Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis.

BACKGROUND: Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in EVC or EVC2. Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum. METHODS: We conducted molecular studies in 46 individuals from 43 unrelated families with a preliminary clinical diagnosis of EvC and 3 affected individuals from a family with WAD and retrospectively analysed clinical data. The deleterious effect of selected variants of uncertain significance was evaluated by cellular assays. MAIN RESULTS: We identified pathogenic variants in EVC/EVC2 in affected individuals from 41 of the 43 families with EvC. Patients from each of the two remaining families were found with a homozygous splicing variant in WDR35 and a de novo heterozygous frameshift variant in GLI3, respectively. The phenotype of these patients showed a remarkable overlap with EvC. A novel EVC2 C-terminal truncating variant was identified in the family with WAD. Deep phenotyping of the cohort recapitulated 'classical EvC findings' in the literature and highlighted findings previously undescribed or rarely described as part of EvC. CONCLUSIONS: This study presents the largest cohort of living patients with EvC to date, contributing to better understanding of the full clinical spectrum of EvC. We also provide comprehensive information on the EVC/EVC2 mutational landscape and add GLI3 to the list of genes associated with EvC-like phenotypes.

Clinical Variability in a Family with Noonan Syndrome with a Homozygous PTPN11 Gene Variant in Two Individuals

Objective: Noonan syndrome (NS) is characterized by dysmorphic facial features, short stature, congenital heart defects, and varying levels of developmental delays. It is a genetic, multisystem disorder with autosomal dominant inheritance and is the most common of the RASopathies. In approximately 50% of patients, NS is caused by variants in the Protein Tyrosine Phosphatase Non-Receptor Type 11 (PTPN11) gene. The aim of this study was to evaluate two patients with a previously reported PTPN11 homozygous variant for the first time and seven other kindred members carrying the same heterozygous variant in terms of clinical, biochemical, genetic, and response to treatment. Methods: Nine patients diagnosed with NS due to the same variants in the PTPN11 gene were included in the study. Results: The median (range) age at diagnosis was 11.5 (6.8-13.9) years and the mean follow-up duration was 4.7 (1-7.6) years. In eight patients (88.9%), short stature was present. The height standard deviation score of the patients on admission was -3.24±1.15. In six of the patients, growth hormone treatment was initiated. Cardiovascular or bleeding disorders were not detected in any of the patients. Three (33.3%) had hearing loss, two (22.2%) had ocular findings and one (11.1%) had a horseshoe kidney. The mean psychomotor development performance score was 84.03±17.09 and the verbal score was 82.88±9.42. Genetic analysis revealed a variant in the PTPN11 gene [c.772G>A; (p.Glu258Lys)] that had been previously described and was detected in all patients. Two patients were homozygous for this variant and short stature was more severe in these two. Conclusion: A previously described in PTPN11 affected nine members of the same kindred, two with homozygous inheritance and the remainder being heterozygous. To the best of our knowledge, these are the first homozygous PTPN11 case reports published, coming from two related consanguineous families.

Evaluation of Clinical and Laboratory Findings in the Differential Diagnosis of Central Precocious Puberty and Premature Thelarche.

Aim: In this study, it was aimed to examine the clinical and laboratory findings that can be used to predict central precocious puberty (CPP) in cases whose breast development started before the age of 8. Materials and Methods: The chronological age, anthropometric measurements, bone age (BA), hormone test results and pelvic ultrasonography findings of the cases were recorded. Those with a peak luteinizing hormone (LH) level of ≥5 IU/L in the gonadotropin-releasing hormone (GnRH) stimulation test were classified as CPP and those with a peak LH level of <5 IU/L were classified as prepubertal cases. A receiver operating characteristic (ROC) analysis was performed to determine the diagnostic accuracy of laboratory variables. Findings: A total of 297 female cases were included in the study. The age at the time of admission, height-standard deviation score (SDS), BA, the long axis of the uterus and the volumes of the right and left ovaries of the cases diagnosed with CPP were found to be significantly higher than those of the prepubertal group. The cut-off value providing the best sensitivity (99%) and specificity (99%) for the peak LH was found to be 4.55; the cut-off value providing the best sensitivity (94%) and specificity (85%) for the peak LH/follicle-stimulating hormone (FSH) ratio was found to be 0.32 and the cut-off value providing the best sensitivity (47%) and specificity (93%) for the basal LH was found to be 0.13. Conclusion: We believe that in female cases with early breast development, a peak LH level of ≥4.55 may possibly indicate CPP and a basal LH level of <0.13 can significantly rule out CPP.

Metreleptin Treatment in a Boy with Congenital Generalized Lipodystrophy due to Homozygous c.465_468delGACT (p.T156Rfs*8) Mutation in the BSCL2 Gene: Results From the First-year

Congenital generalized lipodystrophy (CGL) is a rare, autosomal recessive disorder characterized by an almost complete absence of body fat. In CGL, patients may have hyperphagia due to leptin deficiency. Recombinant human leptin (metreleptin) has been suggested as an effective treatment option. We present successful treatment with metreleptin in a boy with CGL and results from the first year of follow-up. An eight-month-old boy presented with excessive hair growth and a muscular appearance. On examination he had hypertrichosis, decreased subcutaneous adipose tissue over the whole body and hepatomegaly. Laboratory investigations revealed hypertriglyceridemia, hyperinsulinemia, elevated liver transaminases and low leptin levels. Molecular genetic analysis detected a homozygous, c.465_468delGACT (p.T156Rfs*8) mutation in the BSCL2 gene. A diagnosis of CGL type 2 was considered. Despite dietary intervention, exercise, and treatment with additional omega-3 and metformin, the hypertriglyceridemia, hyperinsulinemia, and elevated liver transaminase levels worsened. Metreleptin treatment was started and after one year hyperphagia had disappeared, and there was dramatic improvement in levels of insulin, hemoglobin A1c, triglycerides and liver transaminases. Hepatosteatosis was lessened and hepatosplenomegaly was much improved. Metreleptin appears to be an effective treatment option in children with CGL that remarkably improved metabolic complications in the presented case. Initiation of metreleptin treatment in the early period may decrease mortality and morbidity, and increase the quality of life in children with CGL.

The clinical and laboratory features of patients with triple A syndrome: a single-center experience in Turkey.

AIM: Triple-A Syndrome (TAS) is a rare autosomal recessive disorder characterized by adrenal insufficiency, achalasia, and alacrimia. This disorder is caused by mutations in the AAAS gene. The aim of this study is to discuss the clinical, laboratory and molecular genetic analysis results of 12 patients with TAS. METHOD: We evaluated 12 patients from 8 families. Clinical and laboratory data were retrospectively collected from the medical records of the patients in the database for the period 2015-2020. All exons and exon-intron junctions of the AAAS gene were evaluated by next-generation sequencing method. Detected variants were classified according to American Collage of Medical Genetics criteria. RESULTS: Alacrimia was found in all patients (100%); achalasia was found in 10 patients (83.3%) and adrenal insufficiency was found in 10 patients (83.3%). In addition, hyperreflexia(6/12), learning disability(5/12), hypernasal speech(5/12), muscle weakness(8/12), delayed walking(7/12), delayed speech(6/12), excessive sweating(7/12), optic atrophy(1/12), epilepsy(1/12), palmoplantar hyperkeratosis(5/12), multiple dental caries(9/12), atrophy of the thenar/hypothenar muscles(4/12) and short stature(4/12) were detected. The DHEA-S levels were measured in 10 patients and were found to be low in 8 of them. In all patients, the sodium and potassium levels were found to be normal. AAAS gene sequencing revealed four previously reported c.1066_1067del (p.Leu356fs*8), c.1432 C > T (p.Arg478*), c.688 C > T (p.Arg230*), and c.1368_1372del (p.Gln456fs*38) variants and two novel homozygous c.1250-1 G > A and c.398_399 + 2del variants in the AAAS gene. CONCLUSION: We detected two novel variants in the AAAS gene. While the classic triad is present in 66.7% of the cases, neurological dysfunction, skin and dental pathologies also occur quite frequently. The earliest and most common finding of TAS is alacrimia. Therefore, adrenal insufficiency should be investigated in all patients with alacrimia and if necessary, genetic analysis should be performed for TAS. In addition, TAS should be followed up with a multidisciplinary approach since it involves many systems.

A rare cause of primary amenorrhea: LHCGR gene mutations.

INTRODUCTION: The luteinizing hormone/choriogonadotropin receptor (LHCGR) plays a critical role in sexual differentiation and reproductive functions in men and women. Inactivating mutations in this gene lead to Leydig cell hypoplasia (LCH), and cause disorders of sex development (DSD) in patients with 46,XY. In this study, it was aimed to discuss the clinical, laboratory and molecular genetic analysis results of nine patients with 46,XY karyotype who had mutations in the LHCGR gene. MATERIALS AND METHODS: The ages, complaints, anthropometric measurements and hormonal results (follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone) of the patients at the time of admission were recorded retrospectively from their medical records. The mutations in the LHCGR gene were investigated using the Sanger sequencing method. FINDINGS: In this study, LHCGR gene mutations were detected in a total of nine patients as a result of the analysis of the index patients presenting with primary amenorrhea from four different families and the examination of the families. In the first three families with no consanguinity between, the same mutation was detected in seven patients in total (Homozygous c.161 + 4A > G). A different mutation was detected in the fourth family (Homozygous p.A483D c.1448C > A). CONCLUSION: In this study, nine patients with karyotype 46,XY, most of whom presented with the complaint of delayed puberty/primary amenorrhea, were diagnosed with LCH. Especially in patients, in whom the elevation of LH is pronounced and there is no testosterone synthesis, LCH should be considered.

Revisiting the Annual Incidence of Type 1 Diabetes Mellitus in Children from the Southeastern Anatolian Region of Turkey: A Regional Report

Objective: The incidence of type 1 diabetes mellitus (T1D) in children has an increasing trend globally, with a variable rate depending on region and ethnicity. Our group first reported T1D incidence in Diyarbakir in 2011. The aim of this study was to evaluate the current incidence rate of pediatric T1D in Diyarbakir, and compare the incidence, and clinical and presenting characteristics of more recent cases with those reported in our first report. Methods: Hospital records of patients diagnosed with T1D in Diyarbakir city between 1st January 2020 and 31st December 2020 and aged under 18 years old were retrieved, and their medical data was extracted. Demographic population data were obtained from address-based census records of the Turkish Statistical Institution (TSI). Results: Fifty-seven children and adolescents were diagnosed with T1D. Of those, 34 were female (59.6%), indicating a male/female ratio of 1.47. The mean age at diagnosis was 9.5±3.9 years (0.8-17.9). TSI data indicated a population count of 709,803 for the 0-18 years age group. Thus the T1D incidence was 8.03/105 in the 0-18 age group and was higher in the 0-14 age group at 9.14/105. The cumulative increase in the incidence of T1D in the 0-14 age group was 26.9% suggesting an increasing rate of 2.7% per year. The frequency of presentation with diabetic ketoacidosis was 64.9%. Conclusion: The annual incidence of pediatric T1D in Diyarbakir city increased from 7.2/105 to 9.14/105 within the last decade. The rate of annual increase was 2.7% in the 0-14 age group comparing this study with our earlier report, with a predominance in male subjects and a shift of peak incidence from the 5-9 year age group in the first study to the 10-14 year age group in this one.

A rare cause of delayed puberty and primary amenorrhea: 17α-hydroxylase enzyme deficiency.

AIM: 17α-hydroxylase enzyme deficiency is a rare form of congenital adrenal hyperplasia (CAH) and is caused by mutations in the CYP17A1 gene. The main clinical findings are delayed puberty and primary amenorrhea in girls, and disorders of sex development in boys. It can also cause hypertension and hypokalemia in both genders. In this study, we aimed to present the clinical, laboratory and genetic results of 13 patients from eight different families who were diagnosed with complete 17α-hydroxylase enzyme deficiency. METHODS: The age, symptoms, anthropometric measurements, blood pressure, Tanner stages, and hormonal and chromosome analysis results at the time of admission were recorded from the medical records of the patients. Whole gene next-generation sequencing of CYP17A1 gene was performed to detect mutations. Multiplex ligation dependent probe amplification (MLPA) method were used to detect deletions in the seven patients who had no point mutation were detected in the CYP17A1 gene. RESULTS: The average age of the patients at the time of admission was 14.8 (range: 12.9-16.6) years. Also at this time, all patients were in adolescence and were raised as females. The karyotypes of eight patients were 46,XY, and of five patients were 46,XX. Ten patients presented with delayed puberty and primary amenorrhea, one patient with delayed puberty and hypertension, and two patients with hypertension and/or hypokalemia. Hypertension and hypokalemia were detected in nine and seven patients, respectively. CONCLUSIONS: P450c17 enzyme deficiency should be considered in patients presenting with delayed puberty or primary amenorrhea in the adolescence period and diagnosed with hypergonadotropic hypogonadism, if hypertension and hypokalemia accompany. Early diagnosis prevents the occurrence of important health problems such as hypertension, psychological problems, and gender identity disorders, which affect the majority of these patients.

Electrocardiographic data of children with type 1 diabetes mellitus.

BACKGROUND: Adult patients diagnosed with type 1 diabetes mellitus are at risk for ventricular arrhythmias and sudden cardiac death. AIM: The objective of our study is to evaluate the electrocardiographic data of children diagnosed with type 1 diabetes mellitus and to determine the possibility of arrhythmia in order to prevent sudden death. METHODS: Electrocardiographic data of 60 patients diagnosed with type 1 diabetes mellitus and 86 controls, who were compatible with the patient group in terms of age and gender, were compared. RESULTS: The duration of diabetes in our patients with type 1 diabetes mellitus was 5.23 ± 1.76 years, and the haemoglobin A1c levels were 9.63% ± 1.75%. The heart rate, QRS, QT maximum, QT dispersion, QTc minimum, QTc maximum, QTc dispersion, Tp-e maximum, Tp-e maximum/QTc maximum and the JTc were significantly higher compared to the control group. There was no significant correlation between the duration of type 1 diabetes mellitus and HbA1c levels and the electrocardiographic data. CONCLUSION: We attributed the lack of a significant correlation between the duration of type 1 diabetes mellitus and the haemoglobin A1c levels and the electrocardiographic data to the fact that the duration of diabetes was short, since our patients were children. We believe that patients with type 1 diabetes mellitus should be followed up closely in terms of sudden death, as they have electrocardiographic changes that may cause arrhythmias compared to the control group. However, more studies with longer follow-up periods are necessary to support our data.

Is cranial imaging necessary in girls between 6-8 years diagnosed with central precocious puberty?

AIM: There is no clear consensus on whether a cranial MRI should be performed in all cases of central precocious puberty(CPP). In this study, we aimed at evaluating the incidence of intracranial lesions and analyzing cranial imaging results in females with CPP. METHODS: In the retrospective study medical records of the case, the age at the time of admission, anthropometric measurements, bone age, Tanner stages, serum follicle-stimulating hormone (FSH), serum luteinizing hormone(LH), serum estradiol (E2) levels, the peak LH level during the gonadotropin-releasing hormone (GnRH) stimulation test and the cranial MRI findings at the time of the diagnosis of CPP were collected. RESULTS: The mean age diagnosis of the 154 girls included in the study was 6.9 ±1.08. Nine (5.8%) of 154 patients were diagnosed with organic-caused CPP. Four of the nine cases diagnosed with organic CPP had a previously known CNS pathology. The other five cases did not have any neurological findings at the time of diagnosis. Incidental lesions were detected at cranial MRI of nine of the 145 cases diagnosed with idiopathic CPP. The basal E2, basal LH, basal FSH, peak LH and peak LH/FSH levels of the cases with organic CPP were higher than those with idiopathic CPP. CONCLUSIONS: In our study, approximately 90% of organic CPP due to intracranial lesions were between 6-8 years. Therefore, we believe that cranial imaging should be performed in all females with CPP.

A rare and preventable aetiology of neurodevelopmental delay and epilepsy: familial glucocorticoid deficiency.

OBJECTIVES: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterised by isolated glucocorticoid deficiency. Melanocortin receptor 2 (MC2R) mediates the functions of adrenocorticotropic hormone (ACTH) in the adrenal cortex. MC2R accessory protein (MRAP) is a transmembrane protein involved in the trafficking of MC2R to the cell surface. Mutations in MC2R and MRAP genes cause FGD type 1 and 2. In the present case series, we evaluate the clinical characteristics and long-term follow-up of six cases with FGD due to mutations in MC2R and MRAP. CASE PRESENTATION: Data of six cases with FGD (five with mutations in MC2R and one with a mutation in MRAP) who were being followed at our paediatric endocrine centre was evaluated. Diagnosis of FGD was considered in case of elevated ACTH and inappropriately low cortisol level, and exclusion of other aetiologies. The main presenting complaints were hyperpigmentation and hypoglycaemic convulsion in all cases. During a follow-up period of 26-115 months, one patient with homozygous 560delT mutation in MC2R, one female with G226R mutation in MC2R and one female with IVS3ds+1delG mutation in MRAP had a neurodevelopmental delay (NDD), while the other three patients had normal neurodevelopment. CONCLUSIONS: FGD patients due to MC2R and MRAP mutations with early diagnosis and compliance to the hydrocortisone therapy had normal neurodevelopment, while delay in diagnosis and poor compliance was associated with severe hypoglycaemic convulsions and subsequent complications NDD.

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.

The association between electrocardiographic data and obesity in children and adolescents.

BACKGROUND: There are not enough studies investigating the relationship between obesity and ECG abnormalities in children and adolescents. This study aims to investigate the relationship between obesity and electrocardiographic data in children and adolescents for early diagnosis to prevent arrhythmia or sudden death in later stages of life. PATIENTS AND METHODS: A total of 65 children and adolescents with obesity applied to our pediatric endocrinology outpatient clinic with nonspecific complaints and without any known chronic illnesses; 76 healthy children and adolescents were included in the study. Anthropometric and laboratory data, blood pressure measurements, and 12-lead electrocardiography data of all participants were collected. RESULTS: There was a statistically significant difference between the obese and the control group in terms of triglycerides, total cholesterol, high density lipoprotein, low density lipoprotein levels, and systolic blood pressure. According to electrocardiographic findings, there was a statistically significant difference between the two groups in terms of heart rate (p=0.008), PR duration (p<0.001), left ventricular hypertrophy (p=0.02), P maximum (p=0.04), P dispersion (p<0.001), QRS duration (p<0.001), QT minimum (p=0.007), QT maximum (p=0.03), QT dispersion (p=0.024), QTc minimum (p=0.002), QTc dispersion (p=0.003), Tp-e minimum (p=0.007), and Tpe maximum (p=0.003) variables. CONCLUSIONS: There were significant differences between the electrocardiographic evaluation of obese group compared to the control group in our study, which may be associated with risk of cardiac arrhythmia. These differences require monitorization in terms of cardiac arrhythmia and risk of sudden death. Further studies with longer follow-up time are needed to support the potential clinical outcomes of our findings.

Clinical and Hormonal Profiles Correlate With Molecular Characteristics in Patients With 11ß-Hydroxylase Deficiency.

BACKGROUND: Given the rarity of 11ß-hydroxylase deficiency (11ßOHD), there is a paucity of data about the differences in clinical and biochemical characteristics of classic (C-11ßOHD) and nonclassic 11ßOHD (NC-11ßOHD). OBJECTIVE: To characterize a multicenter pediatric cohort with 11ßOHD. METHOD: The clinical and biochemical characteristics were retrospectively retrieved. CYP11B1 gene sequencing was performed. Seventeen plasma steroids were quantified by liquid chromatography-mass spectrometry and compared to that of controls. RESULTS: 102 patients (C-11ßOHD, n = 92; NC-11ßOHD, n = 10) from 76 families (46,XX; n = 53) had biallelic CYP11B1 mutations (novel 9 out of 30). Five 46,XX patients (10%) were raised as males. Nineteen patients (19%) had initially been misdiagnosed with 21-hydroxylase deficiency. Female adult height was 152 cm [-1.85 SD score (SDS)] and male 160.4 cm (-2.56 SDS).None of the NC-11ßOHD girls had ambiguous genitalia (C-11ßOHD 100%), and none of the NC-11ßOHD patients were hypertensive (C-11ßOHD 50%). Compared to NC-11ßOHD, C-11ßOHD patients were diagnosed earlier (1.33 vs 6.9 years; P < 0.0001), had higher bone age-to-chronological age (P = 0.04) and lower adult height (-2.46 vs -1.32 SDS; P = 0.05). The concentrations of 11-oxygenated androgens and 21-deoxycortisol were low in all patients. The baseline ACTH and stimulated cortisol were normal in NC-11ßOHD. Baseline cortisol; cortisone; 11-deoxycortisol; 11-deoxycorticosterone and corticosterone concentrations; and 11-deoxycortisol/cortisol, 11-deoxycorticosterone/cortisol, and androstenedione/cortisol ratios were higher in C-11ßOHD than NC-11ßOHD patients (P < 0.05). The 11-deoxycortisol/cortisol ratio >2.2, <1.5, and <0.1 had 100% specificity to segregate C-11ßOHD, NC-11ßOHD, and control groups. CONCLUSION: NC-11ßOHD can escape from clinical attention due to relatively mild clinical presentation. However, steroid profiles enable the diagnosis, differential diagnosis, and subtyping of 11ßOHD.

Frequency of Celiac Disease and Spontaneous Normalization Rate of Celiac Serology in Children and Adolescent Patients with Type 1 Diabetes

Objective: The prevalence of celiac disease (CD) varies between 1% and 10% in patients with type 1 diabetes mellitus (T1DM). This study aimed to determine the frequency of spontaneous recovery of celiac serology and the biopsy-proven CD (BPCD) frequency in patients with T1DM. Methods: The data of 668 patients with available celiac serology tests from a total of 779 patients who were followed for the last 10 years with the diagnosis of T1DM were retrospectively evaluated. Results: Positive serology was detected in 103 out of 668 (15.4%) patients. There was spontaneous normalization in 24 (23.3%), fluctuation in 11 (10.7%) and permanently positive serology in 68 (66%). In 46 out of 53 (86.8%) patients with positive serology and biopsy, CD diagnosis was confirmed by biopsy (BPCD). The frequency of BPCD was 6.9%, and the serology in 76.1% was positive at the time of diagnosis of T1DM. The weight, height and body mass index-standard deviation score at diagnosis were lower in patients with BPCD compared to the group without CD. An anti-tissue transglutaminase-IgA (anti-TTG-IgA) level of 11.8 times the upper limit of normal was the most sensitive (93%) and specific (90%) cut-off for BPCD (area under the curve: 0.95; 95% confidence interval: 0.912-1; p<0.001). Conclusion: In our cohort, the frequency of positive serology for CD was 15.4%, while the rate of BPCD was 6.9%. The majority (97.8%) of cases were diagnosed within the first five years of T1DM. In 23.3% of cases, positive anti-TTG-IgA spontaneously resolved without a gluten-free diet (GFD). Therefore, serological follow-up instead of immediate duodenal biopsy or GFD therapy, particularly for patients with asymptomatic and mild anti-TTG IgA level, is warranted.

Identification of Three Novel and One Known Mutation in the WFS1 Gene in Four Unrelated Turkish Families: The Role of Homozygosity Mapping in the Early Diagnosis

Objective: Bi-allelic mutations in the wolframin gene (WFS1) cause Wolfram syndrome 1 (WS1 or DIDMOAD) characterized by nonautoimmune diabetes mellitus, optic atrophy, diabetes insipidus, sensorineural deafness, urinary tract abnormalities, and neuropsychiatric disorders. Patients presenting with an incomplete phenotype of WS1 were evaluated using homozygosity mapping and subsequent whole-exome sequencing. Methods: Four unrelated consanguineous Turkish families, including seven affected children, and their unaffected parents and siblings were evaluated. Homozygosity mapping was performed, followed by whole-exome sequencing of WFS1. Mutations were classified according to results of "in silico" analyses, protein prediction, and functional consequences. Results: Homozygosity mapping confirmed shared homozygous regions on chromosome 4 (chr4p16.1) between the affected individuals, that was absent in their unaffected siblings. Exome sequencing identified three novel (c.1215T>A, c.554G>A, c.1525_1540dup) and one known (c.1522_1523delTA) mutations in WFS1. All mutations were predicted to cause stop codon leading to early termination of protein synthesis and complete loss-of-function. All patients were found to be homozygous for the change, with parents and other unaffected siblings being carriers. Conclusion: Our study expands the mutation spectrum of WSF1 mutations with three novel mutations. Homozygosity mapping may provide enrichment for molecular genetic analysis and early diagnosis of WS1 patients with incomplete phenotype, particularly in consanguineous pedigrees.

Cytochrome P450 oxidoreductase deficiency caused by a novel mutation in the POR gene in two siblings: case report and literature review.

INTRODUCTION: P450 oxidoreductase (POR) deficiency is a rare form of congenital adrenal hyperplasia. In both genders, it can lead to ambiguous genitalia, impaired steroidogenesis, and skeletal findings similar to those of Antley-Bixler syndrome. CASES: We describe two cases of POR deficiency. The first case was an 8.5-year-old girl who was admitted to our clinic due to ambiguous genitalia. Karyotype was 46, XX. There were mild dysmorphic facial findings and mild metacarpophalangeal joint deformity. The patient's basal cortisol and ACTH levels were normal, while 17-hydroxyprogesterone (17OHP) levels were high. Peak cortisol response to the ACTH stimulation test was found to be insufficient. Our second case, a sibling of the first case, was admitted for routine checkup at the age of 15 months. As in our first case, there were dysmorphic facial findings and metacarpophalangeal joint deformity. The genital structure was normal. Karyotype was 46, XY. Basal cortisol and ACTH levels were normal, while 17OHP level was slightly high. Peak cortisol response to the ACTH stimulation test was found to be insufficient. Based on our findings, POR deficiency was considered in both of these cases and NM_000941.3:c.929_937delTCTCGGACT(p.Ile310_Ser313delinsThr) (homozygous) mutation was detected in the POR gene that had not previously been described. CONCLUSION: We detected a novel variant in the POR gene in two sibling cases with adrenal insufficiency, dysmorphic face, and mild skeletal findings. While the detected mutation caused ambiguous genitalia in the female case, it did not cause ambiguous genitalia in the male case.

Clinical Characteristics of 46,XX Males with Congenital Adrenal Hyperplasia

Objective: To retrospectively evaluate the follow-up data in patients with 46,XX congenital adrenal hyperplasia (CAH) who were raised male. Methods: A national database was created. The data of patients were asked to be recorded in the data form. Results: The median (range) age of diagnosis was three (0.1-18.3) years in 44 patients. Twenty nine cases were diagnosed after the age of two years. Most (95.4%) cases were stage 4-5 virilized. Hysterectomy and bilateral salpingoopherectomy, at a median age of 7.25 (2.4-25.3) years, was performed in 35 cases. Testicular prostheses were placed in 11 (25%) cases at a median age of 11.2 (2.8-17) years. The median final height was 149.2 (132.8-172) cms in 38 patients, including simple virilizing (n=18), salt-wasting (n=6), and 11-beta hydroxylase (n=12). Of the 16 patients above the age of eighteen, university education was completed in 25%. Conclusion: It was seen that most (65.9%) of the 46,XX CAH cases raised male were diagnosed after two years of age. In these cases, hysterectomy and bilateral salpingoopherectomy, genital corrective surgeries and testicular prosthesis operations were performed in a very wide age rage.

A Retrospective Analysis of Children and Adolescents With Diabetic Ketoacidosis in the Intensive Care Unit: Is It Significant that the Blood Ketone Level Becomes Negative in Diabetic Ketoacidosis?

INTRODUCTION: Diabetic ketoacidosis (DKA) is the most common cause of acute morbidity and mortality in children and adolescents with type 1 diabetes mellitus (T1DM). Because DKA management is associated with complications, endocrine communities have published guidelines and attempted to set standards for DKA diagnosis and management worldwide. In this study, for the patients followed up in the intensive care unit who have been treated according to DKA protocols, clinical and laboratory characteristics, differences between new and old diagnosed patients, and results of treatment were evaluated. METHODS: The records of 67 patients hospitalized in the pediatric intensive care unit for the past two years were reviewed retrospectively. Patients were grouped as newly diagnosed and old diagnosed diabetics. RESULTS: The mean age of the patients was 8.66 ± 5.0 years (3 months to 17.9 years) and 39 (58.2%) were male. Forty-five patients (67.1%) presented with mild DKA and 22 (33.9%) with severe DKA. Fourteen (63.6%) of the severe DKA cases were newly diagnosed with T1DM. Six patients had hyponatremia (corrected serum Na level <135 mmol/L) and five had hypernatremia (serum Na level >145 mmol/L). Only one of the hyponatremic patients had severe acidosis, while four of the hypernatremic patients had severe acidosis. At the 14th hour, blood glucose levels were below 200 mg/dl, blood ketones became negative in 5.8 hours, and at 9.1 hours, blood pH and/or HCO3 levels were normalized, recovery criteria were completed, and subcutaneous (SC) insulin injection was started. Of the patients, 38 (56.7) were newly diagnosed with T1DM. The mean age of newly diagnosed T1DM patients was smaller (7.40 ± 4.96) than those with old diagnosis, respiratory rates (RRs) were higher and pCO2 levels were lower on admission. Blood glucose, blood ketone negativity, acidosis, and Glasgow coma score (GCS) scores of the newly diagnosed T1DM patients improved later than the previous diagnoses. Only one patient under two years of age with a pH of 6.89 was given HCO3. None of the patients had symptomatic brain edema and death. CONCLUSIONS: As a result, DKA is an acute and serious complication of diabetes, whose results are promising when managed only with minimal individual changes according to guidelines. Bicarbonate administration is not needed except in patients with very severe acidosis. Bedside blood ketone monitoring seems to be important because it allows for early enteral feeding.

Left and right ventricular functions may be impaired in children diagnosed with subclinical hypothyroidism.

Subclinical hypothyroidism (SH) may influence both ventricular functions. The aim of this study was to evaluation the findings of Tissue Doppler Imaging (TDI) and other echocardiography modalities in children with SH. We compared left ventricular mass index (LVMI) and TDI parameters of patients with SH and children with euthyroidism. Subclinical hypothyroidism was diagnosed when thyroid stimulating hormone level was higher than the reference value of the laboratory (> 4.2 mIU/L) and free thyroxine level was in normal range. The study included a group of 35 patients with SH and a control group of 38 children with euthyroidism (mean age was 7.6 ± 3.5 years and 9.0 ± 2.4 years, respectively). LVMI was significantly higher in the patient group (p = 0.005). TDI parameters including mitral septal ejection time was lower (p = 0.003) and mitral septal myocardial performance index was higher (p = 0.009) in the patient group. Right ventricular TDI revealed that tricuspid lateral E/Ea and tricuspid septal E/Ea were higher (p = 0.015 and p = 0.024, respectively) and tricuspid septal Ea/Aa and ejection time were lower (p = 0.018 and p = 0.017, respectively) in the patient group. SH may lead to increase LVMI. Left ventricular systolic and diastolic TDI parameters (lower mitral septal ejection time, higher mitral septal myocardial performance index) as well as right ventricular systolic (lower tricuspid septal ejection time) and diastolic (higher tricuspid septal and lateral E/Ea, lower tricuspid septal Ea/Ea) functions may be also impaired in children with subclinical hypothyroidism. TDI is a useful method used for the assessment of the effect of SH on cardiac functions.