prenatal diagnosis of mpph syndrome

RESEARCH LETTER

Prenatal diagnosis of MPPH syndromeBart De Keersmaecker1, Hilde Van Esch2, Dominique Van Schoubroeck1, Filip Claus3, Philippe Moerman4 and Luc De Catte1*

1Department of Obstetrics and Gynecology, University Hospitals, Leuven, Belgium2Department of Genetics, University Hospitals, Leuven, Belgium3Department of Radiology, University Hospitals, Leuven, Belgium4Department of Pathology, University Hospitals, Leuven, Belgium*Correspondence to: Luc De Catte. E-mail: [email protected]

ABSTRACTWe report the prenatal sonographic detection of a fetus with megalencephaly, polymicrogyria, postaxial polydactyly andhydrocephaly. Only 14 patients have been reported in the literature so far, all but one were diagnosed postnatally. Thepolymicrogyria in the frontoparietal lobe was confirmed by prenatal magnetic resonance imaging. Additionally, ahypoplastic thymus as seen in a 22q11 deletion was present. Although polymicrogyria along with pre-axial polydactylyhas been described in 22q11 deletion, the diagnosis of Di George syndrome was ruled out. The etiology ofmegalencephaly, polymicrogyria, postaxial polydactyly and hydrocephaly has not been revealed yet. A dominant as wellas recessive inheritance has been suggested. © 2013 John Wiley & Sons, Ltd.

Funding sources: NoneConflicts of interest: None declared

INTRODUCTIONSince the initial report in 2004,1 a small number of cases ofmegalencephaly and perisylvian polymicrogyria with postaxialpolydactyly and hydrocephalus (MPPH) syndrome have beenreported with some variability in the extent of features.2–8

The etiology of this disorder is presumed to be genetic andrecently an overlap with the macrocephaly-capillary syndrome(MCM) has been suggested.6 Prenatal diagnosis remainschallenging. Megalencephaly, hydrocephalus and polydactylyare detectable by prenatal ultrasound.

The diagnosis of polymicrogyria, however, is more easilymade by magnetic resonance imaging (MRI), revealing anirregularity of the cortical surface or an irregular scallopedappearance of the gray to white matter junction. Here, wepresent a case of antenatally diagnosed MPPH syndromeby ultrasound and MRI and subsequently confirmed byhistopathology. In addition, we discuss how to distinguishMPPH from other syndromes associated with polymicrogyriasuch as the 22q11 microdeletion syndrome.

CASE REPORTA 33-year-old G2P1 with a blankmedical history was seen for thefirst time at 20weeks of gestation for a routine morphology scan.Both parents were healthy and nonconsanguineous, and familyhistory was unremarkable. At ultrasound, a bilateral ventricu-lomegaly was documented (atria of the lateral ventricles of 12and 14mm)(normally <10mm), which was confirmed atsubsequent evaluation 3weeks later (14 and 16mm). Maternalserological investigation for toxoplasmosis and cytomegalovirus

(CMV) was negative. Ultrasound examination at 26 5/7weeks ofgestation in a tertiary center confirmed the ventriculomegaly.The atria of the right and left lateral ventricles measured 15 and14mm, respectively, and both anterior horns were 6mm. Thefourth ventricle was prominent (7 and 4mm in transverse andanterior–posterior views, respectively). At themidsagittal section,the length of the corpus callosum was 39mm (P50=33.7mm)although the splenium seemed hypoplastic. The biparietaldiameter (78mm) and the occipitofrontal diameter (91.3mm)were above the 95th percentile. In addition, amild hypertelorismand a large retrocerebellar space of 11mm were reported.Postaxial polydactyly, which was not observed by the referringphysician, was diagnosed at both hands and at the right foot,with the left foot being normal. The amount of amniotic fluidwas normal. Informed consent was obtained from the parentsprior to the diagnostic tests. Genomic DNA was extracted fromamniocytes according to standard procedure guidelines.Comparative genome hybridization was performed usingthe Oxford Gene Technology CytoSure™ ISCA oligoarray set(Oxford Gene Technology, Oxford, UK) containing 105k DNAoligonucleotideswith aminimumresolution of 200kb, accordingto the manufacturer’s recommendations. Mutation analysis ofthe novel genes involved in MPPH, AKT3, PIK3CA and PIK3R2,was performed in collaboration with the laboratory of Prof. W.Dobyns. No mutation could be detected in either of the genes.

The prenatal MRI findings at 26 6/7weeks confirmed theultrasound findings of a head circumference of 266mm (>95thpercentile) and ventriculomegaly. The corpus callosumappeared complete, but thinner than expected. The Sylvian

Prenatal Diagnosis 2013, 33, 292–295 © 2013 John Wiley & Sons, Ltd.

DOI: 10.1002/pd.4039

fissure was sloping and rather stretched. Bilaterally, there was aribbed lining of the frontoparietal cortex. Differential diagnosisincluded polymicrogyria and redundant gyration due to dilatedventricles. Vermis and cerebellar hemispheres had a normalaspect. No intracranial signs of ischemia or bleeding weredetected. Postaxial polydactyly on both hands was confirmed.

At 27 5/7weeks, an additional ultrasound scan was performed.A bilateral ventriculomegaly of 14mm was confirmed.Both anterior horns remained dilated (6.8 and 9.7mm).Polymicrogyria of the right frontal region was present (Figure 1).The pons and medulla oblongata had a slithering aspect.Bilaterally postaxial polydactyly on both hands was confirmed.

From these phenotypic features, a tentative diagnosis ofMPPH spectrum was made. This disorder is characterized byvisual impairment, developmental delay, intellectual disabilityand often epilepsy and facial dysmorphism in varyingdegrees.1–4 All findings were discussed with the parents, and theyopted for a termination of pregnancy. A female fetus of 1375 gwas born. Postmortem MRI and pathologic investigationconfirmed the presence of polydactyly, ventriculomegaly,megalencephaly (brain weight three times the normal forgestational age) and bilateral polymicrogyria in the frontoparietalregion with a dysplastic cortex of four layers (Figure 1). Anextremely hypoplastic thymus was an added finding.

DISCUSSIONTo our knowledge, this is first report of MPPH in the secondtrimester of pregnancy, supported by additional examinations.The MPPH syndrome is a very rare disorder with only 15 casesreported to date.1–8 All but one were diagnosed postnatallyranging from day 1 up to 18months of age (Table 1). Mildventriculomegaly has been reported prenatally in associationwith MPPH syndrome, but prenatal MRI and ultrasound wereonly described in the patient reported by Gripp et al.6

A patient with megalencephaly, ventriculomegaly andpolymicrogyria was diagnosed at 31weeks of gestation, but theinitial prenatal diagnosis ofMPPHwas revised soon after deliveryon the basis of the presence of capillarymalformations related tomacrocephaly-capillary malformation syndrome (MCM, OMIM

602501). MCM and MPPH are closely related disorders. InMCM syndrome, typical vascular skin abnormalities are present,but these are difficult to detect prenatally. Nine of the 15reported cases had hydrocephalus,4,7 requiring ventriculo-peritoneal or ventriculo-atrial shunting in the early months ofpostnatal life. The prominent fourth ventricle in this fetusevolved to normal in follow-up MRI and ultrasound, suggestingan obstruction of the aqueduct as cause of the ventriculomegaly.Megalencephaly, which is a proliferation disorder of the cerebralcortex, has been associated with overgrowth syndromes and canbe either unilateral or bilateral. Measurements of headcircumference and occipital frontal diameter above two standarddeviations may suggest the diagnosis as revealed in our case.Polymicrogyria is a malformation of the cortical developmentresulting in irregular multiple small, partially fused gyri andderangement of the normal cortical lamination, divided byshallow sulci. The polymicrogyric cortex often appears mildlythickened (6–10mm) because of the cortical overfolding.

Midtrimester ultrasound diagnosis of polymicrogyriaremains difficult. Abnormalities of fetal cortical gyration andsulcation have been described in patients with CMVseroconversion during early pregnancy.10

Different types of polymicrogyria have been described, ofwhich the congenital bilateral perisylvian polymicrogyria isthe most frequently encountered type. In our case, thepolymicrogyria was located in the frontoparietal lobe.Polymicrogyria happens to be present in several brainovergrowth syndromes or as the endpoint of variousdestructive processes, but not necessarily occurring at thesame time with cortical development as in congenital CMVinfection, placental hypoperfusion in the second trimester,perinatal cerebral hypoxia ischemia as in twin-to-twintransfusion syndrome, the loss of one fetus in a monochorionictwin pregnancy or maternal drug ingestion.

In MCM patients, the polymicrogyria is mainly located in theposterior fossa, whereas our patient presented with bilateralfrontoparietal polymicrogyria. MCM has combined skin, vascularand connective tissue abnormalities, cutis marmorata, capillaryand possible other angiomas as well as a progressive cerebral

Figure 1 One of the main features of megalencephaly and perisylvian polymicrogyria with postaxial polydactyly and hydrocephalus is present onfetal ultrasound (a) as evidence of the polymicrogyria in the frontal lobe (arrow). PrenatalMRI confirmed the presence of bilateral ventriculomegaly,and the polymicrogyria of the frontoparietal cortex (b)

Prenatal diagnosis of MPPH 293


Table1

Summaryof

thecharacteristicsof

MPPHsynd

romein

theliterature.

Notethat

fina

llyin

2casesthediag

nosis

shifted

towards

themicroceph

alycapillary

malform

ation

Reference

Nr

Prenatal

diag

nosis

Highresolutio

nka

ryotyp

eCGH

Postn

atal

diag

nosisat

Poly-m

icrogy

riaVentricularshun

tPersistence

ofCSP

CC

Add

ition

alman

ifesta

tions

Mirzaa

etal.(

1)

5(2

M,3

F)NA

3/5no

rmal

2/5NA

NA

NA

5/5present

5/5yes

5/5yes

4/5no

rmal

1/5short

duplex

kidn

eys

ASD

/VS

D

Colom

bani

etal.(

2)

1(F)

24w,S

UA,

mild

VMno

rmal

normal

18m

(MRI)

present

NA

yes,cystic

NA

dacryocysto

cele

Tohyam

aet

al.(3

)1(F)

30w,V

Mno

rmal

NA

3m

(MRI)

present

noyes

thin

-

Garavelliet

al.(

4)

1(F)

NA

normal

NA

3m

(MRI)

present

yes(5

m)

yes

short

-

Pisano

etal.(

5)

1(F)

NA

NA

NA

NA

present

NA

yes,cystic

NA

-

Grip

pet

al.(

6)

3(1

F,2M)

(1)N

A(2)V

M,M

C(3)N

A

3/3no

rmal

3/3NA

(1)6

m(M

RI)

(2)1

d(M

RI)

(3)6w

(MRI)

3/3present

(1)yes

(8m)

(2)no

(3)yes

(5m)

3/3NA

1no

rmal

2NA

2/3diag

nosis

convertedto

MCM

Tore

etal.(

7)

1(M

)mild

VMNA

NA

1d,(US,

MRI)

present

noyes,cystic

NA

elon

gatedpituitary

infund

ibulum

Oste

rling

etal.(

8)

2(1

F,1M)

(1)N

A(2)M

C2/

2no

rmal

2/2no

rmal

(1)2w

(MRI)

(2)1

m(CT-scan

)2/

2present

(1)yes

(6m)

(2)no

2/2NA

NA

tumor

ofthecentral

nervou

ssyste

m

Presentcase

1(F)

20w,V

M,

polyda

ctyly26

w,

VM,P

MG

normal

normal

postm

ortem

(MRI,

patholog

y)present

--

thin

absent

thym

us

M,m

ale;

F:female;

NA:n

otavailable;

SUA:singleum

bilical

artery;V

M:ventriculomeg

aly;

MC:m

acrocran

ia;P

MG:p

olym

ycrogy

ria;C

GH:c

ompe

rativege

nomichybridization;

m:m

onth(s);d

:day

;w:w

eek(s);

MRI:m

agnetic

resona

nceimag

ing;

CT-scan

:com

puterized

tomog

raph

y-scan

;CSP

:cavum

septip

ellicidi;CC:c

orpu

sca

llosum;A

SD:a

trial

septal

defect;V

SD:v

entricularsep

tald

efect;MCM:m

icroceph

alyca

pillary

malformation.

B. D. Keersmaecker et al.294


tonsillar herniation. Themorphological ultrasound appearance ofthe anterior part of the corpus callosum was normal, but itwas thinner towards the splenium, matching the observationof Garavelli and Tohyama.3,4 In MPPH syndrome, a higherincidence of cystic cavum septi pellucidi has been described(3/15 cases).2,5 This feature was not illustrated by prenatalimaging in our case. An extremely hypoplastic thymus as in22q11 deletion syndrome was detected on pathologicalexamination. Because polymicrogyria has been describedin 22q11 deletion along with pre-axial polydactyly, a 22q11deletion was ruled out by array-based comparative genomichybridization in our case.9

Recently, the team of Prof. Dobyns identified de novo germline or postzygotic mutations in three core components ofthe phosphatidylinositol 3-kinase–AKT pathway, includingmutations in AKT3, PIK3R2 and PIK3CA in MPPH and MCAP.11

In the majority of their cases, a postzygotic mutation occurred.Sequencing of these three genes in our patient did not reveal amutation. Although we cannot rule out the possibility of very-low-level mosaic mutations, this might also point to theheterogeneity of this group of disorders.

ACKNOWLEDGEMENTSThe authors wish to thank the cooperation of the family inobtaining the necessary medical data for publication. We alsowish to thank the team of Prof. W.B. Dobyns for performing themutation analysis.

WHAT’S ALREADY KNOWN ABOUT THIS TOPIC?

• A few cases of megalencephaly and perisylvian polymicrogyriawith postaxial polydactyly and hydrocephalus (MPPH) syndromehave been reported with some variability in the extent offeatures.

• The diagnosis of polymicrogyria, however, is more easily made bymagnetic resonance imaging (MRI).

WHAT DOES THIS STUDY ADD?

• We discuss the diagnosis of MPPH by ultrasound and MRI.• Wediscuss how to distinguish MPPH from other syndromes associated

with polymicrogyria such as the 22q11 microdeletion syndrome.

REFERENCES1. Mirzaa G, Dodge N, Glass I, et al. Megalencephaly and perisylvian

polymicrogyria with postaxial polydactyly and hydrocephalus. A rare brainmalformation syndrome associated with mental retardation and seizures.Neuropediatrics 2004;35:353–9.

2. ColombaniM, ChouchaneM, Pitelet G, et al. A new case ofmegalencephalyand perisylvian polymicrogyria with post-axial polydactyly andhydrocephalus. Eur J Med Genet 2006;49:466–71

3. Tohyama J, Akasaka N, Saito N, et al. Megalencephaly and polygyriawith polydactyly syndrome. Pediatr Neurol 2007;37:148–51.

4. Garavelli L, Gaureschi E, Errico S, et al. Megalocephaly and perisylvianpolymicrogyria with postaxial polydactyly and hydrocephalus.Neuropediatrics 2007;38:200–3.

5. Pisano T, Meloni M, Chianchetti C, et al. Megalencephaly, polymicrogyriaand hydrocephalus (MPPH) syndrome: a new case with syndactyly. J ChildNeurol 2008;23:916–8.

6. Gripp K, Hopkins E, Vinkler C, et al. Significant overlap and possibleidentity of microcephaly capillary malformation and megalencephaly,

polymicrogyria–polydactyly hydrocephalus syndromes. Am J MedGenet 2009;149A:868–76.

7. Tore HG, McKinney A, Nagar V, et al. Syndrome of megalencephaly,polydactyly and polymicrogyria lacking frank hydrocephaluswith associated MR imaging findings. Am J Neuroradiol2009;30:1620–2.

8. Osterling W, Boyer S, Hedlund G, Bale J. MPPH syndrome: two newcases. Pediatr Neurol 2011;44:370–3.

9. Robin N, Taylor C, McDonald-McGinn D, et al. Polymicrogyriaand deletion 22q11.2 syndrome: window to the etiology of acommon cortical malformation. Am J Med Genet A 2006;140(22):2416–25.

10. Malinger G, Lev D, Lerman-Sagie T. Imaging of fetal CMV infection.Fetal Diagn Ther 2011;29:117–26.

11. Riviere JB, Mirzaa G, O’Roak B, et al. De novo germline and postzygoticmutations in AKT3,PIK3R2 and PIK3CA cause a spectrum of relatedmegalencephaly syndromes. Nat Genet 2012;8:934–40.

Prenatal diagnosis of MPPH 295


prenatal diagnosis of mpph syndrome

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