CFTR Gene

Overview

Gene & Protein Structure

• Location: Chromosome 7p
• Protein class: ATP-binding cassette (ABC) transporter family
• Function: Passive conduit for chloride (Cl⁻) and bicarbonate (HCO₃⁻) transport across plasma membranes of epithelial cells
• Gating mechanism: Cycles between open and closed conformations; regulated by ATP hydrolysis (not active transport against a gradient — uses ATP hydrolysis for channel gating mechanics)
• Tissues expressed: Airway epithelium, intestinal epithelium, pancreatic ducts, sweat glands, biliary epithelium, vas deferens, seminal vesicles, epididymis

Mutations

• Over 2,000 CFTR mutations have been identified
• Approximately 4% of Caucasians are heterozygous carriers
• Homozygous or compound heterozygous mutations cause classic CF disease
• Mutations are classified by their molecular mechanism:

Pathophysiology

• Reduced Cl⁻ and HCO₃⁻ secretion into the airway/ductal lumen
• Sodium hyperabsorption (ENaC is normally inhibited by CFTR)
• Dehydrated, thickened mucus in airways and ducts
• Airway: Chronic bacterial infections (classically Pseudomonas aeruginosa, Staphylococcus aureus), bronchiectasis, progressive lung destruction
• Pancreas: Exocrine insufficiency, malabsorption, CF-related diabetes
• Liver: Biliary cirrhosis
• Reproductive: Congenital bilateral absence of the vas deferens (CBAVD) in virtually all males with CF; CBAVD can occur as an isolated finding with partial CFTR mutations even without full CF

Clinical Relevance Beyond Classic CF

• CBAVD (Congenital Bilateral Absence of Vas Deferens): Found in ~1% of infertile men and up to 6% with obstructive azoospermia; any CFTR mutation can lead to CBAVD without full CF disease (Sexual and Reproductive Health, p. 132)
• CFTR-related metabolic syndrome (CRMS): Newborns with intermediate sweat chloride and one or two CFTR mutations but not meeting full CF diagnosis
• Atypical/monosymptomatic CF: Pancreatitis, bronchiectasis, or sinusitis as isolated presentations

CFTR Modulators (Targeted Therapy)

NF1 and NF2: Neurofibromatosis

NF1 — Neurofibromatosis Type 1 (von Recklinghausen's Disease)

Gene & Protein

• Gene: NF1, located on chromosome 17q11.2
• Protein: Neurofibromin — a GTPase-activating protein (GAP) that is a negative regulator of the RAS–MAP kinase signaling pathway
• Mechanism: Classic tumor suppressor; biallelic loss (two-hit) drives tumor formation
• Inheritance: Autosomal dominant; ~50% familial, ~50% new mutations
• Incidence: ~1 in 2,600–3,000 (most common single-gene neurological disorder)

Pathophysiology

Diagnostic Criteria (NIH — ≥2 required)

Tumors Associated with NF1

• Neurofibromas (cutaneous, subcutaneous, plexiform)
• Plexiform neurofibromas — risk of malignant peripheral nerve sheath tumor (MPNST), ~10% lifetime risk
• Optic nerve gliomas (low-grade astrocytomas)
• Astrocytomas
• Meningiomas
• JMML (juvenile myelomonocytic leukemia) — in children
• Gastrointestinal stromal tumors (GISTs)

Other Features

• Cognitive/learning disabilities (~50–80%)
• Short stature, macrocephaly
• Cardiovascular: hypertension (renal artery stenosis, pheochromocytoma)
• Scoliosis

NF2 — Neurofibromatosis Type 2

Gene & Protein

• Gene: NF2, located on chromosome 22q
• Protein: Merlin (moesin-ezrin-radixin-like protein) — a cytoskeletal scaffolding protein and tumor suppressor
• Mechanism: Loss of merlin disrupts cell contact inhibition and activates proliferative signaling (mTOR, Rac1, Hippo pathway)
• Inheritance: Autosomal dominant; full penetrance; ~50% new mutations
• Incidence: ~1 in 25,000–40,000 (much rarer than NF1)

Hallmark Feature

Diagnostic Criteria (Manchester Criteria)

• Bilateral vestibular schwannomas, OR
• First-degree relative with NF2 + unilateral vestibular schwannoma, OR
• First-degree relative with NF2 + any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular cataract

Tumors Associated with NF2

Key Differences: NF1 vs NF2

Management Highlights

• NF1: Surveillance for plexiform neurofibromas (MRI), optic gliomas (ophthalmology), blood pressure monitoring; selumetinib (MEK inhibitor) approved for inoperable plexiform neurofibromas in children ≥2 years
• NF2: Annual MRI surveillance; vestibular schwannomas managed with observation, stereotactic radiosurgery (Gamma Knife), or microsurgical resection; bevacizumab used off-label for growing vestibular schwannomas

Adalimumab (Humira)

Class & Structure

• Type: Fully human recombinant monoclonal IgG1 antibody (no murine sequences — reduces immunogenicity compared to infliximab)
• Route: Subcutaneous injection
• Target: Tumor Necrosis Factor-alpha (TNF-α)

Mechanism of Action

FDA-Approved Indications (10 total)

Dosing

Adverse Effects

Contraindications

• Active serious infections (including sepsis, active TB)
• Moderate–severe heart failure (NYHA Class III/IV)
• Prior hypersensitivity to adalimumab
• Active demyelinating disease (relative)

Pre-Treatment Screening (Critical)

Key Pharmacology Notes

• Immunogenicity: Despite being fully human, anti-drug antibodies (ADAs) can still form (~5–10%), reducing efficacy; concomitant methotrexate reduces ADA formation
• Half-life: ~2 weeks (allows every-2-week dosing)
• Biosimilars: Multiple available (e.g., Hadlima, Hyrimoz, Cyltezo, Amjevita) — significant cost reduction
• vs. Infliximab: Adalimumab is SC (self-administered at home) vs. infliximab IV infusion; adalimumab is fully human vs. infliximab chimeric (human/murine)

Pseudohypoparathyroidism (PHP)

Core Concept

Genetics — GNAS Gene

Classification

Albright's Hereditary Osteodystrophy (AHO)

• Short stature
• Brachydactyly (short 4th and 5th metacarpals — "knuckle-knuckle-dimple-dimple" sign)
• Round face
• Obesity
• Subcutaneous ossifications
• Cognitive impairment (variable)
• Short neck

Key distinction: PHP1A = AHO + PTH resistance (maternal mutation) | PPHP = AHO without PTH resistance (paternal mutation) — same GNAS gene, different imprinting

Pathophysiology of Hypocalcemia in PHP

1. PTH resistance in proximal renal tubules → inadequate stimulation of 1α-hydroxylase
2. → Reduced 1,25(OH)₂D (calcitriol) production
3. → Impaired intestinal calcium absorption
4. → Hypocalcemia
5. PTH resistance in kidney also → reduced phosphate excretion → hyperphosphatemia
6. Parathyroid glands compensate with secondary hyperplasia → markedly elevated PTH

Lab Findings

Clinical Features

• Hypocalcemia symptoms: Tetany, perioral numbness, Chvostek's sign, Trousseau's sign, seizures, prolonged QTc
• AHO phenotype (if PHP1A): brachydactyly, round face, obesity, short stature
• Multi-hormone resistance (PHP1A): hypothyroidism (TSH resistance), hypogonadism (LH/FSH resistance), growth retardation (GHRH resistance)
• Ectopic/subcutaneous calcifications
• Basal ganglia calcifications (on CT)

Diagnosis

1. Hypocalcemia + hyperphosphatemia + elevated PTH (rules out true hypoparathyroidism)
2. Ellsworth-Howard test: IV PTH infusion → measure urinary cAMP and phosphate — blunted response confirms PHP
3. GNAS mutation/methylation analysis
4. Clinical phenotype (AHO features)
5. Screen for associated hormone resistance (TSH, LH/FSH)

Management

Pseudohyperparathyroidism (Brief Note)

Donovan Bodies & Donovanosis (Granuloma Inguinale)

Donovan Bodies — What Are They?

• Intracellular clusters of Klebsiella granulomatis organisms found within the cytoplasm of large mononuclear cells (macrophages)
• Appear as dark-staining, safety pin-shaped (bipolar staining) encapsulated coccobacilli
• Seen on Giemsa stain or Wright stain of crush/smear preparations from lesion tissue
• Best visualized in large vacuolated macrophages (also called "Donovan cells")
• Named after Charles Donovan (1863–1951), who first described them in 1905

Causative Organism

Epidemiology

• Rare in the United States and Western Europe (sporadic cases only)
• Endemic in: India, South Africa, Papua New Guinea, South America, Caribbean
• Previously endemic in Australia — now extremely rare
• Classified as an STI but low transmissibility; sexual contact is the primary route; some cases may be non-sexual (fecal-oral in endemic areas)
• Incubation period: 1–12 weeks (can be up to 1 year)

Clinical Features

Hallmark Presentation

Four Clinical Variants

Key Distinguishing Features

• No true lymphadenopathy — but pseudobuboes (subcutaneous granulomas in the inguinal region that mimic buboes) can occur
• Lesions are highly vascular ("beefy red")
• Slowly progressive — weeks to months without treatment
• Can spread to perineum, anus, and inguinal folds by autoinoculation
• Extragenital infection: extension to pelvis, intra-abdominal organs, bones, oral cavity (rare)
• Can coexist with other STIs; secondary bacterial infection common

Differential Diagnosis of Genital Ulcers

Diagnosis

Treatment (CDC Guidelines)

Lesions must be followed until complete epithelialization — relapse can occur months later if treatment stopped prematurely

Complications (if untreated)

• Extensive tissue destruction and scarring
• Lymphedema of genitalia (elephantiasis-like)
• Urethral/vaginal stenosis
• Squamous cell carcinoma of the genitalia (rare, long-standing lesions)
• Disseminated disease (bones, liver, spleen)
• Fistula formation

Leishmania donovani — Visceral Leishmaniasis (Kala-Azar)

The Organism

Epidemiology

• 90% of global VL burden: India/Bangladesh, Sudan/South Sudan, Ethiopia, Brazil
• A VL elimination program in India, Nepal, and Bangladesh has markedly reduced incidence on the Indian subcontinent
• Worldwide incidence is otherwise increasing
• "Kala-azar" = Hindi for "black fever" (referring to skin darkening seen in chronic disease)
• Immunocompromised individuals (esp. HIV coinfection) at highest risk for severe/relapsing disease

Life Cycle & Pathogenesis

1. Sandfly bites → inoculates promastigotes into skin
2. Promastigotes phagocytosed by dermal macrophages → transform into amastigotes
3. Amastigotes replicate within macrophages → spread via lymphatics and bloodstream
4. Disseminate to reticuloendothelial system: liver (Kupffer cells), spleen, bone marrow, lymph nodes
5. Massive macrophage/plasma cell infiltration → organomegaly
6. Suppression of cell-mediated immunity → failure to contain parasite → progressive disease

Clinical Features

Classic Triad

Complications

• Bleeding (thrombocytopenia)
• Secondary bacterial infections (pneumonia, TB — due to immunosuppression)
• Severe malnutrition
• Post-kala-azar dermal leishmaniasis (PKDL): macular/papular/nodular skin rash appearing months to years after treatment — important reservoir for transmission in India/Sudan

Diagnosis

Amastigotes = oval, 2–4 µm, intracellular; contain nucleus + kinetoplast (rod-shaped mitochondrial DNA) — "Donovan-Leishman bodies" (not to be confused with Donovan bodies of donovanosis)

Treatment

First-Line (Non-HIV)

HIV Coinfection (WHO 2022 Guidelines)

• Combination therapy preferred: Liposomal AmB + Miltefosine
  • East Africa (L. donovani): miltefosine × 28 days
  • South/Southeast Asia (L. donovani): miltefosine × 14 days
• Combination vs. monotherapy: 88% vs. 55% parasite clearance at 58 days (Ethiopia RCT)
• Secondary prophylaxis with liposomal AmB monthly recommended until CD4 >200 cells/µL
• High relapse rates in HIV coinfection without secondary prophylaxis

Special Considerations

• Miltefosine: oral, teratogenic — check β-hCG before use; contraception required for 5 months after completion
• Antimonials: resistance widespread in Bihar, India — largely replaced by L-AmB there
• Monitor for PKDL post-treatment (up to 20% in Sudan; ~5% in India)

Comparison: L. donovani Complex Species

Primary Sclerosing Cholangitis (PSC)

Definition & Overview

Epidemiology

• Male predominance (~2:1 male-to-female ratio)
• Median age at diagnosis: 30–40 years
• Prevalence: ~10 per 100,000 in Western countries
• Strongly associated with inflammatory bowel disease (IBD):
  • ~50–75% of PSC patients have IBD (predominantly ulcerative colitis)
  • ~5% of UC patients develop PSC
  • Less common association with Crohn's disease
  • PSC can occur before, after, or even years after proctocolectomy — IBD activity does not parallel PSC activity

Pathogenesis

• Immunogenetic basis: Overlapping but distinct from UC on GWAS; pANCA positive in both IBD and PSC
• Proposed mechanisms:
  • Gut-liver axis: colonic bacteria/antigens trafficked to liver via portal circulation → biliary epithelium injury
  • T-cell mediated periductal inflammation → concentric fibrosis ("onion-skin" fibrosis)
  • Gut-homing lymphocytes aberrantly migrate to liver (MAdCAM-1/α4β7 integrin axis)
• HLA associations: HLA-B8, DR3, DR2 (similar to other autoimmune conditions)

Clinical Features

Laboratory Findings

Diagnosis

Imaging (Cholangiography) — Gold Standard

• MRCP (Magnetic Resonance Cholangiopancreatography): First-line — sensitive, specific, non-invasive, safer; reasonable as initial test
• ERCP (Endoscopic Retrograde Cholangiopancreatography): Traditional gold standard; now reserved for therapeutic intervention (dominant stricture dilation, brushings for cytology)

Cholangiographic Appearance

• "Beaded" appearance: multifocal strictures alternating with normal/dilated segments — classic finding
• Affects both intrahepatic and extrahepatic ducts (large-duct PSC)
• Small-duct PSC: normal cholangiogram but PSC on biopsy; better prognosis

Liver Biopsy

• Not required for diagnosis when cholangiography is typical
• Histology: periductal concentric "onion-skin" fibrosis → duct obliteration → fibrous scar ("tombstone lesions")
• Used for staging and when small-duct PSC or overlap syndrome suspected

PSC Variants

Complications

Management

Medical (No proven disease-modifying therapy)

Endoscopic

• ERCP with balloon dilation ± short-term stenting of dominant strictures — relieves obstruction, improves symptoms
• Brush cytology/biopsies during ERCP to exclude CCA

Surgical

• Liver transplantation: definitive treatment for decompensated cirrhosis; 5-year survival ~85%
  • PSC recurs in the transplant in ~20–25% of cases
  • Cholangiocarcinoma is a relative contraindication (though select patients with early hilar CCA may undergo transplant under research protocols)

Surveillance Recommendations