Search

Introduction Disorders of sexual differentiation (DSD) are conditions of abnormal chromosomal development leading to atypical gonadal and anatomic sexual characteristics. We present the case of two siblings with 46, XX testicular DSD due to a mutation in the nuclear receptor subfamily 5 group A member 1 gene (NR5A1). While there is extensive literature about pathogenic variants of this gene, this is the first variant that has been shown to cause DSD in XX individuals, rather than XY. Case presentation This is the case of a sibling pair with male phenotype and history of hypospadias and hypogonadism in the setting of 46, XX karyotype. Sibling A presented with hypospadias at birth and hypergonadotropic hypogonadism in childhood, initially managed with testosterone. Testicular biopsy revealed bilateral germ cell aplasia with degeneration of seminiferous tubules. Sibling B presented at age 8 with precocious puberty. He had a history of hypospadias and cryptorchidism at birth. Gonadotropins and testosterone levels were prepubertal. Testicular biopsy showed only Sertoli cells. Their adrenal gland and thyroid function was normal, their bone age was advanced. FISH was negative for the SRY gene in both cases, no ovaries or mullerian structures found in pelvic imaging. DSD genetic panels were sent, resulting positive for the R92W variant in NR5A1. Neither of them have intellectual disability; however, sibling B has attention deficit and hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). Family history is remarkable for two uncles that have been unable to conceive. Their mother had oligomenorrhea and difficulty conceiving, typical presentation of a female carrier of this mutation. Discussion and conclusions The majority of DSD in individuals with a 46, XX karyotype are due to congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase deficiency, however, mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. NR5A1 is an essential transcription factor that regulates target genes crucial for normal reproductive physiology and endocrine function, controlling several steps of adrenal and gonadal development. While there is extensive literature about the phenotype caused by variants of NR5A1 in XY individuals, the recurrent heterozygous p.Arg92Trp NR5A1 variant R92W that our patients have, is the only one that has been shown to cause DSD in XX individuals, with variable degrees of testis development. It has previously been described, however, in women with primary ovarian insufficiency (POI). Morevariants of this gene will continue to arise, playing a pivotal role in reproductive endocrinology. Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Introduction Autosomal dominant hypophosphatemic rickets (ADHR) is a condition with variable phenotype in terms of age of presentation, severity, and possible resolution. ADHR is caused by mutations of FGF23, preventing its cleavage, producing high levels of FGF23, which leads to renal phosphate wasting. Studies in mice and adult humans, have shown a correlation between low iron levels and increased FGF23 levels. To our knowledge, three pediatric patients with ADHR resolved with iron supplementation have been reported in the literature. Clinical case We report on identical twins born at 28 weeks and 5 days by cesarean section due to premature rupture of membranes with complicated pregnancy due to twin-to-twin transfusion syndrome. Birth weights were 780 grams (2nd percentile) for twin A, 1,200 grams (50th percentile) for twin B. Hypophosphatemia was documented starting at 2 weeks of life and during the first 6 of months of life, with phosphorus levels between 2.9-3.9 mg/dL for twin A and between 2.4-5.1 mg/dL for twin B. During their NICU admission phosphorus had a positive relationship with the hemoglobin level, which was more severe on twin A. Both were treated with calcitriol and a low dose of phosphorus starting on their 2nd month of life. At 6 months of age, both had persistent hypophosphatemia, more prominently in twin A (2.7mg/dL) with high alkaline phosphatase (1,209 IU/L) and high FGF23 (343 RU/dL). At that time his hemoglobin was 9.8 g/dL and his hematocrit was 29.5%. Both were started on Polyvisol with iron. At 14 months of life phosphorus and calcium were within normal limits, therefore calcitriol and phosphate were discontinued. At 15 months of age their hemoglobin, hematocrit, iron level, and TIBC levels were normal for both twins. Phosphorus was 4.6 and 4.3 mg/dL, alkaline phosphatase reduced significantly to 819 and 413IU/L, and FGF23 normalized to 100 RU/dL and 32 RU/dL on twin A and B respectively. Upon physical examination at 15 months of age, twin A was at the 0.02% for length and weight/length at the 31%; twin B was at the 5% for length and weight/length at the 50%. Both twins had high arched palates. Twin A had craniosynostosis, left renal agenesis, bilateral epicanthal folds, overlapping 2nd toes, and clinodactyly of the fifth digits. Note the donor kid (twin A) had a more severe presentation. Genetic testing showed heterozygous mutation c536G>a (p.Arg179GLN) in the FGF23 gene. This is the same mutation previously reported to be related with ADHR resolved with iron supplementation Conclusion The study of patients with hypophosphatemia and hypophosphaturia should include evaluation of iron status (ferritin, TIBC). Treating iron deficiency on these patients might normalize phosphate levels. This would avoid cumbersome treatment with phosphate and calcitriol. Laboratory values Phosphorus:4-8 mg/dL Alkaline Phosphatase: 130-317 IU/L FGF23: 44-215 RU/dL

Background: Hyperinsulinism is the most common cause of persistent hypoglycemia. It results from different genetic defects, the most common being recessive and dominant mutations in the ABCC8/KCNJ11 genes. The majority of recessive mutations have a poor response to Diazoxide, while dominant mutations are highly variable in both clinical presentation and response to treatment. Prompt recognition and management is critical to avoid irreversible brain damage. Clinical case: A 38-week gestation male, born via emergent c-section due to decreased fetal movement, presented with neonatal hypoglycemia. Pregnancy was uncomplicated and mother had a normal OGTT. Patient had a history of suspected sepsis, seizures, pulmonary hypertension and respiratory distress requiring intubation. Blood glucose was undetectable at birth and required multiple dextrose 10% boluses. A critical sample with a glucose of 47 mg/dL showed an elevated insulin at 30.3 m IU/mL with undetectable ketone levels. Lactic acid, ammonia, cortisol, GH, plasma amino acids, acylcarnitine profile and uric organic acids where all normal for a hypoglycemic state. He required intravenous glucose infusion with GIR up to 17 mg/kg/min to maintain normoglycemia. A brain MRI at 11 days of life showed findings of white matter injury. Subsequent genetic testing identified a heterozygous c.4051G>A (p.Val1351Met) variant in ABCC8, classified as “of uncertain significance”. However, an entry in the ClinVar database (RCV000714711.1) exists from a research lab and was classified as likely pathogenic. Analysis of parental samples showed that the mother was heterozygous for the same genetic variant. She did not have a history of hypoglycemia. Patient was started on diazoxide (8 mg/kg/day) and chlorothiazide with resolution of hypoglycemia. At a follow up visit at 5 months of age, there was no history of hypoglycemia, and no need for adjustments of the diazoxide dose by weight (dose at that time of 7.4 mg/kg/day). Conclusion: The ABCC8 reported here is a dominant mutation causing hyperinsulinemic hypoglycemia responsive to diazoxide with a milder phenotype later in infancy. Longitudinal follow up of the case is warranted to understand the long term progress in patients with this particular mutation. Reference: Adam MP, Ardinger HH, Pagon RA, Wallace SE, et al. None. 1993. Familial hyperinsulinism.

Background: There is limited scientific literature regarding gender non-conforming (GNC) youth in pediatric practice. GNC patients of all ages have an increased risk for psychiatric co-morbidities and suicidal risk. An increasing number of GNC youth are seeking therapeutic options to develop physical characteristics to match their gender identity. The study aim is to describe the prevalence of psychiatric co-morbidities and sexual orientation among GNC pediatric patients in a clinic-based setting in Miami, Florida. A secondary aim is to compare the grade of dysphoria before and after therapeutic interventions among GNC youth. Methods: This is a retrospective chart review on records from 2014–2019 among transgender adolescents attending a pediatric endocrinology clinic in Miami. Data on demographics and clinical characteristics were obtained from electronic medical records. We performed descriptive statistical analysis using SPSS version and reported frequencies and percentages. Results: A total of 158 patients were included in this analysis. There were 107 (67.7%) affirmed males (female to male), 47 (29.7%) affirmed females (male to female), and 4 (2.5%) considered themselves non-binary. Median age at onset of gender dysphoria symptoms and beginning of social affirmation was earlier in affirmed females (7.21 and 12.36 years vs. 9.65 and 13.50 years). Among affirmed males, sexual orientation was self-reported as 38% straight, 47% bisexual, 12% homosexual and 1% asexual vs. among affirmed females, whose sexual orientation was reported as 54.3% straight, 37.1% bisexual and 8.6% homosexual. Prevalence of psychiatric co-morbidities in our study population was 78.5%. Depression was the most frequent diagnosis (66.5%), followed by anxiety (33.5%), attention deficit hyperactivity disorder (10.1%), bipolar disorder (1.9%), bulimia (1.3%), anorexia nervosa (0.6%) and post traumatic stress disorder (0.6%). Psychiatric co-morbidities were more common among affirmed males (84.1% vs. 66%). History of suicidal ideation was more common among affirmed males (70.1%) than affirmed females (49%). Self-injuring (cutting) was more common among affirmed males (56.1%) than in affirmed females (25.5%). Mean age at hormonal treatment onset was similar in both groups (15.75 years in affirmed males vs. 15.58 years in affirmed females). The degree of gender dysphoria before and after starting hormonal treatment, reported on a scale of 0 (no dysphoria) to 10 (highest possible dysphoria), declined for both genders (8.08/10 and 3.99/10) and affirmed females (7.87/10 and 2.96/10). Conclusion: The prevalence of psychiatric co-morbidities, suicidal ideation, and self-injuring behavior is high among GNC youth, but in this population, significantly worse among affirmed males. Both groups had significant improvement in the degree of dysphoria after beginning hormonal treatment.

Background Primary ovarian insufficiency (POI) is characterized by ovarian dysfunction resulting in premature cessation of menses. Excluding patients with gonadal dysgenesis, it is estimated that only 0.01% of adolescents will experience POI. After thorough evaluation, the underlying cause remains elusive in 85-90% of cases. Ovarian function in POI is variable, intermittent, and unpredictable. The lack of well-established criteria and low prevalence in adolescents make the diagnosis and management challenging. Methods Using diagnostic codes we identified all cases of ovarian insufficiency between 2012 and 2018 seen at a children’s hospital in South Florida. We reviewed all cases diagnosed with ovarian insufficiency and chose those meeting current adult diagnostic criteria for POI for further analysis. Patients with missing information, gonadal dysgenesis, eating disorders, gonadal surgeries and/or a history of oncological conditions, or exposure to gonado-toxic treatments, were excluded. We conducted chart reviews, and relevant clinical and diagnostic information was extracted. Results A total of 48 patients diagnosed with ovarian insufficiency were identified; only seven met inclusion criteria. Mean age of diagnosis was 15.5 and 15.2 years respectively for primary and secondary amenorrhea. Patients with POI were evaluated and treated by the pediatrician, endocrinologist, and/or adolescent medicine specialist. Anti-ovarian antibodies were evaluated in all cases, anti-thyroid antibodies in six of the patients, but only two patients were tested for the presence of anti-adrenal antibodies. Karyotype was obtained in all of them, while genetic evaluation of FMR1 gene was performed in two. Finally, only two patients received reproductive counseling or were referred to a fertility specialist. One of them was referred after she had a spontaneous pregnancy and voluntary interruption. Conclusions Anti-ovarian antibodies were always obtained despite their lack of clinical significance in POI. Anti-adrenal antibodies, which are a better diagnostic test, were not evaluated as often as expected. Genetic evaluation was mostly limited to karyotype. Evaluation for FMR-1 premutation may be helpful for the diagnosis and management of the patient, as well as other female relatives. Only two of the seven patients received reproductive counseling or were referred to reproductive medicine. This is a key part of the evaluation and management of POI, since an early and appropriate intervention may improve the chances of fertility preservation as well as promote reproductive health in the adolescent population. Better training in the evaluation and management of patients with POI is needed across pediatric providers that care for these patients.

Background: Hypercalcemia secondary to Vitamin D intoxication is rare; however, over the past years vitamin D supplementation has become frequent due to the changes on recommended levels proposed by some academies, and frequent evaluation of vitamin D25 levels in otherwise healthy children. Toxic levels of vitamin D have been defined by the Endocrine Society as ≥150 ng/mL and by the former Institute of Medicine as ≥100 ng/mL. Case reports: We present two cases of hypercalcemia due to vitamin D intoxication. A 4-year-old male with past medical history of vitiligo, presented to the emergency department after 2 days of emesis. His calcium level was 16.4 mg/dL (8.5-10.2 mg/dL), phosphorus 3.4 mg/dL (2.5 to 4.5 mg/dL), intact PTH

Introduction Peg-Asparaginase and Dexamethasone are both used in the induction therapy for pre-B Acute Lymphocytic Leukemia (ALL) and have overlapping adverse effects. Peg-Asparaginase is an enzyme that causes depletion of asparagine which is an essential amino acid for leukemia cells. Dexamethasone is a long-acting glucocorticoid with a 30-fold increase in anti-inflammatory activity relative to Hydrocortisone. Hyperglycemia and acute pancreatitis are both adverse reactions of Peg-asparaginase and glucocorticoids. Clinical case An 8-year-old male with obesity presented with acute pancreatitis and diabetic ketoacidosis (DKA) following induction therapy for pre-B ALL. The patient was euglycemic at the time of diagnosis. On day 1 induction chemotherapy was administered which included IV vincristine, IT cytarabine and PO dexamethasone (4 mg BID daily). On day 2, patient developed hyperglycemia (167 mg/dL). On day 4 he received IV Peg-Asparaginase (3,800 IU). On day 8 patient returned with back pain, fatigue, polydipsia, polyuria, and Kussmaul breathing. Labs revealed hyperglycemia (1,118 mg/dL), metabolic acidosis with an elevated anion gap (pH 7.14, pCO2 < 17 mmHg, HCO3 4.6 mmol/L, anion gap 36), elevated lipase (2,256 IU/L), mild transaminitis, and elevated creatinine and BUN. Pancreatic ultrasound was consistent with pancreatitis. The patient was admitted to the pediatric ICU for insulin drip and management of pancreatitis. On day 10 he was transitioned to SQ glargine insulin. Chemotherapy was restarted with dexamethasone and vincristine. Patient had persistent hyperglycemia requiring lispro insulin to cover meals and to correct hyperglycemia. His glucose normalized on this treatment and insulin was tapered down to be discontinued 9 days after initially started. His HbA1c was 7.5% (normal