Band 36, Heft 1

Objectives 46, XY difference/disorder of sex development (DSD) is a relatively uncommon group of heterogeneous disorders with varying degree of underandrogenization of male genitalia. Such patients should be approached systematically to reach an aetiological diagnosis. However, we lack, at present, a clinical practice guideline on diagnostic approach in 46, XY DSD from this part of the globe. Moreover, debate persists regarding the timing and cut-offs of different hormonal tests, performed in these cases. The consensus committee consisting of 34 highly experienced endocrinologists with interest and experience in managing DSD discussed and drafted a consensus statement on the diagnostic approach to 46, XY DSD focussing on relevant history, clinical examination, biochemical evaluation, imaging and genetic analysis. Content The consensus was guided by systematic reviews of existing literature followed by discussion. An initial draft was prepared and distributed among the members. The members provided their scientific inputs, and all the relevant suggestions were incorporated. The final draft was approved by the committee members. Summary The diagnostic approach in 46, XY DSD should be multidisciplinary although coordinated by an experienced endocrinologist. We recommend formal Karyotyping, even if Y chromosome material has been detected by other methods. Meticulous history taking and thorough head-to-toe examination should initially be performed with focus on external genitalia, including location of gonads. Decision regarding hormonal and other biochemical investigations should be made according to the age and interpreted according to age-appropriate norms Although LC-MS/MS is the preferred mode of steroid hormone measurements, immunoassays, which are widely available and less expensive, are acceptable alternatives. All patients with 46, XY DSD should undergo abdominopelvic ultrasonography by a trained radiologist. MRI of the abdomen and/or laparoscopy may be used to demonstrate the Mullerian structure and/or to localize the gonads. Genetic studies, which include copy number variation (CNV) or molecular testing of a candidate gene or next generation sequencing then should be ordered in a stepwise manner depending on the clinical, biochemical, hormonal, and radiological findings. Outlook The members of the committee believe that patients with 46, XY DSD need to be approached systematically. The proposed diagnostic algorithm, provided in the consensus statement, is cost effective and when supplemented with appropriate genetic studies, may help to reach an aetiological diagnosis in majority of such cases.

Objectives Tanner staging is the standard for rating sexual maturation (SMR) in boys (pubic hair (PH) and genital (G) development). G staging is tripartite in nature and is prone to ambiguity because it is based upon somewhat vague visual cues that may lead to erroneous assessments and medical errors. Measurement of penile growth (penile girth or diameter) may provide an additional tool (in addition to the orchidometer) to make G staging more valid. Although studies on penile growth (either circumference of width) have been reported, none were longitudinal. Therefore, our objective was to compare penile development in boys – measured as penile diameter (PD) – to PH stage and testicular volume (TV) and secondarily to G stage; moreover, to do so on a longitudinal basis. Methods Charts of 61 boys, ages 6–21 years of age, who were seen longitudinally, were reviewed. Each boy had his PD and TV measured along with his PH and G stage assessed on a quarterly to semi-annual basis. Results PD increased significantly among PH stages II, III, and IV only. PD increased significantly among G stages I, II, III and IV only. PD correlated well with TV. There were significant correlations between PD and TV in all PH stages. However, for G stage correlations were not significant for stages II, III, and IV. PH stage was a better predictor of PD than G stage. Conclusions Measuring PD may be another tool to help in objectifying male SMR during puberty and overcome the vagueness encountered with the visual SMR G stage scales.

Objectives Diabetic cystopathy is a condition characterized by decreased bladder sensitivity, increased bladder capacity, decreased bladder contractility and increased residual urine volume. It can also be considered as an early indicator of autonomic dysfunction. In this study, it was aimed to evaluate bladder functions by uroflowmetry in children and adolescents with the diagnosis of type 1 diabetes mellitus. Methods Type 1 diabetes mellitus children and adolescents were applied uroflowmetry and post-void residual urine volumes were evaluated. The physical examination findings of the patients and the laboratory data of diabetes control were obtained from the clinic files. Results A total of 51 cases aged 72–216 (155.6 ± 35.4) months were enrolled into the study. Diabetes age of the cases was 66.5 ± 46.2(13–180) months. The last one year average of HbA 1c of the patients was found to be 9.7 ± 1.9%. A total of 9.8% had good, 39.2% moderate and 51% poor metabolic control, respectively. While urodynamic evaluation was normal in 36 (70.6%) of 51 participants, voiding dysfunction was found in 15. There was no statistically significant difference between groups with and without voiding dysfunction in terms of age, gender, duration of diabetes, metabolic control and HbA 1c values. Conclusions It is very important to follow up patients with type 1 diabetes mellitus in terms of autonomic dysfunction. Diabetic bladder clinic, which can be observed independently of diabetes duration and metabolic control, is also included in this status. Urodynamic evaluation will be helpful both in demonstrating bladder dysfunction and in preventing possible complications.

Objectives Classic galactosemia is a galactose metabolism disorder due to galactose-1-phosphate uridyltransferase deficiency. In this study we report the clinical features of a cohort of children with classic galactosemia. Methods A retrospective evaluation was made of the files of 42 cases followed up for a diagnosis of classic galactosemia between January 2000 and December 2021. The data were collected of clinical, laboratory and genetic characteristics. Results The cases comprised of 25 (59.5%) girls and 17 (40.5%) boys with a median age of 15 days (range, 1 day to 9 years) at diagnosis. In addition, thirty-six cases (92.3%) could be diagnosed before they were 4 months old by hospitalization with various clinical findings, primarily liver dysfunction. The most common complaints on presentation were jaundice (78.4%) and vomiting (27%) and the most frequently seen genetic pathogenic variant was c.563A>G (p.Gln188Arg) (92.4%). Conclusions It can be emphasized that there is a need for a neonatal screening program for classic galactosemia to be able to increase the possibility of early diagnosis and to be able to start treatment before the development of a severe clinical picture.

Objectives We have previously shown that pituitary cysts may affect growth hormone secretion. This study sought to determine cyst evolution during growth hormone treatment in children. Methods Forty-nine patients with short stature, a pituitary cyst, and at least two brain MRI scans were included. The percent of the pituitary gland occupied by the cyst (POGO) was calculated, and a cyst with a POGO of ≤15% was considered small, while a POGO >15% was considered large. Results Thirty-five cysts were small, and 14 were large. Five of the 35 small cysts grew into large cysts, while 6 of the 14 large cysts shrunk into small cysts. Of 4 cysts that fluctuated between large and small, 3 presented as large and 1 as small. Small cysts experienced greater change in cyst volume (CV) (mean=61.5%) than large cysts (mean=−0.4%). However, large cysts had a greater net change in CV (mean=44.2 mm 3 ) than small cysts (mean=21.0 mm 3 ). Older patients had significantly larger mean pituitary volume than younger patients (435.4 mm 3 vs. 317.9 mm 3 ) and significantly larger mean CV than younger patients (77.4 mm 3 vs. 45.2 mm 3 ), but there was no significant difference in POGO between groups. Conclusions Pituitary cyst size can vary greatly over time. Determination of POGO over time is a useful marker for determining the possibility of a pathologic effect on pituitary function since it factors both cyst and gland volume. Large cysts should be monitored closely, given their extreme, erratic behavior.

Objectives Phototherapy is demonstrated to cause hypocalcemia by decreasing melatonin levels and increasing cortisol levels. However, the relationship between parathyroid hormone (PTH) level and calcium has not been previously evaluated in patients receiving phototherapy. Our study aimed to evaluate the effect of phototherapy on ionized calcium (iCa), total calcium (tCa), corrected calcium (cCa), magnesium (Mg), phosphorus (P), 25-hydroxyvitamin D (25(OH)D), and PTH levels. Methods Infants who were born at term and received inpatient phototherapy for indirect hyperbilirubinemia were included in our study. The patients’ gestational age, birth weight, and phototherapy durations were recorded. Total bilirubin, albumin, iCa, tCa, cCa, Mg, 25(OH)D, and PTH levels before and after phototherapy were compared. Laboratory results were also compared between patients who received phototherapy for ≤24 h, 25–47 h, and ≥48 h. Results A total of 166 term infants were included in the study. The mean duration of phototherapy was 31.9 ± 9.2 h. Albumin levels before and after phototherapy were similar (p=0.246). However, there were significant decreases in iCa, tCa, cCa, Mg, 25(OH)D, and PTH levels after phototherapy (p<0.001), while P level was significantly increased after phototherapy (p<0.001). In addition, P levels increased with >24 h of phototherapy, while iCa, tCa, cCa, Mg, 25(OH)D, and PTH levels decreased significantly with ≥48 h of phototherapy (p=0.002, p=0.008, p=0.001, p=0.012, and p<0.001, respectively). Conclusions This study demonstrates that PTH suppression is one of the causes of phototherapy-induced hypocalcemia.

Objectives To evaluate and present the data regarding clinical, laboratory, radiological and the results of molecular genetic analysis of patients with hyperinsulinemic hypoglycemia in our clinics. Methods A total of 9 patients with CHI followed at Istanbul Medipol University. Data related to gender, age at presentation, birth weight, gestational age, consanguinity, glucose and insulin levels at diagnosis, treatment modalities, response to treatment, the results of genetic analysis and radiological evaluation were gathered from the files. Results The oldest age at presentation was 6 months. K ATP channel mutation was detected in 55% (n: 5). Diazoxide unresponsiveness was seen in 55% (n: 5). Octreotide was effective in 3 of them. 18 F-DOPA PET performed in 4 diazoxide unresponsive patients revealed focal lesion in 3 of them. Spontaneous remission rate was 66% (n:6). All the patients with normal genetic result achieved spontaneous remission. Spontaneous remission was even noted in diazoxide unresponsive patients and in patients with focal lesion on 18 F-DOPA PET. Conclusions Clinical presentation of patients with congenital hypereinsulinism is heterogeneous. Spontaneous remission rate is quite high even in patients with severe clinical presentation. It is important to develop methods that can predict which patients will have spontaneous remission. Reporting the clinical and laboratory data of each patient is important and will help to guide the management of patients with hyperinsulinemic hypoglycemia.

Objectives Studies which report cystatin C’s (Cys-C) role in immunological disorders are increasing. However, data in the pediatric age group is limited. In this study, we aimed to evaluate the association between serum Cys-C levels and thyroid autoantibodies in children and adolescents diagnosed with euthyroid Hashimoto’s thyroiditis. Methods The patient group was included 50 participants aged between 3 and 18 years, and the control group included 50 healthy children matched for age, gender, and body mass index. Patients with hypothyroidism or taking any medication were not included in the study. Fasting glucose, liver enzymes, urea, creatinine, lipid profile, Cys-C, free thyroxine (fT4), free triiodothyronine (fT3), thyroid-stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibodies (TGAb) levels were recorded in all subjects. Results The mean age of control group was 13.5 ± 2.5 years, and the mean age of Hashimoto thyroiditis (HT) group was 14.2 ± 2.7 years, no statistically significant differences existed (p=0.205). Cys-C values were significantly higher in the HT group than in the control group (p=0.041). When all cases were evaluated, Cys-C levels were statistically positively correlated with fT3, TPOAb, and TGAb values (p<0.001, p=0.029, p=0.013 respectively). Conclusions Based on the results of our study, Cys-C levels in children and adolescents with euthyroid Hashimoto thyroiditis were statistically higher than their healthy peers. In conclusion, it can be said that Cys-C may be a factor in the etiopathogenesis of autoimmune thyroiditis, and even small changes in TSH values affect Cys-C levels.

Objectives Familial transmission is observed in approximately 10% of cases with type 1 diabetes mellitus (T1DM). The most important gene determining susceptibility is the human leukocyte antigen complex (HLA) located on chromosome 6. More than 50 susceptible loci are associated with T1DM susceptibility have been identified in genes other than HLA. In this study, it was aimed to investigate the molecular genetic etiology by whole-exome sequence (WES) analysis in cases with familial T1DM with no or weakly detected HLA tissue type susceptibility. We aimed to identify new genes responsible for the development of type 1 diabetes and to reveal new genes that have not been shown in the literature before. Methods Cases with at least one T1DM diagnosis in first-degree relatives were included in the study. In the first step, HLA DQ2 and DQ8 loci, which are known to be associated with T1DM susceptibility, were investigated by. In the second step, the presence of variants that could explain the situation was investigated by WES analysis in patients who were negative for both HLA DQ2 and HLA DQ8 haplotypes, HLA DQ2 negative, HLA DQ8 positive, and HLA DQ2 positive and HLA DQ8 negative patients. Results The mean age and duration of diabetes of the 30 cases (Girl/Male: 17/13) were 14.9 ± 6 and 7.56 ± 3.84 years, respectively. There was consanguineous marriage in 5 (16%) of the families. As a result of filtering all exome sequence analysis data of two cases with DQ2 (DQB1*02) (−) and DQ8 (DQB1*03:02) (−), seven cases with DQ2 (DQB1*02) (+) and DQ8 (DQB1*03:02) (−), and one case with DQ2 (DQB1*02) (−) and DQ8 (DQB1*03:02) (+), seven different variants in seven different genes were detected in five cases. The pathogenicity of the detected variants were determined according to the “American College of Medical Genetics and Genomics (ACMG)” criteria. These seven variants detected were evaluated as high-score VUS (Variants of unknown/uncertain significance). In the segregation study conducted for the mutation in the POLG gene detected in case 5, this variant was detected in the mother of the case and his brother with T1DM. Segregation studies are ongoing for variants detected in other affected individuals in the family. Conclusions In conclusion, in this study, seven different variants in seven different genes were detected in five patients by WES analysis in familial T1DM patients with no or weak HLA tissue type susceptibility. These seven variants detected were evaluated as high-score VUS. POLG might be a novel candidate gene responsible for susceptibility to T1DM. Non-HLA genes directly responsible for the development of T1DM were not detected in any of the cases.

Objectives Congenital generalized lipodystrophy (CGL) is a group of rare autosomal inherited diseases characterized by a widespread loss of adipose tissue. The main purpose of this study was to evaluate the features of Chinese patients with CGL2. Methods Three patients diagnosed with CGL2 from our center were reviewed. Data on clinical features, results of laboratory analyses, and previous treatments were retrospectively collected. This study also reviewed studies that reported patients diagnosed with CGL2 in the last 30 years. Results All patients presented a lack of subcutaneous fat, hypertriglyceridemia, reversed triangular faces, acanthosis nigricans, and hepatomegaly within the first six months of life. All three patients developed splenomegaly, and mental retardation in later life. Dietary control dramatically lowered triglyceride levels in all patients. One patient presented with diabetes mellitus at 1 year-old. Although combined therapy with low fat diet and metformin maintained normal levels of blood lipid and glucose, this patient developed hypertrophic cardiomyopathy at the age of three. By a literature review on all Chinese cases with CGL2, it is known that classic manifestations such as hypertriglyceridemia, hepatomegaly and diabetes mellitus can occur shortly after birth, and early diagnosis and treatment can improve quality of life. In this cohort, the most frequent variations are c.782dupG and c.974dup in the BSCL2 gene. However, the same genotype may have different clinical phenotypes in patients with CGL2. Conclusions This study not only described the clinical and genetic features of three patients with CGL2 in China, but also reviewed literature about CGL2 around the world.

Objectives Congenital Adrenal Hyperplasia (CAH) is a group of genetic diseases characterized by impaired cortisol biosynthesis. 95% of CAH cases result from mutation in the CYP21A2 gene encoding 21-hydroxilase. TNX-B gene partially overlaps CYP21A2 and encodes a matrix protein called Tenascin-X (TNX). Complete tenascin deficiency causes Enlers-Danlos syndrome (EDS). A mono allelic variant called CAH-X CH-1 was recently described, resulting from a CYP21A2 complete deletion that extends into the TNXB. This haploinsufficiency of TNX may be associated with a mild hypermobility form of EDS, as well as other connective tissue comorbidities such as hernia, cardiac defects and chronic arthralgia. Case presentation We report four patients heterozygous for a CAH-X CH-1 allele that do not present clinical manifestations of the EDS. Conclusions All CAH patients, carriers of these TNXA/TNXB chimeras, should be evaluated for clinical manifestations related to connective tissue hypermobility, cardiac abnormalities and other EDS features, allowing for better clinical surveillance management.

Objectives Approximately 90% of “XX males” are positive for SRY . However, there are isolated cases of sex reversal associated to other genes in male-determining pathway. Case presentation We describe a 1.3-old patient with 46,XX karyotype, male phenotypic gender and cryptorchidism. Microarray analysis revealed a de novo 273 kb duplication in the Xq27.1 region that contains SOX3 . FISH with probe specific to SOX3 confirmed a unique genomic location of this duplication, dislocated proximal to the centromere of the X chromosome. Conclusions This rare genetic condition was described in few other isolated cases that have associated SOX3 genetic rearrangements and DSD. Microarray and genome-wide-sequencing presents important part in routine diagnostics, and in delineation of other sex-determination-pathway genes in sex reversal disorders.

Objectives Lower limb deformities in children need careful orthopedic evaluation to distinguish physiological forms from pathological ones. X-linked hypophosphatemia (XLH) is a rare hereditary condition caused by PHEX gene mutations where tibial varum can be the first sign. Case presentation We report a family presenting with severe tibial varum, harbouring a rare PHEX intron mutation, c.1586+6T>C. This is the first clinical description available in literature for this variant. Despite the previous prediction of a mild phenotype in functional study, our patients showed important bone deformities, rickets and impaired growth since infancy followed by severe bone pain, hearing loss and reduced life quality in adulthood. Burosumab therapy improved biochemical and radiological findings in children and ameliorated quality of life in adults. Conclusions This case demonstrated c.1586+6T>C causes a severe XLH phenotype, responsive to Burosumab. Familial genetic screening, enlarged to intronic region analysis, when XLH is suspected, allows precocious diagnosis to start timely the appropriate treatment.

Adrenocortical tumor (ACT) is a rare malignant tumor which usually present with Cushing syndrome and virilization. Paraneoplastic syndromes (PNS) due to neoplasms can occur with peptides or cytokines secreted by the tumor. Here, we report a 13-month-old-male presented with severe masculinization. He had signs of precocious puberty with enlarged testicles, very high testosterone levels but low levels of gonadotrophins, and elevated β-hCG. He underwent a left nephrectomy. The histopathological evaluation revealed a diagnosis of adrenocortical neoplasm. The levels of androgens and β-hCG normalized after the resection of tumor, and the clinical findings improved within few months. We report the first pediatric patient with peripheral precocious puberty due to an ACT that secretes β-hCG as PNS. A β-hCG secreting ACT can cause severe virilization due to increased gonadal androgens stimulated by β-hCG as well as due to increased adrenal androgens from the tumor.

Objectives We aimed to identify the origin of atypical diabetes in a family with four generations of diabetes from South Asia. The family members showed different clinical phenotypes. Members of generation one to three were presumed to have type 2 diabetes and generation four to have type 1 diabetes. Case presentation We performed a genetic analysis of the family using targeted high throughput sequencing. Conclusions We identified a novel nonsense variant in the neurogenic differentiation 1 ( NEUROD1 ) gene, co-segregating with diabetes. The variant was located in the DNA-binding domain, altering a protein residue that was very well conserved among different species.