Incidental Findings on Brain Magnetic Resonance Imaging (MRI) in Pediatric Endocrine Patients.

OBJECTIVE: To explore incidental findings on brain magnetic resonance imaging (MRI) studies of pediatric patients referred due to endocrine disorders. METHODS: A retrospective, observational study conducted in a tertiary referral center. The neuroimaging database of 17,445 brain MRI studies of 11,011 pediatric patients were searched for cases with endocrine referrals and without medical history of malignancy, genetic syndromes, and/or neurologic comorbidities. This database was linked to the pediatric neurosurgical database. Clinical data were retrieved from medical files. RESULTS: In total, 524 patients (50.2% males, mean age 8.5±3.5 years) were referred to brain MRI due to growth disturbances (n = 313), pubertal disorders (n = 183), prolactin hypersecretion (n = 18), central diabetes insipidus (n = 8), and obesity (n = 1). Incidental findings were found in 128 (24.4%) cases. Chiari type 1 malformation was more prevalent in patients with growth disturbances (P<.001). Small pituitary cysts were observed in 20 (3.8%) patients, and pineal cysts in 25 (4.8%) patients, mostly girls (68%, P<.001). White matter lesions were diagnosed in 30 (5.7%) patients, none with clinical evidence of neurologic disease. Brain asymmetry without clinical significance and developmental venous anomalies were observed in 14 (2.7%) and 8 (1.5%) patients, respectively. Twelve patients were diagnosed with intracranial tumors, and 5 required surgical intervention for a histopathologic diagnosis of juvenile pilocytic astrocytoma (n = 3), choroid plexus papilloma (n = 1), or inconclusive (n = 1). The rest were managed conservatively. CONCLUSION: Incidental findings on brain MRIs of pediatric patients referred by endocrinologists are common and raise dilemmas. The spectrum ranges from structural disruptions to tumors. Decision-making is individualized and patient-centered.

Prenatal diagnosis for de novo mutations: Experience from a tertiary center over a 10-year period.

BACKGROUND: This study summarizes the results of prenatal diagnosis due to a history of de novo mutation in a previous pregnancy, in a tertiary center in Israel, over a 10-year period. METHODS: We sorted all cases of de novo mutations from a pool of 2,260 pregnancies for which prenatal molecular diagnosis was applied, between the years 2008 and 2017. We identified 122 molecular prenatal diagnosis performed for de novo mutations, in 90 women. RESULTS: While the total number of yearly prenatal diagnoses stayed stable, a linear increase was detected in the number of cases for which the procedure was done due to a previous de novo mutation: from 3 cases in 2008 to 24 cases in 2017. The most common diseases were Rett syndrome (19), neurofibromatosis Type-1 (12) and Tuberous sclerosis (5). Recurrence occurred in 3 of the 90 women (3.3%) and hotspot mutations were identified in two genes accounting for 11 cases. We did not find a difference in paternal age at first occurrence of the de novo mutation between the study group and the control group. CONCLUSION: The large increase in the annual number of prenatal diagnoses performed due to a previous pregnancy with a de novo mutation reflects the growing understanding regarding the role of these mutations in the pathogenesis of genetic diseases.

Pediatric Idiopathic Intracranial Hypertension: Age, Gender, and Anthropometric Features at Diagnosis in a Large, Retrospective, Multisite Cohort.

PURPOSE: To examine anthropometric and maturational characteristics at diagnosis in pediatric idiopathic intracranial hypertension (IIH). DESIGN: Retrospective, international, multisite study. PARTICIPANTS: Pediatric patients (2-18 years of age at diagnosis) with IIH. MAIN OUTCOME MEASURES: Body mass index (BMI), height, and weight Z-scores; sexual maturation. METHODS: Cases of IIH were identified retrospectively based on diagnostic code, pediatric neuro-ophthalmologist databases, or both and updated diagnostic criteria (2013) were applied to confirm definite IIH. Anthropometric measurements were converted into age- and gender-specific height, weight, and BMI Z-scores CDC 2000 growth charts. When available, sexual maturation was noted. RESULTS: Two hundred thirty-three cases of definite IIH were identified across 8 sites. In boys, a moderate association between age and BMI Z-scores was noted (Pearson's correlation coefficient, 0.50; 95% confidence interval [CI], 0.30-0.66; P < 0.001; n = 72), and in girls, a weak association was noted (Pearson's correlation coefficient, 0.34; 95% CI, 0.20-0.47; P < 0.001; n = 161). The average patient was more likely to be overweight at diagnosis at age 6.7 years in girls and 8.7 years in boys, and obese at diagnosis at age 12.5 years in girls and 12.4 years in boys. Compared with age- and gender-matched reference values, early adolescent patients were taller for age (P = 0.002 in girls and P = 0.02 in boys). Data on Tanner staging, menarchal status, or both were available in 25% of cases (n = 57/233). Prepubertal participants (n = 12) had lower average BMI Z-scores (0.95±1.98) compared with pubertal participants (n = 45; 1.92±0.60), but this result did not reach statistical significance (P = 0.09). CONCLUSIONS: With updated diagnostic criteria and pediatric-specific assessments, the present study identifies 3 subgroups of pediatric IIH: a young group that is not overweight, an early adolescent group that is either overweight or obese, and a late adolescent group that is mostly obese. Data also suggest that the early adolescent group with IIH may be taller than age- and gender-matched reference values. Understanding these features of pediatric IIH may help to illuminate the complex pathogenesis of this condition.

Oxandrolone for the treatment of bone marrow failure in Fanconi anemia.

BACKGROUND: A majority of Fanconi anemia (FA) patients will experience bone marrow failure (BMF) and androgen therapy (most often oxymetholone) may be utilized as a treatment to improve BMF-related cytopenias. However, oxymetholone is associated with toxicities making identification of other agents of interest. In this study we aimed to evaluate the toxicity profile and hematologic response in patients with FA who are treated with low-dose oxandrolone, a synthetic non-fluorinated anabolic steroid, similar to oxymetholone, with known dosing thresholds for virilization. PROCEDURE: A single arm, Phase I/II study was designed to treat patients on low-dose oxandrolone. If no toxicity or hematologic response was noted at 16 weeks, a single dose escalation was offered. Subjects were regularly assessed for toxicity, including determinations of virilization, behavioral changes, and liver and kidney function. At 32 weeks, those who demonstrated hematologic response were allowed to continue study treatment, and those without improvement were deemed non-responsive. RESULTS: Nine subjects completed the study and were followed for a median of 99 weeks (46-136 weeks). Three (33.3%) subjects developed mild sub-clinical virilization and continued treatment with a dose reduction. None (0%) had adverse behavioral changes. Two (22.2%) developed elevated liver function tests at 42 and 105 weeks. Seven (77.8%) subjects had a hematologic response. CONCLUSION: Oxandrolone appears to be well-tolerated, has limited toxicities at the administered doses in FA with patients, and may be an alternative androgen for the treatment of BMF in FA.

Laparoscopic repair of a late-presenting Bochdalek diaphragmatic hernia with acute gastric volvulus.

An otherwise healthy 17-year-old boy presented to the paediatric emergency department with acute severe epigastric pain. An admission abdominal radiograph demonstrated gastric dilation, associated with an elevated left hemidiaphragm. Subsequent barium contrast imaging confirmed the diagnosis of organoaxial acute gastric volvulus (AGV). Emergent exploratory laparoscopy revealed AGV with migration of the stomach, spleen, pancreatic tail, splenic flexure, left kidney and adrenal through a left-sided Bochdalek diaphragmatic hernia. Following careful mobilisation of the displaced structures, a mesh closure of the diaphragmatic defect was performed. The patient's postoperative chest radiograph was unremarkable, and he was discharged on the sixth postoperative day after an uneventful recovery. At 2 months the patient was well and asymptomatic, with normal barium contrast imaging results.

[The use of aromatase inhibitors in children].

Aromatase inhibitors are compounds that block aromatase which converts androgens to estrogens. These compounds have been investigated for many years in a variety of conditions in which estrogen blockade is desired. During the past decade, a third generation of aromatase inhibitors has been developed with a much more potent blockade of the enzyme and less side effects. These new aromatase inhibitors are well absorbed after oral administration and, because of a long half life, are given once daily, thereby increasing compliance. The use of aromatase inhibitors is approved for the treatment of estrogen responsive breast cancer. Estrogens play a major role in bone maturation and growth plate fusion in both sexes. Therefore, inhibition of estrogen production may increase final height in a number of conditions where the final height is compromised. Due to their ability to block estrogen production, a number of clinical studies have been conducted to investigate their efficiency in a range of situations where estrogen blockade is desired. These include: peripheral precocious puberty secondary to congenital adrenal hyperplasia, familial male-dominant precocious puberty, and McCune-Albright syndrome, short stature in boys secondary to growth hormone deficiency, familial/genetic short stature, constitutional growth delay or idiopathic short stature. The use of aromatase inhibitors has been investigated also in pubertal gynecomastia. It is important to emphasize that this treatment, although it seems to be safe and encouraging, is still investigational and is not yet approved for routine usage.

Improved growth velocity during thyroid hormone therapy in children with Fanconi anemia and borderline thyroid function.

BACKGROUND: Children with Fanconi anemia (FA) tend to have short stature, mild thyrotropin (TSH) elevation, and borderline low free thyroxine (FT4). Objective was to examine whether thyroid hormone therapy improves linear growth in children with FA and borderline thyroid function tests PROCEDURE: Thyroid function tests were performed in 63 children with FA. Eight subjects participated in a random order, double-blind, cross-over treatment for 7 months with levothyroxine and for 7 months with placebo. Monitoring included growth measurements and laboratory assays at 1, 4 and 7 months of each phase. A 1 month lead in/wash out period was excluded from analysis of each treatment phase. RESULTS: The majority (63%) of FA children had borderline thyroid function tests. All eight FA subjects enrolled in the treatment study had FT4 in the lowest third of the normal range of 0.8-1.8 ng/dL (10.3-23.2 pmol/L) [FT4 0.9 +/- 0.1 ng/dL (mean +/- SD), range 0.8-1.2 ng/dL (10.3-15.4 pmol/L)]. TSH (optimal range 0.5-3 mU/L) was borderline elevated in six of eight subjects (4.0 +/- 1.5 mU/L, 1.9-7.3 mU/L). Growth velocity was slow at baseline and improved significantly during the thyroid phase compared to the placebo phase (2.1 +/- 1.2 cm/year vs. 5.4 +/- 1.7 cm/year, P < 0.05). CONCLUSIONS: Thyroid hormone therapy is safe and may improve linear growth velocity in children with FA who have borderline thyroid function. Subtle hypothyroidism has importance for growth in children. Whether thyroid hormone treatment improves adult height in these children remains to be elucidated.

Abnormalities in glucose tolerance are common in children with fanconi anemia and associated with impaired insulin secretion.

BACKGROUND: To determine prevalence of abnormal glucose metabolism in Fanconi Anemia (FA). PROCEDURE: Thirty-nine children with FA underwent 2-hr oral glucose tolerance test (OGTT). Reference lean adolescents (REF) were older than FA patients (mean +/- SD: FA 8.6 +/- 3.9 years, REF 19.8 +/- 0.3 years, P < 0.001), but comparable in BMI Z-scores (FA 1.25 +/- 0.58, REF -0.02 +/- 0.24; P = 0.24). Patients had normal glucose tolerance (NGT) or abnormal glucose metabolism (AGM) by American Diabetes Association Criteria. Insulinogenic index estimated beta-cell function. Insulin resistance estimation used homeostatic model assessment (HOMA-IR). Insulin secretion estimation relative to insulin sensitivity used disposition index (DI). RESULTS: Among FA patients, 46% had AGM. Compared to REF, there were significant differences in glycemic responses (area under curve: FA-NGT 344 +/- 42, FA-AGM 596 +/- 35, REF 208 +/- 25 mM, P < 0.0001) and insulinogenic index (FA-NGT 105 +/- 29, FA-AGM 44 +/- 8, and REF 173 +/- 41 pM/mM, P < 0.05). Insulin sensitivity did not differ among NGT, AGM, and REF (HOMA-IR: FA-NGT 1.9 +/- 0.4, FA-AGM 2.2 +/- 0.5, REF 1.3 +/- 0.2, P = NS). However, DI was significantly lower in both FA groups than REF [NGT 63.6 +/- 16.5 vs. AGM 26.4 +/- 3.5 (P < 0.048); REF 132.6 +/- 24.5 (NGT and AGM vs. REF, both P < 0.0002)]. CONCLUSION: Abnormalities in glucose metabolism are frequent in young FA patients without prior diagnosis of diabetes, and are associated with marked defects in insulin secretion.

Autocrine prolactin inhibits human uterine decidualization: a novel role for prolactin.

Human prolactin (PRL) and its receptor (PRLR) are markedly induced during human uterine decidualization, and large amounts of PRL are released by decidual cells as differentiation progresses. However, the role of PRL in decidualization is unknown. In order to determine whether PRL plays an autocrine role in decidualization, human uterine fibroblast cells that were decidualized in vitro with medroxyprogestrerone acetate (1 microM), estradiol (10 nM), and prostaglandin E(2) (1 microM) were exposed to exogenous PRL and/or the pure PRLR antagonist delta1-9-G129R-PRL. As measured by quantitative PCR, cells that were decidualized in the presence of exogenous PRL (0.25-2 microg/ml) expressed significantly lower levels of mRNA for the genes that encode insulin-like growth factor binding protein 1 (IGFBP1), left-right determination factor 2 (LEFTY2), PRL, decorin (DCN), and laminin alpha 1 (LAMA1), all of which are known to be induced during decidualization. These effects were blocked when the cells were exposed simultaneously to PRL and the PRLR antagonist, which confirms the specific inhibitory action of PRL on the expression of decidualization markers. In addition, cells exposed to the PRLR antagonist alone expressed higher levels of the marker gene mRNAs than cells that were decidualized in control media. Taken together, these results strongly suggest that PRL acts via an autocrine mechanism to regulate negatively the extent of differentiation (decidualization) of human uterine cells.

A case of macroprolactinoma and elevated insulin-like growth factor-I in a young boy.

UNLABELLED: We report a case of a 10-y-old boy who presented with persistent headache and was found to have a giant prolactinoma. Laboratory evaluation revealed markedly elevated prolactin (PRL) level, thyroid-stimulating hormone (TSH) deficiency, and elevated insulin-like growth factor-I (IGF-I). He had normal random growth hormone (GH) but non-suppressible GH during oral glucose tolerance test (OGTT). Cabergoline treatment was initiated and was well tolerated. Therapy successfully reduced PRL levels, normalized IGF-I levels, and reduced tumor size. CONCLUSION: Our patient presented with a GH-PRL-secreting tumor. Dopamine agonists are recommended as the treatment of choice for prolactinomas. However, there should be careful attention to GH status when treating GH-PRL-secreting tumor with dopamine agonists alone. IGF-I levels should be followed in all patients with prolactinoma, even in those with normal basal GH concentrations, because of the possibility of GH co-secretion.

Autoimmune thyroiditis during leuprolide acetate treatment.

Autoimmune thyroiditis developed in a 9-year-old girl with precocious puberty approximately 8 months after initiation of Leuprolide acetate therapy. In addition, gonadotropin concentrations as measured by radioimmunoassay appeared high. Treatment with levothyroxine, in addition to continued Leuprolide acetate treatment, resolved gonadotropin elevation and hypothyroidism.