Genetic and Systemic Disorders

Chromosomal Abnormalities

Down syndrome

(Trisomy 21). 1:700, 95% have trisomy 21, with increased risk with maternal age; 95% of which the additional chromosomal material is of maternal origin (from meiotic nondysjunction). 4% have translocation of the long arm chromosome 21 (usually onto 22 or 14, commonly inhereted), 1% are mosaics (mixture of 46 or 47 chromosomes, occuring during early embryogenesis); of which are independent of maternal age. Flat facial profile. Most have IQ 25-50. Associations include:

  • 11 rib pairs, 2 manubrial ossification centres (N=1).
  • Hypoplastic posterior arch C1.
  • Hypersegmented sternum (90%) – >4-5 segments, 2 manubrial ossification centres.
  • Short long bones of hands and fingers, short broad middle phalanx little finger causing clindodactyly (abnormal coronal angulation).
  • Flared iliac wings, horizontal acetabular roof, hip dysplasia.
  • Joint laxity with dislocations, DDH, atlantoaxial subluxation (10-20%), patellar dislocations
  • Foot anomalies
  • Cerebellar/vermian hypolasia
  • Moyamoya disease
  • Hearing loss
  • Congenital heart disease (40%) – Most endocardial cushion defect (AVSD’). Others include ASD (ostium primum), VSD.
  • Pulmonary hypoplasia, cysts
  • Duodenal atresia, anal atresia
  • Hirschsprung disease
  • Omphalocoele
  • Abnoral immune responses – Increasing risk of infection esp lungs, and thyroid autoimmunity.
  • Acute leukaemia (AML or ALL) – 10-20x increased risk.
  • Alzheimer disease – Almost all of those >40yo.

Trisomy 18

(Edwards syndrome). Mortality usually <1yo. Associations include:

  • Severe congenital heart disease in 90% – Including ASD, VSD, PDA, dextrocardia.
  • Rocker botton foot, club foot
  • Clenched hand with adducted thumb and short 1st MC, ulnar deviation of fingers, overlapping 2nd and 3rd digits, radial ray abnormalities (eg absent thumb).
  • 11 rib pairs which are thin and hypoplastic.
  • Stippled eiphyses
  • Choroid plexus cysts
  • Agenesis of the corpus callosum, Dandy Walker continuum, neural tube defects
  • Micrognathia, dolichocephaly, strawberry skull (frontal lobe hypoplasia), low set ears, hypertelorism, cleft lip/palate
  • Cystic hygroma
  • Single umbilical artery, cysts, omphalocoele
  • CDH
  • Horseshoe kidney

Trisomy 13

(Patau syndrome). Mortality usually <1yo.

  • Congenital heart disease – Hypoplastic left heart, VSD
  • Holoprosencephaly, hypo/hyper-telorism, clclopia, proboscis
  • Enlarged cisterna magna, hydrocephalus
  • Agenesis of the corpus callosum
  • Neural tube defects
  • Cleft lip, palate, micrognathia
  • Polydactyly
  • Rockerbottom foot
  • Clenched hands with overlapping digits
  • Abdominal wall defects – Omphalocoele, bladder extrophy
  • MCDK, genitourinary anomalies, cryptoorchidism

Chromosome 22q Deletion Syndrome

Spectrum of deletions of q11.2 on long arm of chromosome 22. 1:4000. Variable clinical features.

  • DiGeorge syndrome – Failure of development of 3rd and 4th pharyngeal pouches causing thymic hypoplasia with T-cell immunodeficiency, parathyroid hypoplasia with hypocalcaemia, cardiac malformations (afecting outflow tracts), mild facial anomalies.
  • Veocardiofacial syndrome – Facial dysmorphism, cleft palate, cardiovascular anomalies, learning disabilities. 25% develop schizophrenia.

Turner syndrome

Complete or partial absence of one X chromosome (most 45X0) causing female hypogonadism. 1:2000. Normal mental status. Associations include:

  • Short stature, short limbs, scoliosis
  • Congenital heart disease (25-50%) – Left-sided abnormalities including preductal coarctation, bicuspid aortic valve.
  • Horseshoe kidney, pelvic kidney
  • Aortic root dilation and dissection (uncommon).
  • Short 4th MCs (DDx pseudohypoparathyroidism and pseudo-pseudohypoparathyroidism)
  • Depressed medial tibial platueau, tarsal coalition, osteopenia, Madelung deformity.
  • Cystic hygroma – Lymph stasis with oedema of dorsum of hand and nape of neck leaving neck webbing.
  • Failure to develop secondary sex characteristics. Primary amenorrhea, streak ovaries, streak uterus.
  • Hashimoto thyroiditis – Hypothyroid in 50% with thyroid autoantibodies.
  • Increased risk of glucose intolerance, obesity, insulin resistance, inflammatory bowel disease.

Klinefelter Syndrome

>/= 2 X chromosomes and >/=1 Y chromosome (most 47XXY) causing male hypogonadism. 1:660, rarely diagnosed before puberty. Elongated lower limbssmal atrophic testes, small penis, lack of secondary male characteristics, gynaecomastia. Lower than average IQ. Increased risk of type 2 DM, 50% have mitral valve prolapse.

Noonan Syndrome

Similar clinical features to Turner syndrome, affecting males and females. Normal chromosome number.

Connective Tissue Diseases

Inherited connective tissue diseases include Marfan syndrome, Ehlers-Danlos syndrome, osteogenesis imperfecta, Stickler syndrome. [[Arthritis#Connective Tissue Disorders|Autoimmune diseases]] include SLE, RA, scleroderma, Sjogren syndrome, mixed connective tissue disease. Other acquired diseases include scuvy (vitamin C deficiency causing abnormality in collagen).

Marfan Syndrome

Long arm chromosome 15 (fibrillin-1 gene) with high penetrance, variable expression. 1/10,000. 80% inherited AD, others sporadic. Fibrillin-1 glycoprotein is major component of microfibrils in ECM, scaffolding for elastic fibres; mostly abundant in aorta, ligaments, cilia. Tall, arachnodactyly (long distal extremities), kyphoscoliosis, joint hypermobility, early OA, osteopenia, dolichocephaly, pes planus, ligamentous laxity. Spondylolysis L5, dural ectasia (post scalloping esp L5, S1) with increased dural sac:vertebral body ratio (high specificity and sensitivity) esp L3 (0.47) and S1 (0.57), enalrged neural foramina, increased interpediculate distance, meningocoele. Pectus excavatum or carinatum. Protrusio acetabuli. Ocular lens dislocation (ectopia lentis sup-lat), glaucoma, blue sclera. Cystic medial necrosis of proximal ascending aorta and pulmonary artery -> dissection/IMH, rupture, aortic/pulmonary incompetence. Mitral valve prolapse. Pulmonary cysts. Most die by 50yo from dissection or LVF.

Ehlers-Danlos Syndrome (EDS)

Specturm of disorders with defect in synthesis or structure of fibrillar collagen, most AD (some AR). Different types effect different types of collagen. Very lax skin easy to injury with poor healing, hypermobile joints prone to later contractures, easy bleeding with SC bleding fat necrosis and calcifications esp forearms/shins (fragile vessels, hence angiography dangerous). Kyphoscoliosis, dural ectasia, arachnodactyly, sopndylolysis. Dislocations, flat feet, early OA. Haemarthrosis after minimal trauma. Great vessel aneurysms, dissection, tortuosity, diaphragmatic hearnia. Ruptured cornea, retinal detachment.


AR inborn error of metabolism with acumulation of homocystine in serum and urine, defective collagen synthesis. Scoliosis, dural ectasia, pectus excavatum. Variable arachnodactyly. Osteopenia with vertebral compression fractures. Mental retardation, seizures, joint contractures.

Sytemic Lupus Erythematosus (SLE)

Multisystem autoimmune with vast array of autoantibodies esp antinuclear antibodies (ANAs). Acute or insidious, chronic, remitting, relapsing, esp fever, involving skin, serositis, arthritis, nephritis. F:M 9:1, 1:2500, more common in blacks and Hispanics. Most arise in 20s-30s. ANAs are sensitive, but not specific. Antibodies to double-stranded DNA and Smith (Sm) antigen is virtually diagnostic. Other autoantibodies target red cells, platelets, lymphoytes, phospholipids (incl prothrombin, protein S/C etc antiphospholipid antibodies present in 40-50%), cardiolipin antigen (used in syphilis serology), lupus anticoagulant (Ig interfering with in vitro clotting tests). Hypercoagulable state with venous and arterial thromboses. Most damaged caused by immune complexes (type III hypersensitivity).

  • Skin (50%) – Malar facial butterfly rash, discoid rash, photosensitivity, oral ulcers.
  • Acute necrotising vasculitis – Capillaries, small arteries and arterioles in any tissue. Fibrinoid deposits in the vessel walls, later fibrous thickening with luminal narrowing.
  • Arthritis – Nonerosive synovitis, ligament laxity.
  • Cardiac – Pericarditis (50%), myocarditis (mononuclear infiltration), nonbacterail verrucous (Libman-Sacks) endocarditits (multiple 1-3mm warty deposits on either surface of leaflets), diffuse leaflet thickening (esp mitral and aortic), accelerated atherosclerosis.
  • Splenomegaly
  • Lungs – Pleuritis with effusions (50%), alveolar injury with oedema and haemorrhage, chronic interstitial fibrosis, pulmoanry hypertension
  • Lupus nephritis (50%) – Most immune complex deposition in glomeruli (glomerulonephritis), tubular and peritubular capillary basement membranes.
  • Neurological – Seizures, psychosis ?antibodies agaist synaptic membrane or vasculitis.
  • Haematological – Haemolytic anaemia, leukopenia, lymphopenia, thrombocytopenia

Sjögren Syndrome

Dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) from destruction of lacrimal and salivary glands, Primary (sica syndrome) or secondary (associated with other autoimmune disease) esp RA, others include SLE, polymyositis, scleroderma, vasculitis, mixed connective tissue disease, thyroiditis. 75% positive rheumatoid factory, 50-80% have ANAs, 90% have ribonucleoprotein antigens (SS-A, SS-B). ?Viral infection of salivary glands acusing local cell death and release of self-antigens. Activation of T and B cells causing inflammation, tissue damage of fibrosis of lacrimal and slaivary glands. May also involve other exocrine glands lining respiratory and GI tracts and vagina. Periductal and perivascular lymphocytic infiltration. Mikulicz syndrome is lacrimal and salivary gland enlargement, from Sjogren, sarcoid, luekoemia, lymphoma, other tumours, Diagnosis of Sjorgen syndrome requires biopsy of the lip (minor salivary glands). 5% develop lymphoma (40x increased risk, originating from the dominent B cell clone).

Systemic Sclerosis

(Scleroderma). F:M 3:1, peak 50-60s. Chronic inflammation damaging small vessels, progressive interstitial and perivascular fibrosis in skin and multiple organs (GIT, kidneys, heart, muscles, lungs). Diffuse scleroderma involves widepsread skin at onset with rapid progression and early visceral involvement; limited scleroderma usually confined to fingers, forearms and face wtih late visceral involvement and relatively benign course. Some of those with limited scleroderma develop CREST syndrome with Calcinosis, Raynaud’s phenomenon, oEseophageal dysmotility, Sclerodactyly and Telangiectasia. Almost all are ANA positive.

  • Vasculitis – Intimal proliferation in 100% of digital arteries.
  • Skin – Diffuse sclerotic atrophy of skin. Later tapered clawlike finger fingers, atrophic termianl phalanges, occasionally autoamputation of tips.
  • GIT (90%) – Progressive atrophy and fibrous replacement of muscularis, dysfunction of lower oesophageal sphincter (GOR and Barrets), loss of villi and microvilli in small bowel (may cause malabsorption).
  • MSK – Synovitis with hypertrophy similar to RA, but joint destruction not common. Later fibrosis. 10% develop inflammatory myositis.
  • Renal (2/3) – Intimal thickenign of interlobular arteries (also seen in malignant HTN), causing HTN in 30%, renal failure.
  • Lungs (50%) – Pulmoanry HTN and interstiital fibrosis (UIP).
  • Cardiac – Pericarditis with effusion, myocardial fibrosis.

Mixed Connective Tissue Disease

Features with mixture of SLE, systemic sclerosis and polymositis. May later develop into classicle SLE or systemic slcerosis.

Inborn Errors of Metabolism

Most are due to single genetic defects the code for an enzyme that convers a substrate into product, with accumulation of the substrate.

Lysosomal Storage Diseases

Lysosomal enzymes (acid hydrolases) are synthesized in the endoplasmic reticulum with post-translational modification in the Golgi apparatus. These are required for autophagy (turnover of intracellular organelles) and heterophagy (phagocytosis). Defect in the eynzmes, activators or transport of these enzymes leads to accumulation of partially degraded insoluble macomolecules, which distends lysosomes and may disrupt normal cell functions. This mononuclear phagocyte system is particularly effected with hepatosplenomegaly. Types include:

  • Glycogen storage disease (glycogenoses) – Pompe disease.
  • Mucopolysaccharidoses (MPS) – Accumulation of mucopolysaccharides (glycosaminoglycans, acid-Schiff-positive). All AR (except X-linked recessive Hunter). Progressive coarse facial features, corneal clousding, joint stiffness, mental retardation. Hepatosplenomegaly, skeletal deformities, valvular lesions, subendothelial arterial deposites (esp coronaries), brain lesions. Types include Hurler syndrome (MPS IH), Hunter syndrome (MPS II), Sanfilippo syndrome (MPS III), Morquio syndrome (MPS IV), Maroteaux-Lamy syndrome (MPS VI), Sly syndrome (MPS VII).
  • Mucolipidoses
  • Oligosaccharidoses
  • Lipidoses
    • Niemann-Pick type C and D.
    • Wolman disease
  • Sphingolipidoses
    • Gaucher disease (most common lysosomal storage disease) – AR disorders with defect in glucocerebrosidase, accumulations in phagocytes and occasionally CNS. Causes activation of macrophages with cytokine secretion. More common form develops later with normal lifespan. Gaucher cells are distened phagocytic cells, in the spleen (spelnomagaly causes pancytopaenia/thrombocytopaenia), liver, bone marrow, LN, tonsils, thymus, Peyer’s patches. Expansion of distal femur (Erlenmeyer flask deformity) from marrow infiltration. Generalised osteoporosis, susceptible to fracture and osteomyelitis. H-shaped vertebral bodies from endplate fractures. Bone infarction with focal sclerosis and bone-within-bone appearance or focal cystic lesions. Frequent AVN esp hip. Low T1 and T2 in infiltrated marrow (from marrow packing), patchy or dense, may have transcortical extension. Tx enzyme replacement therapy with marrow signal and liver/spleen size return to normal.
    • Niemann-Pick disease type A and B – Accumulation of sphingomyelin (component of membranes). Massive enlargement of the spleen, generally enlarged LN, widened sulci.
    • Gangliosidoses – Including Tay-Sachs disease, Sandhoff Disease. Mostly affects neurons including CNS, autonomic and retina.
  • Lysosomal transport diseases


(Alkaptonuria). AR lack of homogentisic oxidase with accumulation of homogentisic acid. This binds to collagen causing ion. Deposition in articular cartilage causing fragmentation and osteoarthritis, esp vertebral column.

Phenylketonuria (PKU)

AR, lack of phenylalanine hydroxylase (PAH) causing hyperphenylalaninaemia, lack of conversion into tyrosine. Severe mental retardation by 6/12, seizures, reduced pigmentation.


AR, inability to convert galactose (fom lactose in milk) to glucose, with accumulation of galactose-1-phosphate. Hepatomegaly with faty change then cirrhosis, cataracts, CNS changes with loss of nerve cells, gliosis and oedema esp dentate nuclei, medullary olives.

Transplant Rejection

  • Hyperacute rejection (min-hrs) – Kidney becomes cyanotic, mottle, flaccid. IG and complement deposition in vessels with endothelial injury, thrombi causing infarction.
  • Acute rejection – Within days or suddenly months-years later after termination of immunosuppression. Cellular rejection causes interstitial mononuclear infiltrates (T lymphocytes), oedema, haemorrhage causing focal areas of tubular necrosis, endothelitis; responds well to immunosuppressives. Humoral rejection (rejection vasculitis) from antidonor antibodies causing necrotising vasculitis, thrombosis; causes extensive parenchymal necrosis.
  • Chronic rejection – Progressive renal failure with rising Cr over months. Vascular changes (intimal fibrosis), intersitital fibrosis, atrophy.

Haematopoetic Stem Cell Transplants

Bone marrow translants may cause graft-versus-host (GVH) disease or immunodeficiency. Graft-versus-host disease (GVHD) occurs after immunologically competent cells or their precursors and transplanted into immunologically crippled recipients, with the cells recognising alloantigens (HLA antigens) in the host. Mostly bone marrow transplants, occasionally organs rish in lymphoid cells (eg liver) or transfusion or unirradiated blood. Depletion of donot T cells before transfusion almost eliminates GVHD, but also increase EBV-related B-cell lymphoma and graft failures.

  • Acute GVHD (days-weeks) – Esp skin, liver, intestines with rash (may lead to desquamation), destruction of small bile ducts (jaundice), mucosal ulceration bloody diarrhoea). Most damage from CD8+ T-cells.
  • Chronic GVHD (after acute syndrome or insidious) – Extensive skin injury with fibrosis (resembles systemic sclerosis). Chronic liver disease with cholestatic jaundice, oesophageal strictures. Involution of thymus and depletion of lymphocytes in LNs leading to life-theratening infections. May develop autoimmunity with grafted CD4+ T cells stimulating host B cells.


Amyloid is pathologic proteinaceous deposited in the extraceuular space. It is amorphous, eosinophlic, hyaline, encroaches on ahd produces pressure atrophy of adjacent cells. There is apple-green birefringence on polarising microscopy of specimens stained with Congo red dye. It is probably related to abnormal protein folding, 95% consists of fibril proteins, being AL (amyloid light chains from Lg light chains in plasma cells), AA (amyloid associated from liver), Aβ (from β amyloid precursor in cebrebal lesiosn of Alzheimer and amyloid angiopathy), or others. Amyloidosis may be systemic/generalised (primary from immunocyte disorder) or localised (usually underlying chronic inflammatory or tissue-destructive process).

  • Primary amyloidosis (most common) – Plasma cell dyscrasia, in 5-15% of those with multiple myeloma; but most don’t have MM. Formation of single specifig Ig (monoclonal gammopathy) as well as only light chains (Bence-Jones protei). The light chains may be deposited as amyloid AL type.
  • Reactive systemic amyloidosis – In connnective tissue disorders (RA, AS, IBD), chronic infections (TB, osteomyelitis, bronchiectasis), heroin abuse. AA type.
  • Haemodialysis-associated amyloidosis – High concentrations of β2-microglobuluin which is unable to be filtered thryough dilysis, with deposition in tissues esp synovium, joints, tendon sheaths.
  • Familial amyloidosis – Rare, most limited in geographic areas.
  • Localised amyloidosis – Nodular masses or only evident on microscopy. Most in lung, larynx, skin, bladder, tongue, eye, with lymphocytes and plasam cells at peripheries. Many from AL protein.
  • Endocrine amyloid – Cetain endocrine tumours including medullary thyroid, pancreatic islet cell, pheochromocytomas, undifferentiated stomach, type II diabetes. From polypeptide hormones or unique proteins.
  • Amyloid of aging – Senile systemic amyloidosis (70s-80s) mostly affects heart (senile cardiac amyloidosis) with restrictive cardiomyopathy.


Klippel-Trenaunay-Weber Syndrome

(Klippel-Trenaunay syndrome). Rare, sporadic, unilateral enlarged superficial venous channels ?fetal lateral limb bud vein failed to regress with secondary impaired venous return and tissue overgrowth. Usually lower limb. Triad of large port-wine naevus, gigantism of limb/distal digits (macromelia of entire extremity, focal gigantism of a smaller portion), varicose veins.

Beckwith Wiedemann Syndrome (BWS)

Syndrome of macroglossia, otic dysplasia, omphalocoele, localised gigantism/macrosomia, hemihypertorphy, cardiac anomalies, pancreatic islet cell hyperplasia, nephromegaly, hepatosplenomegaly. Most are sporadic. Increased risk of neoplasias including Wilms tumour, nephroblastomatosis, adrenocortical carcinoma, gonadoblastoma, rhabdomyosarcoma, neuroblastoma, pancreatoblastoma, hepatoblastoma. Also associated with polyhydramnios, placentomegaly with molar degeneration, medullary renal cysts, calyceal diverticula, nephrolithiasis, postnatal hypoglycaemia, hypospadias, cryptorchidism.

Macrodystrophia Lipomatosa

Localised gigantism of unkown aetiology. Overgrowth of adipose and periosteal osteoblasts. Esp fingers and toes.

Apert Syndrome

(Acrocephalosyndactyly). Most sporadic, autosomal dominant from disturbance in development of the brachial arches (esp 1st which froms the maxilla and mandible). Otitis media, conductive hearing loss. Brachycephaly with coronal craniosynostosis, widened metopic and sagittal sutures, hypoplastic midface, shallow orbits with proptosis, enlarged sella, stylohyoid calcification. C-spine fusion, severe symmetric syndactyly with fusion of distal phalanges, metacapls/carpals, absent middle phalanges, missing/supernumery capals/tarsals, pseudoarthroses.

Amniotic Band Syndrome

Congenital amputations and soft tissue defects by fetal entanglement. May be minimal amputation, focal syndactyly, cranial or body wall defects, focal soft tissue constrictions (-> chronic lymphedema).

Arthrogryposis Multiplex Congenita

Rare, sporadic, unknown aetiology ?severely restricted fetal movement eg oligohydramnios. Severe fixed flexion deformities (± soft tissue webs), dislocations, dense joint capsules, long scoliosis, muscle and soft tissue atrophy, disuse osteoporosis. Clubfeet and hands. Normal IQ.

Fibromatosis Colli

Nonneoplastic focal or diffuse enlargement of SCM in an infant ?from birth injury, associated with forceps delivery. Shortening may -> torticollis. Usually resolves over months, responding to passive stretching.