Congenital Adrenal Hyperplasia with Combined 21-hydroxylase deficiency and 17α-hydroxylase/17,20-lyase deficiency: An undervirilized male.

21-hydroxylase deficiency stands as the most prevalent form of congenital adrenal hyperplasia, primarily resulting from mutations in the CYP21A2 gene. On the other hand, mutations within the CYP17A1 gene lead to 17α-hydroxylase/17,20-lyase enzyme deficiencies. The scarcity of 17-OH deficiency is noteworthy, accounting for less than 1% of all congenital adrenal hyperplasia cases. The male patient, born from a first-degree cousin marriage, exhibited several symptoms, including left undescended testis, micropenis, penile chord, left sensorineural hearing loss, and gynecomastia. He reported micropenis as a concern at the age of 13.5 years. His hormone profile revealed high levels of serum 17-hydroxyprogesterone, progesterone, and pregnenolone. In this case with a 46 XY karyotype, suspicions arose regarding Cytochrome P450 oxidoreductase deficiency due to ambiguous genitalia and an atypical hormone profile. Analysis unveiled two distinct homozygous and pathogenic variants in the CYP21A2 and CYP17A1 genes. Notably, mineralocorticoid precursors escalated, while cortisol and sex steroid precursors decreased during the high (250 mcg) dose ACTH stimulation test. The mutation c.1169C > G (p.Thr390Arg) in CYP17A1, which is the second documented case in literature, stands out due to its unique set of accompanying features. Mutations occurring in CYP21A2 and CYP17A1 result in complete or partial enzyme deficiencies, and the detection of homozygous mutations in two different enzyme systems within the steroidogenic pathway is noteworthy.

Adherence to Growth Hormone Treatment in Children During the COVID-19 Pandemic

Objective: Treatment adherence is crucial for the success of growth hormone (GH) therapy. Reported non-adherence rates in GH treatment have varied widely. Several factors may have an impact on adherence. Apart from these factors, the global impact of the Coronavirus disease-2019 (COVID-19) pandemic, including problems with hospital admission and routine follow-up of patients using GH treatment, may have additionally affected the adherence rate. The primary objective of this study was to investigate adherence to treatment in patients receiving GH. In addition, potential problems with GH treatment during the pandemic were investigated. Methods: This was a multicenter survey study that was sent to pediatric endocrinologists during the pandemic period (June-December 2021). Patient data, diagnosis, history of pituitary surgery, current GH doses, duration of GH therapy, the person administering therapy (either parent/patient), duration of missed doses, reasons for missed doses, as well as problems associated with GH therapy, missed dose data and the causes in the recent year (after the onset of the pandemic) were questioned. Treatment adherence was categorized based on missed dose rates over the past month (0 to 5%, full adherence; 5.1 to 10% moderate adherence; >10% non-adherence). Results: The study cohort consisted of 427 cases (56.2% male) from thirteen centers. Median age of diagnosis was 8.13 (0.13-16) years. Treatment indications were isolated GH deficiency (61.4%), multiple pituitary hormone deficiency (14%), Turner syndrome (7.5%), idiopathic GH deficiency (7.5%), small for gestational age (2.8%), and "others" (6.8%). GH therapy was administered by parents in 70% and by patients in 30%. Mean daily dose was 32.3 µg/kg, the annual growth rate was 1.15 standard deviation score (minimum -2.74, maximum 9.3). Overall GH adherence rate was good in 70.3%, moderate in 14.7%, and poor in 15% of the patients. The reasons for non-adherence were mainly due to forgetfulness, being tired, inability to access medication, and/or pen problems. It was noteworthy that there was a negative effect on adherence during the COVID-19 pandemic reported by 22% of patients and the main reasons given were problems obtaining an appointment, taking the medication, and anxiety about going to hospital. There was no difference between genders in the adherence rate. Non-adherence to GH treatment decreased significantly when the patient: administered the treatment; was older; had longer duration of treatment; and during the pandemic. There was a non-significant decrease in annual growth rate as non-adherence rate increased. Conclusion: During the COVID-19 pandemic, the poor adherence rate was 15%, and duration of GH therapy and older age were important factors. There was a negative effect on adherence during the pandemic period.

A Case Series of Three Patients with Cleidocranial Dysplasia: Clinical Presentation and Diagnostic Considerations.

Cleidocranial dysplasia (CCD) is a rare genetic condition that affects the bones and teeth. In our study, we presented three cases of CCD, including one with a new mutation and two with a family history. Case 1 had a unique heterozygous frameshift mutation (NM_001015051,c.762del, p.(Ser256Valfs*2)), while Case 2 and her brother (Case 3) had a common pathogenic missense mutation (NM_001015051,c.674G, p.Arg225Gln), which was also found in their father. The mutation in Case 1 was not reported before. Interestingly, the symptoms in Case 1, with the new mutation, were less severe than the other cases and the previous reports.

Genotype of congenital adrenal hyperplasia patients with testicular adrenal rest tumor.

Testicular adrenal rest tumor (TART) is one of the important complications that can cause infertility in male patients with congenital adrenal hyperplasia (CAH) and should therefore be diagnosed and treated at an early age. The factors that result in TART in CAH have not been completely understood. The aim of this study is to evaluate the genotype-phenotype correlation in CAH patients with TART. METHOD: Among 230 malepatients with CAH who were followed upwith regular scrotal ultrasonography in 11 different centers in Turkey, 40 patients who developed TARTand whose CAH diagnosis was confirmed by genetic testing were included in this study. Different approaches and methods were used for genotype analysis in this multicenter study. A few centers first screened the patients for the ten most common mutations in CYP21A2 and performed Sanger sequencing for the remaining regions only if these prior results were inconclusive while the majority of the departments adopted Sanger sequencing for the whole coding regions and exon-intron boundaries as the primary molecular diagnostic approach for patients with either CYP21A2 orCYP11B1 deficiency. The age of CAH diagnosis and TART diagnosis, type of CAH, and identified mutations were recorded. RESULTS: TART was detected in 17.4% of the cohort [24 patients with salt-wasting (SW) type, four simple virilizing type, and one with nonclassical type with 21-hydroxylase (CYP21A2) deficiency and 11 patients with 11-beta hydroxylase (CYP11B1) deficiency]. The youngest patients with TART presenting with CYP11B1 and CYP21A2 deficiency were of 2 and 4 years, respectively. Eight different pathogenic variants in CYP21A2were identified. The most common genotypes were c.293-13C>G/c.293-13C>G (31%) followed by c.955C>T/c.955C>T(27.6%) and c.1069C>T/c.1069C>T (17.2%). Seven different pathogenic variants were identified in CYP11B1. The most common mutation in CYP11B1 in our study was c.896T>C (p.Leu299Pro). CONCLUSION: We found that 83% TART patients were affected with SW typeCYP21A2 deficiency,and the frequent mutations detected were c.955C>T (p.Gln319Ter), c.293-13C>G in CYP21A2 and c.896T>C (p.Leu299Pro) inCYP11B1. Patients with CYP11B1 deficiency may develop TART at an earlier age. This study that examined the genotype-phenotype correlation in TART may benefit further investigations in larger series.

Endocrine Disruptors and Polycystic Ovary Syndrome: Phthalates

Objective: We aimed to investigate a possible role of the endocrine disruptors phthalates, di-2-ethylhexyl phthalate (DEHP) and mono (2-ethylhexyl) phthalate (MEHP), in polycystic ovary syndrome (PCOS) aetiopathogenesis. We also wished to evaluate the relationship between phthalates and metabolic disturbances in adolescents with PCOS. Methods: A total of 124 adolescents were included. Serum MEHP and DEHP levels were determined by high-performance liquid chromatography. Insulin resistance was evaluated using homeostasis model assessment-insulin resistance, quantitative Insulin Sensitivity Check Index, fasting glucose/insulin ratio, Matsuda index, and total insulin levels during oral glucose tolerance test. Participants were further subdivided into lean and obese subgroups according to body mass index (BMI). Results: Sixty-three PCOS and 61 controls, (mean age 15.2±1.5; range: 13-19 years) were enrolled. Serum DEHP and MEHP concentrations were not significantly different between PCOS and control groups. The mean (95% confidence interval) values of DEHP and MEHP were 2.62 (2.50-2.75) µg/mL vs 2.71 (2.52-2.90) µg/mL and 0.23 (0.19-0.29) µg/mL vs 0.36 (0.18-0.54) µg/mL in PCOS and the control groups respectively, p>0.05. Correlation analysis, adjusted for BMI, showed that both phthalates significantly correlated with insulin resistance indices and serum triglycerides in adolescents with PCOS. Conclusion: Serum DEHP and MEHP concentrations were not different between adolescents with or without PCOS. However, these phthalates are associated with metabolic disturbances such as dyslipidemia and insulin resistance, independently of obesity, in girls with PCOS.

Maturity-onset diabetes of the young: Different diabetes in an infant with cystic fibrosis.

Cystic fibrosis (CF) is one of the most common autosomal recessive and multisystemic diseases. CF affects many systems. One of these systems is the endocrine and exocrine functions of the pancreas, causing cystic fibrosis-related diabetes, which is extremely complex and has unique pathogenesis. Maturity-onset diabetes of the young (MODY) is a rare type of diabetes with autosomal dominant inheritance and is not expected in patients with CF. In this study, we present MODY due to a novel glucokinase gene mutation, which is an unexpected form of diabetes in patients with CF. This is previously unreported in the literature.

Neonatal Hypopituitarism: Approaches to Diagnosis and Treatment

Hypopituitarism is defined as a decreased release of hypophyseal hormones, which may be caused by disease of the pituitary gland disease or hypothalamus. The clinical findings of neonatal hypopituitarism depend on the causes and on presence and extent of hormonal deficiency. Patients may be asymptomatic or may demonstrate non-specific symptoms, but may still be at risk for development of pituitary hormone deficiency over time. Patient history, physical examination, endocrinological, radiological and genetic evaluations are all important for early diagnosis and treatment. The aim of this paper was to present a review of etiological factors, clinical findings, diagnosis and treatment approaches in neonatal hypopituitarism.

ROHHAD Syndrome, a Rare Cause of Hypothalamic Obesity: Report of Two Cases

Rapid-onset obesity with hypoventilation, hypothalamic dysfunction and autonomic dysregulation (ROHHAD) syndrome is a rare disease that is difficult to diagnosis and distinguish from genetic obesity syndromes. The underlying causes of the disease have not been fully explained. Hypothalamic dysfunction causes endocrine problems, respiratory dysfunction and autonomic alterations. Currently there are around 80 reported patients although this is likely due to underdiagnosis due to lack of recognition. We present two female patients suspected of ROHHAD due to weight gain starting in early childhood. Clinical and biochemical findings such as respiratory and circulatory dysfunction, hypothalamic hypernatremia, central hypothyrodism, hyperprolactinemia and central early puberty in these patients matched the criteria for ROHHAD syndrome. ROHHAD syndrome should be considered in the differential diagnosis of monogenic obesity.

Pseudotumour Cerebri Presentation in a Child Under the Gonadotropin-Releasing Hormone Agonist Treatment.

Gonadotropin-releasing hormone analogues are common treatment option in central precocious puberty in childhood as well as in endometriosis, infertility, and prostate cancer in adults. Pseudotumor cerebri is a rare side effect observed in adults. We present the case of a girl with precocious puberty treated with triptorelin acetate who developed pseudotumor cerebri after the 4th dose. She had headaches, and her blood pressure was detected to be above the 99 percentile. There were no causes underlying of hypertension such as cardiac, renal, or endocrine. Neurological examination was normal except bilateral papilledema. Cranial magnetic resonance imaging was normal. Cerebrospinal fluid (CSF) opening pressure was elevated. Triptorelin therapy was ceased and acetazolamide was applied; CSF pressure returned to normal. We observed pseudotumor cerebri after precocious puberty treatment, a finding for the first time ever seen in childhood.

A patient developing anaphylaxis and sensitivity to two different GnRH analogues and a review of literature.

Gonadotropin-releasing hormone analogues are used in the treatment of prostate cancer, breast cancer, endometriosis, and uterine leiomyomas in adults and often in the treatment of precocious puberty in children. Many adverse effects have been reported for gonadotropin-releasing hormone analogues, but anaphylaxis is rarely reported as an adverse effect. Frequent cross-reactions, particularly during childhood, and diversity of the time of onset of anaphylactic manifestations complicate the diagnosis. A patient who exhibited anaphylactic allergic reactions to two different agents used in the treatment of central precocious puberty presented here because the case has an atypical course and is the first in the literature.

Prospective investigation of anterior pituitary function in the acute phase and 12 months after pediatric traumatic brain injury.

PURPOSE: Although head trauma is common in childhood, there is no enough prospective study investigating both acute phase and 12 months after injury. Therefore, a prospective clinical trial was planned to evaluate the pituitary function in childhood in the acute and chronic phase after traumatic brain injury (TBI). METHODS: Forty-one children (27 boys and 14 girls, mean age 7 ± 4.3), who were admitted to neurosurgery intensive care unit due to head trauma, were included. Twenty-one (51.2 %) patients had mild, 10 (24.4 %) had moderate, and 10 (24.4 %) had severe TBI. Twenty-two of them were reevaluated 12 months after TBI. Basal pituitary hormone levels were measured during acute (first 24 h) and chronic phase of TBI. Additionally, in the chronic phase, GHRH-arginine test was used for the diagnosis of growth hormone (GH) deficiency. RESULTS: In the acute phase, 10 patients (24.4 %) had ACTH deficiency, and the overall 44.3 % of patients had at least one pituitary hormone dysfunction. All the pituitary hormone deficiencies during the acute phase were recovered after 12 months. Two patients (9.1 %) had new-onset GH deficiency in the chronic phase, and in one of them, ACTH deficiency was also present. CONCLUSIONS: Present prospective data clearly demonstrated that most of the hormonal changes in the early acute phase were transient, suggesting an adaptive response, and these changes did not predict the hormone deficiencies after 1 year. In the chronic phase, although GH deficiency was present, the frequency of TBI-induced hypopituitarism was clearly lower than the adult patients.

Percentiles and mean values for neck circumference in Turkish children aged 6-18 years.

AIM: To provide neck circumference (NC) percentiles and mean values for Turkish children and to investigate their significance in clinical and epidemiological use. METHODS: Data were obtained from a cross-sectional screening study; DAMTCA II (Determination of Anthropometric Measurements in Turkish Children and Adolescents) in which 5481 subjects from 17 primary, secondary and high schools were included. NC percentiles were produced using the LMS method, and NC was compared with other parameters which define body fat distribution. RESULTS: The smoothed NC curves of 3rd, 5th, 15th, 25th, 50th, 75th, 85th, 90th, 95th and 97th percentiles were constructed by age and gender. The descriptive characteristics of collected data were presented as mean (SD: standard deviation) and median (Min-Max: minimum-maximum) to provide detailed information other than smoothed values. The most prominent finding of this study was that the NC of boys was greater, but not significantly higher, than that of girls until the age of 12 but later a prominent increase in the NC of boys is observed compared with girls. We compared obese and non-obese children in the 6-10, 11-13, 14-18 age groups, NC was found to be an important parameter to define obesity. CONCLUSIONS: This study provides NC percentiles, means and medians values and analyses their significance in obesity evaluation in clinical practice.

Neurofibromatosis type 1 with overlap Turner syndrome and Klinefelter syndrome.

Turner's syndrome is a sex chromosome disorder. Klinefelter's syndrome is one of the most severe genetic diseases. Neurofibromatosis is an autosomal dominant disorder characterized by cafe-au-lait spots and fibromatous tumors of the skin. In this article, we report the overlap of neurofibromatosis-1 with Turner and Klinefelter syndromes. Thus, these disorders might overlap within the same patient. Due to these cases, we suggest that each patient with Turner-like symptoms or Klinefelter's-like syndrome, be carefully examined for café au lait macules before the initiation of hormone replacement treatment.

Neck circumference: an additional tool of screening overweight and obesity in childhood.

UNLABELLED: Obesity, particularly in the upper part of body, is a major health problem. Central obesity is related to cardiovascular disease and metabolic disorders. There are various techniques for assessing upper body fat content for the overweight and obese subjects other than waist circumference (WC). We tried to find out if neck circumference (NC) alone can be used to assess overweight and obesity. Four hundred twelve overweight and obese patients (208 girls and 204 boys) and 555 healthy children (284 girls and 271 boys) aged 6-18 years were recruited for this present study. There were significant and positive correlations between BMI-WC, BMI-NC, and WC-NC (p < 0.001). NC cutoffs for overweight and obesity were determined for each age and pubertal period. NC cutoffs of boys were increased from 28.0 to 38.0. This range was 27.0-34.5 for girls in the same range. We also calculated NC cutoffs for prepubertal and pubertal periods (respectively, 29.0 and 32.5 for boys and 28.0-31.0 for girls). CONCLUSION: NC is a reliable and easy to use tool to determine overweight and obesity in children, and NC is not as good as WC in determining overweight and obesity, both providing similar information.

Hypothalamo-pituitary insufficiency associated with ectrodactyly-ectodermal dysplasia-clefting syndrome.

Ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome is characterized by ectodermal dysplasia, ectrodactyly and facial clefting with multiple congenital anomalies such as urinary tract anomaly, lacrimal duct obstruction, and hearing loss. This syndrome is a rare disease transmitted by autosomal dominant inheritance with variable penetrance. Clinical expression is variable. In EEC syndrome with midline defect hypothalamo-pituitary endocrinopathy is expected, however hormonal disorders in EEC syndrome have rarely been reported. We present two patients with EEC syndrome associated with hypothalamo-pituitary insufficiency.