1. Pro-B cell: Heavy chain gene rearrangement begins (D-J, then V-DJ). Expression of CD19, CD79a.
2. Pre-B cell: Successful heavy chain (μ) rearrangement → μ heavy chain pairs with the surrogate light chain (VpreB + λ5) to form the pre-B cell receptor (pre-BCR).
   • BTK is a critical signalling molecule downstream of the pre-BCR.
   • Pre-BCR signalling through BTK drives: (a) allelic exclusion of the other heavy chain allele, (b) proliferative expansion, (c) light chain gene rearrangement, and (d) survival signals.
3. Immature B cell: Successful light chain rearrangement → surface IgM expression.
4. Mature naive B cell: Co-expression of IgM and IgD; exits bone marrow to periphery.
5. Activated B cell / Plasma cell: After antigen encounter + T-cell help → class-switch recombination, somatic hypermutation, differentiation into plasma cells secreting IgG/IgA/IgE.

Bruton tyrosine kinase (BTK) is a cytoplasmic non-receptor tyrosine kinase of the Tec kinase family. It sits downstream of:

• The pre-BCR (in pre-B cells)
• The BCR (in mature B cells)
• BAFF-R, TLRs, and chemokine receptors on B-lineage cells

When the pre-BCR is engaged, the signalling cascade is:

Pre-BCR → Igα/Igβ (CD79a/CD79b) → Src-family kinases (Lyn, Fyn) phosphorylate ITAMs → SYK recruited → activates BTK → BTK phosphorylates PLCγ2 → IP3 + DAG → Ca²⁺ flux + PKC activation → NF-κB, NFAT → survival, proliferation, and differentiation signals

Without BTK, this signalling cascade is dead at the pre-B cell stage. The pre-B cells cannot receive survival/proliferative signals and undergo apoptosis. Result: maturation arrest.

• Males have only one X chromosome (XY). If their single BTK copy carries a loss-of-function mutation, they have no functional BTK → disease.
• Females have two X chromosomes (XX). A heterozygous carrier female has one normal and one mutant BTK. Due to random X-inactivation (lyonisation), ~50% of her B-cell precursors will inactivate the normal X and express the mutant BTK — these cells die. The other ~50% inactivate the mutant X and express normal BTK — these survive and mature normally. So the carrier female has a skewed X-inactivation pattern in B cells (only the normal-X B cells survive), but she is clinically asymptomatic because she still makes enough normal B cells.

This skewed X-inactivation in B cells of carrier females can be used as a carrier detection test (by looking at X-inactivation patterns using the HUMARA assay or flow cytometry for BTK protein expression).

About one-third to one-half of XLA cases arise from de novo mutations, meaning the mother is not a carrier. This is important for genetic counselling.

• IgG, IgA, IgM levels ^[3]
• Vaccine responses (e.g. anti-tetanus, anti-pneumococcal IgG after immunisation) ^[3]
• T, B, NK cell enumerations (by flow cytometry using CD markers: CD3 for T cells, CD19 for B cells, CD16/CD56 for NK cells) ^[3]

• Lymphocyte subsets: e.g. CD4-CD8-TCRαβ+ cells for autoimmune lymphoproliferative syndrome ^[3]
• Cell function: e.g. expression of CD40-ligand on activated T cells for hyper-IgM syndrome ^[3]

Genetic testing has an important role in: Diagnosis (all cases), Family studies, Prognostication, Prenatal diagnosis, Defining new diseases ^[3]

"B cells absent; severe bacterial infections; all Ig isotypes decreased → X-Linked Agammaglobulinemia. BTK." ^[1]

Pro-B cells: Normal (NI) in XLA — confirming the block is at the pre-B → immature B cell transition, not at the pro-B cell stage ^[1]

• Explain to the family in simple terms: "Your child's body cannot make the special proteins (antibodies) that fight bacteria. This is because of a change (mutation) in a gene on the X chromosome."
• Emphasise that it is not caused by anything the parents did or didn't do during pregnancy
• Explain the lifelong nature of the condition but reassure that effective treatment exists (immunoglobulin replacement)

• Family studies are an important role of genetic testing ^[3]
• Carrier testing for the mother and female siblings (BTK sequencing, X-inactivation studies)
• Prenatal diagnosis is available for future pregnancies if the familial mutation is known ^[3]
• Each son of a carrier mother has a 50% chance of being affected; each daughter has a 50% chance of being a carrier
• De novo mutations (~50%) — the mother may not be a carrier

• For genetic testing of the child: parental consent (child is usually too young for assent)
• For carrier testing of adolescent female siblings: consider assent of the adolescent alongside parental consent; discuss implications sensitively
• For adolescent patients with XLA: involve them in treatment discussions, explain the importance of adherence to immunoglobulin replacement, and discuss transition to adult care

• Most frequent primary immunodeficiency ^[2]
• TNFRSF13B / TACI implicated in 10–15% of patients ^[2]; many have no identified genetic cause
• B cells present but functionally defective (poor class-switch recombination, poor memory B-cell formation)
• Marked decrease of IgG and marked decrease of IgA with or without low IgM levels ^[6]
• Diagnosis established after the 4th year of life (symptoms may be present before) — this age criterion distinguishes it from XLA, which presents in infancy ^[6]
• Switched memory B cells may be absent (and this subset correlates with recurrent respiratory infections and development of bronchiectasis) ^[7]
• Additional features not seen in XLA: polyclonal lymphoproliferation, splenomegaly, lymphadenopathy, ITP, autoimmune haemolytic anaemia, granulomatous disease, increased risk for GI and lymphoid malignancies ^[2]
• Poor antibody response to vaccines (and/or absent isohaemagglutinins) ^[6]

Key distinction: CVID has B cells present, onset usually after age 4, and frequently has autoimmune/lymphoproliferative features absent in XLA.

• Mutation in CD40L (CD40LG) ^[2][7]
• B cells present but cannot undergo class-switch recombination (CSR) — stuck making IgM
• IgG and IgA are low, but IgM is normal or elevated (the hallmark)
• Susceptible to bacteria (like XLA) but ALSO to PJP, Cryptosporidium because CD40L on T cells is also needed for macrophage activation → this condition behaves partly as a combined immunodeficiency ^[2]
• Expression of CD40-ligand on activated T cells is the functional test for diagnosis ^[3]
• Liver disease from Cryptosporidium cholangitis is a distinctive complication

Key distinction from XLA: B cells present, IgM normal/high with low IgG/IgA, susceptibility to opportunistic infections (PJP).

• A maturational delay in immunoglobulin production (not a true PID)
• Presents at 6–12 months with low IgG (after maternal IgG wanes), but the child eventually catches up by age 2–4 years
• B cells present and normal in number
• Vaccine responses may be initially poor but improve over time
• Self-resolving — the key distinction from XLA
• Important to monitor serially rather than label definitively at first encounter

Key distinction: B cells present, IgG eventually normalises, self-resolving.

• Most common PID (prevalence ~1 in 500 in Caucasians, less common in Chinese ~1 in 2,000–5,000)
• Only IgA is low; IgG and IgM are normal
• B cells present
• Most patients are asymptomatic; some have recurrent sinopulmonary infections or GI infections (Giardia)
• Can progress to CVID in a minority

Key distinction: Only IgA low, IgG/IgM normal, B cells present, usually mild.

A male patient with:

1. Onset of recurrent bacterial infections in the first 5 years of life (typically after 6 months when maternal IgG wanes), AND
2. Low IgG, IgA, IgM — panhypogammaglobulinaemia ( < 2 SD below age-matched normal values, measured on at least two occasions) ^[2][9], AND
3. Absent or markedly reduced B cells (CD19+ < 2%) in peripheral blood ^[2][9], AND
4. One of the following confirmatory findings:
   • Absent or markedly reduced BTK protein on flow cytometry (monocytes or platelets), OR
   • Pathogenic mutation identified in the BTK gene on molecular sequencing

"Investigations revealed panhypogammaglobulinaemia and absent B cells in peripheral blood. He was diagnosed to have XLA." — This is the GC lecture case vignette, showing that panhypogammaglobulinaemia + absent B cells in a male child is sufficient for a working diagnosis ^[9].

A male patient with:

• Onset of bacterial infections < 5 years of age, AND
• Panhypogammaglobulinaemia (all isotypes low), AND
• Absent or markedly reduced B cells ( < 2%), AND
• No confirmatory genetic or protein test yet performed, BUT secondary causes excluded

This "probable" category exists because genetic testing may not be immediately available. The clinical and immunological picture is highly specific.

A male patient with:

• Markedly reduced Ig levels and absent B cells, BUT
• Age < 1 year (where transient hypogammaglobulinaemia of infancy has not been fully excluded), OR
• Family history suggestive but lab workup incomplete

Once panhypogammaglobulinaemia is confirmed, the next critical step is to enumerate lymphocyte subsets:

T, B, NK cell enumerations ^[3]

Low B cells only → agammaglobulinaemia — this is the GC lecture teaching point for lymphocyte subset interpretation ^[9].

In some forms of CID, T cell may be normal in count but not in function, or they may be maternally grafted memory T cells in Omenn syndrome, a form of SCID ^[9]. This is not relevant to XLA but is an important caveat when interpreting lymphocyte subsets in the broader PID workup.

Why CD19 and not CD20?

Both CD19 and CD20 are B-cell surface markers. CD19 is expressed from the pro-B cell stage onwards, while CD20 appears slightly later (pre-B/immature B). In XLA, both are absent in the periphery, but CD19 is the standard marker used in clinical flow cytometry panels for B-cell enumeration because of its earlier expression and reliable staining.

Low KREC on newborn screening ^[2]

• KREC = Kappa-deleting Recombination Excision Circles — by-products of immunoglobulin kappa light chain gene rearrangement during B-cell development in the bone marrow
• Analogous to TREC (T-cell Receptor Excision Circles) used for SCID newborn screening
• In XLA, B-cell maturation is arrested → KRECs are not generated → KREC is low/absent on the dried blood spot
• NBS for SCID (using TREC) is now widely implemented; NBS for agammaglobulinaemia (using KREC) is being piloted in some programmes, including considerations in Hong Kong
• NBS allows pre-symptomatic diagnosis → early initiation of IVIG → prevention of infections and end-organ damage

XLA patients cannot produce any immunoglobulins. Immunoglobulin replacement therapy provides pooled polyclonal IgG derived from thousands of healthy plasma donors. This exogenous IgG provides:

• Opsonisation of encapsulated bacteria (Pneumococcus, Haemophilus, Staphylococcus)
• Complement activation via the classical pathway (IgG1 and IgG3 subclasses)
• Toxin neutralisation
• Viral neutralisation (including enteroviruses — the antibodies in the pooled product reflect the collective immunity of the donor population)

The replacement provides passive immunity — the patient is borrowing other people's antibodies. It does not fix the underlying B-cell defect, so it must be given lifelong.

IV immunoglobulin for X-linked agammaglobulinemia — explicitly named as the treatment in the medicine lecture ^[3].

Many [PIDs] are treatable — IV immunoglobulin for X-linked agammaglobulinemia ^[3].

IVIG / SCIG — both are accepted routes in the senior notes ^[2]. The choice depends on patient/family preference, venous access, and local availability.

• IVIG: 400–600 mg/kg IV every 3–4 weeks
  • Start at the lower end and titrate based on trough IgG levels and clinical response (frequency/severity of infections)
  • The dose is weight-based, so it must be recalculated as the child grows
• SCIG: Total monthly dose equivalent to IVIG dose, divided into weekly doses
  • Example: If IVIG dose is 400 mg/kg/month → SCIG dose = ~100 mg/kg/week
  • Administered via small subcutaneous needle(s) into the abdomen, thigh, or upper arm
  • Infusion volume per site is limited (~15–25 mL per site in children), so multiple sites may be needed

• Trough level = serum IgG measured just before the next IVIG dose (or any time for SCIG, since levels are steady)
• Target trough IgG: > 5–8 g/L (some centres aim for > 8 g/L, especially if the patient has established bronchiectasis or continues to have breakthrough infections)
• Why a trough? The IgG level gradually falls between doses (half-life of IgG is ~21 days). The trough represents the minimum protection the patient has. If the trough is too low, the patient is vulnerable in the days before the next infusion.
• Adjust dose/frequency to maintain adequate trough levels

IVIG-specific reactions:

Urticaria after 1st dose IVIG in a boy with XLA — explicitly shown in the GC 144 lecture slide ^[9]. This is a common infusion reaction, especially with the first dose, and is managed by slowing the rate and premedication.

SCIG-specific reactions:

• Local injection-site reactions: Redness, swelling, induration at infusion site — very common (up to 75% initially), usually mild and self-limiting, improve with repeated use
• Systemic reactions are less common with SCIG than IVIG (because absorption is slower)

• Prompt empirical antibiotics — lower the threshold for starting treatment in immunocompromised patients
• Target typical organisms: S. pneumoniae, H. influenzae, S. aureus, Pseudomonas spp.
• Culture-guided therapy: Always send cultures (blood, sputum, CSF, joint aspirate as appropriate) before starting antibiotics, then narrow therapy based on sensitivities
• Prolonged courses may be needed — e.g. 2–4 weeks for sinusitis, pneumonia
• Need for IV antibiotics or hospitalisation to clear infections ^[4] — this is a feature of immunodeficiency and also reflects the clinical reality of managing infections in XLA

• Chronic enteroviral meningoencephalitis is one of the most devastating complications
• Treatment is difficult — no highly effective specific antiviral exists
• High-dose IVIG (containing neutralising antibodies against the specific enterovirus serotype) may be trialled
• Intrathecal immunoglobulin has been used in refractory cases (off-label, limited evidence)
• Pleconaril (a capsid-binding antiviral) has been used investigationally but is not widely available
• Prevention (maintaining adequate trough IgG levels) is far more important than treatment

• Metronidazole (oral, 15 mg/kg/day divided TDS for 5–7 days in children)
• Alternative: Tinidazole (single dose 50 mg/kg, max 2 g)
• Recurrence is common in XLA; some patients need repeated or prolonged courses

Avoid live vaccines — the core principle for any patient with significant immunodeficiency.

• Can be given but will not produce an effective antibody response (because there are no B cells)
• Rationale for still giving them: They may stimulate T-cell memory (which is intact), which could provide some partial protection against certain pathogens. In practice, their benefit is minimal in XLA.
• Examples: IPV, DTaP, Hib conjugate, PCV, Hepatitis B, Hepatitis A, inactivated influenza
• Household contacts should be up-to-date on their vaccinations (including MMR, varicella, influenza) to provide cocoon protection

• HSCT is the standard treatment for SCID ^[2], but NOT routinely indicated for XLA
• Why not? In XLA, the defect is confined to B cells; T cells and NK cells are normal. IVIG replacement effectively controls infections in most patients. HSCT carries significant risks (graft failure, GVHD, conditioning toxicity, infection during immunosuppression, infertility), and these risks generally outweigh the benefit when the patient can be well-managed with lifelong IVIG.
• Exceptions where HSCT may be considered:
  • Life-threatening enteroviral meningoencephalitis refractory to IVIG/antivirals
  • Severe bronchiectasis with progressive respiratory failure despite maximal medical management
  • Patient/family preference after thorough counselling about risks vs benefits

• XLA is a monogenic single-gene disorder affecting a single cell lineage (B cells) — this makes it an attractive target for gene therapy
• Approach: Autologous haematopoietic stem cells are harvested, transduced with a lentiviral vector carrying a functional BTK cDNA, and re-infused
• Status (2025–2026): Phase I/II clinical trials ongoing; not yet standard of care
• Potential advantage: Cures the underlying defect without the alloimmune risks of HSCT (no GVHD)
• Challenges: Achieving sufficient engraftment and BTK expression in B-cell precursors; insertional mutagenesis risk; long-term safety data pending

• Age-appropriate explanation of the disease: "Your body has trouble making the soldiers (antibodies) that fight germs, so we give you extra soldiers through a drip (IVIG) or small injections (SCIG)"
• School: A letter for the school explaining the child's condition, need for regular hospital visits, and potential need for prompt medical attention if unwell. Emphasise that XLA is not contagious
• Physical activity: Generally not restricted; encourage normal childhood activities. Avoid situations with extremely high infection risk (e.g. contact with known active TB cases)
• Adolescent transition: Begin planning transition to adult immunology services at ~14–16 years. Encourage self-management skills: understanding the disease, recognising infection symptoms, self-administering SCIG

• Genetic counselling ^[3]: Carrier testing for the mother and sisters; prenatal diagnosis for future pregnancies
• Psychosocial support: Referral to clinical psychologist/social worker; connect with PID patient support groups (e.g. Jeffrey Modell Foundation, PID International, local Hong Kong PID patient network)
• Sibling testing: Any younger male siblings should have serum Ig and B-cell enumeration; any sisters should be offered carrier testing when age-appropriate (discuss assent)
• Financial support: IVIG is expensive (may cost HK$10,000–30,000+ per month depending on dose/weight). In Hong Kong, IVIG is covered under the Hospital Authority for patients with confirmed PID

Delayed treatment associated with complications such as bronchiectasis ^[3] — this is the single most important complication to know for exams.

HRCT chest showing bronchiectasis — shown in the GC 144 lecture slide as a key image for a Chinese boy with XLA ^[9].

Pathophysiology (from first principles):

1. Absent IgA at the respiratory mucosal surface → bacteria colonise the airways unchecked
2. Absent opsonising IgG → bacteria cannot be efficiently phagocytosed
3. Recurrent lower respiratory tract infections (pneumonia, bronchitis) → each episode triggers an inflammatory cascade: neutrophil infiltration → release of proteases (elastase, MMP) and reactive oxygen species → destruction of bronchial wall elastic tissue, smooth muscle, and cartilage
4. Destroyed bronchial wall loses its structural integrity → permanent irreversible dilatation of the airway lumen = bronchiectasis
5. Dilated airways cannot clear mucus effectively (impaired mucociliary escalator due to destroyed epithelium + loss of normal airway calibre) → mucus pooling → further bacterial colonisation → further infection → further destruction
6. This creates a vicious cycle of infection → inflammation → structural damage → impaired clearance → more infection

Clinical consequences:

• Chronic productive cough with purulent sputum
• Recurrent acute exacerbations (increased cough, sputum volume/purulence, fever, dyspnoea)
• Pseudomonas aeruginosa colonisation in advanced cases — a marker of severity
• Progressive decline in lung function (restrictive and/or obstructive pattern on PFTs)
• Respiratory failure in severe end-stage disease — the leading cause of death in poorly treated XLA
• Haemoptysis (from friable, inflamed granulation tissue in bronchiectatic airways)

Key points for exams:

• Bronchiectasis is irreversible — once established, it cannot be cured, only managed
• The only way to prevent it is early diagnosis and adequate immunoglobulin replacement before cumulative lung damage occurs
• This is the strongest argument for KREC-based newborn screening — catch the disease before the lungs are damaged

CT scan showing sinusitis — shown in the GC 144 lecture slide ^[9].

Pathophysiology: Absent secretory IgA at the sinonasal mucosa → chronic bacterial colonisation of paranasal sinuses → chronic mucosal inflammation → mucosal thickening, polyp formation, impaired sinus drainage.

Consequences:

• Chronic nasal congestion, purulent postnasal drip, facial pain/pressure
• May require functional endoscopic sinus surgery (FESS) in refractory cases
• Impacts quality of life significantly in children and adolescents

• Even with immunoglobulin replacement, some patients experience breakthrough pneumonias (especially if trough IgG is suboptimal)
• Each episode carries a risk of further parenchymal damage
• Organisms: S. pneumoniae, H. influenzae, Mycoplasma pneumoniae, S. aureus

Pathophysiology:

• Giardia lamblia is a protozoan parasite of the small intestine
• Secretory IgA at the gut mucosal surface is the primary defence — it prevents Giardia trophozoites from adhering to the intestinal epithelium
• In XLA, absent mucosal IgA → Giardia colonises freely → chronic infection

Consequences:

• Chronic watery diarrhoea, bloating, flatulence, malabsorption
• Failure to thrive / poor weight gain (malabsorption of fats and fat-soluble vitamins)
• Nodular lymphoid hyperplasia of the small intestine (reactive; sometimes seen on endoscopy or contrast studies — an attempt by the gut-associated lymphoid tissue to respond, though ineffective without functional B cells)
• Recurrence after treatment is very common because the immune defect persists

• From chronic Giardia and/or chronic gut inflammation
• Fat-soluble vitamin deficiencies (A, D, E, K) possible
• Contributes to growth failure

Pathophysiology: Without opsonising antibodies, bacteria disseminate haematogenously and seed the synovial space. The synovium is highly vascular and lacks a basement membrane, making it a vulnerable target.

• Organisms: S. aureus, S. pneumoniae, H. influenzae; also atypical organisms like Mycoplasma and Ureaplasma species (which are important and somewhat characteristic in XLA)
• Mycoplasma/Ureaplasma arthritis is a distinctive feature of agammaglobulinaemia because these organisms are normally controlled by antibodies and are difficult to culture on standard media — may be missed without specific PCR testing
• Can affect large joints (knee, hip, ankle, elbow)
• If not treated promptly, joint destruction and permanent disability can result

• Same haematogenous dissemination mechanism
• Long bones most commonly affected in children (metaphysis is highly vascular in growing bones)

• Enteroviruses can cause a chronic myositis that mimics dermatomyositis
• Features: progressive proximal muscle weakness, elevated CK, skin rash
• Distinguished from true dermatomyositis by: male sex, agammaglobulinaemia, enteroviral PCR positive in muscle/serum
• Very difficult to treat once established

Pathophysiology: Multiple converging factors:

• Chronic infection → increased metabolic demand (catabolic state) + anorexia
• Chronic diarrhoea (Giardia) → malabsorption
• Chronic inflammation → IL-6, TNF-α → growth hormone resistance, impaired IGF-1 signalling

Growth before and after IVIG replacement in a group of Chinese boys with XLA — the GC 144 lecture demonstrates that growth velocity improves after IVIG initiation ^[9], confirming that chronic subclinical infection is a major suppressant of growth. Growth failure is both a complication and a marker of inadequate treatment.

• Recurrent otitis media → chronic middle ear effusion → conductive hearing loss
• In young children, even mild conductive hearing loss during the critical period of language acquisition (0–3 years) can impair speech and language development
• May need ventilation tubes (grommets) if persistent middle ear effusion
• Audiometry and speech/language assessment should be part of routine follow-up

• Frequent hospitalisations, missed school, chronic illness → potential impact on academic performance, peer relationships, and self-esteem
• Chronic fatigue from ongoing subclinical infections
• Anxiety about health, body image (especially in adolescence)
• Protective parenting may limit normal social development