Frontonasal dysplasia is a developmental field defect of cran- iofacial region characterized by hypertelorism and varying degrees of median nasal clefting. In 1967, DeMeyer first described the malformation complex ‘median cleft face syn- drome’ to emphasize the key midface defects. Since then several terms have been introduced: frontonasal dysplasia, fron- tonasal syndrome, frontonasal dysostosis, and craniofrontonasal dysplasia.
GENETICS/BASIC DEFECTS
1. Inheritance
a. Sporadic in most cases
b. Rare autosomal dominant inheritance with variable expression
c. Rare autosomal recessive inheritance d. 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)
b. 22q11 microdeletion
c. Reciprocal translocation t(15;22)(q22;q13)
d. Complex translocation involving chromosomes 3, 7, and 11
3. Rare variants of frontonasal dysplasia/malformation with variable inheritance patterns
4. Embryologically classified as a developmental field defect
5. Extreme variable phenotypic expression
CLINICAL FEATURES
1. Pure frontonasal dysplasia a. Variable mental retardation b. Inheritance pattern
i. Sporadic in majority of cases ii. Familial transmission in few cases c. Cranium bifidum occultum
d. CNS anomalies
i. Frontal cephalocele
ii. Meningocele/meningoencephalocele iii. Agenesis of the corpus callosum
iv. Mild holoprosencephaly v. Hydrocephalus
e. Nasal anomalies
i. Mild colobomas of the nostril
ii. Flattening of the nose with widely separated nares
iii. A broad nasal root iv. Broad nasal tip
v. Notching or clefting of alae nasi (cleft nose) vi. Nasal tag
f. Ocular anomalies i. Hypertelorism ii. Epicanthal folds
iii. Narrowing of the palpebral fissures
iv. Accessory nasal eyelid tissue with secondary displacement of inferior puncti colobomas v. Epibulbar dermoids
vi. Upper eyelid colobomas vii. Microphthalmia
viii. Vitreoretinal degeneration with retinal detachment ix. Congenital cataracts
g. Facial anomalies
i. Widow’s peak configuration of the anterior hair- line in the forehead
ii. Median cleft of upper lip iii. Median cleft palate
iv. Preauricular tag v. Absent tragus vi. Low-set ears h. Other anomalies
i. Conductive deafness ii. Hypoplastic frontal sinuses
iii. Cardiac anomalies, especially teratology of Fallot
iv. Limb anomalies a) Clinodactyly b) Polydactyly c) Syndactyly d) Tibial hypoplasia v. Umbilical hernia vi. Cryptorchidism
2. Other syndromes associated with frontonasal dysplasia or frontonasal malformation
a. Autosomal dominant form of frontonasal dysplasia with vertebral anomalies
b. Acromelic frontonasal dysplasia i. Autosomal recessive disorder ii. Similar frontonasal “dysplasia”
iii. Rare agenesis of the corpus callosum iv. Tibial hypoplasia
v. Polydactyly (duplicated hallux) c. Craniofrontonasal dysplasia
i. Possible X-linked disorder ii. Rare mental retardation iii. Hypertelorism
iv. Craniosynostosis v. Facial asymmetry vi. Broad nasal root vii. Bifid nasal tip
viii. Syndactyly of toes and fingers ix. Split nails
x. Broad first toe
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d. Acrocallosal syndrome
i. Autosomal dominant or autosomal recessive disorder ii. Severe mental retardation
iii. Hypertelorism
iv. Hypoplastic or absent corpus callosum v. Prominent forehead
vi. Small nose vii. Broad nasal bridge viii. Normal nasal tip
ix. Cardiac defects
x. Post-axial polydactyly of hands and feet xi. Pre-axial 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. Macrostomia
ii. Broad and notched nasal tip iii. Fibular hypoplasia
iv. 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. Post-axial polydactyly of hands viii. Pre-axial polysyndactyly of feet
ix. Broad thumbs and halluces x. Syndactyly
k. Frontonasal dysplasia-cardiac defects i. Frontonasal dysplasia
ii. Microcephaly
iii. Cardiac defects, especially tetralogy of Fallot
3. Prognosis depending on severity of defects a. Normal intelligence in most patients
b. Mental retardation affecting 12% of cases without CNS abnormalities
c. Up to 50% of cases with mental retardation compli- cated by agenesis of the corpus callosum
DIAGNOSTIC INVESTIGATIONS
1. Radiography, CT, 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
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 repro- ductive age
2. Prenatal diagnosis a. Ultrasonography
i. Hypertelorism
ii. Frontonasal cephalocele iii. Agenesis of the corpus callosum
iv. Median cleft lip
b. 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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Fig. 1. A newborn with frontonasal dysplasia showing ocular hyper- telorism, cephalocele, hydrocephalus, and cranium bifidum.
Fig. 2. A newborn with 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.
Fig. 3. A mother and a child with frontonasal dysplasia showing hypertelorism and broad and notched nasal tip.
