Adrenal Insufficiency in Children With Eosinophilic Esophagitis Treated With Topical Corticosteroids.

OBJECTIVES: The aim of the study was to identify practices of gastroenterologists screening for adrenal insufficiency (AI) and report prevalence of AI in children with eosinophilic esophagitis (EoE) treated with topical corticosteroids (TCS); compare serum dehydroepiandrosterone sulfate (DHEA-S) levels to morning serum cortisol (MSC) levels as screening tool for AI. METHODS: A multipart study was conducted. In part 1, a survey about screening practices for AI in children with EoE on TCS was sent to gastroenterologists belonging to a PedsGI listserv and to EoE consortia. In part 2, children with EoE on TCS for ≥6 months were prospectively screened for AI with MSC levels. For subjects with a MSC level of <10 µg/dL, a repeat MSC level and/or confirmatory adrenocorticotropic hormone (ACTH) stimulation testing was offered. AI was defined by peak serum cortisol level <18 µg/dL. In part 3, DHEA-S levels were drawn with MSC levels. RESULTS: Seven percent (16/238) of gastroenterologists screened for AI. Providers in EoE consortia were more likely to screen than nonconsortia providers [9/21(43%) vs 7/217(3%); P = 0.0001]. Thirty-seven children were prospectively screened for AI, and 51% (19/37) had a low MSC level. Ten patients had a low-dose ACTH stimulation test (LDST) after 1 or more low MSC levels. Five percent (2/37) of patients were diagnosed with AI. DHEA-S and MSC levels had a moderate correlation (rs = 0.44, P = 0.03). CONCLUSIONS: Gastroenterologists belonging to EoE consortia were more likely to screen for AI. Prevalence of AI in our prospective cohort was 5%. DHEA-S has a moderate correlation with MSC levels, but more data is required to assess utility as a screening tool for AI.

Prevalence of Nephrocalcinosis in Pseudohypoparathyroidism: Is Screening Necessary?

The prevalence of nephrocalcinosis in persons with pseudohypoparathyroidism has not been systematically examined. We conducted a retrospective study of renal imaging and biochemical results in 19 patients with pseudohypoparathyroidism with 49 imaging assessments. No cases of nephrocalcinosis were identified. Routine screening for nephrocalcinosis in pseudohypoparathyroidism may not be necessary.

Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency.

Inactivating mutations in chromodomain helicase DNA binding protein 7 (CHD7) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2% of the IGD cohort (73% missense and 27% splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75% of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings (i) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, (ii) reiterate the emerging genetic complexity of this family of IGD disorders, and (iii) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems.

Characteristics of patients with classic congenital adrenal hyperplasia missed on the newborn screen.

BACKGROUND: Newborn screening for congenital adrenal hyperplasia (CAH) has been in place in the USA for over 20 years. However, not all patients with classic CAH are diagnosed as neonates. OBJECTIVES: Our aim was to characterize patients with classic CAH who were missed on the newborn screen (NBS) in Indiana and determine if discriminating features were present that might have led to earlier detection. METHODS: Medical records of children diagnosed with classic CAH due to 21-hydroxylase deficiency seen at Riley Hospital for Children in Indiana between January 2005 and December 2020 were reviewed. Patient characteristics, visit information and lab results were collected. Statistical analysis was performed using SPSS version 28. RESULTS: A total of 64 patients were identified of whom 12 (19%) were missed on the NBS. Mean age at diagnosis was 21.7 months (range: 2-74 months), 67% were girls and 66% were salt wasters. Eight (67%) presented with clinical evidence of hyperandrogenism, including clitoromegaly (n=7), posterior labial fusion (n=5) and pubic hair (n=2). Screening was pursued due to a family history of CAH in the remaining 4. Genetic confirmation was present in 50%. There was no history of antenatal steroid exposure in any of the missed patients. No differences were seen with regard to sex, ethnicity, gestational age, birth weight, type of CAH or serum 17-hydroxyprogesterone (17OHP) level at diagnosis in patients who were missed compared with those diagnosed on the NBS (14,948 ng/dL vs 16,701 ng/dL, p=0.74). However, the mean testosterone level at diagnosis was lower in patients who were missed compared with those who were diagnosed earlier (68 ± 60.28 vs 196.2 ± 206.0, p=0.02). Positive family history of CAH was present in 42% of the missed patients. Timing of the NBS collection was not different between the two groups, p=0.36. CONCLUSION: Nearly one-fifth of our patients with classic CAH were missed on the NBS. No specific features were identified that distinguished these children from those who were detected at birth. It is critical to maintain a high index of suspicion for CAH in order to recognize these patients as early as possible so as to avoid adverse effects and potential life-threatening adrenal crises.

Patient and Parent Perspectives on Testicular Adrenal Rest Tumors in Congenital Adrenal Hyperplasia.

BACKGROUND: Testicular adrenal rest tumors (TARTs) increase the risk of infertility in males with classic congenital adrenal hyperplasia (CAH). There is no consensus regarding at what age screening testicular ultrasounds should begin and how often they should be repeated. Furthermore, it is unknown whether patients and parents are aware of the significance of TARTs. OBJECTIVE: The objective of the study was to investigate awareness, concern, and screening rates for TARTs in males with classic CAH. METHODS: Males with CAH and parents completed an online questionnaire from 2019 to 2020. Responses to questions about TARTs were analyzed. Fisher's exact test was used to determine statistical significance. RESULTS: Of 123 responders, 14 were males with CAH (range 16-54 years) and 109 were parents of males with CAH (son's age range infancy to 37 years). Of all responders, 74% were concerned about the possibility of TARTs, 48% had discussions about TARTs with their endocrinologist, and 42% were aware of possible infertility in males with CAH. There was no difference between responses provided by affected males and parents for these topics (p ≥ 0.08). Among male responders with CAH, 93% had at least one testicular ultrasound, and 77% had undergone more than one. Among parent responders, 30% of their sons had at least one testicular ultrasound, and 61% had more than one. The frequency, total number, and age when the first testicular ultrasound was obtained were inconsistent in both groups. Fifty percent of male responders with CAH and 11% of sons were referred to a urologist for evaluation. CONCLUSIONS: Although most responders were concerned about TARTs, less than half recalled discussing this issue with their endocrinologist, and less than half were aware of the possibility of infertility. Although TARTs are most often treated medically, several responders were referred to a urologist. Standardized patient education and consensus guidelines are needed for the surveillance and management of TARTs in males with classic CAH.

Do All Patients with Congenital Adrenal Hyperplasia Need to Be on Hydrocortisone Three Times a Day in Order to Have Normal Growth?

BACKGROUND: Three times daily (TID) hydrocortisone (HC) is recommended as the optimal glucocorticoid regimen in growing children with congenital adrenal hyperplasia (CAH). However, a variety of other treatment schemes are used in the clinical setting. OBJECTIVE: The aim of this study was to determine whether there are clinical differences between children being treated with TID HC versus those receiving other glucocorticoid regimens. Furthermore, we sought to determine whether there was evidence of a deleterious effect on growth in children receiving treatment with alternate regimens. METHODS: Medical records of children followed in our pediatric endocrinology outpatient clinic for classic CAH secondary to 21-hydroxylase deficiency during the last 10 years were reviewed. Variables analyzed included sex, age at the most recent visit, glucocorticoid type, frequency and dose (mg/m2/day), height z-score, BMI z-score, ethnicity, most recent bone age, growth velocity z-score, and provider's impression of compliance (good or poor). RESULTS: Of 104 children (51% boys) with CAH, 50 (48%) were on TID HC, 43 (41%) were on prednisone or prednisolone, and 5 (5%) were on dexamethasone. An additional 6 (6%) were on HC administered either 2 or 4 times daily. No differences were seen between TID HC and alternate regimen groups with respect to sex, height z-score, BMI z-score, ethnicity, provider assessment of compliance, ratio of bone age to chronologic age, or growth velocity. The average height z-score was -0.40 ± 1.31 in the TID HC group compared to -0.87 ± 1.33 in the alternate regimen group (p = 0.075). Patients receiving TID HC were younger (p = 0.027) and on a lower glucocorticoid dose (p = 0.001) than those on alternate regimens. CONCLUSIONS: Less than half of our patients with CAH were receiving TID HC. Reassuringly, growth parameters and other indices of disease control were equivalent between patients on conventional HC dosing and other therapeutic approaches. These results suggest that a range of glucocorticoid treatment regimens may be equally viable in children with CAH.

Does clinical management impact height potential in children with severe acquired hypothyroidism?

BACKGROUND: Severe acquired hypothyroidism often results in significant height deficit due to rapid bone age advancement following treatment. Whether gradual correction of hypothyroidism and/or adjunctive growth-promoting therapies (GPTs) augment final adult height (FAH) is controversial. OBJECTIVE: To investigate time to euthyroidism, pace of bone age advancement (deltaBA/deltaCA), and impact of GPTs on FAH. METHODS AND PATIENTS: Retrospective review of 21 children (10.1 +/- 3.0 years) with profound hypothyroidism. RESULTS: Baseline bone age standard deviation score (SDS) was -4.1 +/- 1.8, whereas height SDS was -3.0 +/- 1.1. Average time to euthyroidism was 9.7 months (2.3-33.7 months). Average deltaBA/deltaCA was 2.3 +/- 0.9. Six of 13 patients at FAH received GPTs. No correlation was found between time to euthyroidism and rate of skeletal maturation. No difference in height outcome was seen between those who received GPTs and those who did not. CONCLUSIONS: Neither time to euthyroidism nor use of GPTs significantly affected height potential in our patients.

Unexpected finding of an intact distal vagina in an infant with mixed gonadal dysgenesis.

Mixed gonadal dysgenesis (MGD) is a form of sex chromosome disorder of sex development with large phenotypic variability. Patients with MGD typically have asymmetric and ambiguous genitalia with a combination of Müllerian and Wolffian duct derivatives. Prenatal androgen exposure results in variable degrees of phallic enlargement and a urogenital sinus. Here, we report an infant with ambiguous genitalia due to MGD. Despite marked evidence of prenatal androgen exposure, there was a completely intact distal vagina.

A brother and sister with the same karyotype: Case report of two siblings with partial 3p duplication and partial 9p deletion and sex reversal.

Two siblings with the same male unbalanced karyotype demonstrate sex reversal. The older sib appeared phenotypically female and the younger sib demonstrated a male gender. The female had gonadal dysgenesis with bilateral ovatestes. The male had bilateral testes. The report discusses the phenotypical differences and genes associated with sex reversal.

Newborn screening results in children with central hypothyroidism.

OBJECTIVE: To investigate newborn screening results in children with congenital hypopituitarism, including central hypothyroidism, and to determine whether there were differences between children who had abnormal results and children with normal newborn screening results. STUDY DESIGN: Medical records of children with central hypothyroidism observed in our pediatric endocrinology clinics from 1990 to 2006 were reviewed. RESULTS: Forty-two subjects (22 boys) were identified. Eight children (19%) had a low total thyroxine level (<5.0 mcg/dL) on the newborn screening test. The average total thyroxine level in the remaining 34 subjects was 9.8 +/- 3.4 mcg/dL. Thyrotropin levels were within the reference range in all children. No differences were found in the 2 groups for birth history, jaundice (53% overall), hypoglycemia (36% overall), or micropenis (43% of boys). Fifty-seven percent of children had septo-optic dysplasia, and 98% had multiple pituitary hormone deficiencies. Children with an abnormal newborn screening results were initially examined by a pediatric endocrinologist at an average age of 4.6 +/- 5.0 months, and children with normal newborn screening results were initially examined at an average age of 16.9 +/- 26.7 months (P = .037). CONCLUSIONS: Most children with congenital central hypothyroidism have normal thyroid function at birth. Normal newborn screening results can be falsely reassuring and may contribute to a delay in diagnosis of hypopituitarism despite classic clinical features.

Serendipitous identification of Graves' disease in identical twins with polydipsia.

Graves' disease in adolescents and adults usually presents with classic symptoms including weight loss, frequent stools, irritability, and heat intolerance. However, the clinical manifestations of hyperthyroidism in young children are often subtle, unrecognized, and atypical. Here, we report a 6 year-old girl who presented for evaluation of increased. thirst. Review of systems was negative with respect to weight loss, irritability, palpitations, diarrhea, and school performance problems. Physical exam was unremarkable except for an enlarged thyroid gland. Her identical twin sister, who incidentally accompanied her to clinic, also had a previously unidentified goiter. Testing for diabetes was negative. Further laboratory investigation was consistent with Graves' disease in both girls. Polydipsia is a rare and unusual presenting feature of hyperthyroidism in children. The evolution of this case highlights the importance of maintaining a high index of suspicion for thyroid disease during childhood.

Hyperactivation of p21ras and PI3K cooperate to alter murine and human neurofibromatosis type 1-haploinsufficient osteoclast functions.

Individuals with neurofibromatosis type 1 (NF1) have a high incidence of osteoporosis and osteopenia. However, understanding of the cellular and molecular basis of these sequelae is incomplete. Osteoclasts are specialized myeloid cells that are the principal bone-resorbing cells of the skeleton. We found that Nf1(+/-) mice contain elevated numbers of multinucleated osteoclasts. Both osteoclasts and osteoclast progenitors from Nf1(+/-) mice were hyperresponsive to limiting concentrations of M-CSF and receptor activator of NF-kappaB ligand (RANKL) levels. M-CSF-stimulated p21(ras)-GTP and Akt phosphorylation was elevated in Nf1(+/-) osteoclasts associated with gains of function in survival, proliferation, migration, adhesion, and lytic activity. These gains of function are associated with more severe bone loss following ovariectomy as compared with that in syngeneic WT mice. Intercrossing Nf1(+/-) mice and mice deficient in class 1(A) PI3K (p85alpha) restored elevated PI3K activity and Nf1(+/-) osteoclast functions to WT levels. Furthermore, in vitro-differentiated osteoclasts from NF1 patients also displayed elevated Ras/PI3K activity and increased lytic activity analogous to those in murine Nf1(+/-) osteoclasts. Collectively, our results identify a what we believe to be a novel cellular and biochemical NF1-haploinsufficient phenotype in osteoclasts that has potential implications for the pathogenesis of NF1 bone disease.

Unusual thyroid constellation in Down syndrome: congenital hypothyroidism, Graves' disease, and hemiagenesis in the same child.

We report a girl with Down syndrome who was diagnosed with congenital hypothyroidism in the newborn period due to left thyroid hemiagenesis. Unexpectedly, her hypothyroidism resolved at the age of 3 years. After being off thyroid hormone replacement for 7 years and having normal thyroid function, she developed Graves' disease. Although Graves' disease in association with thyroid hemiagenesis has previously been reported, this represents the youngest patient in whom this scenario has been described. Issues pertaining to thyroid hemiagenesis, autoimmune hyperthyroidism, and thyroid disease in children with Down's syndrome are discussed.

Development of pulmonary hypertension in an infant treated with diazoxide.

Diazoxide is commonly used in the treatment of neonatal hyperinsulinism. We describe a one month-old infant who was treated with diazoxide for prolonged neonatal hyperinsulinism. Shortly after starting diazoxide, she was admitted to the hospital for tachypnea with hypoxemia, and was subsequently diagnosed with laryngomalacia and obstructive apnea. During hospitalization, her clinical course worsened due to the development of severe pulmonary hypertension, presumed due to diazoxide toxicity. Lung biopsy revealed a probable toxic vascular drug reaction. After discontinuing diazoxide, her clinical status improved and eventually returned to baseline.

Pediatric toxic polycystic thyroid.

BACKGROUND: Polycystic thyroid disease (PCTD) is a rare condition and has been described in adults in the setting of subclinical and clinical hypothyroidism. We present the first known case of a pediatric patient with diffuse macrocystic degeneration of the thyroid. CLINICAL PRESENTATION: A 6-year-old previously healthy patient was evaluated after presenting with a 16-month history of an enlarging polycystic thyroid and hyperthyroidism. Markers of autoimmune thyroid disease including thyroid stimulating immunoglobulin (TSI), thyroid stimulating hormone (TSH) receptor antibody, thyroid peroxidase antibody and thyroglobulin antibody were negative. No family history of benign or malignant thyroid or cystic disease was present. The patient underwent a total thyroidectomy without perioperative complication. She remains euthyroid with thyroid hormone replacement therapy. SUMMARY: To our knowledge, this is the first report of PCTD in the pediatric population associated with hyperthyroidism without evidence of autoimmune disease. Somatic activating thyrotropin-receptor gene mutations are known to cause non-autoimmune hyperthyroidism in children, however it is unknown if similar mechanisms are responsible for pediatric PCTD. CONCLUSIONS: Polycystic thyroid degeneration can occur in children and may result in a hyperthyroid state.

Differential effects of hydrocortisone, prednisone, and dexamethasone on hormonal and pharmacokinetic profiles: a pilot study in children with congenital adrenal hyperplasia.

BACKGROUND: Little is known about the comparative effects of different glucocorticoids on the adrenal and growth hormone (GH) axes in children with congenital adrenal hyperplasia (CAH). We sought to compare the effects of hydrocortisone (HC), prednisone (PDN), and dexamethasone (DEX) in children with classic CAH and to investigate a potential role of pharmacogenetics. METHODS: Subjects were randomly assigned to three sequential 6-week courses of HC, PDN, and DEX, each followed by evaluation of adrenal hormones, IGF-1, GH, and body mass index (BMI). Single nucleotide polymorphism (SNP) analysis of genes in the glucocorticoid pathway was also performed. RESULTS: Nine prepubertal subjects aged 8.1 ± 2.3 years completed the study. Mean ACTH, androstenedione, and 17-hydroxyprogesterone (17-OHP) values were lower following the DEX arm of the study than after subjects received HC (p ≤ 0.016) or PDN (p ≤ 0.002). 17-OHP was also lower after HC than PDN (p < 0.001). There was no difference in IGF-1, GH, or change in BMI. SNP analysis revealed significant associations between hormone concentrations, pharmacokinetic parameters, and variants in several glucocorticoid pathway genes (ABCB1, NR3C1, IP013, GLCCI1). CONCLUSIONS: DEX resulted in marked adrenal suppression suggesting that its potency relative to hydrocortisone and prednisone was underestimated. SNPs conferred significant differences in responses between subjects. Although preliminary, these pilot data suggest that incorporating pharmacogenetics has the potential to eventually lead to targeted therapy in children with CAH.

Endocrine Effects of Inhaled Corticosteroids in Children.

Inhaled corticosteroids (ICSs) are widely used as first-line treatment for various chronic respiratory illnesses. Advances in devices and formulations have reduced their local adverse effects. However, as delivery of ICSs to the lungs improves, the systemic absorption increases, and an adverse effect profile similar to, although milder than, oral corticosteroids has emerged. The most serious potential adverse effect is adrenal insufficiency, which can be life threatening. Adrenal insufficiency occurs most in patients taking the highest doses of ICSs but is reported with moderate or even low doses as well. Our recommendations include greater vigilance in testing adrenal function than current standard practice. In patients with diabetes mellitus (types 1 and 2), an increase in glucose levels is likely, and diabetes medication adjustment may be needed when initiating or increasing ICSs. The risk of linear growth attenuation and adverse effects on bone mineral density is generally low but should be considered in the face of additional risk factors. On behalf of the Pediatric Endocrine Society Drugs and Therapeutics Committee, we present a review of the endocrine adverse effects of ICSs in children and offer recommendations relating to testing and referral. Limited data in particular realms diminish the strength of certain recommendations, and clinical judgment continues to be paramount.