EIF2AK4 mutations in pulmonary capillary hemangiomatosis

Abstract

Background: Pulmonary capillary hemangiomatosis (PCH) is a rare disease of capillary proliferation of unknown cause and with a high mortality. Families with multiple affected individuals with PCH suggest a heritable cause although the genetic etiology remains unknown.

Methods: We used exome sequencing to identify a candidate gene for PCH in a family with two affected brothers. We then screened 11 unrelated patients with familial (n = 1) or sporadic (n = 10) PCH for mutations.

Results: Using exome sequencing, we identified compound mutations in eukaryotic translation initiation factor 2 α kinase 4 (EIF2AK4) (formerly known as GCN2) in both affected brothers. Both parents and an unaffected sister were heterozygous carriers. In addition, we identified two EIF2AK4 mutations in each of two of 10 unrelated individuals with sporadic PCH. EIF2AK4 belongs to a family of kinases that regulate angiogenesis in response to cellular stress.

Conclusions: Mutations in EIF2AK4 are likely to cause autosomal-recessive PCH in familial and some nonfamilial cases.

Figure 1.

Pedigree of family 1. The c.1153dupG mutation and the c.3766C>T mutation segregate with pulmonary capillary hemangiomatosis (PCH) in the index family (family 1). The unaffected mother (I-2) and unaffected daughter (II.3) carried the c.1153dupG mutation, and the unaffected father (I-1) carried the c.3766C>T mutation. (+) denotes wild-type alleles and (-) denotes mutation. →, the proband; ○, unaffected females; ■, affected males; □, unaffected males; /, deceased family members.

Figure 2.

PCH of family 1, member II.1, as demonstrated in explanted lung. A, Note the low-power, somewhat nodular, appearance of the areas of increased alveolar thickness (hematoxylin and eosin, original magnification × 40). B, The higher-power image shows that the increased thickness is due to a proliferation of capillaries. Special stains, including elastic stains and the endothelial marker CD31 confirmed this, but are not shown (hematoxylin and eosin, original magnification × 100). C and D, Images are obtained from surgical biopsies of family 1, member II.2 (hematoxylin and eosin, original magnification × 15). C, The thickened septa are less nodular in appearance and, D, somewhat mimic an interstitial pneumonia. Note the thickened pulmonary artery at 12 o’clock (←), a feature typically observed in patients with capillary hemangiomatosis as a manifestation of pulmonary hypertension. See Figure 1 legend for expansion of abbreviation.