Multi-system Disease Flashcards
Modes of Genetic Inheritance
Chromosomal: Numerical, Structural
Single Gene Disorders: Autosomal Dominant, Autosomal Recessive, X-Linked
Multifactorial: Polygenic, Environmental Factors
Why multi-system involvement?
- SEVERAL GENES w/ DIVERSE FUNCTIONS INVOLVED (chromosomal) e.g. extra copies of some/many genes - trisomy, duplications; only single copies of some/many genes - monosomy, deletions, microdeletions (contiguous gene syndromes)
- SINGLE GENE WIDELY EXPRESSED in DIFFERENT TISSUES
- SINGLE GENE TISSUE-SPECIFIC EXPRESSION but TISSUE INTEGRAL PART of MANY DIFFERENT SYSTEMS
Common problems in multi-system disease
- VARIABLE EXPRESSION W/I + BWTN FAMILIES - sometimes difficult to predict phenotypic presentation from genotype
- PRESENT to LARGE VARIETY of DIFFERENT SPECIALISTS
- FHx EASILY MISSED - often need to ask wide range of questions to detect +ve FHx
- +VE = CONSIDERAL SCOPE for SCREENING & PREVENTIVE INTERVENTIONS
Neurofibromatosis type 1: genetics
- AUTOSOMAL DOMINANT: TUMOUR SUPPRESSOR GENE affected (17q)
* VARIABLE EXPRESSION = intra-familial + inter-familial
Neurofibromatosis type 1: presentation
Diagnostic criteria requires ≥ 2 of following:
- CAFÉ AU LAIT SPOTS
- NEUROFIBROMAS
- FRECKLING IN ABNORMAL SPOTS e.g. axilla, under breast, groin
- LISCH NODULES
- OPTIC GLIOMA
- THINNING of LONG BONE CORTEX e.g. leading to #, pseudoarthrosis
- FHx
Further features:
- MACROCEPHALY
- SHORT STARTURE
- DYSMORPHIC FEATURES (“NOONAN LOOK”)
- LEARNING DIFFICULTIES
- EPILEPSY
- SCOLIOSIS
- PSEUDOARTHROSIS of TIBIA
- RAISED BP (due to renal artery stenosis/phaeochromocytoma)
- NEOPLASIA (CNS - optic gliomas, endocrine)
Neurofibromatosis type 1: management
ANNUAL REVIEW of AFFECTED INDIVIDUALS + AT RISK CHILDREN until DIAGNOSIS can be EXCLUDED (5 years)
* BP * SPINE = SCOLIOSIS * TIBIA = UNUSUAL ANGULATION * EYES = VISUAL ACUITY & FIELDS * EDUCATIONAL ASSESSMENT * ASK PT. to REPORT UNUSUAL SYMPTOMS
Neurofibromatosis type 2: genetics
• AUTOSOMAL DOMINANT: TUMOUR SUPPRESSOR GENE affected (chromosome 22)
Neurofibromatosis type 2: presentation
- ACOUSTIC NEUROMAS - usually BILATERAL
- CNS & SPINAL TUMOURS - can affect nn. to arms & legs - LIMB WEAKNESS, PERSISTENT HEADACHES
- FEW CAL SPOTS
- HEARING LOSS - WORSENING OVER TIME
- TINNITUS
- BALANCE PROBLEMS - esp. in dark & walking on uneven ground
Tuberous sclerosis: genetics
- AUTOSOMAL DOMINANT: 2 GENES on DIFFERENT CHROMOSOMES both cause TS w/ IDENTICAL PHENOTYPES (TSC1, TSC2)
- VARIABLE EXPRESSION = severity varies bwtn family members
Tuberous sclerosis: presentation
- LEARNING DIFFICULTIES (40%; AUTISTIC FEATURES COMMON)
- EPILEPSY (/seizures 65%; INFANTILE SPASMS, MYOCLONIC SEIZURES)
- SKIN LESIONS (DEPIGMENTED MACULES, ANGIOFIBROMAS, FIBROUS PLAQUE FOREHEAD, SHAGREEN PATCHES, UNGUAL FIBROMAS)
- KIDNEY = CYSTS & ANGIOMYOLIPOMATA
- EYE = PHAKOMAS in EYE (BENIGN UNLESS ON MACULA)
- HEART = RHABDOMYOMAS
- HAMARTOMAS in DIFFERENT ORGANS
MULTISYSTEM + VARIABLE EXPRESSION (ASYMPTOMATIC - SEVERE MENTAL & occasionally PHYSICAL HANDICAP)
Tuberous sclerosis: screening at risk relatives
- SIBLINGS & PARENTS may be MIDLY AFFECTED
- SURVEILLANCE + GENETIC COUNSELLING
- CLINICAL EXAMINATION: SKIN SIGNS - incl. Woods lamp, NAILS; RETINAL EXAMINATION
- CRANIAL MR SCAN
- RENAL USS
- ECHO
Myotonic dystrophy: genetics
• AUTOSOMAL DOMINANT: CTG REPEAT, exhibits ANTICIPTION w/ INCREASING SEVERITY in EACH GENERATION
Myotonic dystrophy: presentation
- BILATERAL LATE-ONSET CATARACT
- MUSCLE WEAKNESS, STIFFNESS & MYTONIA
- LOW MOTIVATION, BOWEL PROBLEMS, DM
- HEART BLOCK
- DEATH POST-ANAESTHETIC is a RISK IF UNMONITORED
- CONGENITAL MYOTONIC DYSTROPHY (DEATH/SEVERE MUSCLE DISORDER & LEARNING DIFFICULTIES)
