- Email: [email protected]
ABCC6 mutations and early onset stroke: Two cases of a typical Pseudoxanthoma Elasticum
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 8 ) 1 e4
Official Journal of the European Paediatric Neurology Society
Case study
ABCC6 mutations and early onset stroke: Two cases of a typical Pseudoxanthoma Elasticum Marta Bertamino a,*,1, Mariasavina Severino b,1, Alice Grossi c, Marta Rusmini c, Domenico Tortora b, Carlo Gandolfo b, Silvia Pederzoli d, Clara Malattia d, Paolo Picco d, Pasquale Striano e, Isabella Ceccherini c, Maja Di Rocco f, and the Gaslini Pediatric Stroke Group a
Thrombosis and Hemostasis Unit, Istituto Giannina Gaslini, Genoa, Italy Neuroradiology Unit, Istituto Giannina Gaslini, Genoa, Italy c Medical Genetics Unit, Istituto Giannina Gaslini, Genoa, Italy d Rheumatology Unit, Istituto Giannina Gaslini, Genoa, Italy e Pediatric Neurology and Muscular Diseases Unit, Istituto Giannina Gaslini, Genova, Italy f Rare Disease Unit, Istituto Giannina Gaslini, Genoa, Italy b
article info
abstract
Article history:
Pseudoxanthoma elasticum (PXE) is a rare genetic disorder characterized by fragmented
Received 11 September 2017
and mineralized elastic fibers in the mid-dermis of the skin, eye, digestive tract and car-
Received in revised form
diovascular system. Clinical presentation includes typical skin lesions, ocular angioid
14 February 2018
streaks, and multisystem vasculopathy. The age of onset varies considerably from infancy
Accepted 4 April 2018
to old age, but the diagnosis is usually made in young adults due to frequent absence of pathognomonic skin and ocular manifestations in early childhood. We report two children
Keywords:
with PXE presenting with isolated multisystem vasculopathy and early-onset stroke. In the
Pediatric stroke
first patient, diagnosis was delayed until typical dermatologic alterations appeared; in the
Genetics
second patient, next-generation sequencing (NGS) study led to early diagnosis and specific
Magnetic resonance imaging
follow-up, underlying the crucial role in idiopathic pediatric stroke of early genetic testing
Next-generation sequencing
using NGS-based panels. © 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disorder caused by mutations of ABCC6 (ATP-binding
cassette subfamily C member 6; OMIM#603234), encoding a transmembrane ATP-binding efflux transporter. The disease is characterized by the accumulation of mineralized and/or fragmented elastic fibers in the skin, eyes, vascular walls, and gastrointestinal system. The pathogenic mechanism is
* Corresponding author. Thrombosis and Hemostasis Unit, Istituto Giannina Gaslini, Via Gaslini 5, 16147, Genova, Italy. E-mail address: [email protected] (M. Bertamino). 1 These authors contributed equally. https://doi.org/10.1016/j.ejpn.2018.04.002 1090-3798/© 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. Please cite this article in press as: Bertamino M, et al., ABCC6 mutations and early onset stroke: Two cases of a typical Pseudoxanthoma Elasticum, European Journal of Paediatric Neurology (2018), https://doi.org/10.1016/j.ejpn.2018.04.002
2
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 8 ) 1 e4
unknown and no specific treatment is currently available.1 Interestingly, homozygous or compound heterozygous mutation of the ABCC6 gene may also cause generalized arterial calcification of infancy-2 (GACI2), characterized by infantile onset of widespread arterial calcification and/or narrowing of large- and medium-sized vessels, periarticular calcifications, and, occasionally, hypophosphatemic rickets. GACI2 and PXE likely represent two phenotypic manifestations of ABCC6 mutations, sharing ectopic calcifications at the level of arterial walls and/or other organs as a common denominator, rather than two distinct disorders. On the other hand, histological differences have been reported between these two entities, with higher prevalence of intimal thickening resembling fibromuscular dysplasia in PXE.2 Patients with PXE commonly present with skin papules and/or retinal angioid streaks, while vascular lesions and cerebrovascular complications are rarer but may cause severe neurologic impairment.1 The age of onset varies considerably from infancy to old age. Skin and ocular manifestations are usually late-onset and the disease is often diagnosed in the second or third decade of life. Of note, cerebrovascular manifestations may present in childhood, without other organs involvement, often leading to diagnostic delays. We report two PXE children presenting with multisystem vasculopathy and cerebrovascular complications, discussing the diagnostic strategies in the pediatric age group, and the vascular features that may represent useful disease hallmarks.
2.
Case reports
2.1.
Case 1
This 14-year-old girl was referred to our center at age 5 years due to the suspect of cerebral vasculitis and drug-resistant epileptic seizures. She was the second child of healthy unrelated parents, born after uneventful pregnancy and normal delivery. Her family history was unremarkable. At the age of 5 months, she experienced a first, non-prolonged tonic-clonic seizure. Brain MRI and MR angiography (MRA) revealed multiple acute cerebral ischemic infarcts, with focal narrowing of left vertebral artery and petrous segments of the internal carotid arteries (ICAs). The neurologic examination revealed mild left-side hemiparesis. A secondary prevention therapy with acetylsalicylic acid was started. The girl remained stable until the age of 5 years, when she developed a multidrugresistant epilepsy. At admission in our hospital, physical examination revealed an asymmetry of lower-extremity pulse and blood pressure measurements. Basic blood tests, ECG, echocardiography and abdominal ultrasonography were unremarkable. A lower-extremity Doppler ultrasound revealed a fall in blood velocity along the common femoral and tibial arteries. Brain MRI showed chronic evolution of the corticosubcortical infarcts (Fig. 1A), while MRA and digital subtraction angiography (DSA) confirmed bilateral ICAs and left vertebral artery stenosis (Fig. 1BeC), and revealed multiple stenosis of external iliac arteries. A right temporal artery biopsy was unspecific, but excluded inflammation and calcification on vassal wall. One year later, she complained of limbs paresthesias, and MRA showed progression of the stenosis of
the right iliaco-femoral branches. At 6 years of age, physical examination revealed the presence of multiple asymptomatic yellow papules around the neck, suggestive of PXE at histopathologic examination. The ABCC6 gene was screened and a homozygous nonsense mutation (p.R1141*) detected, thus confirming the diagnostic suspect. Both parents were heterozygous carriers. At last follow-up, she had moderate intellectual disability, drug-resistant epilepsy, worsening of cutaneous involvement, but no ocular symptoms. Brain MRI and MRA were unchanged.
2.2.
Case 2
This 5-year-old boy was referred at age 2 years for acute cerebral ischemic stroke. He was the first child of nonconsanguineous parents, born at term after a normal pregnancy. Family history was unremarkable. The child was admitted to the local hospital for right-sided partial seizures and ipsilateral gaze deviation. At admission neurological examination revealed right sided hemiplegia. The psychomotor development was otherwise normal. At physical examination the radial and femoral pulses were difficult to palpate. Cutaneous, gastrointestinal, hematologic and ocular examinations were unremarkable. Brain MRI showed an acute ischemic infarct in the left fronto-insular region (Fig. 1DeE), while the MRA revealed left middle cerebral artery sub-occlusion, and bilateral segmental ICAs agenesis. Severe renovascular hypertension and left ventricular hypertrophy were detected. One month later, MRA and DSA showed improvement of flow signal in the distal branches of left middle cerebral artery, bilateral segmental ICAs agenesis associated with a compensating arterial network, called carotid rete mirabile (CRM), and left vertebral artery stenosis (Fig. 1FeG). Infrarenal aortic tapering and bilateral stenosis of the external iliac arteries with a network of collateral vessels were noted. A femoral artery biopsy revealed fragmentation of the elastic fibers in the vessel wall with no signs of inflammation or calcification. An in-house NGS-based panel, including 15 genes (ABCC6, ACTA2, ATP7A, CBS, CECR1, COL4A1, ELN, GLA, HTRA1, JAG1, NF1, NOTCH3, PCNT, SAMHD1, SLC2A10) responsible for the most common monogenic disorders associated with pediatric ischemic strokes, was tested (Grossi et al., submitted). Two compound heterozygous ABCC6 loss-of-function mutations, c.4182_4182delG (p.Lys1394Asnfs*9) and c.2900G > A (p.Trp967*), were found. Parents were heterozygous for each of the two variants, respectively. Dual therapy with acetylsalicylic acid and clopidogrel was started, associated with proton pump inhibitors and screening of gastric ulcer with fecal occult blood tests. In the following three years, the arterial hypertension regressed spontaneously, and the child had no new cerebrovascular events, showing normal psychomotor development with persisting mild right-sided hemiparesis. Last brain MRI and brain/abdominal MRA were unchanged. Neither skin lesions nor ocular involvement were present at last follow-up.
3.
Discussion
The present cases illustrate the diagnostic challenges of PXE in children presenting with isolated multisystem
Please cite this article in press as: Bertamino M, et al., ABCC6 mutations and early onset stroke: Two cases of a typical Pseudoxanthoma Elasticum, European Journal of Paediatric Neurology (2018), https://doi.org/10.1016/j.ejpn.2018.04.002
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 8 ) 1 e4
3
Fig. 1 e A-C) Brain MRI and DSA of patient 1 at 5 years of life. A) Axial FLAIR images show multiple chronic corticosubcortical infarcts in the left occipital (arrowhead) and right fronto-mesial and precentral regions (thick arrows). Note prominent leptomeningeal collaterals resulting in increased signal intensity within the subarachnoid spaces in the left fronto-parietal regions. Lateral DSA views of the right ICA (B) and left ICA (C) reveal bilateral narrowing of the petrous segments (arrowheads). D-G) Brain MRI and DSA of patient 2 at clinical onset. Axial T2-weighted (D) and diffusion weighted (E) images show an acute left frontal ischemic infarct. F) Frontal DSA view of the ICAs confirms bilateral segmental agenesis of the petrous ICAs (arrows) associated with external carotid artery stenosis and CRM circumventing the site of the agenesis (arrowheads). G) Frontal DSA view of the left vertebral artery depicts a focal intracranial stenosis (arrowhead).
vasculopathy and cerebrovascular complications. Both children underwent a comprehensive pediatric stroke diagnostic protocol, including detailed anamnesis on risk factors (previous infectious disease and vaccination status, recent head trauma, cardiac diseases, cancer, etc), laboratory studies (such as screening for inherited and acquired thrombophilia and metabolic disorders), cardiac evaluation with echocardiography, and neuroradiological examination including both head and neck MR angiography and digital subtraction angiography. We thus excluded the most common causes of pediatric stroke, such as cardioembolic diseases, sickle cell anemia, and other cerebral vasculopathies including moyamoya disease, post-varicella focal cerebral arteriopathy, and vasculitis. In Patient 1 the diagnosis of PXE was delayed for 6 years, until typical cutaneous manifestations appeared. Genetic testing based on Sanger sequencing is time consuming and usually performed once specific clinico-radiological phenotypes become evident. In addition, PXE may have high intra-familiar heterogeneity or incomplete penetrance, with manifestation of the full-blown clinical spectrum appearing even many years after the onset.1 Conversely, in Patient 2 a NGS-based gene panel, including genes related to the most common monogenic disorders associated with pediatric ischemic strokes revealed compound heterozygous truncating mutations of
ABCC6, thus allowing to achieve an earlier diagnosis even in the absence of PXE pathognomonic signs. Of note, in the last decade, there has been a growing interest in the genetic causes of pediatric stroke.3 Once excluded the most common pediatric stroke causes, as previously mentioned, other rare genetic disorders should be considered in the differential diagnosis of idiopathic early-onset stroke and/or cerebral arteriopathies. Indeed, genetic testing using NGS-based panels may allow early diagnoses even in the absence of a clear clinical suspicion, while single gene sequencing requires a well sustained working hypothesis regarding the possible genetic cause. Whole exome sequencing (WES) and whole genome sequencing (WGS) can be used instead when all the hypotheses and specific genetic approaches have already been undertaken without any relevant achievement. Early diagnosis has relevant implications for treatment, follow-up strategies and genetic counseling. Accordingly, although no etiological treatment is currently available, early PXE diagnosis is important to implement specific therapeutic and prevention measures. Given the occurrence of ischemic strokes, we treated the patients with antiplatelet drugs associated with proton pump inhibitors, starting a close screening of gastric ulcer with fecal occult blood test, considering the higher risk of gastrointestinal bleeding reported in these patients. No bleeding
Please cite this article in press as: Bertamino M, et al., ABCC6 mutations and early onset stroke: Two cases of a typical Pseudoxanthoma Elasticum, European Journal of Paediatric Neurology (2018), https://doi.org/10.1016/j.ejpn.2018.04.002
4
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 8 ) 1 e4
complication or ischemic recurrence was observed during the follow-up. Moreover, an ophthalmology screening was started to detect macular degeneration and progressive retinal neovascularization that may result in visual loss if untreated. Interestingly, a wide range of arteriopathies has been reported in PXE, including intra- and extra-cranial aneurysms, arterial stenosis, tortuosity, and occlusion.4 Of note, cerebral arteriopathies are among the most frequent causes of pediatric stroke in children, and currently represent the strongest predictors of arterial ischemic stroke recurrence in this age group.5 Thus, careful evaluation of the site, morphology and evolution of vascular abnormalities on neuroimaging studies is extremely important. Interestingly, a distinctive involvement of the petrous and/or cavernous segments of the ICAs with segmental hypoplasia/aplasia or multiple stenosis, was noted in both the present cases. Similar vascular features have been reported in other patients with PXE, often associated with a compensating arterial network supplied by external carotid artery branches bypassing the absent ICAs segments, called CRM.4 This vasculopathy pattern differs from the moyamoya arteriopathy, affecting the terminal ICAs or proximal circle of Willis with intracranial collaterals, and from the fibromuscular dysplasia, typically involving the cervical ICA segments without collateralization. At present, the causal relationship between PXE and CRM has not been proven. However, given the rarity of these conditions, the probability of an accidental association seems unlikely. CRM is the result of congenital arterial remodeling in response to a signal or trigger, causing fetal or perinatal regression of one or more segments of the ICA. Therefore, it has been speculated that abnormal signaling related to ABCC6 mutations during arterial wall formation may play a pathological role.4 We believe that the involvement of the petrous/cavernous segments of ICAs with CRM might represent a useful disease hallmark in PXE, but future studies with genotypeephenotype correlation on a large number of patients with PXE are needed to confirm the specificity of this vascular pattern. In conclusion, this report highlights the diagnostic challenges of PXE when presenting with isolated vasculopathy and
cerebrovascular complications in children, underlying the potential role of custom NGS-panels as a first, cost-effective approach to the early identification of rare genetic causes of pediatric stroke.
Conflict of interest The authors declare no conflict of interest.
Appendix A. Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.ejpn.2018.04.002.
references
1. Roach ES, Islam MP. Pseudoxanthoma elasticum. Handb Clin Neurol 2015;132:215e21. 2. Li Q, Brodsky JL, Conlin LK, Pawel B, Glatz AC, Gafni RI, Schurgers L, Uitto J, Hakonarson H, Deardorff MA, Levine MA. Mutations in the ABCC6 gene as a cause of generalized arterial calcification of infancy: genotypic overlap with pseudoxanthoma elasticum. J Invest Dermatol 2014 Mar;134(3):658e65. https://doi.org/10.1038/jid.2013.370. Epub 2013 Sep. 5. 3. Munot P, Crow YJ, Ganesan V. Paediatric stroke: genetic insights into disease mechanisms and treatment targets. Lancet Neurol 2011;10:264e74. 4. Vasseur M, Carsin-Nicol B, Ebran JM, Willoteaux S, Martin L, riotis G. Angers PXE Consultation Center group. Carotid Lefthe rete mirabile and pseudoxanthoma elasticum: an accidental association? Eur J Vasc Endovasc Surg 2011;42:292e4. bire G, Friedman NR, Heyer GL, 5. Amlie-Lefond C, Bernard TJ, Se Lerner NB, DeVeber G, Fullerton HJ. International pediatric stroke study group. Predictors of cerebral arteriopathy in children with arterial ischemic stroke: results of the international pediatric stroke study. Circulation 2009;119:1417e23.
Please cite this article in press as: Bertamino M, et al., ABCC6 mutations and early onset stroke: Two cases of a typical Pseudoxanthoma Elasticum, European Journal of Paediatric Neurology (2018), https://doi.org/10.1016/j.ejpn.2018.04.002
Official Journal of the European Paediatric Neurology Society
Case study
ABCC6 mutations and early onset stroke: Two cases of a typical Pseudoxanthoma Elasticum Marta Bertamino a,*,1, Mariasavina Severino b,1, Alice Grossi c, Marta Rusmini c, Domenico Tortora b, Carlo Gandolfo b, Silvia Pederzoli d, Clara Malattia d, Paolo Picco d, Pasquale Striano e, Isabella Ceccherini c, Maja Di Rocco f, and the Gaslini Pediatric Stroke Group a
Thrombosis and Hemostasis Unit, Istituto Giannina Gaslini, Genoa, Italy Neuroradiology Unit, Istituto Giannina Gaslini, Genoa, Italy c Medical Genetics Unit, Istituto Giannina Gaslini, Genoa, Italy d Rheumatology Unit, Istituto Giannina Gaslini, Genoa, Italy e Pediatric Neurology and Muscular Diseases Unit, Istituto Giannina Gaslini, Genova, Italy f Rare Disease Unit, Istituto Giannina Gaslini, Genoa, Italy b
article info
abstract
Article history:
Pseudoxanthoma elasticum (PXE) is a rare genetic disorder characterized by fragmented
Received 11 September 2017
and mineralized elastic fibers in the mid-dermis of the skin, eye, digestive tract and car-
Received in revised form
diovascular system. Clinical presentation includes typical skin lesions, ocular angioid
14 February 2018
streaks, and multisystem vasculopathy. The age of onset varies considerably from infancy
Accepted 4 April 2018
to old age, but the diagnosis is usually made in young adults due to frequent absence of pathognomonic skin and ocular manifestations in early childhood. We report two children
Keywords:
with PXE presenting with isolated multisystem vasculopathy and early-onset stroke. In the
Pediatric stroke
first patient, diagnosis was delayed until typical dermatologic alterations appeared; in the
Genetics
second patient, next-generation sequencing (NGS) study led to early diagnosis and specific
Magnetic resonance imaging
follow-up, underlying the crucial role in idiopathic pediatric stroke of early genetic testing
Next-generation sequencing
using NGS-based panels. © 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disorder caused by mutations of ABCC6 (ATP-binding
cassette subfamily C member 6; OMIM#603234), encoding a transmembrane ATP-binding efflux transporter. The disease is characterized by the accumulation of mineralized and/or fragmented elastic fibers in the skin, eyes, vascular walls, and gastrointestinal system. The pathogenic mechanism is
* Corresponding author. Thrombosis and Hemostasis Unit, Istituto Giannina Gaslini, Via Gaslini 5, 16147, Genova, Italy. E-mail address: [email protected] (M. Bertamino). 1 These authors contributed equally. https://doi.org/10.1016/j.ejpn.2018.04.002 1090-3798/© 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. Please cite this article in press as: Bertamino M, et al., ABCC6 mutations and early onset stroke: Two cases of a typical Pseudoxanthoma Elasticum, European Journal of Paediatric Neurology (2018), https://doi.org/10.1016/j.ejpn.2018.04.002
2
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 8 ) 1 e4
unknown and no specific treatment is currently available.1 Interestingly, homozygous or compound heterozygous mutation of the ABCC6 gene may also cause generalized arterial calcification of infancy-2 (GACI2), characterized by infantile onset of widespread arterial calcification and/or narrowing of large- and medium-sized vessels, periarticular calcifications, and, occasionally, hypophosphatemic rickets. GACI2 and PXE likely represent two phenotypic manifestations of ABCC6 mutations, sharing ectopic calcifications at the level of arterial walls and/or other organs as a common denominator, rather than two distinct disorders. On the other hand, histological differences have been reported between these two entities, with higher prevalence of intimal thickening resembling fibromuscular dysplasia in PXE.2 Patients with PXE commonly present with skin papules and/or retinal angioid streaks, while vascular lesions and cerebrovascular complications are rarer but may cause severe neurologic impairment.1 The age of onset varies considerably from infancy to old age. Skin and ocular manifestations are usually late-onset and the disease is often diagnosed in the second or third decade of life. Of note, cerebrovascular manifestations may present in childhood, without other organs involvement, often leading to diagnostic delays. We report two PXE children presenting with multisystem vasculopathy and cerebrovascular complications, discussing the diagnostic strategies in the pediatric age group, and the vascular features that may represent useful disease hallmarks.
2.
Case reports
2.1.
Case 1
This 14-year-old girl was referred to our center at age 5 years due to the suspect of cerebral vasculitis and drug-resistant epileptic seizures. She was the second child of healthy unrelated parents, born after uneventful pregnancy and normal delivery. Her family history was unremarkable. At the age of 5 months, she experienced a first, non-prolonged tonic-clonic seizure. Brain MRI and MR angiography (MRA) revealed multiple acute cerebral ischemic infarcts, with focal narrowing of left vertebral artery and petrous segments of the internal carotid arteries (ICAs). The neurologic examination revealed mild left-side hemiparesis. A secondary prevention therapy with acetylsalicylic acid was started. The girl remained stable until the age of 5 years, when she developed a multidrugresistant epilepsy. At admission in our hospital, physical examination revealed an asymmetry of lower-extremity pulse and blood pressure measurements. Basic blood tests, ECG, echocardiography and abdominal ultrasonography were unremarkable. A lower-extremity Doppler ultrasound revealed a fall in blood velocity along the common femoral and tibial arteries. Brain MRI showed chronic evolution of the corticosubcortical infarcts (Fig. 1A), while MRA and digital subtraction angiography (DSA) confirmed bilateral ICAs and left vertebral artery stenosis (Fig. 1BeC), and revealed multiple stenosis of external iliac arteries. A right temporal artery biopsy was unspecific, but excluded inflammation and calcification on vassal wall. One year later, she complained of limbs paresthesias, and MRA showed progression of the stenosis of
the right iliaco-femoral branches. At 6 years of age, physical examination revealed the presence of multiple asymptomatic yellow papules around the neck, suggestive of PXE at histopathologic examination. The ABCC6 gene was screened and a homozygous nonsense mutation (p.R1141*) detected, thus confirming the diagnostic suspect. Both parents were heterozygous carriers. At last follow-up, she had moderate intellectual disability, drug-resistant epilepsy, worsening of cutaneous involvement, but no ocular symptoms. Brain MRI and MRA were unchanged.
2.2.
Case 2
This 5-year-old boy was referred at age 2 years for acute cerebral ischemic stroke. He was the first child of nonconsanguineous parents, born at term after a normal pregnancy. Family history was unremarkable. The child was admitted to the local hospital for right-sided partial seizures and ipsilateral gaze deviation. At admission neurological examination revealed right sided hemiplegia. The psychomotor development was otherwise normal. At physical examination the radial and femoral pulses were difficult to palpate. Cutaneous, gastrointestinal, hematologic and ocular examinations were unremarkable. Brain MRI showed an acute ischemic infarct in the left fronto-insular region (Fig. 1DeE), while the MRA revealed left middle cerebral artery sub-occlusion, and bilateral segmental ICAs agenesis. Severe renovascular hypertension and left ventricular hypertrophy were detected. One month later, MRA and DSA showed improvement of flow signal in the distal branches of left middle cerebral artery, bilateral segmental ICAs agenesis associated with a compensating arterial network, called carotid rete mirabile (CRM), and left vertebral artery stenosis (Fig. 1FeG). Infrarenal aortic tapering and bilateral stenosis of the external iliac arteries with a network of collateral vessels were noted. A femoral artery biopsy revealed fragmentation of the elastic fibers in the vessel wall with no signs of inflammation or calcification. An in-house NGS-based panel, including 15 genes (ABCC6, ACTA2, ATP7A, CBS, CECR1, COL4A1, ELN, GLA, HTRA1, JAG1, NF1, NOTCH3, PCNT, SAMHD1, SLC2A10) responsible for the most common monogenic disorders associated with pediatric ischemic strokes, was tested (Grossi et al., submitted). Two compound heterozygous ABCC6 loss-of-function mutations, c.4182_4182delG (p.Lys1394Asnfs*9) and c.2900G > A (p.Trp967*), were found. Parents were heterozygous for each of the two variants, respectively. Dual therapy with acetylsalicylic acid and clopidogrel was started, associated with proton pump inhibitors and screening of gastric ulcer with fecal occult blood tests. In the following three years, the arterial hypertension regressed spontaneously, and the child had no new cerebrovascular events, showing normal psychomotor development with persisting mild right-sided hemiparesis. Last brain MRI and brain/abdominal MRA were unchanged. Neither skin lesions nor ocular involvement were present at last follow-up.
3.
Discussion
The present cases illustrate the diagnostic challenges of PXE in children presenting with isolated multisystem
Please cite this article in press as: Bertamino M, et al., ABCC6 mutations and early onset stroke: Two cases of a typical Pseudoxanthoma Elasticum, European Journal of Paediatric Neurology (2018), https://doi.org/10.1016/j.ejpn.2018.04.002
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 8 ) 1 e4
3
Fig. 1 e A-C) Brain MRI and DSA of patient 1 at 5 years of life. A) Axial FLAIR images show multiple chronic corticosubcortical infarcts in the left occipital (arrowhead) and right fronto-mesial and precentral regions (thick arrows). Note prominent leptomeningeal collaterals resulting in increased signal intensity within the subarachnoid spaces in the left fronto-parietal regions. Lateral DSA views of the right ICA (B) and left ICA (C) reveal bilateral narrowing of the petrous segments (arrowheads). D-G) Brain MRI and DSA of patient 2 at clinical onset. Axial T2-weighted (D) and diffusion weighted (E) images show an acute left frontal ischemic infarct. F) Frontal DSA view of the ICAs confirms bilateral segmental agenesis of the petrous ICAs (arrows) associated with external carotid artery stenosis and CRM circumventing the site of the agenesis (arrowheads). G) Frontal DSA view of the left vertebral artery depicts a focal intracranial stenosis (arrowhead).
vasculopathy and cerebrovascular complications. Both children underwent a comprehensive pediatric stroke diagnostic protocol, including detailed anamnesis on risk factors (previous infectious disease and vaccination status, recent head trauma, cardiac diseases, cancer, etc), laboratory studies (such as screening for inherited and acquired thrombophilia and metabolic disorders), cardiac evaluation with echocardiography, and neuroradiological examination including both head and neck MR angiography and digital subtraction angiography. We thus excluded the most common causes of pediatric stroke, such as cardioembolic diseases, sickle cell anemia, and other cerebral vasculopathies including moyamoya disease, post-varicella focal cerebral arteriopathy, and vasculitis. In Patient 1 the diagnosis of PXE was delayed for 6 years, until typical cutaneous manifestations appeared. Genetic testing based on Sanger sequencing is time consuming and usually performed once specific clinico-radiological phenotypes become evident. In addition, PXE may have high intra-familiar heterogeneity or incomplete penetrance, with manifestation of the full-blown clinical spectrum appearing even many years after the onset.1 Conversely, in Patient 2 a NGS-based gene panel, including genes related to the most common monogenic disorders associated with pediatric ischemic strokes revealed compound heterozygous truncating mutations of
ABCC6, thus allowing to achieve an earlier diagnosis even in the absence of PXE pathognomonic signs. Of note, in the last decade, there has been a growing interest in the genetic causes of pediatric stroke.3 Once excluded the most common pediatric stroke causes, as previously mentioned, other rare genetic disorders should be considered in the differential diagnosis of idiopathic early-onset stroke and/or cerebral arteriopathies. Indeed, genetic testing using NGS-based panels may allow early diagnoses even in the absence of a clear clinical suspicion, while single gene sequencing requires a well sustained working hypothesis regarding the possible genetic cause. Whole exome sequencing (WES) and whole genome sequencing (WGS) can be used instead when all the hypotheses and specific genetic approaches have already been undertaken without any relevant achievement. Early diagnosis has relevant implications for treatment, follow-up strategies and genetic counseling. Accordingly, although no etiological treatment is currently available, early PXE diagnosis is important to implement specific therapeutic and prevention measures. Given the occurrence of ischemic strokes, we treated the patients with antiplatelet drugs associated with proton pump inhibitors, starting a close screening of gastric ulcer with fecal occult blood test, considering the higher risk of gastrointestinal bleeding reported in these patients. No bleeding
Please cite this article in press as: Bertamino M, et al., ABCC6 mutations and early onset stroke: Two cases of a typical Pseudoxanthoma Elasticum, European Journal of Paediatric Neurology (2018), https://doi.org/10.1016/j.ejpn.2018.04.002
4
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 8 ) 1 e4
complication or ischemic recurrence was observed during the follow-up. Moreover, an ophthalmology screening was started to detect macular degeneration and progressive retinal neovascularization that may result in visual loss if untreated. Interestingly, a wide range of arteriopathies has been reported in PXE, including intra- and extra-cranial aneurysms, arterial stenosis, tortuosity, and occlusion.4 Of note, cerebral arteriopathies are among the most frequent causes of pediatric stroke in children, and currently represent the strongest predictors of arterial ischemic stroke recurrence in this age group.5 Thus, careful evaluation of the site, morphology and evolution of vascular abnormalities on neuroimaging studies is extremely important. Interestingly, a distinctive involvement of the petrous and/or cavernous segments of the ICAs with segmental hypoplasia/aplasia or multiple stenosis, was noted in both the present cases. Similar vascular features have been reported in other patients with PXE, often associated with a compensating arterial network supplied by external carotid artery branches bypassing the absent ICAs segments, called CRM.4 This vasculopathy pattern differs from the moyamoya arteriopathy, affecting the terminal ICAs or proximal circle of Willis with intracranial collaterals, and from the fibromuscular dysplasia, typically involving the cervical ICA segments without collateralization. At present, the causal relationship between PXE and CRM has not been proven. However, given the rarity of these conditions, the probability of an accidental association seems unlikely. CRM is the result of congenital arterial remodeling in response to a signal or trigger, causing fetal or perinatal regression of one or more segments of the ICA. Therefore, it has been speculated that abnormal signaling related to ABCC6 mutations during arterial wall formation may play a pathological role.4 We believe that the involvement of the petrous/cavernous segments of ICAs with CRM might represent a useful disease hallmark in PXE, but future studies with genotypeephenotype correlation on a large number of patients with PXE are needed to confirm the specificity of this vascular pattern. In conclusion, this report highlights the diagnostic challenges of PXE when presenting with isolated vasculopathy and
cerebrovascular complications in children, underlying the potential role of custom NGS-panels as a first, cost-effective approach to the early identification of rare genetic causes of pediatric stroke.
Conflict of interest The authors declare no conflict of interest.
Appendix A. Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.ejpn.2018.04.002.
references
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Please cite this article in press as: Bertamino M, et al., ABCC6 mutations and early onset stroke: Two cases of a typical Pseudoxanthoma Elasticum, European Journal of Paediatric Neurology (2018), https://doi.org/10.1016/j.ejpn.2018.04.002