Clinical and Laboratory Characteristics of MODY (Maturity Onset Diabetes of Young) Cases, Genetic Mutation Spectrum and Phenotype-genotype Relationship.

Objective: Maturity-onset diabetes of the young (MODY) occurs due to mutations in genes involved in pancreatic beta cell function and insulin secretion, has heterogeneous clinical and laboratory features, and account for 1-5% of all diabetes cases. The prevalence and distribution of MODY subtypes vary between countries. The aim of this study was to evaluate the clinical and laboratory characteristics, mutation distribution, and phenotype-genotype relationship in a large case series of pediatric Turkish patients genetically diagnosed with MODY. Methods: MODY cases from 14 different pediatric endocrinology departments were included. Diagnosis, treatment, follow-up data, and results of genetic analysis were evaluated. Results: A total of 224 patients were included, of whom 101 (45%) were female, and the mean age at diagnosis was 9.4±4.1 years. Gene variant distribution was: 146 (65%) GCK; 43 (19%) HNF1A; 8 (3.6%) HNF4A, 8 (3.6%) KLF11 and 7 (3.1%) HNF1B. The remaining 12 variants were: PDX (n=1), NEUROD1 (n=3), CEL (n=1), INS (n=3), ABCC8 (n=3) and KJNC11 (n=1). Of the cases, 197 (87.9%) were diagnosed with incidental hyperglycemia, 16 with ketosis (7%) and 7 (3%) with diabetic ketoacidosis (DKA), while 30% presented with classical symptoms of diabetes. Two-hundred (89%) had a family history of diabetes. Anti-GAD antibody was detected in 13 cases, anti-islet antibody in eight and anti-insulin antibody in four. Obesity was present in 16. Distribution of therapy was: 158 (71%) diet only; 23 (11%) intensive insulin treatment; 17 (7.6%) sulfonylureas; 10 (4.5%) metformin; and 6 (2.7%) insulin and oral antidiabetic treatment. Conclusion: This was the largest genetically diagnosed series from Turkey. The most common gene variants were GCK and HNF1A with much lower proportions for other MODY types. Hyperglycemia was the most common presenting symptom while 11% of patients had diabetes-associated autoantibodies and 7% were obese. The majority of patients received dietary management only.

Effect of ACTH Stimulation on Ischemia-Modified Albumin Levels in vivo.

Objective: Ischemia-modified albumin (IMA) formation is associated with increased reactive oxygen species (ROS) production, while cortisol leads to decreased ROS levels. We aimed to evaluate the effect of ACTH stimulation on IMA levels and whether the effect is dose-dependent or not. Methods: A total of 99 subjects with normal ACTH test results were included in the study, where 80 subjects were performed to standard-dose ACTH test while 19 subjects were performed to low-dose ACTH test. Blood samples were collected to determine cortisol and IMA levels; at minutes 0, 30, and 60 following the standard-dose ACTH test and at minutes 0 and 30 following the low-dose ACTH test. Results: IMA levels decreased significantly within 30 minutes and the decrease continued up to 60th minutes (p:0.002) after standard-dose ACTH stimulation. After ACTH stimulation, a weak negative correlation was found between peak cortisol and IMA levels at the 30th minute (r:0.233 p:0.02). There was no significant difference in IMA levels after low-dose ACTH stimulation, despite providing an increase in cortisol (p:0.161). Conclusion: IMA levels decrease rapidly after standard-dose ACTH stimulation, while a decrease in IMA levels is not observed after low-dose ACTH stimulation. The lack of decrease in IMA levels after low-dose ACTH stimulation suggests a possible dose-dependent relationship between ACTH and IMA. The moderate increase in cortisol with no reduction in IMA levels after low-dose ACTH stimulation and the weak correlation between peak cortisol and 30th-minute IMA levels after standard-dose ACTH stimulation suggest that ACTH may have a direct effect on IMA.

Assessment of the Retinal Nerve Fibre Layer, Retina, and Choroid in Osteogenesis Imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) is a genetic disorder in which there are problems in tissues containing type I collagen, predominantly the cornea and sclera in the eye. Although there are many studies on problems with the anterior segment of the eye in patients with OI, studies on posterior structures are limited. Involvement of the sclera may affect the retinal nerve fibre layer (RNFL), which is indirectly related to intraocular pressure. In addition, the retina and choroid containing type I collagen may be affected. The aim of the study was to compare the posterior segment structures of the eye, including the RNFL, retina, and choroid, in patients with OI to those of healthy control subjects. METHODS: This cross-sectional study recruited 19 patients with OI, as well as 22 age- and gender-similar healthy control subjects. Measurements of the RNFL, retina, and choroid were obtained with optical coherence tomography (Spectralis SD-OCT, Heidelberg Engineering, Heidelberg, Germany). RESULTS: Patients with OI (mean age 14.32 ± 5.08 years) and the control group (mean age 13.73 ± 3.56 years) had similar age, refractive error, and intraocular pressure values (p > 0.05). There was no difference between groups in terms of RNFL thickness, including the superonasal, nasal, inferonasal, inferotemporal, temporal, and superotemporal sectors, retinal thickness, and choroidal thickness from five different locations (p > 0.05, for all). CONCLUSION: According to these results, OI does not clinically affect the RNFL, retina, and choroid in childhood.

Unfavorable Effects of Low-carbonhydrate Diet in a Pediatric Patient with Type 1 Diabetes Mellitus

A balanced and healthy diet is very important in type 1 diabetes mellitus (T1DM) in childhood. In addition to regulating blood glucose with diet, diet should also support optimal growth. Low-carbohydrate diet aims to provide daily energy from fats and was originally used for childhood epilepsy. We present a patient with T1DM who experienced unfavorable effects when on a low-carbohydrate diet.

Status of Central Precocious Puberty Cases at the Onset of Coronavirus Disease 2019 Pandemic: A Single-Center Experience.

OBJECTIVE: The onset of puberty in children is occurring at an increasingly earlier ages. During the coronavirus 2019 pandemic, children experienced epidemic-related changes such as stress, sedentary lifestyle, and weight gain. MATERIALS AND METHODS: Auxological, clinical, endocrinological, and radiological data in the files of 57 patients who were given gonadotropin-releasing hormone analog therapy with the diagnosis of central precocious puberty between April 1 and July 1, 2019 (group 1) and April 1 and July 1, 2020 (group 2) were analyzed retrospectively. RESULTS: A total of 27 patients (26 girls, 1 boy) in group 1 and 30 patients (28 girls, 2 boys) in group 2 were diagnosed with central precocious puberty. Mean ages at diagnosis for groups 1 and 2 were 28.54 ± 0.94 and 7.92 ± 0.96 years, respectively (P = .018). Mean bone age at diagnosis for group 1 was 9.78 ± 1.48 (6.8-12), and for group 2 it was 8.78 ± 1.11 (6.5-12) years (P = .013). The mean age of starting treatment in groups 1 and 2 was 8.94 ± 0.17 (6.8-9.8) and 8.07 ± 0.02 (5.8-10) years, respectively (P = .002). Average birth weights for groups 1 and 2 were 950 ± 1100 (2300-3400) and 3180 ± 717 (870-3820) g, respectively (P = .012). Treatment was started when breast stage was T3 in 57.69% of group 1 and T2 in 75% of group 2, and a statistical difference was found between them (P = .006) and uterine length was higher in group 2 (P = .144). CONCLUSION: During the coronavirus 2019 pandemic, patients who start central precocious puberty therapy were of younger age. In our single-center experience, coronavirus 2019 was not seen to have a significant impact on central precocious puberty.

A major health problem facing immigrant children: nutritional rickets.

OBJECTIVES: Nutritional rickets (NR) is still an important problem and one which increasing influxes of immigrants are further exacerbating. This study evaluated cases of mostly immigrant children followed up with diagnoses of NR in our pediatric endocrinology clinic. METHODS: Details of 20 cases diagnosed with NR between 2017 and 2020 were retrieved from file records. RESULTS: Twenty (11 male) cases were included in the study. Three (15%) were Turkish nationals and the others (85%) were immigrants. Hypocalcemia and hypophosphatemia were detected in 17 and 13, respectively. Alkaline phosphatase (ALP) values were normal in two cases, while ALP and parathyroid hormone (PTH) values were elevated in all other cases, and PTH levels were very high (473.64 ± 197.05 pg/mL). 25-hydroxyvitamin D levels were below 20 ng/mL in all cases. Patients with NR received high-dose long-term vitamin D or stoss therapy. Six patients failed to attend long-term follow-up, while PTH and ALP levels and clinical findings improved at long-term follow-up in the other 14 cases. CONCLUSIONS: The elevated PTH levels suggest only the most severe cases of NR presented to our clinic. Clinically evident NR is therefore only the tip of the iceberg, and the true burden of subclinical rickets and osteomalacia remains unidentified. Public health policies should therefore focus on universal vitamin D supplementation and adequate dietary calcium provision, their integration into child surveillance programs, adequate advice and support to ensure normal nutrition, exposure to sunlight, and informing families of the increased risk not only for resident populations but also for refugee and immigrant children.

The alteration of IGF-1 levels and relationship between IGF-1 levels and growth velocity during GnRH analogue therapy.

Background Some studies have examined the effect of gonadal suppression on insulin-like growth factor-1 (IGF-1) levels and the growth velocity (GV) with conflicting results. Methods Forty-four girls treated with gonadotropin-releasing hormone analogue (GnRHa) for central precocious puberty (CPP) were included in the study. IGF-1 levels were examined at the beginning and after 12 months of treatment. Results IGF-1 and IGF-1 standard deviation score (SDS) according to chronological age (CA-IGF-1 SDS) at diagnosis were positively correlated with chronological age (CA), anthropometric measurements, stage of puberty, bone age (BA), BA-CA, follicle-stimulating hormone (FSH), luteinising hormone (LH), oestradiol, uterus length, endometrium thickness and ovarian volume (OV) at diagnosis (p < 0.05). There was no significant difference in IGF-1 levels after treatment. However, there was a negative correlation between ΔIGF-1 SDS and IGF-1 level, CA-IGF-1 SDS and BA-IGF-1 SDS at diagnosis (p < 0.05). There was no correlation between GV and IGF-1, ΔIGF-1. GV was negatively correlated with basal LH level at diagnosis (p = 0.008, r = -0.397). Peak LH levels of the patients who had GV-SDS < 0 were more suppressive than those of the patients who had GV-SDS > 0 after 12 months of treatment. Conclusions It was determined that the IGF-1 level and CA-IGF-1 SDS at baseline were correlated with more advanced pubertal stage prior to treatment. Initiation of treatment with a relatively high level of IGF-1 increased the risk of a decrease in the IGF-1 level. Likewise, the initiation of treatment with a relatively high LH level may increase the risk of low GV, but low GV was not related to the IGF-1 level. Increased sex steroid suppression may increase the risk of low GV.

Experience of intravenous calcium treatment and long-term responses to treatment in a patient with hereditary vitamin D-resistant rickets resulting from a novel mutation.

Background Vitamin D resistant rickets (HVDRR), is a rare autosomal recessive disorder caused by vitamin D receptor (VDR) gene mutations. There is no standard treatment in HVDRR. Case report The patient was a 3-year-old girl presenting with short stature, genu varum deformity, waddling gait and alopecia. She had hypocalcemia, hypophosphatemia, hyperparathyroidism and normal 1.25-(OH)2D levels. The patient was initially treated with calcitriol and high-dose oral calcium (Ca) for 22 months. The patient was treated with continuous high dose intravenous (i.v.) Ca therapy for 4 months, following initial lack of response to oral Ca and calsitriol. At the end of the 4 months, rickets was dramatically improved and did not recur for 3 years after i.v. Ca therapy. DNA sequence analyses of the VDR gene showed a homozygous novel mutation. Conclusions We identified a novel VDR gene mutation, and we concluded that i.v. Ca therapy from the central catheter is a safe treatment in HVDRR.

Antimüllerian Hormone Levels of Infants with Premature Thelarche

Objective: Antimüllerian hormone (AMH) concentrations in mini puberty are higher than those reported for the prepubertal period. In this study we investigated AMH concentrations in infants with premature thelarche (PT). A healthy control group was used for comparison. Methods: Forty five female infants with PT, aged between one and three years and a control group consisting of 37 healthy girls in the same age range were included in the study. Bone age, pelvic ultrasonography, and concentrations of luteinizing hormone, follicle-stimulating hormone (FSH), estradiol and AMH of the patient group were evaluated. Only serum AMH concentration of the control group was evaluated. Results: Median (range) serum AMH concentrations in the subjects were 1.66 ng/mL (11.85 pmol/L) [0.15-6.32 ng/mL (1.07-45.12 pmol/L)] and were significantly lower (p=0.025) than for the control group; 1.96 ng/mL (13.99 pmol/L) [0.60-8.49 ng/mL (4.28-60.64 pmol/L)]. AMH and FSH were negatively correlated (r=-0.360, p=0.015) in infants with PT. There was no correlation between AMH and uterine size, uterine volume, endometrial thickness, fundocervical ratio, ovarian size or volume, follicle size and follicle number. Conclusion: This is the first study that investigates AMH concentrations in infants with PT. The low AMH levels in these infants and the negative correlation between AMH and FSH suggests that AMH may play a role in suppressing pubertal findings during infancy and that decreased AMH may cause PT in infancy.

Subnormal Growth Velocity and Related Factors During GnRH Analog Therapy for Idiopathic Central Precocious Puberty

Objective: Data concerning subnormal growth velocity (GV) and factors that influence this during gonadotropin-releasing hormone analog (GnRHa) therapy for idiopathic central precocious puberty (ICPP) are scarce. We investigated the incidence of subnormal GV and associated factors in patients receiving GnRHa therapy for ICPP. Methods: In this retrospective cohort study, the records of 50 girls who had been diagnosed with ICPP and started on GnRHa treatment before the age of eight years were investigated. Subnormal GV frequency, related factors during GnRHa therapy and the effect on final height were examined. Results: During the treatment, a significant decrease in the annual GV and GV standard deviation score (SDS) of the patients was observed. In 16 (32%) patients GV never declined below -1 SDS, while a decline was noted once and twice in 19 (38%) and 15 (30%) patients respectively. The median age of detection of subnormal GV was 9.9 (4.9-10.9) years. Patients with pubic hair at diagnosis were found to have an increased risk of subnormal GV (p=0.016). There was a significant negative correlation between diagnostic basal luteinizing hormone (LH) level and the first and second year GV SDS (p=0.012 and 0.017 respectively). A significant negative correlation between bone age at diagnosis and 3rd year GV SDS, and 4th year GV SDS (p=0.002 and p=0.038) was also observed. LH suppression significantly increased during treatment (p=0.001). Conclusion: In girls with ICPP the risk of subnormal GV appears highest at the 3rd year of GnRHa treatment, particularly in those patients with, at the time of diagnosis, pubic hair in conjunction with high baseline and peak LH and advanced BA and excessive LH suppression on follow-up.

Investigation of MKRN3 Mutation in Patients with Familial Central Precocious Puberty

Objective: There have been recent advances in the understanding of the etiology of idiopathic central precocious puberty (iCPP) including new genetic associations. The aim of this clinical study was to determine the frequency of MKRN3 mutation in cases of familial iCPP. Methods: Potential sequence variations in the maternally imprinted MKRN3 gene were evaluated in 19 participants from 10 families using next-generation sequencing analysis. Results: MKRN3 variation was found in only one of the 19 (5.3%) subjects. The male patient, who had a medical history of precocious puberty, had a heterozygous mutation, NM_005664.3:c.630_650delins GCTGGGC (p.P211Lfs*16). The father of this patient also had a history of precocious puberty and had the same mutation. p.P211Lfs*16 is a novel variant and it was identified as probably pathogenic by in silico analysis, consistent with the clinical findings. Conclusion: Given that MKRN3 mutation was detected in only one patient, with a paternal history of precocious puberty, this reinforces the importance of accurate family history taking. The detected incidence of MKRN3 variants in our case series was much lower than reported elsewhere which suggests a need for further studies in Turkish iCPP patients.

Clinical and genetic characterisation of a series of patients with triple A syndrome.

Triple A syndrome (TAS) or Allgrove syndrome (OMIM #231550) is a rare autosomal recessive disorder characterised by adrenocorticotropic hormone-resistant adrenal insufficiency, alacrima, achalasia, and neurological and dermatological abnormalities. Mutations in the AAAS gene on chromosome 12q13 encoding the nuclear pore protein ALADIN have been reported in these patients. Between 2006 and 2017, we evaluated six patients with a clinical diagnosis of TAS, based on the presence of at least two symptoms, usually adrenal insufficiency and alacrima. In all cases, genetic analysis revealed homozygous mutations in the AAAS gene. One novel mutation was detected: a homozygous 10-bp deletion (c.1264_1273del, p.Q422NfsX126) in exon 14 of the AAAS gene that caused a frameshift that introduced an aberrant stop codon after 126 amino acids. This genetic variant is likely to be pathogenic because it caused a significant change in protein structure. A precise genotype-phenotype correlation was impossible to establish. CONCLUSIONS: Based on our experience, we recommend that molecular analysis should be performed in the presence of alacrima and at least one more symptom of TAS. Our cases share many clinical features of TAS and underline the variability in this syndrome, as well as the need for thorough investigation following a multidisciplinary approach. What is known: • Triple A syndrome is characterised by achalasia, alacrima, adrenal insufficiency, neurological impairment, and dermatological abnormalities. • A precise genotype-phenotype correlation has proved impossible to establish. What is new: • These cases add to a large number of similar case reports with limited novel information. • The newly identified AAAS gene mutation was reported.

Type 1 rhizomelic chondrodysplasia punctata with a homozygous PEX7 mutation.

BACKGROUND: Rhizomelic chondrodysplasia punctata (RCDP) is a rare peroxisomal disease characterised by punctate calcifications of non-ossified cartilage epiphyseal centres. The main biochemical marker of all RCDP types is a decrease in the levels of plasmalogens. Additionally, the accumulation of phytanic acid can be used as a differential marker between types of RDCP. Due to the biochemical overlap between types 1 and 5 RCDP, a genetic analysis of these genes should be performed in patients to identify the type. CASE PRESENTATION: A 2-month-19-day-old male child presented with symptoms of limited movement and discomfort with movement in the extremities. His sister, who had similar clinical findings, was diagnosed with tetralogy of Fallot and died at 6 months of age. A physical examination revealed an atypical facial appearance, bilateral cataracts, sensitivity to touch in the extremities, shortness in the proximal segments of the long bones, limited movement in both knees and elbows and axial hypotonicity. Laboratory analyses revealed normal ammonia, lactate, plasma and urine amino acids, long chain fatty acids and phytanic acid levels. Rhizomelia, significant metaphyseal expansion, irregularities in the cortex, loss of ossification, fragmented appearance and punctate calcifications in both elbows, both knees and in the femoral epiphysis were seen on the skeletal survey. A homozygote p.L70W (c.209T>G) mutation was found in the PEX7 gene. CONCLUSIONS: Plasma phytanic acid levels can be normal in a patient with type 1 RCDP that develops as a result of a PEX7 gene mutation, as in our case. A molecular genetic analysis and/or fibroblast culture must be conducted in clinically suspicious cases. While no cardiac pathology was found in our case, tetralogy of Fallot was present in his sister with similar clinical findings. The presence of different cardiological phenotypes in the sibling suggested that the genotype-phenotype correlation may not be complete in this disorder.

A Rare Cause of Short Stature: 3M Syndrome in a Patient with Novel Mutation in OBSL1 Gene.

The Miller-McKusick-Malvaux (3M) syndrome is a rare autosomal disorder that can lead to short stature, dysmorphic features, and skeletal abnormalities with normal intelligence. A 16-month-old female patient had been referred to our clinic due to short stature. Case history revealed a birth weight of 1740 grams on the 39th week of gestation, with a birth length of 42 cm and no prior hereditary conditions of clinical significance in her family. On physical examination, her length was 67 cm [-3.6 standard deviation (SD) score], weight 7.2 kg (-2.9 SD score), and head circumference 42 cm (below 3rd percentile). She also had numerous characteristic physical features such as a triangular face, fleshy nose tip, a long philtrum, prominent mouth and lips, pointed chin, lumbar lordosis, and prominent heels. As her growth retardation had a prenatal onset and the physical examination results were suggestive of a characteristic profile, the diagnosis of 3M syndrome was strongly considered. Genetic assessment of the patient revealed a novel homozygous p.T425Nfs*40 [corrected] mutation in the OBSL1 gene. It is recommended that physicians pay further attention to this condition in the differential diagnosis of children with severe short stature.

Congenital Hypothyroidism and Bone Remodeling Cycle.

OBJECTIVE: The present study aimed to evaluate the biochemical markers of bone turnover in children with congenital hypothyroidism during the course of treatment as compared to healthy children selected as controls. METHODS: The study included 31 children with congenital hypothyroidism and 29 healthy children. In both groups, we evaluated serum procollagen type-1 N-terminal propeptide (PINP) and tartrate-resistant acid phosphatase type 5b isoform (TRACP 5b) levels as bone turnover markers. RESULTS: In both groups, thyroid hormone levels were within normal limits. The levels of vitamin D were significantly higher in the cases with congenital hypothyroidism. Although PINP levels were not found to be different, TRACP 5b levels which are related to osteoclastic activities were significantly higher in the control group. CONCLUSION: We did not detect an increase in bone resorption in patients with congenital hypothyroidism, despite long-term treatment with LT4. Our results suggest that with effective vitamin D treatment and thyroxin replacement, congenital hypothyroidism is not a deleterious factor for bone turnover.

ß-3AR W64R Polymorphism and 30-Minute Post-Challenge Plasma Glucose Levels in Obese Children.

OBJECTIVE: In this study, we aimed to investigate the association of W64R polymorphism of the ß3-adrenergic receptor gene (ß-3AR) with childhood obesity and related pathologies. METHODS: ß-3AR gene W64R genotyping was carried out in 251 children aged 6-18 years. Of these subjects, 130 were obese (62 boys) and 121 were normal-weight (53 boys). In the obese group, fasting lipids, glucose and insulin levels were measured. Oral glucose tolerance test (OGTT) was performed in 75 of the obese patients. RESULTS: The frequency of W64R genotype was similar in obese and non-obese children. In obese children, relative body mass index, waist-to-hip ratio, serum lipid, glucose and insulin levels, as well as homeostasis model assessment of insulin resistance (HOMA-IR) scores were not different between Arg allele carriers (W64R and R64R) and noncarriers (W64W). In 75 obese children, OGTT results showed that Arg allele carriers had significantly higher 30-minute glucose levels (p=0.027). CONCLUSION: W64R polymorphism of the ß-3AR gene is not associated with obesity and waist-to-hip ratio in Turkish children. Although there were no relationships between the genotypes and lipid, glucose/insulin levels or HOMA-IR, the presence of W64R variant seemed to have an unfavorable influence on early glucose excursion after glucose loading.