Volume 30, Issue 3

Adrenocortical tumors (ACT) in adulthood and childhood vary in clinical, histopathological, molecular, prognostic, and imaging aspects. ACT are relatively common in adults, as adenomas are often found incidentally on imaging. ACT are rare in children, though they have a significantly higher prevalence in the south and southeast regions of Brazil. In clinical manifestation, adults with ACT present more frequently with glucocorticoid overproduction (Cushing syndrome), mineralocorticoid syndromes (Conn syndrome), or the excess of androgens in women. Subclinical tumors are frequently diagnosed late, associated with compression symptoms of abdominal mass. In children, the usual presentation is the virilizing syndrome or virilizing association and hypercortisolism. Histopathological grading and ACT classification in malignant and benign lesions are different for adults and children. In adults, the described criteria are the Hough, Weiss, modified Weiss, and Van Slooten. These scores are not valid for children; there are other criteria, such as proposed by Wieneke and colleagues. In molecular terms, there is also a difference related to genetic alterations found in these two populations. This review discusses the imaging findings of ACT, aiming to characterize the present differences between ACT found in adults and children. We listed several differences between magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography–computed (PET-CT) and also performed a literature review, which focuses on studied age groups of published articles in the last 10 years regarding cortical neoplasm and imaging techniques. Published studies on ACT imaging in children are rare. It is important to stress that the majority of publications related to the differentiation of malignant and benign tumors are based almost exclusively on studies in adults. A minority of articles, however, studied adults and children together, which may not be appropriate.

Background: Type 1 diabetes (T1D) is a serious chronic illness that imposes significant morbidity and mortality with a major impact on the quality of life (QoL) that became a core issue in diabetes care. Understanding the effect of diabetes on QoL is important for day-to-day clinical management and also for public health policy initiatives aiming at improving health outcomes for those with diabetes. The objective of the study was to assess the QoL in adolescents with T1D and assess the applicability of the use of the “Quality of Life for Youth” questionnaire at the Diabetes, Endocrine and Metabolism Pediatric Unit (DEMPU) clinic. Methods: One hundred and fifty adolescents (82 males and 68 females) (10–18 years), with T1D of at least 1 years’ duration, completed the questionnaire that evaluated symptoms related to diabetes, treatment, activities, parent issues, worries about diabetes and health perception. Higher scores indicated a more negative impact of diabetes and poorer QoL. Results: Males showed a significantly better mean QoL score than females (p=0.004). Different age groups showed different QoL scores (p=0.047). Urban adolescents had a better QoL than rural counterparts (p=0.02). Adolescents with poor QoL had generally lower educational level (p=0.02). Better metabolic control was associated with a better QoL (p=0.01). However, duration of diabetes and body mass index (BMI) had no statistically significant effect on QoL. Conclusions: QoL had a variable significant association with certain socio-demographic and clinical characteristics of diabetics (sex, residence, educational level as well as metabolic control).

Background: To what extent high sensitivity C-reactive protein (hsCRP) is associated with known cardiovascular risk factors in children with type 1 diabetes (T1D) has not been fully explored. Methods: Forty-two T1D children (age: 12+/−1 years) without hypertension, retinopathy, hypothyroidism, albuminuria or other endocrine diseases and 20 controls were studied. Out of the 42 T1D patients studied 57% were prepubertal or early pubertal (Tanner I/II), 38% were pubertal (Tanner III/IV) and 5% post-pubertal (Tanner V). Results: Children with T1D showed higher hsCRP than controls [0.51 (0.31–1.71 vs. 0.20 (0.20–0.90) mg/L, p<0.05]. However, hsCRP levels were not different in subgroup analysis [hemoglobin A 1c (HbA 1c )>7.5% or disease duration>3 years] within the group of children with T1D. Conversely, non-high density lipoprotein (HDL)-cholesterol was different in the subgroup analysis. Moreover non-HDL-cholesterol was correlated with age (r=0.37, p<0.01), disease duration (r=0.36, p<0.01) and fasting glucose (r=0.55, p<0.0001). Conclusions: Non-HDL-cholesterol might be more useful than hsCRP to evaluate future cardiovascular risk in children with T1D.

Background: Malnutrition is reported in pediatric neuromotor disability and impacts the child’s health. We described the nutritional and metabolic status in neurologically impaired (NI) children undergoing surgery. Methods: Anthropometry, body composition, hormonal and nutritional evaluations were performed in 44 NI subjects (13.7±8.0 years). Energy needs were calculated by Krick’s formula. Metabolic syndrome (MS) was defined applying the following criteria (≥3 defined MS): fasting blood glucose >100 mg/dL and/or homeostasis model assessment for insulin resistance (HOMA-IR) >97.5th percentile, trygliceride level >95th percentile, high-density lipoprotein (HDL)-cholesterol level <5th percentile, systolic/diastolic pressure >95th percentile; whilebody mass index – standard deviation score (BMI-SDS) <2 and biochemical malnutrition markers (≥2) defined undernutrition. Results: Energy intake was not adequate in 73.8% of the patients; no correlation between energy intake and BMI was noted. Undernutrition was noted in 34.1% of patients and MS in 11.36% of subjects. Fifty percent of the patients presented with insulin resistance, which was not related to BMI, body composition or other MS components. Conclusions: Nutritional and metabolic monitoring of disabled children and young adults is recommended to prevent adverse outcomes associated with malnutrition.

Background: The aim of the study was to describe the relationship of retinal arteriolar and venular calibre with vascular risk factors in children and adolescents with type 1 diabetes. Methods: In this hospital-based cross-sectional study, the medical files of 483 children and adolescents with type 1 diabetes were audited to collect retinal images and relevant clinical data. Retinal vascular calibre was measured using standardised protocols. Results: After multivariable adjustments, a vascular risk profile that included: older age, higher serum creatinine, higher systolic blood pressure (SBP), higher body mass index (BMI), abnormal estimated glomerular filtration rate (eGFR), lower high-density lipoproteins (HDL) cholesterol, longer duration of diabetes and higher serum sodium was associated with narrower central retinal artery equivalent (CRAE) (95% CI=−4.10/−0.76, p=0.004). A specific risk profile, including higher total cholesterol level, higher BMI, lower physical activity level, higher HbA 1c , higher triglyceride levels, female gender and lower socio-economic status, was associated with wider central retinal vein equivalent (CRVE) (95% CI=1.14/5.62, p=0.003). Conclusions: In summary, these findings support evidence that cardiovascular disease may have its origins early in life. Prospective and/or intervention studies are required to confirm whether the observed associations are involved in the causal pathway for retinal vascular calibre.

Background: The aim of this study was to assess aromatase inhibitor (AI) efficacy in increasing predicted adult height (PAH) and to describe clinical and biochemical safety profiles of AI-treated boys. Methods: A retrospective chart review was conducted at an academic children’s hospital endocrinology clinic. Twenty-one boys with predicted short stature and/or rapidly advancing bone age, divided as Tanner stage (TS) I–III Group 1 (G1, n=9) and TS IV–V Group 2 (G2, n=12), were treated with AIs, either letrozole or anastrozole (mean duration, G1: 2.4 years and G2: 0.9 years). Primary outcomes included PAH, hormonal/biochemical analytes, and clinical data. Results: PAH did not significantly change in either group. Mean peak testosterone significantly increased from baseline to 650±458 ng/dL (p=0.008) in G1 and to 1156±302 ng/dL (p=0.002) in G2. Estradiol did not significantly change in either group. Compared to baseline, G2 showed increased mean FSH (p=0.002), LH (p=0.002), hematocrit (p=0.0001), body mass index (BMI) z-score (p=0.0005), and acne (p=0.01). Conclusions: AIs did not increase PAH, regardless of TS. Boys in late puberty had significant increases in testosterone, gonadotropins, hematocrit, acne, and BMI, but no reduction in estradiol. The potential consequences of these findings are concerning and require long-term study, especially if AIs are started in late puberty.

Background: Bicuspid aortic valve (BAV) represents one of the strongest risk factors for aortic dissection in Turner syndrome (TS). An exact relation between the occurrence of BAV and a particular karyotype has not been established yet. The aim of this study was to determine the association between karyotype and prevalence of BAV. Methods: Sixty-seven TS patients aged between 6.6 and 32.5 years underwent cardiac magnetic resonance imaging (MRI) study. They were divided into four cytogenetic subgroups−45,X karyotype (n=27); 45,X/46,XX mosaicism (n=17); structural abnormalities of the X chromosome (n=10); and 45,X/structural abnormality of the X chromosome mosaicism (n=13). Prevalence of BAV and odds ratio (OR) compared with the general population in the whole study group, and statistical comparison of prevalences of BAV among the individual subgroups were determined. Results: Prevalence of BAV in the whole study group was established as 28.4% [OR 208.3 (95% CI – 103.8–418.0); p-value<0.0001]. Individuals with 45,X karyotype had the highest prevalence of BAV – 40.7%, p-value<0.0001. Presence of any 45,X cell line in karyotype significantly predisposed to BAV (p-value=0.05). Conclusions: The 45,X karyotype is associated with the highest prevalence of BAV. Also, the presence of the 45,X cell line in any mosaic karyotype increases the probability of BAV.

Background: Knowledge concerning energy metabolism in Turner syndrome (TS) is lacking. We compared the resting energy expenditure per fat-free mass (REE/FFM) in TS with other girls with short stature treated with growth hormone (GH) and age-related controls. Methods: We measured prospectively REE by spirometry under fasting conditions in the morning in 85 short prepubertal girls at the start of GH treatment. Diagnoses were TS (n=20), GH deficiency (GHD) (n=38) and small for gestational age (SGA) short stature (n=27). Additionally, 20 age-related controls were studied. Mean ages were 8.3 (TS), 7.1 (GHD), 6.9 (SGA) and 8.5 years (controls). Mean heights were −2.90 (TS), −3.32 (GHD), −3.69 (SGA) and −0.03 standard deviation scores (SDS) (controls). FFM was measured by bioelectrical impedance analysis (BIA). Results: At the start of GH girls with TS showed insignificantly higher REE per FFM (REE/FFM) (mean±SD; 65±9 kcal/kg×day) than did the other female patients (62±9 kcal/kg×day) (p>0.23). The healthy controls had significantly lower REE/FFM (35±4 kcal/kg×day) (p<0.001). Follow-up examination of the patients after 6 or 12 months revealed decreasing REE/FFM in TS (62±9 kcal/kg×day) resulting in comparable REE/FFM in all three patient groups. Conclusions: At baseline short girls with TS had insignificantly higher REE/FFM than short children with SGA or GHD, but in follow-up this difference was not detectable any more. Future studies are necessary to understand this observation.

Background: Anti-Müllerian hormone (AMH) is produced by granulosa cells surrounding follicles that have undergone recruitment from the primordial follicle pool but have not been selected for dominance (preantral and early antral follicles). In healthy girls, serum levels of AMH vary considerably between individuals. We aimed to evaluate the AMH level in girls with premature thelarche (PT) and central precocious puberty (CPP). Methods: Girls with CPP (n=21), PT (n=24) and a control prepubertal group (n=22) were included in the study. Results: AMH levels were significantly higher in the PT group than the prepubertal control group and similar to the CPP group. AMH levels in the CPP group were similar to the prepubertal control group. AMH levels showed a significant negative correlation with luteinizing hormone (LH), free testosterone and dehydroepiandrosterone sulphate (DHEAS) levels in the PT group. AMH levels were negatively correlated with height standard deviation score (HSDS), body mass index (BMI) SDS values and positively correlated with sex hormone binding globulin (SHBG) levels in the CPP group. These levels were positively correlated with SHBG levels in the control prepubertal group. Conclusions: Serum AMH levels in girls with PT was found to be higher than in prepubertal girls. AMH levels in the CPP group were not different compared with the PT and control groups.

Background: The purpose of this study was to analyze the bone age and the upper extremity segmental lengths between the affected and the unaffected side and to reveal the correlation between the difference of bone age and the upper limb length discrepancy in the unilateral spastic cerebral palsy (CP). We also evaluated the relationship between difference of bone age and hand function. Methods: Seventy-eight patients participated in this study. The bone ages of hand-wrists of the patients were determined by the Greulich and Pyle atlas. Upper extremity segmental lengths were measured by radiograph. The side-to side length discrepancy was calculated as a percentage. Hand function was classified according to the Manual Ability Classification System (MACS). Results: There was significant difference in the bone age between the affected and unaffected side (p<0.001). Segmental lengths of the upper extremities showed significant differences between the affected and unaffected side (p<0.001). The hand function of 56 patients was evaluated by MACS and the MACS level showed correlation with difference of side-to-side bone age (r=0.29, p=0.03) and all segmental upper limb length discrepancies (p<0.05). The hand function in the bone-age-delayed group was significantly better than the hand function in the bone-age-symmetrical group (p<0.01). Conclusions: The bone age of the affected side compared to the unaffected side is delayed and the hand function of the affected side is correlated with the difference of side-to-side bone age and the upper limb length discrepancy. Hand function might be helpful for predicting potential limb shortness and delayed bone age.

Background: Primary nonautoimmune hyperthyroidism is a rare cause of neonatal hyperthyroidism. This results from an activating mutation in the thyrotropin-receptor (TSHR). It can be inherited in an autosomal dominant manner or occur sporadically as a de novo mutation. Affected individuals display a wide phenotype from severe neonatal to mild subclinical hyperthyroidism. We describe a 6-month-old boy with a de novo mutation in the TSHR gene who presented with accelerated growth, enlarging head circumference, tremor and thyrotoxicosis. Methods: Genomic DNA from the patient’s and parents’ peripheral blood leukocytes was extracted. Exons 9 and 10 of the TSHR gene were amplified by PCR and sequenced. Results: Sequencing exon 10 of the TSHR gene revealed a novel heterozygous missense mutation substituting cytosine to adenine at nucleotide position 1534 in the patient's peripheral blood leukocytes. This leads to a substitution of leucine to methionine at amino acid position 512. The mutation was absent in the parents. In silico modeling by PolyPhen-2 and SIFT predicted the mutation to be deleterious. Conclusions: The p.Leu512Met mutation (c.1534C>A) of the TSHR gene has not been previously described in germline or somatic mutations. This case presentation highlights the possibility of mild thyrotoxicosis in affected individuals and contributes to the understanding of sporadic non-autoimmune primary hyperthyroidism.

Background The DAX-1 gene is associated with X-linked adrenal hypoplasia congenita (AHC). Our objective was to compare the DAX-1 gene sequence of two male siblings exhibiting different clinical manifestations of AHC. Methods Clinical features were analyzed and laboratory data were collected from both siblings. Genomic DNA was extracted from the peripheral blood leukocytes of the siblings and their parents and the DAX-1 gene exons and intron-flanking regions were amplified by the polymerase chain reaction. The DAX-1 gene sequences were compared following sequencing. Results AHC was diagnosed based on a comprehensive review of the clinical presentation and laboratory tests. Gene analysis revealed a nonsense mutation in DAX-1 gene exon 1 ( c.192C > G ), resulting in a premature termination codon and a truncated 64-amino acid protein product ( p.Tyr64X ). Conclusions Our report provides evidence that defined point mutations in the DAX-1 gene do not necessarily translate into the same clinical manifestations of AHC, even in patients with the same pedigree.

3 β -Hydroxysteroid dehydrogenase type II deficiency ( 3βHSD2 ) congenital adrenal hyperplasia is a rare cause of ambiguous genitalia, resulting in abnormal virilisation in both 46XY and 46XX. We describe a case of 46XY ambiguous genitalia that was misdiagnosed as androgen insensitivity syndrome. The correct diagnosis was made after adrenarche. Genotyping demonstrated compound heterozygosity in two alleles, the previously described c.244G>A ( p.Ala82Thr ), and a novel 931C>T ( p.Gln311* ) variant. We suggest that adrenarche unmasked the condition by driving cortisol production to rates that caused the mutant 3bHSD2 enzyme to become rate limiting for cortisol production. This case illustrates how markedly different the effects of this condition may be on androgen production compared with glucocorticoid and mineralocorticoid production. It also demonstrates how current guidelines based on urinary steroids and cortisol sufficiency may not arrive at the correct diagnosis, and underlines the importance of gene testing in the work-up of disorders of sexual differentiation.

Background: Gordon syndrome (GS) is a rare form of monogenic hypertension characterized by low renin hypertension, hyperkalemia, hyperchloremic metabolic acidosis, and normal glomerular filtration rate. To date, four genes causing GS have been identified as: WNK1 , WNK4 , CUL3 , and KLHL3 . Case presentation: We report three cases of GS in two families. All patients presented with typical clinical features of GS and had a known dominant KLHL3 mutation. Oral thiazide treatment with low salt diet resulted in normalization of blood pressure and serum electrolytes in all three cases. Conclusions: GS should be considered in patients with low renin hypertension and hyperkalemia. Although it is a rare disease, the correct diagnosis of GS is clinically important, as it can easily be treated with a low sodium diet or thiazides. In addition, family studies can identify individuals with undiagnosed GS as all mutations causing this disease, except for some recessive KLHL3 mutations, are dominant mutations.

Autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED) is a rare but devastating primary immunodeficiency disease caused by loss-of-function mutations in autoimmune regulator ( AIRE ) gene on chromosome 21q22.3. The clinical spectrum of the disease is characterized by a wide heterogeneity because of autoimmune reactions toward different endocrine and non-endocrine organs. Here, we report a 17-year-old Turkish girl diagnosed with APECED at 9 years in whom a novel homozygote mutation in AIRE gene p.R15H (c.44G>A) was found. In the clinical course of the patient, chronic liver disease due to autoimmune hepatitis has evolved resulting in hepatopulmonary syndrome (HPS) which has not been reported before in patients with APECED.