Seizure (2008) 17, 378—382

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CASE REPORT Proteus syndrome associated with and Ohtahara syndrome: Report of two cases

Halisson Bastos a,*, Paula Fabiana Sobral da Silva a, Marco Antoˆnio Veloso de Albuquerque a, Adriana Mattos a, Rudimar Santos Riesgo b, Lygia Ohlweiler c, Maria Isabel Bragatti Winckler c, Jose´ Augusto Bragatti d, Rodrigo Dias Duarte e, Denise Isabel Zandona´ f a Child , Hospital de Clı´nicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2350, CEP 90035-003, Porto Alegre, Brazil b Pediatric neurologist, Adjunct professor, Pediatrics, HCPA, UFRGS, Porto Alegre, Brazil c Pediatric neurologists, HCPA, UFRGS, Porto Alegre, Brazil d Clinical neurophysiologist, HCPA, UFRGS, Porto Alegre, Brazil e Radiologist, HCPA, UFRGS, Porto Alegre, Brazil f Medical geneticist, HCPA, UFRGS, Porto Alegre, Brazil

Received 18 May 2007; received in revised form 24 September 2007; accepted 2 November 2007

KEYWORDS Summary The authors report two cases of Brazilian children with most of the Hemimegalencephaly; common syndromic features of Proteus syndrome, such as asymmetric overgrowth of Proteus syndrome; tissues, skin abnormalities, hypotonia and mental retardation. In both patients, a Ohtahara syndrome; refractory , compatible with Ohtahara syndrome, as well as hemimegalen- EEG cephaly, with asymmetric distribution of facial fat, were also diagnosed. # 2007 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Introduction unknown,2—5 started to be described in 2000, with studies reporting mutations in the tumor suppressor 6—8 Proteus syndrome is a rare congenital neurocuta- gene PTEN. neous syndrome that was first described in Clinical manifestations are highly variable, but 8,9 1979.1 The etiology of Proteus syndrome, initially usually affect the brain and other tissues. Main clinical signs are overgrowth of the brain, hemihy- pertrophy,gigantism of the extremities, skin abnorm- * Corresponding author at: Rua Ferreira Viana, 865/503, Pet- alities, multiple hamartomatous tumors and mental ro´polis, CEP 90670-100, Porto Alegre, RS, Brazil. 3,10,11 Tel.: +55 51 3334 1421; fax: +55 51 3061 5270. retardation. Brain radiology findings are also E-mail address: [email protected] (H. Bastos). variable, and may include hemimegalencephaly,

1059-1311/$ — see front matter # 2007 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j..2007.11.001 Proteus syndrome with hemimegalencephaly and Ohtahara syndrome: report of two cases 379 callosal dysgenesis, neuronal migration disorders and required prolonged mechanical ventilation and calcifications.12 Finally, epilepsy and epileptic syn- treatment with antibiotics. dromes, often of early onset and hard to control, such The patient, seen at the emergency department as the Ohtahara syndrome, may be associated.13 at 4 months of age, had a history of flexor spasms of Ohtahara syndrome, an early-infantile epileptic the four extremities that started in the 2nd month of , was first described in 1976,14 and is life at a frequency of 4—5 episodes/day. Prior to characterized by frequent and EEG being admitted at our department, treatment con- burst suppression patterns, in which suppression sisted of monotherapy with phenobarbital (from the phases usually last longer (up to 10 s) than high second to the 4th month of life). voltage spikes (1—3 s).15—17 Clinical signs include Examination showed asymmetric syndromic flexor, extensor, or flexor—extensor spasms, fre- facies, with the left side larger than the right, head quently with clustering, that usually last longer than circumference above the 98th percentile, flexor 10 s and occur during sleeping and waking states. hypertonia of the four extremities with hyperre- Partial may occur in up to one-third of the flexia, and persistence of neonatal reflexes. Delays cases.18 in neurologic and psychomotor development were The etiology of Ohtahara syndrome is heteroge- also identified. neous and includes central nervous system (CNS) Fundus examination revealed a pale optic malformations, such as hemimegalencephaly,19—21 papilla and peripheral scars. Skin findings included , ,22 and other con- a flat hemangioma in the occipital region and ditions.17,23—27 a depigmentosus in the left mandibular The prognosis is poor due to the intractability of region. seizures. Mortality is high, particularly among early- Sleep electroencephalogram (EEG) revealed a onset cases, and estimated survival is 2 years.18 high voltage burst suppression pattern with bursts This report describes and discusses two cases of lasting 1—3 s, slow waves and multifocal spikes at infants seen at Hospital de Clı´nicas de Porto Alegre burst to burst intervals, and prolonged suppression and reviews the pertinent literature. phases, some of which lasted up to 10 s (Fig. 1). Flair magnetic resonance imaging (MRI) revealed left hemimegalencephaly, callosal dysgenesis, Case 1 pachygyria and polymicrogyria (Fig. 2). During follow-up, other drugs were A female infant born prematurely at 35 weeks’ administered in an attempt to control seizures. At gestational age by cesarean delivery due to acute discharge, seizures were partially controlled with fetal distress was admitted to the neonatal ICU and valproic acid, primidone, and vigabatrin.

Figure 1 EEG burst suppression and multifocal paroxysms. 380 H. Bastos et al.

Case 2

A 2-month-old female infant born at full term (38 weeks) by cesarean delivery due to acute fetal distress and presenting respiratory dysfunction and sepsis was admitted to the neonatal ICU for 7 days. Initial examination showed facial asymmetry with marked hypertrophy of right side of face, but neurologic examination did not reveal any other abnormal findings. Cranial tomography showed overgrowth of the right side of brain, gray matter heterotopia in the occipital horn of right lateral ventricle, hypoplasia of the left hemisphere and a hypodense left frontal area. Onset of seizures in the 2nd month of life was characterized by brief epileptic spasms of upper extremities. Electroencephalogram showed a burst suppression pattern. Bursts lasted 3—5 s and were mixed with prolonged bilateral and mildly asym- metric suppression phases with lower amplitude to the left. Valproic acid was initiated and the dose was gradually increased, but there was no improvement of seizures. Better control was obtained after the Figure 2 Flair MRI shows left hemimegalencephaly. association of vigabatrin.

Control EEG carried out at 8 months of follow-up showed disorganized and asymmetric background Discussion rhythms, amplitude attenuation and no sleep spin- dles. Frequent and predominantly frontotemporal The authors report the cases of two infants with paroxysms in the left hemisphere and a hypsarrhyth- clinical signs and examination findings suggestive of mic pattern were also found (Fig. 3). Proteus syndrome, a rare hamartomatous syndrome

Figure 3 EEG shows left temporal lobe delta activity and multifocal paroxysms predominantly in left frontal region. Proteus syndrome with hemimegalencephaly and Ohtahara syndrome: report of two cases 381 of complex and variable characteristics associated disabilities, reduce morbidity and mortality. In addi- with hemimegalencephaly. tion, we hope these findings increase neurologists’ Hemimegalencephaly has already been reported attention towards the possibility of diagnosing this in cases of Proteus syndrome, but there is no con- triple association. sensus about its incidence. After the first descrip- tion of the syndrome,1 several authors have reported an increasing variability of findings. In References 1991, Goodship et al. 28 described associated con- genital anomalies of the CNS in 12 children with 1. Cohen Jr MM, Hayden PW. A newly recognized hamartomatous Proteus syndrome; of these, eight patients showed syndrome. Birth Defects Original Article Ser 1979;15(5B): evidence of hemimegalencephaly. 291—6. In our study, dysmorphic growth, skin abnormal- 2. Wiedemann HR, Burgio GR, Aldenhoff P, Kunze J, Kaufmann ities, CNS malformations and epilepsy were HJ, Schirg E. The Proteus syndrome. Partial gigantism of the hands and/or feet, nevi, hemihypertrophy, subcutaneous observed. Onset of epilepsy was in the 2nd month tumors, or other skull anomalies and possible of life. Epilepsy progressed severely, and Ohtahara accelerated growth and visceral affections. Eur J Pediatr syndrome was diagnosed. 1983;140:5—12. The association of infantile spasms, myoclonias, 3. Benichou JJ, Labrune B, Fomanek A, Denoix C, Oger P.Proteus and partial epilepsy in newborn infants is generally syndrome. Arch Franc¸aises de Pediatrie 1990;47:441—4. 4. Pavone L, Curatolo P,Rizzo R, Micali G, Incorpora G, Garg BP, observed in cases with extensive migration disorders 30 et al. Epidermal nevus syndrome: a neurologic variant with diagnosed as Ohtahara syndrome. Guzzeta et al. hemimegalencephaly, gyral malformation, mental retarda- reported the case of a male newborn with Ohtahara tion, seizures, and facial hemihypertrophy. Neurology syndrome and right hemimegalencephaly who pre- 1991;41(2 (pt 1)):266—71. sented epileptic negative on the 1st day 5. Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham Jr 29 JM, Viljoen DL, et al. Proteus syndrome: diagnostic criteria, of life. Dietrich et al. described three children differential diagnosis and patient evaluation. Am J Med with hemimegalencephaly among eight patients Genet 1999;84:839—95. with early-infantile epileptic encephalopathy with 6. Zhou XP, Marsh DJ, Hampel H, Muliken JB, Gimm O, Eng C. suppression bursts. In spite of these studies report- Germline and germline PTEN mutations associated ing the association between Ohtahara syndrome and with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and . hemimegalencephaly, there is no consensus on the Human Mol Genet 2000;9:765—8. incidence of such occurrence. 7. Smith JM, Kirk EP, Theodosopoulos G, Marshall GM, Walker J, Our review of the literature did not yield any Rogers M, et al. Germline mutation of the tumor suppressor reports of patients with Proteus syndrome asso- PTEN in Proteus syndrome [Letter]. J Med Genet 2002;39: ciated with both hemimegalencephaly and Ohta- 937—40. 8. Cohen Jr MM. Proteus syndrome: an update. Am J Med Genet hara syndrome. To our knowledge, these are the Part C Semin Med Genet 2005;137:38—52. first reports of the triple association, and therefore 9. Turner JT, Cohen Jr MM, Biesecker LG. Reassessment of the it is not possible to describe the incidence of this Proteus syndrome literature: application of diagnostic cri- association or to make comparisons with the litera- teria to published cases. Am J Med Genet 2004;130:111—22. ture. In addition, our study might suggest that the 10. Havard S, Enjolras O, Lessana-Leibowitch M, Escande JP. Proteus syndrome. 8 cases. Annales de Dermatologie et de occurrence of this triple association is underesti- Venereologie 1994;121:303—8. mated. 11. Tattelbaum AG, Dufresne CR. Proteus syndrome: a newly Although prognosis of Proteus syndrome is poor, recognized hamartomatous syndrome with significant cranio- treatment approaches such as anticonvulsant med- facial dysmorphology. J Craniofacial Surg 1995;6:151—60. ication, physiotherapy, and occupational therapy, in 12. Griffiths PD, Welch RJ, Gardner-Medwin D, Gholkar A, McAll- ister V. The radiological features of hemimegalencephaly addition to family support, may be very helpful. 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