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Schizencephaly in LEOPARD Syndrome
Schizencephaly in LEOPARD Syndrome Jao-Shwann Liang, MD*, Yin-Hsiu Chien, MD†, Wuh-Liang Hwu, MD, PhD†, Shu-Jen Yeh, MD*, and Shinn-Forng Peng, MD‡ We report on a 2-year-old boy with facial dysmorphism, multiple lentigines, and hypertrophic cardiomyopathy. Mutation analyses of the patient and his mother revealed a Y279G mutation in exon 7 of the PTPN11 gene. The presence of LEOPARD syndrome was confirmed by a genetic study and clinical phenotypes. Since age 18 months, the patient had manifested frequent seizures that were poorly controlled by multiple anticonvulsants. Neurologic examinations indicated severe developmental delay and sensorineural deafness. Brain imaging demonstrated open-lip schizencephaly in the right frontoparietal area. Central nervous system anomalies are rarely reported in this disease. To the best of our knowledge, this is the first report of LEOPARD syndrome with associated schizencephaly. Psychomotor retardation is not uncommon in LEOPARD syndrome. We advocate brain-imaging studies of patients with LEOPARD syndrome and neurologic abnormalities such as developmental delay or epilepsy. Ó 2009 by Elsevier Inc. All rights reserved. Liang J-S, Chien Y-H, Hwu W-L, Yeh S-J, Peng S-F. Schizencephaly in LEOPARD Syndrome. Pediatr Neurol 2009;41:71-73.
Introduction The acronym LEOPARD (Online Mendelian Inheritance in Man [OMIM] 151100) was coined by Gorlin et al. to denote a syndrome of multiple lentigines, Electrocardiographic-conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of the genitalia, Retardation of growth, and Deafness [1]. The LEOPARD synFrom the *Department of Pediatrics, Far Eastern Memorial Hospital, Taipei, Taiwan; and †Department of Pediatrics and ‡Department of Radiology, National Taiwan University Hospital, Taipei, Taiwan.
Ó 2009 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2009.02.015 0887-8994/09/$—see front matter
drome is a dysmorphogenetic disorder of variable penetrance and expressivity. Diagnostic criteria, as proposed by Voron et al. in 1976, included lentigines plus two other recognized features, or a first-degree relative with lentigines plus three other features in the patient [2]. The diverse manifestations of this syndrome, together with the lack of pathognomonic biochemical markers, make it difficult to diagnose. However, recent molecular studies indicated that LEOPARD syndrome can arise because of mutations in protein-tyrosine phosphatase, nonreceptor type 11 (PTPN11), a gene encoding a tyrosine phosphatase protein termed SHP-2 [3,4]. Mutations of this gene can also produce Noonan syndrome (OMIM 163950). Although neurologic deficits were reportedly associated with LEOPARD syndrome, brain malformations are rarely reported. In this case study, we describe a previously unreported brain malformation in a child with LEOPARD syndrome. Case Report The 2-year-old male proband was the second born child of healthy, unrelated parents. He was born by normal delivery after 39 weeks of uneventful gestation. No teratogen exposure occurred during pregnancy. No perinatal insult was evident. His birth weight was 3350 g, his height was 54 cm, and his head circumference measured 34 cm. He was referred to our clinic because of intractable seizures and global developmental delay. His face was characterized by ocular hypertelorism. Small, dark brown, irregularly shaped macules that varied in size from pinpoint to 5 mm had been evident on his trunk since infancy; the sclera and mucosa were spared (Fig 1). The external genitalia were normal. Echocardiography demonstrated hypertrophic cardiomyopathy. Brainstem auditory-evoked potentials revealed severe hearing impairment (70 dB bilaterally). He exhibited central hypotonia, with left spastic hemiparesis. His developmental milestones were severely delayed. He was bedridden, and could only babble at age 2 years. He developed epileptic seizures at age 1 year and 6 months, with an initial presentation of leftlimb twitching. Magnetic resonance imaging of the brain revealed a wide, open cleft in the right parietal area. Open-lip schizencephaly in association with focal pachygyria was evident (Fig 2). His seizures were poorly controlled even by valproic acid, lamotrigine, and oxcarbazepine. Routine laboratory investigations produced normal results in terms of blood, urine, and TORCH serology. His mother presented with short stature and lentigines on her face and trunk. However, her intelligence and cardiologic tests produced normal results. Mutation analyses of the patient and his mother revealed a Y279 G mutation in exon 7 of the PTPN11 gene.
Discussion The LEOPARD syndrome is a rare autosomal-dominant disorder that exhibits clinical overlap with Noonan syndrome. Recent molecular studies revealed that LEOPARD Communications should be addressed to: Dr. Liang; Department of Pediatrics, Far Eastern Memorial Hospital; No. 21 Nanya South Road, Section 2; Panchiao City, Taipei 22060, Taiwan. E-mail: [email protected] Received May 8, 2008; accepted February 16, 2009.
Liang et al: Schizencephaly in LEOPARD Syndrome 71
Figure 1. Small, dark brown, irregularly shaped macules, varying in size over trunk.
syndrome and Noonan syndrome comprise allelic disorders, caused by different missense mutations in PTPN11 [3,4]. Clinically, the presence of lentigines and deafness distinguish LEOPARD syndrome from Noonan syndrome. The cardiovascular, growth, and dysmorphic findings are identical. Some PTPN11 mutations are specific for patients
Figure 2. Fast spin-echo T2-weighted magnetic resonance imaging (TR/ TE = 4260/101 ms) of the brain in the axial plane. Open-lip schizencephaly is evident in the right frontoparietal area. A cortical venous-flow void (solid arrow) overlies the anterior lip. A pia-ependymal seam (open arrowhead) paves the walls of the right cerebral cleft.
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with LEOPARD syndrome, occurring in exons that code for the protein tyrosine phosphatase domain. Two recurrent mutations in exons 7 (Tyr279Cys) and 12 (Thr468Met) and other rare mutations were reported in LEOPARD syndrome [3,5-7]. Based on clinical manifestations and a molecular study, LEOPARD syndrome was confirmed in our patient. In LEOPARD syndrome, skin manifestations and cardiac problems are the most common clinical signs that warrant medical attention. However, neurologic manifestations are often overlooked. Neurologic defects in LEOPARD syndrome include sensorineural deafness, mental retardation, oculomotor defects, abnormal electroencephalograms, and seizures. Mild learning difficulty was evident in 23 of 80 cases reviewed by Voron et al. [2]. Oculomotor defects were present in 16 of 80 patients, and electroencephalogram abnormalities were present in 11 of 80 patients, in that study [2]. In the series of Digilio et al., 50% of LEOPARD syndrome patients manifested psychomotor retardation [8]. However, the pathogenesis of psychomotor retardation in these patients was unclear. Partial agenesis of the corpus callosum and Chiari I malformation were reported in LEOPARD syndrome [9,10]. However, no other brain malformations were previously reported. Schizencephaly is an uncommon congenital brain malformation that occurs between months 3 and 4 of gestation, and is characterized by gray matter-lined clefts extending from the pial surface to the lateral ventricles. The cause of this abnormality is unclear. Some environmental events, such as organic or viral exposures during pregnancy, comprise potentially related insults. However, familial cases of schizencephaly raise the possibility of a genetic mechanism [11,12]. The extent of cortical involvement is related to clinical manifestations and neurologic outcomes [13,14]. Children with open-lip schizencephaly frequently manifested intractable seizures. In our patient, intractable seizures were also evident, even after treatment with multiple anticonvulsants. The PTPN11 mutations in Noonan syndrome enhance SHP-2 catalytic activity, whereas the activity of representative LEOPARD syndrome mutants is undetectable when assayed using a standard protein tyrosine phosphatase substrate [15]. A previous study revealed that PTPN11 mutations in LEOPARD syndrome cause the defective catalytic function of SHP-2, which interferes with growth factor/ extracellular signal-regulated kinase-mitogen-activated protein kinase-mediated signaling [16]. Although SHP-2 plays an important role in the activation of the Ras/extracellular signal-regulated kinase cascade and in mediating multiple downstream biological responses (e.g., cell proliferation or survival, adhesion, and migration), the effect of defective SHP-2 in neuronal migration remains unclear. In conclusion, to the best of our knowledge, this is the first report of schizencephaly associated with LEOPARD syndrome. Our findings, if they are not merely coincidental, indicate that brain malformations may be a new association in LEOPARD syndrome. In addition, psychomotor retardation
and neurologic deficits are not uncommon in LEOPARD syndrome. In patients with LEOPARD syndrome and neurologic abnormalities such as developmental delay or epilepsy, brain imaging is suggested as part of the diagnostic workup. References [1] Gorlin RJ, Anderson RC, Blaw M. Multiple lentigines syndrome. Am J Dis Child 1969;117:652-62. [2] Voron DA, Hatfield HH, Kalkhoff MD. Multiple lentigines syndrome. Case report and review of the literature. Am J Med 1976;60: 447-56. [3] Digilio MC, Conti E, Sarkozy A, et al. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet 2002;71:389-94. [4] Sarkozy A, Conti E, Seripa D, et al. Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. J Med Genet 2003;40:704-8. [5] Keren B, Hadchouel A, Saba S, et al. PTPN11 mutations in patients with LEOPARD syndrome: A French multicentric experience. J Med Genet 2004;41:e117. [6] Sarkozy A, Conti E, Digilio MC, et al. Clinical and molecular analysis of 30 patients with multiple lentigines: LEOPARD syndrome. J Med Genet 2004;41:e68.
[7] Yoshida R, Nagai T, Hasegawa T, Kinoshita E, Tanaka T, Ogata T. Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome. Am J Med Genet [A] 2004;130A:432-4. [8] Digilio MC, Sarkozy A, de Zorzi A, et al. LEOPARD syndrome: Clinical diagnosis in the first year of life. Am J Med Genet [A] 2006; 140A:740-6. [9] Bonioli E, Di Stefano A, Costabel S, Bellini C. Partial agenesis of corpus callosum in LEOPARD syndrome. Int J Dermatol 1999;38:855-62. [10] Agha A, Hashimoto K. Multiple lentigines (LEOPARD) syndrome with Chiara I malformation. J Dermatol 1995;22:520-3. [11] Nuri Sener R. Schizencephaly and congenital cytomegalovirus infection. J Neuroradiol 1998;25:151-2. [12] Brunelli S, Faiella A, Capra V, et al. Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly. Nat Genet 1996;12:94-6. [13] Packard AM, Miller VS, Delgado MR. Schizencephaly: Correlations of clinical and radiologic features. Neurology 1997;48:1427-34. [14] Liang JS, Lee WT, Peng SS, Yu TW, Shen YZ. Schizencephaly: Correlation between clinical and neuroimaging features. Acta Paediatr Taiwan 2003;43:208-13. [15] Hanna N, Montagner A, Lee WH, et al. Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: Consequences for PI3K binding on Gab1. FEBS Lett 2006;580:2477-82. [16] Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG. PTPN11 (SHP2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem 2006;281:6785-92.
Liang et al: Schizencephaly in LEOPARD Syndrome 73
Introduction The acronym LEOPARD (Online Mendelian Inheritance in Man [OMIM] 151100) was coined by Gorlin et al. to denote a syndrome of multiple lentigines, Electrocardiographic-conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of the genitalia, Retardation of growth, and Deafness [1]. The LEOPARD synFrom the *Department of Pediatrics, Far Eastern Memorial Hospital, Taipei, Taiwan; and †Department of Pediatrics and ‡Department of Radiology, National Taiwan University Hospital, Taipei, Taiwan.
Ó 2009 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2009.02.015 0887-8994/09/$—see front matter
drome is a dysmorphogenetic disorder of variable penetrance and expressivity. Diagnostic criteria, as proposed by Voron et al. in 1976, included lentigines plus two other recognized features, or a first-degree relative with lentigines plus three other features in the patient [2]. The diverse manifestations of this syndrome, together with the lack of pathognomonic biochemical markers, make it difficult to diagnose. However, recent molecular studies indicated that LEOPARD syndrome can arise because of mutations in protein-tyrosine phosphatase, nonreceptor type 11 (PTPN11), a gene encoding a tyrosine phosphatase protein termed SHP-2 [3,4]. Mutations of this gene can also produce Noonan syndrome (OMIM 163950). Although neurologic deficits were reportedly associated with LEOPARD syndrome, brain malformations are rarely reported. In this case study, we describe a previously unreported brain malformation in a child with LEOPARD syndrome. Case Report The 2-year-old male proband was the second born child of healthy, unrelated parents. He was born by normal delivery after 39 weeks of uneventful gestation. No teratogen exposure occurred during pregnancy. No perinatal insult was evident. His birth weight was 3350 g, his height was 54 cm, and his head circumference measured 34 cm. He was referred to our clinic because of intractable seizures and global developmental delay. His face was characterized by ocular hypertelorism. Small, dark brown, irregularly shaped macules that varied in size from pinpoint to 5 mm had been evident on his trunk since infancy; the sclera and mucosa were spared (Fig 1). The external genitalia were normal. Echocardiography demonstrated hypertrophic cardiomyopathy. Brainstem auditory-evoked potentials revealed severe hearing impairment (70 dB bilaterally). He exhibited central hypotonia, with left spastic hemiparesis. His developmental milestones were severely delayed. He was bedridden, and could only babble at age 2 years. He developed epileptic seizures at age 1 year and 6 months, with an initial presentation of leftlimb twitching. Magnetic resonance imaging of the brain revealed a wide, open cleft in the right parietal area. Open-lip schizencephaly in association with focal pachygyria was evident (Fig 2). His seizures were poorly controlled even by valproic acid, lamotrigine, and oxcarbazepine. Routine laboratory investigations produced normal results in terms of blood, urine, and TORCH serology. His mother presented with short stature and lentigines on her face and trunk. However, her intelligence and cardiologic tests produced normal results. Mutation analyses of the patient and his mother revealed a Y279 G mutation in exon 7 of the PTPN11 gene.
Discussion The LEOPARD syndrome is a rare autosomal-dominant disorder that exhibits clinical overlap with Noonan syndrome. Recent molecular studies revealed that LEOPARD Communications should be addressed to: Dr. Liang; Department of Pediatrics, Far Eastern Memorial Hospital; No. 21 Nanya South Road, Section 2; Panchiao City, Taipei 22060, Taiwan. E-mail: [email protected] Received May 8, 2008; accepted February 16, 2009.
Liang et al: Schizencephaly in LEOPARD Syndrome 71
Figure 1. Small, dark brown, irregularly shaped macules, varying in size over trunk.
syndrome and Noonan syndrome comprise allelic disorders, caused by different missense mutations in PTPN11 [3,4]. Clinically, the presence of lentigines and deafness distinguish LEOPARD syndrome from Noonan syndrome. The cardiovascular, growth, and dysmorphic findings are identical. Some PTPN11 mutations are specific for patients
Figure 2. Fast spin-echo T2-weighted magnetic resonance imaging (TR/ TE = 4260/101 ms) of the brain in the axial plane. Open-lip schizencephaly is evident in the right frontoparietal area. A cortical venous-flow void (solid arrow) overlies the anterior lip. A pia-ependymal seam (open arrowhead) paves the walls of the right cerebral cleft.
72 PEDIATRIC NEUROLOGY Vol. 41 No. 1
with LEOPARD syndrome, occurring in exons that code for the protein tyrosine phosphatase domain. Two recurrent mutations in exons 7 (Tyr279Cys) and 12 (Thr468Met) and other rare mutations were reported in LEOPARD syndrome [3,5-7]. Based on clinical manifestations and a molecular study, LEOPARD syndrome was confirmed in our patient. In LEOPARD syndrome, skin manifestations and cardiac problems are the most common clinical signs that warrant medical attention. However, neurologic manifestations are often overlooked. Neurologic defects in LEOPARD syndrome include sensorineural deafness, mental retardation, oculomotor defects, abnormal electroencephalograms, and seizures. Mild learning difficulty was evident in 23 of 80 cases reviewed by Voron et al. [2]. Oculomotor defects were present in 16 of 80 patients, and electroencephalogram abnormalities were present in 11 of 80 patients, in that study [2]. In the series of Digilio et al., 50% of LEOPARD syndrome patients manifested psychomotor retardation [8]. However, the pathogenesis of psychomotor retardation in these patients was unclear. Partial agenesis of the corpus callosum and Chiari I malformation were reported in LEOPARD syndrome [9,10]. However, no other brain malformations were previously reported. Schizencephaly is an uncommon congenital brain malformation that occurs between months 3 and 4 of gestation, and is characterized by gray matter-lined clefts extending from the pial surface to the lateral ventricles. The cause of this abnormality is unclear. Some environmental events, such as organic or viral exposures during pregnancy, comprise potentially related insults. However, familial cases of schizencephaly raise the possibility of a genetic mechanism [11,12]. The extent of cortical involvement is related to clinical manifestations and neurologic outcomes [13,14]. Children with open-lip schizencephaly frequently manifested intractable seizures. In our patient, intractable seizures were also evident, even after treatment with multiple anticonvulsants. The PTPN11 mutations in Noonan syndrome enhance SHP-2 catalytic activity, whereas the activity of representative LEOPARD syndrome mutants is undetectable when assayed using a standard protein tyrosine phosphatase substrate [15]. A previous study revealed that PTPN11 mutations in LEOPARD syndrome cause the defective catalytic function of SHP-2, which interferes with growth factor/ extracellular signal-regulated kinase-mitogen-activated protein kinase-mediated signaling [16]. Although SHP-2 plays an important role in the activation of the Ras/extracellular signal-regulated kinase cascade and in mediating multiple downstream biological responses (e.g., cell proliferation or survival, adhesion, and migration), the effect of defective SHP-2 in neuronal migration remains unclear. In conclusion, to the best of our knowledge, this is the first report of schizencephaly associated with LEOPARD syndrome. Our findings, if they are not merely coincidental, indicate that brain malformations may be a new association in LEOPARD syndrome. In addition, psychomotor retardation
and neurologic deficits are not uncommon in LEOPARD syndrome. In patients with LEOPARD syndrome and neurologic abnormalities such as developmental delay or epilepsy, brain imaging is suggested as part of the diagnostic workup. References [1] Gorlin RJ, Anderson RC, Blaw M. Multiple lentigines syndrome. Am J Dis Child 1969;117:652-62. [2] Voron DA, Hatfield HH, Kalkhoff MD. Multiple lentigines syndrome. Case report and review of the literature. Am J Med 1976;60: 447-56. [3] Digilio MC, Conti E, Sarkozy A, et al. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet 2002;71:389-94. [4] Sarkozy A, Conti E, Seripa D, et al. Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. J Med Genet 2003;40:704-8. [5] Keren B, Hadchouel A, Saba S, et al. PTPN11 mutations in patients with LEOPARD syndrome: A French multicentric experience. J Med Genet 2004;41:e117. [6] Sarkozy A, Conti E, Digilio MC, et al. Clinical and molecular analysis of 30 patients with multiple lentigines: LEOPARD syndrome. J Med Genet 2004;41:e68.
[7] Yoshida R, Nagai T, Hasegawa T, Kinoshita E, Tanaka T, Ogata T. Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome. Am J Med Genet [A] 2004;130A:432-4. [8] Digilio MC, Sarkozy A, de Zorzi A, et al. LEOPARD syndrome: Clinical diagnosis in the first year of life. Am J Med Genet [A] 2006; 140A:740-6. [9] Bonioli E, Di Stefano A, Costabel S, Bellini C. Partial agenesis of corpus callosum in LEOPARD syndrome. Int J Dermatol 1999;38:855-62. [10] Agha A, Hashimoto K. Multiple lentigines (LEOPARD) syndrome with Chiara I malformation. J Dermatol 1995;22:520-3. [11] Nuri Sener R. Schizencephaly and congenital cytomegalovirus infection. J Neuroradiol 1998;25:151-2. [12] Brunelli S, Faiella A, Capra V, et al. Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly. Nat Genet 1996;12:94-6. [13] Packard AM, Miller VS, Delgado MR. Schizencephaly: Correlations of clinical and radiologic features. Neurology 1997;48:1427-34. [14] Liang JS, Lee WT, Peng SS, Yu TW, Shen YZ. Schizencephaly: Correlation between clinical and neuroimaging features. Acta Paediatr Taiwan 2003;43:208-13. [15] Hanna N, Montagner A, Lee WH, et al. Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: Consequences for PI3K binding on Gab1. FEBS Lett 2006;580:2477-82. [16] Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG. PTPN11 (SHP2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem 2006;281:6785-92.
Liang et al: Schizencephaly in LEOPARD Syndrome 73