Facial Dysmorphism, Immunodeficiency, Livedo, and Short Stature

FILS syndrome is a rare genetic disorder (<20 cases in the world literature) characterized by mild facial dysmorphism with malar hypoplasia and high forehead, immunodeficiency leading to recurrent infections. Other striking features are short stature due to growth disorders (with normal growth hormone production and response) leading to short stature and livedo of the face and extremities. The growth disorder that leads to short stature in adulthood is already observed in early childhood, albeit to varying degrees. The head circumference is normal in those affected, so that FILS patients may exhibit relative macrocephaly. Some patients have bone dysplasia and suffer from pain in the extremities.

The main pathogenesis of FILS syndrome is the abnormal expression of the DNA polymerase epsilon, catalytic subunit, caused by variants in the POLE gene. The catalytic subunit of DNA-Pol ε contains two domains: the polymerase domain and the exonuclease proofreading domain. The former is mainly involved in the synthesis of guide chains during DNA replication, while the latter, together with DNA-Pol δ and the mismatch repair (MMR) protein, maintains the stability of the genome and plays a role in maintaining high-fidelity DNA replication and preventing mutations . Due to the different expression levels of POLE in different tissues, a decrease in the polymerase activity of DNA-pol ε can limit the proliferation of T cells, B cells, chondrocytes, osteoblasts and skin fibroblasts, leading to pathological changes in immunity, bone and skin.

Rö: Lacunar bone lesions, cortical thickening and modeling defects on the long bone diaphyses are detectable.

Immunological analyses show a low number of B memory cells and naive T cells, reduced T cell proliferation and reduced IgM, IgG2 and IgG4 titers.

1. Jiang L et al. (2022) Case report: A Chinese boy with facial dysmorphism, immunodeficiency, livedo, and short stature syndrome. Front Pediatr 10:933108.

2. Pachlopnik Schmid J et al. (2012) Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome"). J Exp Med 209:2323-2330.