 \201\201 The hidden faces of Jack, some gunpowder \200\224and a spark We are surrounded by eponyms commemorating the Great and the Good, from the Reith Lectures and the Booker Prize , to the 100 proof of Jack Daniels and Johnnie Walker. Medical eponyms are pickled in som ething almost as intoxicating: the hidden recesses of our own minds. We store away the biza rre, the fearsome, and the mundane \200\224and then, years later, as if playing some dreadf ul game of snap, we match these features with the person sitting in front of us, and say: \200\234Dandy \200\223Walker! \200\235 or \200\234Prader \200\223Wil- li! \200\235 Here we deal a pack and a half (84 cards) to play with, plus a few jok- ers, and fascinating and f rightening games they can be. But as the years go by we wonder more and more about the peop le behind the eponyms. We read about these quacks and geniuses \200\224but it is always rat her unsat- isfying: history shows us everything except the one thing we want to see: the sp ark that made these eponymous characters truly original. We resign ourselves to the fact th at we can only ever see one face of the jack. More years pass and inexplicable events teach us that we all have hidden faces we never directly see or know (p325). So the possibility arises that these hidden faces are regarding each other. That is the sensation we have on c onjuring with the names of Dandy and Walker and the rest: a sensation that we are not alone \200\224that we are accompanied. 639 s e m o r d n y s s u o m y n o p e l a u s u n U . n o i t c a r t s i d e l b a d r o f f a n u n a s \200\231 t i : k n u b n a h t e s r o w s i Whether we are connoisseurs of Johnnie Walker or Dandy \200\223Walker and its diagnosis, we are relying on hidden processes going on in the dark over many years, to give us the spiri t that burns with a steady \202 ame when we are mixed with gunpowder \200\224and that spa rk. This \200\230steady \202 ame \200\231 is the old de \201 nition of alcoholic proof above 100 .1 It is also our reward for having transformed raw knowledge into something ill uminating, by the hidden processes of fermentation and distillation. y r o t s i h l a c i d e M ? y r o t s i h t u o b a s e r a c This special learning sometimes goes to our heads, and, drunk on knowl- edge, we career up and down the wards causing havoc until we learn to apply judgment as well as knowledge (as Benjamin Disraeli observed: in order to be successful as a the Queen \200\231s First Minist er, it is unpardonable to have a good memory: it is vital to be able to forget). o h W Fig 1. Adenoma sebaceum. Fig 2. Periungual \201 broma. Both \201 gures courtesy of Dr Samuel da Silva. 1 Spirits were once graded by the gunpowder test: a mixture of water and alcohol \200\230p roved \200\231 itself if one could pour it on gunpowder and a spark could induce it to burn with a steady \202 ame. If it did not, the liquor was too weak. A \200\230proven \200 \231 liquor was de \201 ned as 100 degrees proof (100 ).18 Briquet \200\231s syndrome (fat-folder syndrome) Hypochondria (p334) with soma- tization wi th >13 medically unexplained symptoms in various organs (see BOX). Bruton sex-linked \200 agammaglobulinaemia See p199. Buchanan \200\231s syndrome (truncus arteriosus) A single art ery arises out of the base of the heart, supplying pulmonary and systemic vasculature. The aorta may be divided. There is cyanosis from birth. Surgical correction is possible. Capgra s syndrome (clonal pluralization of the self)19 A \200\230delusion of doubles \200\231 tha t oneself or a friend has been replaced by an exact clone, who is an impos- tor. Cause: Psy chosis; head injury; B12 \200\201; pituitary or right occipitotemporal le- sion; multiple s clerosis. 20 Quetiapine may help. Myself am ever mine own counterfeit Castleman \200\231s d isease Angiofollicular lymph node hyperplasia + benign vascular mediastinal tumor. 2 types: Hyaline vascular and plasma cell type (T \200\200, anae- mia, weight \200\201). Frank ly mphoma is rare. POEMS syndrome may be present (BOX). 22 Chediak \200\223Higashi syndrome Im munode \201 ciency, hypopigmentation, photo- phobia, nystagmus, weakness, tremor, fever, p latelets \200\201, liver \200\200, lymphoma. WBCs contain big peroxidase granules. Cause : 1q43 mutation (CHS1/LYST gene).23 Fatal in 90% by 10yrs of age without marrow transplanta tion. 24 Conradi \200\223H nermann syndrome (chondrodysplasia punctata) Saddle nose, nasal hypoplasia, frontal bossing, short stature, stippled epiphyses, optic atro- phy, cataracts , IQ \200\201, \202 exural contractures. Cause: Genetic or eff ects of warfarin given dur ing the 1st trimester of pregnancy. 25 Cornelia de Lange syndrome Autosomal dominant mutati on in NIPBL gene on 5p13 causes short stature + abnormal head shape (brows meet in midline) hirsutism, low-set ears, wide-spaced teeth, single palmar crease, IQ \200\201, \201 t s, self- harm, abnormal temporal lobes, recurrent otitis media. 26 Sporadic in 99%. 27 Corr igan \200\231s syndrome This is congenital aortic regurgitation. Cotard \200\231s syndrome (nihilistic delusions) We deny our existence, or believe we are rotting, or we demand buria l, thinking we are a corpse. Nihil is Latin for nothing; a good nihilist will annihilate al l trace of himself, leaving only such trace upon earth as smoke leaves in air, or foam in w ater. Dante Alighieri Inferno XXIV 50 Cause: Depression, alcohol, syphilis, parietal lobe l esion, or just being born, \200\234for there is in everyone a deep instinct which is neith er that for destruction, nor for creation. It is simply the longing to resemble nothing. \200\235 Albert Camus Crigler \200\223Najjar syndrome \200\201Gluconyl transferase activit y causes nonhaemo- lytic unconjugated hyperbilirubinaemia (jaundice CNS signs) in the 1s t days of life. Autosomal dominant form is mild but autosomal recessive form is severe and may need liver transplant before irreversible kernicterus happens. 28 Dandy \200\223Walker syndrome Congenital obstruction of the foramina of Luschka and Magendi leads to progressive enlargement of the head, congested scalp veins, bulging fontanelle, separation of the cran ial sutures, papilloedema, bradycardia ( \201 g 1). \201\227 : Drain the CSF into a body cavity. De Clerambault \200\231s syndrome (erotomania) The patient is persistently delud- e d that a celebrity, a politician, or someone of a higher social status is in love with her. 29 She derives satisfaction from having been \200\230chosen \200\231, and may make trouble by publicizing her view of his feelings. \200\207Always have a chaperone! Homoerotomania may be complicated by Fregoli delusions (eg the love object of a teenage boy was a neighbor believed by him to be his father). Stalking is one manifestation. Also: IQ \200\201; schiz ophrenia; mania; left frontal lobe lesion.30 Diamond \200\223Blackfan syndrome (erythrogene sis imperfecta) \200\201Erythroid pro- duction (Hb \200\201, platelets \200\200, MCV \200 \200) causes pallor limb anomalies. Cause: 25% due to mutations in RPS19 gene on 19q13. 31,32 \201\227: Steroids marrow transplant are tried \200\224or stem-cell transplant fr om a donor embryo created by IVF (pre- implantation genetic diagnosis con \201 rms HLA mat ching). 33 See BOX 4. 640 s e m o r d n y s 21 Michelangelo; Sonnet XLI s u o m y n o p e l a u s u n U 641 Helping people with Briquet \200\231s syndrome (see p334) \200 Give time \200\224don \200 \231t dismiss these patients as just the \200\230worried well \200\231. 34 \200 Explore with the patient the factors perpetuating the illness (disordered physiology, misinformatio n, unfounded fears, misinterpretation of sensa- tions, unhelpful \200\230coping \200\231 b ehavior, social stressors). s e m o r d n y s s u o m y n o p e l a u s u n U Agree a management plan which focuses on each issue and makes sense to the patient \200\231s holistic view of him or herself. \200 Treat any depression (p340, e g escitalopram 35); consider cognitive therapy; make the patient feel understood; broaden t he agenda, negotiating a new understanding of symptoms including psychosocial factors. 36 Cloning our wives In idle moments, we might think that it would be useful to clone our wive s. This is what men with Capgras syndrome have accomplished. But could we really cope with this? Men with Capgras syndrome get very destabilized by not knowing who they are talking t o \200\224the genuine or the fake wife.37 It is an ex- ample of a delusion called the \200 \230clonal pluralization of identities \200\231.38 As such, it is the best example we have of a purely metaphysical disease. When a man with Capgras syndrome asks his wife with all s olicitude: \200\234How are we today? \200\235 \200\224he means every word he utters. And h e never knows the answer. Castleman \200\231s lymph node hyperplasia with POEMS syndrome PO EMS syndrome entails: peripheral neuropathy, organomegaly/hyperplasia, endocrinopathy, a mo noclonal paraprotein, and skin lesions. Interleukin-6 ex- cess is also a feature. Children with unexplained chronic in \202 ammatory symp- toms PUO failure to thrive may need detailed soft tissue tests to reveal associated vascular tumors. Creating donor embryos to donate stem cells: good idea? Bishops, authors, bigots and philosophers like to sound off a bout the morals of creating embryo brothers and sisters for the purpose of providing spare parts \200\224in this case, an umbilical cord for harvesting stem cells \200\224eg to popu- late the failing marrow of a 6-year-old with Diamond \200\223Blackfan syndrome. To create a new human in this way is thought to be using people as means, not ends. Proponents of thi s argument ignore the need to state what would be a \200\230good enough \200\231 reason to create an embryo. Behind the oft-used expression \200\230a much hoped-for baby \200\231 l ies a raft of reasons most parents would rather not look at in too much detail: the hope is often unconsciously sel \201 sh (who will look after me in my old age?). Yet when parents have a very speci \201 c and altruistic motive \200\224they are questioned remorselessly. What patient-centered ethics teaches is that special circumstances require special sensiti vity. Anyone witnessing parents taking these sorts of decisions will be well aware that con - cepts such as \200\230designer babies \200\231 are unhelpful (and in any case guarded ag ainst by the Human Fertilization and Embryology Authority, p293). Fig 1. Dandy \200\223Walker dilatation of the 4th ventricle. The large cyst is actually an enlarged 4th ventricle and not separate from it. The 3rd and lateral ventricles are much en larged, secondarily. Courtesy of Professor Ralph J zefowicz DiGeorge \200\231s syndrome A deletion of chromosome 22q11.2 causes absent thym- us, \201 ts, small parathyroids ( \200\230 Ca2+ \200\201), anemia, lymphopenia, growth hormone \200 \201, \200\201T-cell-immunity. It is related to velo-cardiofacial syndrome: characteristic face, multiple anomalies, eg cleft palate, heart defects, cognitive defects. 39,40 Di Gugl ielmo \200\231s disease (erythromyelosis) Dysplastic RBCs in \201 ltrate liver, spleen & h eart. Hb \200\201; MCV \200\211; WCC \200\201, platelets \200\201; LDH \200\200; B12 \200 \200. Immunoperoxidase stain shows antihaemoglobin antibody. Steroids, splenectomy trans fusions may be tried. 41 Duchenne \200\231s muscular dystrophy x - l i n k e d recessive Mu tations in dystrophin gene (Xp21) result in near-total loss of dystrophin (so muscles get r eplaced by \201 broapi- pose tissue and \200\200cytotoxic C cells). Presents in boys of 1 \200\2236yrs, with a waddling, clumsy gait. No abnormality is noted at birth. Gower \200 \231s maneuver: on stand- ing, he uses his hands to climb up his legs. Distal girdle muscle s are aff ected late; selective wasting causes calf pseudohypertrophy. Wheelchairs are need ed at 9 \200\22312yrs. Prevalence: 1:3500 births. Creatine kinase is \200\200; \200\207me asure in all boys not walking by 1 yrs, so that genetic advice may be given. Scoliosis and many chest infections occur. Muscle biopsy: Abnormal \201 bres surrounded by fat and \201 brous tissue. \201\227 : Aim to maintain walking (eg using knee \200\223ankle \200 \223foot orthoses). Gene therapy may be an option.42 Prednisolone creatine supple- ments can help, but don \200\231t allow wheelchair abandoning. 43 A disease-modifying agent (AVI -4658) is under development. 44 Prognosis: Vital capacity <700mL is a bad sign. Ventilation improves longevity (median age at death is now 31yrs). 45 Carrier \200 : 80% of have abn ormal chemistry. Prenatal screening is available. Ebstein \200\231s anomaly A congenital de fect with downward displacement of the tricuspid valve ( deformed lea \202 ets) atrializ ing the right ventricle causing right-sided heart failure. There may be no symptoms, or cya nosis, clubbing, triple rhythm, systolic, and diastolic murmurs. It can be associated with other cardiac malformations. Tests: ECG: tall P waves, \200\200P \200\223R interval; right bundle branch block. Survival: 67% at 1 year and 59% at 10 years.46,47 Edwards syndrome During meiosis chromosomes undergo condensation, pair- ing, crossing-over, and disjunction. Stringent regulation of the distribution and quantity of meiotic crossovers is critical fo r proper chromosome segregation. Failure to faithfully segregate meiotic chromosomes often results in severe ge- netic disorders, eg Edwards syndrome/trisomy 18 ( \201 g 3), 48 our 2nd commonest trisomy (Down \200\231s is 1st p152). \200 : \200 \211\210 2 : 1 (girls live longer; mean \211\210 10 months). 49 Ehlers \200\223Danlos syndrome Autosomal dominan t is a collagen disease ( \201 gs 1 & 2) with hyper- elasticity. 6 types: Type II, for exa mple, is caused by COL52A mutations; in type IV COL381 mutations upset encoding of type III collagen. \201\231 : Urine pyridinolines. Eisenmenger \200\231s syndrome A congenital hea rt defect which is at \201 rst associ- ated with a left-to-right shunt may lead to pulmon ary hypertension and hence shunt reversal. If so, cyanosis develops ( heart failure and c hest infections), and Eisenmenger \200\231s syndrome is said to exist. Monitor SAO2, PCV & BMI.50,51 Erb \200\231s scapulohumeral dystrophy \200 : \200 \211\210 1:1. Onset: 10 \200\22360yrs. Early sign: can- not raise hands above head, then (in order): deltoid \200 \203erector spinae \200\203trunk muscles \200\203pelvic girdle \200\203thigh. Often mild & asymmetric; lifespan is shortened. Fallot \200\231s tetrad (OHCM p151 \201 g 1) Pulmonary stenosis, overriding aorta, inter- ventricular defect, and RVH. It is the commonest cyanot ic congenital heart disorder (10%; 3 \200\2236/10,000). Signs: Cyanosis as ductus closes, d yspnoea, faints, squatting at play (this \200\200peripheral vascular resistance, so reduce s right-to-left shunt), clubbing, thrills, absent pulmonary part of S2, harsh systolic murm ur at left sternal base. Tests: Hb \200\200. CXR: wooden shoe heart contour + RVH. ECG: RVH . Echo shows anatomy & degree of stenosis. Cardiac CT/MRI helps plan surgery. \201\227 : O 2. Place in knee-chest position. Morphine to sedate and to relax pulmonary out \202 ow. Lo ng-term \200 -blockers. \200\230Total repair \200\231 entails VSD closure and correcting pulmonary stenosis, eg before 1yr, and may result in normal life, with driving possible if no syncopal attacks. Prognosis: Without surgery, mortality rate is 95% by age 20. 20-yr su rvival is 90 \200\22395% after repair. 642 s e m o r d n y s s u o m y n o p e l a u s u n U 643 X-linked muscular dystrophies 1 Duchenne \200\231s muscular dystrophy (severe) 2 Becker mus cular dystrophy (benign) 3 Emery \200\223Dreifuss muscular dystrophy (benign; early contrac tures) 4 McLeod syndrome (benign with acanthocytes) 5 Scapuloperoneal (rare). Myotonic dyst rophy and other autosomal muscular dystrophies 1 Myotonic dystrophy (autosomal dominant; St einert disease) 2 Congenital myotonic dystrophy 3 Facioscapulohumeral muscular dystrophy (L andouzy \200\223Dejerine p468) 4 Early childhood autosomal recessive Duchenne-like limb-gir dle dystrophy 5 Late-onset (Erb-type) autosomal recessive limb-girdle dystrophy (usually s e m o r d n y s s u o m y n o p e l a u s u n U scapulohumeral; rarely pelvifemoral) 6 Autosomal dominant limb-girdle dystrophy 7 Oculopharyngeal muscular dystrophy 8 Distal my opathies 9 Non-progressive myopathies. homepages.hetnet.nl/ b1beukema/ziekspieren.html Fig 2. Elastic skin in Ehlers \200\223Danlos (EDS). Bennett \200\231s paradox: the woman at a drag ball is the true impostor for, unlike everyone else, she is what she seems. So with EDS, which doesn \200\231t behave like a connective tissue dis- ease because it really is one (a true disease of collagen). Other \200\230connective tissue dis- eases \200\231 are really diseases of something else. Fig 1. In Ehlers \200\223Danlos syndrome, skin is poor-healing, fragile, and easily bruised or torn, with wide scars as thin as cigarette paper. Look for piezogenic papules (easily c ompressible outpouchings of fat through defects in the dermis on the sides of the feet). Al so: hypotonic, hypermobile joints; \202 at feet; GI bleeds/perforation; mitral valve prol apse; 52 dissecting aneurysms. 53 Fig 3. Rockerbottom feet, as seen in Ed- wards syndrome. Other signs: rigidity with limb \202 exion, odd low-set ears, receding chin, proptosis, cleft lip/palate umbilical/ingui - nal herniae; short sternum (makes nipples look widely separated). The \201 ngers cannot be extended (index \201 nger overlaps 3rd digit). Reproduced from eMedicine.com, 2007. Available at: http://www.emedicine.com/ped/ topic652.h tm with permission Post-op problems: \200 Residual VSD + pulmonary hypertension, if big \200 Ventricular t achycardia \200 Complete heart block \200 Right ventricular aneurysm \200 SBE (risk i s lowish) \200 Dilated cardiomyopathy \200 Pulmonary or aortic regurgitation. NB: when pregnant (may be unproblematic), do careful fetal echo. 54 Fanconi anemia x-linked or auto- somal recessive Progressive marrow failure + absence of radii, thumb hypoplasia, syndactyl y, missing carpal bones, skin pigmentation, micro- somy, microcephaly, strabismus, cryptorc hidism, IQ \200\201, deafness, short stature, and \200\200risk of leukaemias and solid tum ors. Survival: 70% at 5yrs post-marrow transplant (umbilical cord blood stem cells are also tried, p641). There are 12 groups and subtype A is the commonest. 55,56 \201\227 : Gene t herapy is planned. 57 Galeazzi fracture Radius shaft fracture with dislocation of the dista l radi- oulnar joint. Ganser syndrome Disorientation + pseudodementia + \200\230approximat e answer- ing \200\231, 58 eg the answer to \200\234How many legs has the chair in that co rner got? \200\235 might be: \200\234What corner? I don \200\231t know what a corner is. I don \200\231t see a chair \200 \201 ve. \200\235 Absurd remarks only occur as answers t o questions. Intellectual de \201 - cit is inconstant (hence the \200\230pseudo \200\231) . Hysteria, hallucinations, and \202 uctuating consciousness are common. Causes: Temporop arietal lesion; 59 head injury. 60 Gaucher \200\231s syndrome Autosomal re c e s s i ve Mut ations in glucocerebrosidase gene on chromo- some 1q21 cause Gaucher \200\231s, the commone st lysosomal storage disease. \205\224 present before the age of 20. Three forms are de \201 ned based on the presence of CNS signs. 1 Presents at <5yrs old with splenomegaly. 61 2 Acute neuropathic form (3 \200\2236 months old). 3 Chronic neuropathic form appears like a type 1 with progressive horizontal saccade-initiation failure and developmental delay. Ot her CNS signs: rigid neck, dysphagia, catatonia, re \202 exes \200\200, IQ \200\201. \200 : Measure acid \200 -glucosidase activity in pe- ripheral WBCs. Death may be from pneumo nia or bleeding. \201\227 : IVI of imiglucerase (specialist use only) helps hematology and organomegaly, but not bone indices, in type 1 & 3. 62 Miglustat is an oral inhibitor of gl ucosylceramide synthase (for type I). Prognosis: Worse if early onset. Hand \200\223Sch ll er \200\223Christian syndrome (HSC; Lang- erhans \200\231 cell histiocytosis; histiocytosis x, Letterer \200\223 Siwe eosinophilic granuloma of bone) Monoclonal Langerhans-like cells are pathognomonic of this \200\230neoplastic \200\231, destructive, in \201 ltrative dis ease in which bone, liver, skin, and spleen show lytic foci of eosinophils, plasma cells, a nd histiocytes. Lesions may show on a 99technetium-labeled bone scan. It occurs in children and adults, eg starting with a polyp at the external auditory meatus. Other signs: see MIN IBOX. A lethal \200\230leukemia \200\231 picture is seen in infants. \201\227 : Bone surg ery, steroids, cytotoxics, and radiotherapy may induce remissions. 63,64 *Classic triad; se en in 10% re c e s s i ve Increased \200\200GI & urinary loss of neutral amino acids Hartn up \200\231s disease Autosomal involving a transporter for monoamino-monocarboxylic acids. 65 Look for nia- cin de \201 ciency: diarrhea, dementia, and dermatitis (skin is thick, sc aly, and hy- perpigmented where light-exposed). Also: nystagmus, ataxia, bruxism (teeth gri nding), diplopia, re \202 exes \200\200. Gene: SLC6A19. \201\227: Nicotinamide & B vitami ns. 66,67 Hunter \200\231s syndrome (mucopolysaccharidosis II) x - l i n ke d recessive (33 % are due to a new mutation). Iduronate sulfatase (IDS) de \201 ciency results in deafness , IQ \200\201, short stature, chronic diarrhea, unusual face, hepatosplenomegaly (like Hurl er \200\231s disease, p646 but it is milder and almost always without corneal clouding). Al so look for joint contractures including ankylosis of the tempo- romandibular joint; spinal stenosis; and carpal tunnel syndrome. Death: late childhood (but may be at >30yrs). \201 \231 : De \201 nitive diagnosis is made by enzyme analysis for iduronate sulfatase in leuc ocytes or cultured skin \201 broblasts. Prenatal \201\231 : Ultrasound. 68 \201\227: Hu man recombinant idursulfase. 69 644 s e m o r d n y s s u o m y n o p e l a u s u n U Signs of HSC \200 Diabetes insipidus* \200 Exophthalmos* \200 Lytic bone lesions* \200 Failure to thrive; dyspnoea \200 Scalp lumps/skin erosions \200 Eczema-like rash/ pustules \200 Cord compression \201 ts \200 Ear discharge, stomatitis \200 Honey comb lung \200 Hepatosplenomegaly \200 Lymphadenopathy \200 T \200\200; anemia; \200\201platelets This page intentionally left blank Huntington \200\231s chorea Autosomal dominant A triad of progressive motor, cognitive, and emotional symptoms + spiny neuron loss in the neostriatum, due to excessive repeats of \200\230CAG \200\231 in the huntingtin gene. Normally, there are <28 repeats. Symp- toms us ually do not appear until adulthood ( 30 \200\22350yrs). Penetrance: A large number of repe ats means the disease is more likely. 29 \200\22335 CAG repeats means no signs but they may pass Huntington \200\231s to their children. 36 \200\22339 CAG repeats means \200\201pene trance. If >40 CAG repeats, 100% get Huntington \200\231s disease if they live long enough. Early \201 ndings: \200\201Auditory & visual reaction times (needs spe- cial equipment) then mild chorea ( \202 itting, jerky movements), odd extraocular movements, \200\200re \202 exes, \200\201rapid alternating movements. Unpredictable motor im- pairment is found until chorea starts. Abnormal ocular saccades may indicate imminent manifest signs. Late s igns: Personality change, self-neglect, apathy, clumsiness, \201 dgeting, \202 eeting g rimaces (may be mistaken for mannerisms), chorea, and dementia. Ethical dilemmas surround t esting, as symptoms may only start after procreation has \201 nished. Careful pre-test co unseling is vital. 70 Hunt \200\231s syndrome (pyridoxine cerebral de \201 ciency) Intract able neonatal \201 ts cause death unless given pyridoxine (50mg IV under EEG control). Hu rler \200\231s syndrome (mucopolysaccharidosis 1h; MPS1h) After brie \202 y normal growth, there is physical and mental decline, hydrocephalus, thick skin, hirsutism, coxa valga, no dules over scapulae, and CCF. Cause: \200\201 \200 -L-iduronidase, hence blocking degradat ion of dermatan sulfate & heparan sulfate and \200\200muco poly- saccharides in urine, car tilage, periosteum, tendons, valves, meninges & eye. Skull x-ray: Thick bone; absent fronta l sinuses; deformed pituitary fossa. Marrow: Metachromatic Reilly bodies in lymphocytes. \201\227: \200\207Laronidase must start promptly71 stem cell transplantation. Death is often at \211 10yrs.72 Hutchinson \200\231s triad (congenital syphilis) Deafness + keratit is + pointed teeth. Ivemark \200\231s syndrome This is the association of congenital asplen ia with ostium primum atrial septal defects ( pulmonary valve atresia or stenosis). Karta gener \200\231s syndrome Primary ciliary dyskinesia (in \202 exible, poorly beating cilia) is called Kartagener \200\231s syndrome if associated with situs inversus (dextro- cardia) . 73 Clearance of mucus & bacteria is poor, hence chronic sinusitis and bronchiectasis. \200 infertility, otitis media, and salpingitis are common. \201\227: Anti- biotics, cont inuous or intermittent, are used to treat airway infections. Children are good candidates f or long-term low-dose preventive antibiotics. Kawasaki disease A vasculitis in \202 ames s mall to medium arteries causing aneurysms to form. Cause: Unknown (? reaction to infection) . Median age: 10 months. 74 3 phases: 1 Acute: Lasts 1 \200\2232wks; the child has T \200 \200+ major signs (see BOX 1), also diarrhea jaundice. 2 Subacute: Lasts 2wks: \200 \207coronary arteritis \200\224like PAN; ie non-atheromatous coronary artery disease inf arction in 24% ( \200 : \200 \211\2105:1; commoner than rheumatic fever as a cause of acq uired heart disease). 74 3 Convalescent: Takes 7wks. Tests: ESR & C-reactive protein \200 \200; bili rubin \200\200, AST \200\200, \200 2-globulin \200\200, platelets \200\200. \201\231 \201\231 : Stevens \200\223Johnson syn- drome, measles, streps, infectious mononuc leosis. \201\227 : Aspirin (30 \200\22350mg/ kg/day until fever resolves, then 3 \200\2235 mg/kg/day). Immunoglobulin 2g/kg as a single IVI dose usually causes rapid (diagnostic) imp rovement. 75 If not, a 2nd dose may help. Follow-up: Echo; 3D coronary magnetic resonance a ngi- ography accurately de \201 nes aneurysms (it is a non-invasive alternative when trans thoracic echo quality is insuffi cient, and angiography is too invasive). 76,77 Klinefelter \200\231s syndrome (XXY or XXYY polysomy + variable Leydig cell defect) The chief genetic cause of \200 hypogonadism; 1 : 2000 births manifests in adoles- cence with psychopathy, \200\201cognition, \200\201libido, \200\201sexual maturation. Associations: T4 \200\201, DM, asthma, ?oncogenesis. Androgens and surgery for gynaecomastia may help. Lifespan is no rmal, but arm span may exceed the body length by 10cm. Kugelberg \200\223Welander spinal mu scular atrophy \200\201Anterior horn cell (BOX 2). 646 s e m o r d n y s s u o m y n o p e l a u s u n U 647 Diagnostic criteria for Kawasaki disease Fever for \211 5 days + at least 4 of the followi ng:* 1 Bilateral non-purulent conjunctivitis 2 Neck lymphadenopathy (>1.5cm across) 3 Phary ngeal injection, dry \201 ssured lips, strawberry tongue 4 Polymorphous rash (especially on the trunk) 5 Changes in extremities: arthralgia, palmar erythema or later, \200\207 \201 ngertip s e m o r d n y s s u o m y n o p e l a u s u n U desquamation + swelling of hands/feet. Kawasaki disease may be diagnosed with <4 of these features if coronary artery aneurysms (C AA) are present. \200\207Incomplete forms exist, so get expert help today while wresting w ith this diffi cult, important diagnosis. 78 IVIG given \211 10 days after illness onset r e- solves in \202 ammation but can be too late to prevent coronary artery lesions. 79 Ther e is paradoxical data that incomplete or atypical forms are more likely to have complicatio ns such as CAA: the reason is that Kawasaki thought his disease was always benign and self- limiting, so over-optimism may be built into the de \201 nition of the syndrome. 80 recessive Kugelberg \200\223Welander spinal muscular atrophy (type 3 SMA) Autosomal SMA ent ails loss of anterior horn cells and all the dignity they engender. Start- ing after 18 mon ths old, there is lack of mobility, then wheelchair depend- ence \200\224and often need for help with toileting and, in its later stages, with venti- lation. But as symptoms start du ring the most adaptive years, people with this syndrome often don \200\231t think they are ill, and are resentful when we decide for them when symptoms are pronounced that they shoul d not be resuscitated. Here are two contrasting views from patients with SMA. Life is a mil lstone \200 Let me die now \200\234Let me die at the moment of my choosing, with dignity \200\235. In some jurisdictions (eg Montana, USA) assisted suicide is justi \201 ed in ter mi- nal conditions. Note that terminal doesn \200\231t imply now in its end-stage: it is \200\230an incurable and irreversible condition, for the end stage of which there is no kno wn treatment which will alter its course to death, and which \200 will result in a prema- t ure death. \200\231 Is physician (or carer) assisted sui- cide for those with SMA valid? So me with SMA want this \200\224but not Jane Campbell (see OPPOSITE), SMA \200\231s most voca l victim/non-victim. Message from a militant dynamo \200 \200\234My first big demo \200 I took hun- dreds of [ us] wheelchair users onto Westminister Bridge and stopped the traffi c \200 Not dead yet! p lacards round our necks \200 rights not charity! To my partner: \200\234If I should ever s eek death \200\224there are several times when my [progressive spinal mus- cular atrophy] c hallenges me \200\224I want to guarantee that you are there supporting my continued life an d its value. The last thing I want is for you to give up on me, especially when I need you most. \200\235 And for those with no partner? \200\234It \200\231s our role as a caring so ciety to be that someone \200 \200\23581 Jane Campbell House of Lords 2009 648 Klippel \200\223Feil syndrome Autosomal reces- sive or dominant Congenital fusion of cervic al vertebrae, nystagmus, deafness and CNS signs. The clinical triad seen in 50% is: short n eck, low post erior hairline, and limited neck movement. Mirror movements are said to occur if voluntary movements in one limb are involuntarily mim- icked by the other. Possible cau se: KFS gene on chromosome 8. Landouzy \200\223Dejerine (fascioscapulohumeral) muscular dys trophy Autosomal dominant Deletion on 4q35 results in weakness of the shoulder muscles, eg on combing the hair, appears at 12 \200\22314yrs of age. There is diffi culty in closing th e eyes, suck- ing, blowing, and whistling. Scapulae wing and the lips pout, and the facial expression is \200\230ironed out \200\231. Adult myoglobin is reduced and fetal myoglobin and sarcolemma nuclei are increased. 82,83 Surgical scapulopexy may help. 84 Laurence \200 \223Moon syndrome Autosomal re c e s s i ve Retinitis pigmentosa, obesity, polydacty- ly, h ypogenitalism, \200\201IQ, \200\201body hair, azoospermia, CNS85 and renal abnormalities (calyceal clubbing, cysts, or diverticula; fetal lobulation; end-stage renal fail- ure in 1 5%). It is distinct from Bardet \200\223Biedl syndrome p638 (no polydactyly). Leber \200 \231s hereditary optic atrophy is the commonest mitochondrial DNA dis- order and causes irr eversible blindness/scotomas in young adults, and \200\200risk of neoplasia. A mutation (G \200\203A) in mitochondrial DNA coding for a dehydrogenase enzyme is proposed (a type of c ytoplasmic inheritance). Idebenone may help. 86 Lesch \200\223Nyhan syndrome X-linked (only fully expressed if \200 ) de \201 ciency of hypoxanthine-guanine phosphoribosyl transfer ase (HPRT) causes 3 problems: Uric acid overproduction: Hyperuricaemia (orange crystals in the nappy) causing renal stones renal failure, and gout. CNS: Motor delay, IQ \200\201 ( eg <65), clonus, choreoathetosis, hypotonia, and \201 ts. Behavioral problems: Cognitive dysfunction, compulsive, agitated, self-mutilation (lip/foot biting, head bang- ing, face s cratching \200\224may be unilateral). Smiling aggression to others may oc- cur. \201\231 : Measurement of HPRT enzyme activity in blood. Diagnosis is con \201 rmed by identifying a mutation in the HPRT gene. Prognosis: Death is usually before 25yrs, from renal failure or infection. \201\227: Good hydration (urine \202 ow \200\200); allopu- rinol prevents ur ate stones, but not CNS signs. Deep brain stimulation can stop automutilation, 87 as can (l ess subtle!) removal of teeth. 88 Lewy body dementia A common type of dementia with intracy toplasmic neuronal inclusion bodies ( \201 g 1) in brainstem/cortex + \202 uctuating cog nitive impairment, parkinsonism, hallucinations, and visuoperceptual de \201 cits. \201 \227: Cholinesterase inhibitors (eg rivastigmine). Overlap with Alzheimer \200\231s and Par kinson \200\231s diseases makes treatment hard as antiparkinsonian agents can precipitate d elusions, and antipsychotics worsen parkinsonism. 89 Li \200\223Fraumeni syndrome Families suff er high rates of cancer in their young. As well as devastating families, it fascinates geneticists as families inherit a germ- line nonsense or oncogene-like missense mutation i n one p53 allele; see BOX. Martin \200\223Bell (fragile X) syndrome (semi-dominant; prevale nce: 1 : 5700) is the main form of inherited cognitive impairment, and is a leading single- gene disorder. Cause: A stretch of CGG-repeats in FMR-1 gene (fragile X mental re- tardatio n-1) on Xq27, that lengthens as it is transmitted from generation to generation. Once the r epeat exceeds a threshold length, no fragile X protein is made, and disease results. Signs: \200\201Flexibility in adapting to the changing demands that life brings ( \200\201 atten tional set-shifting), 90 big testes, big jaw, high forehead, \200\201IQ (not always); 91 p oor learning, facial asymmetry, long ears, short temper. Also: hyperactivity, emotional and behavioral problems, anxiety, mood swings, autism, tactile defensiveness (little eye conta ct; no hugging; hype rsensitive to touch & sound, ?from slowed mid-trimester maturation of the sensory cortex). Tests: Prenatal tests are possible. Screening could be general or of h igh-risk groups (eg families with >1 retarded \200 ). Screening for carrier status leads t o labeling and stigmatization, and is rejected by some families. 92 s e m o r d n y s s u o m y n o p e l a u s u n U 649 Fig 1. Lewy body (arrow). NB: there are no generally accepted biomarkers to distin- guish d ementia with Lewy bodies (DLB) from other dementias. Think of DLB when- ever there is progr essive anxiety, depres- sion, apathy, agitation, sleep disorder with psychosis and memory d isorders. The best imaging candidate may be striatal dopamine transporter system scintigrap hy using FP-CIT SPECT.93 EEG is helpful \200\224but dif- \201 cult and the application of criteria needs an expert.94 s e m o r d n y s s u o m y n o p e l a u s u n U Courtesy of Kondi Wong / NLM. Li \200\223Fraumeni syndrome, p53, and the guardian of the genome p53 is a tumor-suppressor gene (chromosome 17p13.1; encoding nuclear phos- phoprotein, a transcription factor allowi ng passage through the cell cycle). In this syndrome, as only one allele is aff ected, deve lopment is normal until a spontaneous mutation aff ects the other allele. Somatic mutation of p53 oc- curs at both alleles in 50 \200\22380% of spontaneous human cancers. Cells with a p53 mutation do not pause in G1 (a phase in which DNA repair takes place, and faulty DNA purged), but proceed straight to S1 (DNA replication), which is why p53 protein is known as the \200\230guardian of the genome \200\231. Examples of cancers caused this way: early-o nset breast cancer; brain tumors; sarcomas; leukemia; lym- phoma; melanoma; adrenal cortex carcinoma. 95 Note that tumors are associated with more than one syndrome, eg adrenal cortex tumors are a ssociated with familial cancer syndromes such as the Beckwith \200\223Wiedemann and Li \200 \223Fraumeni syndromes, the Carney complex (p699), multiple endocrine neoplasia type 1, con genital adrenal hyperplasia, and the McCune \200\223Albright syndrome (p650). 96 In a retrospective study of 200 cancer-aff ected carriers of TP53 germline mutations, 15% d eveloped a 2nd cancer, 4% a 3rd cancer, and 2% a 4th cancer. 97 In some populations (eg in South Brazil) there is a high prevalence of otherwise rare mutations in p53, partly explain ing high rates of colon and other cancers (eg fatal stomach cancers in children as young as 12). 98 McCune \200\223Albright syndrome Polyosteotic \201 brous dysplasia of bone, irregular are as of skin pigmentation and facial asymmetry precocious puberty. Monteggia fracture # of the proximal \205\223 of ulna, with angulation + radial head subluxation, caused forced p ronation. Open reduction/plating aids good align- ment (5wks in plaster). Wait for full uni on ( 12wks) before normal arm use.99 Morquio \200\231s syndrome (mucopolysaccharidosis IV A utosomal re c e s s i ve) Lysosomal storage disease caused by \200\201N-acetylgalactosamin e-6-sulfate sulfatase. Signs: Stature \200\201; deaf; weakness; broad mouth; widely-spaced teeth; aortic regurgitation.100 IQ \200\211. Moyamoya disease Vascular disease at the circl e of Willis causes strokes/TIAs (alternating hemiplegia, dyspraxia, \201 ts, involuntary movements, headache).101 Typical patient: Japanese girl, with triggering infection (eg tons illitis) or hy- perventilation (CO2 \200\201 causes vasoconstriction). Digital subtraction angiogra- phy: Collateral vessel formation \200\230like a puff of smoke \200\231. MRI/CT: Multiple infarc- tions in watershed areas. \201\227: Bypass surgery may be possible.101 Ni emann \200\223Pick disease Autosomal re c e s s i ve A neurovisceral lysosomal lipid storag e disor- der.102 After years of normal growth, there is physical and mental decline, psy- c hosis, wasting, and hepatosplenomegaly from abnormal metabolism of sphin- gomyelin. Other s