Ocular findings in Jansen metaphyseal chondrodysplasia.

Jansen metaphyseal chondrodysplasia (JMC) is an ultra-rare disorder caused by germline heterozygous PTHR1 variants resulting in constitutive activation of parathyroid hormone type 1 receptor. A description of ocular manifestations of the disease is lacking. Six patients with JMC underwent a detailed ophthalmic evaluation, spectral-domain optical coherence tomography (OCT), visual field testing, and craniofacial CT scans. Five of 6 patients had good visual acuity. All patients had widely spaced eyes; 5/6 had downslanted palpebral fissures. One patient had proptosis, and another had bilateral ptosis. Two patients had incomplete closure of the eyelids (lagophthalmos), one had a history of progressive right facial nerve palsy with profuse epiphora, while the second had advanced optic nerve atrophy with corresponding retinal nerve fiber layer (RNFL) thinning on OCT and significant bilateral optic canal narrowing on CT scan. Additionally, this patient also had central visual field defects and abnormal color vision. A third patient had normal visual acuity, subtle temporal pallor of the optic nerve head, normal average RNFL, but decreased temporal RNFL and retinal ganglion cell layer analysis (GCA) on OCT. GCA was decreased in 4/6 patients indicating a subclinical optic nerve atrophic process. None of the patients had glaucoma or high myopia. These data represent the first comprehensive report of ophthalmic findings in JMC. Patients with JMC have significant eye findings associated with optic canal narrowing due to extensive skull base dysplastic bone overgrowth that appear to be more prevalent and pronounced with age. Progressive optic neuropathy from optic canal narrowing may be a feature of JMC, and OCT GCA can serve as a useful biomarker for progression in the setting of optic canal narrowing. We suggest that patients with JMC should undergo regular ophthalmic examination including color vision, OCT, visual field testing, orbital, and craniofacial imaging.

A Germline ZFX Missense Variant in a Patient With Primary Hyperparathyroidism.

A 51-year-old woman with a history of primary hyperparathyroidism (PHPT) with prior parathyroidectomy, osteoporosis, and learning disability was referred for hypercalcemia discovered after a fall. Family history was negative for PHPT, pituitary, enteropancreatic neuroendocrine, or jaw tumors. Dysmorphic facies, multiple cutaneous melanocytic nevi, café au lait macules, long fingers, and scoliosis were observed. Laboratory evaluation showed an elevated parathyroid hormone (PTH) level, hypercalcemia, and hypophosphatemia, all consistent with PHPT. Preoperative imaging revealed a right inferior candidate parathyroid lesion. The patient underwent right inferior parathyroidectomy with normalization of PTH, calcium, and phosphorus. Genetic testing showed a likely pathogenic de novo heterozygous germline missense variant p.R764W in the ZFX gene that encodes a zinc-finger transcription factor previously shown to harbor somatic missense variants in a subset of sporadic parathyroid tumors. Germline variants in ZFX have been reported in patients with an X-linked intellectual disability syndrome with an increased risk for congenital anomalies and PHPT. Further research may determine if genetic testing for ZFX could be of potential benefit for patients with PHPT and developmental anomalies, even in the absence of a family history of parathyroid disease.

Case Report: Nine-year-old with parathyroid adenoma within the piriform sinus.

We present the case of a 9-year-old girl who presented with symptomatic hypercalcemia from primary hyperparathyroidism (PHPT). Laboratory results revealed elevated serum calcium 12.1 mg/dl (ref: 9.1-10.4), elevated ionized calcium 6.8 (ref: 4.5-5.6) mg/dl, phosphorus 3.8 (ref: 3.3-5.1) mg/dl, 25-OH vitamin D 20.1 (30-100) ng/ml, and elevated intact PTH 70 (15-65) pg/ml, consistent with the diagnosis of PHPT. She had persistent hyperparathyroidism after bilateral neck exploration, left thyroid lobectomy, and transcervical thymectomy. Neither inferior gland was identified. No parathyroid tissue was seen on histology. Repeat preoperative imaging identified a 7-mm × 5-mm adenoma on 4DCT not seen on 99Tc-sestamibi parathyroid scan. The patient then underwent a successful redo parathyroidectomy with removal of a submucosal left parathyroid adenoma at the superior aspect of the thyroid cartilage in the piriform sinus. Her biochemical work-up remains consistent with surgical cure 6 months after surgery. Herein, we also review common locations for ectopic parathyroid adenomas. Clinical Trial Registration: NCT04969926.

Phenotypic Profiling and Molecular Mechanisms in Hyperparathyroidism-jaw Tumor Syndrome.

CONTEXT: Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is a heritable form of primary hyperparathyroidism caused by germline inactivating mutations in CDC73 encoding parafibromin and is associated with an increased risk of parathyroid cancer. There is little evidence to guide the management of patients with the disease. OBJECTIVE: (1) Characterize the natural history of HPT-JT, (2) correlate genotype and histology of parathyroid tumors with parafibromin immunostaining, (3) understand molecular changes downstream to CDC73 loss. DESIGN: Retrospective study of patients with HPT-JT syndrome (genetically confirmed or affected first-degree relatives). Independent review of uterine tumor from 2 patients and staining for parafibromin on parathyroid tumors from 19 patients (13 adenomas, 6 carcinomas) was performed. RNA-sequencing was performed in 21 parathyroid samples (8 HPT-JT-related adenomas, 6 HPT-JT-related carcinomas, and 7 sporadic carcinomas with wild-type CDC73). RESULTS: We identified 68 patients from 29 kindreds with HPT-JT with median age at last follow-up of 39 [interquartile range, 29-53] years. A total of 55/68 (81%) developed primary hyperparathyroidism; 17/55 (31%) had parathyroid carcinoma. Twelve of 32 (38%) females developed uterine tumors. Of the 11 patients who had surgical resection for uterine tumors, 12/24 (50%) tumors were rare mixed epithelial mesenchymal polypoid lesions. Four of 68 patients (6%) developed solid kidney tumors; 3/4 had a CDC73 variant at p.M1 residue. Parafibromin staining of parathyroid tumors did not correlate with tumor histology or genotype. RNA-sequencing showed a significant association of HPT-JT-related parathyroid tumors with transmembrane receptor protein tyrosine kinase signaling pathway, mesodermal commitment pathway, and cell-cell adhesion. CONCLUSIONS: Multiple, recurrent atypical adenomyomatous uterine polyps appear to be enriched in women with HPT-JT and appear characteristic of the disease. Patients with CDC73 variants at p.M1 residue appear predisposed to kidney tumors. CLINICAL TRIAL NUMBER: NCT04969926.

Blood-based Proteomic Signatures Associated With MEN1-related Duodenopancreatic Neuroendocrine Tumor Progression.

PURPOSE: Patients with multiple endocrine neoplasia type 1 (MEN1) are predisposed to develop duodenopancreatic neuroendocrine tumors (dpNETs), and metastatic dpNET is the primary cause of disease-related mortality. Presently, there is a paucity of prognostic factors that can reliably identify patients with MEN1-related dpNETS who are at high risk of distant metastasis. In the current study, we aimed to establish novel circulating molecular protein signatures associated with disease progression. EXPERIMENTAL DESIGN: Mass spectrometry-based proteomic profiling was conducted on plasmas procured through an international collaboration between MD Anderson Cancer Center, the National Institutes of Health, and the University Medical Center Utrecht from a cohort of 56 patients with MEN1 [14 with distant metastasis dpNETs (cases) and 42 with either indolent dpNETs or no dpNETs (controls)]. Findings were compared to proteomic profiles generated from serially collected plasmas from a mouse model of Men1-pancreatic neuroendocrine tumors (Men1fl/flPdx1-CreTg) and control mice (Men1fl/fl). RESULTS: A total of 187 proteins were found to be elevated in MEN1 patients with distant metastasis compared to controls, including 9 proteins previously associated with pancreatic cancer and other neuronal proteins. Analyses of mouse plasmas revealed 196 proteins enriched for transcriptional targets of oncogenic MYCN, YAP1, POU5F1, and SMAD that were associated with disease progression in Men1fl/flPdx1-CreTg mice. Cross-species intersection revealed 19 proteins positively associated with disease progression in both human patients and in Men1fl/flPdx1-CreTg mice. CONCLUSIONS: Our integrated analyses identified novel circulating protein markers associated with disease progression in MEN1-related dpNET.

Long-Term Outcomes of Parathyroid Autografts in Primary Hyperparathyroidism.

Context: Autologous implantation of parathyroid tissue is frequently utilized after parathyroidectomy in patients with heritable forms of primary hyperparathyroidism (PHPT). Data on long-term functional outcome of these grafts is sparse. Objective: To investigate long-term outcomes of parathyroid autografts. Methods: Retrospective study of patients with PHPT who underwent parathyroid autografts from 1991 to 2020. Results: We identified 115 patients with PHPT who underwent 135 parathyroid autografts. Median follow-up duration since graft was 10 (4-20) years. Of the 111 grafts with known functional outcome, 54 (49%) were fully functional, 13 (12%) partially functional, and 44 (40%) nonfunctional at last follow-up. Age at time of graft, thymectomy prior to autograft, graft type (delayed vs immediate), or duration of cryopreservation did not predict functional outcome. There were 45 (83%) post-graft PHPT recurrences among 54 fully functional grafts at a median duration of 8 (4-15) years after grafting. Surgery was performed in 42/45 recurrences, but cure was attained in 18/42 (43%) only. Twelve of 18 (67%) recurrences were graft-related while remaining 6 (33%) had a neck or mediastinal source. Median time to recurrence was 16 (11-25) years in neck or mediastinal source vs 7 (2-13) years in graft-related recurrences. Median parathyroid hormone (PTH) gradient was significantly higher at 23 (20-27) in graft-related recurrence vs 1.3 (1.2-2.5) in neck or mediastinal source (P = .03). Conclusions: Post-graft recurrence of PHPT occurs frequently within the first decade after graft and is challenging to localize. Time to recurrence after graft is significantly shorter and PTH gradient higher for graft-related recurrence. Clinical Trial Number: NCT04969926.

Germline- and Somatic-Inactivating FLCN Variants in Parathyroid Cancer and Atypical Parathyroid Tumors.

CONTEXT: Parathyroid cancer (PC) is a rare endocrine neoplasm with high mortality. While surgery is the treatment for patients with the disease, recurrence rates are high, and patients usually succumb to severe hypercalcemia. There is no effective systemic therapy for the disease. OBJECTIVE: To investigate for novel genes causing parathyroid cancer. METHODS: We analyzed the germline DNA of 17 patients with "sporadic" PC and 3 with atypical parathyroid tumors (APTs) who did not have germline CDC73 or MEN1 pathogenic variants. Sequencing of available tumor tissue from 14 patients with PC and 2 with APT was also performed (including 2 patients with no available germline DNA). In addition, sporadic parathyroid adenomas from 74 patients were analyzed for FLCN variants. RESULTS: We identified germline FLCN variants in 3 unrelated patients with PC. The 2 frameshift variants have been described in patients with Birt-Hogg-Dubé (BHD) syndrome, while the pathogenicity of the missense variant c.124G > C (p.G42R) has not been definitively established. Functional analysis of the missense variant showed a potential effect on posttranslational modification. All 3 patients with germline FLCN variants were noted to have renal cysts and 2 had lung cysts, features associated with BHD syndrome. Somatic FLCN variants were identified in tumors from 2 (1 APT) of 16 patients with PC/APT and in none of the 74 sporadic parathyroid adenomas. No second hits in FLCN were noted on sequencing; however, loss of heterozygosity at the locus was demonstrated in 2 of 3 patients with the identified germline FLCN variant. CONCLUSION: The finding of FLCN variants associated with PC may provide the foundation for the development of therapy for this malignancy.

Molecular and Clinical Spectrum of Primary Hyperparathyroidism.

Recent data suggest an increase in the overall incidence of parathyroid disorders, with primary hyperparathyroidism (PHPT) being the most prevalent parathyroid disorder. PHPT is associated with morbidities (fractures, kidney stones, chronic kidney disease) and increased risk of death. The symptoms of PHPT can be nonspecific, potentially delaying the diagnosis. Approximately 15% of patients with PHPT have an underlying heritable form of PHPT that may be associated with extraparathyroidal manifestations, requiring active surveillance for these manifestations as seen in multiple endocrine neoplasia type 1 and 2A. Genetic testing for heritable forms should be offered to patients with multiglandular disease, recurrent PHPT, young onset PHPT (age ≤40 years), and those with a family history of parathyroid tumors. However, the underlying genetic cause for the majority of patients with heritable forms of PHPT remains unknown. Distinction between sporadic and heritable forms of PHPT is useful in surgical planning for parathyroidectomy and has implications for the family. The genes currently known to be associated with heritable forms of PHPT account for approximately half of sporadic parathyroid tumors. But the genetic cause in approximately half of the sporadic parathyroid tumors remains unknown. Furthermore, there is no systemic therapy for parathyroid carcinoma, a rare but potentially fatal cause of PHPT. Improved understanding of the molecular characteristics of parathyroid tumors will allow us to identify biomarkers for diagnosis and novel targets for therapy.

Micronutrient Supplementation and Bone Health After Prophylactic Total Gastrectomy in Patients With CDH1 Variants.

INTRODUCTION: Patients with germline variants in CDH1 who undergo prophylactic total gastrectomy (TG) are at risk of altered nutrient and drug absorption due to modified gastrointestinal anatomy. Bone mineral density loss and micronutrient deficiencies have not been described previously in this patient population. METHODS: In this study we included 94 patients with germline CDH1 variants who underwent prophylactic TG between October 2017 and February 2022. We examined pre- and post-gastrectomy bone mineral density (BMD); serum biomarkers including calcium, phosphorus, alkaline phosphatase, and 25 (OH)-vitamin D; and postoperative adherence to calcium and multivitamin supplementation. RESULTS: Almost all patients (92/94, 98%) lost a substantial amount of weight post-TG, with an average weight loss of 26.5% at 12 months post-surgery. Serum biomarkers of mineral metabolism, namely calcium and phosphorus, did not change significantly after TG. However, average BMD was decreased in all patients at 12 months post-TG. Nonadherence to calcium supplementation was associated with a decrease in BMD. Nonadherence to multivitamin supplementation was associated with greater percent BMD loss in the femoral neck and total hip. CONCLUSIONS: Appropriate micronutrient supplementation and nutritional counseling pre- and postoperatively in patients undergoing prophylactic TG are important to mitigate the long-term effects of gastrectomy on bone health.

Occupational engagement, fatigue, and upper and lower extremity abilities in persons with melorheostosis.

INTRODUCTION: Melorheostosis is a rare bone disorder with limited literature that describes the effect of this disease on functional and motor abilities. As part of a natural history study, four outcome measures were administered to better understand the burden this disease has on a person's ability to engage in basic and instrumental activities of daily living. OBJECTIVE: To investigate the relationship between functional engagement, fatigue, and motor ability in patients with melorheostosis. DESIGN: Cross-sectional data gathered from a longitudinal natural history observational study. SETTING: Rehabilitation department within a single institution. PARTICIPANTS: Forty-seven adult volunteers with melorheostosis were enrolled. Two participants were removed for failure to meet diagnosis eligibility. Thirty patients had lower extremity (LE) osteosclerotic bone lesions, 14 had upper extremity (UE) lesions, and one had lesions in both UEs and LEs. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Activity Card Sort, Second Edition (ACS); Multi-Dimensional Fatigue Inventory; Lower Extremity Functional Scale; Upper Extremity Functional Index. RESULTS: On the ACS, high-demand leisure (HDL) activities were the least retained (p < .001). Of the activities rated most important, HDL activities were the most likely to have been given up (27%). General fatigue (µ = 11.8) and physical fatigue (µ = 11.0) were the two most limiting fatigue constructs. There were moderate negative correlations with HDL activities compared to physical fatigue (r = -0.524, p < .001) and reduced activity fatigue (r = -0.58, p = .001). LE lesions had a large effect on completing LE tasks (d = 0.95) and UE lesions had a medium effect on completing tasks involving the UE (d = 0.69). CONCLUSIONS: Patients with melorheostosis experience fatigue and low engagement in HDL activities. The results of this study underscore the importance of acknowledging activity domain, fatigue constructs, and lesion location to support and provide targeted evidence-based rehabilitative therapy. CLINICAL TRIAL REGISTRATION NUMBER: NCT02504879.

Invasive Testing for Preoperative Localization of Parathyroid Tumors.

Context: The identification of parathyroid tumor(s) in patients with persistent/recurrent primary hyperparathyroidism (PHPT) is critical for a successful reoperative surgery. If noninvasive studies (ultrasound, computed tomography, magnetic resonance imaging, sestamibi) fail to conclusively localize the tumor, invasive procedures (arteriography and selective venous sampling) are performed. Objective: To describe our experience with invasive studies for parathyroid tumor localization and provide follow-up data on selective arterial hypocalcemic stimulation with central venous sampling, a technique developed at our center. Methods: We identified patients who underwent preoperative invasive testing for localization of parathyroid tumor from 1991 to 2020. The result of each invasive localization study [arteriogram, hypocalcemic stimulation and selective venous sampling (SVS)] was categorized as true-positive, false-positive, and false-negative based on histology and biochemical outcome. Results: Ninety-four patients with 96 tumor occurrences underwent invasive testing for parathyroid tumor localization. Arteriogram, hypocalcemic stimulation, and SVS accurately localized the tumor in 47 of 94 (50%), 56 of 93 (60%), and 51 of 62 (82%) tumors, respectively. Hypocalcemic stimulation was more likely to correctly localize the tumor when arteriogram showed a blush [37 of 50 (74%) vs 19 of 43 (44%), P = .01]. When both arteriogram and hypocalcemic stimulation yielded concordant positive findings, SVS did not change management in the 18 cases in which all 3 were performed. Twelve patients remained with persistent PHPT; all had recurrent disease with multiple affected glands. Conclusion: Hypocalcemic stimulation is a useful adjunct in patients with PHPT who require invasive localization and can obviate the need for SVS. Clinical Trial number: NCT04969926.

Metastatic Grade 3 Neuroendocrine Tumor in Multiple Endocrine Neoplasia Type 1 Expressing Somatostatin Receptors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) may occur in 30% to 90% of patients with multiple endocrine neoplasia type 1 (MEN1). However, only 1% of GEP-NETs are grade 3 (G3). Given the rarity of these aggressive tumors, treatment of advanced G3 GEP-NETs in MEN1 is based on the treatment guidelines for sporadic GEP-NETs. We report a 43-year-old male with germline MEN1 followed at our institution, with clinical features including hyperparathyroidism, a nonfunctional pancreatic NET, and Zollinger-Ellison syndrome. On routine surveillance imaging at age 40, computed tomography/positron emission tomography imaging showed 2 arterially enhancing intraluminal masses on the medial aspect of the gastric wall. Anatomical imaging confirmed 2 enhancing masses within the pancreas and a rounded mass-like thickening along the lesser curvature of the stomach. The gastric mass was resected, and pathology reported a well-differentiated G3 NET with a Ki-67 >20%. The patient continued active surveillance. Eighteen months later cross-sectional imaging studies showed findings consistent with metastatic disease within the right hepatic lobe and bland embolization was done. On follow-up scans, including 68Ga-DOTATATE (68Ga-DOTA(0)-Tyr(3)-octreotate) imaging, interval increase in number and avidity of metastatic lesions were compatible with disease progression. Given a paucity of treatment recommendations for G3 tumors in MEN1, the patient was counseled based on standard NET treatment guidelines and recommended 177Lu-DOTATATE treatment. PRRT (peptide receptor radionuclide therapy) with 177Lu-DOTATATE (177Lu-tetraazacyclododecanetetraacetic acid-octreotide) is an important therapeutic modality for patients with somatostatin receptor-positive NETs. However, prospective studies are needed to understand the role of PRRT in G3 NETs.

Case of Recurrent Primary Hyperparathyroidism, Congenital Granular Cell Tumor, and Aggressive Colorectal Cancer.

We present the case of a 53-year-old African-American male with recurrent primary hyperparathyroidism (PHPT), multifocal benign granular cell tumor (GCT), and metastatic colon adenocarcinoma. PHPT was diagnosed on routine blood testing (ionized calcium, 1.66 [1.12-1.32] mmol/L; PTH 110 pg/mL, vitamin D-25-OH-D: 18 ng/mL; PTHrP: undetectable). Medical history was notable for 2 reoccurrences of PHPT with persistent disease after most recent parathyroidectomy. Lymph node (LN) dissection during this last surgery showed a 2-mm focus of poorly differentiated adenocarcinoma in 1/5 LNs. Additionally, the patient had a history of multifocal GCTs diagnosed at age 2 years. On examination, there were no Lisch nodules, axillary, or inguinal freckling, neurofibromas, or café-au-lait macules but a prominent abdominal wall nodule was noted. En bloc resection of a tumor in the tracheoesophageal groove, identified by sestamibi scan, and excision of 4.5-cm abdominal wall nodule showed both masses having histology consistent with GCT. Serum calcium and PTH did not decrease, indicating another unsuccessful surgery. Genetic testing was negative for germline variants in PHPT-associated genes, APC, or genes of RAS-MAPK signaling pathway. The LN finding of metastatic adenocarcinoma prompted an endoscopy and transbronchial biopsy leading to the diagnosis of widely metastatic colonic adenocarcinoma, eventually resulting in his death a year later. The source of the patient's persistent PHPT remained unidentified. This is the first case with coassociation of recurrent PHPT, multifocal GCT, and colon cancer. Whether the disparate tumors in this patient share common driver(s) remains unknown. Prospective surveillance of patients for similar associations may provide clues for a novel syndromic form of PHPT.

Excess 11-Oxygenated Androgens in Women With Severe Insulin Resistance Are Mediated by Adrenal Insulin Receptor Signaling.

CONTEXT: Syndromes of severe insulin resistance (SIR) include insulin receptoropathy, in which all signaling downstream of the insulin receptor is lost, and lipodystrophy, in which some signaling pathways are impaired and others preserved. Women with SIR commonly have ovarian hyperandrogenemia; adrenal-derived 11-oxygenated androgens, produced by CYP11B1, have not been studied. OBJECTIVE: We aimed to evaluate classic pathway androgens (androstenedione, testosterone) and 11-oxygenated androgens in women with SIR and hyperandrogenemia, and to elucidate the role of insulin receptor signaling for 11-oxygenated androgen production by comparing lipodystrophy and receptoropathy. METHODS: Steroid hormones were quantified using LC-MS/MS in a cross-sectional study of 18 women with hyperandrogenemia and SIR (11 lipodystrophy, 7 receptoropathy) and 23 controls. To assess ovarian vs adrenal origin, steroids were compared in receptoropathy patients with (Ovary+) vs without (Ovary-) ovarian function. RESULTS: Compared with controls, classic androgens were elevated in both lipodystrophy and receptoropathy, and 11-oxygenated androgens were increased in lipodystrophy (2.9-fold higher 11ß-hydroxyandrostenedione (11OHA4), 2.4-fold higher 11-ketoandrostenedione (11KA4), 3.6-fold higher 11-ketotestosterone (11KT); P < 0.01), but not receptoropathy. Product-to-precursor ratios for CYP11B1 conversion of androstenedione to 11OHA4 were similar in lipodystrophy and controls but decreased in receptoropathy (6.5-fold lower than control; P = 0.001). Classic androgens were elevated in Ovary + but not Ovary- patients. CONCLUSIONS: 11-Oxygenated androgens are elevated in lipodystrophy but not receptoropathy. In SIR, insulin receptor signaling is necessary for adrenal hyperandrogenemia but not ovarian hyperandrogenemia; excess classic androgens are derived from the ovaries. Insulin receptor signaling increases adrenal 19-carbon steroid production, which may have implications for more common disorders of mild IR.

Fibroblasts from Patients with Melorheostosis Promote Angiogenesis in Healthy Endothelial Cells through Secreted Factors.

Melorheostosis is a rare sclerosing bone disease with associated vascular abnormalities in skin and bone, which is caused by somatic mosaic single nucleotide variations in the MAP2K1 gene, which encodes MAPK/extracellular signal‒regulated kinase (ERK) kinase 1. However, disease pathogenesis is poorly understood. Using patient-derived cells, we found that affected skin fibroblasts carrying the single nucleotide variations have increased activation of ERK1/2, which results in increased expression and secretion of proangiogenic factors, including VEGF. VEGF secretion was strongly reduced in affected cells after treatment with MAPK/ERK kinase 1 inhibitor trametinib. Treatment of healthy endothelial cells on matrigel with conditioned medium from affected fibroblasts induces the adoption of a proangiogenic phenotype. Direct coculture of fibroblasts and endothelial cells further shows that both secreted factors and extracellular matrix are capable of inducing a proangiogenic phenotype in healthy endothelial cells. Blocking VEGF with bevacizumab reduces the proangiogenic effect of affected fibroblasts in both the matrigel and direct coculture angiogenesis models, indicating that elevated VEGF secretion is a key mediator of increased angiogenesis in melorheostosis tissue. In conclusion, this work identifies the role of several important molecular mediators in the pathogenesis of melorheostosis, including MAPK/ERK kinase 1, phosphorylated ERK1/2, and VEGF, all of which have clinically available pharmacologic inhibitors, which could be further explored as therapeutic targets.

Two distinct classes of thymic tumors in patients with MEN1 show LOH at the MEN1 locus.

Patients with the multiple endocrine neoplasia type 1 (MEN1) syndrome carry germline heterozygous loss-of-function mutations in the MEN1 gene which predisposes them to develop various endocrine and non-endocrine tumors. Over 90% of the tumors show loss of heterozygosity (LOH) at chromosome 11q13, the MEN1 locus, due to somatic loss of the wild-type MEN1 allele. Thymic neuroendocrine tumors (NETs) or thymic carcinoids are uncommon in MEN1 patients but are a major cause of mortality. LOH at the MEN1 locus has not been demonstrated in thymic tumors. The goal of this study was to investigate the molecular aspects of MEN1-associated thymic tumors including LOH at the MEN1 locus and RNA-sequencing (RNA-Seq) to identify genes associated with tumor development and potential targeted therapy. A retrospective chart review of 294 patients with MEN1 germline mutations identified 14 patients (4.8%) with thymic tumors (12 thymic NETs and 2 thymomas). LOH at the MEN1 locus was identified in 10 tumors including the 2 thymomas, demonstrating that somatic LOH at the MEN1 locus is also the mechanism for thymic tumor development. Unsupervised principal component analysis and hierarchical clustering of RNA-Seq data showed that thymic NETs formed a homogenous transcriptomic group separate from thymoma and normal thymus. KSR2 (kinase suppressor of Ras 2), that promotes Ras-mediated signaling, was abundantly expressed in thymic NETs, a potential therapeutic target. The molecular insights gained from our study about thymic tumors combined with similar data from other MEN1-associated tumors may lead to better surveillance and treatment of these rare tumors.

Cross-Sectional Imaging Useful in Melorheostosis.

Melorheostosis is a rare disease of bone overgrowth that is primarily diagnosed based on imaging studies. Recently, the association of different radiological patterns of the disease with distinct genetic cause was reported. Several case reports have described the radiological findings in patients with melorheostosis. However, the added value of cross-sectional imaging with CT and MRI beyond X-rays has not been investigated. The aim of the current study was to investigate this existing gap in knowledge. Forty patients with melorheostosis seen at the National Institute of Health Clinical Center were included in the study, and all their imaging studies were analyzed. The sequence of interpretation was X-ray followed by CT and then MRI. CT images were extracted from whole-body 18F-sodium fluoride positron emission tomography/CT studies. The information from CT reclassified the initial X-rays based radiological pattern in 13 patients. Additionally, CT comprehensively identified joint involvement and disease extent. In 76% of patients (n = 29) who underwent MRI, additional findings were noted, ranging from soft tissue edema to identification of soft tissue masses and incidental findings. MRI did not provide additional information on skeletal lesions beyond CT scans. However, it revealed the extension of soft tissue ossification into ischiofemoral space in four patients who complained of deep gluteal pain consistent with ischiofemoral impingement syndrome. In addition, MRI revealed soft tissue edema in 20 patients, 9 of whom had bone marrow edema and periosteal edema in the tibias consistent with shin splints. These findings suggest that select patients with melorheostosis should be evaluated with both CT and MRI, particularly patients in whom the distribution of pain does not correlate with the anatomic location of the disease in plain radiographs. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Cardiovascular Disease Risk Factors and Metabolic Morbidity in a Longitudinal Study of Congenital Adrenal Hyperplasia.

CONTEXT: Patients with congenital adrenal hyperplasia (CAH) are exposed to hyperandrogenism and supraphysiologic glucocorticoids, both of which can increase risk of metabolic morbidity. OBJECTIVE: Our aim was to evaluate cardiovascular and metabolic morbidity risk in a longitudinal study of patients with CAH spanning both childhood and adulthood. DESIGN AND SETTING: Patients with classic CAH followed for a minimum of 5 years during both childhood and adulthood (n = 57) at the National Institutes of Health were included and compared with the US general population using NHANES data. MAIN OUTCOME MEASURES: Obesity, hypertension, insulin resistance, fasting hyperglycemia, and dyslipidemia. RESULTS: Compared to the US population, patients with CAH had higher (P < 0.001) prevalence of obesity, hypertension, insulin resistance, fasting hyperglycemia, and low high-density lipoprotein (HDL) during childhood and obesity (P = 0.024), hypertension (P<0.001), and insulin resistance (P < 0.001) during adulthood. In our cohort, obesity, hypertension, fasting hyperglycemia, and hypertriglyceridemia began prior to age 10. During childhood, increased mineralocorticoid dose was associated with hypertension (P = 0.0015) and low HDL (P = 0.0021). During adulthood, suppressed androstenedione was associated with hypertension (P = 0.002), and high low-density lipoprotein (P = 0.0039) whereas suppressed testosterone (P = 0.003) was associated with insulin resistance. Elevated 17-hydroxyprogesterone, possibly reflecting poor disease control, was protective against high cholesterol (P = 0.0049) in children. Children whose mothers were obese (maternal obesity) had increased risk of obesity during adulthood (P = 0.0021). Obesity, in turn, contributed to the development of hypertension, insulin resistance, and hypertriglyceridemia in adulthood. CONCLUSION: Patients with CAH develop metabolic morbidity at a young age associated with treatment-related and familial factors. Judicious use of glucocorticoid and mineralocorticoid is warranted.

Nonclassic Congenital Adrenal Hyperplasia: What Do Endocrinologists Need to Know?

Congenital adrenal hyperplasia encompasses a group of autosomal recessive defects in cortisol biosynthesis, and 21-hydroxylase deficiency accounts for 95% of such cases. Non-classic 21-hydroxylase deficiency is due to partial enzymatic defects, which present with normal cortisol synthesis, but excessive production of adrenal androgens, including 11-oxygenated androgens. Non-classic 21-hydroxylase deficiency is relatively common, and its phenotype resembles closely that of polycystic ovary syndrome. This review focuses primarily on non-classic 21-hydroxylase deficiency, its clinical features, diagnosis, and management.

11-Oxygenated Androgens Useful in the Setting of Discrepant Conventional Biomarkers in 21-Hydroxylase Deficiency.

CONTEXT: Serum 17-hydroxyprogesterone (17OHP) and androstenedione (A4) are the conventional biomarkers used to assess disease control in patients with 21-hydroxylase deficiency (21OHD). However, discrepancy between the two is not uncommon, limiting interpretation. OBJECTIVE: To evaluate 11-oxyandrogens in discriminating good versus poor disease control in 21OHD in the setting of discrepant 17OHP and A4. METHODS: Retrospective analysis of 2738 laboratory assessments obtained as part of Natural History Study of congenital adrenal hyperplasia (CAH) at the National Institutes Health Clinical Center. Patients with discrepant 17OHP and A4 and available sera were selected. A 15-steroid mass-spectrometry panel was performed in sera from patients with 21OHD and age- and sex-matched controls. Patients were categorized in "good" or "poor" control based on clinical assessment (bone age advancement, signs and symptoms of precocious puberty, menstrual irregularity, hirsutism, or hypogonadotrophic hypogonadism). RESULTS: Discrepant 17OHP and A4 was found in 469 (17%) laboratory assessments. Of these, 403 (86%) had elevated 17OHP with A4 in reference range. Of 46 patients with available sera, 30 (65%) were in good control. Median fold elevation relative to controls was higher in patients with poor versus good control for 11-hydroxytestosterone (median [interquartile range], 2.82 [1.25-5.43] vs 0.91 [0.49- 2.07], P = .003), and 11-ketotestosterone (3.57 [2.11-7.41] vs 1.76 [1.24-4.00], P = .047). Fold elevation of 11-hydroxytestosterone between 3.48 (sensitivity 97%, specificity 47%) and 3.88 (sensitivity 100%, specificity 40%) provided the best discrimination between poor vs good control. CONCLUSION: 11-Oxyandrogens, especially 11-hydroxytestosterone, may be useful in the management of CAH when conventional biomarkers are inconclusive.