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Stroke in children with some genetic pathologies

Autor: Mariana Sprincean Svetlana Hadjiu Ludmila Ețco Cornelia Călcîi Nadejda Bejan Vladimir Egorov Nadejda Lupuşor Olga Tihai Ninel Revenco
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In this article we approach some genetic pathologies and their relationship to stroke in children, highlighting the main clinical features that can lead to their diagnosis. Th e synthesis of literature data suggests that the etiology of stroke in children is multifactorial and genetic diseases are considered to be significant risk factors in over half of the cases. Among the genetic diseases at risk for stroke in children should be noted the following pathologies, as tuberous sclerosis, fi bromuscular dysplasia, Moyamoya disease, MELAS syndrome, hereditary dysplasia of connective tissue, sickle cell disease, hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome), hyperhomocysteinemia, homocystinuria, Fabry disease, cerebrotendineous xanthomatosis, etc. Early recognition of pediatric stroke requires neurological and imagistic investigations as early as possible and the initiation of treatment. Th ese include epidemiological examination, clinical presentation, differential diagnosis, assessment of risk and causal factors, and the correct management of pediatric stroke. Children with tuberous sclerosis have a high risk of embolic events, and may also have secondary hemorrhagic stroke in hypertensive crisis, hemorrhage in a tumor, or rupture of an abnormal vessel. Homocystinuria may cause ischemic stroke and should be suspected in the presence of mental retardation associated with lens dislocation and, occasionally, pectus excavatum. Nutritional deficiencies of folic acid or vitamin B12 deficiency can also cause hyperhomocysteinemia, leading to stroke. Hereditary dysplasia of connective tissue is a risk factor in about 10% of cases.

Conclusions: Stroke in children appears as a result of multiple etiologies including genetic conditions. Recognition of cerebrovascular, neurological, systemic and radiographic manifestations of these genetic diseases can lead to disease-specific diagnostic tests in selected patients with stroke. The comprehensive approach of the patient will ensure the establishment of the right diagnosis, which is fundamental for the decision of the treatment tactics and the subsequent evolution of the disease. In high-risk families it is necessary to perform genetic counseling to reduce the rate of morbidity and mortality and to improve the quality of life of patients and their relatives.

Keywords: genetic diseases, stroke, neurological manifestations, risk factors

A stroke is a rare disease in children, with an estimated incidence between 2 to 13 for 100000 and has a significant impact on morbidity and mortality [1]. The risk factors and clinical manifestations of AVC in the child and adolescent are different from the adult. Among the etiologic factors of stroke in children should be noted the following, namely neonatal encephalopathies, some genetic syndromes, congenital heart anomalies, hereditary dysplasias of connective tissue, vascular pathology, congenital anomalies of vessels, most commonly arteriovenous anomalies, hereditary and acquired prothrombotic states, sepsis, sickle cell anemia, etc. Early recognition of pediatric stroke requires a neurological and imaging investigations as early as possible, and early started treatment. These are related to epidemiological examination, clinical presentation, differential diagnosis, assessment of risk and causal factors, and proper management of pediatric stroke [1]. In infant stroke is manifested by motor disorders, speech and sensitivity deficits [2]. Similarly, stroke may occur during pregnancy or immediately after delivery, with no evident symptoms [3]. Sometimes in the newborn who suffers stroke the clinical symptoms are subtle, or the stroke is asymptomatic until the age of 4 – 8 months, in some cases it develops with seizures or paralysis. As a result, many children have not receiving the appropriate treatment [3]. Stroke is pathology with a high degree of disability, which in 12% cases leads to death, and in 70% cases develops an irreversible neurological deficit [4].

The pediatric stroke includes three subtypes: ischemic stroke (IS), hemorrhagic stroke (HS) and thrombosis of the cerebral venous sinus. IS is manifested by loss of cerebral functions due to decreased cerebral blood flow in the affected area [5]. Quick and accurate diagnosis is vital, and the therapeutic approach varies according to the type of stroke in children [6].

In children clinical manifestations are different from those in adult, are subtle and characteristic with variable clinical polymorphism according to the age of the child. This makes difficulties in diagnosing a stroke, especially in the first 6 hours after the onset of the pathology. Only 30% of children with stroke will present clinical manifestations confirmed by imaging investigations in the period of better therapeutic efficiency [7]. Children of young age will experience atypical manifestations, while older children will experience neurological manifestations described in adults [8]. In older children the neurological manifestations are as follows: hemiparesis, aphasia, hemianopsia, in 30% cases will be present headache, and seizures in 20 – 48% of patients [9]. The presence of nonspecific and variable neurological symptoms requires the assumption of stroke in all cases of acute onset disease in the infant child, with a risk of stroke, using of cerebral imaging investigations [10].

The synthesis of literature data suggests that stroke etiology in children is multifactorial, and genetic diseases are considered to be significant risk factors in over half of the cases. Of the genetic diseases at risk of stroke in children are tuberous sclerosis, fibromuscular dysplasia, Moyamoya disease, MELAS syndrome, hereditary dysplasia of connective tissue, sickle cell disease, hereditary hemorrhagic telangiectasia, i. e., Osler-Weber-Rendu syndrome, hyperhomocysteinemia, homocystinuria, Fabry disease, cerebrotendineous xanthomatosis, etc.

Tuberous sclerosis or Bourneville’s disease, tuberous sclerosis complex, epiloia, hereditary multiple hamartomatosis, is an autosomal dominant genetic disease, which is part of the phacomatosis group and involves benign and non-invasive lesions in different organs. In 67% cases of tuberous sclerosis (TS) this disease resulted from genetic de novo mutations [6]. In a number of patients reported at Mayo Clinic (Rochester, MN, U. S. A.), more than 90% of patients experienced skin lesions, in about 90% showed signs of cerebral pathology, in 70 – 90% of cases had renal anomalies, and in about 50% had retinal hamartomas. Children with tuberous sclerosis have a high risk of embolic events, and may also have HS after a hypertension, hemorrhage in a tumor, or rupture of an abnormal vessel.

Tuberous sclerosis is protein pathology, and random distribution, number, size and location of focal lesions causes various clinical manifestations [3]. Certain lesions, such as renal angiomyolipomatosis, do not occur until a certain age; by contrast, cardiac rhabdomyomatosis occur at the fetus, and almost always regresses spontaneously in childhood. Most of the time clinical signs in infants are scarce, and to establish an early diagnosis it is necessary to use imaging examinations. Patients with ST may have a delay in diagnosis, as some clinical signs with onset during infancy may not be manifested until the adult age [7]. In the study of Seibert et al., 56% of patients were diagnosed in adult age and two third of these patients had symptoms from childhood age.

Homocystinuria may cause IS and should be suspected in the presence of Marfanoid phenotype and mental retardation associated with the dislocation of the lens and occasionally pectus excavatum. Homocystinuria is a rare hereditary condition affecting amino acids metabolism, namely methionine. This autosomal recessive disorder is characterized by abnormal storage of homocysteine and its metabolites methionine, and S-adenosyl derivatives in blood and urine. Although homocystinuria is usually associated with ischemic stroke, the sudden occurrence of stroke as a result of homocystinuria is very rare in infancy. Increasing of thickness of carotid plaques was associated with high levels of homocysteine and with lowering the level of vitamin B12 and with following increasing risk of stroke. This association between homocystinuria and vascular complications was reported for the first time in 1976 [6] and since then, several studies have confirmed this association [8]. Nutritional deficiencies of folic acid or vitamin B12 can also cause hyperhomocystinemia, which leads to stroke.

Fibromuscular dysplasia (FMD) is a hereditary condition that causes cell growth of the arterial walls. Extracellular growth leads to narrowing the arteries and causing reduction of blood flow. It can also cause aneurysms and dissections in the carotid arteries with development of a hemorrhagic stroke.

Moyamoya disease is a rare, progressive, occlusive disease of cerebral arteries, with a special involvement of circle of Willis and the arteries that vascularized it [1]. The affection can cause a transient ischemic attack or stroke with deterioration of brain functions and cause cognitive and developmental delay. Moyamoya disease most commonly affects children, being associated with the following clinical signs: headache, weakness, numbness or paralysis in the face, arm or leg, usually on one side of the body, visual disturbances, aphasia, developmental delay, involuntary movements, and cognitive decline. These symptoms can be triggered by physical exercise, crying, coughing, tension or fever.

MELAS syndrome or mitochondrial myopathy, encephalopathy, lactic acidosis and stroke is a multisystem and progressive neurodegenerative disorder. Cases of MELAS syndrome may occur sporadically or as hereditary transmission on a maternal line with a variable expressiveness of clinical manifestations. Patients with MELAS syndrome may have the following symptoms: mitochondrial encephalopathy, lactic acidosis and stroke events, but also with other manifestations such as headache, seizures, cognitive and verbal disorders, sensory neural deafness, muscle weakness and mental retardation.

Hereditary dysplasias of connective tissue are considered to be significant risk factors in about 10% of cases [11]. Genetic background of ischemic and hemorrhagic accident is often polygenic or multifactorial. It can be determined in some cases by a particular single gene disease, especially in children and young adults. Apart from the mentioned risk factors, many types of dysplasia of connective tissue can cause stroke. Hereditary dysplasias of connective tissue (HDCT) represents a group of hereditary single gene pathology determined by mutations in genes responsible for collagen synthesis and metabolism. HDCT may characterized by severe manifestations, are relatively common and sufficiently understood at the molecular level to provide useful paradigms for a number of associated diseases [13].

Of the most prevalent HDCT should be noted Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta, spondyloepiphyseal dysplasia congenita, achondrogenesis, Stickler syndrome, hereditary angiopathy, Alport syndrome, benign family hematuria, etc. These are caused by mutations in collagen and the extracellular matrix genes. For example, mutations in the COL4A1 gene are considered to be the cause of small vessels anomalies in adults presenting ischemic stroke or intracerebral hemorrhage [14].

Ehlers-Danlos syndrome (EDS) represents a heterogeneous group of hereditary diseases of connective tissue caused by mutations of genes that specify different types of collagen (I, III, V, etc.), characterized by hyperelasticity of skin, hypermobility of joints and tissue fragility [12]. Incidence of pathology is from 1:5000 to 1:50000. There are described three types of hereditary transmission of EDS, i. e., autosomal dominant, autosomal recessive and X-linked recessive.

In some cases familial history is negative, so it can be an isolated spontaneous de novo mutation with following transmission to descendants.

EDS is caused by a series of mutations in genes that control collagen synthesis and metabolism. As a result of hereditary defects, patients with EDS have connective tissue abnormalities with qualitative changes such as resistance, elasticity, and regeneration properties.

Hypermobile type (III) is determined by mutations of type III collagen (COL3A1). The same gene is involved in the pathogenesis of vascular type (IV) of the disease, but the mutations involved are different, and some of them produce more severe phenotypes than others. Vascular type of EhlersDanlos syndrome (IV) is characterized by increased tissue fragility, i. e., fragility of the vessels, stroke, vascular rupture or a dissecting aneurysm of the aorta, as well as intestinal perforations. It was found that 15% of patients with EDS may suffer a stroke as a serious complication until the age of 20, and in 60% before the age of 40 years [12].

In SED clinical manifestations are cutis laxa or skin hyperelasticity, skin texture is soft and velvety, developing atrophic bedsores and ecchymosis, frequent hemorrhages, complicated and lengthy scarring of the wounds. Osteogenesis imperfecta (OI) is a group of single gene diseases, caused by mutations in the COL1A1 and COL1A2 genes which are responsible for the synthesis of type I collagen units, which is manifested by: fragility of bones, blue sclera, progressive hearing loss, teeth defects and retardation of growth [4].

Osteogenesis imperfecta or fragile bone disease is one of the most common skeletal dysplasias. The prevalence of the disease is from 1:10000 to 1:20000. Transmission mode is autosomal dominant in 85 – 90% of cases, and autosomal recessive. OI is determined by mutations in the COL1A1 and COL1A2 genes, responsible for the synthesis of type I collagen units. Type I collagen molecules are made up of two alpha1(I) chains, encoded by the COL1A1 gene on chromosome 17, and an alpha2(II)chain, encoded by the COL1A2 gene on chromosome 7 [14]. Other mutations are mutation in LEPRE1 gene (Leprecan protein) and CRTAP gene encoded cartilage associated protein.

Clinical heterogeneity at least partially explained by allelae and loci heterogeneity, i. e., phenotype varies depending on the type of collagen I chain units, which is also affected depending on the location of the mutation at the level of each locus. There have been described more than 200 different mutations affecting collagen I genes. Clinical manifestations are characterized by a variable expressiveness from the fetal death to subtle symptoms. Details of the neurovascular involvement in OI are still rare. Complications that have been reported, although rare, include ruptured cerebral aneurysm associated with fenestrate vertebral arteries, disease of Moyamoya type, cavernous carotid fistula, and cervical and vertebral artery dissections [14].

Marfan syndrome is a genetic condition with autosomal dominant type of transmission, with a major impairment of connective tissue, with a high clinical variability and pleiotropic manifestations. Marfan syndrome is caused by mutations in the FBN1 gene located on chromosome 15, i. e., 15q21.1, which encodes the glycoprotein called fibrillin-1, essential for the proper formation of the extracellular matrix, including biogenesis and maintenance of fibers elasticity in normal structure of the connective tissue [13]. In the matrix molecules of fibrillin-1 and other proteins forms microfibrils, the latter become part of elastic fibers of skin, ligaments and blood vessels.

Marfan syndrome (MS) manifests by the following clinical symptoms: arachnodactily, extremely long limbs, laxity of ligaments, hypermobility of joints, narrow, thin face, deformities of spines, pectus excavatum or carinatum, aortic dilation, mitral valve prolapse, aortic aneurysm, lens dislocation, corneal flatness, increased axial length of the eyeball, cataract, glaucoma. The most common neurovascular complication in MS is the aortic dissection [14]. There have also been reported spontaneous dissections limited to the common or internal carotid artery. In a retrospective study Wityk et al. described a neurovascular event in approximately 3.5% of patients with MS, most of them experienced transient ischemic attack (65%), IS, usually cardioembolic, 10%, spinal infarction (10%), subdural hematoma (10%) or subarachnoid hemorrhage (5%) [14]. A conclusive relationship between MS and intracranial aneurysms has not been established.

Hereditary hemorrhagic telangiectasia or OslerWeber-Rendu syndrome is a autosomal dominant genetic disorder that leads to abnormal formation of blood vessels in the skin and mucosa and often in internal organs such as lungs, liver and brain. Stroke occurs as a major complication of Osler-Weber-Rendu syndrome from 10 to 19% of [2]. Paradoxical embolism due to pulmonary arteriovenous malformations is the main mechanism of stroke in patients with hereditary hemorrhagic telangiectasia.

Fabry disease is a hereditary X linked condition characterized by a lysosomal storage disorder caused by alpha-galactosidase A activity deficiency. Stroke is a common and serious clinical manifestation of Fabry disease.

Cerebrotendineous xanthomatosis is a hereditary disorder, caused by mutations of the CYP27A1 gene, characterized by abnormal storage of lipids in many parts of the organism [11]. In this disorder in the organism of the patients certain lipids such as cholesterol can not effectively decompose so these fats form fatty yellow nodules called xanthomas, which accumulates in the body, especially in the brain and in tendons. Symptoms may include diarrhea, cataracts and progressive neurological problems, such as seizures, movement disorders, stroke, dysarthria, sensitivity disorders, peripheral neuropathy, hallucinations and depression. Other symptoms may include fragile bones that are prone to fractures and an increased risk of developing cardiac or pulmonary impairment due to the accumulation of lipids [11].


Stroke in children have a multiple etiology including some genetic pathology. This condition in characterized by multiple signs and symptoms, most often subtle, due to which it is difficult to establish early diagnosis. The patient’s evaluation should be carried out by a multidisciplinary team, i. e., geneticist, neurologist, rheumatologist, nephrologist, etc. The comprehensive approach will ensure precise determination of the diagnosis, which is essential for the therapeutic decision and for the prediction of the outcome of disease. In high risk families it is necessary to carry out genetic counseling and family planning in order to reduce of morbidity and mortality and to improve the quality of life of patients and their relatives.


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