Evaluation of aggression level in adolescent girls with classical congenital adrenal hyperplasia.

OBJECTIVE: In patients with classical congenital adrenal hyperplasia (CAH), virilization affects the brain and external genitalia due to antenatal androgen exposure. There are few studies on how the effects of androgens on brain virilization are reflected in behavior. However, there is no study focused on the adolescence period. The aim of this study was to evaluate the level of aggression in adolescent girls with classical CAH (due to 21 hydroxylase and 11ß hydroxylase deficiency) and to investigate the disease-related factors that may affect aggression. DESIGN: Twenty female and 20 male patients aged 13-20 years, diagnosed with classical CAH, with 21 hydroxylase deficiency and 11ß hydroxylase deficiency, and 20 healthy girls and 20 boys from the same age group were included. The Buss-Perry Aggression Scale (BPAS), which consists of four subgroups measuring physical aggression, verbal aggression, hostility, and angry behaviors, was used. RESULTS: The ages of the male and female patients with CAH were 16.30 ± 2.65 and 16.60 ± 2.41 years, respectively. Total aggression scale scores were 73.3 ± 14.6 in adolescent girls with CAH, 74.1 ± 11.2 in healthy girls, 71.5 ± 14.8 in boys with CAH, and 75.3 ± 14.5 in healthy boys (p > .05). There was no difference between the subscale scores of patients and healthy adolescents. Aggression scores in adolescents with CAH increased significantly with age. CONCLUSIONS: In this study, we found no difference between the aggression scores of adolescents with classical CAH compared to their healthy peers. The total aggression score and subscale were similar in unaffected female adolescents.

Unraveling the Genetic Puzzle: Could MAP3K7 Be a Candidate Gene for RASopathies? Case Presentation.

Noonan Syndrome (NS) diagnosis is challenging due to diverse clinical manifestations. Here, our case report highlights MAP3K7's novel role in NS. A 10.4-year-old female patient presented with short stature and suggestive clinical findings of RASopathy. Despite atypical facial features, the patient met two major diagnostic criteria of Van der Burgt.Initial genetic testing for known NS-associated genes did not find any variants. Later, whole exome sequencing (WES) discovered a unique de novo heterozygous variant (c.65C>A, p.(P22H)) in the MAP3K7. This variant, categorized as a variant of uncertain significance (VUS) by the American College of Medical Genetics and Genomics (ACMG) criteria, raised questions about its potential role in NS. The patient's clinical presentation deviated from classical manifestations of MAP3K7-associated syndromes, underscoring the genetic and molecular mechanisms' complexity. Notably, this is the first case reported to associate MAP3K7 variants with NS, advancing knowledge of the condition's genetic causes. Despite challenges in NS diagnosis, proper management, including recombinant growth hormone therapy, is crucial for optimizing growth potential. The case underscores MAP3K7 as a potential candidate gene for NS, and more functional genetic investigations are required to clarify the delicate interaction between genetic abnormalities, the RAS/MAPK pathway, and clinical manifestations observed in NS cases.

Exploring Multiple Endocrinological Issues and Dysautonomia in a Rare Case: Hypoparathyroidism in MIRAGE Syndrome.

MIRAGE syndrome is a rare multisystemic disorder characterized by various manifestations, such as myelodysplasia, susceptibility to infections, growth retardation, adrenal hypoplasia, genital anomalies, and enteropathy. In the literature, there have been rare cases of dysautonomia. We present a 6.5-year-old girl, who was first admitted to our department with short stature. On follow up, she exhibited multiple endocrinological issues, including transient hypothyroidism, primary hypoparathyroidism and dysautonomia, along with multisystem involvement. Further investigations revealed recurrent moniliasis, low IgM levels, and transient monosomy 7 in the bone marrow. Whole exome sequencing revealed a heterozygous pathogenic variant of SAMD9 (c.2159del; p.Asn720ThrfsTer35). Additional complications observed during follow-up included medullary nephrocalcinosis, hypomagnesemia, hypermagnesiuria, hypophosphatemia, decreased glomerular filtration rate, and nephrotic proteinuria. The patient also developed hyperglycemia, which was managed with low-dose insulin. This case highlights the diagnostic challenges and the diverse phenotypic presentation observed in MIRAGE syndrome.

Assessment of the Admission and Follow-up Characteristics of Children Diagnosed with Secondary Osteoporosis.

Objective: Secondary osteoporosis is a condition when the underlying disease or its treatment causes the bone mass to decrease and the bone structure to deteriorate, increasing the risk of fracture. The importance of diagnosis and treatment during childhood and adolescence is due to its long-term negative effects. In this study, our objectives were to determine the diagnostic findings, treatment efficacy, and follow-up characteristics of childhood with secondary osteoporosis. Methods: 61 patients diagnosed with secondary osteoporosis between January 2000 and January 2021 were included in the study. The research is a cross-sectional and descriptive study. Study participants had to be under 18 years of age when the primary underlying disease was diagnosed and received treatment for secondary osteoporosis. Patient data were collected from patient files. Patient data were obtained from patient files in hospitals and were interpreted through the IBM SPSS Statistics for Windows version 20.0 (IBM Corp, Armonk, NY, USA). Results: 61 patients (28 women/33 men) were evaluated. The most common underlying primary diseases in patients with secondary osteoporosis were inflammatory diseases (57.7%), neuromuscular diseases (26.2%), immunodeficiency (13.1%), acute lymphoblastic leukemia (8.2%), metabolic diseases (8.2%), and solid organ transplantation. (8.2%), bone marrow transplantation (6.6%) and epilepsy (6.6%). The average chronological age when secondary osteoporosis was diagnosed was 11.89±4.88 years. They were evaluated for osteoporosis 6.39±5.13 years after the onset of the underlying primary chronic diseases. 78.7% of the patients had one or more chronic drug use. Systemic steroid use was 59%, chemotherapeutics 23%, immunomodulatory drugs 19.7%, antiepileptic drugs 8.2%, inhaled steroids 4.9%, IVIG 1.6%, and antituberculosis drugs 1.6%. Additionally, 1.6% of the patients were using testosterone as replacement, 3.3% L-Thyroxine, 1.6% estrogen, and 1.6% growth hormone. Bone pain was detected in 49.2% of the patients. All patients had vertebral fractures before treatment. Bisphosphonate treatment was given to 45 patients with secondary osteoporosis. There was a statistically significant increase in mean bone mineral density (BMD) and bone mineral content values six months after treatment, (p<0.001). There was a significant increase in BMD Z-score values for chronological and height age (p<0.001). The patients' BMD values increased on average by 31.15% with treatment. Following bisphosphonate treatment, there was a significant reduction in both fracture number and bone pain in patients (p<0.01). When patients who received and did not receive steroid treatment were compared, both groups received similar benefits from bisphosphonate treatment. Conclusion: Secondary osteoporosis is a condition that is influenced by many factors, such as the primary disease causing osteoporosis, chronic medication use, especially steroids. If left untreated, osteoporosis leads to important diseases such as bone pain, bone fractures, immobilization, and reduced linear growth of bone. When used to treat childhood secondary osteoporosis, Bisphosphonates significantly improve BMD and reduce fracture risk.

Evaluation of Growth Characteristics and Final Heights of Cases Diagnosed with Noonan Syndrome on GH Treatment.

Introduction: Proportional short stature is one of the most important features of Noonan Syndrome, and adult height often remains below the 3rd percentile. Although the pathophysiology of short stature in NS patients is not fully understood, it has been shown that GH treatment is beneficial in NS, and it significantly improves the height in respect to the results of short and long-term GH treatment. Methods: In this study, the efficacy of GH therapy was evaluated in children and adolescents with Noonan syndrome who attained final height. In this national cohort study, 67 cases with NS who reached final height from 14 centers were evaluated. Results: A total of 53 cases (mean follow-up time 5.6 years) received GH treatment. Height SDS of the subjects who were started on GH tended to be shorter than those who did not receive GH (-3.26± 1.07 vs. -2.53 ±1.23) at initial presentation. The mean final height and final height SDS in girls using GH vs those not using GH were 150.1 cm and -2.17 SD vs 47.4 cm and-2.8 SD, respectively. The mean final height and final height SDS in boys using GH vs. not using GH were 162.48 ± 6.19 cm and -1.81 SD vs 157.46 ± 10.16 cm and -2.68 ± 1.42 SD, respectively. The Δheight SDS value of the cases was significantly higher in the group receiving GH than in those not receiving GH (1.36 ± 1.12 SD vs. -0.2 ± 1.24, p<0.001). Cardiac findings remained stable in two patients with hypertrophic cardiomyopathy who received GH treatment. No significant side effects were observed in the cases during follow-up. Conclusion: In patients with Noonan syndrome who reach their final height, a significant increase in height is observed with GH treatment, and an increase of approximately +1.4 SDS can be achieved. It has been concluded that GH treatment is safe and effective.

Comprehensive Insights Into Pediatric Craniopharyngioma: Endocrine and Metabolic Profiles, Treatment Challenges, and Long-term Outcomes from a Multicenter Study

Objective: Craniopharyngiomas (CPG) have complex treatment challenges due to their proximity to vital structures, surgical and radiotherapeutic complexities, and the tendency for recurrence. The aim of this study was 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. A further aim was to highlight the difficulties associated with CPG management. Methods: Sixteen centers entered CPG patients into the ÇEDD NET data system. The clinical and laboratory characteristics at presentation, administered treatments, accompanying endocrine, metabolic, and other system involvements, and the patient's follow-up features were evaluated. Results: Of the 152 evaluated patients, 64 (42.1%) were female. At presentation, the mean age was 9.1±3.67, ranging from 1.46 to 16.92, years. The most common complaints at presentation were headache (68.4%), vision problems (42%), short stature (15%), and nausea and vomiting (7%). The surgical procedures were gross total resection (GTR) in 97 (63.8%) and subtotal resection in 55 (36.2%). Radiotherapy (RT) was initiated in 11.8% of the patients. Histopathological examination reported 92% were adamantinamatous type and 8% were papillary type. Postoperatively, hormone abnormalities 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 in 27 (17.8%). The study showed hesitancy among physicians regarding rhGH. The median survival without relapse was 2.2 years. Median (range) time of relapse was 1.82 (0.13-10.35) years. Relapse was related to longer followups 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 (17.1%), neurological deficits in 13 (8.5%) and diabetes mellitus in 5 (3.3%) patients. Conclusion: Recurrence was predominantly due to incomplete resection and the low rate of postoperative RT. Challenges emerged for multidisciplinary regular follow ups. It is suggested that early interventions, such as dietary restrictions and increased exercise to prevent obesity, be implemented.

Clinical Profile of Parathyroid Adenoma in Children and Adolescents: A Single-Center Experience.

OBJECTIVE: Parathyroid adenoma is less common than in adulthood, but its morbidity is higher in children. We aimed to evaluate the clinical characteristics of parathyroid adenoma and our clinical experience since the early disease is often asymptomatic and late diagnosed. MATERIALS AND METHODS: From 2010 to 2020, all children diagnosed with parathyroid adenoma at our institution were reviewed. We evaluated clinical, biochemical, and radiological aspects and follow-up characteristics. RESULTS: Eight subjects (F/M = 6/2) ranged in age from 10 to 17 years. Three were symptomatic. The symptoms and findings were stomachache (n = 3), myalgia (n = 2), weakness (n = 2), pancreatitis (n = 1), constipation (n = 1), nausea (n = 1), bone ache (n = 1), and anorexia (n = 1). Laboratory findings on admission were as follows: the mean calcium was 12.59 ± 1.28 (11.2-15.3) mg/dL and the mean parathyroid hormone was 244.81 ± 173.61 (74.9-645.4) pg/mL. The most common localization was the lower part of the left parathyroid gland. Parathyroid adenoma could not be demonstrated by ultrasonography in 2 patients. Tc-99m-Sestamibi scintigraphy revealed the presence of parathyroid adenoma in only 7 of 8 patients. All underwent parathyroidectomy. In our follow-up, 2 subjects needed reoperation. A molecular analysis of 6 cases could be done. One was MEN1 positive. RET sequence analysis of 2, and Casr, GNA11, and AP2S1 sequence analysis of 3 were normal. CONCLUSION: Parathyroid adenoma should be considered in children older than the first decade with hypercalcemia. Suspected cases should undergo both ultrasonography and scintigraphy. Early diagnosis prevents the patients from serious complications of hypercalcemia such as nephrocalcinosis, diabetes insipid, and arrhythmia. It is significant to perform surgery in centers experienced in parathyroidectomy to minimize postoperative complications.

Evaluation of Abnormal Uterine Bleeding in Adolescents: Single Center Experience

Objective: Abnormal uterine bleeding (AUB) is the most common gynecologic complaint in adolescent girls. The aim of this study was to identify the diagnostic and management differences between those with/without heavy menstrual bleeding. Methods: Retrospective data was collected from adolescents aged 10-19 years, diagnosed with AUB. Adolescents with known bleeding disorders at admission were excluded. All girls were classified according to the degree of anemia; group 1 had heavy bleeding [hemoglobin (Hb) <10 g/dL] and group 2 had moderate or mild bleeding (Hb >10 g/dL). Admission and follow-up characteristics were compared between the two groups. Results: The cohort consisted of 79 girls with a mean age of 14.3±1.8 years and mean age of menarche of 11.9±1.4 years, with 85% experiencing menstrual irregularity in the two years after menarche, rising to 95.3% in group 1 (p<0.01). Anovulation was evident in 80% of the cohort. Of these 79 girls, 13 (16.5%) had polycystic ovary syndrome and two (2.5%) had structural anomalies (uterus didelphys). Three girls (group 1, n=2) had previously undiagnosed clotting factor VII deficiency; no other clotting deficiencies were diagnosed. Nineteen of 34 (56%) with personal (n=2)/family history of thrombosis had MTHFR mutation. None had venous thromboembolism during follow-up of >6 months. Conclusion: The majority of AUB (85%) occurred in the first two years after menarche. A small proportion (3.8%) had undiagnosed clotting factor deficiency. The frequency of MTHFR mutation was 50% in girls with history of thrombosis; however this did not increase the risk of bleeding/thrombosis and so routine evaluation does not appear to be justified.

Familial Clinical Heterogeneity of Medullary Thyroid Cancer with Germline RET S891A Protooncogene Mutation: 7-Year Follow-up with Successful Sorafenib Treatment.

Hereditary forms of Medullary thyroid carcinoma (MTC) are rare. Different phenotypes with the same mutation may be due to differences in the timing of RET activation steps, additional mutations in other regions of the gene, or the co-occurrence of germline and somatic mutations, which is an infrequent possibility. Here, we aim to present the different features and difficulties in the follow-up of three family members with the same germline mutation. A 4-year-old male patient with respiratory distress was diagnosed with MTC and found to have a heterozygous germline mutation C.2671T>G(S891A) in the RET gene (classified as intermediate risk according to ATA). As the tumor was inoperable, treatment with a tyrosine kinase inhibitor (sorafenib) was initiated. Sorafenib has prevented tumor progression for seven years. Whole exome sequencing (WES) did not identify additional mutations. Segregation analysis showed the same mutation in the asymptomatic mother and sister. In our case, thyroid tissues were examined for somatic mutations, and SDHA c.1223C>T (p.S408L) was found. The clinical presentation of rare mutations such as RET p.S891A differed among family members carrying the same germline mutation. Our index case's more severe clinical presentation may be due to an additional somatic mutation. Sorafenib treatment can be an option for advanced MTC and may prevent disease progression.

Clinical Characteristics and Treatment Outcomes of Children with Primary Osteoporosis.

OBJECTIVE: Primary osteoporosis is a rare and essential problem in childhood that can cause severe skeletal deformities. We aimed to reveal the spectrum of primary osteoporosis and assess the effectiveness and safety of bisphosphonates in increasing bone mineral density and reducing fractures. MATERIALS AND METHODS: Patients with primary osteoporosis who received at least one course of pamidronate or zoledronic acid were included in the study. Patients were divided into 2 groups, osteogenesis imperfecta and non-osteogenesis imperfecta subjects. We evaluated bone densitometer parameters, activation scores, pain status, deformity status, and the number of fractures per year in all patients. RESULTS: Of the 31 patients, 21 with osteogenesis imperfect, 3 patients with spondyloocular syndromes, 2 with Bruck Syndrome, and 5 with idiopathic juvenile osteoporosis were included. A total of 21 patients had received pamidronate treatment, while only 4 received zoledronic acid, and 6 of them switched from pamidronate to zoledronic acid. At the end of the treatment, the mean bone mineral density height-adjusted Z-score increased from -3.39 ± 1.30 to -0.95 ± 1.34. The number of fractures per year decreased from 2.28 ± 2.67 to 0.29 ± 0.69. The activation score increased from 2.81 ± 1.47 to 3.16 ± 1.48. The pain decreased significantly. There was no difference in bone mineral density increase in patients treated with pamidronate or zoledronic acid. CONCLUSION: Those with osteogenesis imperfecta were diagnosed at an earlier age with severe deformity and fractures. Pamidronate and zoledronic acid increased bone mineral density in all types of primary osteoporosis.

Mitotically Active Follicular Nodule in Early Childhood: A Case Report with A Novel Mutation in the Thyroglobulin Gene.

Dyshormonogenesis is the failure of thyroid hormone production due to a defect in thyroid hormonogenesis. Loss-of-function mutations in the thyroglobulin(TG) gene are a cause of dyshormonogenesis, leading to gland stimulation by thyroid-stimulating hormone (TSH), resulting in goiter. We report a mitotically active follicular nodule in an 11-year-old female with a novel mutation in the TG gene. The patient had been under follow-up due to congenital hypothyroidism since the neonatal period, and she had normal TSH levels. Genetic test revealed a novel compound heterogeneous mutation [c.2149C>T (p.R717*) (P.Arg717Ter) / c.5361_5362delCCinsG (p.H1787Qfs*3) (p.His1787GlnfsTer3)] in TG gene. She underwent total thyroidectomy for a thyroid nodule that was reported as Bethesda IV on FNAB and noted as suspicious for noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Pathological examination revealed a 16 mm well-demarcated follicular nodule with a solid/insular pattern. Mitotic activity and Ki67 proliferation index were unusually high (10 mitoses/2mm2 and 10% respectively). Marked cellular pleomorphism and nuclear atypia are well-known diagnostic pitfalls in patients with dyshormonogenetic goiter. However, high mitotic activity is a feature that is less emphasized in dyshormonogenetic goiter and may raise suspicion of poorly differentiated carcinoma when observed together with a solid pattern. The absence of signs of invasion, history of congenital hypothyroidism, and awareness of the presence of mutations compatible with dyshormonogenetic goiter can prevent the overinterpretation of such lesions. The risk of cancer development in the dyshormonogenetic thyroid gland is possible in childhood. The close follow-up is life-saving and prevents morbidities and mortalities.

The Effect of Growth Hormone Therapy on Cardiac Outcomes in Noonan Syndrome: Long Term Follow-up Results

Objective: Cardiac involvement is common in Noonan syndrome (NS). Concerns have been raised regarding the effect of recombinant growth hormone (rGH) use on ventricular wall thickness and a possible increased risk of cardiac side effects. This study aimed to investigate the effect of rGH on the development of hypertrophic cardiomyopathy and other cardiac findings in NS. Methods: Patients under the age of 18 years and diagnosed with NS according to the Van der Burgt criteria, were included. Patients were divided into two groups according to those receiving rGH or not at the time of obtaining cardiac measurements. Before and after the treatment, electrocardiographic and echocardiographic (ECHO) assessments were made, including interventricular septal thickness, left ventricular internal diameter, and left ventricular posterior thickness. Results were expressed as Z scores. Results: Twenty-four NS subjects (16 boys, eight girls) were included. At the beginning of the follow up, the overall height standard deviation score was -2.56±0.94. Sixteen were on rGH. The mean rGH treatment duration was 8.3±3.8 years, and the mean dose was 0.22±0.04 mg/kg/week. The final height was 169±8.2 cm, and 10 of 11 patients who reached the final height received rGH. There was no difference between the rGH and non-rGH groups in terms of ECHO parameters pre-and post-treatment. Conclusion: In this cohort, there was no change in ECHO parameters on rGH and during follow-up. These results suggest that rGH is safe in NS patients with cardiac pathology under close follow-up.

Recombinant GH treatment in a case of Costello syndrome with a 5-year follow-up.

Costello syndrome (CS) is a rare member of the group of neuro-cardio-facio-cutaneous diseases known as RASopathies. CS involves characteristic dysmorphic craniofacial features, cardiac defects, and increased cancer susceptibility, depending on the heterozygous activating germline mutations in HRAS. Polyhydramnios and high birth weight are the most common presentations in the perinatal and neonatal periods; while poor postnatal growth, short stature, and failure to thrive are significant issues in infancy. Possible mechanisms of short stature in CS include GH deficiency and feeding difficulties. Only a few reported cases of CS with GH deficiency exist in literature. Here, we describe the 5-yr follow-up of a CS patient with complete GH deficiency treated with recombinant human GH (rhGH) from the age of four years. No significant adverse events regarding progression of hypertrophic cardiomyopathy and tumor development were observed. She has been responsive to treatment with improved growth velocity and height standard deviation scores. She is still under continuous monitoring for concerns on the possible development of cardiac events and malignancies. This case indicated that rhGH therapy is effective for improving the height and growth velocity of CS patients with GH deficiency under close cardiac and oncological monitoring.