Frontonasal Dysostosis in TwoSuccessive Generations

Norman C. Nevin,1* Alan G. Leonard,2 and Barry Jones3

1Regional Genetics Service, Belfast City Hospital Trust, Belfast, Northern Ireland2The Royal Belfast Hospital for Sick Children, Belfast, Northern Ireland3Craniofacial Unit, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom

Frontonasal dysostosis (also called fronto-nasal “dysplasia”) comprises ocular hyper-telorism, median facial cleft affecting noseand/or upper lip, unilateral or bilateral cleftof the alae nasi, anterior cranium bifidumoccultum, or a widow’s peak. Usually it is asporadic disorder, although a few familialcases have been reported. We describe a2-year-old girl with anterior cranium bi-fidum occultum, lipoma of genu and anteriorpart of the corpus callosum, and hypertelor-ism. Her mother had a history of a nasal dripat birth caused by a defect in the cribriformplate and phenotypically, a widow’s peak.This observation suggests either autosomaldominant or X-linked dominant inheri-tance. The family illustrates the importanceof identifying mild expression of frontona-sal dysostosis before genetic counseling.Am. J. Med. Genet. 87:251–253, 1999.© 1999 Wiley-Liss, Inc.

KEY WORDS: frontonasal dysostosis; auto-somal dominant; X-linkeddominant inheritance

INTRODUCTION

Frontonasal dysostosis (FND) comprises hypertelor-ism, broad nasal root, median cleft affecting nose orboth the nose and upper lip, unilateral or bilateral cleftof the alae nasi, lack of formation of the nasal tip, an-terior cranium bifidum occultum, and V-shaped prolon-gation of hair unto the forehead [Sedano and Gorlin,1988]. The term “median face syndrome” has been usedalso to describe the same condition [DeMeyer 1967],frontonasal dysplasia has become the most common(although incorrect) term [Sedano and Gorlin, 1988;Sedano et al., 1970]; the condition is correctly termed

frontonasal dysostosis. Most cases of FND are sporadic,but a few familial cases have been reported [Cohen etal., 1971; Warkany et al., 1973; Fryburg et al., 1993].We describe a mother and daughter with probable fron-tonasal dysostosis; the daughter had hypertelorism,anterior cranium bifidum, but the mother had only anextremely mild expression with widow’s peak and ahistory of a defect in the cribriform plate.

CLINICAL REPORT

The patient, a girl, was born at term following a nor-mal delivery, weighing 2,720 g. When the pregnancywas confirmed, the mother began to take supplemen-tary iron and folic acid. Antibiotics also were takenduring the pregnancy for a chest infection. Throughoutthe pregnancy, ultrasonography was reported as nor-mal. At birth, she had a large mid-line swelling on theforehead and hypertelorism. At age 19 months, she wasreferred. On examination, she had a mid-line swellingon the forehead and hypertelorism (Fig. 1) with theinner canthal (ICD), interpupillary (IPD), and outercanthal (OCD) distances 38, 59, and 83 mm, respec-tively. The shape of the nose was normal, in particularthe tip was not bifid and the alae nasi had no clefts.Eyes were normal on ophthalmological examination.The palate was high, and teeth were normal. Hearingwas normal. Development was appropriate for age; at22 months her receptive and expressive language skillswere normal; she had a relatively large vocabulary andwas beginning to form short phrases. At age 2 years,she was admitted to the craniofacial unit of Great Or-mond Street Hospital for Sick Children NHS Trust.

Magnetic resonance imaging (MRI) scan of brainshowed a well-defined lobular hypodense soft tissuemass in the interspheric fissure anteriorly in the regionof the genu and anterior part of the body of the corpuscallosum (Fig. 2). The corpus callosum was short withpoorly formed body and splenium. In the frontal regioninferiorly, the medial cortices of the frontal lobe ap-peared thickened and lacked detail. There was a skulldefect in the anterior midline extending to just abovethe medial supra-orbital margin and the region of thefrontal sinuses with intracranial content bulgingthrough the defect (Fig. 3). There was lateral displace-ment of the orbits. The floor of the anterior fossa was

*Correspondence to: Norman C. Nevin, M.D., Regional Genet-ics Service, Belfast City Hospital Trust, Lisburn Road, Belfast,Northern Ireland, BT9 7AB. E-mail: nc.nevin@bch.n-i.nhs.uk

Received 28 April 1999; Accepted 13 July 1999

American Journal of Medical Genetics 87:251–253 (1999)

© 1999 Wiley-Liss, Inc.

intact. The callosal lipoma extended with a thin stalkto the area of abnormal tissue in the frontal region.Results of laboratory investigations were normal in-cluding chromosomal analysis (46,XX).

At surgery, the lesion was approached through a bi-coronal flap. There were multiple venous channelsaround the lipomatous lesion. The lipomatous lesion ofthe forehead was excised and a right parietal full thick-ness bone graft was inserted into the defect. She madean excellent recovery.

FAMILY HISTORY

The patient is an only child. The 26-year-old motherand 24-year-old father were nonconsanguineous.Mother is the last of a sibship of three, the eldestbrother who is normal has three normal sons, and theother brother also is normal and has a normal son anddaughter. The family history is unremarkable.

The patient’s mother was born at home following anormal 40-week pregnancy. Since birth, she had had aclear drip from the left nostril. At age 2 years, a nasalpolyp was removed from her left nostril, and at age 31months she had an adenoidectomy. However, the drippersisted. At age 5 1/2 years, she was referred to the

Neurosurgical Department, The Royal Victoria Hospi-tal, Belfast. A skull radiograph was normal with noevidence of a fracture or bony destruction. Roentgeno-grams with Myodil instilled into the left nostril in thehanging position also were normal. At surgery, therewere opaque adhesions along the Sylvian fissurearound the left carotid artery and optic nerve and be-tween the optic nerves. The olfactory nerve appeared

Fig. 3. Skull defect in the frontal region in the mid-line extending tojust above the supra-orbital margin.

Fig. 1. Patient age 19 months showing anterior cranium bifidum occul-tum and hypertelorism.

Fig. 2. MRI scan of brain showing a well-defined lobular soft tissuemass in the interspheric fissure anteriorly in the region of the genu and theanterior body of the corpus callosum.

252 Nevin et al.

normal. No defect was identified in the roof of the eth-moid sinuses. When the left olfactory bulb was re-moved, a 2–3-mm diameter hole was identified in theposterior part of the left cribriform plate. The usualperforations in the cribriform plate were smaller thannormal. The dura was turned down into the hole andsealed with a small quantity of bone wax. She made acomplete recovery with no recurrence of the nasal drip.

Her only clinical signs were a widow’s peak, mildhypertelorism (IPD 54 mm, ICD 25 mm, and OCD 80mm), and the left nostril slightly smaller than the right(Fig. 4). A recent computed tomography scan showed awell-defined area of focal cortical loss in the left frontallobe, consistent with previous surgery. The corpus cal-losum was normal.

DISCUSSION

Mother and her daughter probably have FND. Thepatient had hypertelorism, anterior cranium bifidumoccultum with a mid-line skull defect, and a lipoma ofthe corpus callosum. The mother was mildly affectedwith history of a nasal drip from birth from a small holein the posterior left cribriform plate, mild hypertelor-ism, and a widow’s peak. The combination of abnor-

malities in the mother and daughter clearly are re-lated. It is well recognized that FND may have a vari-able expression [Sedano and Gorlin, 1988; DeMeyer,1967; Warkany et al., 1973]. Most cases are sporadic. Afew familial cases of frontonasal malformation havebeen reported [Cohen et al., 1971; Warkany et al., 1973;Fryburg et al., 1993]. Cohen et al. [1971] mentionedtwo families, one with affected individuals in two suc-cessive generations and the other involving three gen-erations. Two girls with FND, children of the samemother and two different fathers, also were reported byWarkany et al. [1973]. The mother had no apparentsigns of the condition. Fryburg et al. [1993] described amother who had two sons and her brother with variablemanifestations of FND. The mother had wide-set eyes,a wide nose with a broad tip, and a diastasis of theupper central incisors. Her brother and two sons weremore severely affected. The present report and that ofFryburg et al. [1993] are consistent with either auto-somal or X- linked dominant inheritance. The determi-nation of the type of inheritance has not only theoret-ical importance but also has implications for geneticcounseling, especially in determining the risk for chil-dren of affected individuals. Thus, it is important toappreciate that the condition may have a very mildexpression.

Also, FND may be a component of other conditions.Several authors have reported congenital heart abnor-malities in children with FND, in particular tetralogyof Fallot [DeMoor et al., 1987; Guion-Almeida et al.,1996]. An autosomal dominant form of FND with ver-tebral anomalies was described by Reich et al. [1977]also, a syndrome with cerebral anomalies includingagenesis of corpus callosum and Dandy Walker malfor-mation, short neck, short limbs, polydactyly of handsand feet, and cryptorchidism [Toriello et al., 1986].

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