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Keywords:

  • megalencephaly;
  • capillary malformation;
  • polydactyly;
  • syndactyly;
  • connective tissue dysplasia;
  • ventriculomegaly;
  • hydrocephalus;
  • polymicrogyria;
  • cerebellar tonsillar ectopia;
  • mega corpus callosum

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

The macrocephaly-capillary malformation syndrome (M-CM), which we here propose to rename the megalencephaly-capillary malformation syndrome (MCAP; alternatively the megalencephaly-capillary malformation-polymicrogyria syndrome), and the more recently described megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) are two megalencephaly (MEG) disorders that involve a unique constellation of physical and neuroimaging anomalies. We compare the features in 42 patients evaluated for physical and neuroimaging characteristics of MCAP and MPPH and propose a more global view of these syndromes based on classes of developmental abnormalities that include primary MEG and growth dysregulation, developmental vascular anomalies (primarily capillary malformations), distal limb anomalies (such as syndactyly and polydactyly), cortical brain malformations (most distinctively polymicrogyria, PMG), and variable connective tissue dysplasia. Based on these classes of developmental abnormalities, we propose that MCAP diagnostic criteria include progressive MEG with either vascular anomalies or syndactyly. In parallel, we propose that MPPH diagnostic criteria include progressive MEG and PMG, absence of the vascular anomalies and syndactyly characteristic of MCAP, and absence of brain heterotopia. © 2012 Wiley Periodicals, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

The macrocephaly-capillary malformation syndrome (M-CM)—which we propose here to rename the megalencephaly-capillary malformation syndrome (MCAP; alternatively the megalencephaly-capillary malformation-polymicrogyria syndrome)—was first described in a combined cohort of 22 patients in two back-to-back papers in 1997 [Clayton-Smith et al., 1997; Moore et al., 1997]. Since then, more than 130 patients have been reported. This unique disorder features a spectrum of anomalies including primary (congenital or early postnatal) megalencephaly (MEG), prenatal overgrowth, brain and body asymmetry, cutaneous vascular malformations, digital anomalies consisting of syndactyly with or without postaxial polydactyly, and connective tissue dysplasia involving the skin, subcutaneous tissue and joints. The brain imaging features are distinctive and include ventriculomegaly (VMEG) that may progress to hydrocephalus (HYD), asymmetry especially of the lateral ventricles, the cortical malformation polymicrogyria (PMG), large cerebellum leading to posterior fossa crowding and cerebellar tonsillar ectopia (CBTE, or herniation), thickened corpus callosum, and other features as reviewed in two prior reports [Garavelli et al., 2005; Conway et al., 2007].

Given the large constellation of distinctive features, this syndrome has been reviewed many times and several sets of diagnostic criteria were proposed independently [Franceschini et al., 2000; Robertson et al., 2000; Giuliano et al., 2004; Lapunzina et al., 2004; Katugampola et al., 2008; Gonzalez et al., 2009; Wright et al., 2009; Martínez-Glez et al., 2010]. These sets delineated the broad range of features in MCAP together with their cumulative frequencies. However, our review suggests significant redundancy in these criteria. For example, the previously used criteria of macrocephaly (MEG), overgrowth/asymmetry, CBTE, and cerebral and/or cerebellar asymmetry all describe related aspects of brain and body overgrowth [Martínez-Glez et al., 2010].

The less recognized megalencephaly-polydactyly-polymicrogyria-hydrocephalus syndrome (MPPH) was first described in five patients in 2004 and has subsequently been reported in seven additional patients [Mirzaa et al., 2004; Colombani et al., 2006; Garavelli et al., 2007; Tohyama et al., 2007; Pisano et al., 2008; Tore et al., 2009; Osterling et al., 2011]. We first reported this syndrome as distinct from MCAP because of more severe brain abnormalities—since disproven—and lack of vascular malformations and syndactyly, which remains unsettled. Further review of our original five MPPH patients showed that subject LR01-060 (subject 2 here) had abnormalities consistent with MCAP including a large cheek hemangioma as well as a rare vascular ring as reported in another child in our original description of MCAP [Moore et al., 1997]. Further, we recently reported three patients with overlapping features between the original MCAP and MPPH syndromes, showing that many features are common to both disorders. These observations led us to propose that MCAP and MPPH represent a single recognizable yet pleiotropic syndrome with broad clinical variability, or alternatively represent separate disorders associated with different defects of a common molecular pathway [Gripp et al., 2009]. Similarly, the few reports of “megalencephaly, mega-corpus callosum (MegaCC), and complete lack of motor development” also share many—and arguably all—features with MCAP and MPPH [Gohlich-Ratmann et al., 1998].

Here, we analyze detailed data from 42 children (including 11 previously published) with MEG and additional features that overlap with the original MCAP, MPPH, or MEG-MegaCC syndromes and present a broad view of the phenotype, defining groups of linked developmental abnormalities found in this unique MEG spectrum. We use these to guide development of simpler and more flexible diagnostic criteria for MCAP and MPPH syndromes that include MEG and associated brain and body overgrowth, combined with one or more of the following features: developmental vascular anomalies, distal limb anomalies, and/or perisylvian PMG. Most of these children also have mild connective tissue dysplasia, but our data were not complete enough to add this as a major criterion.

From this large group of children with similar developmental and brain abnormalities, we found a core group of children with all of the classic features of MCAP, another group with none of the other (non-brain) abnormalities save for postaxial polydactyly in some, and a third with overlapping features. This uneven distribution of phenotypes could easily be explained by incomplete penetrance and variable expressivity of a single gene disorder as we previously suggested. But the preponderance of data suggests to us that classic MCAP and MPPH are more likely different but overlapping syndromes caused by different genes possibly in the same shared biological pathway. The latter would be comparable to the Noonan, cardio-facio-cutaneous, and Costello syndromes caused by mutations in RAS pathway genes, which have substantial phenotypic overlap.

We modified the name of the more complex syndrome from “M-CM” to MCAP syndrome to reflect the very large brain size—rather than simply large head size—that characterizes this syndrome, and the importance and high frequency of perisylvian PMG.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

Subject Ascertainment

All patients were ascertained through our IRB-approved research programs on human developmental brain disorders at the University of Chicago, Seattle Children's Hospital, and Cedars-Sinai Medical Center in Los Angeles.

Growth Data

Serial growth and occipitofrontal circumference (OFC) data were plotted on the standard Centers for Disease Control and Prevention (CDC) growth charts. All growth measurements were normalized for age and converted to standard deviations (SDs) using the World Health Organization (WHO) Child Growth Standards charts.

Neuroimaging

Brain MRI studies were performed on all patients in this series and reviewed by the authors.

Nosology

Several nosologic problems arose as we reviewed our data, some new and some previously addressed in the literature. First and foremost, MCAP is a disorder of a truly enlarged brain (MEG) rather than generic “macrocephaly” implying a large head due to numerous causes besides MEG, hence our proposed change in this syndrome's name. Second, as previously reported, the predominant vascular anomalies are simple capillary malformations. They present as patchy, reticular stains that most distinctively occur in the midline facial area (in which case the term nevus flammeus has also been historically used) and are scattered over the trunk and limbs [Toriello and Mulliken, 2007; Wright et al., 2009]. While these vascular anomalies may fade with age, they often persist to variable degrees. Both literature reports and our own data indicate that other types of vascular anomalies may occur. It is also important to note that patients with apparent clinical diagnoses of MCAP lacking the characteristic vascular malformations have been described [Franceschini et al., 2000].

We adopted several terms used by Conway et al. [2007] for the neuroimaging features. Specifically, “obstructive VMEG” (or HYD) was assumed if a patient underwent ventricular shunting, while “VMEG” was used to describe ventricular enlargement without a shunt. It is possible that patients with MCAP syndrome and VMEG were shunted even when VMEG was non-obstructive, but we are unable to substantiate this. We opted to use the term “CBTE” rather than “herniation” as the latter implies protrusion through normal tissue (not seen here) while the former simply implies abnormal position of the cerebellar tonsils. We avoided the term “Chiari malformation” implying congenital ectopia, since evidence for this is lacking [Conway et al., 2007; Milhorat et al., 2007]. To objectively assess the severity of CBTE, we measured the distance the cerebellar tonsils extended below the foramen magnum line. We also consolidated all white matter abnormalities including dysmyelination and alterations in the thickness of the white matter, as white matter signal abnormalities [Conway et al., 2007].

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

Phenotype Analysis

We ascertained clinical and neuroimaging data on 42 patients, 25 males and 17 females. Eleven patients were previously reported and are reviewed for emphasis of the core clinical features. The maximum follow-up interval was 11 years. The clinical and neuroimaging features are summarized in Tables I–IV and Supporting Table I.

Table I. The Main Phenotypic Features of MCAP and MPPH Patients (n = 42 Patients; 31 New Cases and 11 Previously Published Cases)
No.DB#SexAgeBirth OFC, SDLast OFC, SD (age)Overgrowth-birthOvergrowth-laterAsymmCut. VMs (face/body)Other VASCPOLY (H/F)SYN feet (H)PMGCONN
  • AAS, atypical absence seizures; ADHD, attention-deficit hyperactivity disorder; AF, anterior fontanel; ALL, acute lymphoblastic leukemia; AVF, arterio-venous fistula; ASD, autism spectrum disorders; AVM, arterio-venous malformation; Asymm, asymmetry; BPP, bilateral perisylvian polymicrogyria; BG, basal ganglia; BS, brainstem; CALs, café au lait spots; CBTE, cerebellar tonsillar ectopia; CBL, cerebellum; CC, corpus callosum; CM, capillary malformation; CONN, connective tissue dysplasia; CT, connective tissue; CV, cardiovascular; CVI, cortical visual impairment; DD, developmental delay; DEV, developmental problems; DYSMY, dysmyelination; F, female; FB, frontal bossing; FTT, failure to thrive; GTCS, generalized tonic-clonic seizures; HCM, hypertrophic cardiomyopathy; HYD, hydrocephalus; ID, intellectual disability; ISS, infantile spasms; JMML, juvenile myelomonocytic leukemia; L, length/left; LD, learning disability; LL discrepancy, leg-length discrepancy; M, male; MAC, macrocephaly; MEG, megalencephaly; MegaCC, mega corpus callosum; MIDB, midbrain; MPPH, megalencephaly-perisylvian polymicrogyria-postaxial polydactyly-hydrocephalus syndrome; N, No; nd, no data available; NF, neurofibromatosis; NMD, neuronal migration disorders; NOS, not otherwise specified; OCD, obsessive-compulsive disorder; OD, optic discs; OFC, occipitofrontal circumference; ON, optic nerves; PF, posterior fossa; PMG, polymicrogyria; poly, polydactyly; PS, partial seizures; PSt, pulmonary stenosis; SD, standard deviation; SVT, supraventricular tachycardia; syn, syndactyly; SZ, seizures; U, unknown which hands/feet; UBOs, unidentified bright objects; VASC, vascular; VHD, valvular heart disease; VMEG, ventriculomegaly; VO, ventriculostomy; VM, vascular malformation; VSD, ventricular septal defect; W, weight; WM, white matter; Y, yes; XAX, extra-axial space.

  • Codes: Vascular anomalies: +/−, face; −/+ body, +/+ face and body. Features of connective tissue dysplasia: (1) skin laxity; (2) joint hypermobility; (3) altered skin and/or connective tissue consistency (soft, thick, doughy).

  • Previously-published patients: LP90-032 [Moore et al., 1997, pt 1]; LP96-057 [Gohlich-Ratmann et al., 1998, pt 2]; LP95-025, LR01-081, LR01-060, LR02-064, LR03-260 [Mirzaa et al., 2004, pts 1–5]; LR08-261, LR08-319, LR08-018 [Gripp et al., 2009, pts 1–3], LR04-373 [Verkerk et al., 2010, pt 8].

  • a

    Underwent several debulking surgeries of the face (because of hemihyperplasia).

Group 1: MCAP syndrome (n = 21)
 1LP90-032*M1y 6m+3.5+4 (nd)+nd+ F+/+34/−++
 2LR01-060*M1y 9m+3.5+4 (8m)+ (L)nd+/−+++
 3LR04-078M2y 6m+5–6+9–10 (2.5m)nd+ F, B+/++−/+−234/234 (34/−)+
 4LR05-139M4y 6m+5–6+8 (9w)+− (9w)+ F, B L > R+/+−−/−−34/−++
 5LR06-220F6y+5.5+4 (6y)− (6y)+/+++
 6LR08-261*F1y 11m+7+7–8 (8w)+− (7m)+/++++
 7LR08-319*M2m+3–4+4+ (W)nd+ F+/+−−/+−23/−++
 8LR08-328M5y+4+6 (5y)− (5y)+ F+/++
 9LR08-338M7m+2+4–5 (7m)++ (7m)+/+23/23+
 10LR08-361M4y+3.5+5.6 (4y)+ (W)nd−/+Possible+
 11LR08-368F6ynd+10 (6y)nd+ (W) (6y)nd+/+23+
 12LR09-006M5y 6m+2+9–10 (5y)+− (2y)+LL disk+/+++/−23/23++
 13LR09-017M11y0+6 (11y)+ (L)− (11y)+ F, HHa−/+++
 14LR10-005F7y>2+3–4 (6y)+− (6y)+ F, B, LL disk+/+23/23++
 15LR11-039M1y 11m+5+5 (23m)− (23m)+ F, HH R > L+/+++
 16LR11-070F3y+5+4 (3y)+− (3y)+/−+nd
 17LR11-072F16mnd+6 (16m)++ (16m)+, B, LL disk−/+(234/−)nd+
 18LR11-076F6.5mnd+7 (6.5m)nd+ (W) (6.5m)+ F, B+/−(23/23)+
 19LR11-153M16mnd+5 (12m)+ (W)− (14m)+ leg+/++++/−−23/23++
 20LR11-200M2y 1m+4+7–8 (6y 1m)++ (W) (2y 1m)+ F, B+/+++
 21LR11-216M2y 2m+2+4 (26m)− (26m)+ F, B+/+234/−+
Group 2: MPPH syndrome (n = 19)
 22LP95-025*F8y>2+2.5 (8y)+− (3.5y)++
 23LP96-057*F2y+2+5 (2y)− (2y)+
 24LR01-081*M1y 9m+2+3 (21m)+ (L)nd++/++++
 25LR01-164M8m+4+4 (8m)ndnd+
 26LR02-064*F9y+2+6 (9y)+ (L)− (7y)++/+−++
 27LR03-034F6m+2+5 (5.5m)+ (L)− (6m)nd+−/−−+
 28LR03-260*M3y+2+5.6 (5m)+ (L)ndnd++/+++
 29LR04-032F4ynd+5–6 (4y)nd+ (4y)+
 30LR04-069M9ynd+8 (9y)nd− (9y)++/−−+
 31LR04-373*F5y+5–6+6 (3.5y)ndnd+
 32LR05-204M4ynd+9–10 (4y)nd+ (2.5m)++
 33LR06-286F5m+5–6+4 (5m)ndnd+ (U)+
 34LR07-041F8mnd+3–4 (3.7m)− (9m)nd++/−−+
 35LR08-252M15mnd (mac at 2m)+4–5 (15m)− (15m)+
 36LR08-263M9y>2+6 (9y)− (10y)+
 37LR08-422M8.5m“mac at birth”+5 (8.5m)− (8.5m)++
 38LR09-216M2y 6m+3+4 (2.5y)− (3y)+
 39LR11-016F4y 6mnd+4 (3.5y)− (3.5y)++
 40LR11-186F4y+5+4 (4y)nd− (4y)+
Group 3: Overlap Group (n = 2)
 41LR06-069M2y 4mnd+8 (28 mm)nd+ (28m)+ F++/++++
 42LR08-018*M11m+2.5+5.5 (7.5m)nd+++
Table II. Neurodevelopment of the MCAP and MPPH Patients
No.DB#Age last assessedDD/estimated severityDevelopmental detailsOther DEV disorderSeizure onset; typesTone
  • a

    Currently treated with Topiramate, Lamotrigine, Oxcarbazepine. Seizures very well-controlled, 1 seizure occurred in the last 2.5 years.

  • b

    Classified as symptomatic localization related epilepsy. Initial seizure resolved without treatment. Following recurrence, the patient was started on valproic acid on which he remained seizure-free for several years. An EEG in 2006 showed multi-focal independent spikes, and generalized spike and slow wave discharges.

  • c

    EEG demonstrated spike and slow wave complexes emanating from the R occipital region. Currently, seizures are poorly controlled with levetiracetam and oxcarbazepine.

Group 1: MCAP syndrome
 1LP90-032*1y 6m+/ndndndnd[DOWNWARDS ARROW]
 2LR01-060*1y 9m+/SevereProfound ID, no language8m, subclinical[DOWNWARDS ARROW]
 3LR04-0782y 6m+/ndndndndnd
 4LR05-1394y 6m+/Mod–sev4.5y Walked with gait trainer/braces but not independently, said non-specific “mama” and “dada,” began to use communication board4y, PS (1–6/day every 2 weeks. On Oxcarbazepine)[DOWNWARDS ARROW]
 5LR06-2206y−/NormalWalked at 2y, first words at 3y, good comprehension. Formal DEV and intelligence assessment normal at 6yN (abnormal EEG)[DOWNWARDS ARROW] Later normal
 6LR08-261*1y 11m+/Possibly severe23m Poor head control, does not sit-up independently, non-verbal[DOWNWARDS ARROW]
 7LR08-319*2m+/ndndnd[DOWNWARDS ARROW]
 8LR08-3285y+/Mod–severe?Crawled at 3y, first words at 2.5 y. At 6y, walks with assistance but with unstable, wide-based gait, developed pincer grasp, had 100 words (15 understandable), good comprehensionHand stereotypies, sensitive to loud noises, & can sit in front of a mirror all days1y 2m, GTCS (×3 episodes)a[DOWNWARDS ARROW] (Generalized)
 9LR08-3387m+/Mild4m Makes good eye contact, vocalizes, smiles, holds head up. 6m Rolled over. 7m Sat independentlySensory integration problems, concern for ASDNormal
 10LR08-3614y+/Severe?2y 10m—began to walk with wide-based gait, non-verbal[DOWNWARDS ARROW]
 11LR08-3686y+/ModWalked at 2y but remained unstable at 3y, non-verbal at 3y, uses only 3 signsSignificant irritability[DOWNWARDS ARROW]
 12LR09-0065y 6m+/Mild–modSat independently at 18m, used signs at 18–24m, walked independently at 4.5y, vocalized 5y, described as “very social”2.5y, clusters of flexion of the head and neck, extension of arms and legsb[DOWNWARDS ARROW] (Mod diffuse)
 13LR09-01711y+/Mild?Walked at 2y, grossly delayed in all areas. At 11y: in 6th grade/special educationOCD, ADHD (on medication)[DOWNWARDS ARROW]
 14LR10-0057y+/Mild7y Ambulatory, verbal, good social skills, in special educationNormal
 15LR11-0391y 11m+/?ModerateRolled over 8m, held head 10m, sat 15m, at 23m bears weight but doesn't walk independently[DOWNWARDS ARROW]
 16LR11-0703y+/MildSat at 7m, crawled 14m, walked 20m, first words 18m. At 3y says 30 words, 2–3 word phrases[DOWNWARDS ARROW]
 17LR11-07216m+/Mild–modAt 16m: walks with a walker, says a few wordsGeneralized [DOWNWARDS ARROW]
 18LR11-0766.5m−/NormalNormal at 6m, no longitudinal dataNormal
 19LR11-15316m+/Severe12m Sits unassisted, vocalizes and beginner pincer grasp, reaches and transfers, DEV age 7m. 15m Fully developed pincer grasp, doesn't crawl, no words. DEV assessment: severe delays in gross motor, expressive and receptive language and communication skills, moderate delay in cognition and mild delays in fine motor and self-help skills[DOWNWARDS ARROW]
 20LR11-2002y 1m+/ModerateAt 2y 1: has 12 signs/words, sits but is unable to walkModerately [DOWNWARDS ARROW]
 21LR11-2162y 2m+/Mod–sevSat at 1y, rolled at 16m. At 26m: doesn't walk, sits independently, says 1 word only, poor communication[DOWNWARDS ARROW]
Group 2: MPPH syndrome
 22LP95-025*8y+/Severe IDProfound ID, no language. DEV age at 39m was 5.5m in gross motor, 6m in fine motor/personal/social, and 7m in languageUnexplained irritability6m; ISS, GTCMixed (neonatal hyptonia, later axial hypotonia and limb spasticity)
 23LP96-057*2y+/Severe IDProfound ID, no language. No gross or fine motor skills, non-verbal. Communicates by eye-pointing and has a social smile[DOWNWARDS ARROW] (Severe)
 24LR01-081*1y 9m+/Severe IDProfound ID, no language9m; ISS AAS[DOWNWARDS ARROW]
 25LR01-1648m+/Possibly severe7m Poor head control, no gross or fine motor skills. DEV age 3mndBirth; AAS ISS (eyes fluttering, arms and legs stiffening, on phenobarbital and clonazepam)Mixed
 26LR02-064*9y+/Severe IDProfound ID, no languageAnxiety, sleep problems4–6m, AAS, CPS, GTCSSpasticity
 27LR03-0346m+/ndDEV age 1.5m at 3.5m, rolled over once or twice at 6mndnd
 28LR03-260*3y+/Severe IDProfound ID; no language. 3y head support present, but not sit or grasp, was non-verbal8m, AAS[DOWNWARDS ARROW]
 29LR04-0324y+/MildWalked at 13m. At 22m: runs well, says 15–20 single-syllable words[DOWNWARDS ARROW]
 30LR04-0699y+/ModModerate DD, ambulatory, verbal[DOWNWARDS ARROW]
 31LR04-373*5y+/ndWalked at 3 years4.5y, 3 febrile SZ of focal onset with secondary generalization (on VPA)[DOWNWARDS ARROW]
 32LR05-2044y+/Mod–severeAmbulatory, moderate cognitive deficit, non-verbalAutistic features, behavioral problemsNeonatal; PS, CPS (refractory)c[DOWNWARDS ARROW]
 33LR06-2865m−/ndNormal development at 5m, no longitudinal datandNormal
 34LR07-0418m+/Severe IDNo signs of psychomotor development; no visual fixation, no eye contactSignificant irritability, intermittent Cheyne–Stokes respirations— (EEG generalized dysfunction)Mixed + opisthotonus
 35LR08-25215m+/Mod–severeInitially good development but later lost skills. Walked at 12m, stopped walking at 15m. 15m Waves bye, speaks 5–6 words, sits unassisted, follows simple commands, feeds himselfNormal
 36LR08-2639y+/ndID. At 9y reads below first grade level, delayed in all areasADHD, defiantnd, GTCS and eye deviation (refractory, on Depakote, multiple episodes)Normal
 37LR08-4228.5m+/ndCrawled at 8m, babbled at 8.5mHand stereotypies8m, nd[DOWNWARDS ARROW]
 38LR09-2162y 6m+/Mild–sevWalked at 2y, single words at 4y. Peabody Developmental Motor Scale: DEV age 23–33m at 3y. Has mild speech and language delay. IQ average 96Stereotypies (hand-flapping)[DOWNWARDS ARROW] (Mild)
 39LR11-0164y 6m+/Severe ID, non-verbal, non-ambulatorySev ID. 4.5y Sits independently but does not walk, non-verbal, DEV age 7mASD (poor eye contact)1y, Multiple types (poorly controlled c/w continuous spike waves of slow wave sleep or electrical status epilepticus of slow wave sleep. Frequency (weekly–monthly)[DOWNWARDS ARROW]
 40LR11-1864y−/ndGlobal developmental delayShort attention span9m, CPS versus atypical absenceBorderline [DOWNWARDS ARROW]
Group 3: Overlap group
 41LR06-0692y 4m+/Mod–severeWalked at ∼26m but remained unsteady until 5y; started vocalizing with indiscriminate words at 26m[DOWNWARDS ARROW]
 42LR08-018*11m+/ndMinor head at control 6m, rolled over at 8mNeonatal, partial NOS[DOWNWARDS ARROW]
Table III. Neuroimaging Features of the MCAP and MPPH Patients
No.DB## MRIs (ages)Brain asymm.CCPMG gradeVMEG or HYDShunt (age)Postnatal CBTEPF decomp. (age)CSPVWM abnlOther MRI findings
  • Codes: VMEG: +++: under pressure (=obstructive).

  • a

    Large cerebellum and a narrow posterior fossa with pressure on the medulla oblongata.

  • b

    Abnormally oriented (inferior) clivus.

  • c

    Patient reportedly became more alert post-decompression.

Group 1: MCAP syndrome
 1LP90-032*1 (birth)+Limited viewsProbable unilateral++ (nd)Limited viewsndndLimited viewsLimited views
 2LR01-060*1 (3m)Stretched2+++ (5m)+ (1–2 mm)++ DYSMY
 3LR04-0781 (2m)+ MildThin1–2+++ (3 mm)+
 4LR05-1393 (11d, 5m, 5y 9m)MegaCC (prog.)2–3+++ (6m)+ (3, 4 mm, resolved)+
 5LR06-2201 (<2y)Normal-mildly thick4a++ DYSMY
 6LR08-261*3 (6m, 11m, 1y 4m)Stretched2++++ (3VO, 8m)+ (1, 3, 4 mm)a+ DYSMYMildly dysplastic CBL vermis
 7LR08-319*2 (prenatal, 1m)+ Very subtleThin2++ (4 mm)++ Immature
 8LR08-3283 (6m, 11m, 5y)StretchedSubtle deep gyri in postfrontal region++++ (3VO, 11m)+ (2–3 mm all)a,b+ DYSMY[UPWARDS ARROW] XAX, mild generalized atrophy
 9LR08-3382 (4m, 8m)Normal+ (1 mm)Mildly [UPWARDS ARROW]XAX, large venous sinus along tentorium
 10LR08-3611 (1d)NormalPossible (low resolution scan at 1d)+ (3 mm)
 11LR08-368Multiple (last 5y)MegaCC2++++ (within 1sty)+ (2 cm)+ (within 1sty)++Thick, fusiform BS
 12LR09-0063 (2.5m, 2y, 4.5y)+ MildThick2++++ (4m)+ (2, 13, 11 mm)a++ [UPWARDS ARROW] Volume (frontally)
 13LR09-0174 (6w, 9m, 23m, 10y 6m)+ mildMegaCC (prog.)4+ (4 mm all)+
 14LR10-0052 (1y, 6y)+Thick/MegaCC?4+ (2, 4 mm)
 15LR11-0393 (1d, 4m, 11m)MegaCC (prog.)2++++ (3m)+ (5 mm, >1 cm, 3 cm)+ (11m)c++Large venous sinus
 16LR11-0702 (birth, 3y)Thicknd++++ (∼8m)+ (resolved)nd
 17LR11-072ndndndnd++++ (9m)++ (16m)ndndnd
 18LR11-076Multiple (<6m)+Stretched++++, 3VO+ndnd
 19LR11-1532 (2m, 7m)Normal2++ (1, 9 mm)++
 20LR11-2002 (22m, 2y)Stretched4+++ (8 mm)++ PPV
 21LR11-2162 (5d, 1y)4++ DYSMYHypoplastic C1 arch
Group 2: MPPH syndrome
 22LP95-025*2 (3y, 8y)+Normal2++++ (1m)++
 23LP96-057*2 (2y, 2y 1m)+MegaCC1+ (Borderline)++ DYSMY
 24LR01-081*1 (3m)Normal-mildly thin1++++ (3.5w)++Bilateral BG hematomas
 25LR01-1642 (3m, 7m)Stretched1++
 26LR02-064*2 (1m, 6y)Normal1++++ (3y)+
 27LR03-0341 (2m)Normal2+++
 28LR03-260*1 (nd)+ MildNormal1++++ (6m)++ PPV
 29LR04-0321 (4y)+ (Mild)Mildly thick2+− Small PFThin WMMild CVH
 30LR04-0691 (nd)Normal2+Limited views
 31LR04-373*2 (3m)Thin2+++ [DOWNWARDS ARROW]WM volume
 32LR05-2042 (5m, 1y)Normal2++ (8 mm)++ DYSMY, PPV
 33LR06-2861 (1d)+Normal2+++ (3 mm)++
 34LR07-0411 (2m)Normal2+++ Mildly [DOWNWARDS ARROW]WM, PPV
 35LR08-2522 (7m, 1y 3m)MegaCC2+ (3 mm on scan#2)++
 36LR08-2631 (7y)Normal1++ (3–4 mm)Small R HIP
 37LR08-4223 (3d, 7m, 19m)Thick2++++ (22m) (IC HTN)+ (0, 8 mm, 1.2 cm)++ DYSMYMildly short MIDB, mildly large pons
 38LR09-2163 (1y 4m, 2y 4m, 4y)+ L > RNormal2++ (6, 8, 8 mm)+ [DOWNWARDS ARROW]WM volume
 39LR11-0162 (2y 7m, 3y 11m)Stretched, mildly thin1++++ (3VO, 14m)+ Mildly thick, PPV
 40LR11-1865 (last at 4y)MegaCC3++++ (5m)+ (9 mm)+ (13m)+Lumbar syrinx on spinal MRI
Group 3: Overlap group
 41LR06-0693 (3m, 3y, 4y)+Thin2++++ PPVMild hypoplasia of L CBL
 42LR08-018*3 (6w, 4m, 6m)+Normal2–3 (L > R)++ (1 mm)a,b++ PPV
Table IV. Frequency of Somatic Overgrowth, Vascular and Digit Malformations in the Megalencephaly Cohort (Excluding Overlap Patients)
 SexSomatic overgrowth (birth)Somatic overgrowth (later)Skin VMOther VMAll VMPolySynAll digit anomalies
  1. Poly, polydactyly; Syn, syndactyly; VM, vascular malformations.

VM14M/7F14/2105/2121/2106/2121/2104/2112/2112/21
No VM09M/10F05/1902/1900/1900/1900/1907/1900/1907/19

Previous reports including our original 1997 and 2004 publications [Moore et al., 1997; Mirzaa et al., 2004] have delineated two primary groups of individuals with MEG and its sequelae, variable somatic overgrowth, and vascular, digital, and cortical malformations: MCAP and MPPH. We asked whether these qualitative observations could be verified by statistical analysis in this large group of patients. We began by selecting MEG as a mandatory inclusion criterion, then separated other anomalies into groups based on presumed mechanism or affected tissues. These included (1) vascular malformations, (2) digit anomalies, and (3) accelerated somatic growth. We did not consider the cortical malformation PMG (observed in 36/42 patients), connective tissue dysplasia (our data were incomplete), and several other abnormalities that did not fit well into one of these groups.

We separated the subjects into two groups based on the presence or absence of vascular malformations (Table IV), and used Fisher's exact test to correlate vascular malformations with other abnormalities. First, we found a significant correlation between vascular malformations and somatic overgrowth at birth (P = 0.0140), but not later growth (P = 0.4124). In contrast, vascular malformations and digital anomalies were not correlated (P = 0.2248). Our clinical experience suggested that syndactyly was more associated with vascular malformations (MCAP), while polydactyly was seen without vascular malformations (MPPH). We therefore separated digital anomalies into polydactyly and syndactyly, and found an extremely significant correlation between vascular malformations and syndactyly (P < 0.0001), but not polydactyly (P = 0.2922). We noticed that the vascular malformation group included more males than females, while the other group had nearly equal males and females, but the difference was not significant (P = 0.3375).

These results validated our initial separation into groups with and without vascular malformations, which we therefore maintained. Subject LR08-018 had a poorly substantiated umbilical hemangioma and was placed in an overlap group. Similarly, subject LR06-069 had no vascular anomalies, yet overgrowth and facial asymmetry with bilateral postaxial polydactyly, and was therefore considered an overlap patient. This initial statistical analysis left us with 21 subjects in the vascular malformation or MCAP group, 19 in the no vascular malformation or MPPH group, and 2 in an overlap group (Table I). Next we discuss the relevant physical findings of the MCAP and MPPH syndrome patients. Given that both syndromes share the neuroimaging and developmental abnormalities, these will be discussed together.

Clinical Findings

Megalencephaly (MEG)

Thirty subjects had evidence of congenital MEG, defined as an OFC of 2 or more SD above the mean for age and gender. Only one MCAP subject had a documented normal birth OFC of 0 SD. Birth OFC data were unavailable for the remaining 11 subjects. Among the subjects with congenital MEG, birth OFCs ranged from +2 to +7 SD above the mean for gestational age (Fig. 1). Two patients had birth OFCs of +5.5 and +3.5 SD above the mean at unknown gestational ages, and three reportedly had birth OFCs larger than +2 SD or were “macrocephalic” at birth, with no measurements available.

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Figure 1. Birth OFC data for MCAP and MPPH syndrome patients. Birth OFC data (SDs) on 20 subjects are plotted against gestational age (weeks).

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Serial OFC measurements were plotted for all patients (Figs. 2–4), and all had evidence of progressive MEG. Moreover, in multiple subjects undergoing neurosurgical shunting for obstructive VMEG, head growth trajectory continued to increase at a clearly accelerated rate after shunt placement, emphasizing that the primary underlying cause of macrocephaly in this spectrum is progressive brain overgrowth or MEG and the contribution of MEG to the increasing OFC markedly exceeds that of VMEG.

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Figure 2. Documented and serial OFC data for MCAP and MPPH syndrome patients. Serial OFC measurements are plotted by age for MCAP syndrome patients (A: males, B: females) and MPPH syndrome patients (C: males; D: females). Of note, times of neurosurgical shunt placement are indicated by arrows.

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Figure 3. Scatter plot of head growth data points (cm). The black linear regression line demonstrates a significantly increased head size for age for all patients.

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Figure 4. Scatter plot of head growth data points (SD). The black linear regression line demonstrates a significantly increased head size for age for all patients.

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The largest observed OFCs (+9–10 SD) were seen in four patients: Patients 3 (LR04-078), 11 (LR08-368), 12 (LR09-006) from the MCAP group and Patient LR05-204 from the MPPH group. Patient 3 had an OFC of +9–10 SD at 2.5 months with mild-to-moderate VEMG. No further follow-up or brain MRI data are available. Patients 11 and 12 had HYD and underwent shunting procedures at <1 year of age, yet continued to have markedly large OFCs at 6 and 5 years, respectively. Patient 32 had an OFC of +9–10 at 4 years with mild VMEG but no HYD.

Cutaneous vascular malformations

Capillary malformations present in the MCAP subjects involved the body and face in 15, midline face (or a nevus flammeus) only in 3 and body only in 2 patients. These malformations ranged in appearance from mild to severe (Fig. 6). Cutaneous infantile hemangiomas in various locations were seen in 6 subjects. A patient from the first MPPH cohort with complex cardiovascular abnormalities (ASD, VSD, right-sided aortic arch, vascular ring, and an aberrant left subclavian artery) and no congenital cutaneous vascular anomalies developed a large parotid infantile hemangioma that was detected by CT scan at age 2 years and spontaneously involuted a few years later (Fig. 5K). This patient is therefore reclassified as MCAP here. Additionally, two patients had prominent venous patterns in the head and neck regions.

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Figure 5. Photographs of MCAP patients 13 (LR09-017; AD), 9 (LR08-338; E–H), 2 (LR01-060; IK) and 4 (LR05-139; LP). Note macrocephaly, frontal bossing, dolichocephaly, somatic and facial asymmetry, toe syndactyly, and various vascular anomalies including capillary malformations and infantile hemangiomas. Image (K) shows the hemangioma beneath the cheek detected by CT scan in patient 2 (LR01-060) that later self-resolved (red arrow) and images (L–O) demonstrate resolution of the midline facial capillary malformation and cutis marmorata of the hand present in patient 4 during infancy.

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Figure 6. Photographs of patient 3 (LR04-078). Note the prominent forehead (D), extensive capillary malformations (A-F1), bilateral 2-3-4 toe syndactyly (G,H), 3-4 finger syndactyly (F1,F2), and postaxial polydactyly of the right hand (F1).

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Distal limb anomalies

Eleven of the 20 MCAP subjects had syndactyly, including 4 with polysyndactyly. Most had 2-3 soft-tissue toe syndactyly. Three had 2-3-4 or 3-4 toe syndactyly, and 3 had finger syndactyly (2-3, 2-3-4, and 3-4). Seven MPPH patients had postaxial polydactyly. Additional digital anomalies include sandal-gap toes in 2 subjects, and individual patients with brachydactyly, broad thumbs and toes, overlapping toes, and hypoplastic toe nails.

Somatic growth and asymmetry

Nineteen children (14 MCAP and 5 MPPH) had a birth weight, length (or both) 2 or more SD above the mean. The association of somatic overgrowth and vascular anomalies was statistically significant. However, later growth data indicates that only 3/14 MCAP patients remained large for age at 7 months, 16 months, and 2 years 1 month, and 2 patients were overweight at 6.5 months and 6 years. In contrast, only 2 patients with MPPH had evidence of overgrowth at 2.5 months and 4 years, respectively. Supplementary Figures 1 and 2 demonstrate recorded weight and height or length data for MCAP patients. No MCAP patients had birth weights and/or length ≤2 SD below the mean, however 2 subsequently had a height of −2 SD, and 1 had a weight and height of −2 SD.

Fifteen patients had variable degrees of facial and somatic asymmetry including 14 MCAP patients and one overlap patient. At least five had clinically reported hemihypertrophy and/or leg-length discrepancy. One patient underwent multiple elective debulking surgeries of the subcutaneous tissue of the face.

Internal vascular abnormalities

Several patients had internal vascular anomalies. Patient LR11-070 had a vascular malformation on the cricoid cartilage confirmed by bronchoscopy, and an abdominal hemangioma confirmed by MRI. Two patients had complex anomalies involving the vasculature of the heart: the patient with the vascular ring, aberrant left subclavian artery, right-sided aortic arch, ASD and VSD mentioned above, and another with a vascular ring and two VSDs. In a number of patients, dilated transverse sinuses are evident on MRI, in association with overgrowth of the contents of the posterior fossa [Conway et al., 2007].

Connective tissue dysplasia

At least 24 patients had variable degrees of connective tissue dysplasia, and our experience suggests that this may be underreported. The most common feature is variable skin hyperelasticity. The consistency of the skin and subcutaneous tissue was abnormal with soft skin and thick doughy subcutaneous tissue described in at least 10 patients. Eights patients also had joint hypermobility.

Dysmorphic features

Variable dysmorphic facial features were reported in nearly all patients. The most common are dolichocephaly, frontal bossing, depressed nasal bridge and telecanthus, or hypertelorism. See supporting Table I for additional information.

Neurodevelopment

Developmental delay and intellectual disability

Developmental delay ranging from mild to severe was present in nearly all patients. Eleven were profoundly handicapped (non-verbal, non-ambulatory). Seven of these had VMEG and underwent ventricular shunting at ages ranging from 3.5 weeks to 3 years. Interestingly, 6 of these patients also had the most severe grade of PMG, PMG extending beyond the perisylvian region, involving one or both (PMG grade 1) [Leventer et al., 2010].

Only one patient had evidence of normal development on longitudinal follow-up. Patient LR06-220 is a girl who had early developmental delay, but began to walk at 2 years and talk at 3 years. A formal developmental assessment at age 6 years documented normal intelligence. Features consistent with MCAP included birth OFC of +5.5 SD, and later OFC of +4 SD at 6 months, midline facial capillary malformation, strawberry hemangioma on the labia, and a surgically-corrected PDA. She did not have overgrowth, asymmetry, or digital anomalies. Her brain MRI showed grade 4 PMG (the least severe grade that involves the posterior perisylvian region only), and patchy abnormal T2 signal intensities consistent with dysmyelination. She did not have VMEG, her cerebellum was large and her posterior fossa was small, but without clear CBTE.

Of note, follow-up (or longitudinal) developmental data of variable quality at age 5 years or older were available for only 11 of our 42 patients. More long-term data are necessary to define the degree of intellectual disability in these MEG syndromes.

Other developmental and behavioral problems

Six patients had autistic features, the most common being hand stereotypies seen as early as age 8 months. One of these patients was profoundly handicapped at 4.5 years (patient LR11-016). Another (patient LR05-204) was non-verbal with moderate cognitive delay at 4 years. The remaining 3 had mild-to-moderate developmental delay. Three patients with severe delay had unexplained irritability (patients LR08-368, LP95-025, LR07-041). And at least two patients had attention deficit hyperactivity disorder with one having obsessive-compulsive disorder as well.

Seizures

Seizures were present in 16 subjects. The age of onset varied from neonatal to 4.5 years. Five had two or more types of seizures and 3 had refractory epilepsy. The patients with severe epilepsy also had severe bilateral perisylvian polymicrogyria (BPP) (grades 1 and 2). Three patients had well-controlled epilepsy, and 1 had a history of 3 febrile seizures only. Of note, infantile spasms were seen in 3 MPPH subjects (Patients LP95-025, LR01-081, LR01-164).

Tone abnormalities

The neurological exam was dominated by hypotonia, present in 30 patients. Several severely handicapped children had mixed tone or spasticity; one of them had neonatal hypotonia, and several more had normal neonatal tone.

Other medical problems

Besides the complex cardiovascular anomalies mentioned above, several patients had single cardiac lesions including a VSD and an ASD that closed spontaneously in 1 patient each, a surgically repaired PDA in 2 patients (1 of whom was premature at 32 weeks of gestation; the gestational age of the other is unknown).

Genital abnormalities (such as cryptorchidism, micropenis, hypospadias) were seen in 5 subjects. Bilaterally duplicated kidneys, cystic kidney disease, uretero-pelvic junction obstruction, and dilated renal pelvis were reported in individual patients. Optic atrophy was seen in 4 patients, 1 patient had microphthalmia requiring enucleation and ocular prosthesis placement. One patient had supraventricular tachycardia successfully treated with Digoxin. One patient had two subcutaneous lipomas in the neck and gluteal region that measured 1.5 cm × 1 cm and were static in size. No additional benign or malignant growths were reported in our cohort. One patient had a goiter. Three required a gastrostomy tube (G-tube) placement, 3 had scoliosis and 2 had kyphosis.

Among this cohort, one MPPH patient (patient 34) was deceased. She was born at a gestational age of 41 + 3 weeks, had very poor postnatal growth, profound global developmental delay, and a history of severe irritability, discomfort, frequent opisthotonus, and intermittent Cheyne–Stokes respirations. An MRI at 2 months showed mild VMEG and no CBTE. At age 8 months, she was admitted to the hospital with a respiratory tract infection that progressed to significant oxygen-dependency and increased irritability and discomfort. She passed away shortly after comfort care was provided.

Neuroimaging Findings

All patients underwent brain imaging and serial MRIs were obtained in 24 subjects. The main neuroimaging findings are summarized in Table III, and are demonstrated in Figures 7 and 8. All patients had MEG on brain MRI evidenced by a prominent forehead and a large cranium-to-face proportion.

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Figure 7. T1-weighted mid-sagittal, parasagittal, and axial MRI images of patient 11 (LR08-368; AD), T1-weighted mid-sagittal and parasagittal and T2-weighted axial images of patients 32 (LR05-204; EH), 35 (LR08-252; IL), and 3 (LR04-078; MP). Note the apparent megalencephaly (large cranium-to-face ratio), perisylvian polymicrogyria (PMG; white arrowheads), ventriculomegaly (M–P), and thick corpus callosum (I). Additionally, white matter signal intensities are evident (C,G,K,L).

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Figure 8. Dynamic MRI changes over time. AC: Progressive CBTE in patient 15 (LR11-039); DF: progressive CBTE in patient 37 (LR08-422); GI: resolved CBTE in patient 4 (LR05-139), and MegaCC in patient 13 (LR09-017; JL).

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Ventriculomegaly (VMEG) and obstructive VMEG (or hydrocephalus)

VMEG was seen in 34 subjects (15/21 MCAP; 17/19 MPPH; 2/2 overlap patients). Seventeen underwent ventricular shunting although in some we found no evidence for obstructive VMEG. These included 7/19 MPPH patients. The ages at shunt placement ranged from 3.5 weeks (patient LR01-081) to 3 years (patient LR02-064), with an average age of 9.7 months. Nearly all had mild-to-moderate residual ventricular enlargement on follow-up scans.

Polymicrogyria (PMG)

Clear PMG was observed in 36 subjects. It was predominantly BPP in distribution and in 18 subjects corresponded to BPP grade 2 (PMG extending beyond the perisylvian region but not to either pole). Three patients lacked evidence for clear PMG, 1 of whom had subtle microgyri in the posterior frontal region, and another had a low resolution scan at 1 day of age. We did not have enough MRI views on 2 patients to assess for the presence or absence of PMG.

Cerebellar tonsillar (and hemispheric) ectopia (CBTE)

Cerebellar tonsillar ectopia was seen in 27 patients (18/21 MCAP; 9/19 MPPH), and was clearly progressive on serial scans in 7. The degree of CBTE was assessed by measuring the distance of the cerebellar tonsils below the foramen magnum line. CBTE was seen in MRI scans done as early as a few days and therefore may have been congenital in some patients (such as patients LR05-139, LR08-361, LR11-039). Four underwent posterior fossa decompression, and although we are not aware of symptoms of brainstem compression, one reportedly became more alert post-decompression. Interestingly, patient LR05-139 in our series had progressive CBTE of 3 and 4 mm at 11 days and 5 months, respectively. However, a follow-up brain MRI at 5 years and 9 months showed complete resolution of the CBTE (Fig. 8G–I). Patient 16 also had “resolved” CBTE by report. This is the first report of resolution of CBTE in these syndromes.

Abnormalities of the corpus callosum

The corpus callosum was markedly thick (mega-CC) in 7 subjects (4 MCAP and 3 MPPH), and was moderately thick (yet to a milder degree) in 4–5 more. Notably, thickening of the corpus callosum was seen following ventricular shunting in patients with VMEG. However, it was also observed in one patient lacking VMEG (patient LR09-017) as well. The corpus callosum was thin, stretched, or both in 11 subjects and normal in 16.

Cranial asymmetry

Variable degrees of symmetry of the brain and lateral ventricles were seen in 13 subjects, with mild asymmetry in 5. None of the patients in this cohort had hemimegalencephaly.

Other MRI findings

Various white matter abnormalities were seen collectively in 28 subjects, and included dysmyelination, and thick, thin, or immature WM. Cavum septum pellucidum et vergae was seen in 25. Additional MRI findings include large venous sinuses (2 patients), enlarged extra-axial space (2 patients), a hypoplastic and dysplastic cerebellar vermis (1 patient), mild hypoplasia of a cerebellar hemisphere (1 patient), and a small hippocampus (1 patient).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

Our analysis of a large series of children with congenital or early postnatal MEG shows that some have all features of classic MCAP defined in the literature, while others share the characteristic brain features (MEG, VMEG-HYD, PMG, often with mild asymmetry, and CBTE). but lack one or more of the key features usually used to define MCAP syndrome—that is, have MPPH syndrome. This is most likely due to absence of the key features, but may also be partly due to changes over time, in which capillary malformations and connective tissue dysplasia may resolve. Our current set of observations suggests an obvious hypothesis: that original MCAP, MPPH, and MEG-MEGCC comprise overlapping syndromes with shared pathogenesis (i.e., a shared biological pathway) or comprise a single pleiotropic syndrome. Given this hypothesis, we approached the problem of classification and the related issue of diagnostic criteria more broadly to allow us to include a larger group of children with overlapping phenotypes. This approach differs significantly from prior reports, which proposed at least 6 sets of diagnostic criteria for the most common, classic MCAP syndrome. We will briefly review these syndromes and then propose simpler diagnostic criteria.

Three Megalencephaly Syndromes

Classic MCAP syndrome in the literature

This well-known syndrome is characterized by unique physical and neuroimaging findings, with more than 130 patients reported in the literature. There are numerous other reports of patients with similar and overlapping features. This syndrome has been reviewed in the literature by multiple groups, who proposed multiple clinical diagnostic criteria sets (Table V).

Table V. Series of Subjects Reported With Classic MCAP (M-CM) Syndrome
PublicationNLITDiagnostic criteria
  • a

    Reviewed neuroimaging features: LIT, literature review; N, number of reported patients.

Robertson et al. 2000523+
Franceschini et al. 2000226+
Giuliano et al. 2004739+
Lapunzina et al. 2004669+
Garavelli et al. 200510a10a
Conway et al. 200717a65a
Katugampola et al. 2008175
Wright et al. 200912100+
Gonzalez et al. 20093>75
Martínez-Glez et al. 201013132+

These efforts helped delineate the broad range of features present in this syndrome and their cumulative frequencies. All have proposed major and minor criteria with variations in their stringency ranging from only 1 to 5 major criteria, and a larger number (on average 7–8) of minor diagnostic criteria. Other than MEG being the single most consistent feature, both categories of criteria have included a variable number of the following features: capillary malformations (somatic or midline facial), overgrowth or asymmetry, digital anomalies, developmental delay, hypotonia, dysmorphic facial features (such as frontal bossing), and neuroimaging features such as VMEG (and/or HYD) most commonly. Up to 34 or more other physical and neuroimaging features have been reported in MCAP syndrome.

Megalencephaly-postaxial polydactyly-polymicrogyria-hydrocephalus (MPPH) syndrome

This syndrome was initially reported in a cohort of 5 subjects, and has now been reported in seven more [Mirzaa et al., 2004; Colombani et al., 2006; Garavelli et al., 2007; Tohyama et al., 2007; Pisano et al., 2008; Tore et al., 2009; Osterling et al., 2011] and 3 MPPH–MCAP overlap patients [Gripp et al., 2009]. Three additional patients with an MPPH-like phenotype (including two first cousins) and a submicroscopic chromosome 5q35 deletion including the NSD1 locus have also been reported [Verkerk et al., 2010]. Collectively, these patients share a unique constellation of primary MEG (in 18/18), PMG (18/18), HYD (13/18), or VMEG (4/18, subtle in 1), and postaxial polydactyly (10/18).

The megalencephaly-polymicrogyria-mega-corpus callosum (MEG-PMG-MegaCC) syndrome

This syndrome was first reported in 1998 in three patients, with six more reported thereafter [Gohlich-Ratmann et al., 1998; Dagli et al., 2008; Pierson et al., 2008; Bindu et al., 2010; Hengst et al., 2010]. Classic features include a distinctly thick corpus callosum, severe PMG with incomplete opercularization of the sylvian fissure, and severe developmental handicap with complete lack of motor development. Additional findings seen with variable frequency include VMEG with no overt HYD (in at least 5 subjects), large cerebellum with CBTE (2 subjects), prominent perivascular spaces, and cavum septum pellucidum.

Diagnostic Criteria

Our ongoing ascertainment of patients with MEG and overlapping features of these three MEG syndromes leads us to suggest that there is a marked degree of clinical overlap between these syndromes, especially, the MPPH and MEG-PMG-MegaCC syndromes whose features are highly overlapping and so are considered together here. Therefore, the genes causing these syndromes may belong to a single molecular pathway or they may constitute a large spectrum of anomalies.

With regard to MCAP syndrome, review of our data and the literature suggests that many MCAP-associated anomalies describe different facets of the same core feature. For example, MEG, somatic overgrowth and brain/body asymmetry are all manifestations of dysregulated growth (or growth dysplasia) and thus are likely to share pathogenesis. Thus, using several of these as distinct diagnostic criteria seems inappropriate. Similarly, capillary malformations, prominent venous patterns, venous aneurysms, infantile hemangiomas, and malformations of the cardiac great vessels (including vascular rings) represent abnormalities of vasculogenesis. We hypothesize that most of the major features of MCAP and MPPH syndromes may be classified into 5 groups of anomalies involving (1) early overgrowth, (2) vascular anomalies, (3) distal limb anomalies, (4) malformations of cortical development, and (5) connective tissue dysplasia. Accordingly, we propose using a broader view of these syndromes based on these classes of developmental abnormalities—rather than individual features—as summarized in Table VI and in the sections that follow.

Table VI. Core Features of MCAP and MPPH Syndromes
Core featuresSupportive features
  1. MCAP syndrome is diagnosed in the presence of MCAP core feature (1) plus either (2) or (3).

  2. MPPH syndrome is diagnosed in the presence of MPPH feature (1) with (2) but without vascular anomalies, syndactyly, or heterotopia.

  3. Diagnostic criteria: These proposed criteria are the most inclusive and common features of MCAP and MPPH syndromes. Other subgroups within these two broad disorders, especially within MPPH syndrome, may need to be delineated in the future.

MCAP (megalencephaly-capillary malformation) syndrome
 (1) Early overgrowth (brain > somatic tissues)
  Progressive megalencephaly (MEG)Selective brain overgrowth:Secondary features:
 Ventriculomegaly/hydrocephalus Hypotonia
 Cerebellar tonsillar ectopia Developmental delay
 Abnormally thick (mega-) corpus callosum Distinctive facial features (frontal bossing, dolichocephaly)
Somatic and cranial growth dysplasia: 
 Congenital somatic overgrowth 
 Somatic or cranial asymmetry 
 (2) Developmental vascular disorders (abnormal vasculogenesis)
  Capillary malformations (midline face and body)Other vascular abnormalities: 
 Infantile hemangiomas 
 Venous aneurysms/prominent venous pattern 
 Vascular rings/aberrant vasculature 
 (3) Distal limb anomalies
  Syndactyly (2-3, 3-4, 2-3-4; toe or finger)Other distal limb anomalies: 
 Polydactyly 
 Polysyndactyly 
 Sandal-gap toes 
 (4) Cortical brain malformations
  Polymicrogyria (PMG) Secondary features:
  Seizures
  Developmental delay
 (5) Connective tissue dysplasia
  Skin hyperelasticity Secondary features:
  Joint hypermobility  Hypotonia
  Thick, doughy subcutaneous tissue  Gross developmental delay
MPPH (megalencephaly-perisylvian polymicrogyria-postaxial polydactyly-hydrocephalus) syndrome
 (1) Early overgrowth (brain > somatic tissues)
  Progressive megalencephaly (MEG)Selective brain overgrowth:Secondary features:
 Ventriculomegaly/hydrocephalus Hypotonia
 Cerebellar tonsillar ectopia Developmental delay
 Abnormally thick (mega-) corpus callosum Distinctive facial features (frontal bossing, dolichocephaly)
 (2) Cortical brain malformations
  Polymicrogyria (PMG) Secondary features:
  Seizures
  Developmental delay
 (3) Distal limb anomalies
  Postaxial polydactyly  

Classes of Developmental Abnormalities in MCAP Syndrome and Medical Management Issues

(1) Overgrowth: Megalencephaly (MEG), associated growth dysplasia and other MEG-associated features. The MEG in these MEG syndromes is most often congenital and universally progressive. Most children cross OFC percentiles during the first year of life, and while head growth may level off in early childhood, it typically remains at +3 or more SD above the mean. MEG represents a disorder of increased proliferation or decreased apoptosis of neuroprogenitor cells, or both. The process of generalized brain overgrowth may be accompanied by secondary overgrowth of specific brain structures, such as the ventricles, the corpus callosum, and the cerebellum. The dynamic MCAP-associated changes we have seen on serial brain imaging include (1) VMEG and HYD, (2) CBTE, and (3) MegaCC. Our series provides clear, retrospective but largely anecdotal evidence for progression from VMEG to HYD and progression of CBTE. We also reviewed children with marked VMEG who did not progress to frank HYD, and have documented spontaneous resolution of severe CBTE in one child.

Given the high risk of HYD and CBTE in MCAP syndrome, frequent MRI screening is recommended. While no standard recommendations currently exist, a brain MRI approximately every 6 months until age 2–3 years seems reasonable. More frequent imaging is recommended if there are concerning factors such as very rapidly enlarging OFCs, progressive VMEG/HYD, and rapidly progressive CBTE. It is more difficult to assess the need for treatment. We generally favored early treatment of HYD in the hope of reducing the risk of progressive CBTE, but we do not have objective evidence to support this. Minimally invasive 4th ventriculostomy has worked in a few recent cases, but more experience and longitudinal follow-up are needed. We do not have sufficient data to support a general approach to management of CBTE. Given our observation of regression (improvement) in one boy, non-surgical management of CBTE in MCAP may be appropriate in asymptomatic patients, but such patients should be followed closely. While there is strong evidence for progressive cerebellar overgrowth, the complete resolution of CBTE observed in one individual might be attributed to disproportionately accelerated skull growth relative to cerebellar growth. Furthermore, no patient undergoing posterior fossa decompression had symptoms of secondary impingement on the brainstem or corticospinal tracts, although one patient reportedly became more alert postoperatively. Surgical management (i.e., posterior fossa decompression) should be considered on a case-by-case basis, especially when symptoms of brainstem compression appear or when syringomyelia is found, and we stress caution in the individual management of patients. More data are certainly necessary to guide the general approach for this particular and potentially life-threatening complication, which is a common concern in MCAP syndrome. Future use of quantitative MRI studies to accurately measure the cerebellar and posterior fossa volumes will be necessary to further understand the growth patterns of these structures.

Moreover, MCAP appears to be associated with generalized overgrowth involving congenital overgrowth or macrosomia, somatic asymmetry, and brain asymmetry. While congenital overgrowth/macrosomia typically normalize, some children have subsequent poor growth, and some have growth hormone deficiency of unknown cause. The asymmetry often persists. Therefore, this syndrome appears to be one of generalized growth dysregulation. It is clearly evident that brain overgrowth is characteristically disproportionate to body overgrowth, and the largest OFCs reach +10 SD whereas the largest weights only reach +4 SD above the mean.

(2) Developmental vascular disorders (or features of abnormal vasculogenesis). The predominant type of vascular abnormalities observed in children with MCAP syndrome consist of capillary malformations anywhere on the body or face, and may be isolated or extensive (and may appear to resemble cutis marmorata). While these may fade, they often persist, and appearance may vary with changes in temperature. Additional vascular abnormalities include infantile hemangiomas that may be internal or external in location, aberrant vessels, vascular rings, dilated veins, and venous aneurysms in some patients.

(3) Distal limb anomalies. Polydactyly and syndactyly are well-recognized features of MCAP syndrome. However, our data suggest that syndactyly (specifically 2-3 toe syndactyly) is a specific feature of MCAP syndrome (P < 0.0001) and polydactyly is more commonly seen in MPPH syndrome, although this association is not statistically significant. Sandal-gap toes are also frequently seen, possibly due to associated toe syndactyly of the adjacent digits. Leg-length discrepancy requiring orthopedic intervention has also been reported and is secondary to asymmetric overgrowth. The overgrown limb is not expected to grow at a disproportionate or relentless rate as seen in other overgrowth conditions such as Proteus syndrome [Biesecker et al., 1999].

(4) Cortical brain malformations: PMG and secondary neurologic sequelae (developmental delay, seizures, and tone abnormalities). PMG was observed in a large majority of our cohort. It was predominantly BPP in distribution. While few reports in the literature have mentioned PMG, we posit it is an under-recognized feature [Conway et al., 2007]. Patients with PMG (specifically of the frontal region) often have spasticity and pseudobulbar problems as older children, while younger children have hypotonia and are not spastic, and may have pseudobulbar problems.

Developmental delay. The majority of patients with MCAP and MPPH syndromes have some degree of developmental delay, although the range of developmental disability varies from severe cognitive disability to mild or no cognitive problems. The degree of developmental disability appears to be related mostly to the presence or absence of seizures, HYD, and cortical dysplasia, such as PMG. The most severely delayed children in our cohort also had the most severe PMG. Longitudinal data reveal that most children make steady developmental progress, albeit at a slower rate. Motor delays are probably caused by multiple factors including MEG, other cortical brain malformations, hypotonia, limb asymmetry or overgrowth, and connective tissue dysplasia.

Seizures. Seizures were observed in 16/42 patients. We recognize this frequency is much less than that seen in typical PMG, where the epilepsy risk is as high as 80% [Leventer et al., 2010]. The severity of epilepsy seems to correlate with the degree of PMG in our cohort. While not seen in our series, children with hemimegalencephaly generally tend to have more severe seizures of earlier onset with poor neurocognitive outcome [Barkovich et al., 2005].

Tone abnormalities. Hypotonia, and particularly neonatal hypotonia, is a frequent finding in MCAP syndrome. This may be primarily central (secondary to MEG and associated brain abnormalities), and partially peripheral (secondary to mild connective tissue dysplasia resulting in lax joints).

Other developmental problems. Other developmental abnormalities reported in our patients include autistic features, ADHD, OCD, and anxiety-related issues. Autistic features were seen in six patients, a frequency that is higher than that seen in previous reports of these syndromes, suggesting that autism is part of the neurocognitive phenotype of these MEG disorders.

The early literature describing primary (or idiopathic) MEG reported that it was associated with variable degrees of developmental delay, tone abnormalities, and seizures, and also that idiopathic MEG could be associated with fully normal cognitive and motor function or substantial neurologic disability [Schreier et al., 1974; Alvarez et al., 1986; Lewis et al., 1989; Barkovich et al., 2005]. Therefore developmental delay and tone abnormalities are non-specific features secondary to MEG, and do not represent primary diagnostic criteria by themselves. Similarly, the distinctive facial appearance seen in children with MCAP syndrome (with frontal bossing, round face, and dolichocephaly) is most likely secondary to the underlying brain overgrowth, as well as related to neonatal hypotonia and thickened and soft subcutaneous tissue.

(5) Connective tissue dysplasia. A distinct yet variable degree of connective tissue dysplasia appears to be a very common feature of MCAP syndrome. The manifestations of this include skin laxity, altered skin, joint hypermobility, ligamentous laxity, and/or connective tissue consistency with the connective tissue being described as thick, soft, and doughy. This connective tissue dysplasia is milder than that of other connective tissue disorders, such as cutis laxa, and is unlike that of Ehlers–Danlos syndrome. Our experience suggests it generally tends to be more severe with extensive cutaneous capillary malformations.

Other Medical Issues

Malignancy

Given evidence of early overgrowth, some patients with MCAP syndrome are screened for overgrowth-associated malignancies, such as Wilms tumor or hepatoblastoma. Surprisingly, there are only two reports of Wilms tumor in MCAP syndrome [Lapunzina et al., 2004; Wright et al., 2009]. In our cohort, one patient had two subcutaneous lipomas, which were stable in size. Therefore, the evidence so far indicates that the risk of malignancies in MCAP syndrome is lower than in classic overgrowth syndromes, such as Beckwith–Wiedemann syndrome [Cohen, 2005]. At the present time, we have found insufficient evidence to guide specific screening protocols for MCAP or MPPH syndrome patients. Reported malignancies in the literature include two meningiomas (which given the rarity of meningiomas in the pediatric population, seems to be a true, albeit rare, association) [Moore et al., 1997; Conway et al., 2007] and a single report of leukemia [Moore et al., 1997]. Recently, an MPPH syndrome patient with a medulloblastoma was reported [Osterling et al., 2011].

Structural cardiovascular disease

A few patients with MCAP have developmental vascular abnormalities involving the vasculature of the heart that we hypothesize are secondary to the overall phenomenon of dysregulated vasculogenesis, while a few more have isolated structural heart malformations of unknown pathogenesis. Thus, an echocardiogram should be considered in children with suspected MCAP. Moreover, a few affected individuals have had arrhythmias, with sudden death reported in at least one patient [Yano and Watanabe, 2001]. One subject in our series had supraventricular tachycardia that was successfully treated with Digoxin. It is unclear whether this was caused by an underlying defect in the cardiac conduction system or secondary to brainstem compression from brain and cerebellar overgrowth with compromise of the vagal nerves. Nevertheless, until further clarification of arrhythmias in this syndrome is provided, assessment of cardiac conduction anomalies seems prudent.

Gastrointestinal

A number of children with MCAP syndrome have feeding and swallowing difficulties, often requiring gastrostomy and tube feeding. This is most likely due to a number of factors, including the underlying brain abnormality (or abnormalities), especially PMG, poor tone, and gastroesophageal reflux disease (GERD).

The Genetics of MCAP and MPPH Syndromes

All reported patients to date have been sporadic. Given the clinical similarities between these syndromes and PTEN-related disorders, multiple patients have undergone PTEN sequencing with negative results.

Family history

Multiple patients in our cohort had a family history of MEG, most commonly on the paternal side of the family. The father of patient 9 had an OFC of +6 SD above the mean, and was large at birth. The patient's paternal uncles, grandparents, and paternal aunts all reportedly had MEG, but their OFCs were smaller than the father's. The fathers of patient 38 and 39 had MEG (with an OFC of +2 SD) and patient 38's father had a history of mild hypotonia in childhood. To our knowledge, these family members do not have other features suggestive of MCAP or MPPH syndromes. Patient 13 had a paternal cousin with intellectual disability and autism. Patient 16 has multiple members with MEG on the maternal side of his family. The maternal great grandmother had a history of acromegaly, and a maternal great-aunt had a child with MEG who passed at age 5 months without known cause.

Mosaicism

Interestingly, two MCAP patients in our cohort had linear and segmental capillary malformations that appear to follow Blaschko lines in a pattern suggestive of cutaneous mosaicism, a finding that has been reported previously in at least one patient suspected to have MCAP syndrome [Mégarbané et al., 2003].

The Classes of Developmental Abnormalities in MCAP and MPPH Syndromes and Their Diagnostic Criteria

While we agree in general with most of the existing proposals for diagnostic criteria for MCAP syndrome, our data suggest that these may be too limiting. To accommodate the broad spectrum of anomalies seen in children with MCAP syndrome, we assigned all of the more common features to one of 5 major classes of developmental abnormalities. These include:

  • (1)
    Megalencephaly and associated growth dysregulation including selective brain overgrowth and variable degrees of somatic and cerebral overgrowth and asymmetry. We propose this is a mandatory feature and associated with one of the following two groups of features:
  • (2)
    Developmental vascular abnormalities that are most commonly cutaneous but may be internal. These are not restricted to capillary malformations but include a broad range of vascular abnormalities (such as hemangiomas, prominent and dilated veins, venous aneurysms, vascular rings, aberrant vessels).
  • (3)
    Distal limb malformations, and, specifically, including syndactyly of the fingers/toes.

Additional abnormalities supportive of MCAP syndrome include:

  • (4)
    Cortical brain malformations, and most predominantly PMG, which, despite our bias of ascertainment, may be a defining and under-recognized feature of this syndrome, and
  • (5)
    Distinctive connective tissue dysplasia that is variable and less severe than that seen with other connective tissue disorders such as Ehlers–Danlos syndrome.

Based on the above, we propose simpler and more uniform diagnostic criteria for MCAP and MPPH syndromes. We will define MCAP syndrome as MEG with either developmental vascular anomalies or syndactyly. PMG, connective tissue dysplasia, and somatic asymmetry are supportive features. MPPH is characterized by MEG, PMG, and sometimes postaxial polydactyly but lacks vascular anomalies, syndactyly or heterotopia, as we suggest the former two are characteristic and defining features of MCAP syndrome, and the latter is a feature we have recognized in subsets of patients that appear distinct (Table VI).

We readily acknowledge that our series is strongly biased towards children with MEG and PMG based on our longstanding interest in these developmental brain disorders. Thus, patients with MCAP-like features combining other findings, such as vascular malformations and syndactyly without either MEG or PMG, might also be part of the spectrum. Such patients might be better ascertained via a pediatric dermatology service. Thus, our criteria are less restrictive than previous criteria and yet might still be too restrictive. Furthermore, given our broad definition and view of MPPH syndrome, future delineation of subgroups with a shared pathogenesis within the MCAP and MPPH spectra may occur, but we do not have data to support this yet. Further studies by groups with different patterns of ascertainment are likely to resolve these issues.

Overlap of MCAP and MPPH Syndromes With the RASopathies

We have observed distinct similarities between MCAP syndrome and disorders of the RAS pathway. Neurofibromatosis type 1 is a disorder of true MEG [Cutting et al., 2002], whereas Noonan, Costello, and cardiofaciocutaneous (CFC) syndromes have a high incidence of relative MEG and VMEG. In a systematic review of 28 patients, absolute or relative MEG was found in 100% of patients, and more specifically an evolving MEG and cerebellar enlargement in patients with Costello/CFC syndrome [Gripp et al., 2010]. Additional MCAP-like features seen with other RASopathies include vascular malformations, skin, and connective tissue dysplasia. It is therefore reasonable to speculate that MCAP and MPPH syndromes may be caused by an underlying defect in a RAS-related pathway.

In summary, MCAP and MPPH syndromes are distinct MEG disorders. The previously reported diagnostic criteria emphasized clinical features within the same biological phenomena several different times. Moreover, the different combinations of anomalies are variable enough that all prior proposed diagnostic criteria appear too restrictive in our experience, and may include only the most severe (or classic) patients. Here, we broaden the view of these recognizable syndromes based on classes (or categories) of developmental abnormalities, which undoubtedly provide clues regarding the underlying major biologic developmental pathways.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

We wish to thank the patients' families and their referring physicians for contributing to this study. We appreciate support from the Steven Spielberg Pediatric Research Center, the NIH/NICHD Program Project Grant (HD36657 to J.M.G.), the Medical Genetics NIH/NIGMS Training Program Grant (5-T32-GM08243 to J.M.G.), and the Cedars-Sinai General Clinical Research Center Grant (M01-RR00425) for samples collected under CSMCIRB Protocols 0463 and 4232 (J.M.G.), and NIH/NINDS grant (NS058721 to W.B.D.).

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  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

Additional supporting information may be found in the online version of this article.

FilenameFormatSizeDescription
ajmg_34402_sm_SupplFig1.tif131KFig. 1: Scatter plot of weight data points for MCAP patients (by standard deviations).
ajmg_34402_sm_SupplFig2.tif139KFig. 2: Scatter plot of length/height data points for MCAP patients (by standard deviations).
ajmg_34402_sm_SupplTab1.doc117KTable I: Additional clinical data of MCAP and MPPH patients (n=42 patients; 31 new cases and 11 previously-published cases)

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