Context Pathogenic germline MAX variants are associated with pheochromocytoma and paraganglioma (PPGL), pituitary neuroendocrine tumors and, possibly, other endocrine and non-endocrine tumors. Objective To report two families with germline MAX variants, pheochromocytomas (PC) and multiple other tumors. Design Clinical, genetic, immunohistochemical, and functional studies. Setting University Hospitals in Australia Participants Two families with germline MAX variants. Interventions Usual clinical care. Main Outcome measures Phenotyping; germline and tumor sequencing; immunohistochemistry of PC and other tumors; functional studies of MAX variants. Results Family A has multiple individuals with PC (including bilateral and metastatic disease) and two children (to date, without PC) with neuroendocrine tumors (paravertebral ganglioneuroma and abdominal neuroblastoma, respectively). One individual has acromegaly; immunohistochemistry of PC tissue showed positive GHRH staining. Another individual with previously resected PCs has pituitary enlargement and elevated IGF-1. A germline MAX variant (c.200C>A, p.Ala67Asp) was identified in all individuals with PC and both children, with loss-of-heterozygosity in PC tissue. Immunohistochemistry showed loss of MAX staining in PCs and other neural crest tumors. In vitro studies confirmed the variant as loss-of-function. In Family B, the proband has bilateral and metastatic PC, prolactin-producing pituitary tumor, multi-gland parathyroid adenomas, chondrosarcoma, and multifocal pulmonary adenocarcinomas. A truncating germline MAX variant (c.22G>T, p.Glu8*) was identified. Conclusions Germline MAX mutations are associated with PCs, ganglioneuromas, neuroblastomas, pituitary neuroendocrine tumors, and, possibly, parathyroid adenomas, as well as non-endocrine tumors of chondrosarcoma and lung adenocarcinoma, suggesting MAX is a novel multiple endocrine neoplasia gene.

We previously showed that CRH-mediated stimuli, including exogenous CRH, cause ACTH hypersecretion in many myotonic dystrophy (DM) patients. We confirmed this by giving naloxone, a stimulator of endogenous CRH release, to a large number of DM patients and controls. DM patients, first degree relatives, and normal controls received i.v. naloxone at 1400 h, and blood was taken for ACTH (RIA) and cortisol (high pressure liquid chromatography) measurements from 15 min before to 120 min after naloxone treatment. DM patients had basal ACTH levels approximately twice those of controls, and their ACTH responses were 4 times those of controls. In contrast, DM basal cortisol levels were not significantly different from those of relatives and were slightly higher than those of normal subjects. Cortisol responses were similar in the three groups, probably due to attenuation at high levels of adrenocortical stimulation, although some patients with inappropriately low cortisol responses for their level of ACTH stimulation warrant further investigation. Nineteen of the 36 patients whose ACTH responses were greater than 3 SD above the normal mean were classed as hyperresponders. Seven patients, who were tested more than once, had reproducible responses relative to those of the normal subjects. We conclude that ACTH hypersecretion after CRH-mediated stimuli, including naloxone, is an inherent, but variable, feature of DM, caused by expression of the genetic mutation at the anterior pituitary. The mechanism is probably a defect in the intracellular pathway initiated by CRH-receptor interaction as a result of abnormal levels of a cAMP-dependent kinase, DMPK, the product of the gene undergoing mutation in DM.

We conclude that in the diagnosis of central hypoadrenalism, ACTH [1-24] stimulation tests may give misleading results compared to the IHT. The use of low bolus doses of ACTH [1-24] (1.0, 0.5 or 0.1 microg) or a high dose prolonged infusion does not greatly improve the sensitivity of ACTH [1-24] testing. Dynamic tests that provide a central stimulus remain preferable in the assessment of patients with suspected ACTH deficiency.