Frontonasal Dysplasia
Frontonasal dysplasia is a developmental field defect
of craniofacial region characterized by hypertelorism
and varying degrees of median nasal clefting. In 1967,
DeMeyer first described the malformation complex
“median cleft face syndrome” to emphasize the key
midface defects. Since then, several terms have been
introduced: frontonasal dysplasia, frontonasal syn-
drome, frontonasal dysostosis, and craniofrontonasal
dysplasia (currently recognized as a syndrome distinct
from frontonasal dysplasia) (Dubey and Garap 2000).
Synonyms and Related Disorders
Frontonasal malformation; Frontorhiny; Median facial
cleft syndrome
Genetics/Basic Defects
1. Inheritance
a. Sporadic in most cases.
b. Rare autosomal dominant inheritance with vari-
able expression.
c. Recessive mutations in the homeobox gene
ALX3 cause a recurrent pattern of frontonasal
malformation (Twigg et al. 2009).
d. Rare autosomal recessive inheritance: disruption
of ALX1 causes autosomal-recessive ALX-related
frontonasal dysplasia (Uz et al. 2010).
e. Rare X-linked dominant inheritance.
2. Rare association with chromosome anomalies
a. Partial trisomy 2q and partial monosomy 7q from
a balanced maternal t(2;7)(q31;q36) (Chen et al.
1992)
H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_100,
# Springer Science+Business Media, LLC 2012
b. 22q11 microdeletion (Stratton and Payne 1997)
c. Reciprocal translocation t(15;22)(q22;q13)
(Fryns et al. 1993)
d. Complex translocation involving chromosomes
3, 7, and 11 (Stevens and Qumsiyeh 1995)
3. Rare variants of frontonasal dysplasia/malforma-
tion with variable inheritance patterns
4. Embryologically classified as a developmental field
defect (Sedano and Gorlin 1986)
5. Extreme variable phenotypic expression
6. Pathogenesis (Twigg et al. 2009)
a. Formation of the human face is an exquisitely
orchestrated developmental process involving
multiple tissue swellings (the frontonasal, medial
and lateral nasal, and maxillary and mandibular
prominences) derived from the neural crest
(Moore and Persaud 2007).
b. During a critical period between 4 and 8 weeks
of human fetal development, these processes
must undergo cell proliferation and tissue
fusion to form the orbital, nasal, and oral struc-
tures (Yoon et al. 2000; Moore and Persaud
2007).
c. Disturbance to this developmental sequence
causes frontonasal malformation, a very hetero-
geneous group of disorders characterized by
combinations of hypertelorism, abnormal nasal
configuration, and oral, palatal, or facial clefting,
sometimes associated with facial asymmetry,
skin tags, ocular or cerebral malformations,
widow’s peak, and anterior cranium bifidum
(DeMeyer 1967; Sedano et al. 1970; Sedano
and Gorlin 1986; van der Meulen and
Vaandrager 1989; Guinon-Almeida et al. 1996;
Tan and Mulliken 1997; Losee et al. 2004).
897
898 Frontonasal Dysplasia

iv. Limb anomalies

Clinical Features a) Clinodactyly
b) Polydactyly
1. Pure frontonasal dysplasia (Dubey and Garap 2000) c) Syndactyly
a. Variable mental retardation d) Tibial hypoplasia
b. Inheritance pattern v. Umbilical hernia
i. Sporadic in majority of cases vi. Cryptorchidism
ii. Familial transmission in few cases 2. Autosomal-recessive frontonasal dysplasia in two
c. Cranium bifidum occultum distinct families (Uz et al. 2010)
d. CNS anomalies a. Bilateral extreme microphthalmia
i. Frontal cephalocele b. Bilateral oblique facial cleft
ii. Meningocele/meningoencephalocele c. Complete cleft palate
iii. Agenesis of the corpus callosum d. Hypertelorism
iv. Mild holoprosencephaly e. Wide nasal bridge with hypoplasia of the ala nasi
v. Hydrocephalus f. Low-set, posteriorly rotated ears
e. Nasal anomalies 3. Other syndromes associated with frontonasal dys-
i. Mild colobomas of the nostril plasia or frontonasal malformation (Martinelli et al.
ii. Flattening of the nose with widely separated 2002)
nares a. Autosomal dominant form of frontonasal dyspla-
iii. A broad nasal root sia with vertebral anomalies
iv. Broad nasal tip b. Acromelic frontonasal dysplasia
v. Notching or clefting of alae nasi (cleft nose) i. Autosomal recessive disorder
vi. Nasal tag ii. Similar frontonasal “dysplasia”
f. Ocular anomalies iii. Rare agenesis of the corpus callosum
i. Hypertelorism iv. Tibial hypoplasia
ii. Epicanthal folds v. Polydactyly (duplicated hallux)
iii. Narrowing of the palpebral fissures c. Craniofrontonasal dysplasia
iv. Accessory nasal eyelid tissue with second- i. Possible X-linked disorder
ary displacement of inferior puncti ii. Rare mental retardation
colobomas iii. Hypertelorism
v. Epibulbar dermoids iv. Craniosynostosis
vi. Upper eyelid colobomas v. Facial asymmetry
vii. Microphthalmia vi. Broad nasal root
viii. Vitreoretinal degeneration with retinal vii. Bifid nasal tip
detachment viii. Syndactyly of toes and fingers
ix. Congenital cataracts ix. Split nails
g. Facial anomalies x. Broad first toe
i. Widow’s peak configuration of the anterior d. Acrocallosal syndrome
hairline in the forehead i. Autosomal dominant or autosomal reces-
ii. Median cleft of upper lip sive disorder
iii. Median cleft palate ii. Severe mental retardation
iv. Preauricular tag iii. Hypertelorism
v. Absent tragus iv. Hypoplastic or absent corpus callosum
vi. Low-set ears v. Prominent forehead
h. Other anomalies vi. Small nose
i. Conductive deafness vii. Broad nasal bridge
ii. Hypoplastic frontal sinuses viii. Normal nasal tip
iii. Cardiac anomalies, especially tetralogy of ix. Cardiac defects
Fallot x. Postaxial polydactyly of hands and feet
Frontonasal Dysplasia
xi. Preaxial polydactyly of feet
xii. Syndactyly of toes
xiii. Clinodactyly
e. Oral-facial-digital syndrome
i. X-linked disorder
ii. Variable mental retardation
iii. Agenesis of the corpus callosum
iv. Median cleft lip and palate
v. Lobated/bifid tongue
vi. Clinodactyly
vii. Syndactyly
viii. Polydactyly
f. Oculo-auriculo-frontonasal dysplasia
i. Frontonasal dysplasia
ii. Ocular dermoids
iii. Eyelid colobomata
iv. Preauricular tags
g. Fronto-facio-nasal dysplasia
i. Autosomal recessive disorder
ii. Frontonasal dysplasia
iii. Ocular dermoids
iv. Preauricular tags
v. Cerebral lipoma
h. Acro-fronto-facio-nasal dysplasia I
i. Autosomal recessive disorder
ii. Frontonasal dysplasia
iii. Macrostomia
iv. Broad and notched nasal tip
v. Fibular hypoplasia
vi. Polydactyly
vii. Short stature
i. Acro-fronto-facio-nasal dysplasia II
i. Autosomal recessive disorder
ii. Frontonasal dysplasia
iii. Microcephaly
iv. Nasal midline groove with blind dimples
v. Broad thumbs
vi. Syndactyly
j. Greig acrocephalopolysyndactyly
i. Autosomal dominant disorder
ii. Mild mental retardation
iii. Mild features of frontonasal dysplasia
iv. Macrocephaly
v. Broad nasal root
vi. Normal nasal tip
vii. Postaxial polydactyly of hands
viii. Preaxial polysyndactyly of feet
ix. Broad thumbs and halluces
x. Syndactyly
899
k. Meinecke frontonasal dysplasia-cardiac defects
i. Frontonasal dysplasia
ii. Microcephaly
iii. Cardiac defects, especially tetralogy of
Fallot
4. Prognosis depending on severity of defects
a. Normal intelligence in most patients
b. Mental retardation affecting 12% of cases with-
out CNS abnormalities
c. Up to 50% of cases with mental retardation com-
plicated by agenesis of the corpus callosum
Diagnostic Investigations
1. Radiography, CT, and MRI of the brain
a. Anterior cranium bifidum
b. Agenesis of the corpus callosum
c. Lipoma of the corpus callosum
d. Arhinencephaly
e. Hydrocephalus
2. Chromosome analysis for chromosome etiology
3. Molecular genetic diagnosis of ALX1 and ALX3
mutations: not available clinically
Genetic Counseling
1. Recurrence risk
a. Patient’s sib
i. Autosomal dominant disorder: not increased
in de novo case unless a parent is affected
ii. Autosomal recessive disorder: 25%
iii. X-linked dominant disorder: 50% when the
mother is a carrier
iv. Chromosome disorder: not increased in a
de novo case; risk of unbalanced segregation
from a carrier parent
b. Patient’s offspring
i. Autosomal dominant disorder: 50%
ii. Autosomal recessive disorder: not increased
unless the spouse is a carrier
iii. X-linked dominant disorder: 50%
iv. Chromosome disorder: not surviving to
reproductive age
2. Prenatal diagnosis
a. Ultrasonography (Martinelli et al. 2002)
i. Hypertelorism
ii. Frontonasal cephalocele
900
iii. Agenesis of the corpus callosum
iv. Median cleft lip
b. 3-D ultrasonography: increasingly helpful in
identifying facial features (Johnstone et al. 2008)
c. Amniocentesis for associated chromosome
anomaly
3. Management
a. Speech therapy
b. Maxillofacial surgeries for functional and
cosmetic improvement
i. Cleft lip/palate
ii. Hypertelorism
iii. Nose
c. Psychosocial and/or psychiatric support
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902 Frontonasal Dysplasia

Fig. 1 (a, b) A newborn with a

frontonasal dysplasia showing
ocular hypertelorism,
cephalocele, hydrocephalus,
and cranium bifidum

b
Frontonasal Dysplasia 903

Fig. 2 (a–g) A newborn with a b c

frontonasal dysplasia and
arrhinencephaly resulting
from unbalanced segregation
of a maternal t(2;7)(q31;q36).
The patient had partial trisomy
2q and partial monosomy 7q,
iris coloboma, tetralogy of
Fallot, and limb anomalies

e
d

f g
904 Frontonasal Dysplasia

b
Fig. 4 A 2-year-old girl with frontonasal dysplasia

Fig. 3 (a, b) A mother and a child with frontonasal dysplasia

showing hypertelorism and broad and notched nasal tip