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Prenatal diagnosis of frontonasal dysplasia with anterior encephalocele

April 2013
Journal of the Turkish German Gynecology Association 14(1):50-2

April 2013
14(1):50-2

DOI:10.5152/jtgga.2013.12

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PubMed

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CC BY-NC-ND

Authors:

Hülya Kayserili

Koc University

Atil Yuksel

İstanbul University, İstanbul Medical School, İstanbul, Türkiye

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Frontonasal dysplasia is a rare congenital anomaly affecting the eyes, nose and forehead, and occurs sporadically in most of the cases. A 24-year-old woman was referred to our unit at 27 weeks gestation due to the preliminary diagnosis of encephalocele. The sagittal and axial sonography of the fetal face depicted a midline mass measuring 3.8 × 4.2 cm, projecting anteriorly between the fetal orbits and extending from the the upper aspects of the forehead to the nasal bridge, which was consistent with the frontal (anterior) encephalocele. There were prominent hypertelorism and two facial clefts, and the nostrils were extremely separated. Following genetic counseling, the couple requested termination of pregnancy. Fetal pathologic examination confirmed the diagnosis of frontonasal dysplasia and anterior encephalocele with no additional major malformation. The fetal karyotype was normal and no mutation in the ALX1 gene was found, excluding ALX1-related frontonasal dysplasia in the differential diagnosis. Fetuses with neural tube defect may suffer from associated syndromes and disorders, as with our case. The presence of frontonasal dyplasia should be considered when an anterior encephalocele is detected by ultrasonography.

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Prenatal diagnosis of frontonasal dysplasia with

anterior encephalocele

Anterior ensefaloselin eşlik ettiği frontonazal displazinin prenatal tanısı

Aytul Çorbacıoğlu Esmer1, İbrahim Kalelioğlu1, Hülya Kayserili2, Atıl Yüksel1, Recep Has1

1Department of Obstetrics and Gynecology, İstanbul University İstanbul Faculty of Medicine, İstanbul, Turkey

2Department of Medical Genetics, İstanbul University İstanbul Faculty of Medicine, İstanbul, Turkey

Address for Correspondence:

Aytul Çorbacıoğlu Esmer , Department of Obstetrics and Gynecology, İstanbul University İstanbul Faculty of Medicine, İstanbul, Turkey

Phone: +90 542 311 92 40 e.mail: aytulcorbacioglu@gmail.com

doi:10.5152/jtgga.2013.12

Frontonasal dysplasia is a rare congenital anomaly affecting the eyes,

nose and forehead, and occurs sporadically in most of the cases. A

24-year-old woman was referred to our unit at 27 weeks gestation due

to the preliminary diagnosis of encephalocele. The sagittal and axial

sonography of the fetal face depicted a midline mass measuring 3.8

x 4.2 cm, projecting anteriorly between the fetal orbits and extending

from the the upper aspects of the forehead to the nasal bridge, which

was consistent with the frontal (anterior) encephalocele. There were

prominent hypertelorism and two facial clefts, and the nostrils were

extremely separated. Following genetic counseling, the couple re-

quested termination of pregnancy. Fetal pathologic examination con-

firmed the diagnosis of frontonasal dysplasia and anterior encepha-

locele with no additional major malformation. The fetal karyotype

was normal and no mutation in the ALX1 gene was found, excluding

ALX1-related frontonasal dysplasia in the differential diagnosis. Fe-

tuses with neural tube defect may suffer from associated syndromes

and disorders, as with our case. The presence of frontonasal dyplasia

should be considered when an anterior encephalocele is detected

by ultrasonography. (J Turkish-German Gynecol Assoc 2013; 14: 50-2)

Key words: Frontonasal dysplasia, anterior encephalocele, prenatal

diagnosis, ultrasound, congenital anomaly

Received: 30 July, 2012 Accepted: 22 August, 2012

Frontonazal displazi gözleri, burnu ve alnı etkileyen nadir bir konjeni-

tal anomalidir ve çoğunlukla sporadik olarak meydana gelir. 24 yaşın-

daki bir kadın 27. gestasyonel haftada ensefalosel ön tanısıyla kliniği-

mize refere edildi. Fetal yüzün sagital ve aksiyal ultrason kesitlerinde

3.8 x 4.2 cm büyüklüğünde, fetal orbitaların arasından öne doğru bir

çıkıntı oluşturan ve alnın üst kısmından burun köküne kadar uzanan

frontal (anterior) ensefalosel ile uyumlu orta hat yerleşimli bir kitle

saptandı. Belirgin hipertelorizm ve iki tane fasiyal kleft mevcuttu ve

burun delikleri aşırı derecede ayrık duruyordu. Genetik danışmanlık

verildikten sonra çift gebeliğin sonlandırılmasını talep etti. Fetusun pa-

tolojik değerlendirmesinde frontonazal displazi ve anterior ensefalo-

sel tanısı doğrulandı ve ek bir majör bulgu saptanmadı. Fetal karyotip

normaldi ve ALX1 genininde mutasyon olmaması nedeniyle ayırıcı

tanıda ALX-1 ile ilişkili frontonazal displazi dışlandı. Nöral tüp defekti

olan fetuslarda bizim olgumuzda olduğu gibi eşlik eden sendrom ve

hastalıklar görülebilir. Ultrason ile anterior ensefalosel tanısı koyuldu-

ğu zaman, frontonazal displazinin de beraberinde bulunma olasılığı

akla getirilmelidir. (J Turkish-German Gynecol Assoc 2013; 14: 50-2)

Anahtar kelimeler: Frontonazal displazi, anterior ensefalosel, pre-

natal tanı, ultrason, konjenital anomali

Geliş Tarihi: 30 Temmuz 2012 Kabul Tarihi: 22 Ağustos 2012

Introduction

Frontonasal dysplasia, also known as median cleft syndrome,

frontonasal syndrome and frontonasal dysostosis, is a rare

congenital anomaly affecting the eyes, nose and forehead

(1). A spectrum of abnormalities can be seen, ranging from

mild hypertelorism to cleft face malformation (2). Frontonasal

dysplasia is defined as the presence of two or more of the

following symptoms: 1) true ocular hypertelorism, 2) anterior

cranium bifidum occultum (a skin-covered gap in the bones

of the forehead), 3) broadening of the nasal root, 4) median

facial cleft affecting the nose, upper lip and palate, 5) uni-

lateral or bilateral clefting of alae nasi, 6) lack of formation

of nasal tip, 7) a V-shaped or widow’s peak frontal hairline

(3). Hypertelorism is the main and invariable component (4),

and the male:female ratio has been reported to be 2:1 (5).

There are several variations of frontonasal dysplasia, such as

cranio-frontonasal dyplasia, oculoauriculofrontonasal dyspla-

sia, acrofrontofacionasal dysostosis 1, acrofrontofacionasal

dysostosis 2, Teebi type hypertelorism, acromelic frontonasal

dysplasia, frontofacionasal dysplasia, cerebrofrontofacial syn-

drome, Pai syndrome and Shanske syndrome (2).

Only a few prenatally diagnosed cases have been reported

in the literature (4, 6, 7). In this paper, we aimed to present a

prenatally diagnosed case of frontonasal dyplasia with ante-

rior encephalocele.

Case Report

A 24-year-old woman, gravida 4 para 1, was referred to our

unit at 27 weeks gestation due to the prenatal diagnosis of

encephalocele. The sagittal and axial sonography of the fetal

Abstract Özet

Case Report

face depicted a midline mass measuring 3.8 x 4.2 cm, projecting

anteriorly between the fetal orbits and extending from the the

upper aspects of the forehead to the nasal bridge, which was

consistent with the frontal (anterior) encephalocele (Figure

1a and 1d). There were two facial clefts and the nostrils were

extremely separated (Figure 1b). There was hypertelorism with

an external orbital diameter measuring 51 mm and an internal

orbital diameter measuring 23 mm (Figure 1c). Aside from the

aforementioned malformations, there were no additional fetal

abnormalities and the size of fetus was appropriate for gesta-

tional age.

Following genetic counseling, the couple requested a termi-

nation of pregnancy. A fetal blood sample was obtained via

cardiocentesis and feticide was applied in the same session

because of advanced gestational age. Termination of pregnancy

was induced with intravaginal prostaglandin and a 1250 g male

fetus was delivered. The postmortem examination revealed a

soft-tissue mass measuring 4.5 x 5 cm and extending from the

hairline to the nasal tip with a palpable bone defect (Figure 2a

and 2b). The hypertelorism was prominent due to the encepha-

locele. The eyes were asymmetrical, with the left eye located

more superiorly than the right eye, and the palpebral fissures

were short. Two clefts were noted. The nasal root was broad

and the nostrils were separated by the cleft on the left-hand side

(Figure 2c) The distance between the two alae nasis measured

3.1 cm. The frenulum extended to the tip of the tongue, restrict-

ing lingual movement. 3D fetal CT depicted the bone defect

between the frontal, nasal and etmoidal bones (Figure 2d).

The fetal karyotype was normal and sequencing of ALX1 gene

revealed no mutation.

Discussion

Embryologically, frontonasal dysplasia is suggested to be a

result of the migration arrest of olfactory epithelium into the

nasal capsule between the 4th and 6th weeks of embryogen-

esis (5). The nasal capsule does not form normally, leaving a

central defect in which the forebrain area protrudes forming

the anterior encephalocele (4). Anterior encephalocele is a

rare condition and diagnosed as a soft-tissue mass overlying the

lower aspect of the frontal bone (8). Fetuses with neural tube

defects may suffer from associated syndromes and disorders,

as with our case in which anterior encephalocele was associ-

ated with frontonasal dysplasia. The diagnosis of associated

anomalies plays an important role in prenatal care, because the

risk of neural tube defect in subsequent fetuses and the preven-

tive effect of maternal folic acid intake in these cases may be

different from those of nonsyndromic multifactorial neural tube

defects (9).

Frontonasal dysplasia can be isolated or associated with other

malformations (5). Distal limb abnormalities such as syndac-

tyly, polydactyly, clinodactyly or tibial/fibular hypoplasia are

associated sonographic findings in craniofrontal dysplasia,

acrocallosal syndrome, acromelic frontonasal dysplasia, acro-

frontofacionasal dysostosis 1 and 2, oral-facia-digital syndromes

and Greig acrocephalopolysindactyly (4). Also, an association

between frontonasal dysplasia and severe anomalies of the

calvarium and central nervous system has been described (4).

Therefore, a thorough search for cranial and limb malforma-

tions is recommended for the differential diagnosis (4). In our

Figure 1. Fetal ultrasonography at 27 weeks gestation. (a) Axial

scan of the fetal head showing anterior cephalocele (asterix). (b)

Frontal view showing bilateral facial clefts (arrow) and nostrils

widely separated (double arrow). (c) Frontal view depicting severe

hypertelorism (O, orbits). (d) Sagittal scan showing the abnormal

profile and cephalocele (asterix)

Figure 2. Postnatal appearance of the fetus. (a) Frontal view of the

specimen showing anterior cephalocele (asterix). (b) Lateral view of

the specimen showing anterior cephalocele (asterix). (c) Frontal view

showing two facial clefts (white arrows) and the nostrils extremely

separated from each other (black arrows). (d) 3D CT scan showing

the cranium bifidum (arrow)

Written informed consent was obtained from the patient for publication of

this case report and any accompanying images

J Turkish-German Gynecol Assoc 2013; 14: 50-2

Esmer et al.

Prenatal diagnosis of frontonasal dysplasia 51

case, encephalocele was the only associated finding and there

were no extracranial malformations.

Genetic aspects of frontonasal dysplasia are not well-defined.

Although frontonasal dysplasia occurs sporadically in most of

the cases, autosomal dominant and X-linked patterns, as well

as 22q11 microdeletion have been reported in the literature

(1,10,11). In general, the possibility of this syndrome occurring

in the next sibling is suggested to be 25% (12). Recently, auto-

somal-recessive mutations in aristaless-like homebox genes

ALX1 (13), ALX3 (14) and ALX4 (15) have been described.

While ALX3 and 4 predominantly play a role in the formation

of the final shape of the nose, ALX1 expression is essential for

building oral and nasal cavities as well as proper eye develop-

ment during early embryogenesis (13). Therefore, ALX1-related

frontonasal dysplasia is the most severe form, with a phenotype

similar to the fetus in the present report. For this reason, the

presence of a mutation in ALX1 gene was investigated but no

mutation was found, excluding ALX1-related frontonasal dys-

plasia in the differential diagnosis.

In this report, we have presented a rare case of prenatally diag-

nosed frontonasal dyplasia associated with anterior encepha-

locele. Frontonasal dyplasia should be considered in the dif-

ferential diagnosis when an anterior encephalocele is detected

by ultrasonography.

Conflict of interest

No conflict of interest was declared by the authors.

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Esmer et al.

Prenatal diagnosis of frontonasal dysplasia

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A 39-year-old woman, gravida 3, para 1, was referred to level II ultrasound at 16w5d of gestation with suspected midline facial anomaly, as detected at routine obstetrics scan. The parents were non-consanguineous, with uneventful medical and family history. First-trimester screening for Down syndrome showed a low risk for common trisomies. A normal fetal biometry and anatomy were observed. The ultrasound examination showed a fetus with BPD (biparietal diameter) and a BPD/FOD (fronto-occipito diameter) <5th centile and a BPD/FL <3rd centile for expected gestational age.

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Genetic control of craniofacial morphogenesis requires a complex interaction of numerous genes encoding factors essential for patterning and differentiation. We present two Turkish families with a new autosomal recessive frontofacial dysostosis syndrome characterized by total alopecia, a large skull defect, coronal craniosynostosis, hypertelorism, severely depressed nasal bridge and ridge, bifid nasal tip, hypogonadism, callosal body agenesis and mental retardation. Using homozygosity mapping, we mapped the entity to chromosome 11p11.2–q12.3 and subsequently identified a homozygous c.793C→T nonsense mutation in the human ortholog of the mouse aristaless-like homeobox 4 (ALX4) gene. This mutation is predicted to result in a premature stop codon (p.R265X) of ALX4 truncating 146 amino acids of the protein including a part of the highly conserved homeodomain and the C-terminal paired tail domain. Although the RNA is stable and not degraded by nonsense-mediated RNA decay, the mutant protein is likely to be non-functional. In a skin biopsy of an affected individual, we observed a hypomorphic interfollicular epidermis with reduced suprabasal layers associated with impaired interfollicular epidermal differentiation. Hair follicle-like structures were present but showed altered differentiation. Our data indicate that ALX4 plays a critical role both in craniofacial development as in skin and hair follicle development in human.

Un nouveau cas de diagnostic anténatal de dysplasie frontonasale

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Fuel Energ Abstr

In a 30-year-old patient, the systematic second trimester fetal ultrasound discovered major facial abnormalities suggesting a frontonasal dysplasia (FND). The fetal karyotype was normal but no additional genetic testing was performed. Fetal MRI found an important hypertelorism and an asymmetric cerebral ventricle, with a partially visualized corpus callosum. After several consultations and interviews, the couple made a formal demand for pregnancy interruption, which was approved. Fetal pathologic examination confirmed the diagnosis of FND with no other major associated malformation. This rare pathology results from a midline facial dysgraphia comprising a hypertelorism, a large nasal base, a large clefted nose tip and, a V-shaped hair implantation on the forehead. It often occurs sporadically, of unknown cause, related to a defect in the embryonic nasal capsule development. Syndromic forms have been described with cerebral lesions and possible intellectual deficiency. Consequently, a long and difficult surgical management is necessary, at the expense of poor aesthetic outcome. Seven cases of prenatally diagnosed FND have been reported in the literature, three of which had 3D ultrasound. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

[A new prenatal diagnosis case of frontonasal dysplasia].

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Anterior (nasofrontal) encephalocele and chondrodysplasia at 21 weeks' gestation

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PRENATAL DIAG

Disruption of ALX1 Causes Extreme Microphthalmia and Severe Facial Clefting: Expanding the Spectrum of Autosomal-Recessive ALX-Related Frontonasal Dysplasia

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May 2010
AM J HUM GENET

We present an autosomal-recessive frontonasal dysplasia (FND) characterized by bilateral extreme microphthalmia, bilateral oblique facial cleft, complete cleft palate, hypertelorism, wide nasal bridge with hypoplasia of the ala nasi, and low-set, posteriorly rotated ears in two distinct families. Using Affymetrix 250K SNP array genotyping and homozygosity mapping, we mapped this clinical entity to chromosome 12q21. In one of the families, three siblings were affected, and CNV analysis of the critical region showed a homozygous 3.7 Mb deletion containing the ALX1 (CART1) gene, which encodes the aristaless-like homeobox 1 transcription factor. In the second family we identified a homozygous donor-splice-site mutation (c.531+1G > A) in the ALX1 gene, providing evidence that complete loss of function of ALX1 protein causes severe disruption of early craniofacial development. Unlike loss of its murine ortholog, loss of human ALX1 does not result in neural-tube defects; however, it does severely affect the orchestrated fusion between frontonasal, nasomedial, nasolateral, and maxillary processes during early-stage embryogenesis. This study further expands the spectrum of the recently recognized autosomal-recessive ALX-related FND phenotype in humans.

A case report of frontonasal dysplasia

Article

Mar 2010

The following report describes a case of mild frontonasal dysplasia, a rare congenital anomaly affecting the nose and frontal bone. Our patient was referred at 2 months of age with a complex nasal skin and tip deformity. This report outlines management of this patient and reviews the literature with regard to presentation and classification of this condition.

Frontorhiny, a Distinctive Presentation of Frontonasal Dysplasia Caused by Recessive Mutations in the ALX3 Homeobox Gene

Article

Jun 2009
AM J HUM GENET

We describe a recessively inherited frontonasal malformation characterized by a distinctive facial appearance, with hypertelorism, wide nasal bridge, short nasal ridge, bifid nasal tip, broad columella, widely separated slit-like nares, long philtrum with prominent bilateral swellings, and midline notch in the upper lip and alveolus. Additional recurrent features present in a minority of individuals have been upper eyelid ptosis and midline dermoid cysts of craniofacial structures. Assuming recessive inheritance, we mapped the locus in three families to chromosome 1 and identified mutations in ALX3, which is located at band 1p13.3 and encodes the aristaless-related ALX homeobox 3 transcription factor. In total, we identified seven different homozygous pathogenic mutations in seven families. These mutations comprise missense substitutions at critical positions within the conserved homeodomain as well as nonsense, frameshift, and splice-site mutations, all predicting severe or complete loss of function. Our findings contrast with previous studies of the orthologous murine gene, which showed no phenotype in Alx3(-/-) homozygotes, apparently as a result of functional redundancy with the paralogous Alx4 gene. We conclude that ALX3 is essential for normal facial development in humans and that deficiency causes a clinically recognizable phenotype, which we term frontorhiny.

Frontonasal dysplasia: A family presenting autosomal dominant inheritance pattern

Article

Feb 2009
GENET COUNSEL

Frontonasal dysplasia (FND, also called frontonasal dysostosis or median cleft face syndrome) includes a spectrum of abnormalities affecting the eyes, forehead and nose, and resulting from midfacial dysraphia. The clinical picture is highly variable, but major findings in FND include ocular hypertelorism, a broad nasal root, median cleft affecting nose or both the nose and upper lip, and widow's peak. It is usually a sporadic disorder, although a few familial cases have been reported. We report here a three-generation family with multiple affected members with frontonasal dysplasia. This observation suggests autosomal dominant inheritance. Furthermore, some of the features e.g. over-riding toes, nail changes, vertical crease on plantar region of the feet in the index patient were not reported up to now.

Frontonasal dysplasia, severe neuropsychological delay, and midline central nervous system anomalies: Report of 10 Brazilian Male patients

Article

May 2009
AM J MED GENET A

Here we report on 10 male patients with frontonasal dysplasia, cleft lip/palate, mental retardation, lack of language acquisition, and severe central nervous system involvement. Imaging studies disclosed absence of the corpus callosum, midline cysts, and an abnormally modeled cerebellum. Neuronal heterotopias were present in five patients and parieto-occipital encephalocele in three patients. We suggest that this pattern found exclusively in males, most likely represents a newly recognized syndrome distilled from the group of disorders subsumed under frontonasal dysplasia.