Noonan syndrome is a disease that occurs in 1 in 1,000-2,500 live births, mostly inherited in an autosomal dominant manner. Noonan syndrome is a clinically and genetically heterogeneous disease that may be accompanied by growth retardation, prominent facial dysmorphic features, congenital heart defects, hypertrophic cardiomyopathy, skeletal anomalies, bleeding diathesis, ectodermal anomalies, lymphatic dysplasias, cryptorchidism, and cognitive disorders. Some of the patients with NS may experience various clinical issues related to immunodeficiency, such as recurrent infections. This article discusses a very rarely seen case of a 15-year-old male patient with Noonan syndrome having common variable immunodeficiency disease.

OBJECTIVE:Longitudinal data on the composition of salivary microorganisms in type 1 diabetes mellitus (T1DM) patients are lacking. This study aimed to characterize and compare the salivary microbiota of children with and without T1DM in a longitudinal approach. We hypothesized that the bacterial composition in saliva differs between healthy and T1DM children in a 1-year period. METHODS:Overall, 55 children (4-15 years old; 26 with T1DM, 29 healthy controls) completed the study. Oral examinations (plaque index, bleeding on probing, and Decayed, Missing, Filled Teeth index) and unstimulated saliva sampling were performed at baseline and after 1 year. Microbial composition was assessed via 16S rRNA gene sequencing (V1-V3 region) and referenced against the Human Oral Microbiome Database. RESULTS:Beta diversity analysis (Principal coordinate analysis (PCoA)) showed greater separation between groups at baseline than at follow-up. Linear discriminant analysis effect size identified that T1DM was associated with Fusobacterium species, whereas Rothia species associated with health. Alpha diversity indexes (Chao 1, Shannon and Simpson) showed no significant differences between the groups (P > 0.05). CONCLUSION:Our results demonstrated that the salivary microbiota of T1DM children is significantly distinct from healthy controls during 1-year of follow-up. Future studies are needed to reveal whether improved T1DM management benefits microbial composition. CLINICAL SIGNIFICANCE:The microbial shift in diabetic children may contribute to increased susceptibility to oral diseases, highlighting the importance of preventive dental care in this population.

Malignancies, autoimmune diseases, viral and fungal infections, as well as aseptic meningitis due to certain drugs are frequently seen. Antibiotics, intravenous immunoglobulin (IVIG), non-steroidal anti-inflammatory drugs are often considered responsible. The incidence following IVIG infusion is 0.067%; however, symptoms may start to show up anywhere from 6 h to 4 days following infusion. It is challenging to diagnose and is easily overlooked because of symptoms and clinical findings that might arise from a variety of conditions, including headaches, stiff necks, and vomiting. We present a patient with Noonan syndrome who was diagnosed with common variable immunodeficiency due to recurrent illness, had IVIG replacement therapy, and developed aseptic meningitis following the initial course of treatment. No similar case has been documented before in the literature. Noonan syndrome may also be related with an increased incidence of IVIG-associated aseptic meningitis, while the explanation for this association is unclear.

OBJECTIVE:Triple-A syndrome occurs due to the dysfunction of the ALADIN protein as a result of a mutation in the AAAS gene. ALADIN is involved in redox homeostasis in human adrenal cells and steroidogenesis. It has also been shown to have important roles in DNA repair and the protection of cells against oxidative stress. We planned to investigate serum thiol/disulfide homeostasis, which is a part of redox hemostasis in patients with Triple-A syndrome.PATIENTS AND METHODS:The study included patients with the Triple-A syndrome (26 patients) and healthy children (26 patients). Thiol and disulfide levels of patients and healthy groups were compared. In addition, patients with the Triple-A syndrome were divided into 2 subgroups according to the mutation type, and their thiol and disulfide levels were compared.RESULTS:Triple-A syndrome patients had increased native thiol (SH), total thiol (SH+SS) concentrations, and native thiol/total thiol (SH/SH+SS) ratios than healthy controls. However, Triple-A syndrome patients had lowered disulfide (SS), disulfide/native thiol (SS/SH), and disulfide/total thiol (SS/SH+SS) ratios than the controls. When the group with the p.R478* mutation and the group with other mutation were compared, disulfide level, disulfide/native thiol ratio, and disulfide/total thiol ratio were statistically higher in the group with the p.R478* mutation, while native thiol/total thiol ratio was found to be lower. However, no statistical difference was found between native thiol and total thiol levels.CONCLUSIONS:This is the first study in the literature to evaluate thiol-disulfide homeostasis in patients with the Triple-A syndrome. Patients with Triple-A syndrome had an increased level of thiol compared with healthy controls. Comprehensive studies are needed to clarify these thiol levels, which are thought to be compensatory. Also, mutation type affects thiol-disulfide levels.

OBJECTIVE:Since Cushing's disease (CD) is less common in the paediatric age group than in adults, data on this subject are relatively limited in children. Herein, we aim to share the clinical, diagnostic and therapeutic features of paediatric CD cases.DESIGN:National, multicenter and retrospective study.PATIENTS:All centres were asked to complete a form including questions regarding initial complaints, physical examination findings, diagnostic tests, treatment modalities and follow-up data of the children with CD between December 2015 and March 2017.MEASUREMENTS:Diagnostic tests of CD and tumour size.RESULTS:Thirty-four patients (M:F = 16:18) from 15 tertiary centres were enroled. The most frequent complaint and physical examination finding were rapid weight gain, and round face with plethora, respectively. Late-night serum cortisol level was the most sensitive test for the diagnosis of hypercortisolism and morning adrenocorticotropic hormone (ACTH) level to demonstrate the pituitary origin (100% and 96.8%, respectively). Adenoma was detected on magnetic resonance imaging (MRI) in 70.5% of the patients. Transsphenoidal adenomectomy (TSA) was the most preferred treatment (78.1%). At follow-up, 6 (24%) of the patients who underwent TSA were reoperated due to recurrence or surgical failure.CONCLUSIONS:Herein, national data of the clinical experience on paediatric CD have been presented. Our findings highlight that presenting complaints may be subtle in children, the sensitivities of the diagnostic tests are very variable and require a careful interpretation, and MRI fails to detect adenoma in approximately one-third of cases. Finally, clinicians should be aware of the recurrence of the disease during the follow-up after surgery.

BackgroundThis cross-sectional study aimed to evaluate salivary concentrations of macrophage activation-related chemokines and mitogen-activated kinase kinase (MAPKK)-degrading proteolytic activity in children and adolescents with and without type 1 diabetes mellitus (T1DM). MethodsA total of 122 children and adolescents (65 T1DM patients, 50.8% female, mean age:10.9 years; 57 systemically healthy controls, 36.8% female, mean age: 9.5 years) were included in the study. Salivary concentrations of interferon gamma inducible protein-10 (IP-10), monocyte chemoattractant protein (MCP)-1, MCP-2, MCP-3, MCP-4, macrophage-derived chemokine (MDC), macrophage migration inhibitory factor (MIF), monokine induced by interferon gamma (MIG), and macrophage inflammatory protein-1 alpha (MIP-1 & alpha;) were quantified using a bead-based technique. MAPKK-degrading proteolytic activity was detected using fluorescent peptide substrates. ResultsThe T1DM group had higher plaque index (PI%, p = 0.032) and bleeding on probing (BOP%, p = 0.045) scores, and lower decayed, missing, filled teeth (dmft/DMFT, p = 0.002) index scores compared to the healthy controls. Compared to the controls, salivary MCP-1 (p = 0.007), MCP-3 (p < 0.001), MIG (p = 0.007), and MIP-1 & alpha; (p = 0.033) concentrations were elevated whereas MCP-4 concentrations decreased (p < 0.001) in the T1DM group. After adjusting for age, PI%, BOP%, and dmft/DMFT scores, significant differences in salivary concentrations of MIG (p = 0.033) and MIP-1 & alpha; (p = 0.017) were observed between the groups. Moreover, protease activities directed to the cleavage sites of MEK23-18 (p = 0.001), MKK6b7-22 (p = 0.007), MKK451-66 (p = 0.005), MKK7b37-52 (p = 0.034), and MKK7b69-84 (p = 0.009) were elevated in the T1DM group. ConclusionT1DM disrupts the salivary macrophage activation-related chemokine profile and dysregulates proteolytic MAPKK cleavage. These findings can be an outcome of the impaired systemic immune response in T1DM.

Background: H syndrome is a rare genodermatosis deriving from a mutation in the SLC29A3 gene and affecting numerous systems, particularly the skin. The syndrome exhibits different clinical characteristics involving several systems, most beginning with the letter "H." The most common clinical findings are cutaneous hyperpigmentation, flexion contracture in the fingers, hearing loss, short stature, insulin-dependent diabetes mellitus, heart anomalies, hepatosplenomegaly, and hypogonadism. Fewer than 150 cases have been reported so far and vast majority of them consisted with patients with Arab ethnicity. Case Presentation: We describe a patient presenting with short stature, developing diabetes mellitus at follow-ups, with homozygous deletion determined in exon 3 of the SLC29A3 gene, and diagnosed with H syndrome, reported due to the presence and rarity of renal involvement (hematuria and proteinuria). Conclusion: In conclusion, despite its rarity, endocrinologists, rheumatologists/nephrologists, and dermatologists need to be aware of H syndrome as a pleiotropic syndrome. H syndrome should be considered in the differential diagnosis of patients with cutaneous hyperpigmentation (particularly in the bilateral thigh and calf region) together with proteinuria/hematuria. In addition, periodic urine analysis should be performed in patients with H syndrome.

Objective: The marked variation in the timing of puberty despite similar living conditions shows that many factors are effective in determining the onset of puberty. Many factors, such as genetic and environmental factors, stress, socioeconomic status, metabolic rate, and body fat ratio, affect the age of puberty onset. Recent studies have shown that the age of puberty onset has shifted to earlier ages. The increasing prevalence of childhood obesity is deemed to contribute this change. Therefore, we planned the present study to determine the rates of obesity and overweight, to evaluate the association between obesity, bone age, and height age, and to examine the association between obesity and hormone profile. Materials and Methods: The medical records of 206 patients diagnosed with idiopathic precocious puberty who were being followed up at the Pediatric Endocrinology outpatient clinic of Sakarya Training and Research Hospital between October 2018 and October 2021 were retrospectively reviewed. Anthropometric data (age, gender, height, weight, body mass index, and puberty stage), bone age, height age, and weight age of the patients were recorded from the medical records. Patients were grouped as normal weight, overweight, and obese by body mass index (BMI). Results: Of the included patients, 97.6% (201 patients) were female and 2.4% (5 patients) were male. One hundred and thirty-one patients (63.6%) had normal weight, 40 (19.4%) were overweight and 35 (17%) had obesity. Significant differences were found between the groups (normal weight, overweight and obese) in terms of weight age, BMI percentile, height age, bone age, and bone age standard deviation score (SDS) (p =

Objective: Nutrition and exposure to various chemicals, including environmental pollution, insecticides, and plant phytoestrogens (having oestrogen-like effects), are environmental factors that affect puberty onset. The aim of this study was to identify the effects of propolis, which has been reported to have oestrogenic effects, on precocious puberty and the reproductive system in prepubertal female rats (ovary, endometrium, breast). Methods: Thirty-four 25-day-old, prepubertal, female Sprague-Dawley rats were included. Rats were randomly divided into the propolis (n=17) and control groups (n=17). The primary endpoint was the number of rats that developed vaginal opening, a sign of puberty, at 12-day follow-up. In addition, the effect of propolis on ovary, uterus and breast tissue was evaluated histologically. Results: Vaginal patency occurred earlier (about 7.5 days sooner) in the propolis group and all animals in the propolis group had vaginal patency by day 12. The number of ovarian follicles (in all follicles), endometrial thickness, and mammary gland secretory gland area were significantly higher in the propolis group than in the control group (all p<0.001). In addition, Ki-67 activity in the endometrium, breast tissue and ovary was more intense in the propolis group compared to the control group (all p<0.001). Conclusion: Propolis triggers precocious puberty in female rats, possibly by interacting with the oestrogen receptor. The mechanism of action of propolis should be considered before prescribing it. In addition, further studies are needed to explore the mechanism of action of propolis and to determine the component of propolis that triggers puberty.

Amaç: Bu çalışmanın amacı, çocuklarda erken puberte ile pineal kistler arasındaki ilişkinin değerlendirilmesidir. Gereç ve Yöntemler: Erken puberte tanılı 122 olgu ve 122 kontrol grubu çocuğun beyin MR görüntüleri pineal kist varlığı ve boyutları açısından değerlendirildi. Pineal kistler boyutlarına göre gerçek kist ve kistik transformasyon olarak değerlendirildi. Erken puberte ve kontrol grubu pineal kist/kistik transformasyon varlığı açısından karşılaştırıldı. Erken puberte grubunda pineal kist saptanan, kistik transformasyon saptanan ve kist/kistik transformasyon saptanmayanların pik ve bazal LH değerleri karşılaştırıldı. Bulgular: Ki-kare testi ile erken puberte ile pineal kist arasında ve erken puberte ile pineal kistik transformasyon arasında anlamlı ilişki saptanmadı (sırasıyla p=0,2537ve p=0,8797). Erken puberte grubunda kist/kistik transformasyon izlenmeyen, kistik transformasyon saptanan ve kist saptananlar arasında pik ve bazal LH değerleri açısından anlamlı farklılık bulunmadı (sırasıyla p=0,566 ve p=0,367). Sonuç: Çalışmamızın sonuçlarına göre , pineal kistler ile erken puberte arasında herhangi bir ilişki saptanmamıştır. Bu nedenle, erken puberte tanılı olgularda MR incelemelerde saptanan pineal kistlerin insidental bulgu olarak kabul edilmeleri doğru bir yaklaşımdır.

Objective: The aim of this study is to assess the correlation between precocious puberty and pineal cysts in children. Materials and methods: The brain MRI scans of 122 patients with precocious puberty and 122 children in control group were evaluated for the presence and size of pineal cysts. Pineal cysts were assessed as true cyst and cystic transformation in terms of their sizes. The presence of pineal cysts/cystic transformation was compared between the two groups. In the precocious puberty group, the baseline and peak LH levels of patients with pineal cyst, cystic transformation and no cyst-cystic transformation were compared. Results: The chi-square test indicated no significant correlation between precocious puberty and pineal cyst, and between precocious puberty and pineal cystic transformation (p=0.2537 and p=0.8797 respectively). There was no significant difference in the basale and peak LH levels between the patients with pineal cyst, cystic transformation and no cyst-cystic transformation in the precocious puberty group (p=0.566 and p= 0.367 respectively). Conclusion: According to the results of the present study, there was no correlation between pineal cysts and precocious puberty. Therefore, it is a correct approach to accept pineal cysts detected in MRI scans as incidental findings in cases with precocious puberty.

Type 1 diabetes mellitus (T1DM), a chronic autoimmune disease characterized by insulin deficiency, is related to periodontal diseases in children and adolescents. Our aim was to profile salivary human beta-defensin (hBD)-2 and hBD-3 concentrations in relation to periodontal and T1DM status in children and adolescent populations. Unstimulated saliva samples were collected from 66 participants including periodontally healthy T1DM patients (T1DM + C; n = 18), T1DM patients with gingivitis (T1DM + G; n = 20), systemically and periodontally healthy individuals (SH + C: n = 15), and systemically healthy gingivitis patients (SH + G; n = 13). Full mouth plaque index (PI), bleeding on probing (BOP), probing pocket depth (PPD), and clinical attachment level (CAL) were recorded. Salivary hBD-2 and hBD-3 concentrations were evaluated by sandwich ELISA method. A p value of < 0.05 was considered statistically significant. Salivary hBD-3 concentrations were lower in T1DM groups in comparison to systemically healthy counterparts (SH + G vs. T1DM + G; p < 0.001 and SH + C vs. T1DM + C; p < 0.001). Salivary hBD-2 levels did not differ between related groups. The difference in hBD-3 concentrations between T1DM and control groups was still significant (p = 0.008) after being adjusted for PI%, BOP%, and age. In the limits of study, T1DM patients were found to have decreased salivary hBD-3 concentrations, regardless of their gingival inflammatory status. Altered salivary hBD-3 concentration can partly explain why diabetic children are more prone to periodontal diseases.

Spondyloenchondrodysplasia ( SPENCD) with immune dysregulation ( SPENCDI) is a rare autosomal recessive inherited immuno-osseous dysplasia characterized by spondylo-metaphyseal enchondromas, along with immune dysregulation ranging from immunodeficiency to autoimmune disorder. Here, we present two cousins with ACP5 gene mutation who had severe short stature with mild hypogammaglobulinemia, nephrotic syndrome, autoimmune thyroiditis and cerebral calcification (Case 1); and in the other (Case 2), there was no clinical findings other than severe short stature, CD4 + -T cell lymphopenia and non-autoimmune compensated hypothyroidism. We wanted to emphasize that monogenic causes should be considered in the etiology of early-onset nephrotic syndrome due to the detection of a mutation in the ACP5 gene (her actual diagnosis was changed to SPENCDI.) 5 years after the diagnosis of nephrotic syndrome in the first case, and that the renal involvement may occur without SLE in patients with ACP5 mutation. Severe short stature was a common finding in both cases. We underlined that the clinic can be different even in the same mutation, due to the absence of cerebral calcification and renal involvement in the second case, which is a cousin with Case 1. As a result, endocrinologists, immunologists, rheumatologists, nephrologists and orthopedists should be aware of this syndrome, because SPENCDI causes a pleiotropic (due to more than one phenotypic effect of a gene) clinical picture. Severe short stature may be the only presenting sign of patients with SPENCDI. In addition, in the presence of early-onset nephrotic syndrome and autoimmune thyroiditis, the patient should be evaluated for this type of monogenic disorders as well.

Thyroid nodules are less frequent in children than in adults. A higher rate of malignancy is highlighted in this group. We aimed to analyze the clinical, laboratory, and ultrasound (US) findings of children and adolescents with benign and malignant thyroid nodules. This was a retrospective review of children and adolescents evaluated at a tertiary pediatric institution between 2007 and 2019. Patients with autonomously functioning nodules, autoimmune thyroid diseases, and a history of oncohematological disorders were excluded. A total of 102 patients with 131 nodules were identified. The study population included 57 females (55.9%); the average age was 10.6 ±4 years. Thirty-five nodules (26.7%) ranging 4.5-36 mm had a fine-needle aspiration (FNA) done: 45.7% ( n = 16) were benign, 11.4% ( n = 4) were classified as atypia, and 8.5% ( n = 3) were consistent with papillary carcinoma. Fourteen patients (13.7%) underwent surgery. Five (4.9%) were finally diagnosed with papillary thyroid cancer. Of the 6 patients with benign FNAs, all except one, which was initially reported as atypia by an earlier FNA but was later diagnosed with papillary carcinoma, had a colloid nodular goiter. Of the 3 patients with atypia FNAs, one was found to be papillary carcinoma. One hundred twenty-five benign nodules (21 based on cytology and/or histology, 104 on clinical and imaging follow-up) were diagnosed. Nodule size, microcalcifications, solid parenchyma, and pathologic lymph node alterations were associated with malignancy, but nodule growth was not. Conclusion : Diagnostic approach and management of children with thyroid nodules should be based on a stepwise evaluation including clinical, laboratory, and US findings. Of the 102 patients identified, 4.9% had thyroid carcinoma below the range described in previous literature. What is Known: • Thyroid nodules are less frequent in children than in adults but more frequently malignant. Research on factors associated with malignancy have mostly been conducted in adults; further studies in pediatric thyroid nodules are warranted. What is New: • Microcalcifications, pathologic lymph node alterations, solid parenchyma, and larger nodule size are associated with malignant nodules, but nodule growth is not always suggestive of thyroid malignancy. The incidence of thyroid malignancy in this population was below the reported worldwide incidence in children with thyroid nodules.

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 GCKMODY while less than 20% of cases were diagnosed with HNF1A-MODY.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an early onset systemic autoimmune genetic disorder caused by mutation of the forkhead box protein 3 (FOXP3) gene. Enteropathy, endocrinopathy and skin manifestations are considered the classic triad of IPEX syndrome. However, patients with IPEX syndrome display a variety of phenotypes including life threatening multi-organ autoimmunity. Here, we present the case of two siblings with IPEX syndrome with the same hemizygous mutation, but with different types of symptomology at onset of the disease.

BACKGROUND:Allgrove syndrome (OMIM 231550) is a rare autosomal recessive disease characterized by non-CAH primary adrenal insufficiency (non-CAH PAI), alacrima, and achalasia. It is caused by mutations in the AAAS gene. The syndrome is also associated with variable progressive neurological impairment and dermatological abnormalities.METHODS AND RESULTS:We diagnosed 23 patients from 14 families with Allgrove syndrome, based on the presence of at least two characteristic symptoms, usually adrenal insufficiency and alacrima, between 2008 and 2018. A previously described nonsense variant of AAAS was detected in 19 patients from 12 families at homozygous state. Another novel homozygous mutation (c.394-397delCTGT) in AAAS was detected in four patients from two families. Presenting symptoms were alacrima (23/23; 100%), adrenal insufficiency (18/23; 78%), achalasia (13/23; 57%), short stature/growth retardation (16/23; 70%), hyperreflexia (15/23; 65%), palmoplantar hyperkeratosis (13/23; 57%), hyperpigmentation of the skin (10/23; 43%), hypoglycemia-induced convulsion (7/23; 30%), swallowing difficulty and vomiting (6/23; 26%). Serum DHEAS concentrations were low in all patients (23/23; 100%).CONCLUSIONS:Clinical symptoms vary even among patients carrying the same mutation. Triple A syndrome should be considered in the etiology of non-CAH PAI in Arab populations and in Southeast Turkey. Any child with non-CAH PAI should be evaluated for the presence of alacrima and/or achalasia or family history of alacrima and/or achalasia. Children with alacrima and/or achalasia should also be investigated for adrenal insufficiency. Definitive molecular diagnosis is essential for early diagnosis and management of adrenal insufficiency, neurological symptoms, and growth retardation in patients and early diagnosis of as yet asymptomatic cases in the family, together with genetic counseling.

Duplications of 20q are rare. Here we report a 15 years old boy with de novo duplication of 17.1 Mb at chromosome 20q. We made a comparison with the other isolated 20q duplication cases. There are phenotypic similarities between the patients who have the same affected chromosomal regions. We also showed a clinical follow up of the patient. There may be a relationship with Glaucoma and Graves disease between the chromosomal region and these diseases may occur at the other patients when they get older.