Pediatr Blood Cancer 2014;61:962–963
HIGHLIGHT 1 by Nupur Mittal,
MD,
* and Paul M. Kent, MD2
Insights Into the Genetic Basis of Familal Hemophagocytic Lymphohistiocytosis (Commentary on Qian et al., page 1034)
I
n 1952, Dr James Farquhar, a Scottish pediatrician noticed the familial recurrence of a disease affecting male and female siblings aged 2 months, causing fever, cytopenia, hepatosplenomegaly, and rapidly leading to death despite treatment with antibiotics and steroids [1]. In the 6 decades since we have evolved an understanding of familial hemophagocytic lymphohistiocytosis (FHL) that has also greatly enhanced our understanding of the immune system. In this issue of Pediatric Blood and Cancer, Qian et al. extend our knowledge of the genetic underpinnings of this rare and deadly disease [2]. As recently as December 1999, the first FHL-related gene was described [3,4]. Over the subsequent decade we have learned that FHL is a very heterogeneous autosomal recessive disorder. To date, OMIM lists, five genetic lesions in four genes: PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5). Current knowledge allows a genetic defect to be identified in variable proportions of patients, depending on ethnic origin. For example, bi-allelic mutations in FHL-3 are identified in approximately 50% of North American patients. Specifically the subject of Qian’s review, the FHL-3 mutations in UNC13D are found in 30% of Caucasion, 90% of Koreans, but is rare in patients of African descent [5–8]. The authors point out that although FHL-3 is an autosomal recessive disorder, several symptomatic patients have been described who have a mutation identified on only 1 allele [6,7]. Zhang et al. postulate that this can occur if a second allele is mutated in the promoter region, a non-coding region, on a different gene or there exists a complex rearrangement that is undetectable by current methods [6]. In this issue Qian et al. report their findings from a study in which they performed genetic testing of the UNC13D gene, including DNA sequencing of three recently reported non-coding mutations to investigate the prevalence of these mutations in a large North American cohort of 1709 patients with clinical diagnosis of HLH. This study uncovers familial cases not previously recognized allowing for counselling after screening. In addition, the authors identify mutations that cannot be detected by conventional testing in a North American cohort which may explain genetic basis in several patients who were thought to be heterozygous, or carriers. Furthermore, they report 8 new mutations in UNC13D for the first time and together with previously diagnosed FHL3 patients in their registry, these lesions account for nearly a 1/3 of the FHL3 patients. Indeed, recent work on the deep intronic (c.118-308C>T) and inversion mutations of UNC13D in Northern European and Korean patients revealed founder effects [4,8].
C
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25006 Published online 25 February 2014 in Wiley Online Library (wileyonlinelibrary.com).
The expanded panel of identifiable lesions offered by Qian et al. can identify bi-allelic mutations, raising important questions pertaining to follow up, treatment, preemptive transplant, and genetic and antenatal counselling. Currently the indications of genetic testing for familial HLH are for confirmation of diagnosis in a symptomatic individual, pre-symptomatic testing of at-risk siblings, carrier identification in individuals with a family history of FHL and prenatal diagnosis of an at-risk fetus, after confirmation of bi-allelic mutations in the parents [6]. In addition, even though the typical age of presentation for familial HLH is within infancy, some affected individuals may present later in life [9]. An attempt at identification of a complete genotype achieved by this type of testing may aid consideration of pre-symptomatic bone marrow transplantation and timely treatment in at risk genetically affected siblings and children with an atypical phenotype (for example acute liver failure, acute encephalopathy) [10]. The decision to prophylactically transplant asymptomatic affected individuals is complex, but, at the least such individuals may be monitored carefully and a suitable stem cell donor identified. Additionally such screening may have value in that, mutations in the FHL related genes have shown an increased frequency of lymphoma, leukemia, diabetes mellitus, multiple sclerosis, and juvenile arthritis [3]. More FHL data on correlations between genotype and phenotype in a large cohort of patients are needed to inform clinicians about screening asymptomatic individuals in a cost effective manner. Qian et al. have taken an important step towards this goal.
REFERENCES 1. Farquhar J, Claireaux A. Familial haemophagocytic reticulosis. Arch Dis Child 1952;27:519–525. 2. Qian Y, Johnson JA, Connor JA, et al. The 253-kb inversion and deep intronic mutations in UNC13D are present in North American patients with familial hemophagocytic lymphohistiocytosis 3. Pediatric Blood Cancer 2014; doi: 10.1002/pbc.24955. [Epub ahead of print].
1
Department of Pediatrics, Division of Pediatric Hematology Oncology, Rush University Medical Center, University of Illinois At Chicago and John. H. Stroger hospital (Tri- institutional fellowship), Chicago, Illinois; 2Department of Pediatrics, Division of Pediatric Hematology Oncology, Rush University Medical Center, Chicago, Illinois Correspondence to: Nupur Mittal, 1725 West Harrison Street, Suite 710 Chicago, IL 60612-3824. E-mail: [email protected]
Received 2 February 2014; Accepted 4 February 2014
Highlight 3. Cetica V, Pende D, Griffiths GM, et al. Molecular basis of familial hemophagocytic lymphohistiocytosis. Hematologica 2010;95:538–541. 4. Arico` M, Janka G, Fischer A, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia 1996;10:197–203. 5. Meeths M, Chiang SCC, Wood SM, et al. Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D. Blood 2011;118:5783–5793. 6. Zhang K, Filipovich AH, Johnson J, et al. Hemophagocytic lymphohistiocytosis, familial. GeneReviewsTM [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2013. 2006 Mar 22 [updated 2013 Jan 17].
Pediatr Blood Cancer DOI 10.1002/pbc
963
7. Zur Stadt U, Beutel K, Kolberg S, et al. Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: Molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A. Hum Mutat 2006;27:62–68. 8. Seo JY, Song JS, Lee KO, et al. Founder effects in two predominant intronic mutations of UNC13D, c.118-308C>T and c.754-1G>C underlie the unusual predominance of type 3 familial hemophagocytic lymphohistiocytosis (FHL3) in Korea. Ann Hematol 2013;92:357–364. 9. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr 2007;166:95–109. 10. Horne A, Ramme KG, Rudd E, et al. Characterization of PRF1, STX11 and UNC13D genotypephenotype correlations in familial hemophagocytic lymphohistiocytosis. Br J Haematol 2008;143:75–83.
HIGHLIGHT 1 by Nupur Mittal,
MD,
* and Paul M. Kent, MD2
Insights Into the Genetic Basis of Familal Hemophagocytic Lymphohistiocytosis (Commentary on Qian et al., page 1034)
I
n 1952, Dr James Farquhar, a Scottish pediatrician noticed the familial recurrence of a disease affecting male and female siblings aged 2 months, causing fever, cytopenia, hepatosplenomegaly, and rapidly leading to death despite treatment with antibiotics and steroids [1]. In the 6 decades since we have evolved an understanding of familial hemophagocytic lymphohistiocytosis (FHL) that has also greatly enhanced our understanding of the immune system. In this issue of Pediatric Blood and Cancer, Qian et al. extend our knowledge of the genetic underpinnings of this rare and deadly disease [2]. As recently as December 1999, the first FHL-related gene was described [3,4]. Over the subsequent decade we have learned that FHL is a very heterogeneous autosomal recessive disorder. To date, OMIM lists, five genetic lesions in four genes: PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5). Current knowledge allows a genetic defect to be identified in variable proportions of patients, depending on ethnic origin. For example, bi-allelic mutations in FHL-3 are identified in approximately 50% of North American patients. Specifically the subject of Qian’s review, the FHL-3 mutations in UNC13D are found in 30% of Caucasion, 90% of Koreans, but is rare in patients of African descent [5–8]. The authors point out that although FHL-3 is an autosomal recessive disorder, several symptomatic patients have been described who have a mutation identified on only 1 allele [6,7]. Zhang et al. postulate that this can occur if a second allele is mutated in the promoter region, a non-coding region, on a different gene or there exists a complex rearrangement that is undetectable by current methods [6]. In this issue Qian et al. report their findings from a study in which they performed genetic testing of the UNC13D gene, including DNA sequencing of three recently reported non-coding mutations to investigate the prevalence of these mutations in a large North American cohort of 1709 patients with clinical diagnosis of HLH. This study uncovers familial cases not previously recognized allowing for counselling after screening. In addition, the authors identify mutations that cannot be detected by conventional testing in a North American cohort which may explain genetic basis in several patients who were thought to be heterozygous, or carriers. Furthermore, they report 8 new mutations in UNC13D for the first time and together with previously diagnosed FHL3 patients in their registry, these lesions account for nearly a 1/3 of the FHL3 patients. Indeed, recent work on the deep intronic (c.118-308C>T) and inversion mutations of UNC13D in Northern European and Korean patients revealed founder effects [4,8].
C
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25006 Published online 25 February 2014 in Wiley Online Library (wileyonlinelibrary.com).
The expanded panel of identifiable lesions offered by Qian et al. can identify bi-allelic mutations, raising important questions pertaining to follow up, treatment, preemptive transplant, and genetic and antenatal counselling. Currently the indications of genetic testing for familial HLH are for confirmation of diagnosis in a symptomatic individual, pre-symptomatic testing of at-risk siblings, carrier identification in individuals with a family history of FHL and prenatal diagnosis of an at-risk fetus, after confirmation of bi-allelic mutations in the parents [6]. In addition, even though the typical age of presentation for familial HLH is within infancy, some affected individuals may present later in life [9]. An attempt at identification of a complete genotype achieved by this type of testing may aid consideration of pre-symptomatic bone marrow transplantation and timely treatment in at risk genetically affected siblings and children with an atypical phenotype (for example acute liver failure, acute encephalopathy) [10]. The decision to prophylactically transplant asymptomatic affected individuals is complex, but, at the least such individuals may be monitored carefully and a suitable stem cell donor identified. Additionally such screening may have value in that, mutations in the FHL related genes have shown an increased frequency of lymphoma, leukemia, diabetes mellitus, multiple sclerosis, and juvenile arthritis [3]. More FHL data on correlations between genotype and phenotype in a large cohort of patients are needed to inform clinicians about screening asymptomatic individuals in a cost effective manner. Qian et al. have taken an important step towards this goal.
REFERENCES 1. Farquhar J, Claireaux A. Familial haemophagocytic reticulosis. Arch Dis Child 1952;27:519–525. 2. Qian Y, Johnson JA, Connor JA, et al. The 253-kb inversion and deep intronic mutations in UNC13D are present in North American patients with familial hemophagocytic lymphohistiocytosis 3. Pediatric Blood Cancer 2014; doi: 10.1002/pbc.24955. [Epub ahead of print].
1
Department of Pediatrics, Division of Pediatric Hematology Oncology, Rush University Medical Center, University of Illinois At Chicago and John. H. Stroger hospital (Tri- institutional fellowship), Chicago, Illinois; 2Department of Pediatrics, Division of Pediatric Hematology Oncology, Rush University Medical Center, Chicago, Illinois Correspondence to: Nupur Mittal, 1725 West Harrison Street, Suite 710 Chicago, IL 60612-3824. E-mail: [email protected]
Received 2 February 2014; Accepted 4 February 2014
Highlight 3. Cetica V, Pende D, Griffiths GM, et al. Molecular basis of familial hemophagocytic lymphohistiocytosis. Hematologica 2010;95:538–541. 4. Arico` M, Janka G, Fischer A, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia 1996;10:197–203. 5. Meeths M, Chiang SCC, Wood SM, et al. Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D. Blood 2011;118:5783–5793. 6. Zhang K, Filipovich AH, Johnson J, et al. Hemophagocytic lymphohistiocytosis, familial. GeneReviewsTM [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2013. 2006 Mar 22 [updated 2013 Jan 17].
Pediatr Blood Cancer DOI 10.1002/pbc
963
7. Zur Stadt U, Beutel K, Kolberg S, et al. Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: Molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A. Hum Mutat 2006;27:62–68. 8. Seo JY, Song JS, Lee KO, et al. Founder effects in two predominant intronic mutations of UNC13D, c.118-308C>T and c.754-1G>C underlie the unusual predominance of type 3 familial hemophagocytic lymphohistiocytosis (FHL3) in Korea. Ann Hematol 2013;92:357–364. 9. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr 2007;166:95–109. 10. Horne A, Ramme KG, Rudd E, et al. Characterization of PRF1, STX11 and UNC13D genotypephenotype correlations in familial hemophagocytic lymphohistiocytosis. Br J Haematol 2008;143:75–83.
