Identification of a novel homozygous NR5A1 variant in a patient with a 46,XY disorders of sex development.

OBJECTIVES: Nuclear receptor subfamily 5 group A member 1 (NR5A1) is a transcription factor critical for the development of various organs. Pathogenic variants in NR5A1 are associated with a spectrum of disorders of sex development (DSD). CASE PRESENTATION: A 15-month-old baby, raised as a girl, was referred for genital swelling and ambiguous genitalia. Born to healthy consanguineous parents, the baby had a phallus, perineal hypospadias, labial fusion, and a hypoplastic scrotum. Hormonal evaluation showed normal levels, and ultrasonography revealed small gonads and absence of Müllerian derivatives. Post-human chorionic gonadotropin (hCG) testing indicated an adequate testosterone response. The karyotype was 46,XY, and in it was found a homozygous NR5A1 variant (c.307 C>T, p.Arg103Trp) in a custom 46 XY DSD gene panel. Notably, the patient exhibited complete sex reversal, hyposplenia, and no adrenal insufficiency. CONCLUSIONS: Previously, NR5A1 pathogenic variants were considered to be dominantly inherited, and homozygous cases were thought to be associated with adrenal insufficiency. Despite the homozygous pathogenic variant, our patient showed hyposplenism with normal adrenal function; this highlights the complexity of NR5A1 genotype-phenotype correlations. These patients should be monitored for adrenal insufficiency and DSD as well as splenic function.

Evaluation of Serum Advanced Glycation End Product Levels and Microvascular Complications in Children and Adolescents with Type 1 Diabetes Mellitus.

OBJECTIVE: Advanced glycation end products (AGEs) are irreversible macromolecules formed by nonenzymatic reactions due to chronic hyperglycemia. The aim of this study was to assess the relationship between AGEs and the microvascular complications of children and adolescents with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: Twenty-six T1DM patients with microvascular complications and 58 complication-naive patients who were similar regarding age, sex, and pubertal status enrolled in the study. Anthropometric, biochemical, ophthalmologic, and neurologic variables were compared with serum AGEs levels by the fluorescence method. RESULTS: There was no significant difference observed between the patients with complications and those without complications in terms of serum levels of AGEs and other biochemical parameters. However, the duration of T1DM and urine microalbumin-creatinine ratio (uACR) were significantly higher in the complication-positive group (P < .001). Serum levels of AGEs were found to be similar when retinopathy, peripheral, and optic neuropathy were separately compared with the complication-naive group (P > .05). However, patients with nephropathy had significantly higher serum levels of AGEs than patients without complications (P = .023). In addition, there was a significant positive correlation between serum AGEs levels and uACR (P = .042) but not other parameters (P > .05). CONCLUSION: This study is the first to evaluate the association between serum AGEs levels and microvascular complications in children and adolescents with T1DM. Our study highlights that serum AGEs levels are significantly correlated with nephropathy but not with retinopathy and neuropathy. Further long-term studies with a larger sample size are required to establish a better relationship between diabetic complications and AGEs. Cite this article as: Kirkgöz T, Acar S, Küme T, et al. Evaluation of serum advanced glycation end product levels and microvascular complications in children and adolescents with type 1 diabetes mellitus. Turk Arch Pediatr. 2024;59(1):31-37.

Genetic diagnosis of congenital hypopituitarism in Turkish patients by a target gene panel: novel pathogenic variants in GHRHR, GLI2, LHX4 and POU1F1 genes.

Objective: Congenital hypopituitarism (CH) is a rare disease characterized by one or more hormone deficiencies of the pituitary gland. To date, many genes have been associated with CH. In this study, we identified the allelic variant spectrum of 11 causative genes in Turkish patients with CH. Materials and methods: This study included 47 patients [21 girls (44.6%) and 26 boys (55.4%)] from 45 families. To identify the genetic etiology, we screened 11 candidate genes associated with CH using next-generation sequencing. To confirm and detect the status of the specific familial variant in relatives, Sanger sequencing was also performed. Results: We identified 12 possible pathogenic variants in GHRHR, GH1, GLI2, PROP-1, POU1F1, and LHX4 in 11 patients (23.4%), of which six were novel variants: two in GHRHR, two in POU1F1, one in GLI2, and one in LHX4. In all patients, these variants were most frequently found in GLI2, followed by PROP-1 and GHRHR. Conclusion: Genetic causes were determined in only 23.4% of all patients with CH and 63% of molecularly diagnosed patients (7/11) from consanguineous families. Despite advances in genetics, we were unable to identify the genetic etiology of most patients with CH, suggesting the effect of unknown genes or environmental factors. More genetic studies are necessary to understand the etiology of CH.

Clinical and Genetic Characteristics of Patients with Common and Rare Types of Congenital Adrenal Hyperplasia: Novel Variants in STAR and CYP17A1.

Objectives: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases characterized by salt wasting or virilization. 21 hydroxylase deficiency (21-OHD) accounts for 90-95% of all cases of CAH and caused by the genetic defects of CYP21A2. Other forms include 3-ß-hydroxysteroid dehydrogenase deficiency, 11-ß-hydroxylase deficiency (11ß-OHD) (%5-8), 17-α-hydroxylase deficiency (17α-OHD), and steroidogenic acute regulatory protein (STAR) defects (congenital lipoid adrenal hyperplasia) with mutations in HSD3B2, CYP11B1, CYP17A1, and STAR, respectively. Objectives: Herein, we aimed to present the clinical and genetic features of 64 patients with various types of CAH. Methods: Sixty-four patients with CAH, monitored in the Izmir Dr. Behcet Uz Children Hospital Division of Pediatric Endocrinology, were retrospectively analyzed for the clinical, laboratory, and genetic data. Results: Fifty-six patients (87.5%) had 21-OHD and four patients (6.3%) had 17α-OHD, three patients (4.7%) had 11ß-OHD, and one patient (1.5%) had STAR defect. The most common presenting features in 21-OHD were ambiguous genitalia. Patients with 21-OHD were diagnosed earlier than the rare groups. Disease-causing variants of CYP21A2 were identified in 46 patients. The most common mutations were IVS2, Q318X, I172N, and large deletions. Three patients with 11ß-OHD were presented with enlargement of penis and early pubic hair at the median presenting age of 26 months. 17α-OHD deficiency was detected in 4 cases. Genetic analysis revealed two different homozygous CYP17A1 variants. The patient with STAR defect was presented with dehydration and cholestasis in 44 days of the life. Genetic analysis of patient with STAR deficiency revealed a novel homozygous variant. Conclusion: The current study reported a genotype-phenotype correlation consistent with literature data in CAH cases with 21-OHD. This study also reported novel homozygous variants in STAR and CYP17A1 genes that lead to rare types of CAH.

A Null Mutation of TNFRSF11A Causes Dysosteosclerosis, Not Osteopetrosis.

Dysosteosclerosis (DOS) is a rare sclerosing bone dysplasia characterized by unique osteosclerosis of the long tubular bones and platyspondyly. DOS is inherited in an autosomal recessive manner and is genetically and clinically heterogeneous. To date, four individuals with DOS who have five different TNFRSF11A mutations have been reported. Based on their data, it is hypothesized that mutations producing aberrant mutant RANK proteins (missense or truncated or elongated) cause DOS, while null mutations lead to osteopetrosis, autosomal recessive 7 (OPTB7). Herein, we present the fifth case of TNFRSF11A-associated DOS with a novel homozygous frame-shift mutation (c.19_31del; p.[Arg7CysfsTer172]). The mutation is predicted to cause nonsense mutation-mediated mRNA decay (NMD) in all RANK isoform transcripts, resulting in totally null allele. Our findings suggest genotype-phenotype relationship in TNFRSF11A-associated OPTB7 and DOS remains unclear, and that the deficiency of TNFRSF11A functions might cause DOS, rather than osteopetrosis. More data are necessary to understand the phenotypic spectrum caused by TNFRSF11A mutations.

Screening of non-syndromic early-onset child and adolescent obese patients in terms of LEP, LEPR, MC4R and POMC gene variants by next-generation sequencing.

OBJECTIVES: Non-syndromic monogenic obesity is a rare cause of early-onset severe obesity in the childhood period. The aim of this study was to screen four obesity related genes (LEP, LEPR, MC4R and POMC) in children and adolescents who had severe, non-syndromic early onset obesity. METHODS: Next-generation sequencing of all exons in LEP, LEPR, MC4R and POMC was performed in 154 children and adolescents with early onset severe obesity obesity. RESULTS: Fifteen different variants in nineteen patients were identified with a variant detection rate of 12.3%. While six different heterozygous variants were observed in MC4R gene (10/154 patients; 6.5%), five different variants in POMC gene (four of them were heterozygous and one of them was homozygous) (6/154 patients; 3.9%) and four different homozygous variants in LEPR gene (3/154 patients; 1.9%) were described. However, no variants were detected in the LEP gene. The most common pathogenic variant was c.496G>A in MC4R gene, which was detected in four unrelated patients. Six novel variants (6/15 variants; 40%) were described in seven patients. Four of them including c.233C>A and c.752T>C in MC4R gene and c.761dup and c.1221dup in LEPR gene were evaluated as pathogenic or likely pathogenic. CONCLUSIONS: In conclusion, MC4R variants are the most common genetic cause of monogenic early-onset obesity, consistent with the literature. The c.496G>A variant in MC4R gene is highly prevalent in early-onset obese patients.

Trend in initial presenting features of type 1 diabetes mellitus over a 24 year period in Turkey: a retrospective analysis of 814 cases.

BACKGROUND: The study aim was to examine changes in trends of presenting features during the diagnosis of patients followed up with newly diagnosed Type 1 diabetes mellitus (T1DM) over the past 24 years. METHODS: The study was retrospective. Patients with a diagnosis of T1D between the years of 1996-2019 were included. Patients diagnosed in the first half of the period comprised Period I, and those from the second half comprised Period II. Patient data were extracted from medical records and included gender distribution, year of diagnosis, age at diagnosis, duration of symptoms, type of admission, frequency of diabetic ketoacidosis (DKA) and biochemical parameters. Subsequently, temporal changes in trends of these parameters were sought. RESULTS: For the whole cohort the gender distribution was equal; 404 (49.6%) were girls and 410 (50.4%) were boys. Mean age at diagnosis was 8.5±4.2 years and age groupings at presentation were: 23.2% (n = 189) aged 0-4; 39.2% (n = 319) aged 5-9; 27.5% (n = 224) aged 10-13; 10.1% (n= 82) aged 14-18. At presentation 72 (12.7%) had hyperglycemia, 230 (40.6%) had diabetic ketosis, and 264 (46.6%) had DKA. In those with DKA, mild DKA was found in 103 (39.0%), moderate DKA in 81 (30.6%), and severe DKA in 80 (30.3%). While the frequency of DKA was 54.9% between 1996 and 2007 (Period I), this significantly decreased to 44.4% between 2008 and 2019 (Period II). Girls and boys had a similar rate of T1DM, and this did not change over time. Three peak ages of diagnosis were evident; 5-7, 8-10, 12-14 years of age. CONCLUSIONS: The frequency of DKA decreased and the frequency of admission with hyperglycemia and ketosis increased during the study period, which may have repercussions for mortality and morbidity rates and aid in improved treatment outcomes.

How Vitamin D Levels of Children Changed During COVID-19 Pandemic: A Comparison of Pre-pandemic and Pandemic Periods

Objective: The synthesis of vitamin D is related to sun exposure, thus the restrictions during the Coronavirus disease-2019 (COVID-19) pandemic may have affected the levels of vitamin D in all age groups. The aim of this study was to evaluate vitamin D levels of healthy children and adolescents during the first year of the pandemic. Methods: The study group included healthy children and adolescents who were admitted for general check-ups and evaluated with 25(OH)D levels. Then, it was divided into two groups: Group 1 "pre-pandemic", and Group 2 "pandemic". Vitamin D levels were recorded from the hospital database and were compared according to age groups, gender, and the season, retrospectively. Results: The study group [mean age=90.29±59.45 median age=79 interquartile range (IQR): 102 months, male/female: 1409/1624] included 3033 children and adolescents (Group 1/Group 2 n=1864/1169). Although the mean 25(OH)D levels among preschool children did not differ between groups, the vitamin D levels of school-aged children and adolescents were significantly lower in the pandemic period than in the pre-pandemic period [Group 1 median=16.50 (IQR: 10.5) vs Group 2 median=15.9 (IQR: 11.3) in 6-12 age group (p=0.026); Group 1 median=13.30 (IQR: 10.2) vs Group 2 median=11.20 (IQR: 9.7) in 12-18 age group (p=0.003)]. Moreover, the 25(OH)D levels of adolescents showed seasonal variance with lower levels in winter, and unexpectedly, in summer. Conclusion: Pandemic-related restrictions have caused significant decreases in vitamin D levels of school-aged children and adolescents. We suggest that children and adolescents should be given vitamin D supplementation in order to maintain sufficient levels of vitamin D during the pandemic.

Catch-up Growth and Discontinuation of Fludrocortisone Treatment in Aldosterone Synthase Deficiency.

BACKGROUND: Aldosterone synthase deficiency (ASD) caused by mutations in the CYP11B2 gene is characterized by isolated mineralocorticoid deficiency. Data are scarce regarding clinical and biochemical outcomes of the disease in the follow-up. OBJECTIVE: Assessment of the growth and steroid profiles of patients with ASD at the time of diagnosis and after discontinuation of treatment. DESIGN AND METHOD: Children with clinical diagnosis of ASD were included in a multicenter study. Growth and treatment characteristics were recorded. Plasma adrenal steroids were measured using liquid chromatography-mass spectrometry. Genetic diagnosis was confirmed by CYP11B2 gene sequencing and in silico analyses. RESULTS: Sixteen patients from 12 families were included (8 females; median age at presentation: 3.1 months, range: 0.4 to 8.1). The most common symptom was poor weight gain (56.3%). Median age of onset of fludrocortisone treatment was 3.6 months (range: 0.9 to 8.3). Catch-up growth was achieved at median 2 months (range: 0.5 to 14.5) after treatment. Fludrocortisone could be stopped in 5 patients at a median age of 6.0 years (range: 2.2 to 7.6). Plasma steroid profiles revealed reduced aldosterone synthase activity both at diagnosis and after discontinuation of treatment compared to age-matched controls. We identified 6 novel (p.Y195H, c.1200 + 1G > A, p.F130L, p.E198del, c.1122-18G > A, p.I339_E343del) and 4 previously described CYP11B2 variants. The most common variant (40%) was p.T185I. CONCLUSIONS: Fludrocortisone treatment is associated with a rapid catch-up growth and control of electrolyte imbalances in ASD. Decreased mineralocorticoid requirement over time can be explained by the development of physiological adaptation mechanisms rather than improved aldosterone synthase activity. As complete biochemical remission cannot be achieved, a long-term surveillance of these patients is required.

Molecular Diagnosis of Monogenic Diabetes and Their Clinical/Laboratory Features in Turkish Children

Objective: Monogenic diabetes is a heterogeneous disease that causes functional problems in pancreatic beta cells and hyperglycemia. The aim of this study was to determine the clinical and laboratory features, the admission characteristics and distribution of monogenic form of diabetes in childhood in Turkey. Methods: Patients aged 0-18 years, who were molecularly diagnosed with monogenic diabetes, and consented to participate, were included in the study. Results: Seventy-seven (45.6%) female and 92 male cases with a mean age of 8.18±5.05 years at diagnosis were included. 52.7% of the cases were diagnosed with monogenic diabetes by random blood glucose measurement. The reason for genetic analysis in 95 (56.2%) of cases was having a family member diagnosed with diabetes under the age of 25. At the time of diagnosis, ketone was detected in urine in 16.6% of the cases. Mean hemoglobin A1c on admission, fasting blood glucose, fasting insulin, and c-peptide values were 7.3±2.1%, 184.9±128.9 mg/dL, 9.4±22.9 IU/L, 1.36±1.1 and ng/L respectively. GCK-MODY was found in 100 (59.2%), HNF1A-MODY in 31 (18.3%), and variants in ABCC8 in 6 (3.6%), KCNJ11 in 5 (3%), HNF4A in 2 (1.2%), and HNF1B in 2 (1.2%). Conclusion: Recent studies have indicated HNF1A-MODY is the most frequent of all the MODY-monogenic diabetes cases in the literature (50%), while GCK-MODY is the second most frequent (32%). In contrast to these reports, in our study, the most common form was GCK-MODY while less than 20% of cases were diagnosed with HNF1A-MODY.

A novel synonymous homozygous variant [c.2538G>A (p.Thr846Thr)] in TRPM6 in a patient with hypomagnesemia with secondary hypocalcemia.

OBJECTIVES: Hypomagnesemia 1, intestinal (HOMG1) is characterized by neurological symptoms that occur due to hypocalcemia and hypomagnesemia and caused by mutations in the TRPM6. Most of the identified variants in TRPM6 lead to premature termination: nonsense, frameshift, deletion, and splice site mutations. CASE PRESENTATION: Herein, we report a 1.5 month-old case who presented with convulsion due to hypocalcemia and hypomagnesemia in the early infancy. Sequencing of TRPM6 revealed a novel homozygous synonymous variant [c.2538G > A (p.Thr846Thr)] in the last codon of exon 19, which is most likely to affect the splicing. We report a novel homozygous synonymous variant in the TRPM6 leading to HOMG1, expanding the mutational spectrum. CONCLUSIONS: Synonymous mutations that were previously considered as harmless should be evaluated at the nucleotide level, keeping in mind that they may affect splicing and cause to the disease.

Investigating the Efficiency of Vitamin D Administration with Buccal Spray in the Treatment of Vitamin D Deficiency in Children and Adolescents

Objective: The aim of this study was to evaluate the efficiency of a buccal spray form of vitamin D compared to single oral dose (stoss therapy) and oral drops therapy in the treatment of vitamin D deficiency. Methods: Ninety healthy children and adolescents (3-18 years) with vitamin D deficiency [serum level of 25-hydroxyvitamin D (25(OH) D) <12 ng/mL] were randomized to receive vitamin D3 buccal spray (2000 U, n=30, group 1) for six weeks, oral drops (2000 U, n=30, group 2) for six weeks and a single oral dose (300 000 U) vitamin D3 (n=30, group 3). Serum calcium, phosphorus, alkaline phosphatase, parathyroid hormone and 25(OH)D levels of the patients were measured at baseline and after the treatment on the 42nd day. Results: All three groups had a significant increase in serum 25(OH)D concentrations (p<0.001). In group 1, baseline mean 25(OH)D was 8.0±0.41 ng/mL, which rose to 22.1 (17.8-28.2) ng/mL after treatment with a mean increase of 15.6±1.3 ng/mL. Similarly in group 2, baseline, post-treatment and mean increase in 25(OH)D concentrations were 7.9±0.45 ng/mL, 24.4 (20.6-29.6) ng/mL and 17.3±1.1 ng/mL while for group 3 these values were 7.6±0.47 ng/mL, 40.3 (29.4-58.4) ng/mL and 34.3±3.2 ng/mL, respectively. Conclusion: We conclude that vitamin D3 supplementation with buccal spray and oral drops is equally effective in terms of raising vitamin D concentrations in short-term treatment of vitamin D deficiency.

The effect of ketogenic diet on thyroid functions in children with drug-resistant epilepsy.

BACKGROUND: Ketogenic diet (KD) remains a valuable treatment option for children with drug-resistant epilepsy. However, it may cause many well-known adverse effects such as dyslipidemia or kidney stones. But, its effects on thyroid functions are largely unknown. PURPOSE: The aim of this study was to investigate the effects of the KD on thyroid functions in children with drug-resistant epilepsy. METHOD: A total of 66 children (35 females) aged 3-193 months (median, 52 months) with drug-resistant epilepsy who received a KD for at least 12 months were enrolled in the study. All children were started on KD with 3:1 ratio which was then adjusted as clinically necessary. Serum free-thyroxine (FT4) and thyroid stimulating hormone (TSH) concentrations were measured before starting treatment and at the first, sixth and twelfth months of treatment. Changes in FT4 and TSH concentrations over 12 months were analyzed. RESULTS: Median serum FT4 and TSH concentrations, and the frequencies of patients with low FT4 and high TSH concentrations did not change significantly in the study sample over the 12-month study period. Serum FT4 levels increased significantly and TSH concentrations decreased insignificantly in four patients receiving L-thyroxine replacement therapy. During the 12-month treatment period, BMI-SDS increased, and the number of antiepileptic drugs decreased significantly. CONCLUSION: It appears that KD therapy does not impair thyroid functions in children with drug-resistant epilepsy. KD can be used safely along with L-thyroxine replacement even in children with pre-existing subclinical hypothyroidism.

Identification of two AMH gene variants in two unrelated patients with persistent Müllerian duct syndrome: one novel variant.

INTRODUCTION: Persistent müllerian duct syndrome (PMDS) is a rare form of 46, XY disorder of sex development characterized by the persistence of the müllerian structures (uterus, fallopian tubes, the upper part of the vagina) in phenotypically and genotypically normal males. This disease occurs as a result of impairment in the synthesis, release or effect of anti-Müllerian hormone (AMH) during the embryonic period. Approximately 85-88% of PMDS cases have been reported to have AMH or AMHRII mutation. CASE: Herein, we report two PMDS cases from unrelated two families who presented with bilateral undescended testes, persistence of müllerian remnants, and low/undetectable serum AMH levels. Molecular genetic analysis revealed two homozygous variants in AMH. The first one is a novel missense variant (c.1315C > T), the latter is a frameshift variant caused by a deletion (c.343_344delCT), which is less frequently reported type in AMH. CONCLUSION: The diagnosis of PMDS should be kept in mind in patients with externally normal males, bilateral cryptorchidism, and signs of müllerian remnants on laparoscopy.

Detection of SHOX Gene Variations in Patients with Skeletal Abnormalities with or without Short Stature

Objective: SHOX gene mutations constitute one of the genetic causes of short stature. The clinical phenotype includes variable degrees of growth impairment, such as Langer mesomelic dysplasia (LMD), Léri-Weill dyschondrosteosis (LWD) or idiopathic short stature (ISS). The aim of this study was to describe the clinical features and molecular results of SHOX deficiency in a group of Turkish patients who had skeletal findings with and without short stature. Methods: Forty-six patients with ISS, disproportionate short stature or skeletal findings without short stature from 35 different families were included. SHOX gene analysis was performed using Sanger sequencing and multiplex ligation-dependent probe amplification analysis. Results: Three different point mutations (two nonsense, one frameshift) and one whole SHOX gene deletion were detected in 15 patients from four different families. While 4/15 patients had LMD, the remaining patients had clinical features compatible with LWD. Madelung's deformity, cubitus valgus, muscular hypertrophy and short forearm were the most common phenotypic features, as well as short stature. Additionally, hearing loss was detected in two patients with LMD. Conclusion: This study has presented the clinical spectrum and molecular findings of 15 patients with SHOX gene mutations or deletions. SHOX deficiency should be especially considered in patients who have disproportionate short stature or forearm anomalies with or without short stature. Although most of the patients had partial or whole gene deletions, SHOX gene sequencing should be performed in suspected cases. Furthermore, conductive hearing loss may rarely accompany these clinical manifestations.

Long-term monitoring of Graves' disease in children and adolescents: a single-center experience

Background/aim: Graves' disease (GD) is more severe, requires a more complex treatment, and has a lower probability of achieving remission in children than in adults. There is no consensus on the appropriate duration of antithyroid drug (ATD) treatment. Surgical or radioactive iodine (RAI) treatments are not definitive and generally result in permanent hypothyroidism. This study's goal was examining the effectiveness of ATD treatment in children and adolescents with GD and determining the risk factors of remission and relapse. Materials and methods: This retrospective study included 45 patients (36 females and 9 males, median age 12.5 years) aged 4­18 who were diagnosed with GD between 2003 and 2017. All patients initially were treated with an ATD. ATD treatment was discontinued at a mean of 23.2 ± 13.2 months (10­37 months). Results: Patients were classified into remission (n = 24) and relapse groups (n = 21). The duration of initial ATD treatment in the remission group was longer (26.91 ± 5.17 months) than in the relapse group (19.09 ± 7.14 months) (P = 0.01). The total ATD treatment duration was statistically longer in the remission group (42.14 ± 14.35 months) than in the relapse group (26.95 ± 16.13 months) (P = 0.03). Conclusion: Long-term initial ATD treatment and long-term total ATD treatment were evaluated as positive parameters for the remission of Graves' disease in children and adolescents. Our findings showed that the chance of long-term remission increases in direct proportion to the initial ATD treatment duration and the total ATD treatment duration.

Three Siblings with Idiopathic Hypogonadotropic Hypogonadism in a Nonconsanguineous Family: A Novel KISS1R/GPR54 Loss-of-Function Mutation

Idiopathic hypogonadotropic hypogonadism (IHH) is a rare disease caused by defects in the secretion of gonadotropin releasing hormone (GnRH) or the action of GnRH on the pituitary gonadotrophes. KISS1R is one of the genes which, when mutated, cause IHH and mutations of this gene are responsible for about 2-5% of patients with normosmic IHH (NIHH). In this report, we present three siblings with NIHH due to a compound heterozygous KISS1R mutation. Genetic studies were carried out in the 14 year old index case with IHH and three siblings, two of whom were prepubertal. Genomic DNA was extracted from peripheral leukocytes and KISS1R gene was sequenced by using standard polymerase chain reaction amplification procedures. In molecular analysis of the index case, a compound heterozygous mutation was determined in KISS1R gene c.969C>A (p.Y323X) (known pathogenic) and c.170T>C (p.L57P) (novel). Mutation c.170T>C (p.L57P) was inherited from the mother while c.969C>A (p.Y323X) was inherited from the father. The same genotype was also found in two of the three siblings. A compound heterozygous mutation of the KISS1 gene, including one novel mutation, was found to cause NIHH and also incomplete puberty in a non-consanguineous family.

A Mutation in INSR in a Child Presenting with Severe Acanthosis Nigricans.

Rabson-Mendenhall syndrome (RMS) is an autosomal recessive disorder due to mutations in the insulin receptor gene (INSR) which is mapped to 19p13.2. RMS is characterized by acanthosis nigricans, generalized lanugo, tooth and nail dysplasia, high nasal bridge, and growth retardation. A 5-year-old female patient was referred due to acanthosis nigricans and generalized lanugo. On her physical examination, severe acanthosis nigricans of the neck, axillae, the external genitalia and antecubital regions, generalized lanugo, mildly decreased subcutaneous fat, dysmorphic facial features, and polydactyly on her left hand were noted. Insulin resistance and impaired glucose tolerance were found. Sequence analysis of the INSR in the patient revealed c.3529+5G>A mutation in homozygous state. RMS should be suspected in a patient with characteristic physical features and insulin resistance.

Retinal Ganglion Cell Loss in Children With Type 1 Diabetes Mellitus Without Diabetic Retinopathy.

BACKGROUND AND OBJECTIVE: Early diabetic retinal changes in children with type 1 diabetes mellitus (T1DM) without diabetic retinopathy (DR) were examined using spectral-domain optical coherence tomography (SD-OCT). PATIENTS AND METHODS: Sixty children with T1DM without DR and 60 normal children were enrolled in the study. SD-OCT was used to measure the ganglion cell-inner plexiform layer (GC-IPL) and retinal nerve fiber (RNFL) thicknesses in all participants. RESULTS: The GC-IPL thickness was significantly decreased in all quadrants except the superior-nasal quadrant in children with diabetes (P < .05). However, the RNFL thickness in all quadrants was not significantly different between the groups (P > .05). CONCLUSIONS: There was a decreased GC-IPL thickness in children with T1DM without DR, suggesting that T1DM has an early neurodegenerative effect on retinal ganglion cells that occurs when the vascular component of DR is absent. SD-OCT may be more useful than ophthalmoscopic evaluation for detecting the earlier retinal structural changes of diabetes. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:473-477.].

Metabolic control and periodontal treatment decreases elevated oxidative stress in the early phases of type 1 diabetes onset.

OBJECTIVE: Recently, increasing concern has been focused on the contribution of oxidative stress in the pathology of periodontal disease and diabetes mellitus. Firstly, the present study aimed to analyze gingival crevicular fluid (GCF), salivary, and serum oxidative status in children with type 1 diabetes mellitus (T1DM) at diagnosis and systemically healthy children with and without gingivitis. Additionally, the diabetic patients were reevaluated after diabetes and periodontal treatment. DESIGN: The study groups were composed of 32 T1DM patients at diagnosis, and age- and gender-matched thirty-six systemically healthy children with (G) and without (H) gingivitis. The diabetic patients who took insulin therapy (1.5 units/kg/day totally) and periodontal treatment (oral hygiene education with professional scaling) were reevaluated after 3 months. The levels of total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) were recorded. RESULTS: GCF, salivary, and serum OSI were elevated in group T1DM compared to the other groups at baseline (p<0.05), and decreased in group T1DM at reevaluation compared to baseline (p<0.05). GCF OSI was positively correlated with periodontal clinical parameters (p<0.05). Glycated hemoglobin was positively correlated with GCF TOS (r=0.302, p=0.007), GCF OSI (r=0.346, p=0.002), salivary TOS (r=0.326, p=0.046), and serum TOS (r=0.239, p=0.044). CONCLUSION: The instability in the oxidative status that accompanies diabetes may be considered a significant pathogenic factor of diabetes-related periodontal inflammation.