Band 25, Heft 5-6

Poor linear growth and inadequate weight gain are very common problems in cystic fibrosis (CF) children. The most important factors involved in growth failure are undernutrition or malnutrition, chronic inflammation, lung disease, and corticosteroid treatment. Nutritional support and pharmacological therapy with recombinant human growth hormone are essential for a good management of children with CF, although these children are shorter and lighter than healthy children, and despite the catch-up growth observed after diagnosis, deficit in length/height and weight continues to be seen until adulthood. Early diagnosis is essential to ensure better nutritional status and growth, potentially associated with better respiratory function and prognosis. The aims of this review are try to explain etiology and pathogenetic mechanisms of growth failure in CF children and clarify their role in the disease morbidity and in clinical outcome, especially in relation to progressive decline of pulmonary function.

Context: Worldwide, only nine cases of revealing slipped capital femoral epiphysis (SCFE) associated with primary hyperparathyroidism (PHP) have been reported. Case illustration: This study included adolescent subjects with the described association, the clinical course, and exhibiting the leading pathogeneses. Methods: Here, we reviewed all known cases and developed an effective approach to the management of SCFE and PHP. Results: In cases of emergency, SCFE fixation is primarily done regardless of any preexistent hypercalcemia due to PHP and followed by parathyroidectomy as soon as possible. In cases of mild and moderate hypercalcemia, whether SCFE fixation is followed by parathyroidectomy and vice versa or resolved during a single operating session depends on manifest side effects due to hyercalcemia. Patients with severe hypercalcema should undergo urgent parathyroidectomy, followed by immediate orthopedic surgery, even as a simultaneous procedure. This is to avoid onset of hypercalcemic side effects or worsening of preexisting side manifestations resulting from hypercalcemia. Conclusion: Our report demonstrates that SCFE presenting with hypercalcemia, with signs of low bone density, or in atypical age deserves further workup for secondary causes. In addition, the newly developed systematic approach toward achieving an effective, efficient management should help to improve the patients’ long-term outcome.

Background: Thyroid dysgenesis (TD) is usually sporadic. In approximately 2%–8% of TD cases, familial TD has been identified. Aims: The aim of this study is to define the prevalence of thyroid developmental anomalies in first-degree relatives of children with TD-caused congenital hypothyroidism (CH). Methods: The investigation included 102 relatives of 33 children with CH and TD (study group) and 27 relatives of 12 normal children (comparative group). All the individuals were subjected to thyroid ultrasound and serum thyroid stimulating hormone (TSH) and free T4 (FT4) determinations. Statistical analysis was based on Fisher’s exact test. Results: TD-caused familial CH was noted in 2 of 33 (6%) children with CH. Asymptomatic thyroid developmental anomaly was seen in 1 of 102 (1%) relatives – left thyroid lobe hypoplasia in the mother of a girl with CH and thyroid severe hypoplasia. Familial prevalence of asymptomatic TD in the study group was observed in 1 of 32 families (3.13%). None of the comparative group members demonstrated any thyroid developmental anomalies. Conclusions: The prevalence rate of thyroid developmental anomalies in the study group is slightly higher than in the comparative group. These disturbances are asymptomatic.

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and results in mental retardation if untreated. Eighty-five percent of CH cases are due to disruptions in thyroid organogenesis and are mostly sporadic, but about 2% of thyroid dysgenesis is familial, indicating the involvement of genetic factors in the aetiology of the disease. In this study, we aimed to investigate the Mendelian (single-gene) causes of non-syndromic and non-goitrous congenital hypothyroidism (CHNG) in consanguineous or multicase families. Here we report the results of the second part (n=105) of our large cohort (n=244), representing the largest such cohort in the literature, and interpret the overall results of the whole cohort. Additionally, 50 sporadic cases with thyroid dysgenesis and 400 unaffected control subjects were included in the study. In familial cases, first, we performed potential linkage analysis of four known genes causing CHNG ( TSHR , PAX8 , TSHB , and NKX2-5 ) using microsatellite markers and then examined the presence of mutations in these genes by direct sequencing. In addition, in silico analyses of the predicted structural effects of TSHR mutations were performed and related to the mutation specific disease phenotype. We detected eight new TSHR mutations and a PAX8 mutation but no mutations in TSHB and NKX2-5 . None of the biallelic TSHR mutations detected in familial cases were present in the cohort of 50 sporadic cases. Genotype/phenotype relationships were established between TSHR mutations and resulting clinical presentations. Here we conclude that TSHR mutations are the main detectable cause of autosomal recessively inherited thyroid dysgenesis. We also outline a new genetic testing strategy for the investigation of suspected autosomal recessive non-goitrous CH.

Background: Ovarian cysts are rare conditions in the pediatric age group. They are characterized by different clinical presentations and by the need to establish adequate type and timing of treatment in order to prevent complications, such as ovarian necrosis after torsion and infertility. The diagnostic approach should differentiate benign occasional findings, such as follicular cysts, from neoplastic lesions, and functional cysts which can occur either isolated or in the context of McCune-Albright syndrome. Our aim was to review all the patients affected by ovarian pathologies seen in our department in the past 5 years, in order to establish a protocol for the correct management of these conditions. Methods: In the past 5 years we studied 133 patients diagnosed with ovarian lesion. We subdivided the patients into three groups according to age: group A (age <6 months: 66 cases); group B (pre-pubertal patients, age 7 months to 10 years: 10 cases); and group C (pubertal patients, age 11–14 years: 57 cases). We collected historical and clinical data and assigned specific cut-off values in order to perform statistical analysis (Fisher’s exact test) comparing the three groups. Results: Ultrasound examination proved to be indispensable in the early detection of ovarian lesions and for identifying the correct treatment. Cyst size, and moreover appearance with ultrasound, were important considerations when selecting the most appropriate therapeutic approach. The larger lesions were found in group B, giving symptoms that required hospitalization (pelvic pain, nausea and vomiting) and leading to increased incidence of postoperative complications. Laparoscopic surgery appeared to be safe and effective for the treatment of ovarian pathologies. Conclusion: The management of ovarian lesions in children must be based on a minimally invasive approach, based on the patient’s age and ultrasound findings. Treatment should be conservative, with ovariectomy undertaken only when essential. In adolescents, only cysts larger than 6 cm that do not resolve with estro-progestinic therapy within 6 months should be surgically approached; in infants, any signs of cyst complications must be addressed surgically.

Background: Cardiovascular disease affects >50% of Turner syndrome (TS) patients. With newer imaging modalities, this prevalence increases and the spectrum of recognized anomalies broadens. Objective: To determine the prevalence and hemodynamic significance of partial anomalous pulmonary venous return (PAPVR) in adolescents and young adults with TS using transthoracic echocardiogram (TTE) and cardiac magnetic resonance (CMR), and to study the association with phenotype. Methods: The records of 39 young TS patients who had received TTE and CMR were reviewed. Results: PAPVR was diagnosed in seven (18%) patients; six were newly diagnosed by CMR after normal TTE. In one subject, PAPVR was associated with right ventricular enlargement and a pulmonic blood flow (Qp) to systemic blood flow (Qs) ratio of 1.9:1.0, necessitating surgical repair. In other subjects with and without PAPVR, Qp:Qs and the right ventricle to left ventricle end-diastolic volume ratio were statistically different. Other clinical features were not predictive of PAPVR. Conclusions: The prevalence of PAPVR is high in TS, and it may be hemodynamically significant. Diagnosis by TTE can be difficult. Appropriate screening and management are indicated.

Our study aimed to assess uterine development in Turner syndrome patients and its relation to dose and type of estrogen therapy; and karyotype. Pelvic ultrasound was used to assess uterine size and shape, and ovarian volume in 40 Turner syndrome patients. Information on hormone replacement therapy was collected from patients’ notes. Among the 40 patients studied, 57.5% started estrogen therapy and 30% were taking progestins. Sixty-five per cent had immature uterus, 17.5% had fully mature uterus and 17.5% had transitional uterus. Uterine volume was associated with age (p<0.001), height (p=0.002), weight (p=0.001), years of estrogen use (p<0.001), estrogen dose (p=0.016), current estrogen use (p=0.001) and Tanner breast stage (p<0.001). Uterine volume was not affected by the type of estrogen used (p=0.40) and karyotype (p=0.40). Patients with Turner syndrome treated with estrogen (of adequate dose and duration) may attain a normal, mature uterine size and configuration, even at a late start of hormone replacement therapy and regardless of karyotype.

Aim: To investigate uterine and ovarian ultrasonography in healthy girls and establish reliable cut-off limits in the Turkish population. Methods: The study was performed on 90 girls between 6 and 16 years of age with bone age, hormonal evaluation and pelvic ultrasounds. Total uterine length (TUL), anteroposterior diameters of corpus (COAP), anteroposterior diameters of cervix (CEAP), fundus/cervix ratio (F/C), uterine volume (UV), ovarian volume (OV) and morphology were obtained. The data were stratified according to various pubertal stages and ages. Results: Age-related increases of pelvic organs were noted after 10–10.9 years. Significant correlation was detectable between age and OV, TUL and UV in pubertal girls, but age only correlated with OV in prepubertal girls. A cut-off value of 4 cm for TUL, 2.57 cm 3 for UV and 1.58 cm 3 for OV were the best discrimination values for entering puberty. Conclusion: The data herein may be useful in screening cases around puberty when continuous changes take place.

Objective: We assessed the gonadal function in boys with a newly diagnosed neoplastic disease prior to chemotherapy. Eighty-four boys (48 prepubertal and 36 pubertal) were evaluated, including 50 with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL), 10 with Hodgkin lymphoma (HL), and 24 with solid tumors. The control group consisted of 24 healthy prepubertal and 24 pubertal boys. The levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), inhibin B, and testosterone were determined, and testicular volumes were measured. Results: Patients in prepuberty and early puberty (Tanner stages 1–3) diagnosed with ALL/NHL or solid tumor presented normal serum reproductive hormone levels, whereas in ALL/NHL patients in Tanner stages 4–5, the mean values of inhibin B were significantly lower (45.18±33.85 vs. 153.57±71.44 ng/L, p=0.0027). In patients with HL in Tanner stages 4–5, a statistically significant lower mean inhibin B level (100.44±67.45 vs. 153.57±71.44 ng/L, p=0.0027), higher mean FSH level (6.3±3.6 vs. 4.6±2.2 mIU/mL, p=0.05), and higher mean LH level (5.9±4.0 vs. 3.6±1.8 mIU/mL, p=0.05) were observed. No statistically significant differences were noted in assessed hormones in patients with solid tumors, independently of Tanner stage. Conclusion: Our analysis indicates that adolescents with ALL/NHL and HL prior to treatment, exhibit reduced levels of inhibin B, which indirectly suggests the possibility of spermatogenesis dysfunction.

Objective: We hypothesized that body mass index (BMI) and DNA variants would predict age at menarche in polycystic ovarian syndrome (PCOS). Subjects: Subjects aged 18–45 years with PCOS defined by the National Institutes of Health criteria (n=522) and controls with regular menstrual cycles and no hyperandrogenism (n=472) were studied. Methods: Age at menarche was compared between PCOS cases and controls and examined as a function of multiple parameters. Results: There was a strong inverse relationship between BMI and age at menarche in PCOS (r=–0.32, p=5×10 –11 ). The chromosome 6 rs7759938-T variant was associated with earlier age at menarche in women with PCOS (12.60±0.09 vs. 13.41±0.23 years; genotype TT vs. CC; p=0.006). Age at menarche was predicted by PCOS status (β=0.512, p<0.001), reported weight group at 10–14 years (β=–0.432, p<0.001), current BMI (β=–0.0202, p=0.01), and genotype (β=0.169, p=0.02). Conclusions: Age at menarche in women with PCOS is influenced by BMI and genetic variants near LIN28B .

Objective: To investigate vitamin D status in children with Hashimoto thyroiditis. Subjects and methods: The study group consisted of 78 children recently diagnosed as Hashimoto thyroiditis and 74 subjects as the control group. Parameters of calcium metabolism, thyroid function tests, and 25-hydroxyvitamin D [25(OH)D] levels were measured. Results: Vitamin D deficiency rate was significantly higher in the Hashimoto group compared with the control subjects (73.1% vs. 17.6%, p<0.0001). In the Hashimoto group, mean 25(OH)D levels were significantly lower compared with the control group (31.2±11.5 vs. 57.9±19.7 nmol/L, p<0.001) and was inversely correlated with the anti-thyroid peroxidase (anti-TPO) levels (r=–0.30, p=0.007). Conclusion: The higher vitamin D deficiency rates besides lower vitamin D levels in the Hashimoto group together with the inverse correlation between vitamin D and anti-TPO suggest that vitamin D deficiency may have a role in the autoimmune process in Hashimoto thyroiditis in children.

Objective: To determine the feasibility of non-invasive evaluation of adrenal response in healthy prepubertal children by standardized exercise tests. Methods: On separate occasions, healthy prepubertal children performed a submaximal cycling test, a maximal cycling test, and a 20-m shuttle-run test. Salivary cortisol levels were determined before exercise, and 1 and 15 min after exercise. Results: Immediately after cessation of the cycling and shuttle-run tests, salivary cortisol levels remained unchanged or decreased. Fifteen minutes after the shuttle-run test, salivary cortisol levels increased significantly. This increase in salivary cortisol levels was not observed 15 min after the cessation of the cycling tests. Conclusion: The results of this study demonstrate a different response in salivary cortisol levels after standardized cycling and running tests in prepubertal children. The increase in salivary cortisol levels found after a short standardized running test suggests that this may be a practical non-invasive method for evaluating adrenal response in healthy prepubertal children.

Eighty-seven male volunteers were grouped according to bone age (BA): 10–12 years (n=25), 13–15 years (n=36), and 16–18 years (n=26), and the following were recorded for each: weight (kg), height (m), BMI (kg/m 2 ), calcium intake from three 24-h food recalls (mg/day), puberty evaluation by Tanner stages, bone biomarker (BB) evaluation, serum osteocalcin (OC), bone alkaline phosphatase (BAP), carboxyterminal telopeptide (S-CTx), and bone mineral density (BMD) evaluations by dual-energy X-ray absorptiometry (g·cm 2 ) in the lumbar spine, proximal femur, and the whole body. BBs showed similar behaviors, and very high median values were observed for individuals aged 13–15 years (BAP=155.50 IU/L, OC=41.63 ng/mL, S-CTx=2.09 ng/mL). Lower median BB values were observed with advancing BA between 16 and 18 years (BAP=79.80 IU/L, OC=27.80 ng/mL, S-CTx=1.65 ng/mL). Stepwise multiple regression analysis showed body weight associated with BA as independent variables with greater determination power for S-CTx (r 2 =0.40) and OC (r 2 =0.21). For BAP, stepwise analysis showed body weight and whole-body BMD (r 2 =0.34). All predictive models showed significance (p<0.01). A high turnover for both bone formation and resorption biomarkers, particularly from 13 to 15 years of BA, were observed along with very low values in the 16–18 age range. Weight and BA were significant in determining predictive equations of OC and of S-CTx, whereas for BAP, weight and BMD of full body were selected.

Pamidronate (PAM) infusion is the standard treatment in children with osteogenesis imperfecta (OI). Zoledronic acid (ZOL) is a bisphosphonate with higher potency and faster intravenous infusion, but its efficacy and safety has not been established for OI patients. We report an open-label, prospective, and randomized clinical analysis to study the safety and efficacy of ZOL compared with PAM in 23 children with OI. They were selected to receive PAM (PAM group), 1 mg/kg/day, over 2 days or ZOL (ZOL group), 0.025–0.05 mg/kg/day, over 2 days every 3–4 months according to their ages, during a 1-year follow-up. They were observed for clinical and biochemical parameters, side effects, bone mineral density (BMD), and fracture rate. After treatment, the PAM and ZOL groups average lumbar spine (LS) BMD increased by 51.8% (p=0.053) and 67.6% (p=0.003), respectively. Parallel improvement was seen in LS Z-score in the PAM and ZOL groups, with scores of –5.3 to –3.8 (p=0.032) and –4.8 to –2.3 (p=0.007), respectively. LS Z-score for the ZOL group at the end of treatment was higher compared with the PAM group but only a borderline significance (p=0.053). The total alkaline phosphatase (AP) in the ZOL group significantly decreased from baseline at third and fourth infusion (p=0.032). Mild side effects were similar in both groups, but no severe clinical symptoms were reported. In conclusion, the present study shows that the use of ZOL in the dosage and period studied was safe and efficient to promote a clinical and densitometric improvement, similarly to PAM. Further studies are needed to establish optimal dosing and long-term safety.

The use of bisphosphonates in children to treat low bone mineral density has increased. Safety and efficacy of pamidronate has been previously demonstrated. However, little research has been done on pamidronate infusion in the home health setting for patients with metabolic bone disease. Data were collected via a survey to assess satisfaction and convenience of infusions. Adverse events were measured by collecting calcium levels before and after infusions. Infusion costs were estimated from the standard orders from one home health agency and our infusion center. We found no difference in the rates of hypocalcemia between the two groups. The survey results showed high satisfaction for both groups, with higher scores in the home health group for convenience and stress. Home health infusions showed lower cost and less absenteeism from school and work. Home health-based pamidronate infusion appears to be safe, less expensive, and is associated with high patient satisfaction.

Aim: The aim of this study is to evaluate the clinical, anthropometric, hormonal, and radiological characteristics of children with central diabetes insipidus (DI). Methods: Case records of 34 children (22 boys and 12 girls) with documented central DI referred to the Pediatric Endocrinology and Adolescent Clinic of Dokuz Eylul University Faculty of Medicine were reviewed. The mean age at diagnosis was 6.4±5.6 years (range, 0.08–16 years). All patients underwent anterior pituitary function assessment and magnetic resonance imaging of pituitary at diagnosis. The median duration of follow-up was 7.9±4.5 years. Results: The etiology of central DI was organic in 22 (64.7%) patients, trauma in 2 (5.9%) patients, and idiopathic in 10 (29.4%) patients. Organic causes consisted of craniopharyngioma in 7 patients, Langerhans cell histiocytosis in 4 patients, germinoma in 4 patients, holoprosencephaly in 3 patients, astrocytoma in 1 patient, cavernous hemangioma in 1 patient, Rathke’s cleft cyst in 1 patient, and autoimmune polyendocrinopathy in 1 patient. Anterior pituitary hormone deficiencies were documented in 18 (53%) patients. Organic central DI group had a greater prevalence of anterior pituitary hormone deficiency when compared with the idiopathic group (66% and 10%, respectively; p=0.007). The final height of patients with organic etiology were significantly lower than the idiopathic group (155 and 178, cm respectively; p=0.021). Conclusions: Etiological diagnosis is possible in a significant proportion (70.6%) of children with central DI. Findings of this study suggest that accompanying anterior pituitary hormone deficiencies and short stature may be considered as indicators of organic etiology.

Objective: The aim of this study was to perform audiological evaluation of children with type 1 diabetes mellitus (DM). Methods: One hundred DM patients (200 ears) were included in the study. Pure-tone audiometry at frequencies of 0.25, 0.5, 1, 2, 4, and 8 kHz; immittance measures including tympano\xadmetry and acoustic reflex testing; transient evoked otoacoustic emission (TEOAE); and auditory brainstem response (ABR) testing were performed in the patients. The results were statistically compared with metabolic control of DM, positive and negative autoantibodies, duration of DM, and present concomitant Hashimoto and celiac diseases. Results: The proportion with a result of ‘fail’ for the TEOAE test in the DM patients was not statistically significant among all groups (p>0.05). The autoantibodies, blood glucose level, and present concomitant Hashimoto and celiac diseases were not associated with prolonged ABR latencies. However, ABR peripheral transmission time (wave I) was significantly delayed with the increasing duration of DM (p<0.05). Conclusion: Pediatric patients with type 1 DM do not frequently present with cochleovestibular symptoms, but show higher audiometric thresholds and the absence of or reduction in TEOAE amplitudes. In ABR testing, the increase in the peripheral transmission time (wave I) is more suggestive of retrocochlear alterations in pediatric cases of type 1 DM compared with conventional audiometric tests (e.g., pure-tone audiometry and OAEs), which may indicate possible initial auditory neuropathy. Further longitudinal investigations on a wide range of control and pediatric subjects with DM will be necessary to confirm the present data and to detect initial auditory neuropathy.

Background: Forty-three percent of New York City’s (NYC) school-age children are overweight or obese, placing them at risk for heart disease and type 2 diabetes mellitus (T2DM). Objective: The objective of this study was to determine if an intensive after-school dance and lifestyle education program would reduce risk factors for heart disease, T2DM, and improve lifestyle choices. Subjects: Subject include 64 fourth- and fifth-grade students at an elementary school in NYC. Methods: Students received freestyle dance and lifestyle classes for 16 weeks and were evaluated for changes in body composition, endurance, biochemical measurements, and lifestyle choices. Results: Significant improvements in BMI percentiles were found among children in the overweight and obese categories as well as in endurance and biochemical measurements that reflect heart disease and diabetes risk. Improvement was also reported in lifestyle choices. Conclusion: An intensive after-school dance and lifestyle education program can reduce risk factors for heart disease and T2DM and improve lifestyle choices among elementary school children.

Aims: The aims of this study were to determine neutrophil gelatinase-associated lipocalin (NGAL) levels in normoalbuminuric and normotensive adolescents with type 1 diabetes and to assess the relationship between NGAL and clinical and laboratory variables. Methods: Forty-six adolescents with type 1 diabetes [male/female (M/F) ratio, 24/22; median age, 14.5 years; range, 12.2–16 years; diabetes duration, 4.8 years; range, 2.6–6.7 years; hemoglobin A1c (HbA1c), 7.9%; range, 7.2%–9.2%] and 21 healthy controls (M/F, 7/14; median age, 14.8 years; range, 13.6–15.5 years) were compared regarding clinical, laboratory, and ambulatory blood pressure monitoring variables. Results: Median blood and urine glucose, HbA1c, urine NGAL/creatinine ratio [13.2 (range, 8.3–43.1) vs. 4.8 (range, 2.9–20.2), p=0.015], and daytime systolic and diastolic blood pressure (BP) standard deviation score and BP loads were found higher in diabetic adolescents. Urine NGAL levels were found to be correlated with albumin/creatinine ratio (r=0.452, p=0.002), whereas plasma NGAL levels were correlated with nighttime systolic BP load (r=0.309, p=0.037). Patients with high-normal albuminuria (n=6) had higher urine NGAL levels [48.7 ng/mL (range, 27.9–149.1 ng/mL) vs. 14.3 ng/mL (range, 3.5–41 ng/mL), p=0.014] and urine NGAL/creatinine ratio [39.3 ng/mg (range, 21.1–126.3 ng/mg) vs. 11.8 ng/mg (range, 6.3–40.9 ng/mg), p=0.03] compared with those of controls and higher urine NGAL levels compared with that of diabetic adolescents with low-normal albuminuria [n=40, 11.2 ng/mL (range, 6–23.4 ng/mL), p=0.004]. Conclusions: Normoalbuminuric and normotensive adolescents with type 1 diabetes have elevated urinary NGAL values, which might indicate kidney injury.

Objective: We aimed to evaluate the association between serum lipocalin-2 level and clinical and metabolic parameters in obese children. Methods: The study included obese children with a body mass index (BMI) >95th percentile who presented to Kecioren Teaching and Research Hospital with the complaint of weight gain and healthy children with a BMI <85th percentile. The height and weight of the patients were measured for compartment of anthropometric data. Fasting blood glucose, insulin, lipid profile, and serum lipocalin-2 level were measured to evaluate the laboratory parameters. Results: The study included 33 obese and 34 healthy non-obese children. Comparison of data on the obese subjects with those of the healthy subjects shows differences in BMI, BMI-SDS, triglyceride, insulin, and homeostasis model assessment index-insulin resistance levels between the two groups were statistically significant (p<0.05), whereas serum lipocalin-2 was not statistically significant (p>0.05). There was no statistically significant difference in serum lipocalin-2 levels when obese and control groups were reclassified as prepubertal and pubertal (p>0.05). Conclusions: In this study, we did not find any relationships among serum lipocalin-2 level, anthropometric parameters, or metabolic parameters. According to the results of this study, we do not suggest routine investigation of serum lipocalin-2 level in obese subjects for risk stratification of the obesity-related complications.

Background: Despite metabolic disorders in HIV-infected children being widely described, there is still a lack of agreed criteria for diagnoses and management. Numerous studies are coming from other settings and results are heterogeneous when assessing several analytical and clinical parameters. Objectives: To describe the prevalence of metabolic disorders and associated risk factors in the Spanish National cohort of HIV-infected pediatric patients (CoRISpe). Methods: This was a cross-sectional study following all vertically HIV-infected children and adolescents in three referral centers included in the CoRISpe. Metabolic data (fasting lipids, glucose and insulin levels and thyroid hormone levels) were collected. Fat distribution was clinically assessed by expert clinicians. Results: We included 157 patients [median age 13 years, interquartile range (IQR) 10–16]. Median duration of antiretroviral therapy was 10.2 years (IQR 5.0–13.0). Almost 20% of patients had insulin resistance and this was associated with hepatitis C co-infection, current use of stavudine (d4T) and hypertriglyceridemia. Hypercholesterolemia and hypertriglyceridemia were found in 23.9% and 24.8% of patients and were associated with current use of protease inhibitors (p=0.042 and p=0.022, respectively). Abnormal fat distribution was observed in 63 patients (40.5%): lipoatrophy in 32 (20.4%), lipohypertrophy in eight (5.1%) and a mixed pattern in 23 patients (14.6%), and it was significantly associated with previous exposure to stavudine (p<0.001). Conclusions: Metabolic disorders are a significant problem in our HIV-infected pediatric population. We need to encourage the development of global strategies and the creation of consensus guidelines that can decrease the cardiovascular risk in this population.

Context and objective: Ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), have key roles in appetite control and growth regulation. To date, only few mutations of GHSR have been identified in children with obesity and short stature. We hypothesized that mutations in ghrelin or GHSR will result in disrupted growth and weight regulation in children. Design: A total of 98 subjects (38 females and 60 males) were enrolled with failure to thrive (FTT) (n=9), GH deficiency (GHD) (n=44), idiopathic short stature (ISS) (n=22) or obesity (n=23). The coding exons of both ghrelin and GHSR genes were screened for mutations by sequencing. Results: Seven different sequence changes were identified in GHSR , two of them novel and five described previously. One previously described sequence change (p.L72M) in the ghrelin gene was identified in five patients; however, the same variant was identified at a higher rate in controls. A high rate of sequence changes was shown in ghrelin and its receptor, GHSR , in our population, but none of these changes affected the coding region of the protein. Conclusions: Despite the major role of ghrelin in growth and appetite regulation, our results indicate that mutations in ghrelin and GHSR do not explain short stature and weight regulation disorders in children in our population.

Splenogonadal fusion is a rare congenital malformation where an abnormal union occurs between the spleen and gonad or mesonephric derivatives. Although it occurs in females it is much less prevalent than in males (male:female ratio, 16:1), but this may partly be because of the inaccessibility of the female gonads leading to under-diagnosis. To our knowledge this is the first case of splenogonadal fusion associated with sex reversal reported in the literature.

Deletions and mutations in the 5-α-reductase type 2 ( SRD5A2 ) gene have been identified in 46,XY disorders of sexual differentiation (DSD). The clinical spectrum is heterogeneous, varying from a normal female external genital appearance to clitoromegaly and isolated micropenis or microphallus associated with hypospadias of various degrees. We describe a 46,XY DSD patient with a homozygous c.307C>T (p.R103X) mutation in the SRD5A2 gene. The case presented with a normal female external genital phenotype.

Complete androgen insensitivity syndrome (AIS) is an X-linked disorder of sex development. Surgical management entails timely gonadectomy given the risk of malignant transformation. Our patient presented at age 15 years with primary amenorrhea. Initial laboratory testing showed elevated testosterone, luteinizing hormone, anti-Müllerian hormone levels, and 46,XY karyotype. Imaging studies showed no uterus, ovaries, and identified two candidate gonads. She underwent bilateral gonadectomy. Pathology reports revealed Sertoli cell and intratubular germ cell tumors located in separate gonads. Our case is the first report of the youngest patient with AIS with bilateral gonadal tumors derived from different histological origins. We also review literature for reports of AIS patients with gonadal tumors. Currently, there is no consensus for the timing of gonadectomy in AIS patients. However, given the varying potential for malignant transformation of gonads in AIS patients with different phenotypes, development of a standardized treatment guideline is indicated.

The most common reason for refractory hypoglycemia in newborns is congenital hyperinsulinism. We report a girl with congenital hyperinsulinism due to novel homozygous mutation (c.2041-25 G>A; aberrant splicing mutation) in the ABCC8 gene encoding SUR1 and during somatostatin analog (octreotide) discontinuation developed by nonhypoglycemic seizures. The newborn (birth weight of 3750 g) was referred to our clinic because of hypoglycemic seizures at 4 h postnatal. On admission, blood glucose was 24 mg/dL and intravenous glucose infusion was started. The patient’s insulin level was 27 mIU/mL during the hypoglycemic period. Phenobarbital (5 mg/kg/day) was added because of short-acting generalized clonic seizures. Although the patient received high doses of diazoxide, esidrex, and octreotide approximately for 2 months, hypoglycemic episodes continued. Then the patient had near-total pancreatectomy, and pathology confirmed a diffuse form of congenital hyperinsulinism. There was homozygous mutation in the ABCC8 gene encoding SUR1, which confirmed the diagnosis of autosomal recessive congenital hyperinsulinism. During octreotide discontinuation, the patient developed nonhypoglycemic seizures, which were controlled by restarting the previous doses. In the light of in vitro and in vivo studies on antiepileptic effects of somatostatin, we believe that seizures in our case have developed secondary octreotide discontinuity.

We report a rare case of monozygotic (MZ) twins who developed simultaneous onset of type 1 diabetes mellitus (T1DM). Laboratory finding showed similar values of blood sugar, pH, glycosylated hemoglobin, and C-peptide. Urinary sugar and ketones were detected in both. Endocrine and immunological assessment showed similar results. No evidence (clinical or serological) of recent viral or bacterial infection was found. In the 4 years of follow-up, the twins also showed a similar course of disease. Concordance rates for T1DM are high in MZ twins; nevertheless, a simultaneous onset and a similar course of disease are unusual, as well as the HLA allelic variants of our patients. This extraordinary concordance in a pair of MZ twins could be the consequence of a greater environmental similarity or the role of genetic factors other than HLA genes in our twins.

17-β-Hydroxysteroid dehydrogenase type 3 (17βHSD-3) converts Δ4 androstenedione (A) to testosterone (T) in the testes. This enzyme plays a key role in androgen synthesis and it is essential for normal fetal development of male genitalia. 17βHSD-3 deficiency is a rare cause of 46,XY disorders of sexual development. Here, we report a 16-year-old 46,XY patient with 17βHSD-3 deficiency raised as a female and significantly virilized in puberty. A homozygous 7 base pair deletion on exon 10 was determined in HSD17B3 gene (c.777-783del_GATAACC). Our patient had one of the very rare mutations, which was previously unencountered in Turkish patients with 17βHSD type 3, and she is the second reported case with this deletion.

The purpose of this study is to report clinical, optical coherence tomography (OCT), and fluorescein angiogram/indocyanine green angiography (FA/ICG) findings in patients with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) enzyme deficiency in two siblings. A 13-year-old girl and her 14-year-old brother presented with progressive decrease in central vision. Clinically, there were blond-looking fundi, diffuse retinal pigment epithelial (RPE) disruption/atrophy in the macula and peripheral retina with choriocapillaris atrophy in both of them. OCT showed RPE irregularity and diffuse disruption of the RPE layer. FA/ICG imaging demonstrated transmitted choroidal fluorescence secondary to diffuse RPE atrophy with no evidence of leakage. Electroretinogram and electrooculogram findings were suggestive of primary abnormality of pigment epithelium. The boy died of cardiac/respiratory illness, whereas his sister is alive at the last follow-up. Abnormal chorioretinal findings in LCHAD patients should be carefully followed. Regular follow-up is recommended to monitor the ocular and systemic status.

Type 1 diabetes is one of the most widely studied complex genetic disorders and the genes in human leukocyte antigen (HLA) locus are reported to account approximately 40%–50% of familial aggregation of type 1 diabetes. Genetic markers are helpful in assessing the risk of type 1 diabetes in the general population as well as in close relatives of a patient with type 1 diabetes. The major genetic determinants of this disease are polymorphisms of class II HLA genes encoding DQ and DR. The major susceptibility genes for type 1 diabetes are in the HLA region, and over 90% of patients carry genotypes DR4, DQ8 and/or DR3, DQ2. Absence of the above alleles makes type 1 diabetes very unlikely, especially if the subject carries protective genotypes such as DR2 and/or DQ6. In this brief report of a consanguineous Saudi family, four offsprings inherited one or both of balanced reciprocal translocations from their father. Two offsprings, one with a translocation and the other without, developed type 1 diabetes during early childhood. Both these diabetic children were found to have HLA genotype DQ 2/8, whereas the father and the youngest daughter, both carrying two sets of balanced translocations as well as the protective HLA genotype DQ6, were free of diabetes during several years of observation. This underscores the influence of HLA genotype DQ 2/8 in the susceptibility and DQ6 in the protective effect on type 1 diabetes even in individuals with gross chromosomal abnormalities.

Middle cranial fossa arachnoid cysts (MFACs) are frequently asymptomatic. Here, we report the case of a 10-year-old boy with growth hormone deficiency (GHD) and an MFAC. His linear growth had followed the –2.5 SD line. On physical examination, his height was 120.8 cm (–2.6 SD), and the level of insulin-like growth factor 1 was low (87 ng/mL). GH provocative tests revealed GHD and brain magnetic resonance imaging (MRI) revealed an MFAC. We started treatment with GH replacement therapy (0.175 mg/kg/week). At the age of 12 years and 9 months, there were no interval changes in the features of the MFAC on the brain MRI. As his height was 145.5 cm (–1.7 SD) at the age of 13 years and 4 months, the therapy seems to be successful without sequelae. GH replacement therapy is suggested to be safe and effective to treat patients with GHD associated with arachnoid cysts.

Objective: To report a 7-year-old young girl who was found unresponsive and found to be in severe diabetic ketoacidosis (DKA). Presence of obesity, acanthosis nigricans, and strong family history of type 2 diabetes mellitus (T2DM) along with negative pancreatic autoimmune antibody evaluation suggested T2DM as the culprit. Methods: We present clinical findings, laboratory test results, and imaging reports as well as follow-up on this unique presentation of T2DM. Results: A 7-year-old girl was found unresponsive at home. Initial evaluation demonstrated severe DKA and diminished neurologic status. CT-scan of the head did not demonstrate cerebral edema. Her neurologic status deteriorated dramatically on four separate occasions requiring reintubation twice. She was transitioned to intensive insulin management, requiring up to 2 units/kg/day insulin. Her insulin sensitivity improved dramatically prior to discharge. Now 18 months from diagnosis, she remains on basal insulin and metformin. Conclusions: New-onset T2DM is an increasing event in youth. Reports suggest that these youth may acutely deteriorate as opposed to the typical longer duration of onset in youth with new-onset type 1 diabetes mellitus. Attention to effective screening of those at risk and increasing public awareness of T2DM in youth is important and may reduce the risk of such dreadful presentations as described in the current report. The balance between insulin deficiency and insulin resistance is variable at different phases of the condition. This highlights the need for study of the natural history of T2DM in youth.

Growth hormone (GH) is the most frequently used treatment in children with idiopathic short stature (ISS). Aromatase inhibitor (AI) therapy is still in an experimental state, and both final height (FH) and long-term efficacy data in ISS have not been published. We present a 14.5-year-old boy with ISS and a height of 142.7 cm [standard deviation score (SDS) –2.79]. Based on the baseline bone age (BA) of 13.5–14 years, his predicted adult height (PAH) by Bayley/Pinneau was 154 cm (SDS –3.77)–158.2 (SDS –3.15). After a 5-year letrozole monotherapy, FH was 169 cm (SDS –1.57) showing a height difference between PAH and FH from 10.8 to 15 cm. No permanent side effects of the medication have been observed. Both a transient occurrence and a spontaneous recovery of decreased bone mineral apparent density were seen, verified by dual-energy X-ray absorptiometry. Spinal magnetic resonance imaging revealed no vertebral abnormalities. AI therapy might be an effective and low-cost alternative to the use of GH. Further controlled trials should prove efficacy and safety of long-term AI therapy in boys with ISS.

Rabson-Mendenhall syndrome (RMS) is a genetic disorder characterized by severe insulin resistance and somatic characteristics. Recombinant insulin-like growth factor 1 (r-IGF-1) is used to treat RMS, as the IGF-1 and insulin receptors share homology. However, the effect of r-IGF-1 varies in patients and it is difficult to manage metabolic status appropriately in r-IGF-1 resistant cases. We report a Japanese boy with RMS who showed resistance to r-IGF-1 therapy and a novel mutation in the insulin receptor in the tyrosine kinase domain. Mutations in this region disturb tyrosine kinase catalytic activity in IGF-1 receptors as a result of dominant negative effects. We consider this mutation to be the cause of resistance to r-IGF-1. The patient also exhibited radiographical features of medullary sponge kidney and had severe nephrocalcinosis and hypokalemia, indicating Bartter syndrome. However, analysis revealed no mutations in the responsible genes and the etiology of the renal abnormalities therefore remains unknown.

Congenital hyperinsulinism (CHI) is the most frequent cause of severe, persistent hypoglycemia in infancy and childhood. We report a case of CHI with diffuse pancreatic abnormality diagnosed preoperatively using the 68 Ga octreotide (DOTA NOC) positron emission tomography scan. Genetic analysis revealed homozygous ABCC8 splicing mutation. Subtotal (95%) pancreatectomy was done, and the infant remained euglycemic and was discharged on breast feeds. The patient is continuously followed up and is asymptomatic until 9 months.

Macrophage activation in hemophagocytic lymphohistiocytosis (HLH) leads to severe inflammation resulting in cytopenias and multi-organ dysfunction. Septo-optic dysplasia (SOD) is an as-yet unaffiliated disorder that manifests with optic, hepatic, endocrine and/or constitutional defects. We detail the first reported occurrence of both HLH and SOD in one patient. This two-month old patient presented with acute hepatitis, direct hyperbilirubinemia, anemia and thrombocytopenia. Treatment followed standard of care practices for SOD and HLH. The patient subsequently underwent an allogeneic bone marrow transplant within eight months of diagnosis and remained in full remission at day +90. We suggest considering a diagnosis of HLH in patients with SOD who present with severe liver failure refractory to standard therapy.

Primary familial hypomagnesemia is a rare genetically determined disorder characterized by a selective defect in magnesium (Mg) absorption. Mutations of the transient receptor potential melastatin 6 ( TRPM6 ) gene, which codes for TRPM6, the basic channel for intestinal Mg absorption and a new member of the transient receptor potential (TRP) family of cation channels, result in primary hypomagnesemia. Here we present a 14-year-old Turkish girl whose first symptoms manifested as neonatal tetany at 17 days old. During her follow-up, she was mainly taking high-dose oral Mg therapy. However, intravenous Mg and calcium (Ca) therapies were given during symptomatic attacks. When her requirements for Ca and Mg were increased during the pubertal growth period, which overlapped with increased loss of Mg during the summer, oral Ca and active vitamin D (calcitriol, Rocaltrol ® ) were added. Calcitriol is needed because hypomagnesemia results in decreased production and resistance to the actions of active vitamin D, which leads to the disturbance of intracellular signal transmission. Although high-dose oral Mg is reported as a sufficient therapy in most of the patients with primary familial hypomagnesemia, addition of active vitamin D to the usual oral Mg and Ca therapy seems very useful, as in this patient.

Although hemangiomas, benign tumors of vascular origin, are very common among children and represent the most frequent benign tumor at that age, their association with other malformations constitutes a rare neurocutaneous disorder called PHACE syndrome. This condition is characterized by posterior fossa anomalies, hemangioma of the face, arterial alterations, cardiac defects, and eye anomalies (as represented by the acronym PHACE); sternum defects, endocrinopathies, and thyreopathies may be present as well. In this report, we describe a case of congenital hypothyroidism due to an empty thyroid site, as demonstrated by ultrasound, in an Italian child.

Background: Celiac disease (CD) is an autoimmune enteropathy characterized by villus atrophy and malabsorption of essential nutrients. Vitamin D deficiency has been described in autoimmune diseases, but its status in prepubertal children with CD has not been adequately studied. Objective: To determine the vitamin D status of prepubertal children with CD. Study design: A retrospective study of prepubertal children aged 3–12 years with CD (n=24) who were compared to prepubertal, non-CD children of the same age (n=50). Children were included in the study if they had a diagnosis of CD by intestinal biopsy, and were not on a gluten-free diet (GFD). Patients were excluded if they had diseases of calcium or vitamin D metabolism, or were receiving calcium or vitamin D supplementation or had other autoimmune diseases. All subjects had their serum 25-hydroxyvitamin D [25(OH)D] level measured. Results: There was no difference in 25(OH)D level between the CD and non-CD children (27.58±9.91 vs. 26.20±10.45, p=0.59). However, when the patients were subdivided into obese and non-obese groups, the non-obese CD patients had a significantly higher 25(OH)D level than the obese normal children (28.39±10.26 vs. 21.58±5.67, p=0.009). In contrast, there was no difference in 25(OH)D level between non-obese CD patients and non-obese normal children (28.39±10.26 vs. 30.64±12.08, p=0.52). The season of 25(OH)D measurement was not a significant confounder (p=0.7). Conclusions: Our data showed no difference in 25(OH)D levels between normal children and those with CD when adjusted for body mass index.

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