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A patient with polymerase E1 deficiency (POLE1): clinical features and overlap with DNA breakage/instability syndromes.

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 - BMC Med. Genet. (2015)

Bottom Line: We performed exome sequencing on a girl with a suspected chromosome instability syndrome that manifested as growth retardation, microcephaly, developmental delay, dysmorphic features, poikiloderma, immune deficiency with pancytopenia, and myelodysplasia.She was homozygous for a previously reported splice variant, c.4444 + 3A > G in the POLE1 gene, which encodes the catalytic subunit of DNA polymerase E.This is the second family with POLE1-deficency, with the affected individual demonstrating a more severe phenotype than previously described.

View Article: PubMed Central - PubMed

Affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO, 64108, USA. ithiffault@cmh.edu.

ABSTRACT

Background: Chromosome instability syndromes are a group of inherited conditions associated with chromosomal instability and breakage, often leading to immunodeficiency, growth retardation and increased risk of malignancy.

Case presentation: We performed exome sequencing on a girl with a suspected chromosome instability syndrome that manifested as growth retardation, microcephaly, developmental delay, dysmorphic features, poikiloderma, immune deficiency with pancytopenia, and myelodysplasia. She was homozygous for a previously reported splice variant, c.4444 + 3A > G in the POLE1 gene, which encodes the catalytic subunit of DNA polymerase E.

Conclusion: This is the second family with POLE1-deficency, with the affected individual demonstrating a more severe phenotype than previously described.

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Related in: MedlinePlus

Clinical characteristics of CMH812. Several congenital abnormalities were found, including (A) microcephaly, facial dysmorphism (small and bird-like face, malar and mandibular hypoplasia, prominent nasal bridge and columella, downslanting palpebral fissures, small mouth and low set, posteriorly rotated ears) (B) short stature with shortened long bones but no evidence of dysplasia or craniosynostosis. No major anomalies were found on imaging of her abdomen, brain, brain vasculature or heart. Genitalia and pubertal development were normal. No malabsorption or pituitary or thyroid insufficiency was found. (C-D) Skin findings in CMH812, showing one hypo- and three hyperpigmented patches on the skin. Biopsy of the skin was performed but not diagnostic. Microscopic examination displayed focal parakeratosis and mild spongiosis.
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Fig1: Clinical characteristics of CMH812. Several congenital abnormalities were found, including (A) microcephaly, facial dysmorphism (small and bird-like face, malar and mandibular hypoplasia, prominent nasal bridge and columella, downslanting palpebral fissures, small mouth and low set, posteriorly rotated ears) (B) short stature with shortened long bones but no evidence of dysplasia or craniosynostosis. No major anomalies were found on imaging of her abdomen, brain, brain vasculature or heart. Genitalia and pubertal development were normal. No malabsorption or pituitary or thyroid insufficiency was found. (C-D) Skin findings in CMH812, showing one hypo- and three hyperpigmented patches on the skin. Biopsy of the skin was performed but not diagnostic. Microscopic examination displayed focal parakeratosis and mild spongiosis.

Mentions: Patient CMH812 is a female infant born to healthy non consanguineous Palestinian parents, weighing 1745 g and measuring 38.1 cm at birth. 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 (Figure 1A, B). Initial clinical suspicion was for primordial dwarfism such as Seckel type 1 syndrome, however her microcephaly was not as severe. Over several months, lacy reticular pigmentation was noted of the face and extremities. She had recurrent pruritic papular eruptions and skin findings progressed to include appearance of poikiloderma (Figure 1C, D). Erupted teeth were found to be small and dysplastic. She developed a feeding aversion necessitating a gastrostomy tube. Growth remained poor postnatally (Figure 2). Her motor milestones were delayed but social development was normal.Figure 1


A patient with polymerase E1 deficiency (POLE1): clinical features and overlap with DNA breakage/instability syndromes.

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 - BMC Med. Genet. (2015)

Clinical characteristics of CMH812. Several congenital abnormalities were found, including (A) microcephaly, facial dysmorphism (small and bird-like face, malar and mandibular hypoplasia, prominent nasal bridge and columella, downslanting palpebral fissures, small mouth and low set, posteriorly rotated ears) (B) short stature with shortened long bones but no evidence of dysplasia or craniosynostosis. No major anomalies were found on imaging of her abdomen, brain, brain vasculature or heart. Genitalia and pubertal development were normal. No malabsorption or pituitary or thyroid insufficiency was found. (C-D) Skin findings in CMH812, showing one hypo- and three hyperpigmented patches on the skin. Biopsy of the skin was performed but not diagnostic. Microscopic examination displayed focal parakeratosis and mild spongiosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4630961&req=5

Fig1: Clinical characteristics of CMH812. Several congenital abnormalities were found, including (A) microcephaly, facial dysmorphism (small and bird-like face, malar and mandibular hypoplasia, prominent nasal bridge and columella, downslanting palpebral fissures, small mouth and low set, posteriorly rotated ears) (B) short stature with shortened long bones but no evidence of dysplasia or craniosynostosis. No major anomalies were found on imaging of her abdomen, brain, brain vasculature or heart. Genitalia and pubertal development were normal. No malabsorption or pituitary or thyroid insufficiency was found. (C-D) Skin findings in CMH812, showing one hypo- and three hyperpigmented patches on the skin. Biopsy of the skin was performed but not diagnostic. Microscopic examination displayed focal parakeratosis and mild spongiosis.
Mentions: Patient CMH812 is a female infant born to healthy non consanguineous Palestinian parents, weighing 1745 g and measuring 38.1 cm at birth. 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 (Figure 1A, B). Initial clinical suspicion was for primordial dwarfism such as Seckel type 1 syndrome, however her microcephaly was not as severe. Over several months, lacy reticular pigmentation was noted of the face and extremities. She had recurrent pruritic papular eruptions and skin findings progressed to include appearance of poikiloderma (Figure 1C, D). Erupted teeth were found to be small and dysplastic. She developed a feeding aversion necessitating a gastrostomy tube. Growth remained poor postnatally (Figure 2). Her motor milestones were delayed but social development was normal.Figure 1

Bottom Line: We performed exome sequencing on a girl with a suspected chromosome instability syndrome that manifested as growth retardation, microcephaly, developmental delay, dysmorphic features, poikiloderma, immune deficiency with pancytopenia, and myelodysplasia.She was homozygous for a previously reported splice variant, c.4444 + 3A > G in the POLE1 gene, which encodes the catalytic subunit of DNA polymerase E.This is the second family with POLE1-deficency, with the affected individual demonstrating a more severe phenotype than previously described.

View Article: PubMed Central - PubMed

Affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO, 64108, USA. ithiffault@cmh.edu.

ABSTRACT

Background: Chromosome instability syndromes are a group of inherited conditions associated with chromosomal instability and breakage, often leading to immunodeficiency, growth retardation and increased risk of malignancy.

Case presentation: We performed exome sequencing on a girl with a suspected chromosome instability syndrome that manifested as growth retardation, microcephaly, developmental delay, dysmorphic features, poikiloderma, immune deficiency with pancytopenia, and myelodysplasia. She was homozygous for a previously reported splice variant, c.4444 + 3A > G in the POLE1 gene, which encodes the catalytic subunit of DNA polymerase E.

Conclusion: This is the second family with POLE1-deficency, with the affected individual demonstrating a more severe phenotype than previously described.

Show MeSH
Related in: MedlinePlus