8.9 Genetics and Syndromes
Congenital anomalies, whether single or multiple, can be induced by environmental and teratogenic insults as well as chromosomal or single-gene defects. This chapter includes only the most common and relevant syndromes with associated craniofacial anomalies. The otolaryngologist may be primarily involved in managing the otolaryngologic manifestations of these syndromes but may also play an important role in the early identification and referral for genetic counseling in children with suspected genetic or syndrome features.
Epidemiology
Major congenital anomalies diagnosed within the first year of life affect ~ 3% of neonates and congenital defects contribute to nearly 20% of infant deaths. Of the defects affecting children with multiple congenital anomalies, 62% are otolaryngologic in nature. In the case of multiple anomalies where the underlying cause has been identified, 84% have an otolaryngologic feature.
Relevant Definitions
Association: Nonrandom occurrence of a pattern of anomalies that are not identified as a sequence or syndrome; for example, CHARGE (c oloboma of the eye, h eart defects, a tresia of the nasal choanae, r etardation of growth and/or development, g enital and/or urinary abnormalities, and e ar abnormalities and deafness) association.
Sequence: Pattern of multiple defects resulting from a single primary malformation or insult—e.g., Pierre Robin′s sequence. The fact that a cluster of anomalies is defined as a sequence does not exclude Mendelian inheritance.
Syndrome: Cluster of anomalies in which all features are pathologically related; for example, Down′s syndrome, fetal alcohol syndrome.
Relevant Associations, Sequences, and Syndromes
Achondroplasia
Inheritance: Autosomal dominant
Genetic loci: Spontaneous mutation leading to a defect in fibroblast growth factor receptor-3
General: Most common cause of short-limbed dwarfism; advanced paternal age is a risk factor
Relevant features: Frontal bossing, midface hypoplasia, obstructive sleep apnea
Associated features: Shortened limbs, long narrow trunk, lumbar lordosis, limited elbow extension, genu varum, compression of craniovertebral junction (can lead to central apnea and sudden death), hypotonia
Branchio-oculo-facial (BOF) syndrome
Inheritance: Autosomal dominant
Genetic loci: Not yet identified
Relevant features: Branchial cleft sinuses, lacrimal duct obstruction, conductive hearing loss, pseudocleft of upper lip, auricular malformations (low-set, malformed)
Associated features: Low birth weight, growth and developmental delay, premature aging
Catel-Manzke′s syndrome
Inheritance: X-linked (speculated)
Genetic loci: Not yet identified
Relevant features: Cleft palate, micrognathia, auricular malformations
Associated features: Cardiac septal defect, growth delay, hyperphalangy (increased number of phalanges) of index finger
CHARGE association
Inheritance: Sporadic
Genetic locus: 8q12.1, 7q21.1
General: Coloboma iris, heart defects, choanal atresia, retarded growth, genital hypoplasia, ear abnormalities
Additional relevant features: Auricular anomalies (prominent, folded ears, absent helix) conductive/sensorineural hearing loss, micrognathia, midface hypoplasia, dysphagia, short neck
Additional associated features: Short stature, ptosis, microphthalmos, omphalocele, cryptorchism, syndactyly, renal hypoplasia, delayed skeletal maturation, pituitary defects, hypocalcemia
Costello′s syndrome
Inheritance: Autosomal dominant and/or gonadal mosaicism
Genetic loci: HRAS or KRAS gene mutation on chromosome 11p15.5
Relevant features: Auricular malformations (low-set, thick lobes), oral, nasal, and anal papillomas
Head and neck features: Macrocephaly, epicanthic folds, coarse facial features, strabismus, thick lips, depressed nasal bridge, curly hair
Associated features: growth and developmental delay; hypertrophic cardiomyopathy; thin, deep-set nails; skin hyperpigmentation; deep plantar/palmar creases; short neck; tight Achilles tendons
Cri du chat syndrome
Inheritance: De novo mutations most common, can result from unbalanced translocation/recombination in a parent (12%)
Genetic loci: Partial and variable deletion of short arm of chromosome 5
Relevant features: Narrowed endolarynx (diamond-shaped), persistent interarytenoid cleft, microcephaly, round face, hypertelorism, micrognathia, epicanthal folds, low-set ears
Associated features: Hypotonia, severe psychomotor and developmental delay
Down′s syndrome
Inheritance: Sporadic
Genetic loci: Trisomy 21
General: Most common genetic disorder associated with mental retardation and developmental delay; advanced maternal age risk factor (> 35 years); 1:800 live births
Relevant features: Microcephaly, midface retrusion, upslanting palpebral fissures, epicanthal folds, macroglossia, frequent OM with effusion, sleep apnea, auricular anomalies (small, low-set, overfolding of upper helices), middle and inner ear anomalies
Associated features: Congenital cardiac defects (40%), hypotonia, joint laxity, and underdeveloped cervical vertebra (risk of atlantoaxial subluxation/dislocation), flat occiput, three fontanels, excess nuchal skin, short stature, clinodactyly 5th digit, single palmar crease
Ectrodactyly–ectodermal dysplasia–clefting (EEC) syndrome
Inheritance: Autosomal dominant (variable expression)
Genetic loci: 7q11.2-q21.3
Relevant features: Cleft lip and/or cleft palate; blue irides; lacrimal duct defects; blepharophimosis; partial anodontia; light, spare, thin, wiry hair
Associated features: Hyperkeratosis, hypotrichosis, hypohidrosis, hypoplastic nipples, anomalies of the extremities (syndactyly, ectrodactyly), genitourinary defects
Fragile X syndrome
Inheritance: X-linked
Genetic loci: Xq27.3
General: Second most common cause of genetic developmental delay
Relevant features: Prominent ears, large jaw, long face, high-pitched speech
Associated features: Mitral valve prolapse, behavioral disturbance, macroorchidism, joint hypermobility, pes planus
Fraser′s (cryptophthalmos) syndrome
Inheritance: Autosomal recessive
Genetic loci: FRAS1 or FREM2 gene 13q13.3, 4q21
Relevant features: Ear anomalies (aural atresia, cupped ears); laryngeal stenosis/atresia; hypoplastic, notched nares; bilateral cryptophthalmos; eyebrow anomalies
Associated features: Developmental delay (50%), partial cutaneous syndactyly, genital anomalies, renal hypoplasia/agenesis
Larsen′s syndrome
Inheritance: Autosomal dominant (known), possible recessive form speculated
Genetic loci: 3p21.1–p14.1
Relevant features: Cleft palate, flat facies, depressed nasal bridge, hypertelorism, prominent frontal boss
Associated features: Congenital joint dislocation; long, nontapering fingers with short fingernails; spinal deformities
Marshall′s syndrome
Inheritance: Autosomal dominant
Genetic loci: 1q21
Relevant features: Sensorineural hearing loss; short nose with flat nasal bridge and midface; anteverted nares; large eyes; prominent, protruding upper incisors
Associated features: Cataracts, myopia, short stature, calvarial thickening, spondyloepiphyseal abnormalities
Miller′s syndrome (postaxial acrofacial dysostosis)
Inheritance: Autosomal recessive
Genetic loci: Not yet identified
General: Facial features similar to Treacher Collins′s syndrome with limb anomalies
Relevant features: Cleft lip and/or cleft palate; malar hypoplasia and/or vertical bony cleft; micrognathia; hypoplastic cup-shaped ears; down-slanting palpebral fissures, coloboma; ectropion
Associated features: Absence of fifth digit on all limbs, accessory nipples
Möbius′s syndrome
Inheritance: Sporadic
Genetic loci: 13q12.2–q13
Relevant features: Congenital cranial nerve VI and VII palsy, orofacial dysmorphism
Associated features: Limb malformations, developmental delay
Mucopolysaccharidoses
General: Storage diseases secondary to lysosomal enzyme deficiencies
Examples: Hunter′s, Hurler′s, Morquio′s, Sanfilippos, etc., syndromes
Relevant features: OME, sensorineural hearing loss, obstructive sleep apnea
Associated features: Developmental delay, short stature
Nager′s syndrome (Nager acrofacial dysostoses)
Inheritance: Autosomal dominant
Genetic loci: 9q32
General: Facial features similar to Treacher Collins with limb anomalies or deficiencies
Relevant features: Aural atresia, cleft palate, auricular malformations (low-set, rotated posteriorly), malar hypoplasia, high nasal bridge, down-slanting palpebral fissures, absence of lower eyelashes
Associated features: Hypoplasia of radial limbs; development and cognition normal
Noonan′s syndrome
Inheritance: Autosomal dominant
Genetic loci: 12q24
Relevant features: Neck webbing, auricular anomalies (low-set), down-slanting palpebral fissures, ptosis, hypertelorism
Associated features: Low posterior hairline, short stature, pectus excavatum, pulmonic stenosis, bleeding diathesis
Opitz′s G syndrome (BBB syndrome)
Inheritance: X-linked recessive and autosomal dominant
Genetic loci: 22q11
General: Midline defects
Relevant features: Cleft lip and/or cleft palate, laryngeal clefting, auricular anomalies (ears rotated posteriorly), micrognathia, flattened nasal bridge, anteverted nostrils, hypertelorism
Associated features: Developmental delay, hypospadias, cryptorchidism, hernias
Oro-facial-digital syndrome
Inheritance
Type I: X-linked dominant, lethal in males
Type II: Autosomal recessive (speculated)
Genetic loci
Type I: Xp22.2–p22.3 CXORF5 gene
Type II: Not yet identified
Relevant features
Type I: Median cleft lip, cleft palate, bifid tongue, oral frenula and clefts, hypoplastic nasal alae, lateral displacement of inner canthi
Type II: Midline partial cleft palate, cleft tongue, low nasal bridge, broad nasal tip, conductive hearing loss, lateral displacement of inner canthi
Associated features
Type I: Developmental delay (variable), asymmetric digits, polycystic kidney disease
Type II: Partial reduplication of the hallux and 1st metatarsal, bilateral polydactyly of the hands and polysyndactyly of the feet
Oto-palatal-digital syndrome
Inheritance
Type I: X-linked (intermediate expression in female carriers)
Type II: X-linked (mild expression in female carriers)
Genetic loci
Type I: Xq28
Type II: Xq28
Relevant features
Type I: Moderate conductive deafness, cleft palate, frontal and occipital bossing, thickened frontal bone and skull base, hypertelorism, small mouth and nose
Type II: Conductive hearing loss, cleft palate, frontal bossing, auricular anomalies (low set, malformed), flat nasal bridge, micrognathia, small mouth, down-slanting palpebral fissures
Associated features
Type I: Broad distal digits with short nails, developmental delay, small stature and trunk, pectus excavatum
Type II: Late closure of fontanels, microcephaly, flexed overlapping finger, short broad thumbs and hallux, bowing of radius, ulna, femur and tibia, flattened vertebral bodies
Pierre Robin′s sequence
Genetic loci: 2q32.3–q33.2 (in some cases)
General: Up to 80% of children with Pierre Robin′s sequence are also affected by a named syndrome (most commonly Stickler′s).
Relevant features: Triad = glossoptosis, micrognathia, cleft palate; airway and feeding difficulty
Associated features: Developmental delay, hypospadias, cryptorchidism, hernias
For further information on Pierre Robin′s sequence, see Chapter 8.8.
VATER association
Inheritance: Sporadic
Genetic loci: No chromosomal anomaly identified
Relevant features: Malformation of the vertebrae, anus, trachea, esophagus, radial and renal structures
VACTERL association: As above, plus cardiac and limb anomalies
Velocardiofacial syndrome (Shprintzen′s syndrome, 22q11 deletion syndrome)
Inheritance: Autosomal dominant
Genetic loci: 22q11 deletion
General: 10% associated with DiGeorge′s syndrome (hypocalcemia, thymic aplasia)
Relevant features: Velopharyngeal incompetence, high arched/cleft palate (overt or submucous), conductive hearing loss, square nasal root, prominent nasal dorsum, deficiency of nasal alae, retrognathia, medial displacement of carotid artery (25%)
Associated features: Mild developmental delay, short stature, cardiac defects (85%), increased risk of psychiatric disorders, slender hands/fingers
Van der Woude′s syndrome
Inheritance: Autosomal dominant
Genetic loci: 1q32 (incomplete penetrance)
Relevant features: cleft lip and/or cleft palate, lower lip pits, absent central/lateral incisors, canines, bicuspids
Associated features: Developmental delay, hypospadias, cryptorchidism, hernias
The following syndromes (of which hearing loss is a primary feature) are covered in Chapter 8.12:
Alport′s syndrome
Apert′s syndrome
Branchio-oto-renal syndrome
Connexin-26 deafness
Crouzon′s syndrome
Goldenhar′s syndrome
Jervell and Lange-Nielsen′s syndrome
Neurofibromatosis (NF1 and NF2)
Norrie′s syndrome
Osteogenesis imperfecta
Oto-palato-digital syndrome
Pendred′s syndrome
Stickler′s syndrome
Treacher Collins′s syndrome
Usher′s syndrome
Wildervanck′s syndrome
Waardenburg′s syndrome
X-linked hearing loss
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