To describe a case series of two siblings with compound heterozygous phenylalanine aminoacyl-tRNA synthetase A (FARSA) mutations presenting with growth restriction, severe gastric dysmotility, developmental delay, cystic subpleural interstitial lung disease (ILD), and diffuse cerebral white matter microcysts.

Aminoacyl-tRNA synthetases are ubiquitous and essential components of protein synthesis. These enzymes are responsible for ligating the proper aminoacid to tRNA for use in gene transcription and protein production.  Mutations have been discovered and associated with a multitude of pathogenic phenotypes involving multiple organ systems.   

N/A

The male sibling presented for evaluation after an early life complicated by frequent emesis and failure to thrive.  A gastric tube was placed at 10 months of age.  Finger clubbing at 2.5 years prompted chest imaging which revealed severe cystic interstitial lung disease.  The patient was microcephalic, hypotonic, and had global developmental delay.  MRI brain revealed diffuse microcysts in the subcortical white matter.  Dysmorphisms characterized by frontal bossing, posteriorly rotated ears, high arched palate, persistent fetal fingertip pads, prognathia, ptosis and cryptorchidism were present.  Whole exome sequencing revealed a compound heterozygous mutation of the FARSA gene (c.1040C>Tp.P347L and c.880_888delCAGCGGGTCp.Q294_V296del). 

The sister of the patient was also discovered to have the same FARSA gene mutations when screened as part of her brother’s evaluation.  She was small for gestational age and required a gastric tube early in life that was later able to be removed by age 3.  She had executive function cognitive deficits but was otherwise developmentally normal.  Chest imaging revealed subpleural cysts similar to the proband.

This case series describes novel FARSA mutations and a clinical phenotype that has not previously been described.  Both patients had cystic ILD, developmental delay, and early enteric motility issues with excessive vomiting and prolonged gastric tube requirement.  Additionally, the proband suffered from multiple congenital dysmorphisms and cystic subcortical brain disease.