A. FD/MAS: Growth hormone (GH) excess in MAS is associated with craniofacial morbidity. We conducted a retrospective cross-sectional analysis of the cohort of subjects with GH excess and MAS seen at the NIH to determine if early diagnosis and treatment of MAS-associated GH excess prevents optic neuropathy and hearing impairment. Twenty-two subjects with MAS-associated GH excess and 21 control MAS subjects without GH excess were included in the study. Biochemical testing included random GH, nadir GH after glucose load, nadir GH on frequent sampling, and IGF-I Z-score. Subjects underwent imaging, ophthalmological, audiological, and otolaryngological assessment. The association of optic neuropathy and hearing impairment to age at GH excess diagnosis and treatment was measured. Treated subjects received octreotide, pegvisomant, transphenoidal surgery, and/or radiotherapy as indicated. Of 129 subjects with MAS, 26 (20%) were diagnosed with GH excess based on elevation of two measures of GH function. Of these, 22 subjects were candidates for pharmacological intervention. Optic neuropathy was significantly correlated with intervention status. No cases were seen in the early intervention group, (treated before age 18), or the control group. Four of seven (57%) of the subjects in the late intervention group (treated after age 18) experienced optic neuropathy. Comparison by Fisher's exact test demonstrated a protective effect of early treatment (odds ratio of 0.027, p = 0.0058). Early diagnosis and intervention was not associated with reduction in hearing deficits (odds ratio, 1.25;p = 1.00). The mean head circumference SD-score was significantly higher in the late treatment group (6.08;range, 2.70 to 22.56) than the early intervention group (2.67;range, -0.65 to 6.72) or control groups (2.13;range, -2.06 to 7.79) (p = 0.003). This study demonstrated that early diagnosis and treatment of GH excess in MAS can prevent optic neuropathy and craniofacial expansion. The sinonasal structures are commonly involved with FD. The natural history and treatment of sinonasal disease is poorly defined. We conducted a study to characterize the spectrum, symptoms, progression, and effects of endocrine dysfunction on sinonasal disease in FD/MAS. To accomplish this a retrospective review of records and imaging studies of the cohort of subjects with FD/MAS seen at the NIH was performed. Subjects underwent a comprehensive evaluation that included otolaryngologic and endocrine evaluation, and imaging studies. Head and facial computed tomography scans were analyzed, and the degree of fibrous dysplasia (FD) was graded using a modified Lund-MacKay scale. Those followed for >4 years were analyzed for progression. A total of 106 patients meeting inclusion criteria were identified with craniofacial FD. A majority (92%) demonstrated sinonasal involvement. There were significant positive correlations between the sinonasal FD scale score and chronic congestion, hyposmia, growth hormone excess, and hyperthyroidism (P <.05 for all). Significant correlations were not found for headache/facial pain or recurrent/chronic sinusitis. Thirty-one subjects met the criteria for longitudinal analysis (follow-up mean, 6.3 years;range, 4.4-9 years). Those who demonstrated disease progression were significantly younger than those who did not (mean age, 11 vs. 25 years). Progression after age of 13 years was uncommon (n = 3) and minimal. Concomitant endocrinopathy or bisphosphonate use did not have any significant effect on progression of disease. In conclusion, sinonasal involvement of fibrous dysplasia in PFD/MAS is common. However, symptoms are usually few and mild, and disease progression occurs primarily in young subjects. Concomitant endocrinopathy is associated with disease severity, but not progression. B. FGF23: TIO is a rare disorder of phosphate wasting due to FGF23-secreting tumors that are often difficult to locate. We present a systematic approach to tumor localization and postoperative biochemical changes in 31 subjects with TIO. All had failed either initial localization, or relocalization (in case of recurrence or metastases) at outside institutions. Functional imaging with Indium-octreotide with single photon emission computed tomography (octreo-SPECT or SPECT/CT), and ⁸fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) were performed, followed by anatomic imaging (CT, MRI). Selective venous sampling (VS) was performed when multiple suspicious lesions were identified or high surgical risk was a concern. Tumors were localized in 20 of 31 subjects (64.5%). Nineteen of 20 subjects underwent octreo-SPECT imaging, and 16 of 20 FDG-PET/CT imaging. Eighteen of 19 (95%) were positive on octreo-SPECT, and 14 of 16 (88%) on FDG-PET/CT. Twelve of 20 subjects underwent VS;10 of 12 (83%) were positive. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were as follows: sensitivity = 0.95, specificity = 0.64, PPV = 0.82, and NPV = 0.88 for octreo-SPECT;sensitivity = 0.88, specificity = 0.36, PPV = 0.62, and NPV = 0.50 for FDG-PET/CT. Fifteen subjects had their tumor resected at our institution, and were disease-free at last follow-up. Serum phosphorus returned to normal in all subjects within 1 to 5 days. In 10 subjects who were followed for at least 7 days postoperatively, intact FGF23 (iFGF23) decreased to near undetectable within hours and returned to the normal range within 5 days. C-terminal FGF23 (cFGF23) decreased immediately but remained elevated, yielding a markedly elevated cFGF23/iFGF23 ratio. Serum 1,25-dihydroxyvitamin D₃(1,25D) rose and exceeded the normal range. In this systematic approach to tumor localization in TIO, octreo-SPECT was more sensitive and specific, but in many cases FDG-PET/CT was complementary. VS can discriminate between multiple suspicious lesions and increase certainty prior to surgery. Sustained elevations in cFGF23 and 1,25D were observed, suggesting novel regulation of FGF23 processing and 1,25D generation. C. Hypoparathyroidism: Nephrocalcinosis is a complication of hypoparathyroidism associated with significant morbidity. The two primary imaging modalities for the detection of nephrocalcinosis include ultrasonography (US) and computed tomography (CT). Few studies have compared these modalities. The objective of the study was to determine the superior method for assessing nephrocalcinosis. A retrospective, blinded analysis design was employed. Twenty-two hypoparathyroid subjects and 7 controls were studied. Contemporaneous renal US and CT images were reviewed in triplicate by 4 blinded radiologists. Nephrocalcinosis was classified using a 0-3 scale (0 = no nephrocalcinosis, 3 = severe nephrocalcinosis). Intraobserver agreement was high, with an overall weighted kappa of 0.83 for CT and 0.89 for US. Interobserver agreement was similar between modalities, with kappas of 0.74 for US and 0.70 for CT. Only moderate agreement was found between US and CT scores, with an intermodality kappa of 0.47 and 60% concordance. Of discordant pairs, 81% had higher US scores and 19% had higher CT scores. Of nephrocalcinosis seen on US and not CT, 45%, 46%, and 9% were grades 1, 2, and 3, respectively. Overall, US scores were higher than CT with a cumulative odds ratio (95% confidence interval) of 5.97 (2.60, 13.75) (P <.01). In controls, 100% of US ratings were 0, and 95% of CT ratings were 0. In conclusion, US is superior to CT for assessment of mild to moderate nephrocalcinosis in patients with hypoparathyroidism. This finding, in combination with its low cost, lack of radiation, and portability, defines US as the preferred modality for assessment of nephrocalcinosis.
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