200 Short Communication Megalencephaly and Perisylvian Polymicrogyria with Postaxial Polydactyly and Hydrocephalus (MPPH): Report of a New Case Author L. Garavelli 1 , E . G u a r e s c h i 1 , 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 t 4 , P. J . V a n D e r S p e k 5 , G. Frigieri 2 , P. Z o n a r i 6 , E. Albertini 1 , E . D e l l a G i u s t i n a 7 , S. Amarri 1 , G Banchini1 , W. B. Dobyns 8 , G . N e r i 3 Affi liation A f fi liation addresses are listed at the end of the article Key words Abstract many overgrowth syndromes. In 2004 Mirzaa ᭹ ᭤ megalencephaly & 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- (>97 th 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 (>97 th 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 T2 -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] .