1. A Review of Pediatric Syndromes
Jamie Tibbo, PGY-5
Department of Otolaryngology
July 25, 2008

2. CHARGE Syndrome Autosomal Dominant
Due to a mutation in DNA-binding protein-7 (CHD7) gene
Coloboma- posterior chamber(80%)
Heart anomalies (85%)
Atresia of choana (57%)
Retardation- growth(80%) & mental (70%)
Genital defects (in males)
Ear anomalies (90-100%) & deafness(62%)
Usually bilat and mixed hearing loss

3. DiGeorge Syndrome
Genetic disorder due to microdeletion of Chromosome 22q11.2 (tbx-1 gene)
The same genetic defect as VCF with different phenotypic expression
Characterized by:
Hypocalcemia (due to hypoplastic parathyroids)
Immunodeficiency due to hypoplastic thymus
Congenital heart defects of the outflow tracts (aorta and pulmonary artery).
Reference:

4. Pendred Syndrome Autosomal recessive
SNHL associated with iodine metabolism defect leading to euthyroid goiter
Thyroid abnormality detcted with a perchlorate discharge test (shows abnormal organification of nonorganic iodine)
Temporal bone imaging often show Mondini malformation or enlarged VA’s

5. Treacher-Collins Syndrome (Mandibulofacial dysostosis)
Autosomal dominant, 40% will have family history, other 60% new mutations
TCOF1 gene found on chromosome 5q (TREACLE gene)
Malformation of 1st (& 2nd) branchial arches
Otologic: Malformed ossicles, auricular deformity, aural atresia, CHL present 30% of time, occasional SNHL
50% will have hearing impairment from EAC and/or middle ear malformations
Preauricular fistulas, mandibular and malar hypoplasia, antimongoloid palpebral fissures, coloboma of the lower eyelids, may have cleft lip and palate, normal IQ

6. Treacher-Collins Syndrome (Mandibulofacial dysostosis)
Figure Treacher Collins syndrome. Zygomatic and mandibular hypoplasia, lower lid colobomas, and downslanting palpebral fissures.
Reference: Bailey’s Otolaryngology-Head & Neck Surgery

7. Alport Syndrome 6 subtypes: 3 AR, 3 X-linked
Progressive SNHL (usually 2nd decade)
Varying degrees of renal disease (renal agenesis to mild renal dysplasia identifiable on ultrasound)
Renal disease can be severe in men/boys

8. Apert (acrocephalosyndactyly)
Autosomal dominant, most cases due to spontaneous mutation
Due to a mutation of FGFR-2 (Fibroblast Growth Factor Receptor) gene (10q26)
Common findings:
Craniosynostosis (pre-mature fusion of the cranial sutures)
Severe symmetrical syndactyly
Low-set ears
Cognitive function normal to severe mental retardation
Eyes: down-slanting palpebrael fissures, Hypertelorism, Exophthalmos
Midface hypoplasia
Mandibular prognathism
Possible cleft palate
Nose: Parrot-beaked nose, possible Choanal Atresia
Syndactyly and cervical fusion

9. Apert (acrocephalosyndactyly)
Figure 99.4 Apert syndrome has the additional feature of
syndactyly.
Reference: Bailey’s Otolaryngology-Head & Neck Surgery

10. Crouzon Syndrome (Craniofacial Dysostosis)
Autosomal dominant, 50% due to spontaneous mutations, complete penetrance, variable expresivity
Due to mutation of FGFR-2 (Fibroblast Growth Factor Receptor) gene (10q26)
Common findings:
Craniosynostosis (pre-mature fusion of the cranial sutures)
Hypertelorism
Exophthalmos
Midface hypoplasia
Mandibular prognathism
Parrot-beaked nose
No Syndactyly or cervical fusion
Cognitive function normal to severe mental retardation

11. Branchiootorenal Syndrome (Melnick-Fraser Syndrome)
Autosomal dominant, involves 8q between D8S87 and D8S165 (EYA1 gene)
Branchial cleft anomalies (63%): cysts or fistulae
Otologic malformations:
hearing loss (89%)
preauricular pits (77%)
auricle abnormalities (41%)
ossicular & cochlear malformations
2% of children with severe/profound SNHL
Renal Dysplasia (66%)
agenesis, polycystic kidneys, duplicated ureters; renal abnormalities identifiable on IVP or renal U/S

12. Branchiootorenal Syndrome (Melnick-Fraser Syndrome)
Figure 99.6 Branchio-oto-renal syndrome. This 3-year-old boy has visible cup-ear deformities. He also has branchial cleft fistulae and only one kidney.
Reference: Bailey’s Otolaryngology-Head & Neck Surgery

13. Down Syndrome Craniofacial Features: Brachycephaly Flat occiput
Abnormal small ears
Upslanting palpebral fissures
Epicanthic folds
Short small nose
Midface hypoplasia
Large fissured lips
Large fissured tongue
Dental abnormalities
Short neck
Atlantoaxial subluxation & instability

14. Goldenhar Syndrome (Oculoauriculovertebral spectrum)
Characterized by unilateral facial asymmetry, unilateral external & middle ear changes, vertebral malformations
Ocular findings: upper lid colobomata
Otologic findings: mildly deformed ears to anotia, EAC atresia, ossicular abnormalities
Underdevelopment of mandible, orbit, facial muscles, also may have hemivertebrae of vertebral column
Hemifacial macrosomia often placed in this category
Most cases sporadic, some autosomal dominant reported

15. Goldenhar Syndrome (Oculoauriculovertebral spectrum)
Figure 99.8 Goldenhar syndrome. This 5-year-old boy has facial asymmetry and right microtia.
Reference: Bailey’s Otolaryngology-Head & Neck Surgery

16. Jervell Lange-Nielsen Syndrome
Autosomal recessive; one form linked to a potassium channel gene (KVLQT 1) on 11p15.
Classic presentation:
Deaf child who experiences syncopal episodes during periods of stress, exercise, fright
Profound bilateral congenital SNHL (high frequencies worse)
Heart disease: prolonged QT, large T waves, Stokes-Adams attacks (Cardiac syncope)
Usually terminates fatally with sudden death; treated with ß-blockade

17. Noonan Syndrome
Originally thought to be a variant of Turner Syndrome- used to be referred to as “male version of Turner Syndrome”
Autosomal Dominant
PTPN11 gene (12q24)
Clinical Findings:
Growth Development: 80% have short stature
Facial Features:
Triangular face, hypertelorism, down-slanting eyes, ptosis, strabismus (48%), amblyopia (33%), refractive errors (61%), low-set ears with thickened helices, high nasal bridge, short webbed neck.
Otologic Features: progressive HF-SNHL in up to 50%
Chest/Back Features: pectus carinatum/excavatum, scoliosis
Cardiac Features: pulm valve stenosis common, possibly any defect
Abdominal Features: hepatosplenomegaly (25%)
Genitourinary Features: renal anomalies (10%), undescended testes (50%)
Skeletal Features: bleeding diasthesis,joint laxity (50%), radioulnar synostosis, cervical spine fusion
Skin Findings: lymphedema, prominent pads fingers and toes (67%), follicular keratosis of face and extensor surfaces (14%)
Neurologic Features: hypotonia, Sz disorder (13%)

18. Pierre-Robin Sequence
Triad of:
Retrognathia
Glossoptosis
Cleft palate
Pathology: due to retrognathia which prevents descent of the tongue into the oral cavity; prevents secondary palate fusion
Associated with a syndrome in 50-80% of cases, most commonly Stickler & VCF syndromes

19. Pierre-Robin Sequence
Figure Robin sequence. This infant required a tracheostomy because of airway compromise from severe micrognathia.

20. Stickler Syndrome
Autosomal dominant, mutation of COL2A1 gene on chromosome 12
responsible for type II collagen gene
COL2A1: typically mild and not significantly progressive hearing loss
COL11A1: more severe hearing loss
COL11A2: non-ocular Stickler syndrome, hearing like COL11A1
Small jaw with Robin sequence & cleft palate
Myopia with retinal detachment & cataracts
Hypermobility & enlarged joints, early onset arthritis, occ. spondyloepiphyseal dysplasia
SNHL or mixed HL in 80%, educationally significant in 15%

21. Usher Syndrome Autosomal recessive, 10% of hereditary deafness
Retinitis pigmentosa causing progressive visual loss.
Patients born deaf secondary to atrophy of organ of Corti.
Ataxia and vestibular dysfunction common
Eye changes detected on electroretinography even before funduscopic changes identified; ophthalmology consult essential

22. Usher Syndrome Four main types:
Type I: profound congenital deafness, RP onset by age 10, no vestibular response; 90% of Ushers
Type II: moderate/severe congenital deafness, onset of RP in teens/twenties, normal or decreased vestibular response, 10% of all cases
Type III: progressive HL, RP begins in puberty, <1% of cases
Type IV: X-linked inheritance, similar to type II

23. Velocardiofacial Syndrome (Shprintzen Syndrome)
Autosomal dominant, characterized by abnormal facies, VPI, CLP, and cardiac anomalies
Hemizygous microdeletion of 22q11
Almond shaped palpebral fissures, deficient nasal alae, tubuar nose with bulbous tip, small mouth
Long face with vertical maxillary excess, malar flatness, mandibular retrusion
Palatal clefting ranges from submucus clefting to overt wide cleft palate with hypernasality
Cardiac anomalies in 80%, most commonly VSD; other anomalies include right sided aortic arch, tetralogy of Fallot, aortic valve disease
Medial displacement of ICA’s present in up to 25% of patients

24. Velocardiofacial Syndrome (Shprintzen Syndrome)
Figure Velocardiofacial syndrome. Broad nose, triangular face, palatal incompetence.

25. Waardenberg Syndrome
Defined by the presence (type I) or absence (type II) of dystopia canthorum; SNHL occurs in 20% in Type I, 50% in Type II
Autosomal dominant
Type I gene locus PAX3 on chromosome 2
Type II gene locus MITF (microphthalmia transcription factor) on chromosome 3 (20% of cases)
Clinical findings
Pigment abnormalities: white forelock, premature graying, vitiligo, heterochromia iridis
Craniofacial abnormalities (dystopia canthorum, broad nasal root, synophrys)
Unilateral or bilateral SNHL
Klein-Waardenburg (Type III): features of WS1 plus blue eyes, hearing impairment, upper limb skeletal dysplasias, muscular hypotonia
Waardenburg-Shah (Type IV): phenotype similar to WS2 plus Hirschprung megacolon; AR

26. Waardenberg Syndrome
Type I: Dystopia canthorum present; this condition is 20 times more common than type II.
Type II: Dystopia canthorum not present; hearing loss is more common in this type (50%) as well as pigmentary disorders.
Type III: Klein-Waardenburg syndrome or pseudo-Waardenburg, no dystopia canthorum but with one-sided ptosis of the upper eyelid and upper limb anomalies.

27. Waardenberg Syndrome
Figure Waardenburg syndrome. This mother and daughter have Waardenburg syndrome type I. Both have hearing loss and dystopia canthorum. The child also has heterochromia irides.

28. Neurofibromatosis 1 (Von Reklinghausen Disease)
Diagnostic criteria includes 2 or more of the following:
Six or more café au lait macules larger than 5 mm in the greatest diameter in prepubertal children and larger than 1.5 cm in postpubertal individuals
Two or more neurofibromas of any type or 1 plexiform neurofibroma
Multiple freckles (Crowe sign) in the axillary or inguinal region
A distinctive osseous lesion, such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudoarthrosis
Optic glioma
Two or more iris hamartomas (Lisch nodules) seen on slitlamp or biomicroscopy examination
A first-degree relative (parent, sibling, offspring) with same disease, as diagnosed by using the above criteria.

29. Neurofibromatosis 1 (Von Reklinghausen Disease)
Mental retardation, learning disabilities, and speech defects are not uncommon
Autosomal dominant. NF1 gene location is in the 17q11.2 region. Fresh mutations represent about 50% of cases

30. Neurofibromatosis 2
Autosomal dominant, with 95% penetrance and linkage to 22q11-q13. The gene has been isolated, and encodes a protein named merlin
Diagnostic criteria include the following:
Bilateral acoustic neuroma seen with CT or MRI or
A first-degree relative with the disease and either unilateral 8th nerve mass, or two of the following:
neurofibroma
meningioma
glioma
schwannoma
juvenile posterior subcapsular lenticular opacity

31. Kartagener Syndrome
Autosomal recessive inheritence. Autosomal dominant or X-linked inheritance has also been suggested
Pansinusitis in childhood, absence of the frontal sinuses, and thick nasal rhinorrhea
Anosmia and nasal polyps are frequent complications.
Mastoid air cells are poorly developed.
Otitis media as a result of eustachian tube dysfunction results in deafness, usually of the conductive type
Recurrent pneumonia and chronic cough are common.
Situs inversus with gross defects in cardiac septation may occur. One-sixth of situs inversus cases have the syndrome
Immobility of the sperm produces sterility in the males; affected females may have decreased fertility. The lack of dynein arms is the most common structural abnormality in the respiratory and fallopian cilia and the sperm tails

32. Sturge-Weber Syndrome (Encephelotrigeminal angiomatosis)
Present at birth with seizure and large port-wine birthmark on side of face
Capillary malformation of the ophthalmic division of the trigeminal nerve.
Associated with vascular malformations of the leptomeninges, leads to ischemic atrophy and cortical calcification
Clinically causes seizures, focal neurologic deficits, developmental delay

33. Pfeiffer’s syndrome
Similar to Apert Syndrome but have digital broadening rather than syndactyly

34. Harlequin Syndrome Severe ichthiosis syndrome
Also known as Ichtheosis Fetalis
Autosomal Recessive
Mutation in the lipid-transporter gene ABCA12 on chromosome 2.
Ears: The pinnae may be small and rudimentary or absent.
Nose: Nasal hypoplasia and eroded nasal alae may occur.

35. Moebius Syndrome (Congenital Facial Diplegia)
Expressionless Face
absence or underdevelopment of the 6th and 7th cranial nerves
First symptom, present at birth, is an inability to suck.
Other symptoms can include: feeding, swallowing, and choking problems; excessive drooling; crossed eyes; lack of facial expression;; eye sensitivity; motor delays; high or cleft palate; hearing problems; and speech difficulties.
Small or absent brain stem nuclei that control the cranial nerves, as well as decreased numbers of muscle fibers, have been reported.
Deformities of the tongue, jaw, and limbs, such as clubfoot and missing or webbed fingers, may also occur. As children get older, lack of facial expression and inability to smile become the dominant visible symptoms.
Reference:

36. Mobius Syndrome (Congenital Facial Diplegia)
Reference:

37. Maffucci syndrome Multiple cavernous hemangiomas
Dyschondroplasia & shortening and deformity of involved bones
Occasional visceral vascular lesions
25% incidence of chondrosarcoma

38. Kasabach-Merritt syndrome
Up till recently associated with hemangioma; skin lesion with red/brown discoloration that suddenly enlarges into a violaceous plaque
Characterized by platelet sequestration, ecchymosis, no female predominance
Histologic lesion: a tufted angioma or kaposiform hemangioendothelioma
Management supportive; heparin contraindicated, use of blood products avoided because of increased trapping within lesion; anemia treated with PRBC’s

39. Melkersen-Rosenthal Syndrome (Chelitis Granulomatosa)
Most cases of sporadic. Familial occurrences suggest an autosomal dominant transmission
Recurrent or persistent lip swelling, facial swelling, facial palsy and furrowed tongue
Swelling of the lips is usually of sudden onset, unilateral, or bilateral. The upper lip is affected in most cases and may remain swollen permanently. This occurs in 75% of patients.
Histologically the swollen tissues exhibit chronic granulomatous changes similar to sarcoidosis or tuberculosis
Auditory and visual disturbances, swelling in the hands and chest, blepharospasm, epiphora, and megacolon may be seen.
The disease begins in childhood or early adulthood.
It is considered a local immune response and vasomotor disturbance affecting the vasa vasorum of the vessels supplying the facial nerve and neighboring structures
Reference: Bailey’s Otolaryngology-Head & Neck Surgery

40. References/Acknowledgments
Bailey’s Otolaryngology-Head & Neck Surgery
Cumming’s Otolaryngology-Head & Neck Surgery
University of Alberta Otolaryngology Notes