Encyclopedia of Medical Immunology

Living Edition
| Editors: Ian MacKay, Noel R. Rose

Clinical Presentation of Polymerase E1 (POLE1) and Polymerase E2 (POLE2) Deficiencies

  • Isabelle ThiffaultEmail author
  • Carol Saunders
  • Nikita Raje
  • Nicole P. Safina
Living reference work entry
DOI: https://doi.org/10.1007/978-1-4614-9209-2_181-1

Synonyms

Introduction/Background

The replicative DNA polymerases (pols) α, δ, and ɛ are central components in DNA replication, repair, recombination, and cell cycle control. Numerous genetic studies have provided compelling evidence to establish DNA polymerase ε (POLε/POLE) as the primary DNA polymerase responsible for leading strand synthesis during eukaryotic nuclear genome replication (Huang et al. 1999; Zahurancik et al. 2015). POLε is a highly conserved multi-subunit polymerase (heterotetramer) consisting of proteins encoded by four genes: POLE1, which encodes a 261 kDa protein comprising the catalytic activity complexed with the POLE2 (59 kDa) subunit, in addition to POLE3 (17 kDa) and POLE4 (12 kDa). POLE2 has no known catalytic activity, but the absence of POLE2 reduce Polε stability (Zahurancik et al. 2015). Polε is involved in several processes which include DNA replication, repair of DNA damage, control of cell cycle progression, chromatin remodeling, and epigenetic regulation of the stable transfer of information from mother to daughter cells. At this time, only two of the DNA polymerase ε subunits have been associated with Mendelian diseases; POLE1 and POLE2. POLε-deficiency patients present with immunodeficiency and other extra-immune manifestations reminiscent of chromosome instability syndromes, such as pre and/or postnatal growth retardation, microcephaly, dysmorphic features, and bone marrow failure.

Clinical Presentation

POLE1

Family 1

POLE1-related deficiency was first reported in a large consanguineous French family with three generations of affected members in which major clinical features included mild facial dysmorphism, immunodeficiency, livedo, and short stature (referred as FILS syndrome) (Pachlopnik Schmid et al. 2012). The FILS phenotype was variable but included malar hypoplasia, relative macrocephaly, recurrent infections, and short stature. Livedo on the cheeks, forearms, and/or legs was present in most patients at birth. With increasing age, telangiectasia was observed on the cheeks. Growth impairment was observed postnatally with normal growth hormone levels. Three affected individuals had bone dysplasia and suffered from pain in extremities. Patients had recurrent infections which include upper and lower respiratory tract infections, pulmonary infections, and meningitis. Allergies, autoimmunity, opportunistic infections, and malignancies were not observed in these patients. Immunological experiments showed decreased IgM and IgG2 levels, reduced isohemagglutinin titers, and a predominant lack of antibodies to polysaccharide antigens. Patients had low memory (CD27+), B cell counts, the proportion of switched B cells and non-switched memory B cells were equally affected. T lymphocytes from affected individuals showed a proliferation defect as well as impaired cell cycle progression. The phenotype was reminiscent of Bloom syndrome but with normal sister chromatid exchange. All affected patients were found to be homozygous for the same variant, POLE1 c.4444+3A>G. This variant confers abnormal splicing of exon 34, resulting in a truncated transcript (Pachlopnik Schmid et al. 2012) and severely decreased expression of POLE1 and POLE2. Heterozygous individuals were asymptomatic. Of note, the patients did not exhibit cancer susceptibility.

Family 2

Patient CMH812 is a female infant born to healthy consanguineous Palestinian parents. The pregnancy was complicated by subchorionic bleeding in the first trimester, fetal abnormalities on ultrasound including intrauterine growth restriction, short long bones, suspected skull abnormalities, and oligohydramnios. TORCH titers were negative. Amniocentesis revealed normal 46,XX karyotype. She was delivered at 37 weeks gestation by elective C-section secondary to breech presentation. Dysmorphic features noted included malar and mandibular hypoplasia. Microcephaly and moderate growth deficiency were also noted postnatally. Initial clinical suspicion was for primordial dwarfism such as Seckel syndrome; however, molecular testing was negative. Over several months, lacy reticular pigmentation was noted on the face and extremities. She had recurrent pruritic papular eruptions and skin findings progressed to include appearance of poikiloderma. Erupted teeth were found to be small and dysplastic. She developed a feeding aversion necessitating a gastrostomy tube. Growth remained poor postnatally. Her motor milestones were delayed but social development was normal. She suffered chronic rhinosinusitis and pulmonary infections with purulent otitis media. At age 20 months, she was admitted to the hospital with pancytopenia, splenomegaly, hepatitis, and acute cytomegalovirus (CMV) infection. Laboratory data showed mild bone marrow myelodysplasia, normal total B, T, and NK cells, low class switched and non-switched memory B cells, and high memory T cells. She had high IgA, initially normal total IgG that gradually trended down and low IgM, IgG2, and IgG4. There was no serologic response to pneumococcal vaccine despite booster dose. Lymphocyte proliferative response to mitogens was normal but absent to tetanus and candida antigens. Immunoglobulin replacement was initiated. She was found homozygous for the previously reported POLE1 splice variant (c.4444+3A>G) by trio exome-sequencing (Thiffault et al. 2015). Although she carried the same variant reported in Family 1, CMH812 seems to have had more significantly impaired growth and immunity. Re-analysis and re-interpretation of exome data did not identify additional variant that may explain the patient’s more severe phenotype.

POLE2

Recently, a 5-year-old male born to consanguinous parents of Saudi origin was reported with a homozygous splicing variant (c.1074-1G>T) in POLE2 (Frugoni et al. 2016). The patient had combined immunodeficiency, facial dysmorphism, and autoimmunity. He had a history of omphalitis and erythroderma in the neonatal period, systemic Bacillus Calmette-Guerin (BCG) infection after immunization, and subsequently, multiple respiratory infections. Diabetes mellitus was diagnosed at 5 months of age. A few months later, he developed severe dyspnea with hypoxia, hepatomegaly, hypothyroidism, and recurrent respiratory infections with pulmonary atelectasis. Laboratory data showed agammaglobulinemia, absence of circulating B cells, and T cell lymphopenia and neutropenia. Replacement therapy with intravenous immunoglobulins was initiated. Later, he developed generalized lymphadenopathy. Lymph node biopsy showed abnormal architecture with lack of follicles, an increased number of CD163+ activated macrophages and activated (CD45RO+) T lymphocytes. At the time of diagnosis, his height and weight were at the 3rd percentile, and had microcephaly (−2.4 s.d.). Dysmorphic features included low anterior hairline, flat supraorbital ridges, downturned corners of the mouth, and a short philtrum. Exome sequencing identified homozygosity for a splicing variant, c.1074-1G>T, in POLE2. This variant confers abnormal splicing of exon 14, resulting in a truncated transcript (Frugoni et al. 2016). However, immunoblot analysis for POLE2 revealed similar levels of expression in patient and control samples. Further analysis of patient’s cell lines for cell cycle progression showed reduced numbers of cells in S phase with an increased proportion of cells in G2/M, indicating a defect that was partially rescued by complementation studies (Frugoni et al. 2016).

Table 1 compares the clinical and cellular features of individuals with Polε-deficiency. Features closely matched those reported in FILS with exceptions of microcephaly and intrauterine growth restriction.
Table 1

Comparison of clinical and immunologic features of POLE1 and POLE2 patients

Clinical features

FILS syndromea

CMH812a

D839

POLE2-patienta

MIM #

615139

615139

615139

n.a

Sex

11 affected (8 males; 6 females)

Female

Male

Male

Origin

French

Palestinian

n.a

Saudi Arabian

Age at diagnosis

3–33 years old

2 years old

25 years old

10 months

Variant

Homoz. c.4444+3A>G

Homoz. c.4444+3A>G

Het. c.1085A>GC (Tyr362Cys), no second variant detected

Homoz. c.1074-1G>T

RS ID

rs398122515

rs398122515

n.a

rs368577291

gnomAD MAF

1/30962 (0.007%)

1/30962 (0.007%)

1/246264 (0.0009%)

5/243070 (0.004%)

Microcephaly

n.a

Malar hypoplasia

n.a

Sloping head

n.a

n.a

Palpebral fissures, upslanting

n.a

n.a

Palpebral fissures, downslanting

n.a

n.a

Epicanthic folds

n.a

n.a

Micrognathia

n.a

n.a

External ear abnormalities

n.a

n.a

Short philtrum

n.a

Long philtrum

n.a

n.a

Clinodactily

n.a

n.a

Syndactily

n.a

n.a

Growth retardation

n.a

Short stature

n.a

Bone disease or anomalies

n.a

n.a

Skin abnormalities

n.a

Intellectual disability

n.a

n.a

Developmental delay

n.a

n.a

Low hairline

n.a

n.a

Recurrent infections

Brain anomalies/degeneration

n.a

n.a

n.a

Dyspnea

n.a

n.a

n.a

Endocrine

n.a

Diabetes, hypothyroidy

Immunologic features

Pancytopenia

n.a

n.a

Agammaglobulinemia

n.a

n.a

n.a

Thrombocytopenia

n.a

n.a

CID

2/14

SCID

n.a

-

n.a

n.a

Neutropenia

n.a

-*

n.a

B cell lymphocytopenia

n.a

T cell lymphocytopenia

n.a

CD19

n.a

n.a

N

CD3

N

n.a

CD4

n.a

N

CD8

n.a

N

N

IgA

N

IgE

N

N

n.a

IgG

↓**

Low N

IgM

Anti-pseudomonas polysaccharide IgG

n.a

n.a

Autoimmunity

-

n.a

n.a

Sister chromatid

N

N

n.a

n.a

DNA breakage studies

N

n.a

n.a

Radiosensitivity

n.a.

n.a

n.a

Clinical phenotype

FILS

FILS-related disease

Polyclonal lymphoproliferation (CVI)

CVI

Gene

POLE1

POLE1

POLE1

POLE2

Mode of inheritance

AR

AR

?

AR

n.a, not reported/applicable; −, negative; ■, positive; N, normal range; ↓, decreased; ↑, increased; AR, autosomal recessive; CVI, common variable immunodeficiency; -*, Transient pancytopenia associated with CMV infection; ↓**, IgG2 and IgG 4 ↓. Total IgG N; Homoz, homozygous; Het., heterozygous

aConsanguineous family reported

Laboratory Findings/Diagnostic Testing

Similar to the evaluation of other immunodeficiency syndromes, laboratory work is guided by the immune system defect. Basic screening includes complete blood counts and differential measurement of quantitative immunoglobulins (IgG, IgA, and IgM), pre- and post-vaccine titers, and lymphocyte enumeration. Other specialized immunological testing including lymphocyte proliferation to mitogen and antigen stimulation and T cell receptor Vβ spectratyping can be helpful.

The diagnosis of POLε-deficiency is established in a proband with the clinical findings listed above who has biallelic pathogenic variants in POLE1 or POLE2. Two approaches to molecular genetic testing should be considered; multi-gene panel for immunodeficiency syndromes or symptom-driven next-generation sequencing.

Treatment/Prognosis

Treatment of Manifestations: As with other immunodeficiency syndromes, the goal for treatment of immunodeficiency associated with POLE1 and POLE2 deficiencies is to minimize or eliminate infections and monitoring to control immune dysregulation with targeted therapy. Immunoglobulin replacement is useful in the patients with frequent infections and humoral immunodeficiency. Preventative antibiotics may provide additional protection. Other treatments may include Vitamin E and folic acid supplementation; standard chemotherapy protocols for malignancies (adopted to individual tolerance); growth hormone replacement therapy for individuals who have growth failure (likely needs to be used with caution in this group of patients due to potential risk of malignancy) and treatment for autoimmune complications such as autoimmune thyroid disease as described for POLE2 deficient patient. Additional supportive therapy including special education, speech and language therapy, behavioral therapy, occupational therapy, and community services for families would be beneficial.

Surveillance: For affected individuals: Periodic follow up to monitor developmental progress, physical growth, and frequency of infection and/or autoimmunity; in those with weight loss, assessment for malignancy should be considered, lifelong monitoring of immune biomarkers, and careful monitoring by an oncologist.

For carriers (heterozygotes): Parents should be monitored for malignancy, particularly colorectal and endometrial cancers.

Genetic Counselling: POLε-deficiency is inherited in an autosomal recessive manner. At conception, each siblings of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing are possible if both of the pathogenic variants have been identified in an affected family member.

Discussion/Summary

In summary, the clinical and immunologic features of patients with pathogenic variants in POLE1 or POLE2 result in variable immunodeficiency and other extra-immune manifestations. For this reason, POLε deficiency may be a more apt description of these disorders. At this time, no genotype-phenotype correlation in POLε-deficiency patients can be drawn due to the small number of patients. The impact of POLε holoenzyme deficiency causing impaired lymphocyte proliferation, altered cellular survival, and/or defective DNA repair/replication in patients with POLε defects remains to be investigated. Somatic mutations in human POLε have been demonstrated in cancers and are thought to contribute to genomic instability. Functional studies in yeast showed that heterozygosity for a pathogenic allele can cause complete Mismatch repair (MMR) deficiency, and that subsequent loss of heterozygosity is not required for the development of POLε-related tumors (Huang et al. 1999; Zahurancik et al. 2015). Taken together, longitudinal follow up studies of carrier individuals of germline POLE1 and POLE2 deficiency are needed to delineate the potential role in cancer susceptibility.

References

  1. Frugoni F, Dobbs K, Felgentreff K, Aldhekri H, Al Saud BK, Arnaout R, Ali AA, Abhyankar A, Alroqi F, Giliani S, Ojeda MM, Tsitsikov E, Pai SY, Casanova JL, Notarangelo LD, Manis JP. A novel mutation in the POLE2 gene causing combined immunodeficiency. J Allergy Clin Immunol. 2016;137: 635–8.e631.CrossRefGoogle Scholar
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  3. Pachlopnik Schmid J, Lemoine R, Nehme N, Cormier-Daire V, Revy P, Debeurme F, Debre M, Nitschke P, Bole-Feysot C, Legeai-Mallet L, Lim A, De Villartay JP, Picard C, Durandy A, Fischer A, De Saint Basile G. Polymerase epsilon1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”). J Exp Med. 2012;209:2323–30.CrossRefGoogle Scholar
  4. Thiffault I, Saunders C, Jenkins J, Raje N, Canty K, Sharma M, Grote L, Welsh HI, Farrow E, Twist G, Miller N, Zwick D, Zellmer L, Kingsmore SF, Safina NP. A patient with polymerase E1 deficiency (POLE1): clinical features and overlap with DNA breakage/instability syndromes. BMC Med Genet. 2015;16:31.CrossRefGoogle Scholar
  5. Zahurancik WJ, Baranovskiy AG, Tahirov TH, Suo Z. Comparison of the kinetic parameters of the truncated catalytic subunit and holoenzyme of human DNA polymerase varepsilon. DNA Repair (Amst). 2015;29: 16–22.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Isabelle Thiffault
    • 1
    • 2
    • 4
    Email author
  • Carol Saunders
    • 1
    • 2
    • 4
  • Nikita Raje
    • 3
    • 4
    • 5
  • Nicole P. Safina
    • 3
    • 4
    • 6
  1. 1.Center for Pediatric Genomic MedicineChildren’s Mercy HospitalKansas CityUSA
  2. 2.Department of Pathology and Laboratory MedicineChildren’s Mercy HospitalKansas CityUSA
  3. 3.Department of PediatricsChildren’s Mercy HospitalKansas CityUSA
  4. 4.University of Missouri–Kansas City School of MedicineKansas CityUSA
  5. 5.Pediatric Allergy, Asthma and Immunology ClinicChildren’s Mercy HospitalKansas CityUSA
  6. 6.Division of Clinical GeneticsChildren’s Mercy HospitalKansas CityUSA

Section editors and affiliations

  • Jolan Walter
    • 1
  1. 1.USF HealthTampaUSA