200 Short Communication

Megalencephaly and Perisylvian with Postaxial Polydactyly and (MPPH): Report of a New Case

Author L. Garavelli 1, E . G u a r e s c h i1 , S. Errico 1, A . S i m o n i 2, P. Bergonzini 2 , M. Zollino 3 , F. Gurrieri3 , G. M. Mancini 4, R . S c h o t4 , P. J . V a n D e r S p e k5 , G. Frigieri2 , P. Z o n a r i6 , E. Albertini 1, E . D e l l a G i u s t i n a7 , S. Amarri 1 , G Banchini1 , W. B. Dobyns 8, G . N e r i3

Affi liation A f fi liation addresses are listed at the end of the article

Key words Abstract many overgrowth syndromes. In 2004 Mirzaa ᭹ ᭤ & et al. reported fi ve non-consanguineous patients ᭹᭤ perisylvian polymicrogyria Megalencephaly (MEG), or enlargement of the with a new MCA/ MR syndrome characterized ᭹᭤ postaxial polydactyly brain, can either represent a familial variant with by severe congenital MEG with polymicrogyria ᭹ ᭤ hydrocephalus normal cerebral structure, or a rare brain malfor- (PMG), postaxial polydactyly (POLY) and hydro- ᭹ ᭤ MPPH syndrome mation associated with developmental delay and cephalus (HYD). The authors argued that these neurological problems. MEG has been split into fi ndings identifi ed a new and distinct malfor- two subtypes: anatomical and metabolic. The mation syndrome, which they named MPPH. latter features a build-up inside the cells owing We report on a new case of MPPH, the fi rst to to metabolic causes. Anatomical MEG has been be described after the original series (Mirzaa et al., detected in many different conditions, including 2 0 0 4 ) .

Introduction drome, which they named MPPH. Here we & describe a female infant affected with this new Megalencephaly (MEG), literally meaning large condition. brain, can manifest itself either as a variant with typically normal brain structure, or as a rarely observed cerebral malformation which leads to Case Report mental retardation with developmental delay & and neurological diseases. MEG has been subdi- The girl is the fi rst child of healthy non-consan- received 23.04.2007 vided into two types: anatomical and metabolic guineous parents. She has a healthy male twin. accepted 04.07.2007 [4] . Apart from the mild familial type, anatomical She was born at 38 weeks gestation by Cesarean

Bibliography MEG has been described in a wide variety of situ- section. Birth weight was 3,130 g, length 49 cm DOI 10.1055/s-2007-985908 ations, some of which are overgrowth syndromes, and head circumference 36 cm. APGAR scores Neuropediatrics 2007; such as Sotos [11] and Weaver-Smith syndrome were 4, 6 and 8 at 1, 5 and 10 minutes, respec- 38: 200– 203 [1] , overgrowth syndromes with vascular anom- tively. On examination at 3 months her head cir- © Georg Thieme Verlag KG alies like Macrocephaly-cutis marmorata tel- cumference was 46.5 cm (>97 th centile; > + 2 SD), Stuttgart · New York angiectatica congenital syndrome [3, 6, 9] , length 60.5 cm (75 th centile) and weight 6,750 g ISSN 0174-304X Bannayana-Riley-Ruvalcaba and Proteus syn- (>97th centile) She had a large head, with very dromes [2] and skeletal dysplasias. Metabolic large fontanelles, the anterior fontanelle measur- Correspondence Dr. L. Garavelli MEG is a condition in which cerebral enlarge- ing 7 × 8 cm and the lambdoid 0.5 × 0.5 cm. She Struttura Semplice Dipartimen- ment is due to edema or an accumulation of met- had a high forehead, slightly down-slanting tale di Genetica abolic products, without an increase in the palpebral fi ssures, hypertelorism, with an inner Clinica Dipartimento Ostetrico- number of cells. canthal distance of 2.7 cm (>97th centile) and an Ginecologico e Pediatrico In 2004 Mirzaa et al. described fi ve non-related outer canthal distance of 7.7 cm (>97 th centile), Arcispedale S. Maria Nuova patients with a previously unknown MCA/ MR depressed nasal bridge, and hypoplastic, slightly Azienda Ospedaliera syndrome which features severe congenital MEG inverted nipples (᭹ ᭤ F i g . 1 ). She had postaxial Viale Risorgimento 80 42100 Reggio Emilia with polymicrogyria (PMG), postaxial polydac- polydactyly that consisted of extra digits on both Italy tyly (POLY) and hydrocephalus (HYD) [8] . The hands and her left foot and bilateral transverse Tel.: + 39 / 0522 / 29 62 44/29 62 41 authors claimed that these clinical aspects repre- palmar creases ( ᭹ ᭤ F i g . 1 ). She had generalized Fax: + 39 / 0522 / 29 62 66 sented a new and distinct malformation syn- hypotonia and developmental delay and hydro- [email protected]

Garavelli L et al. Megalencephaly and Perisylvian Polymicrogyria … Neuropediatrics 2007; 38: 200– 203 Short Communication 201

Fig. 1 a– f Craniofacial phenotype (a , b ), right hand: postaxial polydactyly ( c ), left foot: postaxial polydactyly ( d ), hand X-rays: postaxial polydactyly ( e), feet X-rays: postaxial polydactyly ( f).

cephalus was present and required shunting at the age of 5 are summarized in ᭹ ᭤ Table 1 and consist of generalized MEG, months. which can be symmetrical or slightly asymmetrical, widespread Investigations including karyotyping at 600-band resolution, PMG, more severe in the perisylvian regions, HYD requiring FISH telomeric rearrangements were all normal. Numerous met- treatment with shunt, and POLY. abolic studies were also normal including serum lactate, ammo- MEG and PMG were present in all fi ve patients described by Mir- nia, amino acids, organic acids, cholesterol, very long chain fatty zaa et al. [8] and POLY only in three of them. HYD was reported acids, and transferrin isoelectric focusing. Genomic DNA hybrid- in four of the fi ve patients, but the remaining patient developed ization on Affymetrix 100 K SNP arrays, analyzed by the copy HYD and was later shunted ( ᭹ ᭤ Table 1). The cause of HYD was not number tool (CNAT program version 2.0) provided by Affyme- evident in every patient, although aqueductal stenosis was possi- trix, did not reveal submicroscopic chromosomal aberrations ble in all cases. Thus, MEG, PMG and HYD treated with a shunt (microdeletions/ duplications). X-rays of her hands and feet have been observed in all 6 patients, and POLY in 4 of the 6. showed postaxial polydactyly on both hands and her left foot All patients had severe mental retardation and four of the origi- without metacarpal and metatarsal fusion ( ᭹ ᭤ F i g . 1 ). nal fi ve, plus our own, had generalized hypotonia. One patient A brain CT scan and MRI demonstrated MEG, PMG, hypoplasia of developed spasticity. Three had seizures and one had a patho- the posterior portion of the corpus callosum and of the splenium logical, epileptiform EEG, as in our patient. and HYD (᭹ ᭤ F i g . 2 ). Heart and abdominal ultrasound and the At birth the head circumference measured between + 2 and + 4 ophthalmological evaluation were normal. SD and successively it was between + 2 and + 5 SD. The corpus callosum was normal or thin in 4 out of 5 cases and slightly dys- morphic in one. Our patient presented hypoplasia of the poste- Discussion rior portion of the corpus callosum and of the splenium. All & patients had persistence of the cavum septi pellucidi, with or This girl has all of the clinical manifestations of MPPH, a new without cavum vergae. recognizable MCA / MR syndrome described by Mirzaa et al. All patients were sporadic, so at the present time the cause of (2004) in fi ve unrelated patients [8] . The main clinical fi ndings this new syndrome remains unknown.

Garavelli L et al. Megalencephaly and Perisylvian Polymicrogyria … Neuropediatrics 2007; 38: 200– 203 202 Short Communication

Fig. 2 a– d MRI of the brain at the age of 1 month (a , b ) and at the age of 5 months (c , d):

Sagittal SE T1 -weighted (a-TR = 460 msec, TE = 10 msec) images show enlargement of the head and hypoplasia of the posterior portion of the trunk and of the splenium of the corpus callosum (arrows).

Axial EPI T2 -weighted (b-TR = 3800, TE = 100, 16 shots) and axial FLAIR (d-TR = 8802, TE = 133, TI = 2200) images show asymmetric lateral ventricle enlargement, cavum septi pellucidi, hypoplasia of the splenium of the corpus callosum (arrows in d ), opening of both Sylvian fi ssures secondary to abnormal opercularization and perisylvian polymicrogyria (arrows in b ); the perisylvian cortex seems slightly thickened because of densely packed gyri, with a bumpy cortical surface and with irregularity of the cortical-white matter junction.

Parasagittal right FSE T 2-weighted (c-TR = 5500, TE = 96 msec, ET = 16) image shows better delineated PMG, extending beyond the perisylvian areas (big arrows), involving the entire frontal lobe (small arrows).

The differential diagnosis must be carried out with the condition Table 1 Clinical fi ndings in 6 patients with MPPH (Mirzaa et al., 2004) described by Pavone et al. in 2005 [10] , with complex brain mal- Literature Present Literature formation with rhombencephalosynapsis, preaxial hexadactyly Case (Total) and facial and skull anomalies, but in this last case the cerebral M / F 3 / 2 F 3 / 3 malformation is more complex, the polydactyly is preaxial, and initially ofc + 2 – 4 sd 5 / 5 + 6 / 6 thus different, and the unusual facial, eyebrows and skull anoma- later ofc + 2 – 5 sd 5 / 5 + 6 / 6 lies are so peculiar that they cannot be considered comparable. profound mental retardation 5 / 5 + 6 / 6 The differential diagnosis must be also placed with MEG-PMG- seizures 3 / 5 − 3 / 6 mega-corpus-callosum [7] . However, all patients reported by hypotonia 4 / 5 + 5 / 6 Mirzaa et al. [8] and our own case presented a normal or thinned postaxial polydactyly 3 / 5 + 4 / 6 corpus callosum, while none of the patients described with MEG- symmetric megalencephaly 3 / 5 + 4 / 6 PMG-mega-corpus-callosum had POLY [7, 8] . Another condition asymmetric megalencephaly 2 / 5 − 2 / 6 that must be considered in the differential diagnosis is the mac- perisylvian polymicrogyria grade 5 / 5 + 6 / 6 1– 2 rocephaly-cutis marmorata telangiectatica congenita syndrome hydrocephalus that required 5 / 5 + 6 / 6 (M-CMTC – MIM 602501): some patients with this condition shunting * have had MEG, PMG and HYD, but the skin is really peculiar [6]. corpus callosum normal to 4 / 5 − 4 / 6 Apart from (HMEG) and the associated mildly thin syndromes, MEG has seldom been associated with cortical dys- corpus callosum short/ 1 / 5 + 2 / 6 plasias or other brain malformations in the more recent litera- dysmorphic ture. Nevertheless, on examination of the older literature, it is cavum septi pellucidi et vergae 5 / 5 − 5 / 6 evident that brain malformations were actually described in the other anomalies pale optic nerves; atrial septal defect; past. In a survey of 31 patients that included some autopsy data, ventricular septal defect; vascular ring; duplicated kidneys 10 had cortical malformations such as and PMG, * Updated data on patient 4 (Mirzaa et al., 2004), who developed HYD and required a while 25 had severe mental retardation [5] . Thus one can infer shunt at age 3 years that this new syndrome has probably been seen in the past, even

Garavelli L et al. Megalencephaly and Perisylvian Polymicrogyria … Neuropediatrics 2007; 38: 200– 203 Short Communication 203

if it was not clearly described before the work published by Mir- 3 Clayton-Smith J , Kerr B , Brunner H , Tranebjaerg L , Magee A , Hennekam RCM et al . Macrocephaly with cutis marmorata, haemangioma and zaa et al. in (2004). syndactyly – a distinctive overgrowth syndrome . Clin Dysmorphol The present report confi rms the existence of this new condition. 1997 ; 6 : 291 – 302 4 DeMyer W . Megalencephaly in children. Clinical syndromes, genetic patterns and differential diagnosis from other causes of megaloceph- aly . Neurology 1972 ; 22 : 634 – 643 Acknowledgments 5 Dekaban AS , Priestly BL . Megalencephaly . In: Vinken PJ, Bruyn G (Eds), & Handbook of Clinical Neurology . Amsterdam: North Holland , 1977 ; The authors wish to thank the co-operating family members for 6 4 – 6 6 0 the necessary medical data and photographs for publication. 6 Garavelli L , Leask K , Zanacca C , Pedori S , Albertini G , Della Giustina E et al . MRI and neurological fi ndings in macrocephaly – cutis mar- Furthermore, the authors wish to thank Marco Bonazzi and morata teleangiectasica congenita syndrome: report of ten cases and Amos Rainieri for their excellent photographs. review of the literature . Genetic Counselling 2005 ; 16 : 117 – 128 7 Gohlich-Ratmann C , Baethmann M , Lorenz P , Gartner J , Goebel HH , Engelbrecht V et al . Megalencephaly, mega corpus callosum and com- Affi liation plete lack of motor development: a previously undescribed syndrome. 1 Department of Pediatrics and Genetic Unit, S. Maria Nuova Hospital, Reggio Am J Med Genet 1988 ; 79 : 161 – 167 Emilia, Italy 2 Department of Pediatrics, Carpi Hospital, Carpi, Italy 8 Mirzaa G , Dodge NN , Glass I , Day C , Gripp K , Nicholson L , Straub V , Voit T , 3 Institute of Medical Genetics, Catholic University of Rome, Rome, Italy Dobyns WB . Megalencephaly and perisylvian polymicrogyria with 4 Department of Clinical Genetics, Medical Faculty, Erasmus Medical Center, postaxial polydactyly and hydrocephalus: a rare brain malformation Rotterdam, The Netherlands syndrome associated with mental retardation and seizures. Neurope- 5 Department of Bioinformatics, Medical Faculty, Erasmus Medical Center, diatrics 2004 ; 35 : 353 – 359 Rotterdam, The Netherlands 9 Moore CA , Toriello HV , Abuelo DN , Bull MJ , Curry CJR , Hall BD et al . 6 Department of Neuroscience, Neuroradiology, Carpi Hospital, Carpi, Italy Macrocephaly-cutis marmorata telangiectatica congenita: a distinct 7 Department of Neuropsychiatry, S. Maria Nuova Hospital, Reggio Emilia, Italy disorder with developmental delay and connective tissue abnormali- 8 Departments of Human Genetics, Neurology and Pediatrics, The University of ties . Am J Med Genet 1997 ; 70 : 67 – 73 Chicago, Chicago, IL, USA 1 0 Pavone P , Incorpora G , Ruggieri M . A complex brain malformation syn- drome with rhombencephalosynapsis, preaxial hexadactyly plus facial and skull anomalies . Neuropediatrics 2005 ; 36 : 279 – 283 R e f e r e n c e s 1 1 Schaefer GB , Bodensteiner JB , Buehler BA , Lin A , Cole TR. The neuroimag- 1 Amir N , Gross-Kieselstein E , Hirsch HJ , Lax E , Silverberg-Shalev R . ing fi ndings in Sotos syndrome. Am J Med Genet 1997 ; 68 : 462 – 465 Weaver-Smith syndrome. A case study with long-term follow-up . Am J Dis Child 1984 ; 1 3 8 : 1 1 1 3 – 1 1 1 7 2 Biesecker LG , Happle R , Mulliken JB , Weksberg R , Graham Jr JM , Viljoen DL . Proteus syndrome: Diagnostic criteria, differential diagnosis and patient evaluation . Am J Med Genet 1999 ; 84 : 389 – 395

Garavelli L et al. Megalencephaly and Perisylvian Polymicrogyria … Neuropediatrics 2007; 38: 200– 203