Interdisiplinary and intraobserver reliability of the Greulich-Pyle method among Turkish children.

OBJECTIVES: Greulich-Pyle (GP) is one of the most used method for bone age determination (BAD) in various orthopedic, pediatric, radiological, and forensic situations. We aimed to investigate the inter- and intra-observer reliability of the GP method between the most relevant disciplines and its applicability to the Turkish population. METHODS: One-hundred and eighty (90 boys, 90 girls) patients with a chronological age younger than 18 (mean 9.33) were included. X-rays mixed by the blinded investigator were evaluated by two orthopedists, two radiologists, and two pediatric endocrinologists to determine skeletal age according to the GP atlas. A month later the process was repeated. As a statistical method, Paired t-test was used for comparison, an Intraclass Correlation Coefficients test was used for reliability and a 95 % confidence interval was determined. Results were classified according to Landis-Koch. RESULTS: All results were consistent with chronological age (p<0.001), according to the investigators' evaluations compared with chronological age. At the initial evaluation, the interobserver reliability of the method was 0.999 (excellent); at the second evaluation, the interobserver reliability was 0.997 (excellent). The intra-observer reliability of the method was 'excellent' in all observers. When results were separately evaluated by gender, excellent intraobserver correlation and excellent correlation with chronological age were found among all researchers (>0.9). When X-rays were divided into three groups based on age ranges and evaluated, 'moderate' and 'good' correlations with chronological age were obtained during the peripubertal period. CONCLUSIONS: The GP method used in skeletal age determination has excellent inter- and intra-observer reliability. During the peripubertal period, potential discrepancies in bone age assessments should be kept in mind. This method can be used safely and reproducibly by the relevant specialists.

Challenges in the Management of a 7-Year-Old Child with Thyrotropin-Secreting Pituitary Adenoma and the Review of the Literature.

INTRODUCTION: Thyrotropin-producing pituitary adenoma (TSHoma) is a very rare disease, representing less than 1% of the pituitary tumours and presenting with elevated thyroid hormones and normal/high TSH concentrations. CASE PRESENTATION: A 7-year-old boy with nervousness was referred by his psychiatrist for elevated free T4, T3, and TSH levels. Initial evaluation revealed an elevated α-subunit. Pituitary magnetic resonance imaging (MRI) demonstrated a macroadenoma. The patient underwent a trans-sphenoidal tumour resection (TSS) which showed positive immunohistochemical staining for TSH, growth hormone, and prolactin in tumoral tissue. Euthyroidism was achieved for 1 year after TSS, then recurrence of tumour with elevated TSH and thyroid hormone levels necessitated a re-operation with TSS followed by gamma-knife radiosurgery. The euthyroid state was achieved and lasted for 2.5 years this time, but due to the recurrence, medical treatment had been commenced with cabergoline and octreotide. Euthyroidism was maintained for the last 4 years on monthly octreotide treatment. A repeat MRI demonstrated no pituitary mass, but a mass in the sphenoidal sinus had been detected. Removal of this mass by surgery did not achieve euthyroidism. 68Ga-DOTA-TATE positron emission tomography/computed tomography showed residual tissue extending from the pituitary region to the sphenoid sinus. The patient's bone age was advanced by 2 years at diagnosis which became 4 years in 1 year after the diagnosis and remained so throughout follow-up, leading to a final height of -3.3 SDS below his target height at the age of 16 years. CONCLUSION: The diagnosis, treatment, and follow-up of TSHomas are challenging, and short stature due to accelerated bone maturation is a complication of paediatric TSHomas.

Early postnatal metabolic profile in neonates with critical CHDs.

BACKGROUND: Cyanotic CHD is a life-threatening condition that presents with low oxygen saturation in the newborn period. Hypoxemia might cause alterations in the metabolic pathways. In the present study, we aimed to evaluate the early postnatal amino acid and carnitine/acylcarnitine profiles of newborn infants with cyanotic CHD. METHODS: A single centre case-control study was conducted. Twenty-seven patients with cyanotic CHD and 54 healthy newborn controls were enrolled. As part of the neonatal screening programme, results of amino acid and carnitine/acylcarnitine were recorded and compared between groups. RESULTS: Twenty-seven neonates with cyanotic CHD and 54 healthy newborns as controls were enrolled in the study. Cyanotic CHD neonates had higher levels of alanine, phenylalanine, leucine/isoleucine, citrulline, ornithine, C5, C5-OH; but lower levels of C3, C10, C12, C14, C14:1, C16, C16.1, C18, C5-DC, C6-DC, C16-OH, C16:1-OH when compared with the healthy controls. CONCLUSION: This study showed that there are differences between patients with cyanotic CHD and healthy controls in terms of postnatal amino acid and carnitine/acylcarnitine profiles.

A novel deletion involving the first GNAS exon encoding Gsα causes PHP1A without methylation changes at exon A/B.

Individuals affected by pseudohypoparathyroidism type 1A (PHP1A) display hyperphosphatemia and hypocalcemia despite elevated PTH levels, as well as features of Albright Hereditary Osteodystrophy (AHO). PHP1A is caused by variants involving the maternal GNAS exons 1-13 encoding the stimulatory G protein α-subunit (Gsα). MLPA and aCGH analysis led in a male PHP1A patient to identification of a de novo 1284-bp deletion involving GNAS exon 1. This novel variant overlaps with a previously identified 1438-bp deletion in another PHP1A patient (ref. Li et al. (2020) [13], patient 2) that extends from the exon 1 promoter into the up-stream intronic region. This latter deletion is associated with reduced methylation at GNAS exon A/B, i.e. the differentially methylated region (DMR) that is demethylated in most pseudohypoparathyroidism type 1B (PHP1B) patients. In contrast, genomic DNA from our patient revealed no evidence for an epigenetic GNAS defect as determined by MS-MLPA and pyrosequencing. These findings thus reduce the region, which, in addition to other nucleotide sequences telomeric of exon A/B, may undergo histone modifications or interacts with transcription factors and possibly as-yet unknown proteins that are required for establishing the maternal methylation imprints at this site. Taken together, nucleotide deletions or changes within an approximately 1300-bp region telomeric of exon A/B could be a cause of PHP1B variants with complete or incomplete loss-of-methylation at the exon A/B DMR. In addition, when investigating patients with suspected PHP1A, MLPA should be considered to search for structural abnormalities within this difficult to analyze genomic region comprising GNAS exon 1.

Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis Due to CLDN16 Gene Mutations: Novel Findings in Two Cases with Diverse Clinical Features.

Biallelic loss of function mutations in the CLDN16 gene cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), and chronic kidney disease. Here we report two cases of FHHNC with diverse clinical presentations and hypercalcemia in one as a novel finding. Pt#1 initially presented with urinary tract infection and failure to thrive at 5.5 months of age to another center. Bilateral nephrocalcinosis, hypercalcemia (Ca: 12.2 mg/dl), elevated parathyroid hormone (PTH) level, and hypercalciuria were detected. Persistently elevated PTH with high/normal Ca levels led to subtotal-parathyroidectomy at the age of 2.5. However, PTH levels remained elevated with progressive deterioration in renal function. At 9-year-old, she was referred to us for evaluation of hyperparathyroidism and, hypomagnesemia together with hypercalciuria, elevated PTH with normal Ca levels, and medullary nephrocalcinosis were detected. Compound heterozygosity of CLDN16 variants (c.715G>A, p.G239R; and novel c.360C>A, p.C120*) confirmed the diagnosis. Pt#2 was a 10-month-old boy, admitted with irritability and urinary crystals. Hypocalcemia, hypophosphatemia, elevated PTH and ALP, low 25(OH)D levels, and radiographic findings of rickets were detected. However, additional findings of hypercalciuria and bilateral nephrocalcinosis were inconsistent with the nutritional rickets. Low/normal serum Mg levels suggested the diagnosis of FHHNC which was confirmed genetically as a homozygous missense (c.602G > A; p.G201E) variant in CLDN16. Yet, hypocalcemia and hypomagnesemia persisted in spite of treatment. In conclusion, FHHNC may present with diverse clinical features with mild hypomagnesemia leading to secondary hyperparathyroidism with changing Ca levels from low to high. Early and accurate clinical and molecular genetic diagnosis is important for proper management.

Neonatal Problems and Infancy Growth of Term SGA Infants: Does "SGA" Definition Need to Be Re-evaluated?

Introduction: The exact definition of small-for-gestational-age (SGA) infant is still controversial among clinicians. In this study, we aimed to understand which definition is better in terms of establishing both early postnatal problems and growth. In this way, we compared early neonatal problems and infancy growth of term infants with birth weight (BW) < -2 SDS and with BW between 10th percentile (-1.28 SDS) and -2 SDS. Methods: A single center retrospective cohort study was conducted. Preterm infants, multiple gestations and newborns with any congenital anomalies were excluded from the study. Study group was defined as Group 1 (n = 37), infants BW < -2.00 SDS; Group 2 (n = 129), between -1.28 and -2.00 SDS; and Group 3 (n = 137), randomly selected newborns with optimal-for-gestational-age (BW between -0.67 and +0.67 SDS) as a control group. Results: The incidence of severe hypoglycemia was highest in Group 1 (%10.8) and Group 2 and 3 had similar rates of severe hypoglycemia (0.8 and 0.7%, respectively). The incidence of polycythemia was 5.4% in Group 1 and was significantly higher than Group 3 (0.0%) while it was 2.3% in Group 2. Short stature (length < -2 SDS) ratio at the age of 1 and 2 years were similar in each group. Overweight/obesity ratio at the age of 1 were 9.5, 20.8 and 16.7% in each group, respectively (p = 0.509). Conclusion: This study was planned as a pilot study to determine potential differences in the problems of hypoglycemia, polycythemia, and growth according to the differences in definition. Short term disturbances such as hypoglycemia and polycythemia are found to be higher in infants with a BW SDS below -2. From this point of view, of course, it will not be possible to change the routine applications immediately, however this study will be an initiative for discussions by making long-term studies.

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.

Rapid molecular diagnosis of ALB gene variants prevents unnecessary interventions in familial dysalbuminemic hyperthyroxinemia.

OBJECTIVES: Familial dysalbuminemic hyperthyroxinemia (FDH) is an autosomal dominant condition caused by heterozygous gain-of-function mutations in the human ALB gene. CASE PRESENTATION: We report, a three-year-old boy with FDH due to p.R242P (or p.R218P without signal peptide) mutation in the ALB gene with a phenotype characterized by extremely high serum total and free thyroxine concentrations. His parents had normal thyroid function tests (TFT), so the mutation detected in this patient is assumed "de novo". Although the most frequent variant was p.R242H in Caucasians and p.R242P in Japanese, our patient had p.R242P variant. CONCLUSIONS: Early identification of FDH is fundamental to prevent unnecessary repeats of TFT with different methods. We encourage the ALB gene hot spot sequencing initially and indicate that this molecular diagnosis is a rapid and simple method to diagnose FDH in individuals with euthyroid hyperthyroxinemia.

Early Postnatal Metabolic Profile in Neonates With Different Birth Weight Status: A Pilot Study.

Introduction: Restricted or enhanced intrauterine growth is associated with elevated risks of early and late metabolic problems in humans. Metabolomics based on amino acid and carnitine/acylcarnitine profile may have a role in fetal and early postnatal energy metabolism. In this study, the relationship between intrauterine growth status and early metabolomics profile was evaluated. Materials and Methods: A single-center retrospective cohort study was conducted. Three hundred and sixty-one newborn infants were enrolled into the study, and they were grouped according to their birth weight percentile as small for gestational age (SGA, n = 69), appropriate for gestational age (AGA, n = 168), and large for gestational age (LGA, n = 124) infants. In all infants, amino acid and carnitine/acylcarnitine profiles with liquid chromatography-tandem mass spectrometry (LC-MS/MS) were recorded and compared between groups. Results: LGA infants had higher levels of glutamic acid and lower levels of ornithine, alanine, and glycine (p < 0.05) when compared with AGA infants. SGA infants had higher levels of alanine and glycine levels when compared with AGA and LGA infants. Total carnitine, C0, C2, C4, C5, C10:1, C18:1, C18:2, C14-OH, and C18:2-OH levels were significantly higher and C3 and C6-DC levels were lower in SGA infants (p < 0.05). LGA infants had higher C3 and C5:1 levels and lower C18:2 and C16:1-OH levels (p < 0.05). There were positive correlations between free carnitine and phenylalanine, arginine, methionine, alanine, and glycine levels (p < 0.05). Also, a positive correlation between ponderal index and C3, C5-DC, C14, and C14:1 and a negative correlation between ponderal index and ornithine, alanine, glycine, C16:1-OH, and C18:2 were shown. Conclusion: We demonstrated differences in metabolomics possibly reflecting the energy metabolism in newborn infants with intrauterine growth problems in the early postnatal period. These differences might be the footprints of metabolic disturbances in future adulthood.

Cranial MRI Abnormalities and Long-term Follow-up of the Lesions in 770 Girls With Central Precocious Puberty.

CONTEXT: Central precocious puberty (CPP) may arise from central nervous system (CNS) lesions in a few affected girls. Recently, the incidence of girls with CPP has increased mostly in 6-8 year olds, in whom the necessity of magnetic resonance imaging (MRI) is debated. OBJECTIVE: To investigate the frequency, long-term outcome and potential predictors of CNS lesions in a large cohort of girls with CPP. METHODS: A multicenter cohort of 770 Turkish girls with CPP who had systematic cranial MRI between 2005 and 2017. Age at puberty onset was <6 years in 116 and 6-8 years in 654. CNS lesions were followed until final decision(6.2 ± 3.1 years). Potential predictors of CNS lesions were evaluated by univariate analyses. RESULTS: A total of 104/770 (13.5%) girls had abnormal brain MRI. Of these, 2.8% were previously known CNS lesions, 3.8% had newly detected and causally related CNS lesions, 3.1 % were possibly, related and 3.8% were incidental. Only 2 (0.25%) neoplastic lesions (1 low grade glioma and 1 meningioma) were identified; neither required intervention over follow-up of 6 and 3.5 years respectively. Age at breast development <6 years (odds ratio [OR] 2.38; 95% CI 1.08-5.21) and the peak luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio >0.6 (OR 3.13; 95% CI 1.02-9.68) were significantly associated with CNS lesions. However, both patients with neoplastic lesions were >6 years old. CONCLUSION: Although age and LH/FSH ratio are significant predictors of CNS lesions, their predictive power is weak. Thus, systematic MRI seems to be the most efficient current approach to avoid missing an occult CNS lesion in girls with CPP, despite the low likelihood of finding a lesion requiring intervention.

Hereditary vitamin D-resistant rickets: a report of four cases with two novel variants in the VDR gene and successful use of intermittent intravenous calcium via a peripheral route.

Background Hereditary vitamin D-resistant rickets (HVDRR) is caused by vitamin D receptor (VDR) defects. Patients with HVDRR do not respond to standard doses of calcitriol and oral calcium (Ca) treatment and need to be treated with intravenous Ca (IV-Ca) via a central route. However, central catheter-related complications can cause significant morbidity. Case presentation Four unrelated patients with HVDRR presenting with rickets and alopecia totalis were administered intermittent IV-Ca treatment (2-5 times/week) through a peripheral route. No complications such as infection, extravasation or arrhythmias were detected upon peripheral infusion. Peripheral 1-22 months' duration of IV-Ca normalized parathyroid hormone (PTH) and alkaline phosphatase (ALP) in all patients, after which, oral Ca of 200-400 mg/kg/day and calcitriol of 0.5 µg/kg/day were sufficient to maintain normal PTH levels. Molecular studies on the VDR gene showed a previously reported homozygous c.454C > T (p.Q152*) pathogenic variant in two patients. Two novel homozygous variants in the other two patients were detected: (1) c.756-2A > G, which affects the splice acceptor site, and (2) c.66dupG (p.I23Dfs*20) variant leading to a frameshift that results in a premature stop codon. Conclusions Peripheral IV-Ca treatment is an effective and practical alternative treatment mode that provides dramatic clinical benefit in patients with HVDRR.

Nationwide Turkish Cohort Study of Hypophosphatemic Rickets

Objective: Hypophosphatemic rickets (HR) is a rare renal phosphate-wasting disorder, which is usually X-linked and is commonly caused by PHEX mutations. The treatment and follow-up of HR is challenging due to imperfect treatment options. Methods: Here we present nationwide initial and follow-up data on HR. Results: From 24 centers, 166 patients were included in the study. Genetic analysis (n=75) showed PHEX mutation in 80% of patients. The mean follow-up period was 6.7±2.4 years. During the first 3-years of treatment (n=91), mild increase in phosphate, decrease in alkaline phosphatase and elevation in parathyroid hormone (PTH) levels were detected. The height standard deviation scores were -2.38, -2.77, -2.72, -2.47 at initial, 1st, 2nd and 3rd year of treatment, respectively (p>0.05). On follow-up 36% of the patients showed complete or significant improvement in leg deformities and these patients had similar phosphate levels at presentation with better levels in 1st and 2nd years of treatment; even the treatment doses of phosphate were similar. Furthermore, 27 patients developed nephrocalcinosis (NC), the patients showed no difference in biochemical differences at presentation and follow-up, but 3rd year PTH was higher. However, higher treatment doses of phosphate and calcitriol were found in the NC group. Conclusion: HR treatment and follow-up is challenging and our results showed higher treatment doses were associated with NC without any change in serum phosphate levels, suggesting that giving higher doses led to increased phosphaturia, probably through stimulation of fibroblast growth factor 23. However, higher calcitriol doses could improve bone deformities. Safer and more efficacious therapies are needed.

Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease.

CONTEXT: Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75% to 90% of individuals with hypergonadotropic hypogonadism presenting as POI, the molecular etiology is unknown. Common etiologies include chromosomal abnormalities, environmental factors, and congenital disorders affecting ovarian development and function, as well as syndromic and nonsyndromic single gene disorders suggesting POI represents a complex trait. OBJECTIVE: To characterize the contribution of known disease genes to POI and identify molecular etiologies and biological underpinnings of POI. DESIGN, SETTING, AND PARTICIPANTS: We applied exome sequencing (ES) and family-based genomics to 42 affected female individuals from 36 unrelated Turkish families, including 31 with reported parental consanguinity. RESULTS: This analysis identified likely damaging, potentially contributing variants and molecular diagnoses in 16 families (44%), including 11 families with likely damaging variants in known genes and five families with predicted deleterious variants in disease genes (IGSF10, MND1, MRPS22, and SOHLH1) not previously associated with POI. Of the 16 families, 2 (13%) had evidence for potentially pathogenic variants at more than one locus. Absence of heterozygosity consistent with identity-by-descent mediated recessive disease burden contributes to molecular diagnosis in 15 of 16 (94%) families. GeneMatcher allowed identification of additional families from diverse genetic backgrounds. CONCLUSIONS: ES analysis of a POI cohort further characterized locus heterogeneity, reaffirmed the association of genes integral to meiotic recombination, demonstrated the likely contribution of genes involved in hypothalamic development, and documented multilocus pathogenic variation suggesting the potential for oligogenic inheritance contributing to the development of POI.

Incidence of Type 1 Diabetes in Children Aged Below 18 Years during 2013-2015 in Northwest Turkey

Objective: To assess the incidence of type 1 diabetes mellitus (T1DM) in children under 18 years of age in the northwest region of Turkey during 2013-2015. Methods: All newly diagnosed T1DM cases were recorded prospectively during 2013-2015. Total, as well as gender and age group specific (0-4, 5-9, 10-14 and 15-17 age) mean incidences per 100,000 per year were calculated. Results: There were 1,773 patients diagnosed during 2013-2015 (588 cases in 2013, 592 cases in 2014, 593 cases in 2015). Of these, 862 (48.6%) were girls and 911 (51.4%) were boys. The mean age at diagnosis was 9.2±4.2 years and it was not significantly different between girls (9.0±4.1 years) and boys (9.4±4.4 years) (p=0.052). The crude mean incidence was 8.99/100.000 confidence interval (CI) (95% CI: 8.58-9.42). Although mean incidence was similar between boys [8.98/100.000 (CI: 8.40 to 9.58)] and girls [9.01/100.000 (CI: 8.42 to 9.63)], there was male predominance in all groups except for 5-9 year age group. The standardized mean incidence was 9.02/100.000 according to the World Health Organization standard population. The mean incidence for the 0-4, 5-9, 10-14 and 15-17 age groups was 6.13, 11.68, 11.7 and 5.04/100.000 respectively. The incidence of T1DM was similar over the course of three years (p=0.95). A significant increase in the proportion of cases diagnosed was observed in the autumn-winter seasons. Conclusion: The northwest region of Turkey experienced an intermediate incidence of T1DM over the period of the study.

Response to growth hormone treatment in very young patients with growth hormone deficiencies and mini-puberty.

BACKGROUND: The aim of the study was to assess the response to growth hormone (GH) treatment in very young patients with GH deficiency (GHD) through a national, multi-center study. Possible factors affecting growth response were assessed (especially mini-puberty). METHODS: Medical reports of GHD patients in whom treatment was initiated between 0 and 3 years of age were retrospectively evaluated. RESULTS: The cohort numbered 67. The diagnosis age was 12.4±8.6 months, peak GH stimulation test response (at diagnosis) as 1.0±1.4 ng/mL. The first and second years length gain was 15.0±4.3 and 10.4±3.4 cm. Weight gain had the largest effect on first year growth response; whereas weight gain and GH dose were both important factors affecting second year growth response. In the multiple pituitary hormone deficiency (MPHD) group (n=50), first year GH response was significantly greater than in the isolated GH deficiency (IGHD) group (n=17) (p=0.030). In addition first year growth response of infants starting GH between 0 and 12 months of age (n=24) was significantly greater than those who started treatment between 12 and 36 months of age (n=43) (p<0.001). These differences were not seen in the second year. Δ Length/height standard deviation score (SDS), Δ body weight SDS, length/height SDS, weight SDS in MPHD without hypogonadism for the first year of the GH treatment were found as significantly better than MPHD with hypogonadism. CONCLUSIONS: Early onsets of GH treatment, good weight gain in the first year of the treatment and good weight gain-GH dose in the second year of the treatment are the factors that have the greatest effect on length gain in early onset GHD. The presence of the sex steroid hormones during minipubertal period influence growth pattern positively under GH treatment (closer to the normal percentage according to age and gender).

The Distribution of Different Types of Diabetes in Childhood: A Single Center Experience

OBJECTIVE: Type 1 diabetes (T1D) is the most common cause of diabetes in childhood but type 2 diabetes (T2D) and maturity onset diabetes of the young (MODY) are emerging as noteworthy causes of diabetes at young ages. The aim is to determine the distribution, trends and clinical features of the different types of diabetes in childhood in one tertiary center. METHODS: The records of children and adolescents aged 0-18 years who were diagnosed as "diabetes/persistent hyperglycemia" between January 1999 and December 2016, were reviewed. Clinical and laboratory characteristics of the patients at diagnosis and type of diabetes were recorded. RESULTS: The mean ± standard deviation age of 835 patients (48.7% females) at diagnosis was 8.8±4.4 years. Eighty-four percent of the patients were diagnosed as T1D, 5.7% as T2D, 5.3% as clinical MODY and 5% as being cases of other types of diabetes. The frequency of diabetic ketoacidosis (DKA) and severe DKA in T1D were 48.4% and 11.6%, respectively. Fourteen patients (29.2%) with T2D presented with ketosis and two of them (4.2%) had DKA at diagnosis. Antibody positivity was 83.1% in T1D and 14.8% in T2D. A statistically significant increase in the frequency of T2D has clearly been demonstrated in recent years with a frequency of 1.9%, 2.4% and 7.9% in 1999-2004, 2005-2010 and 2011-2016, respectively (p<0.001). In MODY, genetic analysis was performed in 26 (59%) patients and HNF1A and GCK gene mutations were detected in 3 (11.5%) and 14 (53.8%) patients, respectively. CONCLUSION: Although the most frequent cause of DM is T1D in childhood, a trend towards increase in the frequency of T2D in recent years is notable in our population.

CDH3 gene related hypotrichosis and juvenile macular dystrophy - A case with a novel mutation.

PURPOSE: CDH3-related hypotrichosis with juvenile macular dystrophy (HJMD) is an autosomal-recessive entity characterized by congenital sparse scalp hair and macular dystrophy, leading to severe central visual loss. We report a family with HJMD caused by a novel CDH3 gene mutation and review the mutation spectrum in HJMD. A detailed phenotypic assessment for patients whose molecular results were reported previously is also summarized. OBSERVATIONS: We present a 13-year-old Turkish girl who experienced gradual bilateral visual deterioration with marked hair loss. Hair-pull test results and scalp skin texture were normal. The eyebrows and eyelashes were normal, and no abnormality in the teeth, nails, or limbs was detected. Fundus examination revealed bilateral ring-shaped atrophy of the retinal pigment epithelium with patchy intraretinal pigment clumping at the posterior pole. DNA sequencing analysis detected a novel homozygous deletion (c.447_467del (p.149_156del)) in exon 5 of the CDH3 gene of the patient. Both healthy parents and an older brother were heterozygous for the mutation. CONCLUSIONS AND IMPORTANCE: This case of HJMD was related to a novel homozygous mutation, termed c.447_467del (p.149_156del). These findings have significance for the future mutational analysis and genetic counseling of families with HJMD, particularly in our region. The presence of sparse hair in childhood, with or without limb anomalies, should alert clinicians to request an eye consultation. Pediatricians, dermatologists, and ophthalmologists should be aware of the rarely seen entity of juvenile macular dystrophy with hypotrichosis.