Bifid nose

A bifid nose is a rare malformation caused by failure of the medial nasal prominences to fuse during embryonic life. It is characterised by a division of the nose into two halves with a usually adequate airway. A bifid nose is often associated with hypertelorism and a midline cleft.¹ There is a large degree of variability, ranging from a small minimally noticeable groove in the nose tip or columella to complete nasal bifidity, characterised by two half noses with complete clefting of the nasal osteocartilaginous framework. The more severe forms, which are almost always associated with hypertelorism and frequently with a midline cleft and/or a frontal encephalocele, are known as frontonasal dysplasia (median cleft face syndrome), which may be an isolated finding or associated with a syndrome.^{2, 3}

ICD-10: Q30.2 (Fissured, notched and cleft nose) 

The incidence of an isolated bifid nose is unknown. It affects both genders equally. Mild cases may not be identified as a pathological entity but may be seen as a phenotypic variant. A bifid nose with a midline cleft may be considered as an atypical craniofacial cleft (Tessier no 0.)⁴ The incidence of all atypical clefts together has been estimated at 1.4–4.9 per 100,000 births.⁵

The etiology is linked to a defective embryologic development of the nasal placodes between 6 and 9 weeks gestational age. The formation of the nose starts with the nasal placodes (oval thickenings), which appear symmetrically on the frontal prominence by the end of the sixth week of gestation. The nasal pits (future nostrils) divide the placodes into medial and lateral nasal prominences. Due to a migration disorder towards the midline and an arrest in the upper facial development the eyes and nasal placodes maintain their original lateral fetal positions resulting in a bifid nose and hypertelorism.⁶ The forebrain tissue can fill the space between the two nasal placodes which may result in a bossing forehead, an anterior cranium bifidum occultum (skin-covered gap of the skull) or an encephalocele. The time of arrest of the migration determines the severity of malformation.²

The bifid nose is part of a wide spectrum of genetic conditions with overlapping symptoms. There is a large degree of variability in the phenotypic expression, in the associated anomalies and in the severity of the (underlying) condition.

Isolated bifid nose 
The bifid nose may be an isolated anomaly^7,8 considered a distinct entity⁹  or a mild form of frontonasal dysplasia.¹⁰  Most cases are sporadic, but autosomal dominant^{11, 12, 13}  and autosomal recessive traits have been observed.^{14, 15}

Bifid nose as part of a condition 
Conditions in which a bifid nose may be present
•    BNAR syndrome: bifid nose with or without anorectal and renal anomalies (bulbous bifid nose)¹⁶
•    MOTA syndrome: manitoba-oculo-tricho-anal syndrome (broad or bifid nose)¹⁷
•     Fraser syndrome (broad or flat and/or bifid nose)¹⁸ 
 BNAR, MOTA and Fraser syndromes constitute a clinically overlapping group of FRAS-FREM complex diseases¹⁹
•    Cerebro-ocular-nasal syndrome²⁰
•    Trichonobrachycephaly²¹
•    Septo-optic dysplasia ²² (case from own practice)
•    Pai syndrome^{23, 24}
•    22Q11 syndrome²⁵

Frontonasal dysplasia      
This applies to forms of bifid nose associated with other anomalies, mainly limited to the face and head. A constellation of symptoms is associated with frontonasal dysplasia²:
•    hypertelorism
•    broad nasal root
•    median facial cleft of the nose and/or upper lip and palate
•    unilateral or bilateral clefting of the alae nasi
•    absent nasal tip
•    anterior cranium bifidum occultum 
•    V-shaped frontal hairline (Widow’s peak)

Other features may be present like hearing loss, eye defects (coloboma), tetralogy of Fallot, lipoma and/or agenesis of the corpus callosum and sometimes intellectual disability. Most reported cases are sporadic, but a few familial cases have been published. Both autosomal dominant, autosomal recessive and X-linked dominant inheritances have been reported.

There are multiple classification systems for frontonasal dysplasia based on the embryology² or the phenotypic appearance.²⁶ However, the most frequently used nowadays is the classification in three types that are distinguished by their symptoms and genetic causes.

1.    Frontonasal dysplasia type1^{27, 28}

• changes in the ALX3 gene on chromosome 5q12.1, autosomal recessive  
• Type 1 patients typically have a long philtrum with prominent bilateral swellings and ptosis.

2.    Frontonasal dysplasia type2 ^29,30,31

• changes in the ALX4 gene on chromosome 11p11.2, autosomal dominant  
• Type 2 patients typically have microphtalmia, skull defects, alopecia and varying degrees of intellectual disability. Males with type 2 often have genital abnormalities. 

3.    Frontonasal dysplasia type3^{32, 33}

• changes  in the ALX1 gene on chromosome 12q11.2, autosomal recessive
• Type 3 patients typically have anophthalmia or microphthalmia, low-set and backwards rotated ears and severe facial abnormalities.

Subtypes of frontonasal dysplasia
There are several subtypes of frontonasal dysplasia with other extra facial anomalies. The most frequently mentioned subtype is: Acromelic frontonasal dysplasia^{34, 35}: Frontonasal dysplasia combined with central nervous system anomalies (e.g.Dandy-Walker malformation, corpus callosum agenesis, encephalocele, hydrocephalus, intellectual disabilities) and skeletal anomalies (acromelic shortening, underdeveloped or absent tibia , preaxial polydactyly of the feet and talipes). There is a risk for mental retardation. Males affected with acromelic frontonasal dysplasia sometimes have undescended testes.
Blaas found frontonasal dysplasia in 6.7% of 30 holoprosencephaly cases.³⁶

Another merge defect of the medial nasal processes and related to bifid nose is a broad nose (potato nose), which is probably another expressions of the same developmental defect.³⁷ In some conditions there is a cleft in a bulbous nose. (trichonobrachycephaly³⁸, FRAS-FREM complex diseases)
 

Hypertelorism, clefts, encephalocele, cranium bifidum occultum, eye and ear abnormalities and corpus callosum agenesis are the most frequent associated anomalies, usually in the context of frontonasal dysplasia.

Associations for the subtypes of frontonasal dysplasia are: central nervous system anomalies (e.g. Dandy-Walker malformation, periventricular heterotopia, lipomas, corpus callosum agenesis), skeletal abnormalities (rhizomelic shortening, syndactyly, polydactyly, talipes), urogenital abnormalities, anorectal anomalies and tetralogy of Fallot.
Most individuals with frontonasal dysplasia have normal intelligence, but intellectual disability is possible depending on the underlying condition (e.g. frontonasal dysplasia type 2 and the subtypes acromelic frontonasal dysplasia and acrofrontofacionasal dysostosis syndrome carry a risk of intellectual disability.)

Most cases are sporadic. Reports consistent with different patterns of inheritance for isolated bifid nose, frontonasal dysplasia or the subtypes have been published.^{11-15, 27-33}

An unusually flat nose (absent nasal tip), absent nasal bones or even an absent nose³⁹ in the profile plane, may alert the ultrasonographer. Orbital distance should be measured as hypertelorism (even borderline hypertelorism) can support the diagnosis. Three-dimensional ultrasound can be of help.^39,40,41,42 Three-dimensional multiplanar ultrasound is very helpful in identifying exact planes³⁹, for example, it can play a role in evaluating the tip of the nose and establishing the diagnosis. Surface rendered images can be very informative.^40,41,42 MRI may be helpful to detect skull, brain or facial anomalies.^40,43,44
As the face is formed at 10 week’s gestational age an early diagnosis is feasible. A few case reports describing first trimester diagnoses are published.^41,42 
When a bifid nose is suspected the patient should be send to an expert centre for an advanced ultrasound examination to rule out associated anomalies and genetic consultation.
 

Facial tumors, proboscises, encephaloceles, amniotic band syndrome or atypical clefts have to be considered in the differential diagnosis of bifid nose.
In mild cases of bifid nose, the nose will appear flat (due to the the missing nasal tip) in the profile plane. In this situation especially Binder syndrome, Wolf-Hirschhorn or other conditions with flat or small noses should be included in the differential diagnosis.
 

Life expectancy for isolated bifid nose is normal in most cases. The treatment is surgical and is based on the specific phenotypic presentation. Staged reconstruction is usually necessary to restore function and appearance of the face. The severity of the facial anomaly determines the functional, psychosocial and cosmetic impact on the life of a patient. It has to be kept in mind that even minor forms cause severe facial disfigurement. 

The associated anomalies have a major impact on the prognosis and whether or not surgical intervention can help to improve the associated health problems. 
Intelligence is normal in most cases; however some (sub)types of frontonasal dysplasia carry a risk for intellectual disability (e.g. frontonasal dysplasia type 2, acromelic frontonasal dysplasia, acrofrontofacionasal dysostosis syndrome.)

When a bifid nose is recognised on ultrasound examination a detailed scan should be performed to exclude other anomalies. Three-dimensional ultrasound and MRI can be very informative. Three dimensional surface rendered images may help parents to understand the condition and come to terms with the facial malformation. Genetic counselling is strongly recommended and invasive procedures are usually necessary to differentiate between the several genetic conditions associated with bifid nose. A team approach is necessary and should include various pediatric specialists and a psychologist.

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