Analysis of therapy monitoring in the International Congenital Adrenal Hyperplasia Registry.

OBJECTIVE: Congenital adrenal hyperplasia (CAH) requires exogenous steroid replacement. Treatment is commonly monitored by measuring 17-OH progesterone (17OHP) and androstenedione (D4). DESIGN: Retrospective cohort study using real-world data to evaluate 17OHP and D4 in relation to hydrocortisone (HC) dose in CAH patients treated in 14 countries. PATIENTS: Pseudonymized data from children with 21-hydroxylase deficiency (21OHD) recorded in the International CAH Registry. MEASUREMENTS: Assessments between January 2000 and October 2020 in patients prescribed HC were reviewed to summarise biomarkers 17OHP and D4 and HC dose. Longitudinal assessment of measures was carried out using linear mixed-effects models (LMEM). RESULTS: Cohort of 345 patients, 52.2% female, median age 4.3 years (interquartile range: 3.1-9.2) were taking a median 11.3 mg/m2 /day (8.6-14.4) of HC. Median 17OHP was 35.7 nmol/l (3.0-104.0). Median D4 under 12 years was 0 nmol/L (0-2.0) and above 12 years was 10.5 nmol/L (3.9-21.0). There were significant differences in biomarker values between centres (p < 0.05). Correlation between D4 and 17OHP was good in multiple regression with age (p < 0.001, R2 = 0.29). In longitudinal assessment, 17OHP levels did not change with age, whereas D4 levels increased with age (p < 0.001, R2 = 0.08). Neither biomarker varied directly with dose or weight (p > 0.05). Multivariate LMEM showed HC dose decreasing by 1.0 mg/m2 /day for every 1 point increase in weight standard deviation score. DISCUSSION: Registry data show large variability in 17OHP and D4 between centres. 17OHP correlates with D4 well when accounting for age. Prescribed HC dose per body surface area decreased with weight gain.

Hypogonadism: Is It Always Hypogonadotropic in an Adolescent With a Cleft Palate? A Surprising Case of Klinefelter Syndrome.

Pituitary hormone deficiencies may occur in children with midline defects; in these cases, hypogonadism is usually hypogonadotropic. Herein, we report a boy at the age of 13.8 years with mild mental retardation, previously operated for complete cleft palate (isolated) and presented with hypoglycemia due to isolated secondary adrenal insufficiency, who further had a decrease in testicular size with increased follicle-stimulating hormone level (hypergonadotropic hypogonadism) and diagnosed with Klinefelter syndrome. Klinefelter syndrome in childhood is rarely diagnosed and cases are observed in a wide spectrum. Although some regional duplications of the X chromosome also show midline defects such as spina bifida-neural tube defects, mental retardation, hypopituitarism (mostly growth hormone deficiency); coexistence of Klinefelter syndrome and isolated secondary adrenal deficiency/midline defect in our case may also be coincidental. However, to our knowledge, this is the first case in literature with this association in a patient with a 47, XXY karyotype.

A novel NEUROG3 mutation in neonatal diabetes associated with a neuro-intestinal syndrome.

Neonatal diabetes mellitus (NDM) is a rare form of non-autoimmune diabetes usually diagnosed in the first 6 months of life. Various genetic defects have been shown to cause NDM with diverse clinical presentations and variable severity. Among transcriptional factor genes associated with isolated or syndromic NDM, a few cases of homozygous mutations in the NEUROG3 gene have been reported, all mutated patients presenting with congenital malabsorptive diarrhea with or without diabetes at a variable age of onset from early life to childhood. Through a targeted next-generation sequencing assay for monogenic diabetes genes, we aimed to search for pathogenic deleterious mutation in a Turkish patient with NDM, severe malabsorptive diarrhea, neurointestinal dysplasia and other atypical features. In this patient, we identified a novel homozygous nonsense mutation (p.Q4*) in NEUROG3. The same biallelic mutation was found in another affected family member. Of note, the study proband presents with abnormalities of the intrahepatic biliary tract, thyroid gland and central nervous system, which has never been reported before in NEUROG3 mutation carriers. Our findings extend the usually described clinical features associated with NEUROG3 deficiency in humans, and question the extent to which a complete lack of NEUROG3 expression may affect pancreas endocrine function in humans.

Mutational analysis of PHEX, FGF23 and CLCN5 in patients with hypophosphataemic rickets.

CONTEXT: Hypophosphataemic rickets (HR) is a group of rare hereditary renal phosphate wasting disorders caused by mutations in PHEX, FGF23, DMP1, ENPP1, CLCN5 or SLC34A3. OBJECTIVE: To investigate underlying genetic defects in patients with hypophosphataemic rickets. METHODS: We analysed genomic DNA from nine unrelated families for mutations in the entire coding region of PHEX, FGF23, DMP1, ENPP1, CLCN5 or SLC34A3 by PCR sequencing and copy number analysis. RESULTS: A total of 14 patients were studied. PHEX mutations were identified in 12 patients from seven families. Five of them were novel mutations present in eight patients: c.154G>T (p.E52*), c.401_402insGCCAAA (p.Q134_K135insPK), c.1600C>T (p.P534S), g.22016715_22056805del (40-kb deletion including promoter and exons 1-3) and c.2242_2243delCT (p.L748 fs*48). Four patients had previously reported mutations: c.1768+1G>A and c.1807G>A (p.W602*). Novel CLCN5 (c.1205G>A, p.W402*) and FGF23 (c.526C>G, p.R176G) mutations were found in two patients from the remaining two families. Many of the mutations were de novo: c.154G>T and c.2242_2243delCT in PHEX and c.526C>G in FGF23. Furthermore, we characterized the breakpoint of the novel PHEX g.22016715_22056805del and the c.2242_2243delCT, which is 6 bp from the stop codon, resulting in a frameshift and extension of the reading frame by 42 amino acids. CONCLUSIONS: Novel and de novo mutations are frequent and PHEX mutations are still the most common genetic defects in the Turkish population. Gene copy number analysis should be considered in patients with negative results by conventional PCR-based sequencing analysis. The current study further expands the mutation spectrum underlying HR.

Next-generation sequencing reveals deep intronic cryptic ABCC8 and HADH splicing founder mutations causing hyperinsulinism by pseudoexon activation.

Next-generation sequencing (NGS) enables analysis of the human genome on a scale previously unachievable by Sanger sequencing. Exome sequencing of the coding regions and conserved splice sites has been very successful in the identification of disease-causing mutations, and targeting of these regions has extended clinical diagnostic testing from analysis of fewer than ten genes per phenotype to more than 100. Noncoding mutations have been less extensively studied despite evidence from mRNA analysis for the existence of deep intronic mutations in >20 genes. We investigated individuals with hyperinsulinaemic hypoglycaemia and biochemical or genetic evidence to suggest noncoding mutations by using NGS to analyze the entire genomic regions of ABCC8 (117 kb) and HADH (94 kb) from overlapping ~10 kb PCR amplicons. Two deep intronic mutations, c.1333-1013A>G in ABCC8 and c.636+471G>T HADH, were identified. Both are predicted to create a cryptic splice donor site and an out-of-frame pseudoexon. Sequence analysis of mRNA from affected individuals' fibroblasts or lymphoblastoid cells confirmed mutant transcripts with pseudoexon inclusion and premature termination codons. Testing of additional individuals showed that these are founder mutations in the Irish and Turkish populations, accounting for 14% of focal hyperinsulinism cases and 32% of subjects with HADH mutations in our cohort. The identification of deep intronic mutations has previously focused on the detection of aberrant mRNA transcripts in a subset of disorders for which RNA is readily obtained from the target tissue or ectopically expressed at sufficient levels. Our approach of using NGS to analyze the entire genomic DNA sequence is applicable to any disease.

Spondyloenchondrodysplasia Due to Mutations in ACP5: A Comprehensive Survey.

PURPOSE: Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases. METHODS: We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations. RESULTS: We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy. CONCLUSIONS: Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia.

Hoffmann's syndrome and pituitary hyperplasia in an adolescent secondary to Hashimoto thyroiditis.

BACKGROUND: Diffuse muscle hypertrophy is a rare complication of acquired hypothyroidism. When accompanied by stiffness, weakness, and painful muscle cramps, the condition is known as Hoffmann's syndrome (HS). HS is usually seen in young adults due to long-standing untreated primary hypothyroidism. We report a very rare case of HS with muscle hypertrophy and pituitary hyperplasia complicating hypothyroidism in an adolescent. CASE: A 12-year-old male admitted with muscle pain, headache, and fatigue. He had marked hypertrophy of both calf and shoulder muscles. Laboratory tests indicated elevated muscle enzymes and lipids with an elevated thyrotropin and low thyroxine levels. Hashimoto thyroiditis was confirmed on thyroid studies. He had also papilledema bilaterally and magnetic resonance imaging showed an enlargement of the pituitary gland. Treatment with thyroid hormone resulted in complete improvement of symptoms within 3 months. CONCLUSIONS: HS is a rare but treatable form of acquired myopathies and can be seen in children due to untreated hypothyroidism. All patients with an acquired myopathy and muscular pseudohypertrophy should be screened regarding thyroid hormones.

Bilateral galactocele in a male infant with Down syndrome and congenital hypothyroidism.

Galactocele is an uncommon benign breast lesion. Its cause is unknown. Here, we report a male infant with Down syndrome and congenital hypothyroidism during the newborn period. At follow up, when he was 6 months old, bilateral mammillary swelling was detected and diagnosed as galactocele. Although thyroid hormone levels were normal, serum prolactin levels were elevated. Cyst aspiration was performed on the left side and 6 months after the aspiration of the cyst on the left side, both cysts had clinically and sonographically regressed. No recurrence was observed at the end of the 4th year.

Hormonal control during infancy and testicular adrenal rest tumor development in males with congenital adrenal hyperplasia: a retrospective multicenter cohort study.

IMPORTANCE: Testicular adrenal rest tumors (TARTs), often found in male patients with congenital adrenal hyperplasia (CAH), are benign lesions causing testicular damage and infertility. We hypothesize that chronically elevated adrenocorticotropic hormone exposure during early life may promote TART development. OBJECTIVE: This study aimed to examine the association between commencing adequate glucocorticoid treatment early after birth and TART development. DESIGN AND PARTICIPANTS: This retrospective multicenter (n = 22) open cohort study collected longitudinal clinical and biochemical data of the first 4 years of life using the I-CAH registry and included 188 male patients (median age 13 years; interquartile range: 10-17) with 21-hydroxylase deficiency (n = 181) or 11-hydroxylase deficiency (n = 7). All patients underwent at least 1 testicular ultrasound. RESULTS: TART was detected in 72 (38%) of the patients. Prevalence varied between centers. When adjusted for CAH phenotype, a delayed CAH diagnosis of >1 year, compared with a diagnosis within 1 month of life, was associated with a 2.6 times higher risk of TART diagnosis. TART onset was not predicted by biochemical disease control or bone age advancement in the first 4 years of life, but increased height standard deviation scores at the end of the 4-year study period were associated with a 27% higher risk of TART diagnosis. CONCLUSIONS AND RELEVANCE: A delayed CAH diagnosis of >1 year vs CAH diagnosis within 1 month after birth was associated with a higher risk of TART development, which may be attributed to poor disease control in early life.

Warburg Micro syndrome.

Micro syndrome is an autosomal recessive disorder characterized by severe intellectual disability, microcephaly, congenital cataract, microcornea, microphthalmia, agenesis, or hypoplasia of the corpus callosum and hypogenitalism. We report an 11-month-old boy who was referred for assessment of micropenis and cryptorchidism. Sequence analysis of exon 8 of the RAB3GAP1 gene confirmed the presence of a splice donor mutation (748+1G>A) in the homozygous state.

Clinical features and management of diabetic ketoacidosis in different age groups of children: children less than 5 years of age are at higher risk of metabolic decompensation.

OBJECTIVE: To characterize the clinical features and biochemical status at presentation of diabetic ketoacidosis (DKA) in different age groups of children, and to analyze the outcomes of a certain treatment protocol. METHODS: We reviewed records of patients with DKA who were admitted to our hospital between January 2007 and December 2010. Patients were divided into three subgroups according to age, and the results were compared between these groups. RESULTS: One hundred thirty-four episodes in 111 patients (64 females, 47 males) were analyzed. Of these 134 episodes, 60% was in patients with new-onset diabetes and 40% was in those with established diabetes. Patients younger than 5 years had lower C-peptide and HbA1c levels than older patients at clinical onset. They were also given more alkali therapy. The initial conscious level was found closely related to plasma osmolality and serum sodium levels. Seven of 11 patients with recurrent DKA were females. No major complication was observed. CONCLUSION: Our study indicates that younger children are at higher risk for severe metabolic decompensation and require more attention and closer monitoring during treatment. We suggest the use of low-dose insulin in this subgroup of patients with DKA without slowing the correction of acidosis.

Is there a secular trend regarding puberty in children with down syndrome?

Introduction: There are very few studies on the age of onset and end of puberty in children with Down syndrome (DS). Also, data regarding the course of puberty in these children compared to their healthy peers is limited. Moreover, there is limited information regarding the effects of factors such as obesity and hypothyroidism on the puberty process in children with DS. Our aim in our study is to determine whether the pubertal development of children with DS differs from their healthy peers and from previous studies conducted with DS children. Methods: The medical records of DS children were examined retrospectively. The anthropometric measurements and the age of onset of pubertal stages, and menarche were recorded. The patients' age at puberty onset, the puberty processes, and age at menarche were compared with their healthy peers and previously published data on children with DS. Results: Of the 140 Down syndrome patients followed in our clinic, 51 of whom with puberty constituted the study group. The mean age of onset of puberty was 10.3 ± 1.0 years in our group (10.0 ± 0.8 years for girls, 10.6 ± 1.2 years for boys, respectively). Obesity occurred in 46% of pubertal girls with DS. The age of menarche in girls with DS was 11.8 ± 0.7 years. The menarche age of girls with DS was significantly different from healthy girls. In the DS boys, only the Tanner V stage ages were different from the healthy children. True- precocious-puberty was detected in three children. Conclusion: Although breast development begins later in females with DS than in their healthy peers; menarche is detected earlier than in their peers and a tendency towards obesity in the whole population. While the age of pubertal onset was similar to healthy children in male patients, our findings suggest that their puberty duration is longer.

Psychometric Properties of the Turkish Version of the Diabetes Strengths and Resilience Measure for Adolescents with Type 1 Diabetes

Objective: Resilience in diabetes refers to the capacity overcome diabetes-related challenges to achieve favorable psychosocial and health outcomes. Despite the known benefits of resilience in adolescents with type 1 diabetes mellitus (T1DM), there tends to be more emphasis on risk factors in research and practice. This study evaluated the psychometric properties of the Diabetes Strengths and Resilience Measure for Adolescents with Type 1 Diabetes (DSTAR-Teen) in Turkey. Methods: This descriptive, methodological study was conducted between October 2020 and May 2021. The Turkish DSTAR-Teen was administered to 120 adolescents with T1DM, and the data were evaluated using Cronbach's alpha coefficients, factor analyses, test-retest correlation, and item-total score correlations. Results: The Turkish DSTAR-Teen has 12 items in two factors that explained 50.64% of the total variance. Confirmatory factor analysis revealed goodness-of-fit and comparative fit indices of 0.92 and 0.95, respectively. The total Cronbach's alpha value of the scale was 0.85. Item-total score correlations ranged from 0.49 to 0.74 (p<0.001). Conclusion: Our analyses showed that the Turkish DSTAR-Teen is a valid and reliable instrument in Turkish adolescents with T1DM. The Turkish DSTAR-Teen can be used to evaluate strengths and resilience associated with diabetes management in adolescents with T1DM in Turkey.

The Prevalence of Obesity Among Children With Type 2 Diabetes: A Systematic Review and Meta-analysis.

Importance: The childhood obesity epidemic is presumed to drive pediatric type 2 diabetes (T2D); however, the global scale of obesity in children with T2D is unknown. Objectives: To evaluate the global prevalence of obesity in pediatric T2D, examine the association of sex and race with obesity risk, and assess the association of obesity with glycemic control and dyslipidemia. Data Sources: MEDLINE, Embase, CINAHL, Cochrane Library, and Web of Science were searched from database inception to June 16, 2022. Study Selection: Observational studies with at least 10 participants reporting the prevalence of obesity in patients with pediatric T2D were included. Data Extraction and Synthesis: Following the Meta-analysis of Observational Studies in Epidemiology reporting guideline, 2 independent reviewers in teams performed data extraction and risk of bias and level of evidence analyses. The meta-analysis was conducted using a random-effects model. Main Outcomes and Measures: The primary outcomes included the pooled prevalence rates of obesity in children with T2D. The secondary outcomes assessed pooled prevalence rates by sex and race and associations between obesity and glycemic control and dyslipidemia. Results: Of 57 articles included in the systematic review, 53 articles, with 8942 participants, were included in the meta-analysis. The overall prevalence of obesity among pediatric patients with T2D was 75.27% (95% CI, 70.47%-79.78%), and the prevalence of obesity at diabetes diagnosis among 4688 participants was 77.24% (95% CI, 70.55%-83.34%). While male participants had higher odds of obesity than female participants (odds ratio, 2.10; 95% CI, 1.33-3.31), Asian participants had the lowest prevalence of obesity (64.50%; 95% CI, 53.28%-74.99%), and White participants had the highest prevalence of obesity (89.86%; 95% CI, 71.50%-99.74%) compared with other racial groups. High heterogeneity across studies and varying degrees of glycemic control and dyslipidemia were noted. Conclusions and Relevance: The findings of this systematic review and meta-analysis suggest that obesity is not a universal phenotype in children with T2D. Further studies are needed to consider the role of obesity and other mechanisms in diabetes genesis in this population.

Treatment of congenital adrenal hyperplasia in children aged 0-3 years: a retrospective multicenter analysis of salt supplementation, glucocorticoid and mineralocorticoid medication, growth and blood pressure.

Objectives: International guidelines recommend additional salt supplementation during infancy in classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The influence of corticoid medication and growth has not been assessed. Aim: To investigate the current use of salt supplementation, fludrocortisone (FC) and hydrocortisone (HC) dosage as well as weight, height, BMI and blood pressure (BP) in CAH children aged 0-3 years. Methods: Retrospective multicentre analysis using data from the I-CAH registry. Salt-treated (ST) and non-salt-treated (NST) children were compared regarding FC and HC dosage, weight, height and BP at 0, 3, 6, 9, 12, 18, 24, 30, and 36 months. Results: We analysed 2483 visits of 331 patients born after year 2000 in 13 countries (male, n = 145) with 203 ST patients (61%). NST children had significantly higher FC dosages at 1.5-4.5 months and higher HC dosages until 1.5 months of age. No differences in weight, length and BP between subgroups were observed. Children of the whole cohort showed increased BMI-SDS during the study period and about half of the reported BP readings were >P95. Conclusion: In children treated with additional salt supplementation, FC and HC dosages are lower during the first months of life but without differences in weight, length and BP until 3 years of age compared to NST children. All children showed an increase in BMI-SDS and a high rate of BP readings >P95 until 3 years, indicating the start of weight gain and negative effects on blood pressure already in very early life.

Increased Severe Cases and New-Onset Type 1 Diabetes Among Children Presenting With Diabetic Ketoacidosis During First Year of COVID-19 Pandemic in Turkey.

Introduction: There have been some significant changes regarding healthcare utilization during the COVID-19 pandemic. Majority of the reports about the impact of the COVID-19 pandemic on diabetes care are from the first wave of the pandemic. We aim to evaluate the potential effects of the COVID-19 pandemic on the severity of diabetic ketoacidosis (DKA) and new onset Type 1 diabetes presenting with DKA, and also evaluate children with DKA and acute COVID-19 infection. Methods: This is a retrospective multi-center study among 997 children and adolescents with type 1 diabetes who were admitted with DKA to 27 pediatric intensive care units in Turkey between the first year of pandemic and pre-pandemic year. Results: The percentage of children with new-onset Type 1 diabetes presenting with DKA was higher during the COVID-19 pandemic (p < 0.0001). The incidence of severe DKA was also higher during the COVID-19 pandemic (p < 0.0001) and also higher among children with new onset Type 1 diabetes (p < 0.0001). HbA1c levels, duration of insulin infusion, and length of PICU stay were significantly higher/longer during the pandemic period. Eleven patients tested positive for SARS-CoV-2, eight were positive for new onset Type 1 diabetes, and nine tested positive for severe DKA at admission. Discussion: The frequency of new onset of Type 1 diabetes and severe cases among children with DKA during the first year of the COVID-19 pandemic. Furthermore, the cause of the increased severe presentation might be related to restrictions related to the pandemic; however, need to evaluate the potential effects of SARS-CoV-2 on the increased percentage of new onset Type 1 diabetes.

Multiple pterygium syndrome: mimicking the findings of Turner syndrome.

Multiple pterygium syndrome (MPS or Escobar syndrome) is a rare, generally autosomal recessive disorder characterized by multiple congenital joint contractures and multiple skin webs. An 11.5-year-old girl with a working diagnosis of Turner syndrome (TS) was referred for her phenotypic features and growth retardation. Pterygium of the neck, low posterior hairline, widely spaced nipples, cubitus valgus, upslanting palpebral fissures, hypertelorism, micrognathia, low-set ears, downturning corners of the mouth, long philtrum, high-arched palate, digital and intercrural webbings, and aplasia of the labia majora were indicative of MPS (Escobar syndrome). Her mental status was normal. Facial asymmetry was present due to cervical webs. Normal karyotype, gonadal functions, and cardiac and urinary system findings helped in excluding TS. Genetic diseases associated with skin webs were revised in differential diagnosis.

Kocher-Debré-Sémélaigne syndrome with pericardial effusion.

Kocher-Debré-Sémélaigne syndrome (KDSS) is a rare association of muscular pseudohypertrophy and hypothyroidism in children. We report an 11-year-old female child with hypothyroidism and limb muscle pseudohypertrophy with pericardial effusion. The patient presented with hypertrichosis only. She had dull facies and marked hypertrophy of both calves and cervical muscles. Pericardial effusion was confirmed on investigations. Muscle pseudohypertrophy was a striking feature, and hypothyroidism was confirmed on thyroid studies. Pericardial effusion is known in hypothyroidism but has been very rarely reported with KDSS.

Surgical Practice in Girls with Congenital Adrenal Hyperplasia: An International Registry Study.

In this article international trends in surgical practice in girls with congenital adrenal hyperplasia (CAH) are evaluated. All cases that had been classified in the I-CAH/I-DSD registry as 46,XX CAH and who were born prior to 2017 were identified. Centers were approached to obtain information on surgical decision making. Of the 330 included participants, 208 (63.0%) presented within the first month of life, and 326 (98.8%) cases were assigned female. Genital surgery had been performed in 250 (75.8%). A total of 64.3, 89.2, and 96.8% of cases residing in Europe, South America and Asia, respectively, had at least one surgery. In a logistic regression model for the probability of surgery before the second birthday (early surgery) over time an increase of probability for early vaginal surgery could be identified, but not for clitoral surgery or both surgeries combined. Genitoplasty in girls with CAH remains controversial. This large international study provides a snapshot of current practice and reveals geographical and temporal differences. Fewer surgeries were reported for Europe, and there seems to be a significant trend towards aiming for vaginal surgery within the first 2 years of life.