Prenatally diagnosed periventricular nodular heterotopia: Further delineation of the imaging phenotype and outcome

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Prenatally diagnosed periventricular nodular heterotopia: Further delineation of the imaging phenotype and outcome B. Deloisona,b,c, P. Sonigof, A.E. Millischer-Bellaichef, T. Quibelg, M. Cavallinb,d,e, G. Benoisth, C. Quelini, P.S. Joukj, D. Levk, M. Alisonl, C. Baumannm, C. Beldjordn, F. Razavio, B. Bessièreso, N. Boddaertb,f, Y. Villea,b,c, L.J. Salomona,b,c,1, N. Bahi-Buissonb,d,e,∗,1 a

Department of Obstetrics and Gynecology and SFAPE Société Française pour l’Amélioration des Pratiques Echographiques, Necker Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France b Université Paris Descartes - Sorbonne Paris Cités, France c EA 7328 FETUS, Université Paris Descartes, France d Institut Imagine-INSERM UMR-1163, Embryology and genetics of congenital malformations, France e Pediatric Neurology, Necker Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France f Pediatric Radiology, Necker Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France g Department of Obstetrics and Gynecology, Poissy Saint-Germain Hospital, Poissy, France h Department of Obstetrics and Gynecology, Caen Hospital, Caen Basse Normandie University, France i Clinical Genetic Department, Rennes Hospital, France j Clinical Genetic Department, Grenoble Hospital, France k Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel l Pediatric Radiology, Robert Debre Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France m Clinical Genetics Department, Robert Debre Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France n Department of Molecular Genetics, Cochin-Port-Royal Université Paris Descartes - Sorbonne Paris Cités, Paris, France o Fetopathology Necker Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France

A R T I C LE I N FO

A B S T R A C T

Keywords: Periventricular nodular heterotopia Prenatal Fetal ultrasound Fetal MRI

Objectives: Periventricular nodular heterotopia (PNH) is a malformation of cortical development which presents with heterogeneous imaging, neurological phenotype and outcome. There is a paucity of comprehensive description detailing the prenatal diagnosis of PNH. The aim of this study is to report neuroimaging features and correlated outcomes in order to delineate the spectrum of prenatally diagnosed PNH. Methods: It was a retrospective study over 15 years in five tertiary centers. All fetuses with prenatally diagnosed PNH were collected. Fetal ultrasound and MRI were reviewed and genetic screening collected. Prenatal findings were analyzed in correlation to fetopathological analyses and post-natal follow up. Results: Thirty fetuses (22 females and 8 males) with PNH were identified. The two major ultrasound signs were ventriculomegaly associated with dysmorphic frontal horns (60%) and posterior fossa anomalies (73.3%). On MRI, two groups of PNH were identified: the contiguous and diffuse PNH (n = 15, 50%), often associated with megacisterna magna, and the non-diffuse, either anterior, posterior or unilateral PNH. FLNA mutations were found in 6/11 cases with diffuse PNH. Additional cortical malformations were exclusively observed in non diffuse PNH (9/15; 60%). Twenty-four pregnancies (80%) were terminated. Six children aged 6 months to 5 years are alive. Five have normal neurodevelopment (all had diffuse PNH) whereas one case with non diffuse PNH has developmental delay and epilepsy. Conclusion: PNH is heterogeneous but patients with diffuse PNH are a common subgroup with specific findings on prenatal imaging and implications for prenatal counseling.

∗

Corresponding author. Hôpital Necker-Enfants-Malades, 149 rue de Sèvres, 75015, Paris, France. E-mail address: [email protected] (N. Bahi-Buisson). 1 The 2 authors equally contributed to this work. https://doi.org/10.1016/j.ejmg.2018.10.015 Received 17 November 2017; Received in revised form 24 October 2018; Accepted 28 October 2018 1769-7212/ © 2018 Published by Elsevier Masson SAS.

Please cite this article as: Deloison, B., European Journal of Medical Genetics, https://doi.org/10.1016/j.ejmg.2018.10.015

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1. Introduction

to those with diffuse PNH (Gonzalez et al., 2013; Parrini et al., 2006). Recent advances in imaging techniques have allowed prenatal diagnosis of PNH, initially suspected at ultrasound (US) (Bargallo et al., 2002; Blondiaux et al., 2013; Mitchell et al., 2000) and subsequently confirmed on MRI examination. This diagnosis is usually made during the last trimester of pregnancy and does not allow comprehensive genetic screening. Prenatal counseling is therefore highly challenging, given the heterogeneity of PNH and is mainly based on imaging characteristics. Consequently, identifying the key features defining the neurological outcome on fetal MRI is a major challenge. In order to evaluate the spectrum of prenatally diagnosed PNH, we undertook a retrospective study on a large cohort of fetal cases and correlated prenatal findings to the postnatal outcome and/or fetopathological features and genetic results.

Heterotopia represent malformations of cortical development in which neurons do not migrate to their proper final location. Heterotopia are characterized by macroscopic collections of heterotopic neurons with many forms and sizes, ranging from periventricular nodular heterotopia (PNH), the most common form, to periventricular linear heterotopia, consisting of a smooth layer of grey matter lining the ventricular wall, to columnar heterotopia, a linearly arranged collection of neurons that span the cerebral mantle from the pia to the ependyma, to large subcortical heterotopia that consist of curvilinear swirls of grey matter originating from deep sulci, which wind their way through the cerebral mantle to the ependyma (Barkovich et al., 2012). PNH, are characterized by variably sized nodules of neurons along the walls of the lateral ventricles, the location of the embryonic ventricular zone (Barkovich et al., 1996, 2005; Eksioglu et al., 1996). PNH can be bilateral or unilateral, contiguous or non contiguous. Recent studies have demonstrated that PNH results from the impairment of the initiation of neuronal migration (Ferland et al., 2009; Sarkisian et al., 2008) or can be related to abnormal proliferation and differentiation of neuronal progenitors (Cappello, 2013). PNH is an extremely heterogeneous disorder with regard to both clinical and brain imaging presentation and genetic causes. PNH occurs either as an isolated malformation. They can be part of at least 15 additional phenotypes, in association with other brain abnormalities including polymicrogyria, hydrocephalus, cerebellar hypoplasia, and microcephaly, or in association with frontonasal dysplasia, limb abnormalities, fragile X syndrome, and ambiguous genitalia (Gonzalez et al., 2013; Mandelstam et al., 2013; Pisano et al., 2012; Sheen et al., 2004; Wieck et al., 2005). Regarding clinical outcome, PNH is observed with a wide spectrum of neurological presentation ranging from asymptomatic individuals to severely disabled patients with refractory epileptic encephalopathy (Dobyns et al., 1996; Dubeau et al., 1995; Fink et al., 1997; Masruha et al., 2006; Parrini et al., 2006). Underlying etiologies are heterogeneous. Filamin A (FLNA) gene mutations account for an X-linked dominant form of PNH that mainly affects female patients and has familial transmission but also occurs sporadically (Clapham et al., 2012; Fox et al., 1998; Sheen et al., 2001). FLNA-PNH mutations are described as ‘classical bilateral PNH’, and are characterized by bilateral symmetric nodules lining the ventricles, especially the frontal horns and the anterior bodies, are often diffuse and contiguous and also often associated with megacisterna magna (Parrini et al., 2006). Patients with classical bilateral PNH can develop seizures in early adulthood but usually have normal intelligence or only mild intellectual disability (Chang et al., 2005; Parrini et al., 2006). A rare autosomal recessive form caused by mutations in the ARFGEF2 gene is characterized by microcephaly and delayed myelination in addition to PNH (Sheen et al., 2004). More recently, mutations or haploinsufficiency of the C6orf70 gene and NEDD4L mutations were found to be responsible for bilateral PNH (Conti et al., 2013) or syndromic form of PNH ((Broix et al., 2016). PNH has also been found in many syndromes, either with chromosomal rearrangements, of these duplication of 5p15.1 or 5p15.33 (Sheen et al., 2003), 6p25 deletion (Cellini et al., 2012), 5q14 deletion (Cardoso et al., 2009) or Xp22 deletion (van Kogelenberg et al., 2010) or with several single gene disorders (Ferland et al., 2006; Moro et al., 2006; Sheen et al., 2010), and some presumably more disruptive causes (Barth and van der Harten, 1985; Okumura et al., 2009). These forms of PNH are often associated with poor developmental outcome with severe developmental delay and early-onset epilepsy. Some authors have noted that according to the location of the PNH (anterior, posterior or diffuse), the occurrence of specific brain malformations may differ, suggesting that some prognostic information may be obtained based on the MRI analysis. Indeed, patients with posteriorly predominant PNH demonstrate more developmental disorders of the cerebral cortex and the brainstem compared

1.1. Patients and methods We reviewed all cases of prenatally diagnosed multiple subependymal heterotopia managed in five tertiary referral centers from 1999 to 2013. Scattered and isolated subependymal gray matter heterotopia were not included in this study. Gestational age assessment was based on crown-rump length (CRL) or certain Last Menstrual Period (LMP) in all pregnancies. Prenatal routine screening included ultrasound examination at 11–14 weeks, 20–24 weeks and 30–34 weeks respectively. In case of a suspected brain anomaly on US and/or history of brain anomaly in siblings, US examinations were offered on a monthly basis and prenatal MRI was routinely planned at around 30 weeks. In all cases, at least one US examination was performed within two weeks before MRI. Prenatal US examinations were performed using high-frequency probes for the transabdominal (4–8 MHz) and transvaginal (5–9 MHz) ultrasound examinations. GE E8 expert or Voluson 730 (GE Medical Systems, Ultrasound and Primary Care Diagnostic, Gif sur Yvette, France) were used over the previous 10 years. Trained operators (performing more than 1000 US examination/year) performed the targeted neurosonographic examinations including serial transverse, sagittal and coronal views obtained through the fontanelle. The transvaginal approach was used in all cases but breech presentation. 1.2. Image analysis Neurological anomalies diagnosed on US were retrieved in all cases. MRI examination was performed on a 1.5-T unit (Signa; GE, Milwaukee, Wis), using a phased-array abdominal coil. The MRI protocol included: (i) an anatomic MRI sequence of the whole fetus in three orthogonal planes; (ii) A FIESTA 2D sequence: TR 3.7 ms, TE 1.6 ms; matrix 512 × 512; FA: 60°, section thickness, 6 mm; (iii) an anatomical analysis of the fetus brain with a T2 weighted sequence in the three orthogonal planes; (iv) T2 Fast Spin Echo:TR 10000ms, TE 120ms; matrix 256 × 256; cm; FA: 90°, section thickness: 4 mm. PNH was described as small nodular periventricular foci of low signal intensity at MRI, similar to that of the grey matter. PNH locations were classified according to the ventricular segments affected. Those in the frontal horns and/or bodies of the lateral ventricles were classified as anterior PNH (aPNH), while posterior PNH referred to heterotopia located only in the trigone, temporal horns or occipital horns of the lateral ventricles. Heterotopia located in all the ventricular segments were classified as diffuse PNH (dPNH). Malformations of cortical development associated with the presence of PNH were recorded according to the recent classification (Barkovich et al., 2012). Associated brain anomalies including corpus callosum or cisterna magna anomalies as well as cerebral biometry and ventricles size were retrieved (Gandolfi Colleoni et al., 2012; Guibaud and des Portes, 2006). Ventriculomegaly was defined as a ventricular diameter of the atrium equal or superior to 10 mm (Salomon et al., 2011; Salomon and Garel, 2007). In view of the potential familial occurrence of PNH, maternal brain MRI was offered after diagnosis had been 2

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confirmed in fetus.

2.1. Image analysis

1.3. Genetic analysis

Patients were referred to a tertiary center following ultrasound abnormalities that were detected at a mean gestational age of 29.1 weeks ( ± 4.1 weeks). These consisted of ventriculomegaly with dysmorphic frontal horns (18 cases; 60%), corpus callosum agenesis (2 cases; 7%) or dysgenesis (6 cases; 20%), and abnormal posterior fossa (22; 73.3%), often in combination. Additional cerebral anomalies included megalencephaly, microcephaly and occipital meningocele. Extra-cerebral malformations were rare, and included bilateral hydronephrosis, micrognathia and severe growth restriction. In 4 cases only (13%) irregular borders of the cerebral ventricles or square shaped frontal horns were noted on ultrasound examination prior to MRI examination (Fig. 2). The remaining fetal PNH cases were overlooked on ultrasound and only diagnosed at fetal MRI. We are not aware of any case where PNH was suspected based on ultrasound, and not confirmed on MRI over the study period. US abnormalities are summarized in Supplementary Table 2. The diagnosis of PNH was subsequently confirmed on MRI performed at 30 weeks (range 25–36). Fifteen fetuses had bilateral symmetric and contiguous nodules of grey matter lining the lateral ventricles, defined as diffuse PNH (dPNH) (Parrini et al., 2006) (Fig. 3). Some fetuses had dPNH associated with abnormal corpus callosum (Fig. 3). Eight had anterior PNH (aPNH) with non contiguous nodules lining the frontal horns, bodies of the lateral ventricles (Fig. 4). Three had posterior PNH (pPNH) with nodules restricted to the trigones, temporal and occipital horns and three remaining fetuses had unilateral clusters of nodules in the occipital or posterior temporal horn (Fig. 4). MRI detected additional cortical malformations in 9 cases, the most frequent being bilateral and focal polymicrogyria (PMG) (Fig. 4) (including one with schizencephaly), often combined with macrocephaly (3 cases) or megalencephaly (one case) or microcephaly (one case). The remaining cases showed extensive lobar cortical dysplasia (n = 3). Hemispheric asymmetry was suspected in one case, and later confirmed by neuropathological studies. No case with agyria-pachygyria was identified. Remarkably, cortical malformations were exclusively observed in aPNH or pPNH (9/15; 60%) and never in dPNH (p=0.001). Noteworthy, while male fetuses rarely showed dPNH (1/15) (though this did not reach statistical significance), they were more commonly affected by anterior or posterior PNH, representing one third of the cases showing anterior or posterior PNH (5/15) (p=0.16). Fetal Brain MRI (n = 29) also demonstrated further abnormalities of

Karyotyping was offered on amniotic fluid and FLNA mutation screening (by denaturing high performance liquid chromatography) was also performed in terminated fetuses or in children from 2006 onwards when a familial history was reported. Array CGH was routinely performed from 2011 onwards. 1.4. Outcome data Counseling of parents was always performed by neuropediatricians and the decision to terminate the pregnancy or not was made by the parents, after receiving extensive multidisciplinary information on the status and prognosis of their fetus and of the associated anomalies. In our country, termination of pregnancy (TOP) is permitted when a severe fetal abnormality is detected, regardless of gestational age. Delivery records were reviewed and pregnancy outcomes were collected in all cases. Information on the outcomes of live-born infants was retrieved from neuropediatric and neuroradiological records. Informations on terminated fetuses and perinatal deaths were retrieved from medical and pathological records and full macroscopic and histological examinations of terminated fetuses were performed to confirm PNH, evaluate brain anatomy, and detect possible associated abnormalities that were overlooked during prenatal US/MRI examination. 1.5. Statistical analysis Stata 9.2 for Windows (StataCorp LP, TX 77845 USA) was used for statistical analyses. The study was approved by the ethics committee of the University Hospital of Necker Enfants Malades, Paris, France and the relevant local institutional review boards. 2. Results Over the study period, 30 cases of prenatal PNH were identified (Fig. 1). Over the same period, more than 2000 prenatal brain-targeted US and MRI examinations were performed. There were 22 females (73.3%) and 8 males (26.7%). The socio-demographic details of the study population are shown in Supplemental Table 1.

Fig. 1. Framework demonstrating the PNH characteristics and associated cerebral malformations and outcome. CC corpus callosum, TOP termination of pregnancy, MCM (Mega Cisterna Magna), M male, F female * 3 out of the 15 non diffuse PNH did not show cortical, cerebellar, corpus callosum malformations or MCM one had macropephaly (case 19) suspected pachygyria that was not confirmed in the neuropathological examination (case 25) severe ventriculomegaly (case 28). TOP was performed in all three cases, no neurological prognosis can be given.

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Fig. 2. 2D ultrasound views of the fetal brain of case 9. On the left is a coronal view demonstrating irregular and large squared frontal horns. On the right is a parasagittal view showing irregular borders of the ventricles.

inherited from the mother was considered as non-pathogenic (although we could not exclude a low penetrant variant). Screening for FLNA mutations was performed in 11 cases with dPNH and identified a pathogenic mutation in 6 cases, of these 3 were inherited. In non-diffuse PNH, FLNA mutation screening was performed in 2 cases and was negative (Table 2).

the corpus callosum (8; 27.6%), including thick and dysmorphic (2/8), partial or complete agenesis (3/8) and hypoplasia of corpus callosum (3/8). Corpus callosum anomalies were more frequent in aPNH or pPNH (n = 6/15; 40%) than dPNH (n = 2/14; 14.3%) (p=0.21). Of note, one further case (who did not have an MRI), with dPNH diagnosed upon neuropathological examination, also had partial corpus callosum agenesis on ultrasound. Infratentorial abnormalities were common and mainly consisted of increased fluid-filled space of the posterior fossa (i.e. megacisterna magna) (n = 17/29; 58.6%), mostly in dPNH (14/14; 100% versus 5/ 15; 33.3% in the non diffuse PNH (p < 10−4). By contrast, cerebellar hypoplasia/dysplasia (n = 3; 10.3%) were only observed in non-diffuse, aPNH or pPNH (p=0.22). Besides cerebral anomalies, no remarkable anomalies were reported, neither cardiac nor limb abnormalities that were systematically searched on US and MRI investigations. Imaging characteristics are summarized in Supplementary Table 2 and individual data are shown in Table 1. Out of eleven maternal brain MRI performed, three showed dPNH in three asymptomatic carrier mothers.

2.3. Outcome data After parental counseling and because of uncertain neurological prognosis, 24 parents (80%) decided to terminate the pregnancy in accordance to local laws at a mean gestation age of 32.6 weeks of gestation ( ± 2.8 weeks). Six children aged 6 months to 5 years are alive. Five have normal neurodevelopment (all were dPNH) whereas one developed developmental delay and epilepsy at the age of two years (pPNH). In case of TOP, fetopathological examination was performed in 21/ 24 cases (87.5%) and confirmed prenatal imaging findings in all cases. Remarkably, among the 10 female fetuses with dPNH, nodular heterotopia was also found lining the fourth ventricles in two cases. In the 15 non-diffuse PNH, cortical malformations observed on MRI were confirmed. Pathological exams also further refined cerebellar malformations, such as cerebellar dysplasia. The outcome of the 30 pregnancies is shown in the flow chart (Fig. 1).

2.2. Genetic analysis Standard karyotype was performed in all but 3 cases that were explored with array CGH. In one case, a deletion of 1.7 MB in 2p22.3 locus

Fig. 3. Selected fetal MRI aspect of non diffuse PNH. dPNH in a 30 GW female fetus (case 5) showing contiguous nodules lining all the ventricular walls of the lateral ventricles (white arrowheads) in FSE weighted T2 axial section (A) and coronal section (B). Sagittal images (C) show normal corpus callosum and enlargement of the fluid spaces of the posterior fossa. dPNH in a 35 GW female fetus (case 9) showing extensive and contiguous nodules lining all the ventricular walls of the lateral ventricles in FSE weighted T2 axial section (D) and coronal section (E). Coronal section also demonstrates dysmorphic and verticalized frontal horns, indirect sign of corpus callosum agenesis. Sagittal image (F) shows agenesis of the corpus callosum and enlargement of the fluid spaces of the posterior fossa with mega cisterna magna.

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Fig. 4. Selected fetal MRI aspect of non diffuse PNH. pPNH in 36 GW male fetus (case 23), showing focused mostly noncontiguous nodules, in FSE weighted T2 axial section (A) with abnormal gyral pattern in right parietal lobe (C). Sagittal image (B) shows thin corpus callosum and normal posterior fossa. Axial sections show moderately enlarged lateral ventricles (C). Non diffuse PNH of a 32 GW fetus (case 27) showing asymmetrical frontal horns (D, white arrow), non extensive and non contiguous nodules lining the walls of the occipital ventricles (E, white arrows), short and thin corpus callosum, vermian hypoplasia and megacisterna magna in sagittal Fast Spin Echo weighted T2 (F, black arrowhead), pPNH of a 30 GW male fetus (case 17) showing bilateral occipital non contiguous nodules, in FSE weighted T2 axial section (G) and coronal section (H). Note also the ventriculomegaly most prominent on right ventricle. Sagittal image (I) shows cerebellar hypoplasia but normal corpus callosum.

3. Discussion

mainly diagnosed on the follow up MRI performed due to another brain anomaly, such as ventriculomegaly or mega cisterna magna (Bargallo et al., 2002; Malinger et al., 2007; Mitchell et al., 2000). Indeed, MRI performs better than US because of higher tissue contrast though lower spatial resolution. Nevertheless, motion artifact as well the presence of the periventricular germinal matrix, which is prominent in early brain development and does not involute until the 26th week (Mitchell et al., 2000) and may hamper such diagnosis as one may face the potential difficulty of distinguishing subependymal heterotopic gray matter from normal germinal matrix on MRI images. In line with postnatal data, dPNH represent the most common group of PNH in prenatal diagnosis (Parrini et al., 2006). These cases are characterized by bilateral symmetric nodules lining the ventricles, especially the frontal horns and the anterior bodies, often diffuse and contiguous, often associated with mega cisterna magna(Parrini et al., 2006). This form of dPNH is predominantly observed in women, with FLNA mutations found in 80–100% familial cases (Parrini et al., 2006; Sheen et al., 2001) and 20–30% of sporadic females patients (Clapham et al., 2012; Fox et al., 1998; Guerrini et al., 2004; Parrini et al., 2006; Sheen et al., 2001). Consistently, in our series, dPNH were identified mainly in female fetuses, but also in one male. Of these, 3 were familial cases. FLNA mutations were found in all 3 familial cases and in 3/8 sporadic cases. Of note, no FLNA genomic rearrangements were detected on array CGH. A few males with unusual hemizygous mutations including distal truncating and hypomorphic missense mutations, and somatic mosaicism have been reported to survive past infancy.(Fergelot et al., 2012; Guerrini et al., 2004; Kasper et al., 2013; Oegema et al., 2013; Sheen et al., 2001). In our cohort, only one male patient was found with dPNH, contrasting with previous series in which males represented 44.9% patients of the cohort (Parrini et al., 2006). It is noteworthy that among these, only 7% were found to harbor FLNA mutations (Parrini et al., 2006).

Our data is of great importance as it offers new insights into the nosology of prenatally detected PNH that could improve prenatal counseling. Our study examined the imaging characteristics of 30 fetuses with PNH and allowed us to distinguish two distinct malformation groups: the diffuse and the non-diffuse either unilateral, anterior or posterior PNH, both with a different presentations. The overall information that can be drawn from this study is that (i) the ‘dPNH represents the most common homogeneous group of PNH, (ii) associated malformations of cortical development are more frequent in non-diffuse, either unilateral, aPNH or pPNH. The main difficulty with counseling for prenatal PNH is that diagnosis is performed late in pregnancy. Ultrasound (US) anomalies, if ever detected, usually appear in the third trimester as was found in our study (29. weeks ± 4.1 weeks) while heterotopia are formed early during brain development. Recent studies have emphasized the three main features suggestive of PNH on US: (i) a square shape of the frontal horns (ii) irregular outer borders of the lateral ventricles, (iii) periventricular intermediate echogenicity or hyperechoic nodules protruding into the ventricular lumen (Blondiaux et al., 2013). In agreement with previous studies (Blondiaux et al., 2013), we found that dysmorphic square shaped frontal horns are the most common presentation that leads to MRI (63.3%). The association with increased fluid spaces in the posterior fossa is an additional key diagnostic feature. This was more frequently found in our series than previously reported (73.3% versus 27.3%in previous report (Blondiaux et al., 2013)) and is usually associated with dPNH. However, our study highlights that antenatal US usually fails at picking up PNH even with detailed neuroscan in the context of other brain anomalies. Better knowledge of the main abnormal features reported in our study should allow higher detection rates at the time of US. In our study, as in previous reports, PNH were 5

6

31

37

30

30

32

42

36

36

28

33

36

19/F

20/F

21/F

22/F

23/M

24/F

25/M

26/F

27/M

28/M

39

15/F

18/F

40 25 26 29 40

10/F 11/F 12/F 13/F 14/F

29

26 30

8/M 9/F

17/M

22 33

6/F 7/F

30

27 31 30 26 34

1/F 2/M 3/F 4/F 5/F

16/F

Maternal Age

Case #

ND

ND

ND

ND

ND

ND

ND

ND

ND

Negative

ND

ND

Negative ND c.5184C > T (splice mutation) ND c.263_265delAGA (p. (Lys88Met89delinsMet)) c.1065+1G > A (splice mutation)* ND

ND ND Negative c.1021delA (p.(Thr341ProfsX10) c.2175_2176delCA (p.Asp725Glufs95)* Negative c.6710delG (p.Gly2237Glufs109) Negative Negative

FLNA Mutation

diffuse diffuse diffuse diffuse diffuse

diffuse diffuse diffuse diffuse diffuse

Bilateral anterior frontal Bilateral anterior frontal Bilateral Temporal and occipital Bilateral anterior frontal Bilateral anterior frontal Bilateral Temporal and occipital horns Bilateral anterior frontal

Unilateral temporal horn Bilateral Temporal and occipital horns Unilateral occipital horn Bilateral anterior frontal Unilateral occipital Bilateral diffuse

Bilateral diffuse

Bilateral Bilateral Bilateral Bilateral Bilateral

Bilateral diffuse Bilateral diffuse

Bilateral diffuse Bilateral diffuse

Bilateral Bilateral Bilateral Bilateral Bilateral

Subgroup PNH

MCM 12 mm MCM 11 mm MCM 12 mm MCM –

– – – > 12 mm 10–12 mm

29

33

30

32

27

36

33

25

28

32

34

– > 15 mm

34

36

–

–

27

–

–

36

–

33

36

–

MCM 8 mm

32

28

10–12 mm

10–12 mm

> 12 mm

10–12 mm

10–12 mm

> 12 mm

> 12 mm

33

33

30

33

33

30,1 34 30,2 34 ND

32 33

25 33

28 34 33 32 28

GA (week) at MRI

MRI

Vermian Dysplasia MCM 14 mm

– 10–12 mm

Cerebellar hypoplasia MCM

10–12 mm

28

34

MCM 11 mm

10–12 mm

MCM 14 mm

MCM

MCM MCM

– > 12 mm

> 12 mm

MCM MCM 12 mm

MCM 12 mm MCM 14 mm MCM MCM 11 mm MCM

Posterior fossa anomaly

10–12 mm 10–12 mm

– 10 mm 10 mm 10 mm 10 mm

Ventriculomegaly

33

N/A

22 32 24,8 32 22

26 22

26 N/A

28 33,6 33 N/A 28

GA (week) at US

US

Normal

Normal

Normal

Thick dysmorphic Normal

Partial Agenesis Thin

Normal

Hypoplasia

Normal

Normal

Normal

Normal

Normal

Normal Complete Agenesis Normal Hypoplasia Normal Normal

Normal Normal

Normal Normal Normal Normal Normal

Corpus callosum

–

Cortical Dysplasia

PMG-frontal SCZ

Hemispheric atrophy –

abnormal focal gyration Bilateral PMG

–

Posterior PMG

–

–

–

MCM

MCM

–

–

–

–

Cerebellar dysplasia MCM

Cerebellar dysplasia –

Cerebellar dysplasia

MCM

MCM

– abnormal focal gyration –

MCM MCM MCM MCM

– – – –

MCM MCM

MCM MCM

– – – –

MCM MCM MCM MCM MCM

Posterior fossa anomaly

– – – – –

Gyration anomaly

–

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

No

Y

Y

Y Y Y Y Y

Y Y

Y Y

No No No No No

TOP

(continued on next page)

ND

ND

ND

– Fœtal Macrosomy

ND

ND

ND

–

–

Microcephaly

ND

ND

ND

– occipital meningocele –

Normal

Macrocephaly

Normal

ND

–

–

ND

PNH

Normal Normal ND ND ND

Normal Normal

Normal Normal

ND ND ND PNH PNH

MRI

Parental

Macrocephaly

Macrocephaly

– – – –

– –

– –

– Macrocephaly – – –

Other findings

Table 1 Individual US and MRI Features on PNH. M male; F Female; PNH periventricular nodular heterotopia; - absent; PMG polymicrogyria; MCM megacisterna magna; NA Not available; ND Not Done; Y: Yes; N No; Mega Cisterna Magna was defined as enlargement of the cisterna magna greater than 10 mm * In two cases (5 and 15) the FLNA mutation was inherited from an affected mother. In other cases, mutations were de novo. The mutation c.5184C > T is predicted to give a splice site mutation (human splicing finder software).

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–

Megalencephaly

ND

Y

Other forms of PNH, either aPNH or pPNH or unilateral PNH, represent a significant group of PNH diagnosed prenatally, as these cases represent half of the cohort presented here. This group of PNH is heterogeneous but significantly associated with cortical malformations (60%). Of these, disorders secondary to abnormal neuronal organization (i.e PMG) were most frequently followed by disorders due to abnormal proliferation (mostly macrocephaly). They were found either with aPNH or pPNH. This finding contrasts with data on living patients, in which cortical malformations are particularly associated with bilateral pPNH (Gonzalez et al., 2013; Mandelstam et al., 2013; Parrini et al., 2006). Macrocephaly was also associated either with aPNH or pPNH with PMG. Finally, cerebellar hypoplasia was found in two cases with PNH. Rather than discrete subtypes of malformations, our data suggest that “non diffuse” PNH encompass a continuum of brain malformations often resulting from abnormal neurogenesis, neuronal migration or organization. One of the most challenging issues in the prenatal counseling of PNH is the prediction of neurological outcome. Most patients with dPNH have normal intelligence or only mild intellectual disability, although some patients with dyslexia have been reported (Chang et al., 2005). They often develop seizures, which vary considerably in severity and age at onset (Parrini et al., 2006; Sole et al., 2009). Behavioural and psychiatric comorbidities including depression, anxiety, attention deficit hyperactivity disorder, schizophrenia and autism have been reported in PNH patients (Fry et al., 2013). Moreover, when associated with FLNA mutations, PNH can be associated with extra-cerebral features, such as patent ductus arteriosus, mitral or aortic valvular abnormalities to coarctation of the aorta, and ascending aorta aneurysm (de Wit et al., 2009, 2011a; Kyndt et al., 2007)a propensity for premature stroke, coagulopathy, thrombocytopenia, small joint hyperextensibility, Ehlers-Danlos syndrome, gut dysmotility and severe congenital lung disease comprising bilateral atelectasis, lung cysts, tracheobronchomalacia, pulmonary arterial hypertension and longterm oxygen dependence (de Wit et al., 2011b; Masurel-Paulet et al., 2011; Sheen and Walsh, 2005). These extracerebral symptoms may alter the prognostic of the disorder and compromise the quality of life of patients, although most cannot be predicted prenatally. Normal neurodevelopmental outcome is also associated with isolated or scattered subependymal gray matter heterotopia which represent one of the main incidental findings in the general pediatric population 0.4% of healthy children (Jansen et al., 2017). By contrast, non-diffuse PNH are often associated with poor neurodevelopmental outcome, epileptic encephalopathy and in some cases, with polymalformative syndromes (Guerrini et al., 2004; Parrini et al., 2004). To our knowledge, this is the largest series published thus far of periventricular nodular heterotopia recognized in utero. We do, however, acknowledge the limitations of our study, which are similar to those commonly encountered in clinical series of prenatal diagnosis of abnormal cerebral findings. Twenty-four (80%) pregnancies with PNH diagnosed in utero were terminated and of these 10 (30%) with dPNH, despite having been acknowledged to have a better outcome. Moreover, among the living patients, the postnatal assessment of survivors was performed by the attending pediatricians with no standardized protocol. Another limitation of our study is the lack of extensive genetic analyses in the earlier cases that were managed before the availability of array CGH and FLNA sequencing in routine practice. However, this does not weaken the most important finding that two distinct groups of PNH should be differentiated in the fetal period with the help of targeted US and MRI examination: the classical being mostly associated with a better neurological outcome and the non-diffuse with a more severe outcome. Finally, the retrospective nature of this study with a wide variety of imaging protocols and GA at evaluation did not allow a comprehensive evaluation of all brain structures in every fetus. Nevertheless, the large number of fetal cases presented here provides results that can optimize prenatal counseling for PNH.

31,4 – > 12 mm 32

24

25 30/M

Negative

Bilateral anterior frontal Bilateral anterior frontal ND 28 29/F

GA (week) at US

–

33

GA (week) at MRI

–

Thick dysmorphic Hypoplasia

Bilateral PMG

Y – Perisylvian PMG

–

Posterior fossa anomaly Gyration anomaly Corpus callosum MRI Posterior fossa anomaly Ventriculomegaly US Subgroup PNH FLNA Mutation Maternal Age Case #

Table 1 (continued)

ND

MRI

Other findings

Parental

TOP

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7

GA (weeks) at TOP

26,8 35

33,2

31

31 NA 23 34,6

35 35 35

NA 35 35 29

36 34,3 35

34

33

Case

6 9

10

11

12 13 14 15

16 18 19 20 21 22 23 24,

8

25 26 27

29

30

Bilateral anterior frontal

Unilateral temporal Unilateral occipital Bilateral anterior frontal Unilateral occipital Diffuse Bilateral anterior frontal Bilateral anterior frontal Bilateral Temporal and occipital Bilateral anterior frontal Bilateral anterior frontal Bilateral Temporal and occipital Bilateral anterior frontal

Diffuse Diffuse Diffuse Diffuse

Diffuse

Diffuse

Diffuse Diffuse

PNH

Thin

Thick

– Y

Thin Normal Normal

Normal Normal Normal Hypoplasia Normal Partial Agenesis Thick Thin

Y Y Mod

Mild – Mod Mod Y Y – Y

– Y Mod Y

Hypoplasia Septal Agenesis Normal Normal Partial Agenesis Normal

Normal

– Mod

Normal Complete Agenesis

Corpus Callosum

Mod Mod Colpocephaly

Ventriculomegaly

Normal MCM Cerebellar Vermian and Hemispheric dysplasia

Pachygyria Frontal PMG-SCZ Cortical dysplasia Frontal and Perisylvian PMG Bilateral PMG

Normal

Normal

MCM MCM Normal Vermian Dysplasia MCM Normal Normal Normal

Focal Temporal PMG Normal Normal Temporo-occipital PMG Normal Focal Frontal PMG Bilateral PMG Hemispheric atrophy

Normal

Normal

Normal Normal Normal Normal

Posterior Fossa Anomalies

Normal Nodular Heterotopia (at the level of the 4th V and cerebellar hemispheres) MCM Nodular Heterotopia (at the level of the 4th V) Nodular Heterotopia (at the level of the 4th V and cerebellar hemispheres) MCM MCM Normal MCM

Normal Normal

Gyration

–

–

– – –

Macrocephaly – – Diaphragmatic hernia, Pulmonary hypoplasia, adrenal hyperplasia and hyperplasia of Islets of Langerhans Macrocephaly – Macrocephaly – Occipital Encephalocele – – –

–

–

– –

Other findings

Table 2 Neuropathological Studies in patients with PNH. Y Yes; N No; ND Not Done; NA Not Available; - Absent; Mod.: Moderate; in bold are figured the 3 cortical malformation not diagnosed on MRI, but suspected; PMG: Polymicrogyria; SCZ: schizencephaly For cases 7, 8 and 28, No neuropathological examination was performed.

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4. Conclusion

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Our observations emphasize the importance to distinguish two groups of PNH, dPNH classical and “non diffuse” either aPNH, pPNH and unilateral PNH non classical for the prenatal counseling. Mildly enlarged and square shaped irregular frontal horns and bodies of the lateral ventricles, together with megacisterna magna are key features often associated with dPNH. Our results suggest that dPNH can be associated with good early developmental outcome, particularly in female fetuses with maternally-inherited FLNA mutations. In contrast, patients with non-diffuse forms of PNH (aPNH, pPNH or unilateral PNH) are more likely to have other brain anomalies affecting either the corpus callosum or gyration pattern which may have implications for developmental outcome. Acknowledgments We are grateful for the contribution of the fetopathologists: Maryse Marcy-Bonnière, Anne-Lise Delezoide, Philippe Gosset, Fabien Guimiot, Philippe Loget, Jelena Martinovich, to this work. We would like to thank Tania Attie-Bitach, Edith Andrini, Aude Fleurier, Agnes Guet, Valerie Malan, Philippe Parent, Marlene Rio Jonathan Rosenblatt who have volunteered their time to provide clinical data and imaging to participate in the research to make this article possible. The research leading to these results has received funding from the European Union Seventh Framework Program FP7/2007-2013 under the project DESIRE (grant agreement n°602531). Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.ejmg.2018.10.015. References Bargallo, N., Puerto, B., De Juan, C., Martinez-Crespo, J.M., Lourdes Olondo, M., 2002. Hereditary subependymal heterotopia associated with mega cisterna magna: antenatal diagnosis with magnetic resonance imaging. Ultrasound Obstet. Gynecol. 20 (1), 86–89. Barkovich, A.J., Guerrini, R., Kuzniecky, R.I., Jackson, G.D., Dobyns, W.B., 2012. A developmental and genetic classification for malformations of cortical development: update 2012. Brain 135 (Pt 5), 1348–1369. Barkovich, A.J., Kuzniecky, R.I., Dobyns, W.B., Jackson, G.D., Becker, L.E., Evrard, P., 1996. A classification scheme for malformations of cortical development. Neuropediatrics 27 (2), 59–63. Barkovich, A.J., Kuzniecky, R.I., Jackson, G.D., Guerrini, R., Dobyns, W.B., 2005. A developmental and genetic classification for malformations of cortical development. Neurology 65 (12), 1873–1887. Barth, P.G., van der Harten, J.J., 1985. Parabiotic twin syndrome with topical isocortical disruption and gastroschisis. Acta Neuropathol. 67 (3–4), 345–349. Blondiaux, E., Sileo, C., Nahama-Allouche, C., Moutard, M.L., Gelot, A., Jouannic, J.M., Ducou le Pointe, H., Garel, C., 2013. Periventricular nodular heterotopia on prenatal ultrasound and magnetic resonance imaging. Ultrasound Obstet. Gynecol. 42 (2), 149–155. Broix, L., Jagline, H., E, L.I., Schmucker, S., Drouot, N., Clayton-Smith, J., Pagnamenta, A.T., Metcalfe, K.A., Isidor, B., Louvier, U.W., Poduri, A., Taylor, J.C., Tilly, P., Poirier, K., Saillour, Y., Lebrun, N., Stemmelen, T., Rudolf, G., Muraca, G., Saintpierre, B., Elmorjani, A., Deciphering Developmental Disorders, s., Moise, M., Weirauch, N.B., Guerrini, R., Boland, A., Olaso, R., Masson, C., Tripathy, R., Keays, D., Beldjord, C., Nguyen, L., Godin, J., Kini, U., Nischke, P., Deleuze, J.F., BahiBuisson, N., Sumara, I., Hinckelmann, M.V., Chelly, J., 2016. Mutations in the HECT domain of NEDD4L lead to AKT-mTOR pathway deregulation and cause periventricular nodular heterotopia. Nat. Genet. 48 (11), 1349–1358. Cappello, S., 2013. Small Rho-GTPases and cortical malformations: fine-tuning the cytoskeleton stability. Small GTPases 4 (1), 51–56. Cardoso, C., Boys, A., Parrini, E., Mignon-Ravix, C., McMahon, J.M., Khantane, S., Bertini, E., Pallesi, E., Missirian, C., Zuffardi, O., Novara, F., Villard, L., Giglio, S., Chabrol, B., Slater, H.R., Moncla, A., Scheffer, I.E., Guerrini, R., 2009. Periventricular heterotopia, mental retardation, and epilepsy associated with 5q14.3-q15 deletion. Neurology 72 (9), 784–792. Cellini, E., Disciglio, V., Novara, F., Barkovich, J.A., Mencarelli, M.A., Hayek, J., Renieri, A., Zuffardi, O., Guerrini, R., 2012. Periventricular heterotopia with white matter abnormalities associated with 6p25 deletion. Am. J. Med. Genet. 158A (7), 1793–1797. Chang, B.S., Ly, J., Appignani, B., Bodell, A., Apse, K.A., Ravenscroft, R.S., Sheen, V.L.,

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