Current concepts in normal and abnormal puberty.
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Adrenal Hyperplasia, Congenital↗
Biomedical subjects
Todd D Nebesio
Publications and source records attributed to Todd D Nebesio.
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.
Animals↗
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.
Animals↗
Pubic hair of infancy: endocrinopathy or enigma?
Pubic hair of infancy is a rare condition that has not been well-characterized. A retrospective chart review of infants <12 months of age who presented to our pediatric endocrine clinics with isolated pubic hair over the last 5 years was performed. Eleven patients were identified (6 male and 5 female). The average age at diagnosis was 8.3 +/- 2.0 months. The majority of patients (73%) had pubic hair in an atypical location. Growth pattern, laboratory evaluation, and bone-age radiographs were unremarkable for all the infants. Of the infants that returned for follow-up, pubic hair resolved by the age of 11.0 +/- 1.5 months. From our experience and review of the literature, we suggest that isolated pubic hair of infancy is a benign entity. However, long-term follow-up needs to be done to determine if pubic hair of infancy is an atypical variant of premature adrenarche, which may place these patients at risk for later adult disease.
Diagnosis, Differential↗
Giant cell fibroblastoma masquerading as prepubertal gynecomastia.
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Child, Preschool↗
A 10-year-old girl with coexistent moyamoya disease and Graves' disease.
There are rare reports of young women with moyamoya disease associated with Graves' disease; we are unaware of any previous reports of this association in prepubescent girls. We report a 10-year-old girl who presented with multiple bilateral strokes. Cerebral angiography demonstrated moderate to severe stenosis of her bilateral distal internal carotid arteries and proximal anterior and middle cerebral arteries, which was greater on the right. Thyroid function tests demonstrated suppressed thyroid-stimulating hormone and elevated thyroid hormone levels. Serum antiphospholipid antibody screen demonstrated mild elevations of antiocardiolipin IgG. Possible mechanisms predisposing individuals to concurrent moyamoya and Graves' disease are discussed.
Child↗
Infant with classic congenital adrenal hyperplasia (CAH) born to a mother with classic CAH.
We report a female infant with classic congenital adrenal hyperplasia (CAH), secondary to 21-hydroxylase deficiency, who was born to a mother with salt-wasting CAH.
Adrenal Hyperplasia, Congenital↗
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.
Adolescent↗