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Autosomal recessive mutations in the gene CECR1 cause an inflammatory vasculopathy with a highly varied clinical presentation that often meets the criteria for polyarteritis nodosa and can occur with early-onset strokes, according to findings from two separate reports on families with several affected members as well as unrelated affected persons.
All but 2 of the combined total of 33 patients in both studies were younger than 18 years at the onset of disease, including 13 with a history of lacunar strokes and 12 who met criteria for polyarteritis nodosa (PAN) from the Paediatric Rheumatology European Society and the European League Against Rheumatism for those with an onset before 18 years of age or from the American College of Rheumatology at an onset of 18 years of age or older.
The studies identified 12 CECR1 (cat eye syndrome chromosome region, candidate 1) variants that encoded dysfunctional adenosine deaminase 2 (ADA2) proteins. In one report, Israeli and German researchers described individuals who presented primarily with features of polyarteritis nodosa. They identified mutations in 16 patients from five families of Georgian Jewish ancestry and four siblings from one family of German ancestry, as well as single cases in three unrelated patients of Georgian Jewish ancestry and 1 Turkish patient who had been referred to them (N. Engl. J. Med. 2014;370:921-31).
In the other report, researchers from the National Institutes of Health studied nine patients with pediatric onset of disease, including five patients from the United States, one from the United Kingdom, and three from Turkey, including one pair of siblings. Eight of the patients presented with a history of lacunar strokes (N. Engl. J. Med. 2014;370:911-20).
Both reports used whole-exome sequencing in most cases and candidate-gene sequencing in others to detect autosomally recessive mutations in CECR1 (cat’s eye syndrome chromosome region, candidate 1) that cause a deficiency in adenosine deaminase 2 (ADA2), including cases with heterozygous compound mutations. Cell culture experiments indicated that ADA2 is a growth factor for endothelial and leukocyte development and differentiation, and modeling of the mutations’ effects in zebrafish resulted in intracranial hemorrhages.
One of the main differences between the two studies was in the differing presentation of patients, with mainly strokes in the NIH study but more PAN-like disease and peripheral nervous system involvement in the Israeli and German study.
All of the patients in the Israeli and German study had highly variable disease severity, even within families. Of the 19 Georgian Jewish patients, 18 had cutaneous manifestation of the disease, mainly livedo reticularis, although some had ischemia and necrosis of the fingers and toes. Fever was present in 11, and myalgia and/or arthralgia occurred in 12. Ten had visceral features, six of which were gastrointestinal, and eight had neurologic disease, most of which occurred peripherally. Among the four German siblings, all had peripheral neuropathy, three had symptomatic or subclinical brain infarctions, three had cutaneous manifestations, and three had myalgia and/or arthralgia, but none had visceral involvement. The single Turkish patient had most of these clinical manifestations except for peripheral or central nervous system involvement. Not all of the 24 patients in the Israeli and German study were fully evaluated for PAN, but nearly all were suspected of having the disease.
The NIH team compiled cases that were most striking for the history of early-onset ischemic lacunar stroke in eight of the nine patients, including five from the United States who had strokes before the age of 5 years but showed no signs of cerebral vasculitis on MR angiography. Three patients also had hemorrhagic stroke or hemorrhagic transformation. All patients had recurrent fever, eight had livedo racemosa, and five had ophthalmologic involvement. Only the two Turkish siblings had a diagnosis of PAN.
The spectrum of disease observed in the studies could be related to what CECR1 mutation is present, with 12 overall reported in the two studies, according to one of the NIH study investigators, Dr. Daniel L. Kastner, a rheumatologist and scientific director of the National Human Genome Research Institute. He also is head of the inflammatory diseases section in the medical genetics branch of the Institute.
"It wouldn’t be surprising to me if certain mutations are associated with certain clinical presentations," he said in an interview.
The most common mutation reported among the Georgian Jewish patients – all of whom were diagnosed with PAN – was also found in the NIH study’s three Turkish patients, two of whom had a PAN diagnosis. This variant had a carrier frequency of about 10% in a control group of 246 unrelated Georgian Jewish controls, which would predict based on Mendelian genetic principles that 1 in 400 individuals in the Georgian Jewish population in Israel would carry two copies of the variant. The individuals who were homozygous for that variant in the Israeli and German study showed variability in phenotype, ranging from a diagnosis of diagnosed PAN to milder disease not meeting the full criteria for PAN. Given the relative commonality of the variant, ADA2-associated disease in Georgian Jewish people and other populations is likely underdiagnosed or being misdiagnosed for other conditions because of the clinical variability, Dr. Kastner said.
NIH investigators have talked with Dr. Peter Merkel, principal investigator and director of the Vasculitis Clinical Research Consortium, about conducting collaborative studies to look for variants of ADA2 in others who have nonfamilial PAN and did not have early-onset disease. "Even if they don’t [have variants in ADA2], it may still be the case that the pathway is somehow important and studies of biopsies from those patients would in some way allow us to connect that pathway to their disease. But that’s unknown," Dr. Kastner said.
When Dr. Kastner and his associates were looking for the mutations in other genetics databases, they found that whole-exome sequencing of 47 pairs of siblings with late-onset ischemic stroke in the Siblings With Ischemic Stroke Study had detected two brothers who each were heterozygous carriers of one of the mutations discovered in the study. Their ischemic strokes were similar in distribution to those seen in children with two mutations. "So it’s at least possible, although at this point it’s not formally proven, [that] that perhaps carrying one copy of this mutation, as opposed to having two as these kids have, could put you at some risk for having stroke later on in life. And it may be that, similarly, having one copy of a variant in this gene would predispose to other forms of vasculitis as well."
In three of the patients in the NIH study, treatment with low doses of fresh frozen plasma as a replacement therapy for ADA2 deficiency has appeared to be safe, but getting enough of it into patients and knowing whether it will last long enough are questions that the investigators are currently trying to answer, Dr. Kastner said. Initially, Dr. Kastner said his group was hesitant to use anti–tumor necrosis factor-alpha agents to treat patients because of the known, but small risk of demyelination with their use, which would not have been appropriate to try in patients who already had neurologic problems, because it would be very hard to tell if further lesions would be caused by underlying disease or the drug. However, when the Israeli group reported success with anti-TNF-alpha agents in their patients (and ultimately reported that 10 patients had a clinically significant therapeutic response), the NIH investigators decided to try them. Treatment with etanercept in five patients has reduced the occurrence of fevers in all and improved urticarial papules and plaques observed in three patients.
Pediatric rheumatologists who have patients with vasculitis or are suspected of having vasculitis should keep CECR1 mutations in mind now that the cause and some of the natural history and possible treatments for early-onset disease are known. Rheumatologists seeing adult patients with PAN could consider these mutations as a possible cause and at least note that some of these pathways may be important in their patients even if they don’t have mutations in CECR1, advised Dr. Kastner. He had no financial conflicts to disclose.
Autosomal recessive mutations in the gene CECR1 cause an inflammatory vasculopathy with a highly varied clinical presentation that often meets the criteria for polyarteritis nodosa and can occur with early-onset strokes, according to findings from two separate reports on families with several affected members as well as unrelated affected persons.
All but 2 of the combined total of 33 patients in both studies were younger than 18 years at the onset of disease, including 13 with a history of lacunar strokes and 12 who met criteria for polyarteritis nodosa (PAN) from the Paediatric Rheumatology European Society and the European League Against Rheumatism for those with an onset before 18 years of age or from the American College of Rheumatology at an onset of 18 years of age or older.
The studies identified 12 CECR1 (cat eye syndrome chromosome region, candidate 1) variants that encoded dysfunctional adenosine deaminase 2 (ADA2) proteins. In one report, Israeli and German researchers described individuals who presented primarily with features of polyarteritis nodosa. They identified mutations in 16 patients from five families of Georgian Jewish ancestry and four siblings from one family of German ancestry, as well as single cases in three unrelated patients of Georgian Jewish ancestry and 1 Turkish patient who had been referred to them (N. Engl. J. Med. 2014;370:921-31).
In the other report, researchers from the National Institutes of Health studied nine patients with pediatric onset of disease, including five patients from the United States, one from the United Kingdom, and three from Turkey, including one pair of siblings. Eight of the patients presented with a history of lacunar strokes (N. Engl. J. Med. 2014;370:911-20).
Both reports used whole-exome sequencing in most cases and candidate-gene sequencing in others to detect autosomally recessive mutations in CECR1 (cat’s eye syndrome chromosome region, candidate 1) that cause a deficiency in adenosine deaminase 2 (ADA2), including cases with heterozygous compound mutations. Cell culture experiments indicated that ADA2 is a growth factor for endothelial and leukocyte development and differentiation, and modeling of the mutations’ effects in zebrafish resulted in intracranial hemorrhages.
One of the main differences between the two studies was in the differing presentation of patients, with mainly strokes in the NIH study but more PAN-like disease and peripheral nervous system involvement in the Israeli and German study.
All of the patients in the Israeli and German study had highly variable disease severity, even within families. Of the 19 Georgian Jewish patients, 18 had cutaneous manifestation of the disease, mainly livedo reticularis, although some had ischemia and necrosis of the fingers and toes. Fever was present in 11, and myalgia and/or arthralgia occurred in 12. Ten had visceral features, six of which were gastrointestinal, and eight had neurologic disease, most of which occurred peripherally. Among the four German siblings, all had peripheral neuropathy, three had symptomatic or subclinical brain infarctions, three had cutaneous manifestations, and three had myalgia and/or arthralgia, but none had visceral involvement. The single Turkish patient had most of these clinical manifestations except for peripheral or central nervous system involvement. Not all of the 24 patients in the Israeli and German study were fully evaluated for PAN, but nearly all were suspected of having the disease.
The NIH team compiled cases that were most striking for the history of early-onset ischemic lacunar stroke in eight of the nine patients, including five from the United States who had strokes before the age of 5 years but showed no signs of cerebral vasculitis on MR angiography. Three patients also had hemorrhagic stroke or hemorrhagic transformation. All patients had recurrent fever, eight had livedo racemosa, and five had ophthalmologic involvement. Only the two Turkish siblings had a diagnosis of PAN.
The spectrum of disease observed in the studies could be related to what CECR1 mutation is present, with 12 overall reported in the two studies, according to one of the NIH study investigators, Dr. Daniel L. Kastner, a rheumatologist and scientific director of the National Human Genome Research Institute. He also is head of the inflammatory diseases section in the medical genetics branch of the Institute.
"It wouldn’t be surprising to me if certain mutations are associated with certain clinical presentations," he said in an interview.
The most common mutation reported among the Georgian Jewish patients – all of whom were diagnosed with PAN – was also found in the NIH study’s three Turkish patients, two of whom had a PAN diagnosis. This variant had a carrier frequency of about 10% in a control group of 246 unrelated Georgian Jewish controls, which would predict based on Mendelian genetic principles that 1 in 400 individuals in the Georgian Jewish population in Israel would carry two copies of the variant. The individuals who were homozygous for that variant in the Israeli and German study showed variability in phenotype, ranging from a diagnosis of diagnosed PAN to milder disease not meeting the full criteria for PAN. Given the relative commonality of the variant, ADA2-associated disease in Georgian Jewish people and other populations is likely underdiagnosed or being misdiagnosed for other conditions because of the clinical variability, Dr. Kastner said.
NIH investigators have talked with Dr. Peter Merkel, principal investigator and director of the Vasculitis Clinical Research Consortium, about conducting collaborative studies to look for variants of ADA2 in others who have nonfamilial PAN and did not have early-onset disease. "Even if they don’t [have variants in ADA2], it may still be the case that the pathway is somehow important and studies of biopsies from those patients would in some way allow us to connect that pathway to their disease. But that’s unknown," Dr. Kastner said.
When Dr. Kastner and his associates were looking for the mutations in other genetics databases, they found that whole-exome sequencing of 47 pairs of siblings with late-onset ischemic stroke in the Siblings With Ischemic Stroke Study had detected two brothers who each were heterozygous carriers of one of the mutations discovered in the study. Their ischemic strokes were similar in distribution to those seen in children with two mutations. "So it’s at least possible, although at this point it’s not formally proven, [that] that perhaps carrying one copy of this mutation, as opposed to having two as these kids have, could put you at some risk for having stroke later on in life. And it may be that, similarly, having one copy of a variant in this gene would predispose to other forms of vasculitis as well."
In three of the patients in the NIH study, treatment with low doses of fresh frozen plasma as a replacement therapy for ADA2 deficiency has appeared to be safe, but getting enough of it into patients and knowing whether it will last long enough are questions that the investigators are currently trying to answer, Dr. Kastner said. Initially, Dr. Kastner said his group was hesitant to use anti–tumor necrosis factor-alpha agents to treat patients because of the known, but small risk of demyelination with their use, which would not have been appropriate to try in patients who already had neurologic problems, because it would be very hard to tell if further lesions would be caused by underlying disease or the drug. However, when the Israeli group reported success with anti-TNF-alpha agents in their patients (and ultimately reported that 10 patients had a clinically significant therapeutic response), the NIH investigators decided to try them. Treatment with etanercept in five patients has reduced the occurrence of fevers in all and improved urticarial papules and plaques observed in three patients.
Pediatric rheumatologists who have patients with vasculitis or are suspected of having vasculitis should keep CECR1 mutations in mind now that the cause and some of the natural history and possible treatments for early-onset disease are known. Rheumatologists seeing adult patients with PAN could consider these mutations as a possible cause and at least note that some of these pathways may be important in their patients even if they don’t have mutations in CECR1, advised Dr. Kastner. He had no financial conflicts to disclose.
Autosomal recessive mutations in the gene CECR1 cause an inflammatory vasculopathy with a highly varied clinical presentation that often meets the criteria for polyarteritis nodosa and can occur with early-onset strokes, according to findings from two separate reports on families with several affected members as well as unrelated affected persons.
All but 2 of the combined total of 33 patients in both studies were younger than 18 years at the onset of disease, including 13 with a history of lacunar strokes and 12 who met criteria for polyarteritis nodosa (PAN) from the Paediatric Rheumatology European Society and the European League Against Rheumatism for those with an onset before 18 years of age or from the American College of Rheumatology at an onset of 18 years of age or older.
The studies identified 12 CECR1 (cat eye syndrome chromosome region, candidate 1) variants that encoded dysfunctional adenosine deaminase 2 (ADA2) proteins. In one report, Israeli and German researchers described individuals who presented primarily with features of polyarteritis nodosa. They identified mutations in 16 patients from five families of Georgian Jewish ancestry and four siblings from one family of German ancestry, as well as single cases in three unrelated patients of Georgian Jewish ancestry and 1 Turkish patient who had been referred to them (N. Engl. J. Med. 2014;370:921-31).
In the other report, researchers from the National Institutes of Health studied nine patients with pediatric onset of disease, including five patients from the United States, one from the United Kingdom, and three from Turkey, including one pair of siblings. Eight of the patients presented with a history of lacunar strokes (N. Engl. J. Med. 2014;370:911-20).
Both reports used whole-exome sequencing in most cases and candidate-gene sequencing in others to detect autosomally recessive mutations in CECR1 (cat’s eye syndrome chromosome region, candidate 1) that cause a deficiency in adenosine deaminase 2 (ADA2), including cases with heterozygous compound mutations. Cell culture experiments indicated that ADA2 is a growth factor for endothelial and leukocyte development and differentiation, and modeling of the mutations’ effects in zebrafish resulted in intracranial hemorrhages.
One of the main differences between the two studies was in the differing presentation of patients, with mainly strokes in the NIH study but more PAN-like disease and peripheral nervous system involvement in the Israeli and German study.
All of the patients in the Israeli and German study had highly variable disease severity, even within families. Of the 19 Georgian Jewish patients, 18 had cutaneous manifestation of the disease, mainly livedo reticularis, although some had ischemia and necrosis of the fingers and toes. Fever was present in 11, and myalgia and/or arthralgia occurred in 12. Ten had visceral features, six of which were gastrointestinal, and eight had neurologic disease, most of which occurred peripherally. Among the four German siblings, all had peripheral neuropathy, three had symptomatic or subclinical brain infarctions, three had cutaneous manifestations, and three had myalgia and/or arthralgia, but none had visceral involvement. The single Turkish patient had most of these clinical manifestations except for peripheral or central nervous system involvement. Not all of the 24 patients in the Israeli and German study were fully evaluated for PAN, but nearly all were suspected of having the disease.
The NIH team compiled cases that were most striking for the history of early-onset ischemic lacunar stroke in eight of the nine patients, including five from the United States who had strokes before the age of 5 years but showed no signs of cerebral vasculitis on MR angiography. Three patients also had hemorrhagic stroke or hemorrhagic transformation. All patients had recurrent fever, eight had livedo racemosa, and five had ophthalmologic involvement. Only the two Turkish siblings had a diagnosis of PAN.
The spectrum of disease observed in the studies could be related to what CECR1 mutation is present, with 12 overall reported in the two studies, according to one of the NIH study investigators, Dr. Daniel L. Kastner, a rheumatologist and scientific director of the National Human Genome Research Institute. He also is head of the inflammatory diseases section in the medical genetics branch of the Institute.
"It wouldn’t be surprising to me if certain mutations are associated with certain clinical presentations," he said in an interview.
The most common mutation reported among the Georgian Jewish patients – all of whom were diagnosed with PAN – was also found in the NIH study’s three Turkish patients, two of whom had a PAN diagnosis. This variant had a carrier frequency of about 10% in a control group of 246 unrelated Georgian Jewish controls, which would predict based on Mendelian genetic principles that 1 in 400 individuals in the Georgian Jewish population in Israel would carry two copies of the variant. The individuals who were homozygous for that variant in the Israeli and German study showed variability in phenotype, ranging from a diagnosis of diagnosed PAN to milder disease not meeting the full criteria for PAN. Given the relative commonality of the variant, ADA2-associated disease in Georgian Jewish people and other populations is likely underdiagnosed or being misdiagnosed for other conditions because of the clinical variability, Dr. Kastner said.
NIH investigators have talked with Dr. Peter Merkel, principal investigator and director of the Vasculitis Clinical Research Consortium, about conducting collaborative studies to look for variants of ADA2 in others who have nonfamilial PAN and did not have early-onset disease. "Even if they don’t [have variants in ADA2], it may still be the case that the pathway is somehow important and studies of biopsies from those patients would in some way allow us to connect that pathway to their disease. But that’s unknown," Dr. Kastner said.
When Dr. Kastner and his associates were looking for the mutations in other genetics databases, they found that whole-exome sequencing of 47 pairs of siblings with late-onset ischemic stroke in the Siblings With Ischemic Stroke Study had detected two brothers who each were heterozygous carriers of one of the mutations discovered in the study. Their ischemic strokes were similar in distribution to those seen in children with two mutations. "So it’s at least possible, although at this point it’s not formally proven, [that] that perhaps carrying one copy of this mutation, as opposed to having two as these kids have, could put you at some risk for having stroke later on in life. And it may be that, similarly, having one copy of a variant in this gene would predispose to other forms of vasculitis as well."
In three of the patients in the NIH study, treatment with low doses of fresh frozen plasma as a replacement therapy for ADA2 deficiency has appeared to be safe, but getting enough of it into patients and knowing whether it will last long enough are questions that the investigators are currently trying to answer, Dr. Kastner said. Initially, Dr. Kastner said his group was hesitant to use anti–tumor necrosis factor-alpha agents to treat patients because of the known, but small risk of demyelination with their use, which would not have been appropriate to try in patients who already had neurologic problems, because it would be very hard to tell if further lesions would be caused by underlying disease or the drug. However, when the Israeli group reported success with anti-TNF-alpha agents in their patients (and ultimately reported that 10 patients had a clinically significant therapeutic response), the NIH investigators decided to try them. Treatment with etanercept in five patients has reduced the occurrence of fevers in all and improved urticarial papules and plaques observed in three patients.
Pediatric rheumatologists who have patients with vasculitis or are suspected of having vasculitis should keep CECR1 mutations in mind now that the cause and some of the natural history and possible treatments for early-onset disease are known. Rheumatologists seeing adult patients with PAN could consider these mutations as a possible cause and at least note that some of these pathways may be important in their patients even if they don’t have mutations in CECR1, advised Dr. Kastner. He had no financial conflicts to disclose.
FROM NEW ENGLAND JOURNAL OF MEDICINE
