European Journal of Medical Genetics 57 (2014) 32e36

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Short clinical report

Cerebro-fronto-facial syndrome type 3 with polymicrogyria: A clinical presentation of BaraitsereWinter syndrome Hatice Koçak Eker a, *, Betül Emine Derinkuyu b, Sevim Ünal c, Julien Masliah-Planchon d, e, Séverine Drunat d, e, Alain Verloes d, e , Ankara Pediatric Health and Diseases Hematology Oncology Education and Research Hospital, Department of Medical Genetics, Dıs¸kapı, Altındag 06110 Ankara, Turkey b Ankara Pediatric Health and Diseases Hematology Oncology Education and Research Hospital, Department of Radiology, Ankara, Turkey c Ankara Pediatric Health and Diseases Hematology Oncology Education and Research Hospital, Department of Neonatology, Ankara, Turkey d Department of Medical Genetics, APHP-Robert DEBRE University Hospital, Paris VII-Denis Diderot Medical School, Paris, France e INSERM U676, Paris, France a

a r t i c l e i n f o

a b s t r a c t

Article history: Received 20 May 2013 Accepted 21 October 2013 Available online 7 November 2013

BaraitsereWinter syndrome (BRWS) is a rare condition affecting the development of the brain and the face. The most common characteristics are unusual facial appearance including hypertelorism and ptosis, ocular colobomas, hearing loss, impaired neuronal migration and intellectual disability. BRWS is caused by mutations in the ACTB and ACTG1 genes. Cerebro-fronto-facial syndrome (CFFS) is a clinically heterogeneous condition with distinct facial dysmorphism, and brain abnormalities. Three subtypes are identified. We report a female infant with striking facial features and brain anomalies (included polymicrogyria) that fit into the spectrum of the CFFS type 3 (CFFS3). She also had minor anomalies on her hands and feet, heart and kidney malformations, and recurrent infections. DNA investigations revealed c.586C>T mutation (p.Arg196Cys) in ACTB. This mutation places this patient in the spectrum of BRWS. The same mutation has been detected in a polymicrogyric patient reported previously in literature. We expand the malformation spectrum of BRWS/CFFS3, and present preliminary findings for phenotype egenotype correlation in this spectrum. Ó 2013 Elsevier Masson SAS. All rights reserved.

Keywords: Cerebro-fronto-facial syndrome BaraitsereWinter syndrome ACTB Polymicrogyria

1. Introduction BaraitsereWinter syndrome (BRWS) is a well-delineated syndrome characterized by typical dysmorphic features (trigonocephaly, hypertelorism and congenital ptosis, high-arched eyebrows, wide nasal bridge, long philtrum, thin upper lip, pointed chin, ear anomalies), specific pattern of brain malformations (predominantly anterior neuronal migration defects), ocular coloboma, short-webbed neck, postnatal short stature and hearing loss [1,2]. Head circumference tends to develop to microcephaly during infancy. The brain anomalies can result intellectual disability, developmental delay, and intractable seizures [3]. BRWS is caused by de novo missense mutations in the ACTB and ACTG1 genes [4]. After studying several reports, Winter [5] suggested that all these cases have the same syndrome, which he called it as cerebrofronto-facial syndromes. Three types were identified according to neuroimaging findings. The six patients with cerebro-fronto-facial * Corresponding author. Tel.: þ90 312 5969600; fax: þ90 312 3472330. E-mail address: [email protected] (H.K. Eker). 1769-7212/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmg.2013.10.005

syndrome type 3 (CFFS3) had frontal agyriaepachygyria or polymicrogyria (Table 1). Coarse traits, hypertelorism, congenital ptosis, macroblepharon, arched eyebrows, broad nasal root and bridge, long philtrum, macrostomia, thin upper lip, high arched palate, micrognathia, low-set and posteriorly rotated ears with abnormal pinnae, and short-webbed neck are the characteristic traits of CFFS3. Mental retardation, trigonocephaly, loose skin, bifid thumbs or halluces, limitation of movement in large joints, narrow thorax with dysplastic nipples, and genitourinary anomalies were also described [6e13]. Patients with CFFS3 were also reported under the name of FrynseAftimos syndrome (FrAS). Despite the resemblance for facial features and cortical malformations, BRWS and CFFS3 were considered separately, till the identification of mutations in ACTB in some patients originally diagnosed as FrAS or CFFS3 [4,14]. Indeed, CFFS3 patients were usually reported at an older age than BRWS. So Rivière et al. [4] suggested that CFFS3 represents the aged phenotype of BRWS. Furthermore Di Donato et al. [14] offered that CFFS3 could also be an early and severe presentation within the BRWS spectrum.

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Table 1 The brain malformations of patients with CFFS type 3. Patients

Brain anomalies

Guion-Almeida et al., 1992 [6] (CT)

Diffuse cortical atrophy associated with agenesis of the corpus callosum Wide 3rd ventricle Frontonasal dysostosis, etc Hypoplastic corpus callosum

Guion-Almeida et al., 2001 [7] (MRI) Masuno et al., 2000 [8] (MRI) Fryns and Aftimos, 2000 [9] (MRI and CT) Der Kaloustian et al., 2001 [10] (MRI) Milunsky and Capin, 2003 [11] (MRI) Forzano et al., 2004 [12] Valente et al., 2005 [13] (MRI)

Present case (MRI)

Structural anomaly of the corpus callosum Dilatation of the fourth ventricle Frontal pachygyria (both of two unrelated patients) Frontal polymicrogyria (revised by Valente et al. [13]) Frontal pachygyria with thickened cortical mantle Not performed Diffuse pachygyria (polymicrogyric cortex was not ruled out) Dysmorphic ventricles Hypoplastic corpus callosum, etc Frontal polymicrogyria, Hypoplastic corpus callosum, Periventricular heterotopia

CT: Computed Tomography, MRI: Magnetic Resonance Imaging.

2. Clinical report This female neonate was the fifth child of G5-P5-A0 27-year-old healthy mother and 36-year-old healthy father, originating from a small Anatolian village. It wasn’t present a consanguinity between the parents. Her elder sibs were clinically normal. The similar cases were not declared in her family history. The pregnancy was uncomplicated, but fetal ultrasound scan revealed bilateral duplication of the renal pelves, and renal malposition. The delivery was vaginal, at term. Birth weight was 2500 g (1.6 SD), length 43 cm (3.6 SD), head circumference 33.5 cm (0.8 SD), and chest circumference 26 cm (>97th centile), and macroblepharon (palpebral fissure length 25 mm, >95th centile) (Fig. 1A, B). She had wide anterior fontanel (3  3 cm), high frontal hairline, widow’s peak, thick and edematous eyelids, infra-orbital creases, broad nose with wide bridge and broad tip, anteverted nares, long philtrum, thin upper lip with inverted vermillion border, high-narrow palate, flat malar region, microretrognathia, arched eyebrows with medial

Fig. 2. Narrow thorax, wide spaced, hypoplastic and inverted nipples.

hypoplasia, and absence of the medial part of the upper eyelashes. Her ears were low set, posteriorly rotated with thick antihelices, and uplifted ear lobules. The neck was webbed with redundant skinfolds. The thorax was narrow with wide spaced, hypoplastic and inverted nipples (Fig. 2). She further had clubbing of thumbnails, bilateral clinodactyly, hallux varus, sandal gap of toes, and hypoplastic toenails (Fig. 3). External genitalia were normal. Ultrasound scan showed bilateral ureterohydronephrosis, bilateral bifid renal pelves and positional anomaly of the left kidney, which was rotated posteriorly in the vertical plan. Echocardiography revealed right pulmonary veins draining into the superior vena cava (PAPVR; partial anomalous pulmonary venous return), atrial septal defect (ASD), patent ductus arteriosus (PDA), signs of mild pulmonary hypertension and tricuspid insufficiency. Brain magnetic resonance imaging (MRI) taken when she was two weeks old (Figs. 4 and 5) was not optimal due to incomplete myelination, but showed frontal polymicrogyria (cortical thickening, small irregular gyri and indistinct cortical-white matter junction), hypoplasia of the posterior part of corpus callosum, and two nodules of heterotopic gray matter in the periventricular and subependymal regions, one adjacent to the corpus of left ventricular wall and the other adjacent to the atrium of right ventricular wall. The baby was hypotonic, with diminished archaic reflexes. X-ray skeletal survey was normal. Ophthalmologic evaluation, including fundi, was normal. She was successfully treated with digoxin and diuretics and discharged home on the 24th day, but was hospitalized again twice at 3.5 and 5.5 months of age for recurrent

Fig. 1. Craniofacial dysmorphism at the age of 2-weeks. (A) Front view and (B) Lateral view (Photograph is published with consent).

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Fig. 3. Note the hallux varus, sandal gap of toes, hypoplastic toenails.

respiratory tract infections, pneumonia and sepsis. She suffered from chronic heart failure, and acute prerenal failure requiring temporary peritoneal dialysis. At 5.5 months of age, her weight was 2900 g (5.3 SD), length 50 cm (6.4 SD) and head circumference 36 cm (5 SD) [15]. She had neurodevelopmental and growth failure, generalized hypotonia, no head control and increased deep tendon reflexes. She died at home when she was 8 month-old. The family informed us that she had urinary infection treated with antibiotics few days before her death. Chromosome analysis revealed a normal 46,XX karyotype. Genomic analysis with Human Genome CGH Microarray 105A Kit (Agilent TechnologiesÒ) revealed no pathogenic mutation. Direct sequencing of ACTG1 and ACTB genes disclosed the recurrent c.586C>T mutation (p.Arg196Cys) in ACTB. The mutation was predicted to be pathogenic by several prediction softwares (PolyPhen II, SWIFT) and has already been reported in two other patients with BRWS [4,14]. Parental DNA was not available for testing. 3. Discussion We present a new born baby girl with many signs, especially facial appearance and characteristic brain MRI findings, pointing to the diagnosis of CFFS3. According to Winter’s classification [5]; the patients with periventricular nodular heterotopia were classified in

group I, patients with cystic dilatation on VirchoweRobin spaces in group II, and patients with agyriaepachygyria with agenesis of the corpus callosum, or the absence of periventricular nodular heterotopia or cystic areas of the brain in group III. Polymicrogyria is also reported in one patient who was classified in CFFS3 (Table 1). Periventricular nodular heterotopia has not been reported in association with polymicrogyria in CFFS. Our patient had frontal polymicrogyria, two nodules in the periventricular region, and hypoplastic corpus callosum, indicating that partition between group I and III may be clinically irrelevant. We diagnosed clinically our patient as CFFS3, based on the apparent pre-eminence of cortical anomalies. When ACTB and ACTG1 genes were shown to be responsible of BRWS and FrAS [4,14], we checked whether our patient could be linked to this spectrum. Indeed, molecular studies revealed a mutation in ACTB gene that has been already associated with BRWS/CFFS3 [4,14]. We compare these three cases in Table 2. The characteristics of the 10 patients clinically identified as CFFS3 or FrAS are summarized in Table 1 and Table S1 (Supplementary data). The brain anomalies are related to impaired neuronal migration and predominate on anterior areas. Coexistence of polymicrogyria and periventricular/subependymal nodular heterotopia has not been described before, even though subependymal heterotopia together with pachygyria has been reported [14]. Ramer et al. [2] described polymicrogyric areas associated with incomplete subcortical band heterotopia in one patient. However the patient also carried an inv2(p12q14). Intellectual disability and developmental delay ranges from mild to severe, and correlates with the severity of these structural changes. The present case had severe anomalies that may account for the severe delay of her developmental milestones. Seizures are usually absent in neonatal period, starts afterward [3,9e11,13,14]. Head circumference is generally normal at birth, and gradually decreases towards microcephaly as seen in our patient. Restricted movements of the large joints, mild spasticity, disordered posture, behavioral problems and seizures becomes more prominent with aging, and face tends to be coarser after infancy [9e13]. Ear abnormalities are common, and usually in form of small, low-set and/or posteriorly rotated with abnormal pinnae. Hearing loss may be late onset and/or progressive [2e4,10]. Our patient has some unreported findings. Although cardiac involvement has been reported [12,14,16], PAPVR has never been described before. Medial eyebrow hypoplasia and absence of the medial upper eyelashes have not been reported before, although two patients were reported with middle third absent eyelashes

Fig. 4. Cranial T2-weighted MRI: axial planes. In the unmyelinated brain, two nodular heterotopic gray matter in periventricular/subependymal region. a: Adjacent to the atrium of right ventricular wall (arrowhead). b: Adjacent to the body of left ventricular wall (arrowhead).

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Figure 5. a: Cranial T2-weighted MRI: axial plane. Bilateral frontal polymycrogyria characterized with cortical thickening, small irregular gyri and indistinct cortical-white matter junction. b: Cranial T1-weighted MRI: sagittal plane. In the unmyelinated brain corpus callosum was hypoplastic in corpus posterior region (arrowhead).

[6,7]. Mild extremity anomalies have also been rarely described [3]. The patient reported by Der Kaloustian et al. [10] had broad thumbs, incomplete duplication of the low-implanted hallux, and metatarsus varus. Several skeletal malformations have been defined such as narrow shoulder, narrow/broad thorax, thoracic asymmetry, pectus anomalies, scoliosis, rib and/or vertebral abnormalities [2,3,6,7,9e14]. The severity of growth retardation is unusual in our case, but her poor health, with renal and cardiac compromises, might have played a major role. Our patient had recurrent infections. Frequent upper airway or urinary infections, chronic rhinorrhea and diarrhea were noted in some patients [3,10]. ACTB mutations may indeed affect motility or chemotactic defect [17]. Recurrent infections could be a feature of BRWS spectrum. Indeed, severe immunodeficiency was reported in

a child with intellectual deficiency and short stature [17,18] carrying a heterozygous mutation (p.Glu364Lys) in ACTB, but her phenotype was not otherwise described and we don’t know if she would have fitted BRWS or CFFS3 later on. ACTB mutations cause CFFS3 by a gain-of-function or dominant negative mechanism [4]. Rivière et al. [4] suggested that the patients carrying mutations in ACTB or ACTG1 gene have no significantly differences in their clinical presentation, but this has later been challenged by Di Donato et al. [14] who compared two children carrying the same aminoacid change in either gene. Severe cardiac and renal involvement on the present case appears to support the latter authors. According to Johnston et al. [19], the absolute quantity of the normal b-actin against mutant ones in a specific cell and the ACTB:ACTG1 ratio may both determine the

Table 2 Comparison of clinical features in patients with p.Arg196Cys mutation in ACTB gene. Gender

Patient 61456 (Rivière et al. [4])

Patient 3 (Di Donato et al. [14])a

Present case

M

M

F

e n.a.

þ þ

þ þ

n.a. n.a. þ

þ þ þ

þ e e

Growth Short stature Microcephaly Neurological ID/DD Hearing loss Seizures Facial dysmorphism Trigonocephaly Hypertelorism High-arched eyebrows Ptosis Eyes Coloboma Hair

þ þ þ þ

þ þ þ þ

e þ þ e

e n.a.

e Absent axillary hair

Renal anomaly

n.a.

Recurrent infections Neuronal migration disorder

n.a. Pachygyria only a > p

Bilateral hydronephrosis, duplication of the right collecting system þ Frontal polymicrogyriab

e Medial hypoplasia of eyebrows absent medial upper eyelashes Bilateral hydroureteronephrosis, bilateral bifid renal pelves, positional anomaly of the left kidney þ Frontal polymicrogyria, hypoplastic corpus callosum, periventricular heterotopia

M: male. F: female. þ: present. : absent. n.a.:data not available. ID: intellectual disability. DD: developmental delay. Gradient a > p: anterior greater than posterior lissencephaly. a Originally reported by Der Kaloustian et al. [10]. b Revised by Valente et al. [13], and also reported by Rivière et al. [4].

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phenotypic effects, as ACTB and ACTG1 are available at different rates in different cell types. We compared in Table 2 the three patients carrying the same c.586C>T (p.Arg196Cys) mutation. Lack of coloboma and the similarity in urinary system abnormalities such as hydronephrosis, duplication of the collecting system, or presence of recurrent infections, hair deficiencies, frontal polymicrogyria in two out of three patients (Table 2) may indicate more subtle genotype phenotype correlations, with penetrance of cardinal signs that could be mutation-dependant. In conclusion, we suggest that polymicrogyria, absence of eyelashes, eyebrow hypoplasia and sensitivity to infection (possibly due to neutrophil dysfunction) may be new features of BRWS/ CFFS3 spectrum. Furthermore, clinical consistency between the three c.586C>T cases may point to some phenotypeegenotype correlations. Further cases will be necessary to confirm these early findings. Acknowledgment We thank the reviewers for their contributions to this article. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.ejmg.2013.10.005. References [1] M. Baraitser, R.M. Winter, Iris coloboma, ptosis, hypertelorism, and mental retardation: a new syndrome, J. Med. Genet. 25 (1988) 41e43. [2] J.C. Ramer, A.E. Lin, W.B. Dobyns, et al., Previously apparently undescribed syndrome: shallow orbits, ptosis, coloboma, trigonocephaly, gyral malformations, and mental and growth retardation, Am. J. Med. Genet. 57 (1995) 403e409. [3] M. Rossi, R. Guerrini, W.B. Dobyns, et al., Characterization of brain malformations in the BaraitsereWinter syndrome and review of the literature, Neuropediatrics 34 (2003) 287e292.

[4] J.B. Rivière, B.W. van Bon, A. Hoischen, et al., De novo mutations in the actin genes ACTB and ACTG1 cause BaraitsereWinter syndrome, Nat. Genet. 44 (2012) 440e444. S1e2. [5] R.M. Winter, Cerebro-fronto-facial syndrome: three types? Clin. Dysmorphol. 10 (2) (2001) 79e80. [6] M.L. Guion-Almeida, A. Richieri-Costa, Acrocallosal syndrome: report of a Brazilian girl, Am. J. Med. Genet. 43 (1992) 938e941. [7] M.L. Guion-Almeida, A. Richieri-Costa, Frontonasal dysplasia, macroblepharon, eyelid colobomas, ear anomalies, macrostomia, mental retardation and CNS structural anomalies: defining the phenotype, Clin. Dysmorphol. 10 (2001) 81e86. [8] M. Masuno, K. Imaizumi, N. Aida, et al., Frontonasal dysplasia, macroblepharon, eyelid colobomas, ear anomalies, macrostomia, mental retardation, and CNS structural anomalies: another observation, Clin. Dysmorphol. 9 (2000) 59e60. [9] J.P. Fryns, S. Aftimos, New MCA/MR syndrome with distinct facial appearance and general habitus, broad and webbed neck, hypoplastic inverted nipples, epilepsy and pachygyria of the frontal lobes, J. Med. Genet. 37 (2000) 460e 462. [10] V.M. Der Kaloustian, M. Pelletier, T. Costa, et al., A new syndrome with craniofacial and skeletal dysmorphisms and developmental delay, Clin. Dysmorphol. 10 (2001) 87e93. [11] J.M. Milunsky, D.M. Capin, Cerebro-oculo-facial-lymphatic syndrome, Clin. Genet. 63 (2003) 1e6. [12] F. Forzano, F. Faravelli, M. Di Rocco, Cerebro-fronto-facial syndrome: report of a further case, Clin. Dysmorphol. 13 (2) (2004) 121e122. [13] K.S. Valente, S. De Vincentiis, M. Valente, Severe epilepsy and pachygyria associated with peculiar facial traits characterize FrynseAftimos syndrome, J. Child Neurol. 20 (2005) 160e163. [14] N. Di Donato, A. Rump, R. Koenig, et al., Severe forms of BaraitsereWinter syndrome are caused by ACTB mutations rather than ACTG1 mutations, Eur. J. Hum. Genet. (2013 Jun 12), http://dx.doi.org/10.1038/ejhg.2013.130. [15] O. Neyzi, H. Günöz, H. Furman, et al., Body weight, height, head circumference and body mass index reference values, in Turkish children, Turk. J. Pediatr. 51 (2008). [16] J.P. Fryns, Previously apparently undescribed syndrome: shallow orbits, ptosis, coloboma, trigonocephaly, gyral malformations, and mental and growth retardation, Am. J. Med. Genet. 64 (1996) 521e522. [17] H. Nunoi, T. Yamazaki, S. Kanegasaki, Neutrophil cytoskeletal disease, Int. J. Hematol. 74 (2001) 119e124. [18] H. Nunoi, T. Yamazaki, H. Tsuchiya, et al., A heterozygous mutation of betaactin associated with neutrophil dysfunction and recurrent infection, Proc. Natl. Acad. Sci. U. S. A. 96 (1999) 8693e8698. [19] J.J. Johnston, K.K. Wen, K. Keppler-Noreuil, et al., Functional analysis of a de novo ACTB mutation in a patient with atypical BaraitsereWinter syndrome, Hum. Mutat. 34 (2013) 1242e1249.

Cerebro-fronto-facial syndrome type 3 with polymicrogyria: a clinical presentation of Baraitser-Winter syndrome.

Baraitser-Winter syndrome (BRWS) is a rare condition affecting the development of the brain and the face. The most common characteristics are unusual ...
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