DAVID ALBERT FRCS and FIONA CONNELL MBChB MRCPCH
Definition
A syndrome can be defined as a group of symptoms that collectively indicate or characterize a disease, psychological or congenital disorder.
The derivation is from ???-????? (Syn-drome) = running together.
Introduction
ENT surgeons dealing with children need to know the ENT features of a few common syndromes for example Down syndrome, Treacher Collins syndrome and Goldenhar syndrome, as they are likely to meet children with these conditions in their paediatric practice. The ENT surgeon may be presented with two distinct clinical scenarios. Firstly, a patient with a known syndrome who presents with an ENT problem. In this instance, the ENT surgeon needs to be aware of the ENT features of the syndrome so that the appropriate investigations and management can be instigated. The second and less common situation is when the ENT surgeon suspects that a child may have a syndrome which has not yet been diagnosed. This is rightly the province of the geneticist and while it is intellectually stimulating to try to piece together a syndrome it is best to avoid mentioning any suspicions at this stage. Much anxiety can otherwise result from ready access to the internet. Nevertheless they should know how to find out about these less common syndromes. This chapter provides a brief list of the more common ENT related syndromes. Referral to a geneticist is appropriate not only for children with undiagnosed conditions but also for those with the common syndromes so that genetic counselling and genetic testing can be offered both to the immediate family and also to those in the extended family. It may be surprising how many children with known genetic diagnoses who are under multiple hospital specialties, have never seen a geneticist.
A useful book to have in the ENT department is Smith’s Recognizable Patterns of Human Malformation. The book contains pictures of children with genetic syndromes and a brief description of the main clinical features. Also Gorlin’s Hereditary Hearing Loss and its Syndromes is a useful reference source, with a particular emphasis on syndromes incorporating deafness. The London Dysmorphology Database is a computerized database, which is searchable using clinical features, and contains pictures, a brief summary of clinical features, and an abstract as well as lists of useful published papers.
Syndromes of particular relevance to the ENT Clinician
Down syndrome
Genetics
Down syndrome is the most common chromosome disorder and ENT sequelae occur frequently. Most cases of Down syndrome arise from free trisomy of chromosome 21, although a small proportion are caused by translocations in which there is a high recurrence risk. The overall population incidence is between 1 in 650 and 1 in 800 live births. There is a well recognized relationship between increased risk of Trisomy 21 conceptions and maternal age. The risk of Down syndrome in women aged 35 years is 1 in 385 compared to 1 in 28 in women aged 45 years. Antenatal diagnosis is available.
ENT Features
Small ears
Narrow external ear canals: can make it difficult to view TM or insert grommet
Increased incidence of glue ear: age related
Otoacoustic emissions often non-reproducible, even in patients with normal
hearing ability
Abnormal ossicles
Mixed deafness (7%)
Sensorineural deafness (8%)
Airway obstruction from small PNS with large tonsils and adenoids
Macroglossia
Subglottis: one anesthetic tube size smaller than expected
Unstable neck with a risk of atlanto-occipital joint subluxation in 15%, especially during general anaesthetic
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General Features
Typical facial features
Brachycephaly
Upslanting palpebral fissures
Epicanthic folds Brushfield spots (speckling of iris)
Flat facial profile
Small nose with depressed nasal bridge
Mental retardation: variable IQ - can range from 20 to 85
Hypotonia: contributes to delayed motor milestones
Joint laxity
Congenital heart disease
Single palmar crease
Wide sandal gap (gap between first and second toes)
Other medical problems e.g. hypothyroidism, leukaemia
Other congenital problems e.g. duodenal atresia, Hirschsprung disease
Goldenhar Syndrome (Oculo-auriculo-vertebral spectrum/Hemifacial microsomia/First and second arch syndrome)
Genetics
Unilateral or bilateral, asymmetrical congenital defects involving the first and second branchial arches are seen in Goldenhar syndrome. Involvement of other systems is common and needs to be excluded in all cases. The aetiology of the condition is unknown and most cases are a single occurrence (i.e only one family member affected) although cases with dominant and recessive inheritance are reported in the literature. Reported risk factors include maternal diabetes, bleeding in early pregnancy, twinning, high altitude (commoner in populations living at high altitude) and teratogens (thalidomide, retinoic acid derivatives). Various chromosomal abnormalities have also been reported in cases of Goldenhar syndrome.
ENT Features
Microtia: variable severity ranging from partial to complete atresia of the auditory canal and from minor degrees of microtia to complete absence of the external ear. Although the condition is usually unilateral it may occasionally be bilateral but is nearly always asymmetrical (in contrast to another common branchial arch disorder, Treacher Collins syndrome, where the features are symmetrical – see below)
Preauricular skin tags or hillocks of tissue.
Skin tags: in line between tragus and corner of the mouth
Deafness: sensorineural and/or conductive
Macrostomia: occasionally with lateral facial clefting
General Features
Facial asymmetry
Epibulbar dermoid (in which case the acronym Goldenhar syndrome is used)
Vertebral defects
Cardiac defects
Renal anomalies
Mental retardation: uncommon and chromosome analysis should be performed when this is present
Treacher Collins syndrome
Genetics
Treacher Collins syndrome (TCS) is a disorder of branchial arch development and individuals have a characteristic facial appearance. It is inherited in an autosomal dominant manner and the only gene currently known to be associated is TCOF1. A high proportion of cases are caused by new mutations but significant clinical variability is common and so genetic testing may be extremely useful for recurrence risks. Classically, features are bilateral, symmetrical and congenital. There are a number of conditions in which facial features appear similar to Treacher Collins but these occur in association with limb anomalies (acrofacial dysostoses). They are caused by different genes and tend to have low recurrence risks but genetic review is important.
ENT Features
Microtia, dysplastic ears (bilateral ear anomalies)
Auricular pits/fistula/tags
Deafness: usually conductive due to external auditory canal atresia and malformations of the ossicles.
Cleft palate
Micrognathia: cleft palate and micrognanthia together may result in significant airway problems in neonates
Mandibular hypoplasia: occipitomental projection of skull and orthopantogram radiographs can assist in diagnosis
Flat malar region
Prominent nose
Broad mouth
Narrow nasopharynx
Choanal atresia (rare)
General Features
Typical facial features
Downslanting palpebral fissures
Coloboma of inferior eyelid
Sparse eyelashes
CHARGE syndrome (Coloboma – Heart defect – Atresia choanae – Retardation of growth and development – Genital defect – Ear anomalies and/or deafness)
Genetics
CHARGE syndrome has a reported prevalence of 1 in 12 000. Diagnosis of CHARGE syndrome is made on the basis of clinical findings and temporal bone imaging. Mutations in the gene CHD7 can be identified in approximately 65% of cases, mostly due to new mutations. In these cases the inheritance pattern is autosomal dominant.
Patients with choanal atresia (unilateral and bilateral) need to be worked up to exclude features of CHARGE syndrome. Cardiology, ophthalmology and endocrine opinions should be sought, as well as audiology and temporal bone imaging.
ENT Features
Choanal atresia/stenosis (unilateral or bilateral)
Outer ear: short, wide ear with deficient lobe, often protruding, asymmetric
Middle ear: ossicular malformations
Temporal bone abnormalities; absent or hypoplastic semicircular canals
Sensorineural deafness (mild to profound)
General Features
Coloboma – iris, retina, choroids, disc
Microphthalmia
Cranial nerve dysfunction: anosmia, facial palsy, swallowing problems
Genital hypoplasia
Developmental delay (ranges from mild to severe; those with absent semicircular canals will have significant motor delay)
Congenital heart disease
Cleft lip/palate
Facial features: prominent forehead and nasal bridge, flat midface
Growth deficiency
22q11.2 deletion syndrome (Velocardiofacial (VCF) syndrome/DiGeorge syndrome/Shprintzen syndrome)
Genetics
Microdeletion syndrome, inherited in an autosomal dominant pattern, in which the phenotype can be very variable. Features include characteristic facial features in many cases, heart defects, cleft palate, learning difficulties and immune deficiency. About 90% of probands have a de novo deletion of 22q.11.2, but the remaining 10% have inherited it from either parent. Diagnosed cytogenetically using Fluorescence in-situ Hybridisation (FISH).
ENT features
Palate:
Overt, submucous or occult cleft palate
Velopharyngeal insufficiency
Nasal speech (and regurgitation of fluids)
Ears:
Low set, posteriorly rotated ears
Small ears
Prominent/overfolded helices
Absent or hypoplastic ear lobules
Preauricular tags
Chronic otitis media possibly secondary to palatal problems
Sensorineural/conductive hearing loss
Narrow external auditory canals
Airway:
Upper airway obstruction
Chronic sinusitis
Trachael/Laryngeal:
Laryngeal web
Vascular ring
Laryngomalacia
General features
Many have a characteristic facial appearance:
Prominent nasal root
Bulbous nasal tip
Hypoplastic alae nasae
Nasal dimple/bifid nasal tip
Asymmetry of face when crying
Long face
Heart: (in order of frequency of occurrence)
Teratology of fallot
Interrupted aortic archTruncus arteriosus
VSD
Vascular ring
ASD
Other important features:
Mental retardation/developmental delay (variable)
Psychiatric illness
Short stature
Feeding difficulties
Immune deficiency
Parathyroid dysfunction: hypocalcaemia
Craniosynostosis Syndromes
Genetics
Crouzon, Apert, Muenke and Pfeiffer syndromes are part or the FGFR-gene related craniosynostosis syndromes. They follow an autosomal dominant inheritance pattern but new mutations are common. Saethre-Chotzen is a craniosynostosis syndrome, caused by mutations in the TWIST gene.
ENT features
Airway obstruction
Pinna abnormalities: low set, small or posteriorly rotated ears (prominent crus helices in Saethre-Chotzen).
External canal atresia
Middle ear abnormalities: both congenital ossicular fixation and eustachian tube dysfunction
Stapes fixation
Sensorineural deafness
General Features
Craniosynostosis
Hypertelorism
Proptosis
Syndactyly – Apert syndrome
Broad, short thumbs/toes – Pfeiffer syndrome
Alport Syndrome
Genetics
Condition characterised by nephropathy (proteinuria and haematuria) and sensorineural deafness. . It is caused by mutations in genes that code for collagen IV . X-linked Alport syndrome is the most common form, affecting males more severely, but autosomal recessive and dominant forms also exist and therefore it is vital that a thorough family history is obtained.
ENT Features
Hearing loss: high-tone sensorineural (mild to moderately severe) affecting 83% males and 57% females. Usually presents in school-age boys and exhibits a progressive deterioration. Adults tend to retain some hearing capacity and the impairment is more or less stable with time. Hearing aids can be of benefit.
General Features
Renal involvement:
· haematuria in childhood (males average age 3.5 years, females average age 9 years)
· proteinuria (never precedes haematuria, can develop into nephrotic syndrome)
· renal impairment (progression to end-stage renal failure in 100% of males, 15% of females)
Ocular lesions: lenticonus (most commonly anterior lenticonus) and macular flecks
Pendred syndrome
Combination of congenital deafness and thyroid dyshormonogenesis. As this often presents as non-syndromic deafness it is covered in chapter titled Non-syndromic deafness.
Usher syndrome
Genetics
Usher syndrome is characterized by sensorineural hearing loss and progressive retinitis pigmentosa. It is one of the most common types of autosomal recessive syndromic hearing loss and there are three usually distinct types recognized, types 1-3, based on the degree of hearing impairment and vestibular involvement. It presents initially as non-syndromic hearing loss until the RP is diagnosed.
· Type 1
Profound congenital sensorineural deafness
Absent vestibular function (resulting in delayed motor milestones).
(Such a presentation should prompt investigation for Usher syndrome. Children should have the option of cochlear implant assessment in view of the fact that they will ultimately develop severe visual handicap in addition to their deafness.)
Retinitis pigmentosa. Asymptomatic at first (but may be diagnosed presymptomatically by ERG) but symptoms of night blindness and tunnel vision become apparent around late childhood/early puberty.
· Type 2
Congenital mild/ severe sloping sensorineural hearing loss
Normal vestibular function.
RP. Onset is around puberty (slightly later than type 1 on average)
· Type 3
Progressive hearing loss, may be postlingual onset
Normal or absent vestibular function
Retinitis pigmentosa (later and more variable age of onset)
Alstrom syndrome
Genetics
Alstrom syndrome is a rare, autosomal recessive disorder caused by mutations in ALMS1 gene. It is characterised by retinal dystrophy, obesity and deafness. There is considerable clinical variability, even within sibships.
ENT Features
Progressive hearing impairment: tends to develop in second decade
General Features
Progressive retinal degeneration: no light perception by 20 years.
Visual problems can occur soon after birth and usually present within the first six months of life, presenting with photophobia and nystagmus. It is a cone-rod dystrophy in which cones are predominantly affected.
Obesity: develops during early childhood
Non-insulin dependent diabetes mellitus: develops in second/third decade
Renal complications: progressive chronic nephropathy
Cardiomyopathy
Other endocrine involvement
Branchio-oto-renal syndrome
Genetics
Autosomal dominant disorder characterized by external, middle and inner ear anomalies, branchial sinuses and renal dysplasia. It is caused by mutations in the EYA1 gene, and less commonly in the SIX-1 gene. Extreme clinical variability can be observed in the same family.
Patients with ear pits (with or without hearing loss) and branchial defects warrant a renal ultrasound scan.
ENT Features
Ear anomalies: pits in the prehelical region and dysplastic pinnae
Conductive (due to ossicular malformations), sensorineural, or mixed hearing impairment. Inner ear malformations may include Mondini dysplasia of the cochlea, and occasionally, dilated vestibular aqueducts.
Branchial fistulae and/or cysts
Hearing impairment is not always present but the prehelical ear pits are a very highly penetrant feature.
General Features
Renal malformations: duplex collecting system, hydronephrosis, dysplasia, unilateral or bilateral renal agenesis.
Pierre Robin sequence
Genetics
This condition is a disorder of embryological developmental characterized by a cleft palate and a small jaw. The primary anomaly is one of early mandibular retrognathia and this precipitates a sequence of events resulting in the features listed below.
ENT Features
Cleft palate
Retrognathia: airway obstruction, difficult intubation
Small open mouth
Myopathic facies
Prominent nose with squared-off nasal tip
Syndromes less commonly seen by ENT surgeons
Achondroplasia
Genetics
Achondroplasia is the most common cause of disproportionate short stature and affected individuals have a characteristic appearance. It is an autosomal dominant disorder, caused by activating mutations in the FGFR3 gene. Incidence is related to increasing paternal age. 80% of patients have de novo mutations.
ENT Features
Obstructive sleep apnoea or central apnoea
Adenotonsillar hypertrophy
Narrow nasopharynx
Frequent otitis media and glue ear
Sensorineural and conductive hearing loss
Midface hypoplasia
Neurological involvement: cervical spine stenosis can lead to apnoea/sudden death (anaesthetic risk), spinal stenosis/nerve root compression
General Features
Disproportionate short stature
Rhizomelic (proximal) shortening of the limbs. Limitation of elbow extension
Trident configuration of the hands
Tibial bowing
Thoracolumbar kyphosis in infancy
Exaggerated lumbar lordosis, which develops when walking begins
Large head with frontal bossing
Small chest leading to respiratory compromise in infants
Beckwith-Wiedemann Syndrome
Genetics
Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder caused by changes in the activity of growth promoting and suppressing genes, many of which are imprinted, found at 11p15 (including IGF2, H19, LIT1 and CDKN1C). The genetics of BWS are complex and there are different mechanisms responsible for this phenotype. 10-20% of BWS is caused by paternal uniparental disomy 11p15, causing increased expression of paternally expressed growth promoter genes (e.g. IGF2) and absence of maternally expressed growth suppressing genes (e.g. H19). 5-10% cases have mutations in CDKN1C. The recurrence risk depends on the underlying causative mechanism.
ENT Features
Macroglossia (nb. anaesthetic risk) which may occasionally require surgical reduction
Ear lobe creases and/or posterior helical ear pits
Prominent occiput
Naevus Flammeus: a strawberry mark commonly found on the forehead and eyelids
Cleft palate (rare)
General Features
Overgrowth: large birth weight, macrosomia, visceromegaly, hemi-hypertrophy. Growth rate slows around age of about 7/8 years.
Neonatal hypoglycaemia
Omphalocele
Embryonal tumour risk increased: Wilm’s tumour, hepatoblastoma, neuroblastoma, rhabdomyosarcoma
Renal anomalies
Neurofibromatosis type 2 (NF2)
Genetics
Clinically and molecularly distinct condition from Neurofibromatosis type 1. NF2 is inherited in an autosomal dominant pattern and is characterized by the presence of vestibular schwannomas. New mutations in the NF2 gene arise in approximately half of cases.
Diagnostic criteria: one of the following –
· Bilateral vestibular schwannomas
· 1st degree relative with NF2 AND
- Unilateral vestibular schwannoma
OR
- Any 2 of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
· Unilateral vestibular schwannoma AND any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
· Multiple meningiomas AND
- Unilateral vestibular schwannoma
OR
- Any 2 of: schwannoma, glioma, neurofibroma, cataract
ENT Features
Hearing loss, tinnitus or vertigo caused by Schwannoma of the cranial nerves: typically unilateral or bilateral vestibular (acoustic) neuromas. Can cause facial paralysis depending on nerve involvement.
All patients should be referred for genetic counselling as other family members may need to be monitored for the condition or tested to exclude it. Radiation therapy in NF2 patients should be considered carefully as radiation exposure, especially in childhood, can induce/accelerate tumour growth.
General Features
Other central nervous system tumours: meningiomas, ependymomas, spinal tumours, astrocytomas
Peripheral nervous system manifestations: peripheral/subcutaneous schwannomas, cutaneous neurofibromas, NF2 plaques
Café au lait patches
Ocular manifestations: cataracts, retinal hamartomas
Noonan Syndrome
Genetics
Noonan syndrome is a relatively common autosomal dominant disorder and many individuals have a typical facial appearance, as well as cardiac defects and short stature. Mutations in PTPN11 have been identified in 50% of patients. 5-10% of patients with Noonan syndrome have mutations in KRAS gene. Noonan syndrome has a clinically heterogeneous phenotype, even within families.
ENT Features
Low-set, posteriorly rotated ears
Webbing of the neck, low posterior hairline
Variable hearing loss
Micrognathia
General Features
Congenital heart disease: Pulmonary stenosis, ASD, VSD, Tetralogy of Fallot, hypertrophic cardiomyopathy
Mild mental retardation
Short stature
Sternal abnormalities
Widely spaced nipples
Cryptorchidism
Epicanthal folds
Ptosis
Osteogenesis Imperfecta (OI)
Genetics
OI is a group of inherited disorders, otherwise known as ‘brittle bone disease’. The COL1A1 and COL1A2 genes code for collagen type 1 and mutations in these genes are responsible for causing OI. Trivial trauma can result in fractures due to the skeletal fragility. The severity of the disease and deformities depends on the type of OI.
Type I is the commonest form and shows autosomal dominant inheritance. It is a relatively mild form which is non-deforming.
ENT Features (type 1 OI)
Hearing loss
General Features (type 1 OI)
Blue sclerae
Fractures
Mild short stature
Wormian bones visible on skull Xray
Prader-Willi syndrome
Genetics
Prader-Willi syndrome is one of the more common genetic conditions characterized by poor neonatal feeding and childhood-onset obesity as a result of hyperphagia. It is caused by the absence of the paternally derived Prader-Willi syndrome region on chromosome 15. There are several mechanisms by which this can arise for example paternal deletion, uniparental maternal disomy (two maternal copies of the critical region of chromosome 15 but no paternal copy), or abnormalities of methylation control which is the mechanism used to distinguish between maternally and paternally inherited chromosome regions
ENT Features
Obstructive sleep apnoea (OSA): secondary to obesity, a cardinal feature of the disorder.
The role of growth hormone (GH) in exacerbating OSA in Prader-Willi syndrome has been postulated following a series of fatalities of children with Prader-Willi syndrome on GH treatment. This is currently unproven but it has been suggested that GH leads to increased growth of lymphoid tissue in the airway thus worsening already existing hypoventilation or OSA.
General Features
Obesity with hyperphagia
Hypogonadism
Mental retardation
Difficult behaviour
Growth failure/short stature
Hypotonia: particularly in neonatal period
Stickler syndrome
Genetics
Stickler syndrome is a hereditary arthro-ophthalmopathy. Children have a characteristic facial appearance. It is inherited in an autosomal dominant manner and the clinical phenotype can be very heterogeneous, even within families. It is a collagen disorder and the responsible mutations are found in COL2A1 and COL11A1.
ENT Features
Pierre Robin sequence
Cleft palate
Micrognathia
Sensorineural deafness, may be progressive
Glossoptosis
Dental anomalies
Flat facies with depressed nasal bridge, anteverted nares (facial features most evident in childhood)
General Features
Severe myopia resulting from a congenital vitreous anomaly. At risk from retinal detachment.
Joint problems, especially joint hypermobility and premature arthritis
Turner syndrome
Genetics
Turner syndrome is caused by partial or complete absence of an X chromosome in some (Mosaic Turner syndrome) or all cells (Classical Turner syndrome) of the body. It has a frequency of about 1 in 1800 girls.
ENT Features
Increased incidence glue ear
Sensorineural deafness
Webbed neck
Low posterior hairline
General Features
Short stature
Ovarian dysgenesis
Coarctation of aorta, bicuspid aortic valve
Renal anomalies
Mild learning difficulties
Broad chest, widely spaced nipples
Increased carrying angle
Increased incidence of autoimmune conditions: hypothyroidism, coeliac disease, inflammatory bowel disease, diabetes mellitus
Waardenburg syndrome
Genetics
Waardenburg sydrome is the most common type of syndromic autosomal dominant syndromic hearing loss, characterized by hearing loss and pigmentary anomalies. There are four different types. Mutations in the PAX3 gene are responsible for types I and III. Types 1 and 3 are characterized by subtle craniofacial anomalies (below). In types 2 the appearance is normal as in type 4, which is characterized in addition by the association with Hirschprung’s disease. Mutation in the MITF gene cause some case of type II and the genes implicated in type IV include, EDNRB, EDN3 and SOX10.
ENT Features
Congenital sensorineural hearing loss
Hypoplastic nasal alae in type 1
High nasal bridge in type 1
Synophrys and medial eyebrow flare (type 1)
General Features
Pigmentary disturbances: heterochromia iridium, white forelock and eyelashes, premature greying of the hair, hypopigmentation of skin
Dystopia canthorum (lateral displacement of inner canthus of eye): type I
Limb anomalies in type 3 only.
Hirschprung’s disease in type 4 only.
Jervell and Lange-Nielsen syndrome
Genetics
Homozygous form of long QT syndrome characterized by profound congenital deafness (with absent vestibular function ie. delayed motor milestones) and long QT interval on ECG. This rare condition is inherited in an autosomal recessive manner. Disease-causing mutations in the potassium channel gene KCNQ1 and its accessory subunit KCNE1, are responsible. This is an important diagnosis to make because of its high mortality if untreated.
ENT Features
Congenital profound sensorineural deafness, with absent vestibular function.
General Features
Prolonged QTc interval on 12 lead electrocardiogram
Risk of torsade des pointes ventricular tachycardia
Risk of ventricular fibrillation which can culiminate in syncope or sudden death. Can be precipitated by general anaesthesia, fright/stress, exercise (particularly swimming).
Gorlin syndrome
Genetics
Gorlin syndrome is an autosomal dominant syndrome, otherwise known as naevoid basal cell carcinoma syndrome. It is caused by mutations in PTCH, a tumour suppressor gene.
ENT Features
Jaw cysts
Cleft lip and palate
Basal cell naevi/ basal cell carcinoma
General Features
Basal cell naevi/basal cell carcinoma
Macrocephaly
Frontal and biparietal bossing
Palmar/plantar pits
Ocular anomalies: cataracts, developmental defects
Calcification of falx cerebri
Rib or vertebral anomalies
Holoprosencephaly
Genetics
Holoprosencephaly is a genetically heterogeneous disorder. Chromosomal abnormalities are responsible for the majority of cases (e.g Trisomy 13, microdeletion of 7q36). Syndromic causes, familial autosomal dominant and de novo cases have all be described. There are five known genes implicated in the pathogenesis of holoprosencephlay to date (SHH, SIX3, TG1F, ZIC2 and PTCH).
ENT Features
Oral defects: ranging from midline cleft upper lip to single central incisor/absent frenulum
Premaxillary agenesis
Midface hypoplasia
Airway obstruction
Nasal defects ranging from ‘Proboscis’ nose to single nostril
General Features
Eye anomalies ranging from cyclopia or ocular hypotelorism
Mental retardation
Other midline anomalies: congenital heart defects, anal anomalies
Larsen syndrome
Genetics
Larsen syndrome is a rare skeletal dysplasia disorder. It is characterized by multiple joint dislocations and the facial phenotype. Autosomal dominant and recessive forms are reported. Mutations in FLNB (fibrilin B gene) have been found to be causative in the dominant form. Respiratory problems can occur due to upper airway compromise. Skeletal survey is required for diagnosis.
ENT Features
Tracheomalacia and laryngomalacia: lack of rigidity of tracheal and laryngeal cartilage resulting in subglottic stenosis
Flat or depressed nasal bridge
Cleft palate (uncommon)
Conductive hearing loss
General Features
Multiple joint dislocations
Short stature
Short fingers
Broad thumbs
Vertebral/spinal anomalies
Talipes
Hypertelorism
Moebius syndrome
Genetics
Rare condition of congenital cranial nerve palsies (predominantly affecting VIth and VIIth). Other cranial nerves can be involved and a range of other skeletal and orofacial abnormalities reported. It is usually sporadic but dominant transmission has been observed. Vascular disruption during embryogenesis has been implicated in the pathogenesis.
ENT Features
Small mouth
Micrognathia
Hypoglossia
Variable clefting or abberant attachments of tongue: causing restricted movement and speech problems
Cleft palate
Hypodontia
Hearing problems: glue ear
External ear malformations
General Features
Impassive face, facial asymmetry and strabismus due to congenital VI and VII palsy
Delayed motor milestones due to low muscle tone
Respiratory illnesses due to low muscle tone
Limb abnormalities ranging from aplasia to syndactyly
Mucopolysaccharidoses (MPS)
Genetics
Within this group of storage disorders each type has a distinct phenotype but they share many features. Progressive connective tissue organ involvement occurs, resulting from continuous storage of dermatan sulfate in the skeleton, heart valves, spleen, liver, and cornea. Patients appear healthy at birth and have accelerated growth in the first year, followed by deceleration and short stature later in childhood.
Mucopolysaccharidoses are inherited in an autosomal recessive manner with the exception of type II (Hunter syndrome), which is X-linked. For the purposes of this chapter the different types are not described individually but awareness of the ENT complications is advised.
(The features listed below are not universal to every type of mucopolysaccharidoses)
ENT features
Obstructive airway disease and obstructive sleep apnoea.
Diffuse infiltration around airway
Hearing loss
Atlanto-axial instability in types IV and VI
Coarse or rough facial features with thick lips, enlarged mouth and tongue
General Features
Short stature
Skeletal irregularities
Viscero-megaly particularly hepatosplenomegaly
Progressive joint stiffness
Heart disease
Corneal involvement in some types
Mental retardation in some types
Teratogenic syndromes
Fetal Alcohol Syndrome
Genetics
Heavy alcohol exposure in-utero can have multiple effects on the developing fetus. The resulting phenotype is variable.
ENT Features
Sensorineural hearing loss
Cleft lip +/- palate (uncommon)
General Features
Low birth weight
Growth retardation with disproportionately low weight to height relationship
Developmental delay especially impaired fine motor skills and cognition
Attention deficit disorder/behavioural difficulties
Flat malar region
Short palpebral fissues
Smooth philtrum with thin upper lip
Mild to moderate microcephaly
Fetal Cytomegalovirus syndrome
Severity of the syndrome depends on gestation at the time of intrauterine infection. Consequences of first trimester infection are relatively severe whereas third trimester infection can be asymptomatic in the fetus.
Features
Sensorineural deafness
Microcephaly
Learning difficulties and developmental delay
Chorioretinitis
Congenital rubella syndrome
Maternal infection prior to 16 weeks gestation can result in severe consequences for the fetus.
Features
Sensorineural deafness
Growth retardation
Mental retardation
Ophthalmic defects such as cataracts, pigmentary retinopathy
Congenital heart disease: PDA, peripheral pulmonary artery stenosis, septal defects
Summary
This chapter has covered some of the more common genetic syndromes that may be seen in the ENT clinic, with emphasis on ENT-related complications and features. With the advent of Newborn Hearing Screening, hearing loss is diagnosed early, and it is likely that the ENT surgeon may be one of the first health professionals to see a child with a syndrome. It is recommended that patients with features of a syndrome and their families are offered genetic counselling. The genetic review aims to offer a diagnostic service but in addition to this it is important that genetic testing is performed appropriately on the patient and necessary family members. It is also necessary for the family to receive counselling regarding inheritance patterns, recurrence risks and available prenatal diagnosis options. As many of the ENT-related complications will be recurrent, the ENT surgeon may well wish to find out more about the rarer syndromes of those children and adults under his or her care.
Acknowledgements
Maria Bitner-Glindzicz, Reader in Clinical and Molecular Genetics, Institute of Child Health and Great Ormond Street Hospital, London.
Figures (consent acquired in all cases when this was necessary)
1. Goldenhar’s syndrome
2. Treacher-Collins syndrome
3. Crouzon’s syndrome
4. Branchio-oto-renal syndrome (BOR), showing malformation of the pinna and a branchial sinus
5. Pierre-Robin syndrome, showing severe retrognathia, which in this case required a tracheotomy
6. Beckwith-Wiedermann syndrome, showing macroglossia
7. Cornelia de Lange syndrome
8. CHARGE syndrome
9. Waardenburg syndrome
10. Blue sclerae, in a case of osteogenesis imperfecta
References:
Smith’s Recognizable Patterns of Human Malformation. KL Jones. W.B Saunders Company
Oxford Desk Reference Clinical Genetics. HV Firth and JA Hurst. Oxford Medical Publications
Gorlin (Head and Neck and Hereditary Hearing Loss)
LDDB (London Dysmorphology database)
