Inactivating NHLH2 variants cause idiopathic hypogonadotropic hypogonadism and obesity in humans.

Metabolism has a role in determining the time of pubertal development and fertility. Nonetheless, molecular/cellular pathways linking metabolism/body weight to puberty/reproduction are unknown. The KNDy (Kisspeptin/Neurokinin B/Dynorphin) neurons in the arcuate nucleus of the hypothalamus constitute the GnRH (gonadotropin-releasing hormone) pulse generator. We previously created a mouse model with a whole-body targeted deletion of nescient helix-loop-helix 2 (Nhlh2; N2KO), a class II member of the basic helix-loop-helix family of transcription factors. As this mouse model features pubertal failure and late-onset obesity, we wanted to study whether NHLH2 represents a candidate molecule to link metabolism and puberty in the hypothalamus. Exome sequencing of a large Idiopathic Hypogonadotropic Hypogonadism cohort revealed obese patients with rare sequence variants in NHLH2, which were characterized by in-silico protein analysis, chromatin immunoprecipitation, and luciferase reporter assays. In vitro heterologous expression studies demonstrated that the variant p.R79C impairs Nhlh2 binding to the Mc4r promoter. Furthermore, p.R79C and other variants show impaired transactivation of the human KISS1 promoter. These are the first inactivating human variants that support NHLH2's critical role in human puberty and body weight control. Failure to carry out this function results in the absence of pubertal development and late-onset obesity in humans.

Loss-of-function variants in SEMA3F and PLXNA3 encoding semaphorin-3F and its receptor plexin-A3 respectively cause idiopathic hypogonadotropic hypogonadism.

PURPOSE: Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by absent puberty and subsequent infertility due to gonadotropin-releasing hormone (GnRH) deficiency. IHH can be accompanied by normal or compromised olfaction (Kallmann syndrome). Several semaphorins are known potent modulators of GnRH, olfactory, and vomeronasal system development. In this study, we investigated the role of Semaphorin-3F signaling in the etiology of IHH. METHODS: We screened 216 IHH patients by exome sequencing. We transiently transfected HEK293T cells with plasmids encoding wild type (WT) or corresponding variants to investigate the functional consequences. We performed fluorescent IHC to assess SEMA3F and PLXNA3 expression both in the nasal region and at the nasal/forebrain junction during the early human fetal development. RESULTS: We identified ten rare missense variants in SEMA3F and PLXNA3 in 15 patients from 11 independent families. Most of these variants were predicted to be deleterious by functional assays. SEMA3F and PLXNA3 are both expressed along the olfactory nerve and intracranial projection of the vomeronasal nerve/terminal nerve. PLXNA1-A3 are expressed in the early migratory GnRH neurons. CONCLUSION: SEMA3F signaling through PLXNA1-A3 is involved in the guidance of GnRH neurons and of olfactory and vomeronasal nerve fibers in humans. Overall, our findings suggest that Semaphorin-3F signaling insufficiency contributes to the pathogenesis of IHH.

Prevalence and associated phenotypes of PLXNA1 variants in normosmic and anosmic idiopathic hypogonadotropic hypogonadism.

Idiopathic hypogonadotropic hypogonadism (IHH) can be divided into two major forms, normosmic IHH and Kallmann syndrome (KS). Genetic mutations are responsible for the majority of IHH. PLXNA1 has recently been implicated in the GnRH neuron migration and the etiology of KS. We aimed to investigate the prevalence and associated phenotypes of PLXNA1 variants in a large cohort of IHH patients. We screened the whole exome data of 215 IHH patients in a single center for causative PLXNA1 variants. Our studies showed eight novel (p.Arg836His, p.Lys1451Arg, p.Val287Met, p.Val536Ile, p.Ser1850Arg, p.Ile1701Val, p.Arg319Trp, and p.Pro485Leu) and two previously described (p.Arg528Trp and p.Gly720Glu) heterozygous PLXNA1 variants in nine affected individuals from seven unrelated families. Only three of nine patients were anosmic (KS) while the remaining patients showed normal olfactory function (nIHH). Seven of nine patients (77.7%) harbored additional one or two variants in other nIHH/KS-associated genes, including PROKR2, IGSF10, HS6ST1, SEMA3E, CCDC141, FGFR1, NRP1, POLR3A, and SRA1. Our findings indicate that PLXNA1 variants cause not only anosmic but also normosmic IHH with a relatively high prevalence (3.9%). Heterozygous missense PLXNA1 variants appear to be involved together with other IHH gene variants in bringing about the IHH disease phenotype.

Molecular genetic studies in a case series of isolated hypoaldosteronism due to biosynthesis defects or aldosterone resistance.

BACKGROUND AND AIM: Hypoaldosteronism is associated with either insufficient aldosterone production or aldosterone resistance (pseudohypoaldosteronism). Patients with aldosterone defects typically present with similar symptoms and findings, which include failure to thrive, vomiting, hyponatremia, hyperkalemia and metabolic acidosis. Accurate diagnosis of these clinical conditions therefore can be challenging. Molecular genetic analyses can help to greatly clarify this complexity. The aim of this study was to obtain an overview of the clinical and genetic characteristics of patients with aldosterone defects due to biosynthesis defects or aldosterone resistance. DESIGN AND PATIENTS: We investigated the clinical and molecular genetic features of 8 consecutive patients with a clinical picture of aldosterone defects seen in our clinics during the period of May 2015 through October 2017. We screened CYP11B2 for aldosterone synthesis defects and NR3C2 and the three EnaC subunits (SCNN1A, SCNN1B and SCNN1G) for aldosterone resistance. RESULTS: We found 4 novel and 2 previously reported mutations in the genes CYP11B2, NR3C2, SCNN1A and SCNN1G in 9 affected individuals from 7 unrelated families. CONCLUSION: Molecular genetic investigations can help confidently diagnose these conditions and clarify the pathogenicity of aldosterone defects. This study may expand the clinical and genetic correlations of defects in aldosterone synthesis or resistance.

Mutations in FEZF1 cause Kallmann syndrome.

Gonadotropin-releasing hormone (GnRH) neurons originate outside the CNS in the olfactory placode and migrate into the CNS, where they become integral components of the hypothalamic-pituitary-gonadal (HPG) axis. Disruption of this migration results in Kallmann syndrome (KS), which is characterized by anosmia and pubertal failure due to hypogonadotropic hypogonadism. Using candidate-gene screening, autozygosity mapping, and whole-exome sequencing in a cohort of 30 individuals with KS, we searched for genes newly associated with KS. We identified homozygous loss-of-function mutations in FEZF1 in two independent consanguineous families each with two affected siblings. The FEZF1 product is known to enable axons of olfactory receptor neurons (ORNs) to penetrate the CNS basal lamina in mice. Because a subset of axons in these tracks is the migratory pathway for GnRH neurons, in FEZF1 deficiency, GnRH neurons also fail to enter the brain. These results indicate that FEZF1 is required for establishment of the central component of the HPG axis in humans.

MCM9 mutations are associated with ovarian failure, short stature, and chromosomal instability.

Premature ovarian failure (POF) is genetically heterogeneous and manifests as hypergonadotropic hypogonadism either as part of a syndrome or in isolation. We studied two unrelated consanguineous families with daughters exhibiting primary amenorrhea, short stature, and a 46,XX karyotype. A combination of SNP arrays, comparative genomic hybridization arrays, and whole-exome sequencing analyses identified homozygous pathogenic variants in MCM9, a gene implicated in homologous recombination and repair of double-stranded DNA breaks. In one family, the MCM9 c.1732+2T>C variant alters a splice donor site, resulting in abnormal alternative splicing and truncated forms of MCM9 that are unable to be recruited to sites of DNA damage. In the second family, MCM9 c.394C>T (p.Arg132(∗)) results in a predicted loss of functional MCM9. Repair of chromosome breaks was impaired in lymphocytes from affected, but not unaffected, females in both families, consistent with MCM9 function in homologous recombination. Autosomal-recessive variants in MCM9 cause a genomic-instability syndrome associated with hypergonadotropic hypogonadism and short stature. Preferential sensitivity of germline meiosis to MCM9 functional deficiency and compromised DNA repair in the somatic component most likely account for the ovarian failure and short stature.

An emerging, recognizable facial phenotype in association with mutations in GLI-similar 3 (GLIS3).

Neonatal diabetes and hypothyroidism (NDH) syndrome was first described in 2003 in a consanguineous Saudi Arabian family where two out of four siblings were reported to have presented with proportionate IUGR, neonatal non-autoimmune diabetes mellitus, severe congenital hypothyroidism, cholestasis, congenital glaucoma, and polycystic kidneys. Liver disease progressed to hepatic fibrosis. The renal disease was characterized by enlarged kidneys and multiple small cysts with deficient cortico-medullary junction differentiation and normal kidney function. There was minor facial dysmorphism (depressed nasal bridge, large anterior fontanelle, long philtrum) reported but no facial photographs were published. Mutations in the transcription factor GLI-similar 3 (GLIS3) gene in the original family and two other families were subsequently reported in 2006. All affected individuals had neonatal diabetes, congenital hypothyroidism but glaucoma and liver and kidney involvement were less consistent features. Detailed descriptions of the facial dysmorphism have not been reported previously. In this report, we describe the common facial dysmorphism consisting of bilateral low-set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations and report the emergence of a distinct, probably recognizable facial gestalt in this group which evolves with age. © 2016 Wiley Periodicals, Inc.

Inactivating KISS1 mutation and hypogonadotropic hypogonadism.

Gonadotropin-releasing hormone (GnRH) is the central regulator of gonadotropins, which stimulate gonadal function. Hypothalamic neurons that produce kisspeptin and neurokinin B stimulate GnRH release. Inactivating mutations in the genes encoding the human kisspeptin receptor (KISS1R, formerly called GPR54), neurokinin B (TAC3), and the neurokinin B receptor (TACR3) result in pubertal failure. However, human kisspeptin loss-of-function mutations have not been described, and contradictory findings have been reported in Kiss1-knockout mice. We describe an inactivating mutation in KISS1 in a large consanguineous family that results in failure of pubertal progression, indicating that functional kisspeptin is important for puberty and reproduction in humans. (Funded by the Scientific and Technological Research Council of Turkey [TÜBITAK] and others.).

Normosmic idiopathic hypogonadotropic hypogonadism due to a novel homozygous nonsense c.C969A (p.Y323X) mutation in the KISS1R gene in three unrelated families.

OBJECTIVE: The spectrum of genetic alterations in cases of hypogonadotropic hypogonadism continue to expand. However, KISS1R mutations remain rare. The aim of this study was to understand the molecular basis of normosmic idiopathic hypogonadotropic hypogonadism. METHODS: Clinical characteristics, hormonal studies and genetic analyses of seven cases with idiopathic normosmic hypogonadotropic hypogonadism (nIHH) from three unrelated consanguineous families are presented. RESULTS: One male presented with absence of pubertal onset and required surgery for severe penoscrotal hypospadias and cryptorchidism, while other two males had absence of pubertal onset. Two of four female cases required replacement therapy for pubertal onset and maintenance, whereas the other two had spontaneous pubertal onset but incomplete maturation. In sequence analysis, we identified a novel homozygous nonsense (p.Y323X) mutation (c.C969A) in the last exon of the KISS1R gene in all clinically affected cases. CONCLUSIONS: We identified a homozygous nonsense mutation in the KISS1R gene in three unrelated families with nIHH, which enabled us to observe the phenotypic consequences of this rare condition. Escape from nonsense-mediated decay, and thus production of abnormal proteins, may account for the variable severity of the phenotype. Although KISS1R mutations are extremely rare and can cause a heterogeneous phenotype, analysis of the KISS1R gene should be a part of genetic analysis of patients with nIHH, to allow better understanding of phenotype-genotype relationship of KISS1R mutations and the underlying genetic basis of patients with nIHH.

Evaluating Postoperative Outcomes and Investigating the Usefulness of EU-TIRADS Scoring in Managing Pediatric Thyroid Nodules Bethesda 3 and 4

Objective: The aim was to assess postoperative outcomes in pediatric thyroid nodules with atypia of undetermined significance (AUS/FLUS) or suspicious for a follicular neoplasm (SFN) and their respective the European-Thyroid Imaging Reporting and Data System (EU-TIRADS) scores. Methods: Forty-four pediatric patients at a single center with thyroid nodules classified as AUS/FLUS or SFN from August 2019 to December 2022 were retrospectively reviewed. Data on demographics, thyroid function, nodule size, and ultrasonographic features were collected. Postoperative pathologies were categorized into benign, low-risk, and malignant neoplasms according to the World Health Organization 2022 criteria, and EU-TIRADS was used for retrospective radiological scoring. Results: Among 21 (47.7%) of patients who had surgical intervention, 72% had Bethesda 3 and 28% had Bethesda 4 thyroid nodules. Post-surgical histopathological classifications were 43% benign, 19% low-risk, and 38% malignant. Of note, EU-TIRADS 3 and 5 scores were present in 44% and 56% of the benign cases, respectively. Malignant cases tended to produce higher EU-TIRADS scores, with 64% rated as EU-TIRADS 5. Bethesda category 4 nodules had a 66% malignancy rate, significantly higher than the 27% in category 3. Conclusion: A substantial proportion of histologically benign cases were classified as EU-TIRADS 5, suggesting that EU-TIRADS may lead to unnecessary biopsies in benign cases. Malignant cases were more likely to have a higher EU-TIRADS score, indicating a positive correlation with malignancy risk, particularly in Bethesda 4 cases. However, the EU-TIRADS system's predictive value for malignancy in Bethesda 3 cases was poorer.

Body mass index evolution and ovarian function in adolescent girls who received GnRH agonist treatment for central precocious puberty or early and fast puberty.

OBJECTIVES: Gonadotropin-releasing hormone agonist (GnRHa) has been used for central precocious puberty (CPP) or early and fast puberty. It was aimed to assess changes in body mass index (BMI), polycystic ovary syndrome (PCOS) frequency, and anti-Müllerian hormone (AMH) in girls who had been treated with GnRHa. METHODS: Fifty-eight adolescent girls treated with GnRHa for CPP or early and fast puberty (3.75 mg/28 days), between 2011 and 2015, were re-evaluated in 2020-2022 at least 2 years after menstruation. Hormonal analyses were compared with 51 healthy adolescents. RESULTS: In the GnRHa-treated group, a statistically significant increase was observed when the BMI standard deviation score (SDS) at the beginning of the treatment was compared with the BMI SDS at the end of the treatment (p=0.038). A statistically significant decrease was observed when the BMI SDS at the end of the treatment was compared with the BMI SDS in late adolescence (p=0.012). When the BMI SDS at the beginning of the treatment was compared with the BMI SDS in late adolescence, it was observed that there was no statistically significant difference (p=0.196). Of the 58 girls in the GnRHa-treated group, 8 (14 %) had PCOS. Serum AMH levels did not differ between the GnRHa-treated and the control group. CONCLUSIONS: GnRHa treatment causes no adverse effect on BMI, at least in late adolescence. Girls treated with GnRHa were not found to be prone to developing PCOS. AMH levels were similar in the GnRHa-treated group as in the control group.

The First Case of 4H Syndrome with Type 1 Diabetes Mellitus.

4H syndrome is a rare progressive hypomyelinating leukodystrophy. Hypomyelination, hypodontia, and hypogonadotropic hypogonadism are the 3 classic features of 4H syndrome. Biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K gene cause 4H leukodystrophy. Herein, we present clinical features in two siblings with 4H syndrome. The first patient (16 years) presented hypogonadotropic hypogonadism, euthyroid Hashimoto's thyroiditis and type 1 diabetes mellitus. The second patient (13.5 years) showed normal physical, biochemical and hormonal examination at presentation. It was learned that he was followed up for epilepsy between the ages of 6 months and 6 years, his epilepsy medication was discontinued at the age of 6, and he did not have seizure again. T2-weighted magnetic resonance images showed increased signal intensity secondary to hypomyelination at patients. They were subsequently found to have homozygous mutation in the POLR3A gene. 4H syndrome may present with neurological and non-neurological findings in addition to classic features of 4H syndrome. Progressive neurological deterioration may occur and endocrine dysfunction may be progressive. Although multipl endocrine abnormalities associated with this disorder have been reported to date, a case accompanied by type 1 DM has not been seen in the literature. We do not know exactly whether this is coinsidans or the expansion of the phenotype. So that reporting such cases helps to determine the appropriate genotype-phenotype correlation in patients.

Novel sphingosine-1-phosphate lyase mutation causes multisystemic diseases: case report.

BACKGROUND: Sphingosine phosphate lyase insufficiency syndrome (SPLIS) caused by inactivating mutations in the human SGPL1 gene results in congenital nephrotic syndrome, adrenal insufficiency, ichthyosis, immunodeficiency, and a wide range of pathological neurological features. We present a novel mutation in the SGPL1 gene causing hypocalcemia, primary adrenal insufficiency (PAI), nephrotic syndrome, subclinical hypothyroidism, lymphopenia, ptosis, and pathologic neuroimaging findings. CASE: A Turkish male infant presented with bruising at 2 months of age and was diagnosed with hypocalcemia, PAI, and subclinical hypothyroidism. At the age of 15 months, he was admitted to the hospital with ptosis. Other systemic manifestations included persistent lymphopenia and nephrotic syndrome. Magnetic resonance imaging (MRI) of the brain and orbit demonstrated asymmetric contrast enhancement in the left cavernosal sinus, orbital apex, and thinning at the bilateral optic nerve. Whole exome sequencing (WES) revealed a homozygous c.1432C > G (p.Gln478Glu) variant in the SGPL1 gene (NM_003901.4), which has not previously been reported in the literature. CONCLUSIONS: Novel mutations in SGPL1 are still being identified. This case reminded us that SPLIS should not be considered for patients with nephrotic syndrome alone. Still, PAI may also include patients with neurological disorders, hypocalcemia, and pathological neuroimaging findings such as thinning at the bilateral optic nerve.

POU6F2 mutation in humans with pubertal failure alters GnRH transcript expression.

Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by the absence of pubertal development and subsequent impaired fertility often due to gonadotropin-releasing hormone (GnRH) deficits. Exome sequencing of two independent cohorts of IHH patients identified 12 rare missense variants in POU6F2 in 15 patients. POU6F2 encodes two distinct isoforms. In the adult mouse, expression of both isoform1 and isoform2 was detected in the brain, pituitary, and gonads. However, only isoform1 was detected in mouse primary GnRH cells and three immortalized GnRH cell lines, two mouse and one human. To date, the function of isoform2 has been verified as a transcription factor, while the function of isoform1 has been unknown. In the present report, bioinformatics and cell assays on a human-derived GnRH cell line reveal a novel function for isoform1, demonstrating it can act as a transcriptional regulator, decreasing GNRH1 expression. In addition, the impact of the two most prevalent POU6F2 variants, identified in five IHH patients, that were located at/or close to the DNA-binding domain was examined. Notably, one of these mutations prevented the repression of GnRH transcripts by isoform1. Normally, GnRH transcription increases as GnRH cells mature as they near migrate into the brain. Augmentation earlier during development can disrupt normal GnRH cell migration, consistent with some POU6F2 variants contributing to the IHH pathogenesis.

Relationship between metabolic control and neurocognitive functions in children diagnosed with type I diabetes mellitus before and after 5 years of age.

We aimed to investigate the effects of age onset of diabetes, glycemic control and frequency of hypoglycemia on neurocognitive functions in type I diabetic children. Sixty type I diabetic children with diagnosis before (Group 1) or after (Group 2) five years of age and 40 healthy children were tested. Wechsler Intelligence Scale for Children Revised (WISC-R), Stroop Test, and Visual Auditory Digit Span Test Form B were applied to all children in the two groups. Neurocognitive functions such as visual perception, short-term memory and selective attention were seen to be negatively affected at a significant level. Group 1 patients with poor glycemic control were found to have significant dysfunction in verbal, performance and general intelligence. Neurocognitive functions were negatively affected by early onset of diagnosis, poor glycemic control and frequent hypoglycemia in children with type I diabetes mellitus. We suggest that negative effects on neurocognitive functions in type I diabetes should be considered in the follow-up of these patients.

Unilateral exudative retinal detachment as the sole presentation of relapsing acute lymphoblastic leukemia.

Ocular findings are rarely the initial symptom of leukemia, although up to 90% of all leukemia patients have fundus changes during the course of the disease. Herein we report a relapsing acute lymphoblastic leukemia patient with thesole presentation of sudden visual loss and exudative retinal detachment. An 8-year-old boy with acute lymphoblasticleukemia developed sudden visual loss during his first remission period. Bullous retinal detachment with total afferentpupillary defect was observed. Orbital magnetic resonance imaging revealed an intraocular mass lesion; simultaneouslyobtained bone marrow and cerebrospinal fluid samples showed no evidence of leukemic cells. Following local irradiation,and systemic and intrathecal chemotherapy the mass disappeared. Local irradiation, and systemic and intrathecalchemotherapy effectively controlled the isolated ocular relapse of acute lymphoblastic leukemia and eliminated the needfor enucleation.

The utility of annual growth velocity standard deviation scores and measurements of biochemical parameters in long-term treatment monitoring of children with 21-hydroxylase deficiency.

PURPOSE: This study aimed to investigate the utility of annual growth velocity (GV) standard deviation scores (SDSs) and compatibility and effectiveness of biochemical parameters in long-term treatment monitoring and management of 21-hydroxylase deficiency (21-OHD) in children. METHODS: Fifty children with 21-OHD were included in this study, and the biochemical parameters obtained during 402 visits were retrospectively evaluated. The follow-up period was divided between two GV SDS groups (GV SDS < 2 and GV SDS ≥ 2) and compared with auxological, biochemical, and clinical findings. RESULTS: Elevation of 17-hydroxyprogesterone (17-OHP) values was observed at 193/402 visits, and both adrenocorticotropic hormone (ACTH) and total testosterone (tT) were observed at 53 of 193 (27.5%) visits. The calculated cut-off value for 17-OHP was > 4.3 ng/ml, with a sensitivity of 85.48% and specificity of 37.59% in the GV SDS ≥ 2 group. In the GV SDS ≥ 2 group, the corrected final height SDS (cFH SDS) was lower, and the delta height was higher than in the GV SDS < 2 group (p = 0.005 and p = 0.008, respectively). Linear regression analysis of the GV SDSs revealed that 17-OHP values and the hydrocortisone dose (mg/m2) were affected (ß = 0.037, p = 0.035, and ß = - 0.147, p = 0.001, respectively). CONCLUSIONS: Annual GV was critical in the final height (FH) of children with 21-OHD. However, we observed inconsistency between the biochemical parameters in the follow-ups, and there were difficulties in evaluating these markers. Therefore, annual GV SDSs and biochemical findings should be used together in patients with 21-OHD at follow-ups.

Pathogenic Variants in ZSWIM7 Cause Primary Ovarian Insufficiency.

CONTEXT: Primary ovarian insufficiency (POI) is a genetically heterogeneous condition associated with infertility and an increased risk of comorbidities. An increased number of genes implicated in DNA damage response pathways has been associated with POI as well as predisposition to cancers. OBJECTIVE: We sought to identify and characterize patients affected by POI caused by pathogenic variants in genes involved in DNA damage response during meiosis. SETTING: Study subjects were recruited at academic centers. PATIENTS OR OTHER PARTICIPANTS: Individuals with a diagnosis of POI and their family members were enrolled for genetic analysis. Clinical findings, family history, and peripheral blood samples were collected. RESEARCH DESIGN: Exome sequencing was performed on the study participants and their family members (when available). Protein conservation analysis and in silico modeling were used to obtain the structural model of the detected variants in the ZSWIM7 gene. MAIN OUTCOME MEASURE(S): Rare deleterious variants in known and candidate genes associated with POI. RESULTS: Homozygous deleterious variants in the ZSWIM7 gene were identified in 2 unrelated patients with amenorrhea, an absence of puberty, and prepubertal ovaries and uterus. Observed variants were shown to alter the ZSWIM7 DNA-binding region, possibly affecting its function. CONCLUSIONS: Our study highlights the pivotal role of the ZSWIM7 gene involved in DNA damage response during meiosis on ovarian development and function. Characterization of patients with defects in DNA repair genes has important diagnostic and prognostic consequences for clinical management and reproductive decisions.

PLXNB1 mutations in the etiology of idiopathic hypogonadotropic hypogonadism.

Idiopathic hypogonadotropic hypogonadism (IHH) comprises a group of rare genetic disorders characterized by pubertal failure caused by gonadotropin-releasing hormone (GnRH) deficiency. Genetic factors involved in semaphorin/plexin signaling have been identified in patients with IHH. PlexinB1, a member of the plexin family receptors, serves as the receptor for semaphorin 4D (Sema4D). In mice, perturbations in Sema4D/PlexinB1 signaling leads to improper GnRH development, highlighting the importance of investigating PlexinB1 mutations in IHH families. In total, 336 IHH patients (normosmic IHH, n = 293 and Kallmann syndrome, n = 43) from 290 independent families were included in the present study. Six PLXNB1 rare sequence variants (p.N361S, p.V608A, p.R636C, p.V672A, p.R1031H, and p.C1318R) are described in eight normosmic IHH patients from seven independent families. These variants were examined using bioinformatic modeling and compared to mutants reported in PLXNA1. Based on these analyses, the variant p.R1031H was assayed for alterations in cell morphology, PlexinB1 expression, and migration using a GnRH cell line and Boyden chambers. Experiments showed reduced membrane expression and impaired migration in cells expressing this variant compared to the wild-type. Our results provide clinical, genetic, molecular/cellular, and modeling evidence to implicate variants in PLXNB1 in the etiology of IHH.

Changes in the presentation of newly diagnosed type 1 diabetes in children during the COVID-19 pandemic in a tertiary center in Southern Turkey.

OBJECTIVES: The COVID-19 pandemic is a global health problem with high morbidity and mortality. This study aimed to investigate patients who were diagnosed with type 1 diabetes during the pandemic and evaluate the effect of the pandemic on the clinical findings of these patients by comparing them with findings from a year prior. METHODS: Patients diagnosed with type 1 diabetes mellitus between 2019 and 2021 were separated into two groups: Patients diagnosed prepandemic and those diagnosed during the pandemic. RESULTS: The number of newly diagnosed diabetes cases increased from 46 in the prepandemic period to 74 in the pandemic period. The number of cases diagnosed with diabetic ketoacidosis (DKA) in the clinic increased from 58.7 to 91.9%. We found that moderate and severe DKA rates from 18.5 and 14.8% to 23.5 and 22.1%, respectively. Besides, the average HbA1c was higher, while the average bicarbonate was lower in cases diagnosed during the pandemic period compared to the prepandemic period (p=0.048 and p<0.001, respectively). We found that celiac autoantibody positivity antibodies to glutamic acid decarboxylase (anti GAD) positivity, and islet cell antibodies (ICA), ICA and anti GAD positivity coexistence were higher (p=0.045, p=0.008, and p=0.007, respectively) among the patients diagnosed during the pandemic. CONCLUSIONS: We observed an increase in the number of patients newly diagnosed with type 1 diabetes mellitus, an increase in autoantibody positivity, and higher rates and severity of DKA during the COVID-19 pandemic period compared to the prepandemic period.