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Facial Dysmorphism in Leigh Syndrome With SURF-1 Mutation and COX Deficiency
Facial Dysmorphism in Leigh Syndrome With SURF-1 Mutation and COX Deficiency Adnan Yüksel, MD, PhD*, Mehmet Seven, MD†, ¨ mran Cetincelik, MD‡, Gözde Yes¸il, MD†, U and Vedat Köksal, PhD§ Leigh syndrome is an inherited, progressive neurodegenerative disorder of infancy and childhood. Mutations in the nuclear SURF-1 gene are specifically associated with cytochrome C oxidase– deficient Leigh syndrome. This report describes two patients with similar facial features. One of them was a 2½-year-old male, and the other was a 3-year-old male with a mutation in SURF-1 gene and facial dysmorphism including frontal bossing, brachycephaly, hypertrichosis, lateral displacement of inner canthi, esotropia, maxillary hypoplasia, hypertrophic gums, irregularly placed teeth, upturned nostril, low-set big ears, and retrognathi. The first patient’s magnetic resonance imaging at 15 months of age indicated mild symmetric T2 prolongation involving the subthalamic nuclei. His second magnetic resonance imaging at 2 years old revealed a symmetric T2 prolongation involving the subthalamic nuclei, substantia nigra, and medulla lesions. In the second child, at the age of 2 the first magnetic resonance imaging documented heavy brainstem and subthalamic nuclei involvement. A second magnetic resonance imaging, performed when he was 3 years old, revealed diffuse involvement of the substantia nigra and hyperintense lesions of the central tegmental tract in addition to previous lesions. Facial dysmorphism and magnetic resonance imaging find-
From the *Department of Medical Genetic, Division of Pediatric Neurology, Cerrahpas¸a Medical Faculty, Istanbul University, Turkey; † Department of Medical Genetic, Cerrahpas¸a Medical School; ‡ Department of Medical Genetic, S¸is¸li Etfal Research Laboratory, Istanbul, Turkey; and the §Special Molecular Genetic Diagnosis and Research Laboratory, Istanbul, Turkey.
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ings, observed in these cases, can be specific findings in Leigh syndrome patients with cytochrome C oxidase deficiency. SURF-1 gene mutations must be particularly reviewed in such patients. © 2006 by Elsevier Inc. All rights reserved. Yüksel A, Seven M, Cetincelik U, Yes¸il G, Köksal V. Facial dysmorphism in Leigh syndrome with SURF-1 mutation and COX deficiency. Pediatr Neurol 2006;34:486-489.
Introduction Leigh syndrome, or subacute necrotizing encephalomyelopathy, is an early-onset progressive neurodegenerative disorder with a characteristic neuropathology consisting of focal, bilateral lesions in one or more areas of the central nervous system, including the brainstem, thalamus, basal ganglia, cerebellum, and spinal cord [1]. Clinical symptoms depend on which areas of the central nervous system are involved. Clinical features usually emerge in the first few years of life. Hypotonia, failure to thrive, psychomotor regression, ataxia, ocular movement abnormalities, dystonia, swallowing, and respiratory disturbances are the most commonly observed findings [2]. The most common underlying cause is a defect in oxidative phosphorylation. Genetic heterogeneity has been confirmed with the identification of functional or molecular defects in several enzyme systems involved in mitochondrial energy production, including the pyruvate dehydrogenase complex, respiratory chain complexes I-IV (cytochrome C oxidase), and the mitochondria-encoded adenosine triphosphatase 6 subunit of complex V [3,4]. An isolated, generalized defect of cytochrome C oxidase is one of the most common biochemical abnormalities evident in patients with Leigh syndrome. Human cytochrome C oxidase is composed of 13 subunits, of which three are encoded by mitochondrial deoxyribonucleic acid and the remainder by nuclear deoxyribonucleic acid. Loss of function mutation of one of these nuclear genes, SURF-1, is specifically associated with cytochrome C oxidase– deficient Leigh syndrome [4-7]. Many investigators have discussed the imaging findings in Leigh syndrome and have tried to correlate a specific enzyme defect to a homogeneous radiologic pattern. This
Communications should be addressed to: Dr. Yüksel; Akdeniz Caddesi, No: 85, Kat:1; Fatih, Istanbul, Turkey. E-mail: [email protected] Received August 16, 2005; accepted October 31, 2005.
© 2006 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2005.10.020 ● 0887-8994/06/$—see front matter
Figure 2. First patient at 2 years old. Coronal T2-weighted magnetic resonance imaging reveals symmetric T2 prolongation involving the subthalamic nuclei, substantia nigra, and medulla (TR: 5000 ms; TE: 144 ms).
Figure 1. Facial dysmorphic features of the first patient.
report discusses the relationship between clinical and imaging findings in Leigh syndrome with specific enzyme and gene defects. Case Report A 3-year-old male presented with psychomotor regression, developmental delay, and failure to thrive. The neonatal period was unremarkable. At 4 months of age, he was able to roll around and hold his head. He sat at the first year and talked in simple sentences at 2 years of age. At 13 months, his developmental milestones slowed and muscle hypotonia appeared. At 18 months he manifested neurodevelopmental regression, generalized hypotonia, respiratory problems, and absent deep tendon reflexes. On examination at 2 years old, he was conscious and alert. His length, weight, and head circumference were 74 cm, 8500 gm, and 45.2 cm respectively, and all were below the third percentile. He manifested hypotonia and facial dysmorphism including frontal bossing, brachycephaly, hypertrichosis localized mostly on the forehead, lateral displacement of inner canthi, esotropia, maxillary hypoplasia, upturned nostril, long eyelashes, hypertrophic gums, irregularly placed teeth, low-set big ears, and retrognathia (Fig 1). Electromyography was suggestive of neurogenic lesion; motor nerve conduction velocity was slowed. Electroencephalography disclosed no remarkable findings. The first magnetic resonance imaging at 15 months of age disclosed mild symmetric T2 prolongation involving the subthalamic nuclei. A second magnetic resonance imaging at 2 years of age indicated heavy brainstem and subthalamic nuclei involvement without lesions in the basal ganglia (Fig 2).
Cerebrospinal fluid lactate at rest was 65 mg/dL (normal: 8-22 mg/dL). On the cultured fibroblasts, cytochrome C oxidase activity was low at 7 nmol/mg protein/min (normal range was 30-90 nmol/mg protein/min). The coding region of the SURF 1 gene was sequenced and identified a missense mutation, T⬎G at position 530 which would change valine 177 to glycine. It is homozygous for the mutation. The second child was 23 months old when he was referred to us with neuromotor regression and tremor that had been observed during the previous 2 months. He was born to healthy parents who were first cousins. The pregnancy was terminated at 32 weeks. The neonatal period was unremarkable. He gained head control at 8 months and sat unsupported at the age of 1. He has not walked or talked to date. On the examination at 23 months of age, his length, weight, and head circumference were 76 cm, 8000 gm, and 46 cm respectively; all were below the third percentile. He was conscious, alert, and hypotonic. He also manifested facial dysmorphism including prominent forehead, brachycephaly, and prominent eyebrows, hypertrichosis mostly localized on the forehead, epicanthus, long eyelashes, maxillary hypoplasia, low-set large ears, lateral displacement of inner canthi, mild esotropia, upturned nostril, highly arched palate, and irregular teeth. Besides the facial features he had marked skin hyperextensibility (Fig 3). The electromyography revealed polyneuropathy leading to hypotonia. Electroencephalogram yielded no remarkable findings. The metabolic and endocrinologic tests were unremarkable except the cerebrospinal fluid lactate was 52.0 mg/dL (10-22 mg/dL) and the cholesterol levels higher than normal. The first magnetic resonance imaging at 2 years of age revealed a hypointense lesion of subthalamic nuclei and brainstem involvement. A second magnetic resonance imaging was performed at the age of 3, revealing a mild cerebellar and marked cerebral atrophy, diffuse involvement of substantia nigra, hyperintense lesion of the central tegmental tract, and extensive brainstem involvement. Sequence analysis of the SURF 1 gene identified a nonsense mutation, C⬎T at position 244 on the fourth exon of Q82X which would change glutamine to a stop codon. It is homozygous for the mutation.
Discussion Several magnetic resonance image findings of Leigh disease have been reported to date. Typical imaging
Yüksel et al: Facial Dysmorphism in Leigh Syndrome 487
Figure 3. Facial dysmorphic features of the second patient.
findings have been considered as a diagnostic hallmark [8,9]. Bilateral putaminal lesions have long been considered a consistent feature of Leigh syndrome on magnetic resonance imaging studies; however, the magnetic resonance imaging picture may include the medulla, substantia nigra, cerebral peduncles, decussation of superior cerebellar peduncles, brachium of inferior colliculi, subthalamic nuclei, thalamus, periaqueductal region, globus pallidus, and caudate nuclei [8,10]. Cortical involvement might also accompany the basal ganglia and brainstem lesions. The presence of different magnetic resonance imaging findings in Leigh syndrome cases is a result of different biochemical defects which affect mitochondrial functions. Recently, Leigh syndrome cases manifesting SURF-1 gene mutation but not putaminal abnormalities have been reported [7,10,11]. Unfortunately, correlation between magnetic resonance imaging findings and corresponding biochemical and genetic defects has been rather limited so far. Leigh syndrome patients who have SURF-1 gene mutations and cytochrome C oxidase deficiency manifest rather homogeneous clinical findings. In these patients, because of brainstem involvement as in our patients, the disease process develops more severely and at the age of 2 years, generalized hypotonia, truncal ataxia, central respiratory problems, and progressive encephalopathic
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findings are observed. Recently in the Leigh syndrome patients with SURF-1 gene mutations and cytochrome C oxidase deficiency, symmetric T2 prolongation involving the subthalamic nuclei has been reported. Farina et al. reported symmetric T2 prolongation in the subthalamic nuclei and in the brainstem at different levels in all their eight patients with Leigh syndrome/cytochrome C oxidase deficiency with SURF-1 gene mutations [11]. Rahman et al. found a supratentorial leukodystrophic pattern associated with T2 prolongation involving the medulla dentate nuclei in a patient with SURF-1 gene mutation [2]. Salviati et al. demonstrated only brainstem and cerebellar involvement without lesions in the basal ganglia or subthalamic nuclei [12]. Leigh syndrome with SURF-1 mutations is nearly the only disease where subthalamic nuclei are affected bilaterally. Unilateral involvement can be observed in vascular and infectious diseases; however, these cases are associated with hemiballismus [13]. Thus far, bilateral changes have been observed in one patient with mitochondrial encephalopathy similar to Kearns-Sayre syndrome [11]. Finally, Rossi et al. have also reported bilateral involvement of the subthalamic nucleus and brainstem at various levels with mild or even absent basal ganglia abnormalities in three Leigh syndrome cases with SURF-1 gene mutations and cytochrome C oxidase deficiency [5]. Magnetic resonance imaging is an important method to diagnose neurometabolic diseases such as Leigh syndrome or metachromatic distrophy. Thus, as the number of Leigh syndrome patients in whom SURF-1 gene mutations and cytochrome C oxidase deficiency are observed increases, magnetic resonance studies become more important. Also various facial dysmorphic findings observed in the present case were not reported in the previous Leigh syndrome cases in detail. Rossi et al. reported facial dysmorphism in two cases, but they did not specify the exact nature of the facial dysmorphism [5]. At first sight, both patients’ clinical signs, such as mild motor and mental growth retardation, microbrachycephaly, long curled eyelashes, depressed nasal bridge, anteverted nares, thin upper lip, and hirsutism, resembled Cornelia de Lange’s syndrome. However, we exclude this syndrome because the major findings of Cornelia de Lange’s syndrome, such as confluent eyebrows, thin downturned upper lip, micromelia, and genital abnormalities were absent in our patients. In patients with Leigh syndrome, as in specific MRI findings, as well as typical facial findings are crucial for diagnosis. The present two cases must also be reviewed in this respect. Furthermore, SURF-1 gene analysis in these patients is important for prognosis, genetic counseling, and prenatal diagnosis.
References [1] Leigh D. Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry 1951;14:216-21. [2] Rahman S, Blok RB, Dahl HH, et al. Leigh syndrome: Clinical
features and biochemical and DNA abnormalities. Ann Neurol 1996;39:343-51. [3] Di Mauro S, Bonilla E, DeVivo DC. Does the patient have a mitochondrial encephalomyopathy? J Child Neurol 1999;14:23-5. [4] Tiranti V, Hoertnagel K, Carozzo R, et al. Mutations of SURF-1 gene in Leigh Disease associated with cytochrome c oxidase deficiency. Am J Hum Genet 1998;19:369-77. [5] Rossi A, Biancheri R, Bruno C, et al. Leigh Syndrome with COX deficiency and SURF-1 gene mutations: MRI imaging findings. Am J Neuroradiol. 2003;24:1188-91. [6] Bruno C, Biancheri R, Gravaglia B, et al. A novel mutation in the SURF-1 gene in a child with Leigh Syndrome, peripheral neuropathy and cytochrome c oxidase deficiency. J Child Neurol 2002;17:233-36. [7] Pecina P, Gnaiger E, Zeman J, Pronicka E, Houstek J. Decreased affinity for oxygen of cytochrome c oxidase in Leigh Syndrome caused by SURF-1 mutations. Am J Physiol 2004;287:1384-8. [8] Barkovich AJ, Good WV, Koch TK, Berg BO. Mitochondrial
disorders: Analysis of their clinical and imaging characteristics. Am J Neuroradiol 1993;14:1119-37. [9] Medina L, Chi TL, DeVivo DC, Hilal SK. MR findings in patients with subacute necrotizing encephalomyelopathy (LS). Am J Neuroradiol 1990;11:379-84. [10] Topçu M, Saatçi I, Apak A, Söylemezoglu F, Akçoren Z. Leigh Syndrome in a 3-year-old boy with unusual brain MRI imaging and pathologic findings. Am J Neuroradiol 2000;21:224-7. [11] Farina L, Chiapparini L, Uziel G, Bugiani M, Zeviani M, Savoiardo M. MR findings in Leigh Syndrome with COX deficiency and SURF-1 mutations. Am J Neuroradiol 2002;23:1095-100. [12] Salviati L, Freehauf C, Sacconi S, Di Mauro S, Thoma J, Tsai AC. Novel SURF-1 mutation in a child with subacute encephalopathy and without the radiological features of Leigh Syndrome. Am J Med Genet A 2004;128:195–98. [13] Provenzale JM, Schwarzschild MA. Radiologic-clinical correlation: Hemiballismus. Am J Neuroradiol 1994;15:1377-382.
Yüksel et al: Facial Dysmorphism in Leigh Syndrome 489
From the *Department of Medical Genetic, Division of Pediatric Neurology, Cerrahpas¸a Medical Faculty, Istanbul University, Turkey; † Department of Medical Genetic, Cerrahpas¸a Medical School; ‡ Department of Medical Genetic, S¸is¸li Etfal Research Laboratory, Istanbul, Turkey; and the §Special Molecular Genetic Diagnosis and Research Laboratory, Istanbul, Turkey.
486
PEDIATRIC NEUROLOGY
Vol. 34 No. 6
ings, observed in these cases, can be specific findings in Leigh syndrome patients with cytochrome C oxidase deficiency. SURF-1 gene mutations must be particularly reviewed in such patients. © 2006 by Elsevier Inc. All rights reserved. Yüksel A, Seven M, Cetincelik U, Yes¸il G, Köksal V. Facial dysmorphism in Leigh syndrome with SURF-1 mutation and COX deficiency. Pediatr Neurol 2006;34:486-489.
Introduction Leigh syndrome, or subacute necrotizing encephalomyelopathy, is an early-onset progressive neurodegenerative disorder with a characteristic neuropathology consisting of focal, bilateral lesions in one or more areas of the central nervous system, including the brainstem, thalamus, basal ganglia, cerebellum, and spinal cord [1]. Clinical symptoms depend on which areas of the central nervous system are involved. Clinical features usually emerge in the first few years of life. Hypotonia, failure to thrive, psychomotor regression, ataxia, ocular movement abnormalities, dystonia, swallowing, and respiratory disturbances are the most commonly observed findings [2]. The most common underlying cause is a defect in oxidative phosphorylation. Genetic heterogeneity has been confirmed with the identification of functional or molecular defects in several enzyme systems involved in mitochondrial energy production, including the pyruvate dehydrogenase complex, respiratory chain complexes I-IV (cytochrome C oxidase), and the mitochondria-encoded adenosine triphosphatase 6 subunit of complex V [3,4]. An isolated, generalized defect of cytochrome C oxidase is one of the most common biochemical abnormalities evident in patients with Leigh syndrome. Human cytochrome C oxidase is composed of 13 subunits, of which three are encoded by mitochondrial deoxyribonucleic acid and the remainder by nuclear deoxyribonucleic acid. Loss of function mutation of one of these nuclear genes, SURF-1, is specifically associated with cytochrome C oxidase– deficient Leigh syndrome [4-7]. Many investigators have discussed the imaging findings in Leigh syndrome and have tried to correlate a specific enzyme defect to a homogeneous radiologic pattern. This
Communications should be addressed to: Dr. Yüksel; Akdeniz Caddesi, No: 85, Kat:1; Fatih, Istanbul, Turkey. E-mail: [email protected] Received August 16, 2005; accepted October 31, 2005.
© 2006 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2005.10.020 ● 0887-8994/06/$—see front matter
Figure 2. First patient at 2 years old. Coronal T2-weighted magnetic resonance imaging reveals symmetric T2 prolongation involving the subthalamic nuclei, substantia nigra, and medulla (TR: 5000 ms; TE: 144 ms).
Figure 1. Facial dysmorphic features of the first patient.
report discusses the relationship between clinical and imaging findings in Leigh syndrome with specific enzyme and gene defects. Case Report A 3-year-old male presented with psychomotor regression, developmental delay, and failure to thrive. The neonatal period was unremarkable. At 4 months of age, he was able to roll around and hold his head. He sat at the first year and talked in simple sentences at 2 years of age. At 13 months, his developmental milestones slowed and muscle hypotonia appeared. At 18 months he manifested neurodevelopmental regression, generalized hypotonia, respiratory problems, and absent deep tendon reflexes. On examination at 2 years old, he was conscious and alert. His length, weight, and head circumference were 74 cm, 8500 gm, and 45.2 cm respectively, and all were below the third percentile. He manifested hypotonia and facial dysmorphism including frontal bossing, brachycephaly, hypertrichosis localized mostly on the forehead, lateral displacement of inner canthi, esotropia, maxillary hypoplasia, upturned nostril, long eyelashes, hypertrophic gums, irregularly placed teeth, low-set big ears, and retrognathia (Fig 1). Electromyography was suggestive of neurogenic lesion; motor nerve conduction velocity was slowed. Electroencephalography disclosed no remarkable findings. The first magnetic resonance imaging at 15 months of age disclosed mild symmetric T2 prolongation involving the subthalamic nuclei. A second magnetic resonance imaging at 2 years of age indicated heavy brainstem and subthalamic nuclei involvement without lesions in the basal ganglia (Fig 2).
Cerebrospinal fluid lactate at rest was 65 mg/dL (normal: 8-22 mg/dL). On the cultured fibroblasts, cytochrome C oxidase activity was low at 7 nmol/mg protein/min (normal range was 30-90 nmol/mg protein/min). The coding region of the SURF 1 gene was sequenced and identified a missense mutation, T⬎G at position 530 which would change valine 177 to glycine. It is homozygous for the mutation. The second child was 23 months old when he was referred to us with neuromotor regression and tremor that had been observed during the previous 2 months. He was born to healthy parents who were first cousins. The pregnancy was terminated at 32 weeks. The neonatal period was unremarkable. He gained head control at 8 months and sat unsupported at the age of 1. He has not walked or talked to date. On the examination at 23 months of age, his length, weight, and head circumference were 76 cm, 8000 gm, and 46 cm respectively; all were below the third percentile. He was conscious, alert, and hypotonic. He also manifested facial dysmorphism including prominent forehead, brachycephaly, and prominent eyebrows, hypertrichosis mostly localized on the forehead, epicanthus, long eyelashes, maxillary hypoplasia, low-set large ears, lateral displacement of inner canthi, mild esotropia, upturned nostril, highly arched palate, and irregular teeth. Besides the facial features he had marked skin hyperextensibility (Fig 3). The electromyography revealed polyneuropathy leading to hypotonia. Electroencephalogram yielded no remarkable findings. The metabolic and endocrinologic tests were unremarkable except the cerebrospinal fluid lactate was 52.0 mg/dL (10-22 mg/dL) and the cholesterol levels higher than normal. The first magnetic resonance imaging at 2 years of age revealed a hypointense lesion of subthalamic nuclei and brainstem involvement. A second magnetic resonance imaging was performed at the age of 3, revealing a mild cerebellar and marked cerebral atrophy, diffuse involvement of substantia nigra, hyperintense lesion of the central tegmental tract, and extensive brainstem involvement. Sequence analysis of the SURF 1 gene identified a nonsense mutation, C⬎T at position 244 on the fourth exon of Q82X which would change glutamine to a stop codon. It is homozygous for the mutation.
Discussion Several magnetic resonance image findings of Leigh disease have been reported to date. Typical imaging
Yüksel et al: Facial Dysmorphism in Leigh Syndrome 487
Figure 3. Facial dysmorphic features of the second patient.
findings have been considered as a diagnostic hallmark [8,9]. Bilateral putaminal lesions have long been considered a consistent feature of Leigh syndrome on magnetic resonance imaging studies; however, the magnetic resonance imaging picture may include the medulla, substantia nigra, cerebral peduncles, decussation of superior cerebellar peduncles, brachium of inferior colliculi, subthalamic nuclei, thalamus, periaqueductal region, globus pallidus, and caudate nuclei [8,10]. Cortical involvement might also accompany the basal ganglia and brainstem lesions. The presence of different magnetic resonance imaging findings in Leigh syndrome cases is a result of different biochemical defects which affect mitochondrial functions. Recently, Leigh syndrome cases manifesting SURF-1 gene mutation but not putaminal abnormalities have been reported [7,10,11]. Unfortunately, correlation between magnetic resonance imaging findings and corresponding biochemical and genetic defects has been rather limited so far. Leigh syndrome patients who have SURF-1 gene mutations and cytochrome C oxidase deficiency manifest rather homogeneous clinical findings. In these patients, because of brainstem involvement as in our patients, the disease process develops more severely and at the age of 2 years, generalized hypotonia, truncal ataxia, central respiratory problems, and progressive encephalopathic
488
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findings are observed. Recently in the Leigh syndrome patients with SURF-1 gene mutations and cytochrome C oxidase deficiency, symmetric T2 prolongation involving the subthalamic nuclei has been reported. Farina et al. reported symmetric T2 prolongation in the subthalamic nuclei and in the brainstem at different levels in all their eight patients with Leigh syndrome/cytochrome C oxidase deficiency with SURF-1 gene mutations [11]. Rahman et al. found a supratentorial leukodystrophic pattern associated with T2 prolongation involving the medulla dentate nuclei in a patient with SURF-1 gene mutation [2]. Salviati et al. demonstrated only brainstem and cerebellar involvement without lesions in the basal ganglia or subthalamic nuclei [12]. Leigh syndrome with SURF-1 mutations is nearly the only disease where subthalamic nuclei are affected bilaterally. Unilateral involvement can be observed in vascular and infectious diseases; however, these cases are associated with hemiballismus [13]. Thus far, bilateral changes have been observed in one patient with mitochondrial encephalopathy similar to Kearns-Sayre syndrome [11]. Finally, Rossi et al. have also reported bilateral involvement of the subthalamic nucleus and brainstem at various levels with mild or even absent basal ganglia abnormalities in three Leigh syndrome cases with SURF-1 gene mutations and cytochrome C oxidase deficiency [5]. Magnetic resonance imaging is an important method to diagnose neurometabolic diseases such as Leigh syndrome or metachromatic distrophy. Thus, as the number of Leigh syndrome patients in whom SURF-1 gene mutations and cytochrome C oxidase deficiency are observed increases, magnetic resonance studies become more important. Also various facial dysmorphic findings observed in the present case were not reported in the previous Leigh syndrome cases in detail. Rossi et al. reported facial dysmorphism in two cases, but they did not specify the exact nature of the facial dysmorphism [5]. At first sight, both patients’ clinical signs, such as mild motor and mental growth retardation, microbrachycephaly, long curled eyelashes, depressed nasal bridge, anteverted nares, thin upper lip, and hirsutism, resembled Cornelia de Lange’s syndrome. However, we exclude this syndrome because the major findings of Cornelia de Lange’s syndrome, such as confluent eyebrows, thin downturned upper lip, micromelia, and genital abnormalities were absent in our patients. In patients with Leigh syndrome, as in specific MRI findings, as well as typical facial findings are crucial for diagnosis. The present two cases must also be reviewed in this respect. Furthermore, SURF-1 gene analysis in these patients is important for prognosis, genetic counseling, and prenatal diagnosis.
References [1] Leigh D. Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry 1951;14:216-21. [2] Rahman S, Blok RB, Dahl HH, et al. Leigh syndrome: Clinical
features and biochemical and DNA abnormalities. Ann Neurol 1996;39:343-51. [3] Di Mauro S, Bonilla E, DeVivo DC. Does the patient have a mitochondrial encephalomyopathy? J Child Neurol 1999;14:23-5. [4] Tiranti V, Hoertnagel K, Carozzo R, et al. Mutations of SURF-1 gene in Leigh Disease associated with cytochrome c oxidase deficiency. Am J Hum Genet 1998;19:369-77. [5] Rossi A, Biancheri R, Bruno C, et al. Leigh Syndrome with COX deficiency and SURF-1 gene mutations: MRI imaging findings. Am J Neuroradiol. 2003;24:1188-91. [6] Bruno C, Biancheri R, Gravaglia B, et al. A novel mutation in the SURF-1 gene in a child with Leigh Syndrome, peripheral neuropathy and cytochrome c oxidase deficiency. J Child Neurol 2002;17:233-36. [7] Pecina P, Gnaiger E, Zeman J, Pronicka E, Houstek J. Decreased affinity for oxygen of cytochrome c oxidase in Leigh Syndrome caused by SURF-1 mutations. Am J Physiol 2004;287:1384-8. [8] Barkovich AJ, Good WV, Koch TK, Berg BO. Mitochondrial
disorders: Analysis of their clinical and imaging characteristics. Am J Neuroradiol 1993;14:1119-37. [9] Medina L, Chi TL, DeVivo DC, Hilal SK. MR findings in patients with subacute necrotizing encephalomyelopathy (LS). Am J Neuroradiol 1990;11:379-84. [10] Topçu M, Saatçi I, Apak A, Söylemezoglu F, Akçoren Z. Leigh Syndrome in a 3-year-old boy with unusual brain MRI imaging and pathologic findings. Am J Neuroradiol 2000;21:224-7. [11] Farina L, Chiapparini L, Uziel G, Bugiani M, Zeviani M, Savoiardo M. MR findings in Leigh Syndrome with COX deficiency and SURF-1 mutations. Am J Neuroradiol 2002;23:1095-100. [12] Salviati L, Freehauf C, Sacconi S, Di Mauro S, Thoma J, Tsai AC. Novel SURF-1 mutation in a child with subacute encephalopathy and without the radiological features of Leigh Syndrome. Am J Med Genet A 2004;128:195–98. [13] Provenzale JM, Schwarzschild MA. Radiologic-clinical correlation: Hemiballismus. Am J Neuroradiol 1994;15:1377-382.
Yüksel et al: Facial Dysmorphism in Leigh Syndrome 489