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A girl with Cardio-facio-cutaneous syndrome complicated with status epilepticus and acute encephalopathy
Brain & Development 36 (2014) 61–63 www.elsevier.com/locate/braindev
Case report
A girl with Cardio-facio-cutaneous syndrome complicated with status epilepticus and acute encephalopathy Keisuke Wakusawa a,⇑, Satoru Kobayashi a, Yu Abe b, Soichiro Tanaka a, Wakaba Endo a, Takehiko Inui a, Mitsutosi Iwaki c, Shuei Watanabe d, Noriko Togashi d, Takahiro Nara e, Tetsuya Niihori f, Yoko Aoki f, Kazuhiro Haginoya a,b a
Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Sendai, Japan b Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan c Department of Pediatrics, Osaki Citizen Hospital, Osaki, Japan d Department of Neurology, Miyagi Children’s Hospital, Sendai, Japan e Department of Rehabilitation, Miyagi Children’s Hospital, Sendai, Japan f Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan
Received 13 September 2012; received in revised form 18 December 2012; accepted 19 December 2012
Abstract We report a six-year-old girl with Cardio-facio-cutaneous (CFC) syndrome who developed acute encephalopathy after the recurrence of status epilepticus. While epileptic encephalopathy and severe epilepsy have been mentioned as frequent complications of the CFC syndrome, no previous reports have shown a case of the CFC syndrome complicated with acute encephalopathy. Here we discuss the possibility for the linkage between the development of acute encephalopathy and CFC syndrome which is generally susceptible to seizures or epilepsy. Ó 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: CFC syndrome; Acute encephalopathy; Status epilepticus
1. Introduction Cardio-facio-cutaneous (CFC) syndrome is an autosomal dominant syndrome defined by facial anomaly, cardiovascular disease, characteristic skin and hair, and intellectual disability [1–3]. The details of facial anomalies are narrow head, hypoplastic upper eyelid and brow, short nose, low set ears, blepharoptosis, epicanthus, and hypertelorism. Patients with CFC syndrome have curly fragile hair, deep creased palm and ⇑ Corresponding author. Address: Department of Pediatric Neurol-
ogy, Takuto Rehabilitation Center for Children, Azashikaotsu 20, Yumoto, Akiyumachi, Taihaku-ku, Sendai 982-0241, Japan. Tel.: +81 (0) 22 398 2221; fax: +81 (0) 22 397 2697. E-mail address: [email protected] (K. Wakusawa).
sole, and often keratinization, and pigmentation on dark and stretchable skin. Typical cardiovascular problems include hypertrophic cardiomyopathy, atrial septal defect, and pulmonary arterial stenosis. This syndrome is based on the abnormality of any one in KRAS, BRAF, MEK1, and MEK2 gene [1–3]. In this paper, we report a case of the CFC syndrome with BRAF gene mutation complicated with acute encephalopathy after recurrent status epilepticus, and discussed on the possible relationship between CFC syndrome and acute encephalopathy. 2. Case report This 6-year-old girl was born from nonconsanguineous parents via Cesarean section because of placental abruption after 36 weeks of gestation. Her body weight
0387-7604/$ - see front matter Ó 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2012.12.007
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K. Wakusawa et al. / Brain & Development 36 (2014) 61–63
and occipital frontal circumference were 2902 g (+0.0 SD) and 34.5 cm (+1.8 SD), respectively. In the following neonatal period she vomited every time she was nursed, so she was fed 10 times a day in small amounts. She had hypersensitivity to sound and touch. Pendular nystagmus and glaucoma were pointed out at 3 months of age. Her head control was achieved at 4 months of age; rolling, sitting, standing, and walking were achieved at 11, 14, 15, and 38 months, respectively. She gained meaningful words at 13 months of age, and started to phrase a few words at 3 years and 8 months of age. At 4 years and 4 months of age, she had the first episode of status epilepticus associated with fever, which resulted in transient psychomotor regression; she lost meaningful words and the ability of rolling and walk, but recovered fully in 3 months. The interictal electroencephalography (EEG) showed no epileptic discharge. After the second episode of status epilepticus at 4 years and 10 months of age, she was started on medication with valproic acid. She also became afflicted by recurrent diarrhea and respiratory infections around the same period. At 5 years and 11 months of age, she had a generalized tonic-clonic seizure for more than 80 min, which was preceded by sudden vomiting and loss of consciousness. Magnetic resonance imaging (MRI) revealed
Fig. 1. Findings of brain MRI. On the third day after the onset of acute encephalopathy, diffuse high intensity lesions in the thalamus and cortex were observed on diffusion weighted images (DWI) (TR 3300, TE 82, b value: 1000 s/mm2) (a). T2-weighted-images (T2WI) (TR 4000, TE 84) (b) and T1-weighted images (T1WI) (TR 525, TE 27) (c) showed slight narrowing of the anterior horns of lateral ventricles and a diffusely thickened cortical layer. On the third month after the onset of acute encephalopathy, DWI showed the disappearance of high signal intensity over the cortex and thalamus (d). There was cortical laminar necrosis on T1WI (f) and atrophic white matter, which showed diffuse low signal intensity on T1WI and high signal intensity on T2WI (e). The thalamus and basal ganglia also showed atrophic changes.
diffuse high intensity lesions in the pulvinar, cortex, and subcortical white matter on diffusion weighted images (Fig. 1a) and a thickened cortical layer with narrowed anterior horn of the lateral ventricle (Fig. 1b and c). The levels of protein, glucose, and the number of cells in the cerebrospinal fluid showed no remarkable changes. The laboratory data showed no remarkable change except for an increase in leukocyte count and C-reactive protein (10,200/ll and 1.42 mg/dl, respectively). Viral antigen of influenza, and antibodies against herpes simplex and human herpes virus type 6 were not detected, and bacterial culture of the cerebrospinal fluid was negative. Based on the diagnosis of acute encephalopathy, she was treated with methylprednisolone pulse therapy aimed at anti-cytokine mechanisms [4], midazolam, and potassium bromide in the intensive care unit. However, recurrent status epilepticus continued for 8 days and she remained unconscious for 10 days after hospitalization. After the acute event, she suffered from spastic quadriplegia and ballismus in her right upper limb, and mental deterioration was evident. At the 41st day from the start of acute encephalopathy, she was transferred to our facility for rehabilitation. She had curly hair and a dysmorphic face; narrow head, spare brow, short nose, low set ears, epicanthus, and hypertelorism (Fig. 2). The findings on skin, palm and sole were not remarkable. Cardiac ultrasonography revealed no abnormality in her heart. There were no
Fig. 2. The frontal (a) and lateral (b) view of her face, right palm (c) and sole (d). She had curly hair and a dysmorphic face; narrow head, spare brow, short nose, relatively low set ears, epicanthus, and hypertelorism. The findings on skin, palm and sole were not remarkable. The patient’s parents gave permission to publish these images.
K. Wakusawa et al. / Brain & Development 36 (2014) 61–63
remarkable findings in her laboratory data but mutation (Q257R) in the BRAF gene, so she was diagnosed as having the CFC syndrome. The EEG showed a diffuse low amplitude slow waves pattern which was continuously observed. Spikes frequently appeared in the bilateral parietal regions. The MRI on the third month after the onset of acute encephalopathy showed cortical laminar necrosis with atrophy of the thalamus, basal ganglia as well as white matter. The white matter showed a low signal intensity on T1-weighted images and a high signal intensity on T2-weighted images (Fig. 1d–f). On the other hand, the dorso-medial frontal and perisylvian cortices were spared (data not shown). 3. Discussion This report implies that acute encephalopathy is one of the complications of the CFC syndrome with recurrent status epilepticus, although no previous reports have shown a case of the CFC syndrome complicated with acute encephalopathy. We considered whether there is a pathophysiological relationship between mutation in the BRAF gene and acute encephalopathy as well as seizure susceptibility. Considering that patients with the CFC syndrome are frequently complicated with seizures [3], and the mutations in the BRAF gene are the major cause of the CFC syndrome [1–3], the relationship between mutation in the BRAF gene and seizure susceptibility seems possible. Some previous reports also suggested the possible linkage between epileptic severity and mutation in the BRAF gene [5,6]. Of note, the function of the BRAF gene is linked to cell proliferation through the RAS/mitogen activated protein kinase pathway [1]. However, further studies are required to elucidate how the BRAF mutation is linked to the development of epilepsy. Furthermore, the molecular pathophysiology of acute encephalopathy itself remains elusive [7]. Seizure susceptibility may cause the activation of a cytokine cascade and inflammatory signals [8] and such pathological process may also be applicable to our case. The possibility of seizure-related injury or hypoxic ischemic injury also cannot be excluded from the pathophysiology of our case. However, the relationship between acute encephalopathy and seizure susceptibility has been
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considered in patients with a mutation in the neuronal voltage-gated sodium channel alpha subunit type 1 (SCN1A) gene [7,9,10]. Some patients with the Dravet syndrome with SCN1A mutation have been afflicted by acute encephalopathy, where patients developed recurrent status epilepticus and subsequent encephalopathy with sequelae, similar to our patient. Our case may offer some insights into the relationship between seizure susceptibility and acute encephalopathy in the CFC syndrome, although more cases are needed before drawing any conclusions. References [1] Aoki Y, Niihori T, Narumi Y, Kure S, Matsubara Y. The RAS/ MARK syndromes novel roles of the RAS pathway in human genetic disorders. Hum Mutat 2008;29:992–1006. [2] Niihori T, Aoki Y, Narumi Y, Neri G, Cave´ H, Verloes A, et al. Germline KRAS and BRAF mutations in Cardio-facio-cutaneus syndrome. Nat Genet 2006;38:294–6. [3] Abe Y, Aoki Y, Kuriyama S, Kawame H, Okamoto N, Kurosawa K, et al. Prevalence and clinical features of Costello syndrome and Cardio-facio-cutaneus syndrome in Japan: findings from a nationwide epidemiological survey. Am J Med Genet A 2012;158A:1083–94. [4] Munakata M, Kato R, Yokoyama H, Haginoya K, Tanaka Y, Kayaba J, et al. Combined therapy with hypothermia and anticytokine agents in influenza A encephalopathy. Brain Dev 2000;22:373–7. [5] Adachi M, Abe Y, Aoki Y, Matsubara Y. Epilepsy in RAS/ MARK syndrome: two cases of Cardio-facio-cutaneus syndrome with epileptic encephalopathy and a literature review. Seizure 2012;21:55–60. [6] Aizaki K, Sugai K, Saito Y, Nakagawa E, Sasaki M, Aoki Y, et al. Cardio-facio-cutaneus syndrome with infantile spasms and delayed myelination. Brain Dev 2011;33:166–9. [7] Kobayashi K, Ouchida M, Okumura A, Maegaki Y, Nishiyama I, Matsui H, et al. Genetic seizure susceptibility underlying acute encephalopathies in childhood. Epilepsy Res 2010;91:143–52. [8] Lehtimaki KA, Keranen T, Palmio J, Makinen R, Hurme M, Honkaniemi J, et al. Increased plasma levels of cytokines after seizures in localization-related epilepsy. Acta Neurol Scand 2007;116:226–30. [9] Takayanagi M, Haginoya K, Umehara N, Kitamura T, Numata Y, Wakusawa K, et al. Acute encephalopathy with a truncation mutation in the SCN1A gene: a case report. Epilepsia 2010;51:1886–8. [10] Okumura A, Uematsu M, Imataka G, Tanaka M, Okanishi T, Kubota T, et al. Acute encephalopathy in children with Dravet syndrome. Epilepsia 2012;53:79–86.
Case report
A girl with Cardio-facio-cutaneous syndrome complicated with status epilepticus and acute encephalopathy Keisuke Wakusawa a,⇑, Satoru Kobayashi a, Yu Abe b, Soichiro Tanaka a, Wakaba Endo a, Takehiko Inui a, Mitsutosi Iwaki c, Shuei Watanabe d, Noriko Togashi d, Takahiro Nara e, Tetsuya Niihori f, Yoko Aoki f, Kazuhiro Haginoya a,b a
Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Sendai, Japan b Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan c Department of Pediatrics, Osaki Citizen Hospital, Osaki, Japan d Department of Neurology, Miyagi Children’s Hospital, Sendai, Japan e Department of Rehabilitation, Miyagi Children’s Hospital, Sendai, Japan f Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan
Received 13 September 2012; received in revised form 18 December 2012; accepted 19 December 2012
Abstract We report a six-year-old girl with Cardio-facio-cutaneous (CFC) syndrome who developed acute encephalopathy after the recurrence of status epilepticus. While epileptic encephalopathy and severe epilepsy have been mentioned as frequent complications of the CFC syndrome, no previous reports have shown a case of the CFC syndrome complicated with acute encephalopathy. Here we discuss the possibility for the linkage between the development of acute encephalopathy and CFC syndrome which is generally susceptible to seizures or epilepsy. Ó 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: CFC syndrome; Acute encephalopathy; Status epilepticus
1. Introduction Cardio-facio-cutaneous (CFC) syndrome is an autosomal dominant syndrome defined by facial anomaly, cardiovascular disease, characteristic skin and hair, and intellectual disability [1–3]. The details of facial anomalies are narrow head, hypoplastic upper eyelid and brow, short nose, low set ears, blepharoptosis, epicanthus, and hypertelorism. Patients with CFC syndrome have curly fragile hair, deep creased palm and ⇑ Corresponding author. Address: Department of Pediatric Neurol-
ogy, Takuto Rehabilitation Center for Children, Azashikaotsu 20, Yumoto, Akiyumachi, Taihaku-ku, Sendai 982-0241, Japan. Tel.: +81 (0) 22 398 2221; fax: +81 (0) 22 397 2697. E-mail address: [email protected] (K. Wakusawa).
sole, and often keratinization, and pigmentation on dark and stretchable skin. Typical cardiovascular problems include hypertrophic cardiomyopathy, atrial septal defect, and pulmonary arterial stenosis. This syndrome is based on the abnormality of any one in KRAS, BRAF, MEK1, and MEK2 gene [1–3]. In this paper, we report a case of the CFC syndrome with BRAF gene mutation complicated with acute encephalopathy after recurrent status epilepticus, and discussed on the possible relationship between CFC syndrome and acute encephalopathy. 2. Case report This 6-year-old girl was born from nonconsanguineous parents via Cesarean section because of placental abruption after 36 weeks of gestation. Her body weight
0387-7604/$ - see front matter Ó 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2012.12.007
62
K. Wakusawa et al. / Brain & Development 36 (2014) 61–63
and occipital frontal circumference were 2902 g (+0.0 SD) and 34.5 cm (+1.8 SD), respectively. In the following neonatal period she vomited every time she was nursed, so she was fed 10 times a day in small amounts. She had hypersensitivity to sound and touch. Pendular nystagmus and glaucoma were pointed out at 3 months of age. Her head control was achieved at 4 months of age; rolling, sitting, standing, and walking were achieved at 11, 14, 15, and 38 months, respectively. She gained meaningful words at 13 months of age, and started to phrase a few words at 3 years and 8 months of age. At 4 years and 4 months of age, she had the first episode of status epilepticus associated with fever, which resulted in transient psychomotor regression; she lost meaningful words and the ability of rolling and walk, but recovered fully in 3 months. The interictal electroencephalography (EEG) showed no epileptic discharge. After the second episode of status epilepticus at 4 years and 10 months of age, she was started on medication with valproic acid. She also became afflicted by recurrent diarrhea and respiratory infections around the same period. At 5 years and 11 months of age, she had a generalized tonic-clonic seizure for more than 80 min, which was preceded by sudden vomiting and loss of consciousness. Magnetic resonance imaging (MRI) revealed
Fig. 1. Findings of brain MRI. On the third day after the onset of acute encephalopathy, diffuse high intensity lesions in the thalamus and cortex were observed on diffusion weighted images (DWI) (TR 3300, TE 82, b value: 1000 s/mm2) (a). T2-weighted-images (T2WI) (TR 4000, TE 84) (b) and T1-weighted images (T1WI) (TR 525, TE 27) (c) showed slight narrowing of the anterior horns of lateral ventricles and a diffusely thickened cortical layer. On the third month after the onset of acute encephalopathy, DWI showed the disappearance of high signal intensity over the cortex and thalamus (d). There was cortical laminar necrosis on T1WI (f) and atrophic white matter, which showed diffuse low signal intensity on T1WI and high signal intensity on T2WI (e). The thalamus and basal ganglia also showed atrophic changes.
diffuse high intensity lesions in the pulvinar, cortex, and subcortical white matter on diffusion weighted images (Fig. 1a) and a thickened cortical layer with narrowed anterior horn of the lateral ventricle (Fig. 1b and c). The levels of protein, glucose, and the number of cells in the cerebrospinal fluid showed no remarkable changes. The laboratory data showed no remarkable change except for an increase in leukocyte count and C-reactive protein (10,200/ll and 1.42 mg/dl, respectively). Viral antigen of influenza, and antibodies against herpes simplex and human herpes virus type 6 were not detected, and bacterial culture of the cerebrospinal fluid was negative. Based on the diagnosis of acute encephalopathy, she was treated with methylprednisolone pulse therapy aimed at anti-cytokine mechanisms [4], midazolam, and potassium bromide in the intensive care unit. However, recurrent status epilepticus continued for 8 days and she remained unconscious for 10 days after hospitalization. After the acute event, she suffered from spastic quadriplegia and ballismus in her right upper limb, and mental deterioration was evident. At the 41st day from the start of acute encephalopathy, she was transferred to our facility for rehabilitation. She had curly hair and a dysmorphic face; narrow head, spare brow, short nose, low set ears, epicanthus, and hypertelorism (Fig. 2). The findings on skin, palm and sole were not remarkable. Cardiac ultrasonography revealed no abnormality in her heart. There were no
Fig. 2. The frontal (a) and lateral (b) view of her face, right palm (c) and sole (d). She had curly hair and a dysmorphic face; narrow head, spare brow, short nose, relatively low set ears, epicanthus, and hypertelorism. The findings on skin, palm and sole were not remarkable. The patient’s parents gave permission to publish these images.
K. Wakusawa et al. / Brain & Development 36 (2014) 61–63
remarkable findings in her laboratory data but mutation (Q257R) in the BRAF gene, so she was diagnosed as having the CFC syndrome. The EEG showed a diffuse low amplitude slow waves pattern which was continuously observed. Spikes frequently appeared in the bilateral parietal regions. The MRI on the third month after the onset of acute encephalopathy showed cortical laminar necrosis with atrophy of the thalamus, basal ganglia as well as white matter. The white matter showed a low signal intensity on T1-weighted images and a high signal intensity on T2-weighted images (Fig. 1d–f). On the other hand, the dorso-medial frontal and perisylvian cortices were spared (data not shown). 3. Discussion This report implies that acute encephalopathy is one of the complications of the CFC syndrome with recurrent status epilepticus, although no previous reports have shown a case of the CFC syndrome complicated with acute encephalopathy. We considered whether there is a pathophysiological relationship between mutation in the BRAF gene and acute encephalopathy as well as seizure susceptibility. Considering that patients with the CFC syndrome are frequently complicated with seizures [3], and the mutations in the BRAF gene are the major cause of the CFC syndrome [1–3], the relationship between mutation in the BRAF gene and seizure susceptibility seems possible. Some previous reports also suggested the possible linkage between epileptic severity and mutation in the BRAF gene [5,6]. Of note, the function of the BRAF gene is linked to cell proliferation through the RAS/mitogen activated protein kinase pathway [1]. However, further studies are required to elucidate how the BRAF mutation is linked to the development of epilepsy. Furthermore, the molecular pathophysiology of acute encephalopathy itself remains elusive [7]. Seizure susceptibility may cause the activation of a cytokine cascade and inflammatory signals [8] and such pathological process may also be applicable to our case. The possibility of seizure-related injury or hypoxic ischemic injury also cannot be excluded from the pathophysiology of our case. However, the relationship between acute encephalopathy and seizure susceptibility has been
63
considered in patients with a mutation in the neuronal voltage-gated sodium channel alpha subunit type 1 (SCN1A) gene [7,9,10]. Some patients with the Dravet syndrome with SCN1A mutation have been afflicted by acute encephalopathy, where patients developed recurrent status epilepticus and subsequent encephalopathy with sequelae, similar to our patient. Our case may offer some insights into the relationship between seizure susceptibility and acute encephalopathy in the CFC syndrome, although more cases are needed before drawing any conclusions. References [1] Aoki Y, Niihori T, Narumi Y, Kure S, Matsubara Y. The RAS/ MARK syndromes novel roles of the RAS pathway in human genetic disorders. Hum Mutat 2008;29:992–1006. [2] Niihori T, Aoki Y, Narumi Y, Neri G, Cave´ H, Verloes A, et al. Germline KRAS and BRAF mutations in Cardio-facio-cutaneus syndrome. Nat Genet 2006;38:294–6. [3] Abe Y, Aoki Y, Kuriyama S, Kawame H, Okamoto N, Kurosawa K, et al. Prevalence and clinical features of Costello syndrome and Cardio-facio-cutaneus syndrome in Japan: findings from a nationwide epidemiological survey. Am J Med Genet A 2012;158A:1083–94. [4] Munakata M, Kato R, Yokoyama H, Haginoya K, Tanaka Y, Kayaba J, et al. Combined therapy with hypothermia and anticytokine agents in influenza A encephalopathy. Brain Dev 2000;22:373–7. [5] Adachi M, Abe Y, Aoki Y, Matsubara Y. Epilepsy in RAS/ MARK syndrome: two cases of Cardio-facio-cutaneus syndrome with epileptic encephalopathy and a literature review. Seizure 2012;21:55–60. [6] Aizaki K, Sugai K, Saito Y, Nakagawa E, Sasaki M, Aoki Y, et al. Cardio-facio-cutaneus syndrome with infantile spasms and delayed myelination. Brain Dev 2011;33:166–9. [7] Kobayashi K, Ouchida M, Okumura A, Maegaki Y, Nishiyama I, Matsui H, et al. Genetic seizure susceptibility underlying acute encephalopathies in childhood. Epilepsy Res 2010;91:143–52. [8] Lehtimaki KA, Keranen T, Palmio J, Makinen R, Hurme M, Honkaniemi J, et al. Increased plasma levels of cytokines after seizures in localization-related epilepsy. Acta Neurol Scand 2007;116:226–30. [9] Takayanagi M, Haginoya K, Umehara N, Kitamura T, Numata Y, Wakusawa K, et al. Acute encephalopathy with a truncation mutation in the SCN1A gene: a case report. Epilepsia 2010;51:1886–8. [10] Okumura A, Uematsu M, Imataka G, Tanaka M, Okanishi T, Kubota T, et al. Acute encephalopathy in children with Dravet syndrome. Epilepsia 2012;53:79–86.