Detailed Autopsies Performed on Two Females With Myhre Syndrome Elucidate Features of SMAD4 Gain-of-Function Pathophysiology

Abstract

Pathologic studies of Myhre syndrome (OMIM 139201) have provided modest insights into this ultra-rare multisystem disorder, with postmortem examinations being scarce. Morbidity is related to severe congenital heart defects, aortic hypoplasia, airway stenosis, constrictive pericarditis, and restrictive cardiomyopathy. We report two detailed autopsies: the first of an 8-year-old female who succumbed to congenital mitral valve disease and restrictive cardiopulmonary complications. Autopsy documented chronic pericarditis and fibrosing pleuritis, diffuse interstitial pulmonary fibrosis, extensive submucosal interstitial fibrosis of the bladder, and nodular medial hypertrophy of the aorta. The second patient was a 20-year-old female with progressive laryngo-tracheal stenosis, interstitial lung disease, pericardial and peritoneal adhesions, and dermal fibrosis. Both patients had ovarian fibrosis with reduced oocytes. Neuropathologic examination revealed brains below expected weight with hypoxic-ischemic injury. The first patient also had scattered intraparenchymal microcalcifications and a known Chiari I malformation, and the second had a thickened calvarium and dura mater and rounded cerebrum (shortened frontal and occipital lobes). These two patients demonstrate the value of postmortem examination to confirm suspected pathology and elucidate new features. The pleiotropy of Myhre syndrome was demonstrated by complex comorbidities and the devastating impact of indiscriminate fibrosis. Counseling regarding the role of postmortem examination should be considered in the palliative care of Myhre syndrome patients and their families.

Keywords: TGF‐β signaling; airway stenosis; fibrosis; interstitial lung disease; pericarditis; postmortem examination; restrictive cardiomyopathy.