CONGENITAL MYOPATHIES: NEMALINE AND TITINOPATHIES: P.239Congenital titinopathy: severe and atypical presentations

Abstract

Congenital titinopathy is a prenatal/infant-onset genetic muscle disorder caused by recessive TTN mutations. The true prevalence of of this disorder remains unknown, however the number of confirmed cases is climbing exponentially. We have identified four informative congenital titinopathy cases with convincingly pathogenic TTN mutations in trans. These cases extend our understanding of the spectrum of weakness and additional clinical features that can be associated with this emerging titinopathy. The first three cases are severely affected infants. All had a history of reduced fetal movements and were born at term with profound hypotonia and no respiratory effort. All required immediate resuscitation and intubation. One had congenital fractures, two had congenital quadrimelic joint contractures, two had atrial or ventricular septal cardiac defects, and two had intracerebral abnormalities likely secondary to birth trauma. Two died shortly after withdrawal of care on day one of life & three months of age respectively. The third remains reliant on full time ventilatory support (age 9 months). The fourth case is a 21-year-old female who was born with several congenital-titinopathy-like features including congenital contractures (camptodactyly, unilateral talipes), a cardiac abnormality (peripheral pulmonary stenosis), ptosis (congenital), and a high arched palate. However, this patient was not clinically weak at birth and has remained strong over time. She also has a range of striking additional features including Noonan-like facies, a low posterior hairline, neck webbing, short stature and bilateral axillary pterygia. She has no pathogenic-looking variants within established Noonan syndrome/syndrome-like genes. In view of the features present in these patients, we recommend that congenital titinopathy be considered in all weak infants with features suggestive of a primary muscle disorder and in patients with Noonan-like or multiple-pterygia-contracture phenotypes.