Rajab Interstitial Lung Disease With Brain Calcifications

A number sign (#) is used with this entry because of evidence that Rajab interstitial lung disease with brain calcifications (RILCBC) is caused by homozygous or compound heterozygous mutation in the FARSB gene (609690) on chromosome 2q36.

Description

Rajab interstitial lung disease with brain calcifications (RILCBC) is an autosomal recessive multisystem disorder with a highly variable phenotype. Most patients present in infancy or early childhood with poor growth and interstitial lung disease, which may lead to death. Some may also have liver, skeletal, and renal abnormalities, and most have intracranial calcifications on brain imaging. Some may have early impaired motor development, but most have normal cognitive development (summary by Xu et al., 2018).

Clinical Features

Rajab et al. (2009) described 2 interrelated Omani families in which 8 children had brain calcifications of basal ganglia and cortex, mild developmental delay, poor school performance, microcephaly, growth delay, and osteopenia. The widespread brain calcifications were similar to those in Aicardi-Goutieres syndrome (225750) and Coats plus syndrome (612199). Rajab et al. (2009) suggested that the disorder in the Omani families represents a new variant or possibly a new disorder of inherited brain calcification. Zadjali et al. (2018) reported follow-up of the family reported by Rajab et al. (2009), noting that 3 patients had died of pulmonary disease, but the remaining patients were able to complete school and live independently.

Antonellis et al. (2018) reported a boy, born of unrelated parents, with a complex multisystem neurodevelopmental disorder resulting in death at age 32 months. The pregnancy was complicated by oligohydramnios, and the infant showed intrauterine growth retardation. He presented at age 5 months with failure to thrive, developmental delay, inguinal hernia, tachypnea, and chronic cough. He had sunken eyes, prominent cheeks, high-arched palate, hypotonia, joint hyperlaxity, and small scrotum and phallus. Detailed workup identified multiple systemic problems, including hypocalcemia, vitamin A and D deficiency, liver disease with hypoalbuminemia, anasarca, ascites, abnormal liver enzymes, coagulation defects, episodic DVT, osteopenia with rickets, recurrent infections, hypoglycemia, seizures, and chronic interstitial lung disease with pulmonary hypertension and respiratory insufficiency. He also had gastroesophageal reflux disease, anemia, pancytopenia, and increased renal echogenicity, possibly suggesting renal disease. Liver imaging and biopsy showed hepatic steatosis, cirrhosis, bile duct proliferation, cholestasis, and portal hypertension. Brain imaging showed abnormal periventricular white matter, basal ganglia echogenicity, cerebral volume loss, and incomplete closure of the Sylvian fissures, but myelination was normal. The patient showed abnormal eye movements and dysconjugate gaze. Antonellis et al. (2018) noted the phenotypic overlap with patients with mutations in other aminoacyl-tRNA synthetase genes, including AARS (601065), LARS (151350), and MARS (156560).

Xu et al. (2018) reported 5 patients from 4 unrelated families with a similar phenotype comprising early-onset severe interstitial lung disease, hypotonia, and failure to thrive. Lung disease included emphysematous changes, fibrosis, and accumulation of cholesterol granulomas in the alveoli and interstitium. One patient underwent lung transplantation at 8 years of age. Additional features included intracranial calcifications, leukoencephalopathy (1 patient), intracranial aneurysms (2 sibs), hepatic cirrhosis or dysfunction of the liver, intestinal malrotation (2 patients), hypertension, and variable renal abnormalities, including renal artery stenosis, proteinuria, focal segmental glomerulosclerosis, and vesicoureteral reflux. Some patients had nonspecific dysmorphic features, such as frontal bossing, deep-set eyes, full cheeks, micrognathia, and small nose. Three patients had skeletal anomalies, including pectus excavatum, hyperextensibility, scoliosis, and arachnodactyly. Some patients had mild motor delay in infancy, but cognition was not impaired. Three patients died between ages 8 and 10 years of ruptured aneurysm, posttransplantion complications, and cardiac arrest, respectively.

Inheritance

Rajab et al. (2009) suggested autosomal recessive inheritance of the disorder in the Omani families because the parents in each family were first cousins and both girls and boys were affected.

Mapping

By genomewide and fine-mapping analyses of the extended family members and affected individuals in the Omani families, Rajab et al. (2009) found linkage of the disorder (maximum lod of 6.17) at D2S351 and D2S2390 on chromosome 2q36.2.

Molecular Genetics

In a boy with RILDBC, Antonellis et al. (2018) identified compound heterozygous mutations in the FARSB gene (609690.0001 and 609690.0002). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Western blot analysis of patient cells showed a 97% reduction in the FARSB protein and a 66% reduction in the FARSA (602918) protein compared to controls, suggesting a severe reduction in phenylalanyl-tRNA synthetase activity. Antonellis et al. (2018) postulated a loss-of-function effect.

In affected members of a large consanguineous Omani family with RILDBC, previously reported by Rajab et al. (2009), Zadjali et al. (2018) identified a homozygous missense mutation in the FARSB gene (E285K; 609690.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Western blot analysis of patient cells showed that the FARSB mutant protein was expressed at normal levels. Additional functional studies were not performed, but molecular modeling suggested that the mutation occurs in a domain involved in editing activity.

In 5 patients from 4 unrelated families with RILDBC, Xu et al. (2018) identified biallelic mutations in the FARSB gene (see, e.g., 609690.0004-609690.0008). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Analysis of cells derived from 1 patient who carried a missense and a splice site mutation (609690.0004 and 609690.0005) showed decreased protein levels of FARSB and FARSA, but overall protein synthesis was not impaired, suggesting that the disorder results from a different mechanism. Functional studies and studies of patient cells were not performed for the other identified variants, all of which were missense, but molecular modeling predicted that they would affect protein structure.