Technetium-99m methoxy isobutyl isonitrile (99mTc-MIBI; sestamibi) single-photon emission computed tomography (SPECT)/computed tomography (CT) performed for preoperative localization of parathyroid adenomas or for other indications can reveal incidentalomas. Interpretation of such findings can be challenging, particularly when thyroid or other endocrine tumors are also present. Preoperative staging of a 59-year-old female patient with medullary thyroid carcinoma (MTC) showing moderate hypermetabolism on 18F-fluorodeoxyglucose positron emission tomography/CT also detected a slightly hypermetabolic pulmonary nodule (standardized uptake value normalized by body weight max = 2.0 g/mL). A sestamibi SPECT/CT performed because of concomitant primary hyperparathyroidism showed increased uptake by both the MTC and the pulmonary nodule, raising suspicion of MTC metastasis. Lung wedge resection biopsy revealed a sclerosing pneumocytoma (SPC), a rare benign pulmonary tumor not previously known to retain sestamibi. In contrast to classical knowledge that sestamibi uptake by tumors is associated with its retention by mitochondria, immunohistochemical analyses showed that the mitochondrial content of the patient's SPC was low. This case illustrates the behavior of SPC in sestamibi scintigraphy and indicates that SPC is a potential cancer mimicker in this setting.

Congenital hypogonadotropic hypogonadism (CHH) is a condition characterized by absent puberty and infertility due to gonadotropin releasing hormone (GnRH) deficiency, which is often associated with anosmia (Kallmann syndrome, KS). We identified loss-of-function heterozygous mutations in anti-Müllerian hormone (AMH) and its receptor, AMHR2, in 3% of CHH probands using whole-exome sequencing. We showed that during embryonic development, AMH is expressed in migratory GnRH neurons in both mouse and human fetuses and unconvered a novel function of AMH as a pro-motility factor for GnRH neurons. Pathohistological analysis of Amhr2-deficient mice showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in reduced fertility in adults. Our findings highlight a novel role for AMH in the development and function of GnRH neurons and indicate that AMH signaling insufficiency contributes to the pathogenesis of CHH in humans.

Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood.

In vertebrate species, fertility is controlled by gonadotropin-releasing hormone (GnRH) neurons. GnRH cells arise outside the central nervous system, in the developing olfactory pit, and migrate along olfactory/vomeronasal/terminal nerve axons into the forebrain during embryonic development. Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome are rare genetic disorders characterized by infertility, and they are associated with defects in GnRH neuron migration and/or altered GnRH secretion and signaling. Here, we documented the expression of the jagged-1/Notch signaling pathway in GnRH neurons and along the GnRH neuron migratory route both in zebrafish embryos and in human fetuses. Genetic knockdown of the zebrafish ortholog of JAG1 (jag1b) resulted in altered GnRH migration and olfactory axonal projections to the olfactory bulbs. Next-generation sequencing was performed in 467 CHH unrelated probands, leading to the identification of heterozygous rare variants in JAG1. Functional in vitro validation of JAG1 mutants revealed that 7 out of the 9 studied variants exhibited reduced protein levels and altered subcellular localization. Together our data provide compelling evidence that Jag1/Notch signaling plays a prominent role in the development of GnRH neurons, and we propose that JAG1 insufficiency may contribute to the pathogenesis of CHH in humans.