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.

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.

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.

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.

Spurious case of XX maleness in a patient with a history of Wiskott-Aldrich syndrome.

OBJECTIVE: To alert endocrinologists about the potential for karyotype confusion in patients who have undergone bone marrow transplantation. METHODS: Clinical, laboratory, and imaging data are reported on a young adult male patient who initially presented because of concerns about short stature. RESULTS: An 18-year-old fully virilized male patient with a history of Wiskott-Aldrich syndrome had undergone successful bone marrow transplantation in infancy. The donor was his older sister. Many years later, he underwent evaluation because of short stature and was found to have a 46, XX karyotype. This unexpected finding led to several costly laboratory and imaging studies, as well as a new diagnosis of a disorder of sex development. The patient was referred to our medical center for further evaluation of XX sex reversal. A skin biopsy was eventually performed, which revealed a 46, XY karyotype. This unusual case highlights the fact that a peripheral blood specimen from bone marrow transplant recipients reflects the genetic makeup of the bone marrow donor. CONCLUSION: Although the cytogenetic changes that occur in recipients of bone marrow transplants are well known to hematologists and oncologists, they are not commonly recognized by other health care providers. Increased awareness of this potential situation in long-term survivors of bone marrow transplantation is needed.

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.

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.

Neurofibromin-deficient Schwann cells have increased lysophosphatidic acid dependent survival and migration-implications for increased neurofibroma formation during pregnancy.

Neurofibromas are the clinical hallmark of neurofibromatosis Type 1 (NF1), a genetic disorder caused by mutations of the NF1 tumor suppressor gene, which encodes neurofibromin that functions as a GTPase activating protein (GAP) for Ras. During pregnancy, up to 50% of existing neurofibromas enlarge and as many as 60% of new neurofibromas appear for the first time. Lysophosphatidic acid (LPA) is a prototypic lysophospholipid that modulates cell migration and survival of Schwann cells (SCs) and is made in increasing concentrations throughout pregnancy. We addressed the influence of LPA on the biochemical and cellular functions of SCs with a homozygous mutation of the murine homologue of the NF1 gene (Nf1-/-). LPA promoted F-actin polymerization and increased migration and survival of Nf1-/- SCs as compared to wild type (WT) SCs. Furthermore, LPA induced a higher level of Ras-GTP and Akt phosphorylation in Nf1-/- SCs as compared to WT cells. Pharmacologic inhibition or siRNA for the p85beta regulatory subunit of Class I A PI3-K significantly reduced LPA-induced Schwann cell survival and migration. Introduction of NF1-GRD reconstitution was sufficient to normalize the LPA-mediated motility of Nf1-/- SCs. As LPA modulates excessive cell survival and motility of Nf1-/- SCs, which are the tumorigenic cells in NF1, targeting PI3-K may be a potential therapeutic approach in diminishing the development and progression of neurofibromas in pregnant women with NF1.

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.

Neurofibromin plays a critical role in modulating osteoblast differentiation of mesenchymal stem/progenitor cells.

Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1, a pandemic autosomal dominant genetic disorder with an incidence of 1:3000. Individuals with NF1 have a variety of malignant and non-malignant manifestations, including skeletal manifestations, such as osteoporosis, scoliosis and short statures. However, the mechanism(s) underlying the osseous manifestations in NF1 are poorly understood. In the present study, utilizing Nf1 haploinsufficient (+/-) mice, we demonstrate that Nf1+/- mesenchymal stem/progenitor cells (MSPC) have increased proliferation and colony forming unit-fibroblast (CFU-F) capacity compared with wild-type (WT) MSPC. Nf1+/- MSPC also have fewer senescent cells and have a significantly higher telomerase activity compared with WT MSPC. Nf1+/- MSPC have impaired osteoblast differentiation as determined by alkaline phosphatase staining, and confirmed by single CFU-F replating assays. The impaired osteoblast differentiation in Nf1+/- MSPC is consistent with the reduced expression of osteoblast markers at the mRNA level, including osteocalcin and osteonectin. Importantly, re-expression of the full-length NF1 GTPase activating related domain (NF1 GAP-related domain) is sufficient to restore the impaired osteoblast differentiation in Nf1+/- MSPC. Taken together, our results suggest that neurofibromin plays a crucial role in modulating MSPC differentiation into osteoblasts, and the defect in osteoblast differentiation may contribute at least in part to the osseous abnormalities seen in individuals with NF1.

Time course to hypothyroidism after fixed-dose radioablation therapy of Graves' disease in children.

OBJECTIVE: To characterize the development of hypothyroidism in pediatric patients who receive a fixed dose of radioactive iodine (RAI). STUDY DESIGN: Medical records of children treated with fixed-dose RAI for Graves'disease between 1993 and 2001 were reviewed. Multiple variables including sex, age, thyroid hormone levels, thyroid-stimulating immunoglobulin titer, antithyroid medication use, and 24-hour radioiodine uptake were investigated as possible predictive factors for the development of hypothyroidism after treatment. All patients received RAI at a dose of between 13.8 and 15.6 mCi (average, 14.7 mCi; SD, 0.5). RESULTS: Permanent hypothyroidism developed in all 40 patients, although a second dose of RAI was required in one case. The average time to hypothyroidism was 77 days (SD, 32), with a range of 28 to 194 days; 75% of the patients were diagnosed with hypothyroidism between 40 and 90 days. RAI treatment was ineffective in an additional patient, who required subtotal thyroidectomy. CONCLUSIONS: We conclude that a fixed dose of RAI is effective therapy in nearly all pediatric patients with Graves'disease. Factors predicting the time course to hypothyroidism were not identified.