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ACIAL DYSMORPHISM, IMMUNODEFICIENCY, LIVEDO, AND SHORT STATURE; FILS
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A number sign (#) is used with this entry because of evidence that facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) is caused by homozygous mutation in the POLE gene (174762) on chromosome 12q24.
FILS syndrome is characterized by mild facial dysmorphism, mainly malar hypoplasia, livedo on the skin since birth, immunodeficiency resulting in recurrent infections, and short stature (summary by Pachlopnik Schmid et al., 2012).
Pachlopnik Schmid et al. (2012) reported a large multigenerational consanguineous French kindred in which 11 individuals showed a constellation of features, including mild facial dysmorphism, immunodeficiency, livedo, and short stature. Three additional family members displayed 2 or 3 of these 4 features. Facial dysmorphism included high forehead and malar hypoplasia. Livedo, usually present from birth, was present on the skin of the cheeks, forearms, and/or legs of all except 1 patient. With increasing age, telangiectasia became apparent on the cheeks. Growth impairment was observed during early childhood and resulted in variable short stature in adulthood. Head circumference was normal, resulting in relative macrocephaly. Three patients had bone dysplasia with pain, and studies showed lacunar bone lesions, cortical thickening, and modeling defects at the long bone diaphyses. All but 2 patients had immunodeficiency resulting in recurrent respiratory tract infections, and meningitis. Laboratory studies showed decreased IgM and IgG2 levels, reduced isohemagglutinin titers, a lack of antibodies to polysaccharide antigens, and low memory B cell counts. In addition, several patients had low naive T cell counts and decreased T cell proliferation. Allergies, autoimmunity, opportunistic infections, and malignancies were not observed. Sister chromatid exchange was normal.
Thiffault et al. (2015) studied a Palestinian girl (CMH812) who exhibited intrauterine growth retardation (IUGR) and had postnatal short stature and microcephaly. Dysmorphic features included malar and mandibular hypoplasia, prominent nasal bridge and columella, downslanting palpebral fissures, small mouth, and low-set posteriorly rotated ears. Over several months, lacy reticular pigmentation was noted on the face and extremities. Erupted teeth were small and dysplastic. She experienced chronic rhinosinusitis and pulmonary infections with purulent otitis media. At 20 months of age, she was hospitalized with pancytopenia, splenomegaly, hepatitis, and acute cytomegalovirus infection. She was found to have low IgM, IgG2, and IgG4, and showed no serologic response to pneumococcal vaccine or lymphocytic response to pertussis or Candida antigens.
The transmission pattern of FILS in the family reported by Pachlopnik Schmid et al. (2012) was consistent with autosomal recessive inheritance.
By genomewide homozygosity mapping of a large consanguineous French family with FILS, Pachlopnik Schmid et al. (2012) identified a common 2-Mb region on chromosome 12q (lod score of 11).
By homozygosity mapping followed by candidate gene sequencing of a consanguineous French family with FILS, Pachlopnik Schmid et al. (2012) identified a homozygous splice site mutation in the POLE gene (174762.0002). PCR analysis of patient T cells showed 2 types of POLE transcripts, wildtype (10%) and a mutant transcript lacking exon 34 (90%). Studies of patient T cells, B cells, chondrocytes, and osteoblasts showed an impairment in cell proliferation and in G1- to S-phase progression of the cell cycle.
In a 2-year-old Palestinian girl (CMH812) with FILS, Thiffault et al. (2015) performed exome sequencing and identified homozygosity for the same POLE splice site mutation previously found in a French family with FILS by Pachlopnik Schmid et al. (2012). Noting that the girl had more significantly impaired growth and immunity than the French patients with the same mutation, Thiffault et al. (2015) suggested that rare variants in other POLE subunits or MMR genes might act as genetic modifiers; however, no additional rare variants were detected in MMR genes, POLE1-interacting proteins, or other DNA breakage/instability syndrome genes.
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