Recurrent SMAD4 gain-of-function pathogenic variants cause brain and spine abnormalities in 40 patients followed in the MGH Myhre Syndrome Clinic

Myhre syndrome is a rare, distinctive syndrome caused by recurrent SMAD4 gain-of-function pathogenic variants. There are abnormalities of growth (short stature), appearance (distinctive face), hearing (hearing loss), airways (laryngo-tracheal stenosis, restrictive lung disease), the cardiovascular system (aorta hypoplasia, pericarditis, restrictive cardiomyopathy, congenital heart defects), skin (thick skin, abnormal scarring), skeleton (stiff joints, arthropathy), behavior and academic issues (learning/intellectual disabilities, ADHD, Autism Spectrum Disorder), and a fibroproliferative response. The SMAD4 missense variants are found at two sites with a total of 5 variants, mainly p.Ile500Val (rarely, involving p.Ile500Thr, p.Ile500Leu, or p.Ile500Met) and p.Arg496Cys. Because little is known about the central nervous system in Myhre syndrome, a systematic review was performed of brain, neck, and spine imaging by two radiologists and a team of clinical specialists in the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic. We wanted to determine whether the type and frequency of these abnormalities was sufficiently high to provide evidence for routine imaging, and whether they were consistent with SMAD4 dysregulation of the TGFß signaling pathway. Under the IRB protocol, “Natural History of Rare Chromosome and Mendelian Gene Syndromes”, #2015P001173 this analysis was performed on the 40 patients seen in the MGH multispecialty Myhre Syndrome Clinic (2015-2021). We studied CT and MRI/MRA imaging to determine the type and frequency of congenital and acquired features within the head, neck, and spine. We examined the brain MRI/MRA for intracranial findings, vascular abnormalities, topography, and morphology. Head and neck CTA was used to evaluate intracranial and extracranial vessel size, asymmetry, and variant branching patterns. Spine MRI examined the conus position, and looked for evidence of tethering and fibrofatty filar lesions. Aortic and thoracoabdominal CTA was performed in most patients in order to evaluate the aorta dimensions for hypoplasia, and provided additional insights about vertebral segmentation and spinal anatomy. Aortic CTA is offered to children above the age of 6 years unless there was severe aortic disease which necessitated detailed imaging at a younger age. Of the 40 patients, the age range was 3-51 years, with a median of 8 years and a mean of 11.4 years. In this cohort, 22 (55%) patients had SMAD4 variants at position p.Ile500Val, with 2 and 1 patients having a variant at position p.Ile500Thr and p.Ile500Leu, respectively; no patients had a variant at p.Ile500Met. 15 (38%) patients had a variant involving p.Arg496Cys. Imaging included 25/40 (63%) patients who had a brain MRI/MRA, 6/40 (15%) with a CT of the brain, 13/40 (33%) with a spine MRI, and 27/40 (68%) with CTA of the aorta. We noted brain abnormalities in 13/25 (52%) of patients with a brain MRI. They were reported to show white matter hyperintensities in 9/25 (36%) of imaged patients, and low-lying cerebellar tonsils in at least two. Surgery confirmed that one patient with “transitional” tethered cord had classic pathology, and in this patient, there was improved urinary incontinence and constipation after surgical detethering. The outcome in other patients is pending. Vascular abnormalities were seen in 4/40 (10%). Posterior globe flattening and protrusion of optic nerve heads was observed in 7/15 (47%) of patients. Inner ear anomalies were noted in at least two patients on brain MRI, and in an additional patient who had CTA of the brain. A thick calvarium was noted in at least two patients. Spine abnormalities included transitional tethered cord syndrome in 4/40 (10%) of all patients, representing 4/13 (31%) of those imaged. Transitional tethered cord is currently under consideration in a fifth patient. A fibrofatty filar lesion, low (or lower limit of normal) lying conus, and sacralization of L5 have been reported. Additional incidental skeletal abnormalities included platyspondyly, abnormal number of ribs and femoral enostoses. Myhre syndrome causes congenital anomalies of the central nervous system, and it is possible that some features are acquired after birth. While the frequency of brain imaging was 63%, the true frequency of these brain and spine abnormalities is unknown due to the lack of universal imaging. Ongoing radiographic analysis is needed. It is unclear whether white matter hyperintensities and optic nerve abnormalities are congenital anomalies reflecting abnormal development or acquired postnatally. Serial imaging is not available to determine if they progress into adulthood. As additional imaging is performed, we anticipate increased detection of the skeletal and cranial abnormalities, including tethered cord syndrome. How the gain-of-function SMAD4 pathogenic variants cause relatively minor developmental brain and spinal cord anomalies is unknown. It is possible that the white matter hyperintensities are related to small vessel microangiopathy (as in older people without Myhre syndrome).