• Approach: careful history (travel, animals, TB contacts, sexual history, drug use, duration), examination of all lymph node groups (size, consistency, tenderness, fixation) and systemic features (hepatosplenomegaly, rash, oral ulcers, arthritis).
• Investigations: FBC and blood film (EBV mononucleosis - atypical lymphocytes; CML - massively raised WBC), monospot/EBV serology, LFTs, LDH, serum protein electrophoresis (myeloma), CXR (mediastinal widening - lymphoma, TB, sarcoid), HIV, malaria film if travel history; excisional lymph node biopsy if malignancy suspected.
• Thrombocytopenia + fever: think dengue (platelet fall in critical phase), ITP (petechiae), TTP (MAHA pentad), bone marrow infiltration, hypersplenism, severe sepsis/DIC.

Clubbing = increased curvature and volume of nails ± nail bed hypertrophy; loss of Lovibond angle (angle between nail plate and dorsal surface — normally < 160°; in clubbing ≥ 180°). Grades: Grade 1 = ↑ fluctuation of nail bed; Grade 2 = Schamroth sign (diamond-shaped gap lost on opposing fingertips); Grade 3 = bulbous enlargement; Grade 4 = hypertrophic osteoarthropathy (periosteal new bone formation + arthralgia).

Marfan syndrome = autosomal dominant connective tissue disorder caused by mutations in FBN1 gene (fibrillin-1) on chromosome 15 → abnormal fibrillin protein → weakened elastic fibres → aortic + ocular + skeletal + skin involvement.

• Skeletal: Tall stature with disproportionately long limbs + fingers (arachnodactyly — 'spider fingers'); arm span > height; pectus excavatum (hollowed chest) or carinatum (pigeon chest); scoliosis; high arched palate ; hypermobile joints; pes planus
• Cardiovascular (most dangerous): Aortic root dilatation → aortic dissection (#1 cause of death ); aortic regurgitation ; Mitral valve prolapse (mitral regurgitation, palpitations)
• Ocular: Ectopia lentis (upward lens subluxation — superotemporal; in homocystinuria = downward ); myopia; retinal detachment; glaucoma; blue sclera
• Skin: Stretch marks (striae distensae); skin hyperextensibility (though less than Ehlers-Danlos)
• Diagnosis: Revised Ghent criteria (2010) — systemic score + aortic root Z-score + ectopia lentis + FBN1 mutation; Echocardiogram (aortic root measurement) annually
• Management: Beta-blockers (propranolol/atenolol) — reduce aortic root expansion rate + rupture risk; Losartan (ARB — inhibits TGF-β pathway; additive benefit); Avoid contact sports + extreme exertion; Surgical aortic root replacement (if root > 50 mm or rapidly expanding); genetic counselling
• Ghent criteria features: aortic root Z-score >= 2 (most important); ectopia lentis; systemic score includes wrist and thumb sign, pectus carinatum, hindfoot deformity, pneumothorax, dural ectasia, protrusio acetabulae, reduced upper-to-lower segment ratio, arachnodactyly, scoliosis, reduced elbow extension, facial features, striae, myopia, mitral valve prolapse.
• Screening and surveillance: annual echocardiography for aortic root measurement; prophylactic aortic root replacement at root diameter 4.5-5.0 cm or rapid expansion > 0.5 cm/year; ophthalmology (lens subluxation, retinal detachment); FBN1 genetic testing for family screening.
• Differential: homocystinuria (autosomal recessive, downward lens subluxation, intellectual disability, thromboembolism, elevated plasma homocysteine); congenital contractural arachnodactyly (Beals syndrome, FBN2 gene); Loeys-Dietz syndrome (more aggressive aortic disease, uvula bifida).

Genetic counselling = the process by which patients or relatives at risk of a hereditary disorder are advised of: consequences of the disorder; probability of developing/transmitting it; ways in which this may be prevented or ameliorated. Non-directive principle — counsellor gives information/options but does NOT direct the patient's decision.

• Principles: non-directive counselling (provide information and support choices without imposing values); respect for autonomy and confidentiality; benefits of genetic testing must outweigh harms; consider psychological impact; involve the wider family where appropriate.
• Indications: family history of genetic disease, consanguinity, advanced maternal age (Down syndrome risk), recurrent miscarriage, abnormal prenatal screening, carrier testing in high-risk populations (e.g. thalassaemia, sickle cell), and pre-implantation genetic diagnosis for IVF.
• Types of inheritance: autosomal dominant (AD - one mutant allele sufficient; affected parent); autosomal recessive (AR - two mutant alleles needed; carrier parents); X-linked recessive (affected males, carrier females - e.g. haemophilia, G6PD, DMD); mitochondrial (maternal transmission only, variable expression).
• Indications:

• Advanced maternal age (> 35 years → ↑ risk Down syndrome/trisomies )
• Family history of genetic disorder (single gene, chromosomal, multifactorial)
• Recurrent pregnancy loss (≥ 3 miscarriages ) → chromosomal analysis of couple
• Previous child with chromosomal/genetic disorder
• Consanguineous marriage (related parents → ↑ autosomal recessive risk )
• Carrier testing (haemophilia; sickle cell; thalassaemia )
• Ethnicity-based screening (thalassaemia in India/Mediterranean; Tay-Sachs in Ashkenazi Jewish )

• Patterns of inheritance:

• PUO (Petersdorf &amp; Beeson): fever &gt; 38.3 C on several occasions for &gt; 3 weeks, undiagnosed after appropriate investigation; categories - infections (TB, abscess, infective endocarditis), malignancy (lymphoma, leukaemia, RCC), connective-tissue disease (SLE, adult Still&#x2019;s, vasculitis), and miscellaneous (drug fever, thyroiditis).

PATHOGENESIS OF FEVER — PYROGENS

• Exogenous pyrogens (from microorganisms): Bacterial LPS (endotoxin — gram-negative cell wall ); gram-positive cell wall (peptidoglycan ); viral antigens; fungal products → activate macrophages/monocytes
• Endogenous pyrogens (from host cells): IL-1β ; IL-6 ; TNF-α ; IFN-γ — released by activated macrophages → cross blood-brain barrier (BBB) via circumventricular organs
• Hypothalamus (thermoregulatory centre): Endogenous pyrogens → ↑ PGE2 (prostaglandin E2) (via COX-2 pathway) in preoptic area → reset thermostat → vasoconstriction + shivering → fever
• Antipyretics (paracetamol/aspirin/NSAIDs) → inhibit COX → ↓ PGE2 → reduce fever; do NOT reduce normal body temperature (no antipyretic effect on normal thermostat )

• Antipyretic use in PUO: Use paracetamol to control temperature > 39°C; avoid masking diagnostic fever patterns; take cultures at peak temperature (higher bacteraemia )
• PUO categories: classic PUO (community - infections > 35%, malignancy 20%, connective tissue disease 15%, miscellaneous 15-25%, undiagnosed 10-20%); HIV-associated PUO (MAC, CMV, lymphoma, cryptococcus); nosocomial PUO (line infection, CDiff, DVT/PE, drug fever); neutropenic PUO (chemotherapy patients - empirical antibiotics and antifungals).
• Investigations of PUO: FBC, ESR, CRP, LFTs, RFTs, blood cultures (multiple sets), urine MC&S, CXR, ANA, RF, HIV; CT chest/abdomen/pelvis; PET-CT (most useful in detecting occult infection, lymphoma and vasculitis); echocardiography for endocarditis; bone marrow biopsy if haematological malignancy or granuloma suspected.

Acute Phase Response (APR) = stereotyped hepatic reaction to tissue injury, infection, or inflammation; mediated by IL-6, IL-1β, TNF-α → liver produces acute phase proteins.

• CRP - clinical uses: monitoring infection and inflammation (rises within 6-12 h, returns to normal promptly when inflammation resolves); useful in distinguishing bacterial from viral infection (very high CRP > 100 mg/L usually bacterial); monitoring treatment response in RA, IBD, post-surgical infections.
• ESR vs CRP: ESR rises and falls slowly (hours to days for CRP vs days to weeks for ESR); ESR is affected by anaemia, polycythaemia, paraproteins and rouleaux formation; CRP is more sensitive and specific for acute inflammation.
• Negative acute phase reactants: albumin, transferrin, prealbumin and retinol-binding protein fall during the acute phase response (production diverted to positive reactants); low albumin therefore reflects inflammation as well as malnutrition.

Generalised lymphadenopathy (GLA) = enlargement of lymph nodes in ≥ 2 non-contiguous regions (vs localised/regional LAD). Nodes > 1 cm considered enlarged (epitrochlear > 0.5 cm; inguinal > 1.5 cm).

• Approach: History (duration, fever, night sweats, weight loss — B symptoms ); examination (size, consistency, tenderness, fixity); FBC + film (lymphocytosis in CLL/EBV; blast cells in leukaemia ); LDH; ESR; CRP; CXR (mediastinal, hilar nodes); CT CAP; FNAC (first-line for node biopsy in many centres); excision biopsy (gold standard; required for lymphoma diagnosis )
• Investigations for GLA: FBC and film (leukaemia, EBV atypical lymphocytes), LDH (lymphoma activity), HIV, EBV/CMV/toxoplasma serology, CXR (mediastinal nodes - sarcoid, lymphoma, TB), CT chest/abdomen/pelvis (staging), bone marrow trephine if haematological malignancy suspected, excisional lymph node biopsy (most important for diagnosis of lymphoma - not FNA alone).
• Biopsy - when and how: biopsy an enlarged lymph node if malignancy is suspected, if nodes are > 1.5 cm for > 4 weeks without an obvious cause, or if associated with B symptoms (fever, night sweats, weight loss); excisional biopsy preferred (preserves architecture for lymphoma subtyping).
• Red flags: lymph nodes that are hard, non-tender, rubbery, matted or fixed; supraclavicular nodes (Virchow - gastric/intra-abdominal malignancy; left); systemic B symptoms; hepatosplenomegaly; weight loss.

Gene therapy = introduction of genetic material into human cells to correct or compensate for a disease-causing gene mutation. Strategies: Gene replacement (add functional gene); Gene silencing (siRNA/ASO); Gene editing (CRISPR-Cas9 ).

• Vectors for gene delivery:

• Viral vectors: AAV (Adeno-Associated Virus — most widely used clinically; safe; non-integrating; efficient); Adenovirus (strong immune response); Lentivirus (integrates into genome → risk of insertional mutagenesis; used for haemopoietic stem cells ); Retrovirus
• Non-viral: Lipid nanoparticles (LNP — used in mRNA COVID-19 vaccines; efficient for liver; Casgevy gene editing ); electroporation; CRISPR ribonucleoprotein

• Clinical examples:

• Casgevy (Exagamglogene autotemcel) — FDA + UK approved 2023; first CRISPR-Cas9 gene therapy; for sickle cell disease + thalassaemia; edits patients' own HSCs to reactivate fetal Hb (HbF) → reduces sickling/transfusions; potentially curative
• Luxturna (Voretigene neparvovec) — AAV2 vector; RPE65 gene mutation; Leber's congenital amaurosis (inherited blindness); restores vision
• Zynteglo (Betibeglogene autotemcel) — lentiviral vector; for beta-thalassaemia; transfusion independence in 89%
• Hemgenix (Etranacogene dezaparvovec) — AAV5; for Haemophilia B; single infusion → sustained FIX production → eliminates bleeds

• Challenges: Host immune response; insertional mutagenesis (integrating vectors ); off-target CRISPR edits; cost ($1–3 million per treatment ); limited cell types accessible
• Mechanism types: gene addition (insert functional copy of defective gene using AAV or lentivirus); gene editing (CRISPR-Cas9 makes double-strand break at specific target, allowing correction or disruption of a gene); RNA-based therapy (siRNA silences dominant-negative mutant; mRNA provides transient gene expression).
• Approved therapies (2025): Casgevy (sickle cell disease and beta-thalassaemia, CRISPR-Cas9); Luxturna (inherited retinal dystrophy, RPE65, AAV2); Zynteglo (beta-thalassaemia, lentiviral); Hemgenix (haemophilia B, AAV5 FIX); Roctavian (haemophilia A, AAV5 FVIII); Skysona (cerebral adrenoleukodystrophy, lentiviral).
• Safety concerns: immunogenicity to viral vector capsid (pre-existing antibodies may block or cause inflammation); insertional mutagenesis with integrating vectors (risk of activating oncogenes - seen historically with early retroviral trials); off-target CRISPR edits; very high cost limiting access.

• PSA: Prostate cancer (also raised in BPH, prostatitis, post-DRE); screening + monitoring for recurrence.
• CEA: Colorectal cancer (also gastric, pancreatic, lung, breast; smokers); monitors post-resection recurrence, not for screening.
• CA-125: Ovarian (epithelial) cancer (also endometriosis, peritonitis, pregnancy); monitors treatment response.
• CA 19-9: Pancreatic carcinoma and cholangiocarcinoma; also raised in biliary obstruction without malignancy.
• Beta-hCG: Choriocarcinoma, hydatidiform mole, germ-cell tumours (mildly in seminoma).
• CA 15-3: Breast cancer; monitoring of metastatic disease.
• Calcitonin: Medullary carcinoma of thyroid; also family screening in MEN-2.
• Thyroglobulin: Differentiated (papillary/follicular) thyroid carcinoma; follow-up after thyroidectomy.
• AFP: HCC (primary hepatocellular carcinoma ) + Testicular non-seminomatous germ cell tumours + Normal in pregnancy (↑ in fetal serum); neural tube defects (maternal serum AFP ↑ ); Down syndrome (maternal AFP ↓ )
• Alpha-1 fetoprotein as a developmental biomarker: AFP is a foetal serum protein produced by fetal liver and yolk sac — analogous to albumin in adult; declines after birth; production re-activated in hepatocellular carcinoma and germ cell tumours

NK CELLS (NATURAL KILLER CELLS)

• NK cells = innate lymphocytes (CD56+CD3- ) that kill abnormal cells (tumour cells, virus-infected cells) without prior sensitisation and without MHC restriction (distinguishes from cytotoxic T-cells )
• Mechanisms: Missing self (attack cells that lack MHC-I; virus/tumour cells ↓ MHC-I to escape T-cells → NK cells kill these); ADCC (Antibody-Dependent Cell-mediated Cytotoxicity via FcγRIII/CD16 ); release perforin + granzymes; produce IFN-γ
• NK cell deficiency: susceptibility to herpesvirus (CMV, EBV, VZV) and ↑ malignancy risk

TNF-α (TUMOUR NECROSIS FACTOR-ALPHA)

• TNF-α = pro-inflammatory cytokine produced mainly by macrophages (also T-cells, NK cells, mast cells); pleiotropic: mediates inflammation, apoptosis, immune surveillance
• Functions: ↑ vascular permeability; ↑ adhesion molecules; ↑ neutrophil recruitment; fever (endogenous pyrogen ); cachexia/wasting (chronic inflammation — #1 cytokine responsible ); apoptosis of tumour cells; activation of phagocytes
• Pathological: Central to RA; Crohn's; psoriasis; ankylosing spondylitis; septic shock (TNF excess → capillary leak + coagulopathy)
• Anti-TNF therapy: Infliximab (IV mAb); Adalimumab (SC mAb); Etanercept (fusion protein — soluble TNF-R); used in RA, Crohn's, psoriasis, AS; risk: TB reactivation (screen IGRA before ), opportunistic infections, demyelination, lymphoma (modest ↑ risk)

KLINEFELTER'S SYNDROME

Klinefelter's syndrome = 47, XXY karyotype (most common sex chromosome aneuploidy in males; 1:600 male births); extra X chromosome from non-disjunction.

• Clinical features: Tall stature; small firm testes (hyalinised tubules); gynaecomastia (40%; oestrogen excess from ↑ conversion + ↓ testosterone); infertility (azoospermia — most present with infertility); sparse facial/body hair; learning difficulties (in some); ↑ risk breast cancer (due to gynaecomastia) + mediastinal germ cell tumour
• Investigations: Karyotype (47,XXY ); ↓↓ testosterone; ↑ LH + FSH (hypergonadotrophic hypogonadism )

▶ Testosterone replacement from adolescence — improves virilisation, energy, bone density; does NOT restore fertility (azoospermia usually irreversible ); TESE (testicular sperm extraction) + ICSI in some cases

CARPAL TUNNEL SYNDROME (CTS)

CTS = compression of the median nerve at the wrist within the carpal tunnel → sensory ± motor deficits in median nerve distribution . Most common peripheral entrapment neuropathy (prevalence 1–3%).

• Causes: Idiopathic (most common ); Pregnancy (fluid retention); Hypothyroidism; Acromegaly; Rheumatoid arthritis; DM; Obesity; Repetitive hand/wrist use; Amyloidosis; Wrist fracture
• Clinical: Paraesthesia + pain in thumb, index, middle finger + radial half of ring finger (median nerve territory ); worse at night (wakes patient ); 'shaking out' relieves; weakness of thumb opposition (thenar wasting — late ); Tinel's sign (tapping over carpal tunnel → paraesthesia in median distribution ); Phalen's test (wrist flexed for 60 sec → symptoms reproduced )
• Nerve conduction study (NCS) — delayed sensory + motor conduction across the wrist; confirmatory
• Treatment: Wrist splint (neutral position, nocturnal ); address underlying cause (treat hypothyroidism ); corticosteroid injection (wrist injection; temporary relief); surgical carpal tunnel decompression (division of flexor retinaculum) — definitive; for severe/refractory/thenar wasting

• Exertional heat stroke: Young athletes; strenuous exercise in hot weather; diaphoretic
• Classic heat stroke: Elderly/chronically ill; hot weather; ANHIDROTIC ; drugs (anticholinergics, antipsychotics, beta-blockers impair sweating )
• Management: Rapid external cooling (cold water immersion most effective ); IV fluids; benzodiazepines (shivering/seizures ); manage rhabdomyolysis + AKI + DIC + LFT abnormalities

TERMINAL CARE / PALLIATIVE MEDICINE

Terminal care = care provided in the last days/weeks of life; component of palliative care (holistic approach to improve QoL in life-limiting illness). WHO definition: active total care of patients with disease that is no longer responsive to curative treatment.

• Key principles: Pain control (WHO pain ladder: Step 1 = non-opioid [paracetamol/NSAIDs]; Step 2 = weak opioid [codeine/tramadol]; Step 3 = strong opioid [morphine /oxycodone/fentanyl]); symptom control (dyspnoea, nausea, constipation, anxiety ); psychological support; spiritual care; family involvement
• Morphine — gold standard for cancer pain; oral/IV/SC; start low dose (5–10 mg 4-hourly) + PRN breakthrough doses (1/6th of total daily dose ); titrate until adequate analgesia; laxatives always (constipation universal ); antiemetic first 2 weeks
• Syringe driver (CSCI — Continuous Subcutaneous Infusion) — for patients unable to take oral medications; allows combination of opioid + antiemetic + sedative over 24 hrs
• Liverpool Care Pathway (LCP) and Advance Care Planning (DNAR, LPA, preferred place of death )
• Malignant Hyperthermia (not same as heat stroke) — rare, life-threatening hypermetabolic reaction to volatile anaesthetic agents (halothane, sevoflurane, desflurane) or succinylcholine ; RYR1 gene mutation (ryanodine receptor); treat with dantrolene (inhibits Ca²⁺ release from SR) + cooling + body temperature support

Methotrexate (MTX) = folate antimetabolite ; inhibits dihydrofolate reductase (DHFR) → ↓ reduced folates → impaired thymidylate synthesis + purine synthesis → impaired DNA synthesis → ↓ rapidly dividing cells (cancer cells, immune cells).

• Mechanism: folate antagonist - inhibits dihydrofolate reductase (DHFR), which is required to reduce dihydrofolate to tetrahydrofolate (THF); THF is needed for purine and thymidine synthesis; at low doses used in rheumatology and dermatology, the mechanism also involves adenosine release and anti-inflammatory effects.
• Indications: rheumatoid arthritis (anchor DMARD), psoriasis and psoriatic arthritis, inflammatory bowel disease, asthma (adjunct), ectopic pregnancy (systemic), ALL (intrathecal CNS prophylaxis), osteosarcoma, and choriocarcinoma.
• Toxicity monitoring: FBC (myelosuppression - leucopenia, thrombocytopenia), LFTs (hepatotoxicity - transaminitis, fibrosis with long-term use), renal function (renal excretion - hold if eGFR < 30), and chest X-ray (pneumonitis - rare but can be fatal); give folic acid 5 mg weekly (not on MTX day) to reduce mucosal and haematological side effects.
• Folinic acid rescue: high-dose MTX (in oncology) is followed by leucovorin (folinic acid) rescue 24-36 hours later to protect normal cells; measure MTX levels to guide leucovorin dosing; hydration and urinary alkalinisation prevent crystallisation in renal tubules.
• Indications:

• Oncology: ALL (IT MTX for CNS prophylaxis ); NHL; osteosarcoma; choriocarcinoma (highly sensitive — curable with MTX); breast; bladder
• Rheumatology: RA (anchor DMARD ); SLE; psoriasis; psoriatic arthritis; dermatomyositis; vasculitis
• Gastroenterology: Crohn's disease (maintenance); UC (less commonly)
• Gynaecology: Ectopic pregnancy (medical management — dissolves trophoblast); molar pregnancy

• Adverse effects:

• Hepatotoxicity — most important long-term SE; steatosis → fibrosis → cirrhosis; monitor LFTs; avoid alcohol; liver biopsy if cumulative dose > 1.5–3 g (rheumatology )
• Myelosuppression — leucopenia; anaemia; thrombocytopenia; monitor CBC; folinic acid (leucovorin) rescue in high-dose (cancer) protocols
• Pulmonary toxicity — pneumonitis (interstitial pneumonitis — dry cough + dyspnoea + fever + ground-glass on CT); drug hypersensitivity; requires dose reduction/discontinuation
• Mucositis — painful oral ulcers; prevented by folic acid 5 mg/week (give on different day from MTX ) in rheumatological doses
• Teratogenicity — absolute contraindication in pregnancy (folic acid antagonist → neural tube defects + fetal loss); contraception required for ≥ 3 months after stopping (both partners)
• Renal toxicity — dose reduction required if GFR ↓; hold if eGFR < 30 mL/min; renally excreted

• Drug interactions: NSAIDs + trimethoprim (↓ MTX excretion → toxicity ); proton pump inhibitors (↓ renal clearance); penicillin (↑ MTX level)