Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023)

Abstract

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.

Keywords: SMAD4 variants; TGF‐β signaling; autism; connective tissue disease; hearing loss; vasculopathy.

FIGURE 1

Post contrast CT aortic angiogram of a 21-year-old male with Myhre syndrome (pathogenic variant in SMAD4 p.Ile500Thr). 3D volume rendered images (a) anterior view, (b) posterior view demonstrate diffuse narrowing of the thoracoabdominal aorta with the narrowest point at the suprarenal level. (c) Sagittal reconstruction demonstrates proximal celiac artery narrowing. (d) Axial image demonstrates the narrowest point at the suprarenal level (6.8 mm) (white arrow).

FIGURE 2

MR angiogram of the aorta of 21-year-old female (pathogenic variant in SMAD4 p.Ile500Val) with Myhre syndrome and previous history of coarctation repair at the age of 9 months. (a) “candy cane” view and (b) posterior view of 3D volume rendered image of aorta showing diffuse narrowing of the thoracoabdominal aorta (allowing for motion artifacts) and evidence of coarctation repair (white arrow).

FIGURE 3

Eleven-year-old female. Images (a) and (b) are axial T2 weighted imaging of the brain at the level of the corona radiata. Numerous T2 hyperintense punctate foci are seen within the subcortical white matter of both cerebral hemispheres. Image (c) is a magnified axial T2 weighted images showing the same T2 hyperintense punctate foci in the subcortical cerebral white matter.

FIGURE 4

Eight-year-old female patient with images for MRA time-of-flight exam of the head. Images (a–d) caudal to cranial axial MRA images of the head demonstrate straightening of the posterior communicating arteries (image b), M1 segments of the middle cerebral arteries (image c), and straightening of the MCA branch vessels as well as an anomalous branching pattern of the MCA vessels (image d). Images (e–g) 3D maximal intensity projection (MIP) images of the MRA of the head highlight the straightening and anomalous branching pattern of the intracranial vessels.

FIGURE 5

The facial appearance of seven patients with Myhre syndrome at various ages (SMAD4 variants in parentheses): (Ile500Val) Patient A at 10 months, 5 years and 24 years; patient B at 14 months, 8 years, and 13 years; (Ile500Thr) Patients C at 1 months, 7 years, and 19 years, and Patient D at 2, 9, and 14 years; (Ile500Leu) Patient E at 3, 26, and 53 years; (Arg496Cys) Patient F at 9 months, 17 and 35 years; Patient G at 2, 6, and 8 years. All photos obtained with written consent of patient or parent.