ACTA PgDIATR 89 (2000) Clinical observations 1145

Fronto-facio-nasal dysplasia in two sisters with additional findings F Ozkinay, 0 Cogulu, I Akil, C Giindiiz and C Ozlunay Ege University Medical Fuculry, Department of Pediatrics, Bornova-Iznzirmurkey

Fronto-facio-nasal dysplasia (FFND), which was first described in two sibs by Gollop in 1981, is a very rare autosomal recessive disorder (1). The characteristic features of the syndrome are brachycephaly, cranium bifidum occultum, encephalocele, primary telecanthus, lower lid lagophthalmos, blepharophimosis, frontal lipoma, mid-face hypoplasia, deformed nostrils, bifid nose and cleft lip-palate. To date, fewer than 10 cases with FFND have been reported (1-7). We report two sibs who exhibit most of the characteristics of the syndrome with some additional central nervous system findings and inguinal hernia which are described for the first time in this syndrome.

Case reports Two sisters, one of them 3 y the other 2y , were hospitalized with complaints of an abnormally shaped head, abnormal facial appearance and opacity in their eyes (Fig. 1). The parents were second cousins and had another 7-y-old healthy daughter. The father had a cleft lip, which had been operated on and hypertelorism. Parents of the father were first cousins.

Case 1 She was the second child of the family and was born by normal spontaneous delivery at term after an uneventful

pregnancy. Birthweight was 3800 g, birth height and head circumference were not known.

She had previously been hospitalized at the age of 1 mo and had been diagnosed as having fronto-facio-nasal dysptasia. During the first hospitalization, genetic counselling was given to the family. Ultrasonographic examination during the next pregnancy was suggested as being necessary; however, this advice was ignored.

At 3 y, weight was 14.5 kg (at 25th centile), height 90 cm (at 10th centile). She had brachycephaly, cranium bifidum occultum, hypoplasia of frontal bone, asym- metric facial appearance, mid-face hypoplasia, S- shaped and down-slanting palpebral fissures, micro- phthalmia of the right eye and blepharophimosis in both eyes, cataract, high arched palate, micrognathia and sacral dimple. She had normal mental and motor development. X-ray examination showed sacral spina bifida. Cranial MRI revealed hypoplastic falx cerebrii and ossification defects of the cranium, corpus callosum hypoplasia, temporal lob hypoplasia, irregularity in the interhemispheric fissure, and abnormal vascular struc- ture in the occipital region (Figs 2-4). Her chromosome constitution was 46.XX.

Case 2 She was born by normal spontaneous delivery at term with a birthweight of 3200 g. Her cleft lip was operated

Fig. 1 . The facial appearance of the patients.

1 146 Clinical observations ACTA PkDIATR 89 (2000)

Fig. 2. MRI of Case 1 showing corpus callosum hypoplasia. Fig. 4. MRI of case 1 showing temporal lob hypoplasia and abnormal vascular structure in the occipital region.

on at 7 mo and her cleft palate was corrected at 15 mo. At 2 y her weight was 9.3 kg (3rd centile), height 79 cm (3rd centile). She had brachycephaly, cranium bifidum, mid-facial hypoplasia, hypertelorism, bilateral tele- canthus, blepharophimosis, down-slanting palpebral fissures, asymmetric facies, cleft lip and palate which had been operated on, micrognathia, ear deformity and umbilical hernia. Ophthalmological examination showed a small optic disc. Motor and mental develop- ment were normal. MRI revealed hypoplastic corpus callosum. Her chromosomal constitution was 46,XX.

Fig. 3. MRI of Case 1 showing interhemispheric fissure irregularity.

Discussion

The most common features of fronto-facio-nasal syn- drome are blepharophimosis, lagophthalmos, mid-facial hypoplasia, nasal hypoplasia, cleft lip and palate, defect of the alae nasi, which is followed by bifid nose or grooved nasal tip, coloboma of eyelid, S-shaped palpebral fissures, absent eyelashes and brachycephaly (14 ) . The severity of the abnormalities is extremely variable in cases with FFND. As indicated in Table 1, both cases described here had the most common characteristics of the syndrome, but Case 1 had a high arched palate instead of complete clefting.

In Case 1, cranial MRI revealed hypoplastic falx cerebrii, ossification defects of the cranium, corpus callosum hypoplasia, irregularity in the interhemi- spheric fissure and abnormal vascular structure in the occipital region. Case 2 also shdwed corpus callosum hypoplasia on MRI. In cases with FFND reported to date, no central nervous system (CNS) abnormality has been reported except A1 Gazali’s case (5 ) . A1 Gazali et al. reported a case with severe facial clefting, limbic dermoid, hypoplasia of the corpus callosum and multi- ple skin appendages. They suggested that their case could be a severe form of FFND or a newly recognized syndrome. This is because there was no parental consanguinity and the patient had much more severe findings than those in the cases reported previously. With the exception of A1 Gazali’s case, the diagnosis of which is still controversial, corpus callosum hypoplasia and CNS abnormalities, as mentioned above, have not been described in cases seen before with FFND.

Frontonasal dysplasia (FND) and acro-fronto-facio- nasal dysostosis (AFFND) are the disorders most like

Clinical observaticms 1 147 ACTA PRDIATR 89 (2000)

Table 1. Clinical features of fronto-fascio-nasal dysplasia with the findings of oresented cases. Findings of F'FND according to the frequency of previously reported cascs Case 1 Casc 2

Group I (%loo) Blepharophimosis + + Lagophthalmos + + Primary telecanthus + + Midface hypoplasia + + Nasal dysplasia + + Defect of alae nasi + + Cleft lip/ palate + Bifid nosdgrooved nasal tip + + Absent eyelashes - - Coloboma of eyelid + - S-shaped palpebral fissures + + Brachycephaly + +

- Group 2 (675)

Group 3 (%SO)

Corpus callosum lipoma - -

Frontal lipoma - -

Widow's peak - -

Cranium hifidum + + Limbic dermoid of eye - -

Encephalocele - -

Cataract + - Microphthalmia + + Microcornea + + Coloboma of iris - -

H ypospadias - -

Hirschsprung's disease - -

Nasal dermoid - -

Stenotic lacrimal duct + + Intracranial abnormalities" + + Spina bifida + - Small optic disc + Umblical hernia + "Hypoplastic falx cerebrii, ossification defects of the cranium, corpus

callosum hypoplasia, irregularity in the interhemispheric fissure. temporal lob hypoplasia, and abnormal vascular structure in the occipital loh.

Group 4 (%25)

Additional findings

-

-

fronto-fxio-nasal dysplasia. FND is a frontal midline developmental field defect which has heterogeneous etiology. In cases with FND, specific eye findings such as S-shaped palpebral fissures, colobomata of the iris or optic disc, lagophthalmos are not found, whereas nail abnormalities are common. Case 2 presented here has a small optic disc, which is another finding of FFND distinguishing it from FND. AFFND is almost always

associated with camptobrachypolysyndactyly and limb hypoplasia. White et al. suggested that FND is a midline developmental defect with a broad spectrum and FFND and AFFND are specific disorders in the FND devel- opmental defect (3). Various eye abnormalities can also be seen in FFND. The most common and respectively rare eye abnormalities and eye findings observed in our cases are given in Table 1. In addition to these abnormalities a small optic disc was detected in Case 2.

Abnormal findings, which are related to the other parts of the body, are rarely seen in FFND. Fryer et al. described Hirschsprung's disease and hypospadias in a case with FFND (6). We observed spina bifida in Case 1 and umbilical hernia in Case 2.

Because of the parental consanguinity, it is suggested that the father may have a mild form of the disorder and that the mother is a carrier. Parental consanguinity has resulted in two affected children. Another point of view is that the father's hypertelorism and cleft lip could be unrelated to the children's conditions and that those are isolated malformations.

References I . Gollop TR. Frontofacionasal dysostosis-a new autosomal

rcccssivc syndromc (Letter). Am J Med Genet 1981; 10: 409-12 2. Gollop TR, Kioto MM, Martins RM, Luccehesi EA, Alvarenga E.

Frontofacionasal dysplasia: evidence for autosomal recessive inheritance. Am J Med Genet 1984; 19: 301-5

3. White EW, Figuroa R, Flannery DB. Brief clinical report: frontofacionasal dysplasia. Am .I Med Genet I99 I ; 40: 338-40

4. Reardon W, Winter RM, Taylor D, Baraitser M. Frontofacionasal dysplasia: a new case and review of the phenotype. Clin Dysmorphol 1994; 3: 7 0 4

5. Al-Gazali LI, Dawodu AH, Ilamada M, Bakir M, Bakalinova D. Severe facial clefting, limbic dermoid, hypoplasia of the corpus callosum, and multiple skin appendages: severe frontofacionasal "dysplasia" or newly recognized syndrome? Am J Med Genet 1996; 63: 346-7

6. Fryer AE. Child with fronto-facio-nasal dysplasia, Hirschsprung disease and hypospadias. Clin Dysmorphol 1993; 2: 120-2

7. Suthers G, David D, Clark B. Fronto-facio-nasal dysplasia. Clin Dysmorphol 1997; 6: 245-9

Ferda Ozkinny, Ege Univemity Mrdirol Fat-ulty, Department of Pediatrirs, 35 100, Bornova-Izmir/rurke?: (Tel. +232 343 43 43, fux. f232 463 39 16, e-mud, eget(~rn@mrd.rge.c.du.tr~

Received June 21, 1999: revisions received Dec. 13,1999 and Apr. 3, 2000; accepted Apr. 10, 2000