b p.664). b p.182). Antenatal/perinatal (30%) \200 \200 \200 \200 b pp.188, 920). Retinopathy of prematurity ( Hypoxic ischaemic encephalopathy ( Cerebral damage. Optic nerv e hypoplasia. b p.172). Postnatal (20%) \200 \200 \200 Trauma. Infection, e.g. ophthalmic herpes simplex. Juvenile idiopathic arthritis: iritis (b pp.768, 915). Delayed visual maturation Delayed visual maturation Babies with delayed visual maturation ( DVM) appear blind in the \201 rst few months, but their visual behavior improves with age . There are 3 forms: \200 Isolated DVM: and full development of vision between 3 \200\2236mths of age. Motor developm ent may also be delayed. DVM associated with cerebral visual impairment cerebral palsy may initially appear blind. The vision usually improves over years, but may be impaired. DVM as sociated with ocular disease: cataracts, and nystagmus can interfere with early visual deve lopment. Vision improves over years, but with residual de \201 cit. there is no underlying pathology and there is a rapid : e.g. infants with congenital ocular disease, e.g. Children with DVM should be monitored for general developmental issues. Visual impairment t eachers should be involved to help parents to stimulate visual development. 24_McClure_24.indd 912 11/14/2012 3:31:59 PM NYSTAGMUS 913 Nystagmus Nystagmus is an involuntary rhythmic oscillation of one or both eyes (see Table 2 4.2). The direction of the fast phase, the frequency and amplitude of the nystagmus should be noted. Acquired nystagmus always requires investigation (neuro-imaging and/or electrophy siology). Nystagmus may also occur if there is muscle paralysis or weakness (e.g. secondary to myasthenia gravis) (see b p.544). Table 24.2 Types and patterns of nystagmus Type Pattern/cause Congenital motor nystagmus Horizontal jerk Sensory nystagmus (poor vision) Usually horizontal jerk Vestibular nystagmus Horizontal jerk Neurological nystagmus Jerk nystagmus beats towards and worse on lateral gaze Gaze paretic High frequency, low amplitude, any direction. Seen in white matter disorders Pendular Seen with posterior fossa disorders, e.g. downbeat with Arnold-Chiari malformation Upbeat/downbeat One eye elevates while the other depresses,: midline disorders/para-sellar masses See-saw Opsoclonus/ocular \202 utter Bursts of high frequency saccades in all directions, e.g. opsoclonus-myoclonus syndrome 24_McClure_24.indd 913 11/14/2012 3:31:59 PM CHAPTER 24 Special senses 914 Disorders of the eye: infection and in \202 ammatory Eye infections are common in childhoo d and largely due to bacterial or viral infections affecting the conjunctiva. Neonatal conjunctivitis \200\230Sticky eyes \200\231 Common in the neonatal period startin g from the 3rd or 4th day. Swabs are usually negative for signi \201 cant pathogens. Simpl e cleaning measures are usually suf \201 cient. Bacterial infection with either Staphyloco ccus aureus, Pseudomonas aeruginosa, or streptococcal pathogens can occur. (See also b p.14 6). Treatment Topical antibiotic ointment is indicated, e.g. neomycin. Gonococcal conjunctivitis Should be suspected if purulent discharge with swelling of the ey elids oc- curs within the \201 rst 48hr of life. Treatment IV antibiotics required, e.g. cephalosporin. Chlamydial conjunctivitis Usually presents at the end of the \201 rst week of life. Diagn osis established by speci \201 c monoclonal antibody test performed on conjunctival secre- tions. Treatment Two-week course of oral erythromycin or topical tetracycline eye ointment is requ ired. Childhood conjunctivitis May be due to bacteria (e.g. Gram +ve cocci or Haemophilus in \202 uenzae), virus (e.g. adenovirus), or to allergic reaction. Treatment Speci \201 c antibiotic eye drops or ointment (e.g. fusidic acid or gentamicin) for 5 days is required. Allergic conjunctivitis Acute allergic conjunctivitis can cause rapid onset lid swelling an d chemo- sis (conjunctival oedema). Seasonal/perennial forms present with other features of atopy. Vernal kerato-conjunctivits is a chronic allergic con- junctivitis which is painful and can cause photosensitivity due to corneal involvement. Topical mast cell stabilizers a nd antihistamines can improve symptoms. Topical steroids are occasionally necessary, but sh ould only be prescribed by a specialist. 24_McClure_24.indd 914 11/14/2012 3:31:59 PM DISORDERS OF THE EYE: INFECTION AND INFLAMMATORY 915 Peri-orbital cellulitis See b pp.718, 919 Keratitis Keratitis is an in \202 ammation or in fection of the cornea, which can lead to corneal scarring and requires urgent specialist ma nagement. Symptoms in- clude FB sensation, pain, and photophobia with a red eye. It can occ ur due to viral infection, e.g. HSV or adenovirus in conjunction with skin lesions or conju nctivitis. Bacterial keratitis can occur secondary to corneal exposure in the hospital sett ing or secondary to contact lens use. Staphylococcal hypersensitivity is a common cause of keratitis in children with blepharitis. Keratitis can also occur as a toxic effect of chemo therapy. Iritis Also known as anterior uveitis. Refers to in \202 ammation of the uveal tract struc tures (i.e. iris, ciliary body, and choroids). It is characterized by symp- toms of: \200 \200 \200 \200 Ocular pain. Photophobia. Excessive lacrimation. Blurred vision. Signs include: \200 Redness. \200 Miosis. \200 Keratic precipitates on ophthalmoscopi c examination. Long-term disease may be complicated with the development of cataract, glaucoma, and macula r eye degeneration. Causes of iritis \200 \200 \200 e.g. herpes simplex/zoster. Local infection: Trauma or surgery. Systemic disease: \200 Seronegative arthritides \200\224 Reiter \200\231s syndrome, psoriatic arthritis (b pp.777 \200\223779). b p.332). \200 IBD ( \200 b p.768). JIA ( \200 Sarcoidosis. \200 Beh et \200\231s disease. HLA-B27 positive, ankylosing spondylitis, Management Referral to the ophthalmologists and treatment with topical steroid drops/ointme nt and mydriatic agents are required. 24_McClure_24.indd 915 11/14/2012 3:31:59 PM CHAPTER 24 Special senses 916 Eye foreign body Small FBs are usually cleared by tear \201 lm. Occasionally they may lod ge underneath the upper eyelid or become embedded in the cornea caus- ing intense irritatio n and excessive lacrimation. Examination of the eye to locate and remove the FB should be c arried out. \200 \200 Instill topical anesthetic drops. Perform a visual acuity check (where appropriate) and fun doscopy \200\224 examine the anterior chamber and tear \201 lm with a bright light (best done with a slit lamp) and examine the conjunctival sacs. A loose FB usually adheres to a s wab lightly touched to the surface of the conjunctiva, or will be washed out by copious irr igation with saline. Referral to the ophthalmology team to exclude any corneal abrasion cau sed by the FB is usually required. Cataract This refers to an opaci \201 cation of the lens. It may be congenital or ac- quir ed. Causes of cataract \200 Inherited/genetic: \200 \200 Congenital maternal infection: T rauma. Radiotherapy. In \202 ammation: Infection. Metabolic syndromes: \200 galactosaemi a( \200 Wilson \200\231s disease ( \200 Lowes \200\231; \200 Fabry \200\231s ( Other syndromes: Drugs: myotonic dystrophy; Walker-Warburg syndrome. \200 \200 \200 \200 \200 e.g. rubella, toxoplasmosis (b p.182). e.g. chronic iritis. b p.967); b p.976); b p.968). \200 e.g. trisomy 21. e.g. long-term steroid therapy. Absence of the normal bilateral red re \202 ex, or the presence of a white re \202 ex on ophthalmoscopic examination, should raise suspicion of an underlying cataract and immediate referral to an ophthalmologist is required. 24_McClure_24.indd 916 11/14/2012 3:31:59 PM GLAUCOMA 917 Glaucoma This condition is associated with raised intraocular pressure; disc cupping, and v isual \201 eld loss. Primary open angle and secondary closed angle glau- coma are rare in childhood. Congenital glaucoma is also rare and may be due to the abnormal development of the anterior chamber angle. Later-onset glaucoma may result from syndromes that effect eye develop- ment. The infant eye, unlike the adult, can enlarge enormously with high intraocul ar pressures (buphthalmos, \200\230ox-eye \200\231), developing a hazy cornea and excess l acrimation. The treatment is surgical, but is often unsuccessful. Visual prognosis is poor and often results in blindness. 24_McClure_24.indd 917 11/14/2012 3:32:00 PM CHAPTER 24 Special senses 918 Orbit and eyelids Blepharitis and meibomian cyst/chalazion Blepharitis is a common chronic in \202 ammation of the lid margin, which can result in recurrent styes, meibomian cysts a nd, occasionally keratitis. The eyelid margins are red and crusty. Parents should clean their child \200\231s lid margins using a \202 annel soaked in a han d-hot mild baby shampoo solution at bath time. An antibiotic ointment e.g. chloramphenicol can then be applied to the lid margins with a \201 nger- tip. Styes and cysts often respo nd to this treatment too. If a meibomian cyst persists for months and becomes hard, incisio n, and curettage under GA may be required. Congenital eyelid abnormalities \200 Entropion in children. Lower lid are in turned due to a fold of skin close to the lid margi n. This is seen more commonly in oriental children and resolves as the face grows although repeated corneal abrasion may necessitate surgical correction. Congenital bilateral ptosis. Neurological causes can be excluded clinically. If the lid covers the visual axis, amblyop ia will rapidly ensue. Occlusion therapy may be required but, unless the ptosis is severe, surgery is delayed until pre-school age. (in-turned lid) and ectropion (out-turned lid) are uncommon epiblepharon can resemble entropion since the lower lashes ptosis due to levator dystrophy can cause unilateral or Congenital naso-lacrimal duct obstruction \200 \200 A common cause of watery and sticky eye(s) in infancy. Concurrent conjunctivitis is unusual and the eyes are white despite copious discharge. The majority will improve in the \201 rst few months of life. Advise parents to massage the lacrimal sac (located just inferiorly to the medial canthus) \201 rmly with a \201 nger when the baby is feeding. This will express the sac contents into the palpebral \201 ssure where the discharge can be cleaned away with sterile water and a cotton wool pad. It is not necessary to swab the eye or star t topical antibiotics if the eye is white. Symptoms persisting beyond 12mths warrant referr al for consideration of syringe and probing of the tear ducts. \200 Capillary haemangioma of the lid \200 These may be deep and bluish or a super \201 cial \200\230strawberry \200\231 naevus. It can enlarge and cause amblyopia due to ptosis or induced astigmatism in the \201 rst year s of life. Occlusion therapy and spectacle correction are often necessary. Oral propranolol is effective at shrinking the lesion and has replaced oral and steroid injections in the m anagement of sight threatening haemangioma. \200 24_McClure_24.indd 918 11/14/2012 3:32:00 PM ORBIT AND EYELIDS 919 Exclusion of a congenital heart defect and intra-cranial haemangioma associated with PHACES syndrome is necessary prior to propranolol therapy. Port wine stains affected side. Ophtha lmic referral is required for screening. involving the eyelids may cause glaucoma on the Pre-septal, peri-orbital and orbital cellulitis See b p.718 Pre-septal cellulitis \200 This is a bacterial infection involving the eyelids and tissue anterior to the orbital sept um. The source may be from skin, e.g. an infected insect bite, trauma or meibomian cyst, da cryocystitis (lacrimal sac abscess) or deeper, such as sinusitis. Commonest organisms are S treptococcus. Pre-septal cellulitis in a well child can be treated with oral antibiotics. S ince orbital involvement can develop within in hours, children with severe pre-septal cellu litis secondary to URTI who are systemically unwell should be admitted and started on IV an tibiotics (see Orbital cellulitis). Staph. aureus and B haemolytic Peri-orbital cellulitis \200 Infection of the peri-orbital skin. This is usually due to infection by either S. aureus or H. in \202 uenzae type b (if not immunized). May occur s to paranasal or dental abscess i n older children. Children are often systemically unwell with fever, erythema, and tenderne ss over the affected area. This requires prompt treatment with a 5 \200\2237-day course of IV antibiotics. Untreated peri-orbital cellulitis may develop into orbital cellulitis with evolving ocular proptosis, limited ocular movement, and decreased visual acuity. May rarely be complicated with intracranial abscess formation, meningitis, or cavernous sinus thrombo sis. A CT scan of brain should be considered to exclude these complications if suspected. Orbital cellulitis \200 Infective orbital cellulitis arises from bacterial infection of the para- nasal sinuses (co nsider fungal infection in immunosuppressed children). Features include peri-orbital oedema , proptosis, and limited eye movements. An ophthalmic emergency, failure to treat adequatel y will result in visual loss and, potentially, cavernous sinus thrombosis. High dose IV sec ond generation cephalosporin (and metronidazole if over 8yrs) without delay. Nasal deconges tants can be helpful. Children should be co-managed with the ophthalmology and ENT teams. C T scanning may detect orbital abscess formation, which requires surgical drainage. 24_McClure_24.indd 919 11/14/2012 3:32:00 PM CHAPTER 24 Special senses 920 Back of the eye problems Endophthalmitis Infection within the eye may be endogenous (spread of bacterial or fungal infection from the bloodstream) or exogenous (s to trauma or surger y). Symptoms may vary in severity, but include achy pain, photophobia, \202 oat- ers, and loss of vision, the eye is usually red and a pus level within the an- terior chamber (hypo pyon) may be seen. Endophthalmitis requires emer- gency ophthalmic referral and management with systemic and intra-vitreal agents to prevent blindness. Retinopathy of prematurity See also b p.188. This is a \201 brovascular proliferative ret inal disorder occurring in preterm and low birth weight infants. Its development has been a ssociated with high concentrations of inspired oxygen during the neonatal period. Normal re tinal vascularization is not complete until full term. In preterm infants this process is i nterrupted and, on restart- ing, may proceed abnormally with aberrant and proliferative new vessel formation. ROP screening Infants born <31wks gestation, or weighing <1500g are screened from 6wks of a ge until the retina has vascularized. Treatment Indirect laser therapy is used in severe cases. Other medical conditions causing retinopathy Sickle cell disease The deformed RBCs in sickl e cell disease may cause retinal vascular occlu- sion or ischaemia. A proliferative retinop athy with new vessel formation, or a non-proliferative retinopathy with scarring and \201 brosis may develop. Screening is required with laser photocoagulation for new vessel forma - tion (see also b p.621). Diabetes mellitus Diabetic retinopathy is rarely seen in childre n with type 1 diabetes and not usually before onset of puberty and teenage years (see also b pp.414 \200\223 415). Retinitis pigmentosa (RP) This progressive degenerative disorder of the retina is character ized by typical pigmented retinal appearances. It is an important cause of night blindness, reduced central and peripheral vision, and cataracts. It may occur as an isolated \201 n ding or may be part of a systemic disorder. \200 RP + congenital deafness. \200 Usher \200\231s syndrome: Bassen \200\223Kornweig syndrome: malabsorption. Refsum \200\231s disease: dysfunction (b p.972). Kearns \200\223Sayre syndrome: defect (b pp.962 \200\22396 3). RP + abetalipoproteinaemia, ataxia, and RP + polyneuropathy, deafness, and cerebellar RP + ophthalmoplegia, cardiac conduction 24_McClure_24.indd 920 11/14/2012 3:32:00 PM BACK OF THE EYE PROBLEMS 921 Retinal dystrophies A group of inherited disorders causing rod, cone and/or inner retinal c ell dysfunction. Early onset retinal dystrophy may cause blindness in infancy, other forms can cause progressive visual loss during childhood. Rod dystrophies primarily reduce night and peripheral vision. Cone dystrophies primarily re duce color vision, central vision, and cause pho- tophobia. Most children are otherwise hea lthy, but retinal dystrophy can be part of a widespread disorder, e.g. Bardet \200\223Biedl syndrome, Cockayne syndrome, Batten disease, and peroxisomal disorders. Children with earl y onset SN hearing loss should be referred in order to exclude Usher syn- drome. Supportive help with optical and educational aids has been the mainstay of management in the past, bu t recent success with gene therapy gives us some optimism for future treatment. Papilloedema/optic disc swelling There are many causes of optic disc swelling and the term papilloedema is reserved for optic disc swelling secondary to raised ICP. Visual acuity is usually good initially, but symptoms such as visual obscurations (momen- tary loss of visio n when leaning over or coughing) and diplopia secondary to bilateral sixth nerve paresis ma y occur. If left untreated, the papilloe- dematous nerve will start to become atrophic, ini tially causing visual \201 eld constriction and eventually loss of central and color visi on. Optic disc drusen are calci \201 c deposits in the optic nerve head that can mimic optic d isc swelling. Drusen \200\230light up \200\231 on ultrasonography (performed by an ophthal mologist) and this non-invasive test can prevent unnecessary neurological investigation. Optic neuritis/neuropathy In \202 ammation, in \201 ltration, or compression of the optic nerve cause ear- ly loss of central and color vision. Assessment of optic nerve function s hould include: \200 Visual acuity. \200 Visual \201 elds to confrontation (or perimet ry if able). \200 Color vision (ask child to compare brightness of red target in one eye to the other). Pupil reactions look for a relative afferent papillary defect (Fig. 24.2). V isualize the optic disc \200\224 it may be swollen or atrophic. \200 Fig. 24.2 Testing for relative afferent pupillary defect. Left optic neuropathy: both pupil s constrict when light is shone in right eye. When the torch is swung over to shine in left eye, both pupils dilate (relative to the previous constriction). 24_McClure_24.indd 921 11/14/2012 3:32:00 PM CHAPTER 24 Special senses 922 Trauma Chemical injury (alkali/acids/solvents detergents / irritants) Start treatment immed iately, unless penetrating eye injury is suspected. \200 \200 \200 \200 \200 \200 \200 Instill topical anesthesia (Proxymetacaine 0.5% if available). Irrigate with copious saline for 30min. Wait 5 \200\22310min \200\224ascertain nature of chemical. Check pH using litmu s paper inside bottom lid. Continue irrigation until pH is 7. Sweep conjunctival fornices w ith moistened cotton bud. Refer if severe injury and alkali involved otherwise give chloram phenicol ointment tds 2 \200\2233 days and SOS appointment. Corneal abrasion and foreign bodies Symptoms include sharp, stabbing pain, photophobia, and discomfort on blinking. \200 \200 \200 \200 Instill topical anesthetic to facilitate examination. Test visual acuity. Examine with opht halmoscope set on +20 or slit lamp. Instill \202 uorescein and examine with blue light: a re present a sub-tarsal FB is likely. Ask the child to look down, but not close the eyes; e vert the upper lid using a cotton bud placed on the upper lid crease as a pivot point. Use cotton bud to sweep away FB if present. if linear/vertical abrasions Large central corneal abrasions should be referred. Central corneal scar- ring can cause am blyopia to develop in a young child. Otherwise give chlo- ramphenicol ointment tds 1wk with SOS appointment. Blunt trauma Blunt trauma is common in older children (especially boys) due to their propen sity of throwing things at each other! The child usually complains of achy pain and blurred vision. \200 \200 \200 \200 Instill anesthetic to facilitate examination. Check visual acuity. Compare pupil size: Exam ine with ophthalmoscope on +20 for hyphaema (blood in anterior chamber). Check red re \202 ex. Refer to ophthalmologist if hyphaema/traumatic mydriasis is present. traumatic mydriasis may be seen. \200 24_McClure_24.indd 922 11/14/2012 3:32:00 PM TRAUMA 923 Penetrating trauma Suspect penetrating trauma if there is a history of the child falling on to a sharp object (e.g. pencil) or history of high velocity missile, e.g. air gun pel- let. The severity of pain and reduction of vision is variable. \200 \200 \200 \200 Instill anesthetic if child is in pain. Check visual acuity. Examine pupil reactions and lo ok for symmetry. Signs of perforation/penetration include: \200 \200 \200 Refer immed iately, protect eye with hard eye shield and keep nil by mouth. sub-conjunctival hemorrhage; dark pigment on surface or under conjunctiva; distorted pupil and hyphaema. In \202 icted head injury (NAI) See b pp.527, 758, 1000 Severe shaking and shaking/impact injury in infants causes retinal haemor- rhages. Hemorrhages are typically multi-layered: d eep retina haemorrhag- es (blots and white centered hemorrhages), super \201 cial retinal haemor- rhages ( \202 ame shaped hemorrhages) and sub-hyaloid hemorrhages (often associate d with a \202 uid level) occur together. Super \201 cial hemorrhages can disappear withi n days, but the deeper and sub-hyaloid hemorrhages can take months to resolve. Vitreous tra ction on the retina may result in peri- macular folds in severe cases and papilloedema may be present secondary to sub-dural hemorrhage. If NAI is considered, a senior ophthalmologist should be requested to document and, if poss ible, take photographs of the retinal appearance. Often the visual prognosis in such cases is poor, not because of the retinal injury, but because of the associated brain injury. 24_McClure_24.indd 923 11/14/2012 3:32:00 PM This page intentionally left blank 925 Chapter 25 Genetics Useful resources 926 Clinical genetics and genetic counseling 927 When to refer to clinical genetics 928 Taking a family history 930 Genetic testing 932 Chromosome tests 933 Molecula r genetic analysis 934 Practical issues relating to genetic testing 935 Down syndrome 936 C ommon chromosomal disorders 938 Genetic disorders with cardiac features 940 Genetic testing in cognitive impairment 942 Genetic disorders with neuromuscular features 944 Genetic diso rders with dermatological features 946 Genetic disorders of growth 948 Miscellaneous geneti c conditions 950 Miscellaneous congenital malformations 951 25_McClure_25.indd 925 11/14/2012 3:33:34 PM CHAPTER 25 Genetics 926 Useful resources The human genome contains 725,000 genes, so the few common genetic disorde rs in this section are a very tiny sample from an enormous range of genetic disorders. Othe r useful resources for information include the following: Books Cassidy SB, Allanson JE (eds) (2010). Management of genetic syndromes, 3rd edn. New Y ork: Wiley. Firth HV, Hurst JA, Hall JG (2005). Oxford desk reference clinical genetics. Oxford: Oxford University Press. Jones KL (2005). Smith \200\231s recognizable patterns of human malformation. Philadelphia: W.B. Saunders Co Ltd. Reardon W (2008) The bedside dysmorphologist. Classic clinical signs in human malformation syn- dromes and their diagnostic signi \201 cance. Oxford: Oxford University Press. Web-based resources \200\230Online Mendelian Inheritance in Man \200\231 ( \200\230OMIM \200\231). Available at: M www.ncbi.nlm.nih.gov. Directory of clinical genetics services in the UK. Available at: M www.bshg.org.uk. Contact a Family (UK). Available at: M www.cafami ly.org.uk. Geneclinics. Available at: M www.geneclinics.org. Orphanet. Available at: M www. orpha.net. National Organization for Rare Disorders (US). Available at: M www.raredisease.o rg. 25_McClure_25.indd 926 11/14/2012 3:33:35 PM CLINICAL GENETICS AND GENETIC counseling 927 Clinical genetics and genetic counseling De \201 nition of genetic counseling \200\230The process by which individuals or relatives at risk for a disorder that may be hereditary ar e advised of the consequences of the disorder, the probability of transmitting it and the w ays in which this may be prevented, avoided or ameliorated. \200\2311 Role of the clinical geneticist Clinical geneticists are doctors with a wide and varied tra ining in medicine and its sub-specialties whose special expertise is in the identi \201 ca tion and diagnosis of inherited disorders. Inevitably, these skills lend themselves to the assessment of the child with multiple birth defects but clinical geneticists see patients o f all ages and comprising all manner of clinical presentations. When families come to the genetics clinic, they usually have a number of questions, which may be summarized as follows: \200 \200 \200 \200 What is the diagnosis? Why did it happen? Will it happen again? If so, what can be done to ameliorate or prevent it? The main role of the clinical geneticist is to establish an accurate genetic diagnosis, whi ch is essential in order to: \200 \200 \200 \200 \200 Gain an understanding of the condition and possible prognosis. Guide optimal management for the child. Identify other systems that need surveillance, e.g. hearing or vision. Address concerns about events during pregnancy or delivery. Enable accurate genetic advice for pare nts and other family members about the risk of recurrence in future pregnancies. A basic principle of genetic counseling is that advice is non-directive. Reference 1 Firth HV, Hurst JA, Hall JG. (2005). Oxford desk reference clinical genetics. O xford: Oxford University Press. 25_McClure_25.indd 927 11/14/2012 3:33:35 PM CHAPTER 25 Genetics 928 When to refer to clinical genetics A majority of underlying chronic disorders in children a re either clear- ly genetic or have a genetic susceptibility. It is increasingly important for pediatricians to be able to recognize genetic disorders and to know when to enlist the help of a clinical geneticist. Useful de \201 nitions \200 Dysmorphic features: physical features, particularly unusual facial features, that are not usually found in a child of the same age or ethnic background. Abnormal or <2nd centile. growth parameters: height or weight or OFC >98th centile Indications for referral to clinical genetics \200 Congenital anomalies: \200 \200 multiple congenital anomalies; isolated congenital anomaly in conjunction with dysmorphic f eatures/developmental delay/abnormal growth parameters/a family history. Dysmorphic features: esp. in conjunction with developmental delay/ learning disability/cong enital anomaly/abnormal growth parameters. A family history suggestive of a recurrent abnor mality. Developmental delay/learning disability: \200 \200 \200 unexplained severe developmental delay/learning disability; developmental delay/learning di sability in conjunction with dysmorphic features/congenital anomaly/abnormal growth paramet ers/a family history. Multiple problems and no diagnosis: under the care of many specialist s with no unifying diagnosis. New diagnosis of a genetic disorder: \200 \200 \200 Tee nager with a genetic disorder: infancy/early childhood, refer patient back to clinical gene tics in mid- teens so that the young adult understands the genetic basis of their condition and the risks to their own offspring. child with multiple problems and enables explanation of the genetic basis of the condition; essential if the diagnosis may h ave implications for other relatives; important if parents would like advice regarding futu re pregnancies. if a genetic diagnosis was made in 25_McClure_25.indd 928 11/14/2012 3:33:35 PM WHEN TO REFER TO CLINICAL GENETICS 929 25_McClure_25.indd 929 11/14/2012 3:33:35 PM CHAPTER 25 Genetics 930 Taking a family history A very important tool in clinical genetics. One of the key skills i n taking a family history is drawing a family tree with all relevant symbols (see Fig. 25.1 ). The approach described here is intended for routine use in a general pediatric setting. A more detailed approach is indicated when assessing a patient with a known or possible gen etic disorder. Drawing a basic family tree \200 Start with your patient. Draw a female. Next add symbols for your patient \200\231s parents and siblings. Record basic information only, e.g. age, whether they are in good health, and whether there are any concerns regarding development. If an individual has died, note age and cause of death and annotate the family tree with an oblique stroke through the symbol. Ask whether there is any inherited disorder running in the family. Ask whether your patient \200\231s parents are related (consanguinity increases the chance of an AR disorder). Consanguinity is indicated by drawing a double line on the family tree. Ask the key question \200\230Has anybody else in your family had a similar pr oblem to the patient? \200\231 Be aware that some conditions have variable expression, e.g. del 22q11 may present with cleft palate in one member of the family and congenital heart d isease in another. Extend the family tree upwards to include grandparents and sideways to i nclude aunts, uncles, and cousins. If you have not revealed a familial problem by this stag e, do not go further as you are unlikely to have missed an important familial disease with onset in childhood. In the case of a suspected X-linked disorder extend the family tree fur ther on the maternal side (ask a clinical geneticist to help you with this). Shade those pe ople in the family tree affected by the disorder. This will help determine whether there is a genetic problem, and, if there is, it will help to suggest the pattern of inheritance. F or an example of drawing a family tree see Fig. 25.2. 4 symbol for a male; 5 symbol for a \200 25_McClure_25.indd 930 11/14/2012 3:33:35 PM TAKING A FAMILY HISTORY 931 Male, female, unknown sex Miscarriage (sex specified) Clinically affected (specify condition in key) Termination, unaffected and affected Deceased individual (with age died) Stillbirth (with gestation) Partners now separated Proband Consanguinity Consultand Adopted child (if want to include them) Twins (MZ, DZ and uncertain zygosity) Fig. 25.1 Basic family tree symbols. Taken from Firth HV, Hurst JA, Hall JG (2005). Oxford Desk Reference of Clinical Genetics. With permission of Oxford University Press. Hospital/Dep: STRICTLY CONFIDENTAL I Consanguinity yes/no Family No:1234 II III IV P V Source: Date: Drawn by: Source: Date: Updated by: Source: Date: Updated by: KEY ; Duchenne muscular dystrophy Fig. 25.2 Example of a family tree. Firth HV, Hurst JA, Hall JG (2005). Oxford Desk Referen ce of Clinical Genetics. With permission of Oxford University Press. 25_McClure_25.indd 931 11/14/2012 3:33:35 PM CHAPTER 25 Genetics 932 Genetic testing Appropriate situations for genetic testing in a child \200 Diagnostic testing in a chromosome analysis in a child with suspected Down syndrome. The ch ild is asymptomatic, but is preventive or other therapeutic measures are available, e.g. te sting to determine if a child of an affected parent with retinoblastoma (with a known mutat ion) requires screening by frequent periodic examination under anesthesia. This is predicti ve testing and should involve a clinical geneticist. The child is preventive therapeutic me asures are not available, e.g. SMA type 1. Involve a clinical geneticist. The decision to u ndertake a genetic test requires a careful balancing of bene \201 t/harm; each case is ass essed on its individual merits. Generally, testing is done at parental discretion after car eful discussion. child who has features of a genetic disorder, e.g. at risk for a genetic condition for which at risk for a genetic condition with pediatric onset for which Inappropriate situations for genetic testing in a child \200 An asymptomatic child is at risk for a genetic condition that usually has onset in adult li fe for which preventive or effective therapeutic measures are not available, e.g. Huntingto n \200\231s disease. Testing for Practice does vary, but we recommend that testing be defer red until the child is old enough to seek testing in their own right, or at least to take p art in the discussion about testing. Parents sometimes request testing of young children wi thout having necessarily thought through the dif \201 culties this may lead to later on. W e suggest referral to clinical genetics if parents remain keen to perform carrier test. Gen etic testing of children for the should not be performed unless testing is necessary to pre vent substantial harm to the family member. carrier status, e.g. siblings of a child with cystic \201 brosis. bene \201 t of another family member 25_McClure_25.indd 932 11/14/2012 3:33:35 PM CHROMOSOME TESTS 933 Chromosome tests Karyotype analysis A standard chromosome analysis involves a G-banded kary otype viewed by a cytogeneticist using a light microscope. Using this approach, the maxi- m um resolution is 75 \200\22310Mb. One of the major advantages of a chromo- some analysis is that it is a genomic survey, i.e. it looks in outline at the whole genome. The normal male karyotype is 46, XY. The normal female karyotype is 46, XX. Fluorescence in situ hybridiza tion (FISH) Targeted studies are possible at higher resolution using speci \201 c FISH pro bes. Using FISH, it is possible to see the submicroscopic deletions re- sponsible for Willi ams syndrome (7q) and Angelman syndrome (15q), but only if the clinician speci \201 cally requests this. Molecular kayotyping using microarrays Microarray analysis is an ever improving technology which enables much higher resolution DNA analysis than is possible with light microscopy. I t has recently started to be used in clinical practice and has been especially valuable to clinical geneticists in identifying patients with chromosomal ab- normalities previously no t diagnosable by standard techniques. However, it is a specialist tool and is not routinely in use in pediatric settings. There are two main types of array: Targeted arrays These analyze selected regions of the genome, e.g. known syndromes and sub- telomeric regions. Genome-wide arrays These give genome-wide coverage at varying degrees of resolution ranging from 1Mb to 100kb, i.e. 10 \200\223100 times greater resolution than conventional light mi croscopy. It is important to appreciate that at high levels of reso- lution there is consid erable normal variation in the human genome. Copy number variation is routinely identi \201 ed both in pathological states and as normal family variants. Differentiating between the pathological and non- pathological variation is not within the compass of the non-speci alist. 25_McClure_25.indd 933 11/14/2012 3:33:35 PM CHAPTER 25 Genetics 934 Molecular genetic analysis The human genome contains 73,000,000,000 DNA base pairs and 725, 000 genes. In genetic disorders, the pathology may range from a whole extra chromosome, e.g . Down syndrome, to a single DNA base pair alteration, e.g. achondroplasia. Molecular genet ic tests are highly speci \201 c tests that only reveal information about one very speci \201 c gene analysis, generally selected because of a strong clinical diagnosis, e.g. achon droplasia. \200 commonly occurring mutation, analysis is simple and If there is a comparatively inexpensive, e.g. cystic \201 brosis and the CF29 kit tests f or the 29 most common mutations in the Caucasian population, and achondroplasia in which tw o common mutations, G1138A and G1138C in the FGFR3 gene, account for 798% of mutations in c hildren with achondroplasia). If the and takes 72 \200\2236 weeks for most tests. Such test s, based on information obtained from other family members, should involve a clinical genet icist. If the Genetic testing in this situation can be laborious, expensive (often 7 1000) , and only a small proportion may be available as diagnostic tests. In the UK, reporting ti mes are being reduced for these tests and now routinely take about 6 \200\2238wks, even for a very large challenging gene, e.g. FBN1 in Marfan syndrome and TSC1 and TSC2 in tuberous sclerosis. Consult a clinical geneticist about whether genetic testing is appropriate in th ese circumstances. mutation in a family is known, analysis is usually straightforward mutation is unknown, an entire gene may have to be sequenced. 25_McClure_25.indd 934 11/14/2012 3:33:36 PM PRACTICAL ISSUES RELATING TO GENETIC TESTING 935 Practical issues relating to genetic testing Counseling the family before testing Diagnosti c testing Think carefully about the potential impact of the diagnosis you may make with a g enetic test. Some genetic conditions are relentlessly progressive and life-limiting, e.g. D MD. Others imply lifelong impairment of a child \200\231s ability to learn and communicate, e.g. Angelman syndrome, fragile X syn- drome. If you make a genetic diagnosis, it is likel y to remain a permanent aspect of that child \200\231s life. There may be some treatable el ements to the condition, but it is unlikely to be transient or curable. The diagnosis may h ave implications for other family members. The family should preferably be counseled by a c linical geneticist, before a genetic test is performed. Ensure that the parents understand what you are testing for and why. Explain how long it may take to obtain a result and make careful arrange- ments for communicating the result. Predictive testing The circumstances in which this may be appropriate can be complex and ca n vary for different disorders. This should be arranged through a clinical geneticist. 25_McClure_25.indd 935 11/14/2012 3:33:36 PM CHAPTER 25 Genetics 936 Down syndrome Incidence 71 in 600 \200\223700 live births (incidence increases with advanci ng maternal age). Cause The great majority (795%) of babies with Down syndrome have trisomy 21, usually due t o non-disjunction during maternal oogenesis. 72% are the result of a Robertsonian transloca tion. 72% are mosaic, with a normal cell line as well as the trisomy 21 cell line. Clinical features \200 \200 \200 Usually presents at birth. Generalized hypotonia and marked head lag. Facial features: epic anthic folds, a \202 at facial pro \201 le, protruding tongue. Later Brush \201 eld \200\231s spots apparent in the iris (whitish spots). Flat occiput (brachycephaly) and shor t neck. Typical limb features: short broad hands (brachydactyly), short incurved little \201 ngers (clinodactyly), single transverse palmar crease, and a wide \200\230sandal \200 \231 gap between the \201 rst and second toes. Mildly short stature. Intellectual impairm ent becomes apparent. IQ scores range from 25 to 70. Social skills often exceed other intel lectual skills. small low-set ears, up-slanting eyes, prominent \200 \200 