Assisted Reproductive Technology Required to Achieve High Conception Rates, Despite a Low Incidence of Hypogonadotrophic Hypogonadism in Thalassemia and Sickle Cell Disease Patients

Background Early and effective iron chelation has improved life expectancy and decreased disease complications for people with transfusion dependent thalassemia (TDT) and Sickle Cell Disease (SCD). Fertility challenges and pregnancy complications have historically limited reproductive options in this group, however improved disease management has made subfertility a chronic disease complication requiring attention. Despite this, there are very few reports on rates of conception and pregnancy outcomes in this population. Methods A 20 year retrospective analysis (1997 - 2017) was performed to evaluate fertility outcomes in women with TDT and SCD at an Australian referral centre. Patients with TDT and SCD who tried to conceive during the study period were included. Use of assisted reproductive technologies (ART), as well as pregnancy outcomes and neonatal and maternal complications were assessed. Results Eleven women with TDT and 3 with SCD tried to conceive during the study period. Median age at conception was 28 years (range 21-35). A total of 28 pregnancies and 25 live births were reported, including 2 spontaneous early pregnancy losses, a termination for anencephaly and a reduction of triplets. There was 1 multiple gestation in the cohort. At least 1 live birth occurred in 13 of the 14 women (93%). Spontaneous conception was reported in 9 women, of whom 8 had at least one resulting live birth, with a total of 15 live births from spontaneous conception. Of 5 women who were unable to conceive spontaneously, four had a diagnosis of hypogonadotrophic hypogonadism (HH) - two conceived following ovarian stimulation (OS), one required in vitro fertilization (IVF), and one did not pursue IVF following unsuccessful OS. The cause of subfertility was unknown in one patient, who conceived with IVF following failed OS. Three women who had an initial spontaneous conception required assisted reproductive technology (ART) for subsequent pregnancies, with no cause for subfertility identified. Mean ferritin at conception was 2911 mmol/L (range 164 to 8697mmol/L), and there was no association between ferritin at conception and need for ART. A trend was observed between increasing age and use of ART. Nine of the thirteen (69%) women who achieved pregnancy underwent Cesarean section for their first delivery. Prematurity (birth prior to 37 weeks' gestation) occurred in 5 (20%) of live births. Intrauterine growth restriction (IUGR) evidenced by birth weight <10 th centile for gestational age at birth was observed in 7 of 25 births (28%). This included one very low birth weight neonate delivered following induction for suspected IUGR. Respiratory distress syndrome occurred in two neonates in the setting of prematurity (delivered at 31 and 33 weeks gestation), both from women with TDT. Post partum hemorrhage (PPH) occurred after four deliveries in three women with TDT. There were no neonatal or maternal deaths. Conclusions Our data is the first analysis of fertility and pregnancy outcomes in Australian patients with TDT or SCD. Publications in this area are limited, and primarily report on pregnancy outcomes without capturing failure to conceive. Our findings are encouraging, with high conception rates achieved, with the use of ART where needed. Ferritin level did not predict difficulty with spontaneous conception and few of the women (29%) had HH, despite many having significant hyperferritinemia. Overall, 48% of live births resulted from ART, despite 58% of these patients not having a diagnosis of HH. This indicates that pituitary iron deposition with resultant HH alone does not adequately explain subfertility in this population. Our data also highlight the importance of affordable ART access for this patient population despite the clinical gains achieved with effective chelation therapy. Pregnancies were largely uncomplicated with excellent maternal and foetal outcomes. A high rate of IUGR was observed, supporting classification of pregnancy in this population as high risk. Rates of Cesarean section for first delivery were more than double the Australian average, likely in part due to high IUGR rates. Neonatal complications and PPH occurred at general population rates. Guidelines around pregnancy management in this population abound, however large prospective studies are needed to identify those at risk of sub- and infertility, even in the era of effective chelation. Disclosures No relevant conflicts of interest to declare.

Magnetic resonance imaging in Kallmann syndrome: A case report

Kallmann syndrome is a rare genetically inherited condition characterized by hypogonadotrophic hypogonadism and anosmia or hyposmia. It is due to failure of migration of gonadotrophic releasing hormone neuron and olfactory neuron to hypothalamus. This case reports a 39-year-old Maldivian adult with clinical features of Kallmann syndrome and magnetic resonance imaging brain showing absence of olfactory sulcus and bulb.

Reproductive outcomes in women with hypogonadotrophic hypogonadism, a case series study

Background Hypogonadotropic hypogonadism (HH) is a rare condition in which there is gonadal hypofunction due to absence of gonadotropin drive. In this condition, there are very low serum levels of gonadotropins. Pituitary gland may itself have some disease or disorder, or there may be loss of gonadotropin-releasing hormone (GnRH) pulses from the hypothalamus. The pharmacological interventions in HH women formed the basis for superovulation strategies for assisted reproduction techniques (ART) with a special reference to the role of LH and its impact on oocyte and embryo quality. Results The medians ±inter quartile ranges for number of oocytes retrieved, number of MII oocytes, and number of embryos transferred were 5±7, 4±3, and 3±1 respectively. The pregnancy rate was 31.5% for this group of patients. The live birth rate and miscarriage rate were 21% and 11.5% respectively. Conclusion The reproductive outcomes of patients of hypogonadotrophic hypogonadism are reasonable after ICSI and clinical trials are recommended to corroborate this concern.

SUN-032 Digenic Inheritance of PCSK1 and CHD7 Mutations in PAX4 Homozygous Diabetic Male with Normosmic Hypogonadotropic Hypogonadism

Background: Normosmic congenital hypogonadotropic hypogonadism denotes Kallmann syndrome not associated with anosmia or hyposmia. Over the past few years, the availability of next-generation sequencing has started to unravel the complex molecular basis of congenital hypogonadotrophic hypogonadism including digenic or oligogenic pathogenecity in addition to classic monogenic causality (1). Clinical Case: A 22-year-old male patient was referred to the endocrine clinic in 2018 with recent -onset hyperglycemia. His weight was 82.2 kg with a height of 180 cm (BMI of 25.3 kg/m2). Physical examination revealed small testes, micropenis, and no axillary and pubic terminal hair. His smell sense was intact. His hormonal test reveals low testosterone (0.10 ng/mL) and low free testosterone (0.65 pg/mL) levels with inappropriately low gonadotrophins levels. Secretion of LH and FSH increased 2-fold after GnRH stimulation. His bone age was 13-years 6-months old, and brain magnetic resonance imaging showed the presence of olfactory bulbs, and unremarkable findings except for small size of the pituitary gland. There were no signs associated with CHARGE syndrome (coloboma ocular, heart defects, atresia or stenosis of the choanae, retardation of growth and/or development, genitourinary anomalies, and ear abnormalities). Biochemical investigation demonstrated high serum glucose level and high HbA1c (13.8%). To identify variants to cause the phenotype of the proband, we adopted trio-based whole exome sequencing (WES) and candidate gene approach. Candidate genes was listed from the orphanet (https://www.orpha.net). WES of the proband revealed the presence of heterozygote missense mutations of the CHD7 gene (c.6107C>T, p.Pro2036Leu, rs369543203) and PCSK1 gene (c.239G>A, p.Arg80Gln, rs1799904). The missense variants were predicted to have a damaging effect on the encoded protein, by SIFT and PolyPhen-2 analyses. Genetic analyses of his family revealed that his father had the same heterozygote missense mutations of the CHD7 gene, but wild type of PCSK1. Proband’s mother had the same heterozygote missense mutations of PCSK1, but wild type of CHD7. Furthermore, the proband had homozygote missense mutation of PAX4 (c.575G>A, p.Arg192His, rs2233580) known as maturity-onset diabetes of the young (MODY) 9 gene. Both parents have the same but heterozygous mutation of PAX4 p.Arg192His, and pre-diabetic range of hyperglycemia. Conclusion: This is the first case demonstrating digenic inheritance of mutations in PCSK1 and CHD7 as a potential cause of normosmic hypogonadotrophic hypogonadism, interestingly in PAX4 homozygous diabetic male. Reference: (1) Maione L, et al. Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing. Eur J Endocrinol. 2018;178(3):R55-R80.