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Combined immunodeficiency develops with age in Immunodeficiency-centromeric instability-facial anomalies syndrome 2 (ICF2).

von Bernuth H, Ravindran E, Du H, Fröhler S, Strehl K, Krämer N, Issa-Jahns L, Amulic B, Ninnemann O, Xiao MS, Eirich K, Kölsch U, Hauptmann K, John R, Schindler D, Wahn V, Chen W, Kaindl AM - Orphanet J Rare Dis (2014)

Bottom Line: ICF2, caused by biallelic ZBTB24 gene mutations, is acknowledged primarily as an isolated B-cell defect.Here, we extend the phenotype spectrum by describing, in particular, for the first time the development of a combined immune defect throughout the disease course as well as putative autoimmune phenomena such as granulomatous hepatitis and nephritis.We also demonstrate impaired cell-proliferation and increased cell death of immune and non-immune cells as well as data suggesting a chromosome separation defect in addition to the known chromosome condensation defect.

View Article: PubMed Central - PubMed

Affiliation: Pediatric Pneumology and Immunology, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany. horst.von-bernuth@charite.de.

ABSTRACT
The autosomal recessive immunodeficiency-centromeric instability-facial anomalies syndrome (ICF) is characterized by immunodeficiency, developmental delay, and facial anomalies. ICF2, caused by biallelic ZBTB24 gene mutations, is acknowledged primarily as an isolated B-cell defect. Here, we extend the phenotype spectrum by describing, in particular, for the first time the development of a combined immune defect throughout the disease course as well as putative autoimmune phenomena such as granulomatous hepatitis and nephritis. We also demonstrate impaired cell-proliferation and increased cell death of immune and non-immune cells as well as data suggesting a chromosome separation defect in addition to the known chromosome condensation defect.

No MeSH data available.


Related in: MedlinePlus

Phenotype and genotype of index patient withZBTB24mutation. (A) Clinical signs at 8 years-of-age: protruding abdomen due to organomegaly in the otherwise underweight girl of short statue, facial dysmorphism (hypertelorism, epicanthal folds, flat nasal bridge, hypertelorism, slight ptosis, prominent forehead). Large teeth result from a fusion of first molar with the incisors. Fingers and toes showed clubbing. Failure to thrive evident in a percentile height-weight-curve. (B) Pseudo-Pelger-Huët anomaly of neutrophils (Diff-Quick staining, 100x, n = 400 cells, Student’s t-test, p < 0.0001). (C) Site of homozygous ZBTB24 mutation c.1222 T > G (protein domains: BTB, bric-a-bric, tramtrack, broad complex domain; AT hook, DNA-binding domain with a preference for A/T rich regions, Zinc finger C2H2). (D) Electropherogram traces in patient and heterozygous parents (NM_014797) indicating mutation confirmed by Sanger sequencing. Unaltered ZBTB24 mRNA levels and product size is depicted in Additional file 8: Figure S2. (E) Highly conserved amino acids affected by the inherited homozygous mutation (p.C408G). (F) Spontaneous undercondensation of constitutive heterochromatin of chromosomes 1q, 16q, and (to a lesser extent) 9q.
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Fig1: Phenotype and genotype of index patient withZBTB24mutation. (A) Clinical signs at 8 years-of-age: protruding abdomen due to organomegaly in the otherwise underweight girl of short statue, facial dysmorphism (hypertelorism, epicanthal folds, flat nasal bridge, hypertelorism, slight ptosis, prominent forehead). Large teeth result from a fusion of first molar with the incisors. Fingers and toes showed clubbing. Failure to thrive evident in a percentile height-weight-curve. (B) Pseudo-Pelger-Huët anomaly of neutrophils (Diff-Quick staining, 100x, n = 400 cells, Student’s t-test, p < 0.0001). (C) Site of homozygous ZBTB24 mutation c.1222 T > G (protein domains: BTB, bric-a-bric, tramtrack, broad complex domain; AT hook, DNA-binding domain with a preference for A/T rich regions, Zinc finger C2H2). (D) Electropherogram traces in patient and heterozygous parents (NM_014797) indicating mutation confirmed by Sanger sequencing. Unaltered ZBTB24 mRNA levels and product size is depicted in Additional file 8: Figure S2. (E) Highly conserved amino acids affected by the inherited homozygous mutation (p.C408G). (F) Spontaneous undercondensation of constitutive heterochromatin of chromosomes 1q, 16q, and (to a lesser extent) 9q.

Mentions: The index patient was born hypotrophic at term without complications as the first child of non-consanguineous healthy, Caucasian parents of German descent after an uneventful pregnancy. She showed multiple facial anomalies, clubbing of fingers and toes, and fused teeth (Figure 1A). Language and motor development appeared initially normal, but intellectual disability became apparent by the second year of life. Her brain morphology was normal on MRI at 4 years-of-age, apart from a pineal cyst. Growth stagnated at 4.5 years-of-age with height, weight, and head circumference of 101 cm (-4.79 SD), 15 kg (-2.51 SD), and 50 cm (-1.2 SD) at 9 years-of-age (Figure 1A). Bone age was delayed by 4 years at 8 years-of-age, and growth hormone levels were undetectable but could be stimulated.Figure 1


Combined immunodeficiency develops with age in Immunodeficiency-centromeric instability-facial anomalies syndrome 2 (ICF2).

von Bernuth H, Ravindran E, Du H, Fröhler S, Strehl K, Krämer N, Issa-Jahns L, Amulic B, Ninnemann O, Xiao MS, Eirich K, Kölsch U, Hauptmann K, John R, Schindler D, Wahn V, Chen W, Kaindl AM - Orphanet J Rare Dis (2014)

Phenotype and genotype of index patient withZBTB24mutation. (A) Clinical signs at 8 years-of-age: protruding abdomen due to organomegaly in the otherwise underweight girl of short statue, facial dysmorphism (hypertelorism, epicanthal folds, flat nasal bridge, hypertelorism, slight ptosis, prominent forehead). Large teeth result from a fusion of first molar with the incisors. Fingers and toes showed clubbing. Failure to thrive evident in a percentile height-weight-curve. (B) Pseudo-Pelger-Huët anomaly of neutrophils (Diff-Quick staining, 100x, n = 400 cells, Student’s t-test, p < 0.0001). (C) Site of homozygous ZBTB24 mutation c.1222 T > G (protein domains: BTB, bric-a-bric, tramtrack, broad complex domain; AT hook, DNA-binding domain with a preference for A/T rich regions, Zinc finger C2H2). (D) Electropherogram traces in patient and heterozygous parents (NM_014797) indicating mutation confirmed by Sanger sequencing. Unaltered ZBTB24 mRNA levels and product size is depicted in Additional file 8: Figure S2. (E) Highly conserved amino acids affected by the inherited homozygous mutation (p.C408G). (F) Spontaneous undercondensation of constitutive heterochromatin of chromosomes 1q, 16q, and (to a lesser extent) 9q.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC4230835&req=5

Fig1: Phenotype and genotype of index patient withZBTB24mutation. (A) Clinical signs at 8 years-of-age: protruding abdomen due to organomegaly in the otherwise underweight girl of short statue, facial dysmorphism (hypertelorism, epicanthal folds, flat nasal bridge, hypertelorism, slight ptosis, prominent forehead). Large teeth result from a fusion of first molar with the incisors. Fingers and toes showed clubbing. Failure to thrive evident in a percentile height-weight-curve. (B) Pseudo-Pelger-Huët anomaly of neutrophils (Diff-Quick staining, 100x, n = 400 cells, Student’s t-test, p < 0.0001). (C) Site of homozygous ZBTB24 mutation c.1222 T > G (protein domains: BTB, bric-a-bric, tramtrack, broad complex domain; AT hook, DNA-binding domain with a preference for A/T rich regions, Zinc finger C2H2). (D) Electropherogram traces in patient and heterozygous parents (NM_014797) indicating mutation confirmed by Sanger sequencing. Unaltered ZBTB24 mRNA levels and product size is depicted in Additional file 8: Figure S2. (E) Highly conserved amino acids affected by the inherited homozygous mutation (p.C408G). (F) Spontaneous undercondensation of constitutive heterochromatin of chromosomes 1q, 16q, and (to a lesser extent) 9q.
Mentions: The index patient was born hypotrophic at term without complications as the first child of non-consanguineous healthy, Caucasian parents of German descent after an uneventful pregnancy. She showed multiple facial anomalies, clubbing of fingers and toes, and fused teeth (Figure 1A). Language and motor development appeared initially normal, but intellectual disability became apparent by the second year of life. Her brain morphology was normal on MRI at 4 years-of-age, apart from a pineal cyst. Growth stagnated at 4.5 years-of-age with height, weight, and head circumference of 101 cm (-4.79 SD), 15 kg (-2.51 SD), and 50 cm (-1.2 SD) at 9 years-of-age (Figure 1A). Bone age was delayed by 4 years at 8 years-of-age, and growth hormone levels were undetectable but could be stimulated.Figure 1

Bottom Line: ICF2, caused by biallelic ZBTB24 gene mutations, is acknowledged primarily as an isolated B-cell defect.Here, we extend the phenotype spectrum by describing, in particular, for the first time the development of a combined immune defect throughout the disease course as well as putative autoimmune phenomena such as granulomatous hepatitis and nephritis.We also demonstrate impaired cell-proliferation and increased cell death of immune and non-immune cells as well as data suggesting a chromosome separation defect in addition to the known chromosome condensation defect.

View Article: PubMed Central - PubMed

Affiliation: Pediatric Pneumology and Immunology, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany. horst.von-bernuth@charite.de.

ABSTRACT
The autosomal recessive immunodeficiency-centromeric instability-facial anomalies syndrome (ICF) is characterized by immunodeficiency, developmental delay, and facial anomalies. ICF2, caused by biallelic ZBTB24 gene mutations, is acknowledged primarily as an isolated B-cell defect. Here, we extend the phenotype spectrum by describing, in particular, for the first time the development of a combined immune defect throughout the disease course as well as putative autoimmune phenomena such as granulomatous hepatitis and nephritis. We also demonstrate impaired cell-proliferation and increased cell death of immune and non-immune cells as well as data suggesting a chromosome separation defect in addition to the known chromosome condensation defect.

No MeSH data available.


Related in: MedlinePlus