menopausal levels of follicle-stimulating hormone. Iatrogenic cases were excluded.

Results: For the 130 females aged <21 years included in the study, the distribution of POI etiologies was Turner syndrome/mosaicism in 56 (43%), idiopathic in 35 (27%), and other (developmental, genetic, metabolic, adrenal, and autoimmune) in 39 (30%) females. During the years 2009-2016, compared with 2000-2008, the incidence rate of new POI diagnoses per 100,000 person-years doubled (4.5 vs. 2.0; p value <.0001), and incidence rates of idiopathic and other etiologies increased by 2.6 (p value = .008) and 3.0 (p value = .002), respectively. In contrast, the incidence of Turner syndrome was constant (p value = .2). In the age group of 15-21 years, the current incidence of non-Turner POI in adolescents is one per 100,000 person-years.

Conclusions: In this nationwide study, the incidence rate of POI in youth aged <21 years was one tenth of the rate that is commonly cited. A significant increase in the rate of POI in non-Turner females was observed over the last decade. Contributions of environmental and epigenetic factors should be studied.
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May 2020

Combined Gestational Age- and Birth Weight-Adjusted Cutoffs for Newborn Screening of Congenital Adrenal Hyperplasia.

J Clin Endocrinol Metab 2019 08;104(8):3172-3180

The National Newborn Screening Program, Ministry of Health, Tel-Hashomer, Israel.

Context: Congenital adrenal hyperplasia (CAH) was among the first genetic disorders included in newborn screening (NBS) programs worldwide, based on 17α-hydroxyprogesterone (17-OHP) levels in dried blood spots. However, the success of NBS for CAH is hampered by high false positive (FP) rates, especially in preterm and low-birthweight infants.

Objective: To establish a set of cutoff values adjusting for both gestational age (GA) and birthweight (BW), with the aim of reducing FP rates.

Design: This cross-sectional, population-based study summarizes 10 years of experience of the Israeli NBS program for diagnosis of CAH. Multitiered 17-OHP cutoff values were stratified according to both BW and GA.

Participants: A total of 1,378,132 newborns born between 2008 and 2017 were included in the NBS program.

Results: Eighty-eight newborns were ultimately diagnosed with CAH; in 84 of these, CAH was detected upon NBS. The combined parameters-adjusted approach significantly reduced the recall FP rate (0.03%) and increased the positive predictive value (PPV) (16.5%). Sensitivity among those referred for immediate attention increased significantly (94%). There were four false negative cases (sensitivity, 95.4%), all ultimately diagnosed as simple-virilizing. Sensitivity and specificity were 95.4% and 99.9%, respectively, and the percentage of true-positive cases from all newborns referred for evaluation following a positive NBS result was 96%.

Conclusions: The use of cutoff values adjusted for both GA and BW significantly reduced FP rates (0.03%) and increased overall PPV (16.5%). Based on our 10 years of experience, we recommend the implementation of this two parameter-adjusted approach for NBS of classic CAH in NBS programs worldwide.
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August 2019

Bilateral vocal cord paralysis and hypothyroidism as presenting symptoms of Williams-Beuren syndrome: a case report.

Int J Pediatr Otorhinolaryngol 2015 Sep 25;79(9):1582-3. Epub 2015 Jun 25.

The Department of Otolaryngology, Carmel Medical Center, and the Rappaport Faculty of Medicine, Technion-Israel, Institute of Technology, Haifa, Israel. Electronic address:

Williams-Beuren syndrome is a rare neurodevelopmental disorder caused by deletion of 1.5-1.8Mb genes on chromosome 7q11.23. The syndrome was first described as a triad of supra-valvular aortic stenosis, mental retardation, and distinctive facial features. Our patient was referred due to audible inspiratory stridor when he was seven days old. Following endoscopy he was diagnosed with bilateral vocal cord paralysis and was eventually intubated due to respiratory de-compensation followed by tracheotomy. On further workup he was diagnosed with hypothyroidism. Genetic workup supported the diagnosis of Williams-Beuren syndrome. We report here a case with an unusual clinical presentation.
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September 2015

Post-hemorrhagic hydrocephalus and diabetes insipidus in preterm infants.

J Pediatr Endocrinol Metab 2014 Nov;27(11-12):1261-3

We present two cases of transient central diabetes insipidus in preterm neonates with post-hemorrhagic hydrocephalus. Although the association between intraventricular hemorrhage and diabetes insipidus has been described in preterm infants, the association between diabetes insipidus and hydrocephalus, and the fact that such central diabetes insipidus could be reversible with the reduction of ventricular size, either because of spontaneous resolution or the placement of ventriculo-peritoneal shunt is first described here in neonates.
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November 2014

Transient Hypercalcemia in Preterm Infants: Insights Into Natural History and Laboratory Evaluation.

Glob Pediatr Health 2014 21;1:2333794X14560818. Epub 2014 Nov 21.

Technion, Israel Institute of Technology, Haifa, Israel; Department of Neonatology, Bnai Zion Medical Center, Haifa, Israel.

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June 2016

Hepatitis in an infant treated with octreotide for congenital hyperinsulinism.

J Pediatr Endocrinol Metab 2013 ;26(1-2):183-5

Armon Child Center, Haifa, Israel.

Congenital hyperinsulinism is characterized by hypoglycemia caused by several genetic disorders of inappropriate insulin secretion. Octreotide, an analogue of somatostatin, plays a major role in the pharmaceutical treatment of this condition. A 9-month-old infant treated with octreotide developed anicteric hepatitis with no other proven cause. After the discontinuation of this drug, the liver enzymes declined rapidly. Liver function tests should be followed in patients receiving octreotide.
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June 2013

Cognitive and developmental outcome of conservatively treated children with congenital hyperinsulinism.

J Pediatr Endocrinol Metab 2013 ;26(3-4):301-8

Safra Children’s Hospital, Tel Hashomer, Israel.

Background: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infants. Its management can be extremely complicated, and may involve medical therapy and surgery. The mainstay of the treatment is to maintain normoglycemia, since hypoglycemia during infancy can have severe neurological consequences.

Objective: To assess the cognitive and developmental levels and the adaptive skills achieved by children with CHI who were treated medically over the past decade.

Subjects And Methods: Fourteen children with CHI, under the age of 10 years, who received medical treatment only, underwent a physical and neurological examination and standardized assessments that included the Bayley Scale of Infant and Toddler Development, 3rd Edition, or Kaufman Assessment Battery for Children, the Vineland Adaptive Behavior Scales and the Achenbach Child Behavior Checklist (CBCL) parent questionnaire form.

Results: Twelve children (86%) achieved normal range scores in the cognitive and development assessments (Bayley Scale of Infant and Toddler Development or Kaufman Assessment Battery for Children). Only two showed cognitive achievements below the normal range. The Vineland questionnaire, which was based on parental report, showed below normal adaptive skills in eight patients (57%).

Conclusions: In contrast to previous studies showing a high prevalence of neurodevelopmental difficulties in children with congenital hyperinsulinism, our study showed normal cognitive achievements in most children. This may be attributed to the earlier recognition and better management of the disease in the past decade.
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August 2013

Tight junction proteins expression and modulation in immune cells and multiple sclerosis.

J Cell Mol Med 2012 Apr;16(4):765-75

Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.

The tight junction proteins (TJPs) are major determinants of endothelial cells comprising physiological vascular barriers such as the blood-brain barrier, but little is known about their expression and role in immune cells. In this study we assessed TJP expression in human leukocyte subsets, their induction by immune activation and modulation associated with autoimmune disease states and therapies. A consistent expression of TJP complexes was detected in peripheral blood leukocytes (PBLs), predominantly in B and T lymphocytes and monocytes, whereas the in vitro application of various immune cell activators led to an increase of claudin 1 levels, yet not of claudin 5. Claudins 1 and 5 levels were elevated in PBLs of multiple sclerosis (MS) patients in relapse, relative to patients in remission, healthy controls and patients with other neurological disorders. Interestingly, claudin 1 protein levels were elevated also in PBLs of patients with type 1 diabetes (T1D). Following glucocorticoid treatment of MS patients in relapse, RNA levels of JAM3 and CLDN5 and claudin 5 protein levels in PBLs decreased. Furthermore, a correlation between CLDN5 pre-treatment levels and clinical response phenotype to interferon-β therapy was detected. Our findings indicate that higher levels of leukocyte claudins are associated with immune activation and specifically, increased levels of claudin 5 are associated with MS disease activity. This study highlights a potential role of leukocyte TJPs in physiological states, and autoimmunity and suggests they should be further evaluated as biomarkers for aberrant immune activity and response to therapy in immune-mediated diseases such as MS.
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April 2012

Treatment of congenital hyperinsulinism with lanreotide acetate (Somatuline Autogel).

J Clin Endocrinol Metab 2011 Aug 22;96(8):2312-7. Epub 2011 Jun 22.

Pediatric Endocrinology and Diabetes Unit, The Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Tel-Hashomer (affiliated with The Sackler School of Medicine, Tel-Aviv University), 52621 Israel.

Context: Congenital hyperinsulinism (CH) may be treated conservatively in many children with octreotide given by multiple sc injections or via an insulin pump.

Objective: We describe two children treated with a once-monthly injection of a long-acting somatostatin analog.

Patients And Methods: Both patients presented with hypoglycemia 30 min after birth and were subsequently diagnosed with CH. Patients were initially treated with diazoxide, hydrochlorothiazide, frequent feedings, and octreotide via an insulin pump. With this therapy, they were normoglycemic with a good growth rate, normal weight gain, and excellent neurodevelopment. Treatment with the long-acting somatostatin analog lanreotide acetate (Somatuline Autogel), administered by deep sc injection of 30 mg once a month, was started at the ages of 4½ and 4 yr, respectively. Octreotide infusion was gradually weaned over 1 month. Continuous glucose monitoring after discontinuation of pump therapy showed normoglycemia. The first patient has now been treated with the lanreotide acetate for over 5 yr, and the second for 3 yr. Treatment is well-tolerated, and both the patients and their parents are satisfied with the transition from pump therapy to once-a-month injection and prefer it to pump therapy.

Conclusion: Lanreotide acetate may be a safe and effective alternative to octreotide pump therapy in patients with CH, offering an improved quality of life. Longer follow-up of a larger patient group is needed.
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August 2011

Adiponectin levels in adolescent girls with polycystic ovary syndrome (PCOS).

Clin Endocrinol (Oxf) 2009 Dec 6;71(6):823-7. Epub 2009 Apr 6.

Endocrine Clinic, Maccabi Health Care Services, Israel.

Objective: To determine serum adiponectin concentrations in adolescent girls with and without polycystic ovary syndrome (PCOS) and to assess possible correlations of adiponectin levels with insulin and androgen levels.

Design: Prospective case-control study.

Setting: Endocrine clinics in the community.

Patients: Forty-four adolescent girls were grouped as follows: 14 were overweight [body mass index (BMI) standard deviation score >1.645] with PCOS; 16 were lean (BMI SDS <1.036) with PCOS; and 14 were lean (BMI SDS <1.036) without PCOS. Intervention Blood samples were collected from all girls between 8 and 11 am, after an overnight fast.

Main Outcome Measures: Serum levels of adiponectin, leptin, insulin, Müllerian-inhibiting substance, luteinizing hormone, follicle-stimulating hormone, testosterone, 17-alpha-hydroxyprogesterone, androstendione, dehydroepiandrosterone sulphate (DHEAS) and 17beta-oestradiol.

Results: Adiponectin concentrations were significantly decreased in obese adolescents with PCOS (10.5 +/- 5.5 mug/ml) compared with that in lean girls with or without PCOS (16.9 +/- 8.64 and 18.0 +/- 7.4 mug/ml respectively). Leptin levels were significantly elevated in obese adolescents with PCOS compared with the levels in normal weight adolescents with PCOS, and compared with that in normal weight controls. Insulin levels were markedly higher in obese adolescents with PCOS compared with that in normal weight adolescents (12.3 +/- 12.2 vs. 4.5 +/- 2.9, P < 0.05), and compared with that in normal weight PCOS adolescents (7.4 +/- 4.9); however, this difference was not statistically significant. Insulin levels did not differ between normal weight adolescents with PCOS and normal controls. Adiponectin concentrations correlated inversely with BMI, leptin and insulin.

Conclusions: Hypoadiponectinaemia is evident only in obese adolescents with PCOS and therefore does not seem to be involved in the pathogenesis of PCOS in this age group.
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December 2009

Pitfalls in screening programs for congenital hypothyroidism in premature newborns.

Am J Perinatol 2009 May 11;26(5):383-5. Epub 2008 Dec 11.

Department of Neonatology, Bnai Zion Medical Center, Haifa, Israel.

Sick premature infants may display transient hypothyroxinemia secondary to immaturity of the hypothalamic-pituitary axis. Therefore, early screening programs of such infants may be misleading. We present such a case report, with review of the literature and the following suggested recommendations. (1) Screening programs should report thyroid-stimulating hormone (TSH) as well as thyroxine (T(4)) levels in premature infants, which will allow the treating physicians to be aware of possible abnormality that needs to be followed. (2) Sick premature infants and other populations at risk should undergo a full serum thyroid function evaluation including free T(4) and TSH beyond the screening program at discharge or at 30 days of age, whichever comes first. (3) Physicians should use their clinical judgment and experience even in the face of normal newborn thyroid screening test and reevaluate for hypothyroidism when there is a clinical suspicion. Our case report is a reminder of the American Academy of Pediatrics guidelines with practical suggestions for extra caution to avoid missing primary hypothyroidism in sick premature infants.
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May 2009

Control of childhood congenital adrenal hyperplasia and sleep activity and quality with morning or evening glucocorticoid therapy.

J Clin Endocrinol Metab 2008 Dec 9;93(12):4707-10. Epub 2008 Sep 9.

Pediatric Endocrinology, Rambam Medical Center, Haifa 31096, Israel.

Context: Traditionally, hydrocortisone (HC) replacement therapy in congenital adrenal hyperplasia (CAH) is given by three daily doses, albeit not necessarily of equal quantity. Although a higher dose in the morning better imitates the physiological diurnal variation, a late-night higher dose was suggested to better suppress early morning hypothalamic-pituitary-adrenal axis peak activity. Yet, increased night cortisol has been claimed to be associated with sleep disturbances and insomnia.

Objective: Our objective was to evaluate evening vs. morning high-HC dose with respect to disease control, sleep pattern, and daytime activity in children with CAH.

Design: An open-label, cross-over, randomized trial of 15 children with classical CAH was performed. Patients were randomized to receive 50% of the daily HC in the morning or evening for 2 wk; the other two doses included 25% of the daily dose each.

Outcome Measures: Disease control was assessed by 0800-h 17-hydroxyprogesterone, testosterone, androstenedione, and dehydroepiandrosterone sulfate on the last day of each treatment schedule. Sleep and daytime activity were assessed by a 7-d actigraph.

Results: Basal morning androstenedione, 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, and testosterone levels during the high-morning and high-evening HC treatment schedules were comparable. There were no significant differences in sleep or daytime activity.

Conclusions: With respect to disease control, sleep quality and daytime activity were not affected by treatment schedules. We recommend the high-morning dose schedule in replacement therapy of children with CAH.
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December 2008

Metabolic evidence for impaired 17alpha-hydroxylase activity in a kindred bearing the E305G mutation for isolate 17,20-lyase activity.

Eur J Endocrinol 2008 Mar;158(3):385-92

Pediatric Endocrinology, Metabolic Biochemistry Laboratory and Genetics Institute, Rambam Medical Center, Meyer Children's Hospital, Technion-Israel Institute of Technology, 9602 Haifa, Israel.

Context: The CYP17A1 gene encodes many enzymatic reactions including 17alpha-hydroxylase and 17,20-lyase activities. Mutations that selectively ablate the 17,20-lyase activity, causing isolated 17,20-lyase deficiency, are exceedingly rare and may belong to the rarest of all disorders of steroidogenesis. We have previously reported an E305G mutation in the active site of CYP17A1 that apparently causes isolated 17,20-lyase deficiency. Expression studies suggested intact 17alpha-hydroxylase activity which was at odds with subnormal tetracosactrin stimulated cortisol in the patients.

Objectives: To investigate the in vivo activity of the adrenal enzymes, we used the metabolomics approach with urinary steroid profiling by gas chromatography-mass spectrometry.

Patients: Of the 11 subjects investigated, 6 patients in the kindred were found to be homozygous, 4 members were asymptomatic heterozygous, and 1 was homozygous for the wild-type allele.

Results: In the homozygous patients for E305G, both serum and urinary steroids showed a severe lack of androgens (C(19)-steroids) pointing to the absence of 17,20-lyase activities. Furthermore, precursor/product ratios of urinary steroid metabolites characterizing 17alpha-hydroxylase activity showed variable decreases in 17alpha-hydroxylase activities.

Conclusions: The results confirm the complete absence of 17,20-lyase activity in vivo, as in the in vitro expression studies. On the other hand, in vivo 17alpha-hydroxylase activity was partially impaired. Thus, the in vivo metabolic data seem to be more sensitive than the expression study and suggests that this mutation also impairs 17alpha-hydroxylase activity.
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March 2008

The approach to a neonate with a possible prenatal diagnosis of androgen insensitivity syndrome.

J Pediatr Endocrinol Metab 2006 Dec;19(12):1437-43

Department of Neonatology, Bnai Zion Medical Center, B. Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.

The diagnosis of androgen insensitivity syndrome (AIS) can now be made prenatally. We present a patient for whom the diagnosis of AIS was highly suspected prenatally, but the parents preferred to deny it. The clinical findings and the diagnostic evaluation after delivery are presented. A brief discussion of the syndrome, as well as the implications of possible prenatal diagnosis and how to approach it, are provided. Full multidisciplinary diagnostic work-up immediately after delivery, as well as awareness of possible prenatal diagnosis, is the responsibility of the primary care provider for the newborn with suspected AIS.
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December 2006

Prevention of type 1A diabetes: update.

Isr Med Assoc J 2004 May;6(5):301-4

Laboratory for the Research of Diabetes and Obesity, Felsenstein Medical Research Center (Beilinson Campus), Petah Tiqva, Israel.

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May 2004