Frontonasal dysplasia (FND) is a congenital midfacial malformation involving the nose, eyes, and forehead [1]. It is believed to be due to the defective migration of the neural crest cells during embryologic midline nasal development although the exact etiology for the malformation is unknown.

It is known to occur sporadically but autosomal dominant, autosomal recessive, and X-linked patterns have also been reported [1] [2]. Recently there have been studies linking FND with autosomal recessive mutations in the homeobox aristaless-like genes ALX1[3], ALX3 [4], ALX4 [5].

The presentation of FND is variable. To be described as FND the condition should include two or more of the following manifestations: hypertelorism, skin covered gap between the forehead bones (anterior cranium bifidum occultum), midline cleft involving the nose, palate and upper lip, broad base of the nose, clefting of the nasal ala, absence of the nasal tip, and widow's peak hairline along the frontal bone [6]. Twice as many males have been reported to have hypertelorism as compared to females [7]. Other abnormalities such as cataracts, colobomas, conductive hearing loss and corpus callosum agenesis can also be present.

Occasionally FND is associated with certain syndromes and other malformations like central nervous system abnormalities [8], tetralogy of Fallot, tibial aplasia, aural and cerebral anomalies. Individuals with FND usually have a normal intelligence quotient (IQ).

Several authors have published classifications of the highly variable midline facial cleft malformations [9] [10] [11]. DeMyer classified midline clefts into those with normal or excessive tissue (median cleft face syndrome) and those with deficient tissue or holoprosencephaly [9]. Sedano termed the median cleft face syndrome as frontonasal dysplasia [10]. Based on the genetic causes and clinical presentation, three types of FND have been described. In FND type 1 patients have nasal anomalies and ptosis. FND type 2 patients have hair loss with agenesis of the parietal bones, while males could have genital anomalies. FND type 3 individuals have ocular anomalies ranging from anophthalmia to microphthalmia, low set ears, and severe facial anomalies.

• Dysostosis

  These clinical findings suggest a new form of acrofacial dysostosis. [ncbi.nlm.nih.gov]

  […] dysplasia) 756.0 Pierre Robin 756.0 Robin's 756.0 Treacher Collins' (incomplete mandibulofacial dysostosis) 756.0 Tower skull 756.0 with exophthalmos 756.0 Treacher Collins' syndrome (incomplete facial dysostosis) 756.0 Trigonocephaly 756.0 Turricephaly [icd9data.com]

  Abstract We report on 3 male and 2 female infants with acromelic frontonasal dysostosis. [doi.org]

• Short Stature

  We present a mildly retarded boy with frontonasal dysplasia, valvular aortic stenosis, short stature, and small head circumference. In addition, mild genital anomalies and bilateral Sydney lines were present. [ncbi.nlm.nih.gov]

  stature 46,XY TGIF gene mutation 2 M 11 y Midline CL Cleft uvula Left palpebral ptosis, microcornea, and optic nerve atrophy Sphenoethmoidal encephalocele ACC Normal development Short stature Right choanal atresia 46,XY 3 F 9 y Midline CL Bifid nasal [medsci.org]

  Meinecke, P, Blunck, W: Frontonasal dysplasia, congenital heart defect, and short stature: A further observation. J Med Genet 26: 408–409, 1989. Google Scholar 14. Fuenmajor, H Moreno : The spectrum of frontonasal dysplasia in an inbred pedigree. [journals.sagepub.com]

  stature Decreased body height Small stature [ more ] 0004322 Webbed neck Neck webbing 0000465 Showing of 24 | Last updated: 6/1/2019 Frontonasal dysplasia is caused by changes ( mutations ) in different genes. [rarediseases.info.nih.gov]

• Alopecia

  We here report on a female patient presenting with severe FND features along with partial alopecia, hypogonadism and intellectual disability. [ncbi.nlm.nih.gov]

  Individuals with frontonasal dysplasia type 2 can have hair loss (alopecia) and an enlarged opening in the two bones that make up much of the top and sides of the skull ( enlarged parietal foramina ). [ghr.nlm.nih.gov]

  Individuals with frontonasal dysplasia type 2 can have hair loss (alopecia) and an enlarged opening in the two bones that make up much of the top and sides of the skull (enlarged parietal foramina). [medlineplus.gov]

  Other features of type 2 include rapid hair loss, absence of hair ( alopecia ), or having more facial hair than expected ( facial hypertrichosis ). [4] People with type 3 frontonasal dysplasia may be born without eyes ( anophthalmia ) or have very small [rarediseases.info.nih.gov]

• Low Set Ears

  FND type 3 individuals have ocular anomalies ranging from anophthalmia to microphthalmia, low set ears, and severe facial anomalies. [symptoma.com]

  ears Conductive deafness Mental deficiency (8-20%) Seems to be more severe when extracephalic anomalies occur or when hypertelorism is very severe Probability low if features above are not as sever Frontal cutaneous lipoma or lipoma of corpus callosum [en.wikibooks.org]

  Features of frontonasal dysplasia type 3 include eyes that are missing (anophthalmia) or very small ( microphthalmia ) and low-set ears that are rotated backward. [ghr.nlm.nih.gov]

  Features of frontonasal dysplasia type 3 include eyes that are missing (anophthalmia) or very small (microphthalmia) and low-set ears that are rotated backward. [medlineplus.gov]

• Hearing Impairment

  impairment Conductive deafness Conductive hearing loss [ more ] 0000405 Craniosynostosis 0001363 Cryptorchidism Undescended testes Undescended testis [ more ] 0000028 Flat occiput 0005469 Holoprosencephaly 0001360 Hydrocephalus Too much cerebrospinal [rarediseases.info.nih.gov]

• Small Head

  We present a mildly retarded boy with frontonasal dysplasia, valvular aortic stenosis, short stature, and small head circumference. In addition, mild genital anomalies and bilateral Sydney lines were present. [ncbi.nlm.nih.gov]

  small head ( brachycephaly ). [rarediseases.info.nih.gov]

• Suggestibility

  FND seems to be sporadic and multiple environmental factors are suggested as possible causes for the syndrome. However, in some families multiple cases of FND were reported, which suggests a genetic cause of FND. [wikinow.co]

  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. [ncbi.nlm.nih.gov]

• Hypertelorism

  Although several of the typical anomalies are diagnosable by ultrasound in utero (hypertelorism, median cleft lip, anterior cephalocele), very few cases have been reported prenatally, the present being only the third. [ncbi.nlm.nih.gov]

  CT scans of the facial bones revealed hypertelorism, a depressed and bifid nasal bridge, and depression of the floor of the anterior cranial fossa. [cags.org.ae]

• Short Neck

  neck, relatively long trunk with short limbs; cryptorchidism; and polydactyly of hands and feet. [ncbi.nlm.nih.gov]

  Frontonasal dysplasia may be associated with congenital heart abnormalities, in particular, tetralogy of Fallot, vertebral anomalies, agenesis of the cropus callosum, Dandy-Walker malformation, a short neck, short limbs, polydactyly of the hands and feet [cags.org.ae]

  FND may be associated with congenital heart abnormalities, in particular, tetralogy of Fallot ( 3 – 5 ), vertebral anomalies, agenesis of the cropus callosum, Dandy-Walker malformation, a short neck, short limbs, polydactyly of the hands and feet, and [ajnr.org]

  Skeletal deformities may include a short neck, rounded and sloping shoulders, abnormalities involving scapula (Sprengel anomaly) and the clavicle (pseudoarthrosis), broad first toes, short first fingers, brachydactyly, clinodactyly, gaps between the first [mjdrdypu.org]

• Broad Nasal Bridge

  Phenotypic features showed brachycephaly with a broad prominent forehead retracted supra-orbital ridges, prominent ocular hypertelorism, mild downslanting of palpebral fissures and broad nasal bridge. Mouth was tent-shaped with noticeable asymmetry. [mjdrdypu.org]

  Showing of 24 | 80%-99% of people have these symptoms Hypertelorism Wide-set eyes Widely spaced eyes [ more ] 0000316 Wide nasal bridge Broad nasal bridge Broad nasal root Broadened nasal bridge Increased breadth of bridge of nose Increased breadth of [rarediseases.info.nih.gov]

  FND consists of various nasal malformations that result from excessive tissue in the frontonasal process, which results in hypertelorism and a broad nasal bridge. [en.wikipedia.org]

• Congenital Facial Anomaly

  In view of the pre-existing mental retardation and the multiple congenital facial anomalies, further surgical intervention for the intracranial lipoma was refused by the child's parents. [indianpediatrics.net]

• Cryptorchidism

  […] anomalies, including agenesis of corpus callosum and probable Dandy-Walker malformation (absent superior vermis, hypoplastic cerebellum and brain stem, and possible posterior fossa cyst in this case); short neck, relatively long trunk with short limbs; cryptorchidism [ncbi.nlm.nih.gov]

  Less common features include eye abnormalities, missing the connection between the two halves of the brain ( agenesis of the corpus callosum ), hearing loss, and undescended testicles in males ( cryptorchidism ). [1] [2] Most people with the dysplasia [rarediseases.info.nih.gov]

  Males with this form often have genital abnormalities, such as absence of one or both testes from the scrotum (cryptorchidism). [rarediseases.org]

  preauricular skin tags, an absent tragus, low set ears, deafness, small frontal sinuses, mental retardation, encephalocele (protrusion of the brain), spina bifida (split spine), meningoencephalocele (protrusion of both meninges), umbilical hernia, cryptorchidism [en.wikipedia.org]

  Miscellaneous findings Two patients had psoriasis and another single patient had an umbilical hernia, one male presented with cryptorchidism, another patent had a café-au-lait spot, one patient presented herself with an hemangioma and one patient had [nature.com]

• Average Intelligence

  In conclusion, individuals diagnosed with frontonasal dysplasia usually are of average intelligence and can expect a normal life span. The affected individual may die shortly after birth if corrective surgery is not performed as soon as possible. [ncbi.nlm.nih.gov]

Although FND is typically diagnosed in the neonatal period, there have been reports of fetuses being diagnosed antenatally with the malformation [8] [12]. When noticed at birth, the workup should include a detailed history and physical examination for identification of FND as well as associated respiratory problems, cardiac, neurological, and limb malformations. The presence of at least two or more of the characteristic morphological features of FND helps to clinch the diagnosis. Radiological tests like X-ray of the skull and computed tomography (CT scan) are important for confirming the diagnosis. CT scan is the gold standard for diagnosing FND [13].

Other tests like an electrocardiogram or a two-dimensional echocardiogram may be required to detect associated cardiac abnormalities.

Antenatal ultrasound is useful to detect hypertelorism and cranial malformations like encephalocele [8]. There is a high incidence of a craniofacial malformation in the next sibling, so genetic counseling is important since genetic testing is as yet unavailable [14].

• Posterior Fossa Cysts

  We describe a boy with frontonasal "dysplasia"; cerebral anomalies, including agenesis of corpus callosum and probable Dandy-Walker malformation (absent superior vermis, hypoplastic cerebellum and brain stem, and possible posterior fossa cyst in this [ncbi.nlm.nih.gov]

A treatment algorithm for craniofrontonasal dysplasia based on timing and technique is offered to decrease the need for revision and improve outcomes. [doi.org]

What are the treatment options? Treatment for FND begins with an accurate diagnosis and thorough evaluation of the patient’s unique expression of the condition. As a result, Dr. [houstoncraniofacial.com]

The material is in no way intended to replace professional medical care by a qualified specialist and should not be used as a basis for diagnosis or treatment. [orpha.net]

In conclusion, the presence of frontonasal dysplasia in a prenatal ultrasonography should always be followed by a fetal MRI with routine screening for periventricular nodular heterotopias so as to establish a more adequate prognosis for the family. [ncbi.nlm.nih.gov]

Treatment and prognosis No specific treatment is available. Surgical intervention is often required for midline facial defects 9. [radiopaedia.org]

Slavotinek, Subtypes of frontonasal dysplasia are useful in determining clinical prognosis, American Journal of Medical Genetics Part A, 143A, 24, (3069-3078), (2007). Anne V. Hing, Nadia Syed and Michael L. [doi.org]

The prognosis depends on the range of the affected area. We have not found any particular syndrome which would include all our ultrasound findings. Our final diagnosis was a severe frontonasal dysplasia associated with cardiopathy. [sonoworld.com]

Our aim was to evaluate FND patients for distinct phenotypes within the FND spectrum and to determine the evidence for a genetic etiology in each of the different subtypes. [ncbi.nlm.nih.gov]

Summary Epidemiology The prevalence is unknown but the condition is rare. Clinical description The clinical picture is highly variable, but the major findings include hypertelorism, a broad nasal root, a large and bifid nasal tip, and widow's peak. [orpha.net]

The discussion covers the phenotype spectrum, epidemiology, mode of inheritance, pathogenesis, and clinical profile of each condition, all of which is accompanied by a wealth of illustrations. [books.google.com]

As such there is information and no consensus in the published literature regarding the epidemiological statistics. [wikivisually.com]

If a surgical correction is planned, this complete work-up prevents unexpected complications and complements the evaluation of paranasal deformities. [ncbi.nlm.nih.gov]

Before corrective surgery, eye drops and ointment are critical to keep the eye moist and prevent blindness if the child is unable to close their eye. [hopkinsallchildrens.org]

To prevent these complications, an implant made out of alloplastic material could be considered. Implants take less surgery time, are limitlessly available and may have more favorable characteristics than autografts. [en.wikipedia.org]

Religious factors and social customs prevent detailed postmortem examination to study the various internal malformations. This is a severe handicap in learning and understanding the entire spectrum of embryological and structural defects. 1. [ruralneuropractice.com]

1. Koçak H, Ceylaner G. Frontonasal dysplasia: a family presenting autosomal dominant inheritance pattern. Genet Couns. 2009;20:63–68.
2. Nevin NC, Leonard AG, Jones B. Frontonasal dysostosis in two successive generations. Am J Med Genet. 1999;87:251–253.
3. Uz E, Alanay Y, Aktas D, Vargel I, et al. Disruption of ALX1 causes extreme microphthalmia and severe facial clefting: expanding the spectrum of autosomal-recessive ALX-related frontonasal dysplasia. Am J Hum Genet. 2010;86:789–796.
4. Twigg SRF, Versnel SL, Nurnberg G, et al. Frontorhiny, a distinctive presentation of frontonasal dysplasia caused by recessive mutations in the ALX3 homeobox gene. Am J Hum Genet. 2009;84:698–705.
5. Kayserili H, Uz E, Niessen C, et al. ALX4 dysfunction disrupts craniofacial and epidermal development. Hum Mole Genet. 2009;18:4357–4366.
6. Wu E, Vargevik K, Slavotinek AM. Subtypes of frontonasal dysplasia are useful in determining clinical prognosis. Am J Med Genet A. 2007;143A:3069–3078.
7. Kean J, Al-Busaidi SSM, Quaba AA. A case report of frontonasal dysplasia. Int J Pediatr Otorhinolaryngol. 2010;74:306–308.
8. Martinelli P, Russo R, Agangi A, Paladini D. Prenatal ultrasound diagnosis of frontonasal dysplasia. Prenatal Diagn. 2002;22:375–379.
9. DeMyer W. The median cleft face syndrome: differential diagnosis of cranium bifidum occultum, hypertelorism, and median cleft nose, lip and palate.Neurology. 1963;17:961–971
10. Sedano HO, Cohen MM, Jirasek J, Gorlin RJ. Frontonasal dysplasia.J Pediatr. 1970;76:906–913.
11. Tessier P. Anatomical classification of facial, craniofacial, and lateral facial clefts. J Maxillofac Surg. 1976;14:69–92.
12. Esmer AC, Kalelioglu I, Kayserili H, et al. Prenatal diagnosis of frontonasal dysplasia with anterior encephalocele. J. Turk Ger Gynecol Assoc. 2003;14(1): 50-52
13. Taybi H. Pediatric Surgery. 2nd ed. Chicago, IL: Year Book Medical; 1983. Radiology of syndromes and metabolic disorders; p. 235.
14. Fox JW, Golden GT, Edgerton MT. Frontonasal dysplasia with alar clefts in two sisters. Genetic considerations and surgical correction. Plast Reconstr Surg. 1976;57:553–556