Pseudotumor cerebri in patient on leuprolide acetate for central precocious puberty

Background Gonadotropin releasing hormone agonists (GnRHa) are well established as a standard of care for the treatment of central precocious puberty (CPP) worldwide. While numerous delivery systems and routes of administration exist, depot intramuscular injections or sustained-release preparations have been most widely used. Leuprolide acetate is well tolerated among children though some can develop some complications. Case presentation We present a case report of a 6.5 year old girl with central precocious puberty who developed signs of pseudotumor cerebri after 2 doses of leuprolide acetate 3.75 mg given monthly. Systemic exam and other tests to look for the cause did not yield anything. However, fundoscopy showed marked papilloedema with blurred disc margins. After six weeks’ treatment with acetazolamide and withdrawal of the GRNHa the papilloedema resolved. Conclusions If a patient presents with complaints such as headache, nausea, vomiting, and double vision in pediatric patients treated with GnRH analogue one should highly consider the presence of pseudotumor cerebri and fundus examination be performed.

Fanconi Bickel syndrome: clinical phenotypes and genetics in a cohort of Sudanese children

Background Fanconi-Bickel syndrome (FBS) is a rare condition of carbohydrate metabolism, caused by a recessive defect in the facilitative glucose transporter GLUT2 encoded by the SLC2A2 gene and characterized by a wide spectrum of phenotypical features. There is a paucity of reported data on FBS from Sub-Saharan Africa. Here, we describe the clinical, biochemical and genetic characteristics of our patients with FBS from Sudan, a country with a high consanguinity rate. Patients & methods Eleven patients from ten unrelated Sudanese families were included. Clinical & biochemical data were documented and imaging studies done including bone survey and abdominal ultrasound. Liver biopsy was done to confirm the pathological diagnosis in 45% of cases and molecular genetics was performed through contribution with the Exeter genomics laboratory for ten patients. Results Reported consanguinity was 70% among our patients. Growth was significantly impaired at presentation with mean weights of (-5.3 ± 1.8) SD and heights (-5.4 ± 2.5) SD. Severe chest deformity was present in (27%) and all patients showed features of rickets at presentation. Three patients had neonatal diabetes requiring insulin therapy of which one has been reported before. Six families lost undiagnosed siblings with similar clinical presentations. We identified a total of four homozygous pathogenic SLC2A2 variants in our patients, one of whom had a novel mutation. Conclusions FBS is not uncommon in Sudan where there is a high rate of consanguinity. Many cases are likely missed because of variable presentation and lack of public and professionals’ awareness. This is the first series to describe this condition from Sub-Saharan Africa.

Outcomes in children treated with growth hormone for Prader-Willi syndrome: data from the ANSWER Program® and NordiNet® International Outcome Study

Background Growth hormone (GH) deficiency is common in patients with Prader-Willi syndrome (PWS) and leads to short adult stature. The current study assessed clinical outcomes based on real-world observational data in pediatric patients with PWS who were treated with GH. Methods Data from patients previously naïve to treatment with GH who began therapy with somatropin were collected from 2006 to 2016 in the observational American Norditropin® Studies: Web-Enabled Research (ANSWER) Program® and NordiNet® International Outcome Study. Variables affecting change from baseline in height standard deviation scores (HSDS; n = 129) and body mass index standard deviation scores (BMI SDS; n = 98) were determined. Results Patients included in both HSDS and BMI SDS analyses were treated with a mean GH dose of 0.03 mg/kg/d (SD, 0.01 mg/kg/d). Results from the HSDS analysis revealed that baseline age and years on treatment had a significant impact on the change in HSDS. In the BMI SDS analysis, longer GH treatment time led to a greater change in BMI SDS from baseline, and patients with a higher BMI at the start of treatment had a greater decrease in BMI over time. Conclusions GH is effective in the management of children with PWS. Earlier treatment resulted in a greater gain in height, and a longer treatment period resulted in better outcomes for both height and BMI. Trial registration This study was registered with ClinicalTrials.gov (NCT01009905) on November 9, 2009.

Height outcomes in children with growth hormone deficiency and idiopathic short stature treated concomitantly with growth hormone and aromatase inhibitor therapy: data from the ANSWER program

Background Treatment of children with growth hormone deficiency (GHD) or idiopathic short stature (ISS) using GH is only effective for bone growth prior to epiphyseal fusion. Aromatase inhibitor therapy (AIT) blocks estrogen production, thereby delaying epiphyseal fusion. The current study analyzed baseline characteristics and longitudinal data of male patients with GHD or ISS who were treated with GH and concomitant AIT. Methods Data were obtained from the observational American Norditropin® Studies: Web-Enabled Research (ANSWER) Program, which collected efficacy and safety data of patients treated with Norditropin®. A longitudinal cohort approach compared patient characteristics, including chronologic age, bone age, and height standard deviation score (HSDS), in GH-treated males before and after AIT initiation. Results A total of 142 GH-naïve patients with GHD (n = 115) or ISS (n = 27) with mean (± SD) baseline chronological ages of 12.10 ± 3.00 and 10.76 ± 3.07 years, respectively, were analyzed. The majority were classified at advanced Tanner stages II to V. Patients with GHD had mean HSDS of − 1.97 ± 0.78 at baseline and − 0.99 ± 0.88 prior to AIT initiation, while corresponding values for patients with ISS were − 2.15 ± 0.72 and − 1.04 ± 0.79, respectively. In patients evaluated after 2 years of concomitant AIT, mean HSDS had decreased to − 0.40 ± 1.16 and − 0.65 ± 0.52 for patients with GHD and ISS, respectively. Patients with GHD had a mean bone age/chronological age ratio (BA/CA) of 0.91 ± 0.11 at baseline and 0.97 ± 0.10 prior to AIT initiation, while corresponding values for patients with ISS were 0.85 ± 0.16 and 0.99 ± 0.10, respectively. In patients evaluated after 2 years of concomitant AIT, mean BA/CA values were 0.95 ± 0.10 and 0.96 ± 0.06 for patients with GHD and ISS, respectively. Conclusions In this real-world analysis, use of AIT with GH in males appeared to be associated with ongoing growth over 2 years, and AIT likely augmented growth potential as indicated by continued HSDS increase with decreased BA/CA after AIT initiation. Trial registration This trial was sponsored by Novo Nordisk and is registered with ClinicalTrials.gov (NCT01009905). Registered November 11, 2009; retrospectively registered

Klinefelter syndrome and germ cell tumors: review of the literature

Objective The most common presentation of Klinefelter syndrome (KS) is infertility and features of hypogonadism. Currently no consensus exists on the risk of malignancy in this syndrome. Several case reports show an incidence of extragonadal germ cells tumors (eGCT) of 1.5 per 1000 KS patients (OR 50 against healthy population). Malignant germ cell tumors are rare in children. They account for 3% of all children cancers. Young patients with a germ cell tumor are not routinely tested for Klinefelter syndrome. This can therefore result in underdiagnosing. Literature data suggest a correlation between eGCT and KS. To the best of our knowledge there is no precise description of the primary locations of germ cell tumors in KS patients. The purpose of this study is to evaluate age groups and primary locations of extragonadal germ cell tumors in Klinefelter patients. With this data we investigate whether it is necessary to perform a cytogenetic analysis for KS in every eGCT patient. Study design This study is based on case report publications in PubMed/Medline published until march 2020 that described “Klinefelter Syndrome (MeSH) AND/OR extragonadal germ cell tumors”. Publications were included when patients age, location and histology of the germ cell tumor was known. Two double blinded reviewers selected the studies.Results: 141 KS patients with eGCTs were identified. Mean age at presentation was 17.3 years (StDev + − 10.2). In contrast to the extragonadal germ cell tumors in adults, most eGCT in children were mediastinal or in the central nervous system (respectively 90/141; 64% and 23/141; 16% of all tumors). Distribution of histologic subtypes showed that the largest fraction represented a teratoma, mixed-type-non-seminomateus GCT and germinoma, respectively 34/141; 24%, 26/141; 18% and 20/141; 14% of all tumors. Conclusion These data suggest a correlation between primary extragonadal germ cell tumors and Klinefelter syndrome. There appears to be an indication for screening on KS in young patients with an eGCT in the mediastinum. A low threshold for radiologic examinations should be considered to discover eGCT. We emphasize the need for genetic analysis in all cases of a male with a mediastinal germ cell tumor for the underdiagnosed Klinefelter syndrome.

Undervirilized male infant with in utero exposure to maternal use of high dose antifungal therapy

Background Antifungals act on fungal sterols structurally similar to human cholesterol. Ketoconazole reversibly suppresses steroidogenesis by inhibiting cytochrome P450 enzymes and interferes with dihydrotestosterone (DHT) activity by binding to the androgen receptor. Hypospadias was reported in infants exposed to nystatin in utero. Case presentation A male infant exposed to antepartum nystatin presented with severe under-undervirilization and transient adrenal corticosteroid abnormalities. He was born in USA at 31 weeks gestation to a mother treated with vaginal Polygynax capsules (nystatin-100,000 international units, neomycin sulphate-35,000 international units and polymyxin B-35,000 international units) for vaginal discharge in the Ivory Coast. She used approximately 60 capsules between the first trimester until delivery. The infant was born with micropenis, chordee, perineo-scrotal hypospadias and bifid scrotum with bilaterally palpable gonads. The karyotype was 46,XY. No Mullerian structures were seen on ultrasound. Serum 17-hydroxyprogesterone (17 OHP) on newborn screening was high (304 ng/ml, normal < 35). Cortisol response to cosyntropin on the 3rd day of life (DOL) was 10 mcg/ml; the subnormal cortisol response may have resulted from prematurity and the predelivery treatment with betamethasone. The elevation of several adrenal corticosteroids was not consistent with any specific enzymatic defect. Hydrocortisone and fludrocortisone were initiated at another hospital for suspected mild glucocorticoid and mineralocorticoid deficiencies. Genetic screening for adrenal and gonadal developmental defects performed when transferred to our care were normal. All medications were gradually discontinued over 5–8 months. Adrenal and testicular responses to cosyntropin and human chorionic gonadotropin (hCG) were normal at 8 months. Conclusions We report severe undervirilization in a 46,XY infant born to a mother treated with prolonged and high dose nystatin during pregnancy. This presentation suggests that prolonged antepartum use of high dose nystatin could lead to severe but transient defects in androgen synthesis and/or action possibly by acting as an endocrine disruptor. Further studies are warranted to confirm this finding. Thus, endocrine disruptors should be considered in male newborns with atypical genitalia not explained by common pathologies.