Anaemia-based screening for resistance to thyroid hormone alpha in children.

BACKGROUND: The hypothyroid phenotype associated with resistance to thyroid hormone alpha (RTH-α) is associated with a diverse clinical picture. On the other hand, thyroid-stimulating hormone (TSH) levels are normal. Free triiodothyronine (fT3) and free thyroxine (fT4) levels can also be normal; however, normo- or macrocytic anaemia is usually present in reported cases. Diagnosis is challenging and there is limited data regarding screening methods. OBJECTIVE: The study aimed to assess the efficiency of a screening strategy for RTH-α. SUBJECTS AND METHODS: Out of a total of 6540 children evaluated at the outpatient clinics of paediatric neurology over 2 years and who underwent complete blood count and thyroid function tests, 432 were found to have anaemia. Within this group, we identified 42 children without an underlying specific neurological aetiology who exhibited normo- or macrocytic anaemia, normal TSH levels, fT3 levels in the upper half of the normal range or high, and fT4 levels in the lower half of the normal range or low. We excluded one patient who had already been diagnosed with RTH-α and nine patients could not be reached. Subsequently, clinical evaluation, biochemical assessment, and THRA sequencing analysis were conducted on 32 children. The findings were compared with those of the known RTH-α patients in our unit. RESULTS: The median age of the patients was 5.7 (5.1-7.4) years, and 22 of them were males (69%). The main reasons for assessment in paediatric neurology clinics were autism spectrum disorder (n = 12, 38%), epilepsy (n = 11, 34%), and delay in developmental stages (n = 8, 25%). Constipation was present in five of the cases (16%), while the closure of the anterior fontanelle and tooth eruption were delayed in two cases (6%) and one case (3%), respectively. The median length/height and weight standard deviation (SD) scores were 0.3 [(-0.8)-(1.1)] and -0.1 [(-0.8)-(0.3)], respectively. The median fT3, fT4, and TSH levels were 4.6 (4.2-5.0) pg/mL, 0.9 (0.8-1.0) ng/dL, and 2.2 (1.8-3.1) uIU/mL, respectively. Thirteen of the patients (41%) had high fT3 levels, while none of them had low fT4 levels. The normo- or macrocytic anaemia rate was 47% (normocytic/macrocytic, n = 8/7) at the time of reassessment. Serum creatine kinase (CK) was elevated in five patients (16%; one had anaemia). None of the subjects had a pathological variant in THRA. Known RTH-α patients had significantly lower median height SD score, higher rates of delayed tooth eruption and closure of the anterior fontanelle, lower haemoglobin levels, and higher mean corpuscular volume (MCV) and CK levels as compared to those found without RTH-α. CONCLUSIONS: This approach found one known patient with RTH-α but did not reveal any new cases. Notably, normo- or macrocytic anaemia did not persist in nearly half of the screened patients. A screening strategy that takes clinical findings and prominent laboratory features suggestive of RTH-α into account could lower unnecessary genetic analysis of THRA in patients presenting with neurological problems.

Aromatase Inhibitors May Increase the Risk of Cardiometabolic Complications in Adolescent Boys.

INTRODUCTION: Aromatase inhibitors (AIs) are increasingly used in children and adolescents to augment adult height. The aim of this study was to investigate the effects AIs have on cardiac morphology, functions and their relation to several metabolic parameters in adolescent boys. METHODS: Three groups matched for sex (boys, n = 67), age (median age 13.5 years), weight, height, body mass index, and puberty stages were enrolled: (i) Group 1: 23 patients using AIs (only AI (n = 6) or in combination with growth hormone (GH) (n = 17)) for at least 6 months; (ii) Group 2: 22 patients using only GH, and (iii) Group 3: 22 healthy boys. Two-dimensional, M-mode conventional Doppler and tissue Doppler examinations of the left ventricle (LV) were performed. Bioelectrical bioimpedance analyses was conducted and follicle-stimulating hormone, luteinizing hormone, total testosterone, lipid, and hemogram parameters were obtained. RESULTS: Patients in Group 1 had significantly higher serum total testosterone (p < 0.001) and hemoglobin (p < 0.001) levels, fat free mass (p = 0.005), LV mass (LVM) (p = 0.002), as well as increased LV posterior wall diameter (LVPWD) (p = 0.002), interventricular septum diameter (IVSD) (p = 0.019), and myocardial systolic wave velocity (Sm) (p = 0.020) compared to the two other control groups. No significant differences were observed in terms of diastolic and systolic functions and lipid profiles (p > 0.05). There were positive correlations between total testosterone, hemoglobin levels, LVM, LVPWD and IVSD (p < 0.05). CONCLUSION: Increased LVM, LVPWD, IVSD and Sm of patients receiving AI therapy in comparison to the control groups, and the significant correlations of these parameters with total testosterone and hemoglobin levels were determined as potential side effects of AIs. These findings emphasize the need of routine cardiac follow-up in patients using AIs.

Positive effects of ketogenic diet on weight control in children with obesity due to Prader-Willi syndrome.

OBJECTIVE: Prader-Willi Syndrome (PWS) is the most common genetic cause of obesity. Prevention and management of obesity, which represents the main cause of morbidity and mortality in these patients, is essential. Ketogenic diet (KD) is used in the treatment of various disorders, however knowledge of its effect in PWS is lacking. The present study assesses the characteristics of patients with PWS who were on KD. DESIGN AND PATIENTS: This is a retrospective, cross-sectional descriptive study investigating the subjects with PWS, who had received KD for at least 6 months. RESULTS: Ten patients with PWS [median age 52.5 (47-77) months] complied with KD. The median treatment period was 16.5 [11-52] months. Of the daily calorie, 75%-85% were from fat, and 15%-25% from protein + carbohydrate. The baseline body weight standard deviation (SD) score before diet therapy was 2.10 [-1.11-4.11], whereas it was 0.05 [-0.92-1.2] at final evaluation (p = .007). The baseline median BMI SD score before diet therapy was 3.05 [-0.21-3.72], whereas it was 0.41 [-0.87-1.57] at final evaluation (p = .002). The height SD score remained unchanged. Mild hypercholesterolaemia was the most common biochemical abnormality during treatment with KD. CONCLUSION: Our results indicate that KD might have a favourable effect on weight management in PWS.

Clinical Characteristics of Children with Combined Pituitary Hormone Deficiency and the Effects of Growth Hormone Treatment.

AIM: We aimed to describe the clinical characteristics of patients with congenital combined pituitary hormone deficiency (CPHD) and evaluate the first-year growth responses of individuals with CPHD and isolated growth hormone deficiency (IGHD) in order to establish the influence of other hormone deficiencies on growth response. PATIENTS AND METHODS: This retrospective study was conducted in four tertiary care centers in Turkey. The records of patients diagnosed with CPHD (n=39) and severe IGHD (n=50) were collected. Cases with acquired lesions or chronic diseases were not included in the study. Data are presented as median (interquartile range). RESULTS: Among 39 patients (13 females; 33%) with a diagnosis of CPHD, the majority of patients (64%) presented initially with combined deficits at baseline examination, whereas isolated deficiencies (36%) were less prevalent. Among all patients with GH deficiency, TSH, ACTH, FSH/LH, and ADH deficiencies were present in 94%, 74%, 44%, and 9% of patients, respectively. Patients with CPHD were diagnosed at a younger age (4.9 (8.4) vs. 11.6 (4.1), p<0.001, respectively) and had lower peak GH concentrations (0.4 (1.8) vs. 3.7 (2.9), p<0.001, respectively) than patients with IGHD. Patients with IGHD and CPHD had similar first-year growth responses (Δheight SD score of 0.55 (0.63) vs. 0.76 (0.71), respectively, p=0.45). CONCLUSIONS: We established the nature and timing of numerous hormonal deficits emerging over time. We also identified that the existence of CPHD did not hinder growth response.

Systematic genetic testing for recessively inherited monogenic diabetes: a cross-sectional study in paediatric diabetes clinics.

AIMS/HYPOTHESIS: Current clinical guidelines for childhood-onset monogenic diabetes outside infancy are mainly focused on identifying and testing for dominantly inherited, predominantly MODY genes. There are no systematic studies of the recessively inherited causes of monogenic diabetes that are likely to be more common in populations with high rates of consanguinity. We aimed to determine the contribution of recessive causes of monogenic diabetes in paediatric diabetes clinics and to identify clinical criteria by which to select individuals for recessive monogenic diabetes testing. METHODS: We conducted a cross-sectional study of 1093 children from seven paediatric diabetes clinics across Turkey (a population with high rates of consanguinity). We undertook genetic testing of 50 known dominant and recessive causes of monogenic diabetes for 236 children at low risk of type 1 diabetes. As a comparison, we used monogenic diabetes cases from UK paediatric diabetes clinics (a population with low rates of consanguinity). RESULTS: Thirty-four children in the Turkish cohort had monogenic diabetes, equating to a minimal prevalence of 3.1%, similar to that in the UK cohort (p = 0.40). Forty-one per cent (14/34) had autosomal recessive causes in contrast to 1.6% (2/122) in the UK monogenic diabetes cohort (p < 0.0001). All conventional criteria for identifying monogenic diabetes (parental diabetes, not requiring insulin treatment, HbA1c ≤ 58 mmol/mol [≤7.5%] and a composite clinical probability of MODY >10%) assisted the identification of the dominant (all p ≤ 0.0003) but not recessive cases (all p ≥ 0.2) in Turkey. The presence of certain non-autoimmune extra-pancreatic features greatly assisted the identification of recessive (p < 0.0001, OR 66.9) but not dominant cases. CONCLUSIONS/INTERPRETATION: Recessively inherited mutations are a common cause of monogenic diabetes in populations with high rates of consanguinity. Present MODY-focused genetic testing strategies do not identify affected individuals. To detect all cases of monogenic paediatric diabetes, it is crucial that recessive genes are included in genetic panels and that children are selected for testing if they have certain non-autoimmune extra-pancreatic features in addition to current criteria.

The effect of leisure boredom and A1C level on diabetes eating problems in adolescents with type 1 diabetes.

PURPOSE: Eating out of boredom, the changes in daily routine, physical inactivity and longer exposure to screens have made glycemic control difficult at home during the COVID-19 pandemic among adolescents with Type 1 Diabetes Mellitus. Adolescents with diabetes are at higher risk of developing eating problems than are their healthy peers. The aim of this study is to examine the effects of leisure time boredom and A1C level on eating problems in adolescents with Type 1 Diabetes Mellitus. DESIGN AND METHODS: A descriptive, correlational, and cross-sectional design was used in this study. The study was conducted in Turkey, with the participation of 173 adolescents diagnosed with Type 1 Diabetes Mellitus. Convenience sampling was used to recruit patients from pediatric endocrinology outpatient clinics of hospitals. RESULTS: It was determined that the diabetes eating problems of adolescents with Type 1 Diabetes were mostly affected by the level of leisure time and A1C, respectively. In the overall model, 58% (F = 4119.701, p < .001) of the factors affecting diabetes eating problems could be explained by the level of leisure boredom and A1C level. CONCLUSION: It has been found that the adolescents with diabetes with high A1C levels and who cannot use their leisure time and have boredom are more at risk in terms of diabetes eating problems. PRACTICE IMPLICATIONS: It should be determined how the adolescents with diabetes spend their lesiure time by diabetes health care team, which should be supported to develop leisure time skills. Effective use of leisure time and strategies to cope with boredom should also be included in diabetes education.

Bedside sonographic measurements of optic nerve sheath diameter in children with diabetic ketoacidosis.

BACKGROUND: Bedside sonographic assessment of the optic nerve sheath has gained popularity for evaluating intracranial pressure in recent years. OBJECTIVE: To investigate the bedside sonographic measurements of optic nerve sheath diameter (ONSD) and ONSD/eyeball diameter ratios, which are related with cerebral edema (CE), in children with diabetic ketoacidosis (DKA) before and after treatment. METHODS: Children aged 12 months to 18 years, who were diagnosed with DKA were included. The ONSD was measured at 3 mm posterior to the globe in the anterior axial transbulbar view. The eyeball transverse diameter (ETD) and eyeball vertical diameter (EVD) were measured and ratios of ONSD/ETD and ONSD/EVD were calculated. Bedside ultrasound (US) examinations were performed at the beginning and at the end of fluid therapy. RESULTS: About 43 patients were enrolled. About 12 (27.9%) patients had mild, 14 (32.6%) moderate, and 17 (39.5%) severe DKA. At baseline, the ONSD measurements and ratios were significantly higher in severe DKA group than in those with mild or moderate DKA group. All ONSD measurements, ONSD/ETD, and ONSD/EVD ratios at the end of therapy were significantly lower compared with baseline measurements. At the end of therapy, ONSD measurements and ratios were similar among DKA severity groups. CONCLUSION: The ONSD measurements and ratios decreased from the beginning of DKA treatment, which could be considered as an indicator of an increase in intracranial pressure at the time of admission. Ocular US may serve as a promising tool to perform further risk stratification of children with DKA and to identify DKA-related CE.

Comparison of the Effectiveness of Adult Height Prediction Methods in Children with Growth Hormone Deficiency.

Background: In patients with growth hormone (GH) deficiency, the prediction of adult height before initiation of GH treatment can be helpful to guide clinicians and families. However, data regarding the effectiveness of prediction methods in such patients are limited.Objective: We aimed to investigate the accuracy of the three most used adult height prediction methods [Bayley-Pinneau (BP), Roche-Wainer-Thissen (RWT), and Tanner-Whitehouse 2 (TW2)] by comparing their results with the near-adult height (NAH) data of children treated with GH.Methods: A single-center retrospective study was conducted including patients treated with somatotropin due to GH deficiency. Bone age radiographs were reread by three authors. Adult height predictions were made using BP, RWT, and TW2 methods for each patient.Results: Forty-nine patients with GH deficiency [median age at diagnosis 10.8 (9.2-12.0) years, 63.3% girls, 69.4% prepubertal] were included. Median differences between predicted adult height (PAH) and NAH standard deviation (SD) scores were -0.5, 0.0, and 0.3 for BP, RWT, and TW2 methods, respectively. The rates of PAH within ±1 SD score of NAH were 54.7%, 62.3%, and 77.4% for BP, TW2, and RWT methods, respectively. RWT was the most accurate method in girls, however, it showed a similar efficiency with TW2 in prepubertal patients or those with delayed bone age between 1-2 years, independent of gender.Conclusions: We found that RWT and TW2 methods may be preferable rather than the BP method for predicting adult height in patients with a diagnosis of GH deficiency.

The relationship of carotid intima-media thickness with anthropometric and metabolic parameters in patients with classic congenital adrenal hyperplasia

Background/aim: We aimed to determine the presence of subclinical atherosclerosis using carotid intima-media thickness (CIMT) and biochemical parameters in children and adolescents with congenital adrenal hyperplasia (CAH). Materials and methods: Thirty-four patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency on regular glucocorticoid treatment for ≥3 years and 31 healthy subjects were included in the study. The patients were divided into two groups according to the degree of control of the clinic, laboratory, and radiological parameters as a) "uncontrolled" [n= 22; with increased height velocity (HV) standard deviation score (SDS) (≥2 SDS), advanced bone age, serum 17-OH progesterone <2.0 and ≥10.0 ng/mL or androstenedione <0.3 and ≥ 3.0 ng/mL] or b) "controlled" [n= 12; with HV SDS < 2, bone age (BA)/ chronologic age (CA) ratio < 1.2, serum 17-OH progesterone between 2 and 10 ng/mL and androstenedione between 0.3 and 3.0 ng/mL]. Ultrasonographic examination of carotid artery was performed by the same radiologist using a B-mode ultrasound system. Results: There was no significant difference between the CAH and control groups in terms of median (IQR) CIMT values [0.47 (0.05) mm and 0.47 (0.07) mm, respectively; p > 0.05]. When subgroup comparisons were done in terms of median (IQR) CIMT values, there was no significant difference among the controlled, uncontrolled, and healthy control groups [0.45 (0.03) mm, 0.47 (0.04) mm, 0.47 (0.07) mm, respectively; p> 0.05]. In addition, CIMT levels were similar according to sex and disease control status. Conclusion: In this study, the CIMT values of CAH cases were similar to those of healthy subjects.

NOVEL VDR MUTATIONS IN PATIENTS WITH VITAMIN D-DEPENDENT RICKETS TYPE 2A: A MILD DISEASE PHENOTYPE CAUSED BY A NOVEL CANONICAL SPLICE-SITE MUTATION.

Objective: Vitamin D-dependent rickets type 2A (VDDR2A) is a rare autosomal recessive disorder caused by mutations in the vitamin D receptor gene (VDR), leading to end-organ resistance to 1,25-dihydroxyvitamin D3 (1,25[OH]2D3). The objective of this study was to investigate VDR mutations in 11 patients from 8 Turkish-Arab families. Methods: All coding exons and intron-exon boundaries of the VDR gene were amplified by polymerase chain reaction from peripheral leukocyte DNA and sequenced. The effect of splice-site mutations on mRNA splicing was evaluated by a customized VDR mini-gene assay. Results: Homozygous VDR mutations were found in all the patients, including four novel mutations: c.473G>T (p.R158L), c.1-4A>G (IVS3-2A>G), c.755+1G>T, and c.352_356delGACAG (p.D118Sfs*7). The c.1-4A>G mutation was located in the canonical splice acceptor site and 4 base pairs from the original ATG start codon. The mutation resulted in both complete (60% of transcripts) and partial exon 4 skipping (15% of transcripts). The latter was due to activation of a cryptic splice acceptor site and did not disrupt the open reading frame. Both c.755+1G>T and c.352_356delGACAG resulted in frameshifts and a premature stop codon. Clinically, all the patients required continued treatment, except for patient IV-3, who presented with alopecia, hypocalcemia, and increased 1,25(OH)2D3 at 1.5 years of age as a result of the c.1-4A>G mutation. He stopped taking medication at 6 years of age and still maintained normal height and biochemical profile. Conclusion: We have identified four novel VDR mutations. Although canonical splice-site mutations cause premRNA splicing errors that usually lead to a severe disease phenotype, mild disease can also occur due to activation of a cryptic splice site. Abbreviations: 1,25(OH)2D3 = 1,25-dihydroxyvitamin D3 (calcitriol); 25OHD3 = 25-hydroxyvitamin D3; PCR = polymerase chain reaction; PTH = parathyroid hormone; VDDR2A = vitamin D-dependent rickets type 2A; VDR = vitamin D receptor.

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.

Anthropometric findings from birth to adulthood and their relation with karyotpye distribution in Turkish girls with Turner syndrome.

To evaluate the anthropometric features of girls with Turner syndrome (TS) at birth and presentation and the effect of karyotype on these parameters. Data were collected from 842 patients with TS from 35 different centers, who were followed-up between 1984 and 2014 and whose diagnosis age ranged from birth to 18 years. Of the 842 patients, 122 girls who received growth hormone, estrogen or oxandrolone were excluded, and 720 girls were included in the study. In this cohort, the frequency of small for gestational age (SGA) birth was 33%. The frequency of SGA birth was 4.2% (2/48) in preterm and 36% (174/483) in term neonates (P < 0.001). The mean birth length was 1.3 cm shorter and mean birth weight was 0.36 kg lower than that of the normal population. The mean age at diagnosis was 10.1 ± 4.4 years. Mean height, weight and body mass index standard deviation scores at presentation were -3.1 ± 1.7, -1.4 ± 1.5, and 0.4 ± 1.7, respectively. Patients with isochromosome Xq were significantly heavier than those with other karyotype groups (P = 0.007). Age at presentation was negatively correlated and mid-parental height was positively correlated with height at presentation. Mid-parental height and age at presentation were the only parameters that were associated with height of children with TS. The frequency of SGA birth was found higher in preterm than term neonates but the mechanism could not be clarified. We found no effect of karyotype on height of girls with TS, whereas weight was greater in 46,X,i(Xq) and 45,X/46,X,i(Xq) karyotype groups.

Can ambulatory blood pressure monitoring detect early diastolic dysfunction in children with type 1 diabetes mellitus: correlations with B-type natriuretic peptide and tissue Doppler findings.

AIM: To evaluate the relationship between 24-h blood pressure (BP) measurements and diastolic heart function evaluated by Doppler tissue imaging and B-type natriuretic peptide (BNP) levels in children with type 1 diabetes mellitus (DM). PATIENTS AND METHODS: A total of 32 diabetic and 18 healthy children were enrolled. Spectral Doppler analysis and tissue Doppler measurements were performed by conventional echocardiography. The 24-h ambulatory BP and serum BNP levels were measured. RESULTS: Analysis of ambulatory blood pressure monitoring (ABPM) recordings showed that median daytime diastolic BP load were significantly higher in diabetic patients compared to controls [12.35 (4.23-27.23) vs. 2.5 (0-8.7), p = 0.007]. Patients with elevated daytime systolic and diastolic BP loads had significantly higher BNP values compared to patients with normal BP load (31.4 ± 24.36 vs. 11.84 ± 11.25 pg/mL, p = 0.03 and 23.21 ± 15.12 vs. 12.12 ± 14.65 pg/mL, p = 0.03, respectively). Isovolemic contraction time (47.43 ± 7.84 vs. 42.27 ± 7.47, p = 0.045), isovolemic relaxation time (68.84 ± 10.43 vs. 58.77 ± 10.02, p = 0.02), and myocardial performance index (0.45 ± 0.10 vs. 0.37 ± 0.09, p = 0.02) as determined by tissue Doppler echocardiography were significantly high in diabetic patients compared to that of control cases. Ratio of mitral peak early diastolic flow velocity (E) to peak early diastolic myocardial velocities by tissue Doppler echocardiography (E') was also higher in patients with elevated daytime systolic BP load (E/E', 6.71 ± 1.97 vs. 4.91 ± 1.02, p = 0.04). CONCLUSION: Elevated BP loads detected by 24-h ambulatory BP measurements in children with type 1 diabetes are associated with increased BNP levels and abnormal tissue Doppler echocardiography indices, indicating early stage cardiac dysfunction.

Characterization of ANKRD11 mutations in humans and mice related to KBG syndrome.

Mutations in ANKRD11 have recently been reported to cause KBG syndrome, an autosomal dominant condition characterized by intellectual disability (ID), behavioral problems, and macrodontia. To understand the pathogenic mechanism that relates ANKRD11 mutations with the phenotype of KBG syndrome, we studied the cellular characteristics of wild-type ANKRD11 and the effects of mutations in humans and mice. We show that the abundance of wild-type ANKRD11 is tightly regulated during the cell cycle, and that the ANKRD11 C-terminus is required for the degradation of the protein. Analysis of 11 pathogenic ANKRD11 variants in humans, including six reported in this study, and one reported in the Ankrd11 (Yod/+) mouse, shows that all mutations affect the C-terminal regions and that the mutant proteins accumulate aberrantly. In silico analysis shows the presence of D-box sequences that are signals for proteasome degradation. We suggest that ANKRD11 C-terminus plays an important role in regulating the abundance of the protein, and a disturbance of the protein abundance due to the mutations leads to KBG syndrome.

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.

Salivary Sex Steroid Levels in Infants and the Relation with Infantile Colic

Objective: The hypothalamic-pituitary-gonadal axis is active during minipuberty, the timing of which coincides with infantile colic. To the best of our knowledge, the relationship between these entities has not been previously investigated. Methods: Saliva samples were collected from 15- to 60-day-old term infants (n=139) between 9 am and 5 pm. Group 1 included infants with infantile colic (n=68, 54.4% female) while the remaining healthy infants constituted Group 2 (n=71, 47.9% female). Salivary levels of estradiol (Esal) in females and testosterone (Tsal) in males were measured by ELISA in duplicate. Results: The median (25th-75th centile) age and birth week for all infants were 33 (29-43) days and 39 (38.1-40) weeks, respectively. Levels of Tsal in males [Group 1, 73.35 (59.94-117.82) pg/mL vs Group 2, 77.66 (56.49-110.08) pg/mL, p=0.956] and Esal in females [Group 1, 3.91 (2.76-5.31) pg/mL vs Group 2, 4.03 (1.63-12.1) pg/mL, p=0.683] were similar. However, in subjects with infantile colic (Group 1), Esal and body mass index (BMI) standard deviation scores of females were slightly correlated (Group 1, rs= 0.393, p=0.016 vs. Group 2, rs= 0.308, p=0.076) and there was a significant correlation between the sampling time and Tsal in males (Group 1, rs= 0.469, p=0.009 vs. Group 2, rs= -0.005, p=0.976). Conclusion: Random salivary sex steroid levels were similar in infants with and without infantile colic. However, in subjects with infantile colic, Esal levels in females were positively correlated with BMI and Tsal levels were higher later in the day among males. Thus, sex steroid production may be altered during minipuberty in subjects with infantile colic.

Deciphering the Clinical Presentations in LMNA-related Lipodystrophy: Report of 115 Cases and a Systematic Review.

CONTEXT: Lipodystrophy syndromes are a heterogeneous group of rare genetic or acquired disorders characterized by generalized or partial loss of adipose tissue. LMNA-related lipodystrophy syndromes are classified based on the severity and distribution of adipose tissue loss. OBJECTIVE: We aimed to annotate all clinical and metabolic features of patients with lipodystrophy syndromes carrying pathogenic LMNA variants and assess potential genotype-phenotype relationships. METHODS: We retrospectively reviewed and analyzed all our cases (n = 115) and all published cases (n = 379) curated from 94 studies in the literature. RESULTS: The study included 494 patients. The most common variants in our study, R482Q and R482W, were associated with similar metabolic characteristics and complications though those with the R482W variant were younger (aged 33 [24] years vs 44 [25] years; P < .001), had an earlier diabetes diagnosis (aged 27 [18] vs 40 [17] years; P < .001) and had lower body mass index levels (24 [5] vs 25 [4]; P = .037). Dyslipidemia was the earliest biochemical evidence described in 83% of all patients at a median age of 26 (10) years, while diabetes was reported in 61% of cases. Among 39 patients with an episode of acute pancreatitis, the median age at acute pancreatitis diagnosis was 20 (17) years. Patients who were reported to have diabetes had 3.2 times, while those with hypertriglyceridemia had 12.0 times, the odds of having pancreatitis compared to those who did not. CONCLUSION: This study reports the largest number of patients with LMNA-related lipodystrophy syndromes to date. Our report helps to quantify the prevalence of the known and rare complications associated with different phenotypes and serves as a comprehensive catalog of all known cases.

Comprehensive Insights into Pediatric Craniopharyngioma: Endocrine and Metabolic Profiles, Treatment Challenges, and Long-term Outcomes with a Multicenter Approach.

Introduction: Craniopharyngiomas (CPG) have complex challenges in treatment due to their proximity to vital structures, surgical and radiotherapeutic complexities, and the tendency for recurrence. This study aims to identify the prevalence of endocrine and metabolic comorbidities observed during initial diagnosis and long-term follow-up in a nationwide cohort of pediatric CPG patients. The study also highlights the associated difficulties in their management. Methods: Sixteen centers entered 152 patients into the ÇEDD NET data system. We evaluated the clinical and laboratory characteristics at presentation, administered treatments, accompanying endocrine, metabolic, and other system involvements, and the patient's follow-up features. Results: Of the evaluated patients, 64 were female, and 88 were male. At presentation, the mean age was 9.1 ± 3.67 (min:1.46-max:16.92) years. The most common complaints at presentation were headache (68.4%), vision problems (42%), short stature (15%), nausea and vomiting (7%). The surgical procedure applied to the patients was gross total resection (GTR) in 97 cases (63.8%) and subtotal resection in 55 cases (36.2%). Radiotherapy was initiated in 11.8% of the patients. In the pathological examination, 92% of the cases were adamantinamatous type, 8% were papillary type. Postoperatively, hormone deficiencies consisted of thyroid-stimulating hormone (92.1%), adrenocorticotropic hormone (81%), antidiuretic hormone (79%), growth hormone (65.1%), and gonadotropin (43.4%) deficiencies. Recombinant growth hormone treatment (rhGH) was initiated on 27 patients. The study showed hesitancy among physicians regarding rhGH. The median survival without relapse was 2.2 years. Median time of relapse was 1.82 years (range: 0.13-10.35 years). Relapse was related to longer follow-ups and reduced GTR rates. The median follow-up time was 3.13 years. Among the last follow-up visits, the prevalence of obesity was 38%, but of these, 46.5% were already obese at diagnosis. However, 20% who were not obese at baseline became obese on follow-up. Permanent visual impairment was observed in 26 patients, neurological deficits in 13 patients, and diabetes mellitus in 5 patients. Conclusion: Recurrence was predominantly due to incomplete resection and the low rate of postoperative radiotherapy. It also emphasized challenges in multidisciplinary regular follow ups and suggested early interventions such as dietary restrictions and increased exercise to prevent obesity.

Thyroid dyshormonogenesis is mainly caused by TPO mutations in consanguineous community.

OBJECTIVE: In this study, we aimed to investigate the genetic background of thyroid dyshormonogenesis (TDH). CONTEXT: Thyroid dyshormonogenesis comprises 10-15% of all cases of congenital hypothyroidism (CH), which is the most common neonatal endocrine disorder, and might result from disruptions at any stage of thyroid hormone biosynthesis. Currently seven genes (NIS, TPO, PDS, TG, IYD, DUOX2 and DUOXA2) have been implicated in the aetiology of the disease. DESIGN: As TDH is mostly inherited in an autosomal recessive manner, we planned to conduct the study in consanguineous/multi-case families. PATIENTS: One hundred and four patients with congenital TDH all coming from consanguineous and/or multi-case families. MEASUREMENTS: Initially, we performed potential linkage analysis of cases to all seven causative-TDH loci as well as direct sequencing of the TPO gene in cases we could not exclude linkage to this locus. In addition, in silico analyses of novel missense mutations were carried out. RESULTS: TPO had the highest potential for linkage and we identified 21 TPO mutations in 28 TDH cases showing potential linkage to this locus. Four of 10 distinct TPO mutations detected in this study were novel (A5T, Y55X, E596X, D633N). CONCLUSIONS: This study underlines the importance of molecular genetic studies in diagnosis, classification and prognosis of CH and proposes a comprehensive mutation screening by new sequencing technology in all newly diagnosed primary CH cases.

Severe short stature due to 3-M syndrome with a novel OBSL1 gene mutation.

3-M syndrome is an underdiagnosed autosomal recessive disorder characterized by severe pre- and postnatal growth retardation with minimal dysmorphic features and distinguishing radiological findings. We report a patient who was first admitted at 7.5 years of age. He was born to consanguineous parents with a birth weight of 2250 g. Physical examination revealed a severe short stature (height, 95 cm; SD score -5.64) and minimal dysmorphic features. Biochemistry, endocrine work-up, and karyotype were normal. Reevaluation at 16.5 years of age revealed a height of 128.5 cm (SD score -5.27), prominent forehead, anteverted nasal openings, fleshy nasal tip, full lips, malar hypoplasia, hyperlordosis, prominent heels, testicular volumes 8-10 mL, and pubic hair consistent with Tanner stage II. Growth hormone trial for a year resulted in inadequate height gain (3 cm). The diagnosis of 3-M syndrome was made upon typical findings (thin long bones with diaphyseal narrowing and tall lumbar vertebrae) in a recent skeletal survey. Genetic analysis disclosed a homozygote frame shift mutation in exon 2: c.457_458delinsT resulting in p.Gly153fs.