Death certificates (Scotland)

Ethics, Generic,

New system from 2015.  Medical Certificate of Cause of Death (MCCD) provides a permanent legal record of the fact of death and enables the family to register the death, make arrangements for the disposal of the body, and settle the deceased’s estate. In addition, a MCCD provides a record of causes of death for public health reasons.

Electronic system available but paper copy remains legal, and family  needs it to register death.

Ideally consultant responsible for patient completes or is at least involved in completion.  This should be recorded in notes.

New system of reviews:

  • In the shorter level 1 review cause of death checked, reviewer will speak to the certifying doctor about anything unusual. If the certifying doctor is unavailable or incapacitated, the Medical Reviewer will discuss the MCCD with the consultant in charge of the case or another member of the team who knew the deceased and / or has access to the clinical records.
  • A level 2 review is similar to a level 1 in that the Medical Reviewer will check the MCCD and speak to the certifying doctor. However, in addition, the Medical Reviewer will also consider relevant documents associated with the death, including health records and results of investigations. They may also wish to view the body.

These review types will be conducted through a random selection process, will be available on request in certain circumstances from interested persons, or may be targeted by Medical Reviewers in response to any emerging pattern that requires further checks.

The last type of review is the “Interested Person” review – provides further reassurance. Includes relatives, any person present at death, healthcare professional involved with deceased etc.  Must be within 3yrs of death, and can only take place if not already reviewed randomly.  Request to medical review service.

Tips for Certifying Doctors

Contact the Death Certification Review Service (DCRS) by phone or email for help, open Monday to Friday 08:30-17:30. There is an on-call medical reviewer available out of hours.

Consider whether there is any reason to report to or discuss the case with the Procurator Fiscal (guidance here) e.g. trauma has been identified as a cause or contributor to death, there is a complaint about the care provided prior to death etc.

If you have discussed a case and agreed with the Procurator Fiscal that the case does not need to be formally reported, then do not tick the “PF” box.

Your writing should be in CAPITALS using BLACK ink throughout when completed by hand.

The time of death is the time that to the best of your knowledge and belief you think the patient died and NOT the time that death was verified.

Use business telephone numbers; do not include personal mobile numbers.

You must not include any abbreviations except HIV or Aids which are both permissible.

The causes must make sense both medically and chronologically. If you use more than one line in section 1 then what is entered in 1a MUST be caused by what is in 1b which MUST be caused by what is in 1c etc. Durations likewise should be sequential.

Sites and organisms in infections, including resistance and routes of infection are important and should be entered if known.

If you wish to enter a cause of death that you believe is the case but you have no confirmatory evidence, you can qualify it with “Probable” or “Presumed”.

If obesity has significantly contributed to the death it should be included.

None of the form is optional and all parts and questions on both sides should be considered and answered as appropriate.

It is the statutory duty of the doctor, who has “attended” the deceased during the last illness, to issue the MCCD. There is no clear legal definition of “attended”, but it is generally accepted to mean a doctor who has cared for the patient during the illness or condition that led to death and so is familiar with the patient’s medical history, investigations and treatment. It is not unlawful to complete a certificate if you have not personally attended the patient but you have to be in a position to certify to the best of your knowledge and belief and willing to be personally accountable having had access to the appropriate records.

If you cannot issue an MCCD you should contact a colleague who can, or discuss/report to the Procurator Fiscal.

[HIS tips – Support around Death (SAD) website]

 

Depigmentation

Dermatology

More obvious in non white races, of course. Or becomes more obvious when surrounding skin becomes tanned, in summer or after holiday.

Generalized

  • Oculocutaneous Albinism is most common. Non-type 1more subtle – in fair skinned families, may only be obvious in comparison with family members.
  • Griscelli, Elejalde and Chediak–Higashi syndromes have been termed “silvery hair syndromes” – generalized, but eyes spared. Griscelli and Elejalde include severe neurological defects, as well as immunological. Immunodeficiency severe in Chediak-Higashi.
  • Menkes is X-linked copper defect, progressive CNS degeneration and death in early childhood.
  • Selenium deficiency? Only really in malnutrition.
  • In later life, homocystinuria.
  • Pityriasis alba –  ill-defined macules or plaques, typically circular or oval, often with mild scaling. Thought to be inflammatory but cause unknown, common in children and young adults. Can be itchy. Usually found on the face, arms, and upper trunk. Recovery takes months to years.

Localized syndromes

  • Ocular albinism – light coloured eyes mostly rather than pink.  Associated with poor visual development. Heterochromia (different coloured eyes, or else different colours in same iris) that develops or worsens soon after birth can be seen with congenital Horner’s syndrome (and with neuroblastoma) – also part of Waardenburg’s (below).
  • Piebaldism looks like vitiligo but is congenital and permanent. Usually affects forehead causing patch of white hair (“forelock”), with or without eyelash and eyebrow involvement.  Autosomal dominant. Can occur in tuberosclerosis.
  • Waardenburg syndrome includes piebaldism, but also heterochromia, or pale blue eyes.  Subtypes have hypertelorism (increased space between eyes), limb defects, Hirschsprungs, deafness.
  • Single depigmented patch: naevus anemicus (vascular, Woods light neg), ash leaf macule of tuberosclerosis (usually multiple) or naevus depigmentosus (identical but single, less likely to be leaf like).
  • In later life, vitiligo (autoimmune), post inflammatory (eg eczema, pityriasis alba), lichen sclerosus and morphoea.

[Hong Liang Tey, Acta Dermato-Venereologica online]

Autosomal dominant polycystic kidney disease

General paediatrics, Genetics, Renal

ADPKD – previously Adult PCKD but now recognized as having manifestations in childhood.  Cf Autosomal recessive disease, severe, renal failure in infancy.

1 in 400 to 1,000 live births, making it the most common monogenic cause of renal failure. The typical age of onset is in middle life, but the range is from infancy to 80 years.  Associated with liver cysts (asymptomatic) and intracranial aneurysms. 10-25% do not have family history (de novo mutations, missing records or mosaicism).

Possible presenting symptoms of renal disease in children with ADPKD are frequency, nocturia and/or, hematuria, urinary tract infection(s) and back, flank or abdominal pain. Often, the earliest symptoms are polyuria and polydipsia, from decreased urinary concentrating ability.

Extrarenal manifestations seen esp hypertension (renin angiotensin system, sodium retention, endothelial dysfunction), also liver cysts (asymptomatic), intracranial cysts and valvular defects but these are only seen in adults. 25% of children are hypertensive by the time they reach adolescence.  (GFR stays stable until around 40yrs, then rapid decline, about 50% have ESRF by 60yrs).

Importantly, children who were diagnosed in utero or within their first 18 months of life, the so-called VEO group, represent a particularly high-risk group of ADPKD patients and should be managed accordingly.  Diagnostic imaging criteria not validated under 15yrs, genetic testing also challenging.

Recommendation from Kidney Disease Improving Global Outcomes (KDIGO) Consortium against screening children for APCKD.  [Also highlight variety of different cystic disorders in children, so recommend thorough clinical assessment for extrarenal manifestations in case syndrome eg Von Hippel Lindau, USS of parents and/or grandparents if negative family history, and USS to look for dysplastic kidneys, glomerulocystic disease, and tuberous sclerosis complex].[Kidney international 2015]

Increasing evidence that hypertension, left ventricular hypertrophy (even between 75th and 95th centile for BP) and increased kidney volume predates symptoms in affected children.  A study of early use of ACE inhibitor halted progression of LVH and fall in renal function.  Adding pravastatin reduced progression of structural kidney disease.  Disease modifying drugs in development.  [BMJ 2016;353:i2957 Editorial, GOS, Birmingham, Evelina].  “We propose an urgent national debate on an improved inclusive approach involving patients and their families and a range of clinicians, ethicists, and commissioners. A few pounds spent now on screening and early intervention could save many thousands later by delaying hypertensive complications and chronic kidney disease.”

Potential for pre-implantation genetic diagnosis.  See Ethics.

Only one drug known to have moderate effect on disease progression in adult ADPKD patients, vasopressin V2 receptor antagonist tolvaptan (recent Cochrane review).  But timing of use unclear.

Psychological impact of having genetic disease that can be passed on to children very common in adult patients.  But a benefit of diagnosis is potential to target modifiable risk factors  – children with normal BP have slower cyst growth.  And knowledge can give sense of control over life decisions, esp reproductive decisions.

Penis problems

Clinical, General paediatrics, OPD, Surgical

The foreskin cannot, and should not, be retracted in newborn babies.  It should gradually begin to separate in the first few years of life. Sometimes it takes until puberty.

Retraction should lead to a pouting appearance of the foreskin. Technically this is not phimosis, which implies an abnormality. Some ballooning with micturition is seen, and is not an indication for surgery.

Can try application of topical steroid cream to speed up separation eg 0.025% betamethasone (1 in 4, or RD) cream twice daily for 2 to 4 weeks.  Gently retract foreskin without causing any discomfort and apply a thick layer of cream to the tightest part of the foreskin.  Steroid creams of higher potency may be tried if this fails.

Inflammation of the foreskin (posthitis), glans (balanitis) responds usually just to hygiene measures – bathing, cleaning, drying. Antibiotics might be needed if spreads on to shaft. Topical steroids can help.

Circumcision if significant phimosis and steroid creams fail.

Smegma pearls

Retained smegma can accumulate into substantial but painless lumps down the shaft of the penis.  Can be ignored.

Balanitis Xerotica Obliterans

A form of lichen sclerosus affecting the tip of the penis. No pouting of foreskin seen on retraction. Can be white, crinkly thickening. Can be bleeding, discomfort. No good evidence for topical steroids, usually surgical treatment.

House dust mite allergy

Allergy, General paediatrics

People assume they are allergic to dust – more likely is that they are allergic to dust mites (HDM).  These are microscopic, and tend to reside in fabrics in the home esp bedding, carpets, sofas.  So your house can be spotless but still be full of mites!

There are a number of different house dust mite species – most are Dermatophagoides (“skin eating”…), D. farinae is the American type, D. pteronyssinus is the European one.

HDM allergy is common in atopic individuals, contributing to eczema, rhinoconjunctivitis and asthma. Eczema usually comes first, but sensitisation (usually develops in young children) seems to predict development of asthma persisting into school age!

Although common, it doesn’t tend to cause immediate reactions, the way cat/dog does, probably because mites don’t fly – so exposure only caused when surfaces disturbed or if skin/nose/mouth/eyes in direct contact. But inflammation may be chronic, from brief, low quantity, frequent exposure. So even with avoidance/ reduction measures, it can take months to see the benefit…

There is cross-sensitivity with shellfish allergy but not fish allergy.

In some parts of the world, mouse and cockroach allergies more of an issue.

Lots of different allergens identified.  der p 1 and 2 are major allergens in mite faeces, in kids with eczema various other allergens found in mite bodies also important. Mite faeces are the most important cause of sensitisation. Composition of skin prick solutions seems to vary…

Avoidance/reduction

Allergy UK has an advice leaflet with different measures for reducing levels of HDM in the home.  Evidence however is that this is difficult to do and rarely seems to have any significant clinical effect!  So no point in doing piecemeal, certainly.

Dust mites need high humidity to get water, so high altitude and air conditioning suppresses them.  They also like temperatures over 20deg. They are photophobic so hide deep in fabrics.

Get rid of carpets, curtains, excess cushions/pillow/throws, move soft toys off bed.

Wash bedding at 60, or tumble dry! Soft toys go in the freezer overnight once a month (in a bag, obviously, to avoid collecting smells). Protective covers for mattresses and hypoallergenic bedding materials.

Some vacuum cleaners are better than others (in theory) eg with HEPMA filter.  Allergy UK approves products (but only if company pay, of course). But the mechanical action of cleaning (plus moving furniture, changing beds etc) can whip particles up into the air (as can emptying the contents of the cleaner) so best done when kids are out, and wait 20 minutes before letting them back in…  Cleaning and replacing filters important too esp if bagless design.

Vacuuming alone resulted in a significant reduction in carpet house dust mite allergen concentration and load. Levels approached pretreatment values by 4 weeks posttreatment in the intensive vacuuming group, whereas combination of dry steam cleaning plus vacuuming lasted up to 8 weeks. 

You can also use a steam cleaner on a mattress!

Evidence for air purifiers is mixed.  If placed on carpet, they can actually disturb more allergen than they remove! You need to close doors and windows of course. Unfortunately the best ones tend to be big, expensive and noisy, and price does not mean good quality. Plus you have to remember to replace the filters. The cheapest Which? recommended one (the Electriq EAP500HC) costs over £200.

In PAXAMA study in the NW England (kids with a history of wheeze requiring a visit to hospital), impermeable covers (blinded!) halved risk of having an emergency hospital attendance over the next year. [Murray 2017] Maximum benefit was seen in under 11yrs, mono-sensitized to mite, living in nonsmoking households, and requiring more ICS.  

[JACI 2018]

Immunotherapy

Systematic review found good evidence of benefit for eczema with immunotherapy against house dust mite, with subcut immunotherapy superior to sublingual. [Journal of Allergy & Clinical Immunology. 151(1):147-158, 2023 PMID 36191689]

Evidence for immunotherapy for allergic rhinitis, at least in adults… Treatment effect from 14 weeks, so not rapid…

No evidence for asthma but given as indication… although research into whether HDM immunotherapy might prevent.

NICE approved Acarizax for moderate to severe HDM rhinitis from age 12 in the NHS in England in January 2025. Acarizax is sublingual therapy (derived from D pteronyssinus and D farinae), indicated in adolescents (12-17 years) as well as adults diagnosed by clinical history and a positive test of house dust mite sensitisation (skin prick test and/or specific IgE) with persistent moderate to severe house dust mite allergic rhinitis despite use of symptom-relieving medication.

NICE appraisal also comments that avoidance/reduction of HDM burden in home is almost impossible and if problems persist, it can induce strong feelings of guilt in parents/carers.

Also, many patients would prefer not to be using regular, large doses of steroids, even if effective.

£80 a month on NHS, has not been submitted to Scottish Medicines Consortium so currently not recommended.

International treatment guidelines refer to a treatment period of 3 years for allergy immunotherapy to achieve disease modification. Efficacy data is available for 18 months of treatment with ACARIZAX in adults; no data is available for 3 years of treatment. If no benefit in first year, no indication to continue.

First dose should be observed and the patient monitored for at least 30 minutes.

Place under the tongue, avoid swallowing for 1 minute, avoid food/drink for 5 minutes.

Contraindications are FEV1 <70% of predicted value despite treatment, or severe asthma exacerbation within the last 3 months.

If oral ulceration, postpone treatment.

Eosinophilic oesophagitis has been reported.

Accidental Adrenaline self-injection

Allergy, Emergency medicine, General paediatrics, Surgical

eg with Epipen or Emerade.

Causes vasoconstriction with potential for gangrene.

Try:

  • warm water immersion
  • local nitroglycerin paste
  • subcut infiltration with a mixture of 1.5mg of phentolamine, 1mL of 2% lidocaine (at site and along course of digital arteries)

[advised by National Poisons Information Service]

n=365 adrenaline injections to hand, 213 to digit.  No cases with clinically apparent systemic effects, only a few patients had ischemia. No patient was admitted or had surgery. [Annals of Emergency Medicine. 56(3):270-4, 2010 Sep. PMID: 20346537]

Familial Hypercholesterolaemia

Cardiology, General paediatrics

Usually LDL receptor gene mutations (on liver, for removing lipids from blood). One Apo-B mutation (on LDL) identified.  Least common is PCSK9 mutation – higher degradation of receptor, most severe.

If normal BMI, elevated LDL, autosomal dom inheritance, normal TFTs then 95% LDL receptor defect.

If one sibling has a LDL double that of another sibling, 99.8% LDL receptor mutation.

Highly heterogeneous in UK, over a 1000 mutations.

Estimated 1/500 in most countries [but in Denmark found 1/137, Holland has found 1 in 232].  So prob only 12% of cases identified in UK, even less in young individuals!

DNA screening cf lipid testing cost effective (and enhances cascade screening).  Using LDL only, 8-15% false neg and pos, due to overlapping of ranges.  Gene scoring (using SNPs) for mutation neg clinical cases helps to find polygenic cases. But 40% less risk of disease so cascade testing less effective.

American college of med genetics have recommended that familial hypercholesterolaemia (FH) mutations detected on whole genome should be reported to patient.

Cases of sudden cardiac death in 4-6yr olds reported in homozygous.  Heterozygous cases still important – 100X coronary risk age 20-40yrs…

Diagnosis

Diagnosis in childhood could save 50 healthy life years!!!  Dutch cascade screening since 1994 stopped last year. Only 1/3 of known paed cases came clinically, hence big gap in case finding.

Simon Broome criteria – (else use Dutch system) distinguishes Definite FH vs Possible.

  • Definite = DNA pos for known mutation, else tendon xanthomata (personal or 1st or 2nd deg relative) plus cholesterol as below.
  • Possible = cholesterol concentrations as below PLUS:
    • Family history of myocardial infarction: aged younger than 50 years in second-degree relative or aged younger than 60 years in first-degree relative.
    • Family history of raised total cholesterol: greater than 7.5 mmol/l in adult first- or second-degree relative or greater than 6.7 mmol/l in child, brother or sister aged younger than 16 years.

Cholesterol cut offs for Simon Broome

Total cholesterol LDL-C
Child/young person > 6.7 mmol/l > 4.0 mmol/l
Adults > 7.5 mmol/l > 4.9 mmol/l

Refer both definite and possible cases for DNA testing. Plus there are age/sex specific cholesterol cut offs for relative of a known case where DNA is negative.  NICE standard is that children with possible FH should be offered diagnostic tests by age 10.

Given how prevalent use of statins is now, it’s harder to get a positive family history! So history of grandparents more important! 10% have no family history

Only 4% of heterozygotes have xanthomas (can be in buttock cleft, but only look if found elsewhere!). Arcus at 6 oclock in children, all round in adults. Palpable in Achilles tendon rather than seen? Pain in achilles often reported! Resolve with treatment.

Management

NL guidelines – 5-7yr diet etc only.  Diet with plant sterols can drop LDL by 7%

Over 10yrs, treatment (high dose, low dose, combination) depends on mutation and LDL. Most experience with pravastatin.

LDL apheresis as treatment.

Excellent safety and tolerance of statins. Significant reduction within 2 years.

Like any regular medication, compare it to toothbrushing.  Do both at the same time!

Most cardiologists don’t consider FH when high cholesterol found. Nurses? Via labs?

Check growth, puberty, healthy lifestyle. Update family pedigree, contraception.

Smoking confers massive additional risk.  Albert Wiegman has had a 5yr old admitting to smoking…

Treating from age 6.

Outcome

10yr follow up submitted – mean age 24yrs. 7 already older than the age their parent had event. LDL still higher than sibs.

 

Boys have higher risk of cardiac death then girls, but smoking gives girls worse risk than boys.

Intima media thickness – increases year on year, so earlier treatment the better?  Even before age 8 significantly different from non FH.

 

In NICE audit, majority of children not on treatment, and being seen in adult lipid clinics.

No evidence that low fat diets etc are affecting growth (limited numbers so far).

Homozygous FH being recommended as rare disease, so deserving of national specialist service.

 

 

 

Peanut allergy

Allergy, General paediatrics

See also Prevention, pregnancy, EAT/LEAP studies and immunotherapy.

One of the most common food allergies, and a frequent cause of anaphylaxis.  Peanut is technically a legume, although there is cross-reactivity with tree nuts so often included when people talk about “nuts”.  Always consider if there are potentially other allergies to lentils, sesame, tree nuts eg cashew etc.

Also known as groundnut or monkey nut.

[Gary Stiefel, Leicester Royal, BSACI guideline peanut allergy]

Diagnosis

Wide range of potential peanut proteins.  In US study, vast majority were Ara h1/2 positive, but European more diverse. h1, h2, h3 most common for systemic reactions.  You would think testing with whole peanut would be more sensitive but component testing probably more sensitive and specific than total IgE – but not better than skin prick testing.

peanut allergy diagnosis BSACI 2017With a decent history, SPT >3mm or IgE >0.35 sufficient.

Before proceeding to a hospital challenge, footnote suggests either 2 negatives, or else both IgE and SPT negative.

Distinguish Pollen Food Syndrome – ie older, rhinitis, oral allergy symptoms with nuts/fruit. These kids will have a milder allergy.  Hazelnut mostly (Cor a1) but almond, walnut too. But can coexist with more severe allergy! Doing grass/birch pollen would support diagnosis, doing components might help assess prognosis. If history unclear, but positive IgE/Skin prick test then do components h2 and h8 (list of different cut offs for different commercial products given, with related specificity/sensitivity, just says positive/negative in flow chart). Footnote suggests adding Ara h 1, 3 and 9 as also suggest primary peanut allergy even if Ara h 2 neg.

Sibling risk 5-9%. Too low to justify routinely screening.  If family likely to just avoid forever, living in fear, then consider SPT to encourage home challenge!?

Prognosis

Up to 20% will outgrow, usually before age 8. Review may not be necessary if PFS only.  Follow up is essentially about education.  Testing can be done periodically, depending on resources.

In a study of adults coming to allergy clinics, 10% of peanut allergic turned out not to be.  Partly this would have been because the diagnosis was wrong (many had never actually reacted to peanut in the past).  Having eczema meant you were more likely to still be positive on testing.  Having asthma and being male made it half as likely you would not be allergic anymore.  But many of the cases described were not formally challenged so these results are of limited value.  [Poster at AAI 2021, Rima Rachid]

Avoidance

Difficult, as often used in biscuits, chocolate, ethnic foods eg satay.

As for any food allergy:

Peanut needs to be specified on food labels under UK/EU law.

Precautionary labels – impossible to eliminate risk. Often these “may contain” warnings and similar just say “nuts” without specifying whether the risk is from peanut or a tree nut (the company may be able to give further information if you enquire directly). 

Snack foods with precautionary labels are higher risk eg biscuits, cakes [Helen Brough].

Balance between convenience and risk (probably a very small risk, as many families ignore these warnings to some degree).  Stratify risk according to type of food, previous reactions, threshold, asthma, illness, time of day, location etc. Crossing the road metaphor – choose a safe place!

Should you avoid all nuts?  Some kids will be allergic to other (tree) nuts, but not all.  Andrew Clark reports v low rate of accidental reactions, 3%, with avoidance of all nuts. But increases quality of life to be allowed other nuts!  Risk assessment for each individual person!

Peanut oil

Probability of any reaction to refined peanut oil is remote (Blom et al, 2017). Little evidence that anyone has ever reacted to refined peanut oil. Code of practice is that presence of UNREFINED peanut oil should be declared on bottles of oil (UK and Europe).

But peanut oil, even if refined, still has to be declared on food labels.  Beware unrefined oil in ethnic foods.  Peanut oil also found in some medicines eg vitamins, antibiotic creams.

Some suspicion that peanut oil in cosmetics and pharmaceuticals might lead to sensitization and subsequent peanut allergy, even if not enough peanut protein to cause a reaction in an allergic person. So advice is avoid if you have a strong family history of allergy.

Immunotherapy

See Peanut immunotherapy.

X-linked lymphoproliferative syndrome (XLP)

General paediatrics, Immunology

(also known as , Duncan’s syndrome)

An immunodeficiency due (in 50% of cases) to SLAM associated protein (SAP) defect, specifically affecting the handling of EBV, affected boys are normal until they meet the virus. Following infection, they develop profound secondary immune deficiency affecting T and NK cell function and antibody responses. The following clinical patterns (not mutually exclusive) are described (and can be presenting features):

  • severe infectious mononucleosis
  • malignant B cell lymphoma (ie monoclonal proliferation)
  • Lymphoproliferation viz hepatosplenomegaly (ie polyclonal proliferation)
  • aplastic anemia
  • panhypogammaglobulinemia
  • haemophagocytic lymphohistiocytosis (HLH)
  • vasculitis

The prognosis is very poor with 75-85% mortality. Confirmation of the diagnosis involves demonstrating EB virus genome in lymphocytes by DNA hybridization, without antibody response to EB nuclear antigen (EBNA). The mothers of affected boys also have abnormal EB virus serology, with persisting very high titers against viral capsid antigen. Treatment is with Rituximab (anti CD20), although EBV receptor is CD21. If diagnosed in a sibling before they are infected by the virus, regular IVIG as passive immunization can be attempted though its efficacy is unproven.

Autosomal forms have been described.

OMIM entry

 

Severe Combined Immunodeficiency (SCID)

General paediatrics, Immunology

Mixed bag of diseases, with combined T and B cell deficits. “Severe” tends to mean severe lymphopenia and panhypogammaglobulinaemia with poor prognosis. Usually a bone marrow problem, with defective maturation of precursors – so depending on where the block is there may or may not be T cells, B cells, NK cells. A problem further down the line at the signalling stage will tend to mean immunoglobulin is produced, but not functional, esp since T cell regulation is needed too. So the clinical picture may be of a combined defect even if B cells and immunoglobulin are present. On the other hand, some defects are “leaky”, ie some precursors do manage to develop past the block by having reversion mutations causing somatic mosaicism. The other possible source of T cells if present is that they may be maternal (do FACS CD3 vs TCR to discriminate). To test, find appropriate T cell markers. Such T cells usually not functional but may ameliorate severity or prevent progression.

Typical presentation

Affected babies appear well at birth and are normally grown. Problems usually start within the first few months of life. Common presentations are:

  • Chronic diarrhoea and failure to thrive – often due to persistent and sometimes multiple gastrointestinal infection, +/-food intolerance.
  • Candidiasis
  • Severe bacterial infections esp pneumonia unresponsive to standard treatment
  • Atypical infections eg Pneumocystis jiroveci/carinii, disseminated BCG infection. PCP can be acute or chronic, causes interstitial pneumonia with disproportional hypoxia for degree of illness, LDH is often raised (non-specific, implies tissue invasion).
  • Reticular skin rash +/-mildly deranged LFTs – Graft-versus-host disease (GVHD) – since you can’t reject foreign tissues, you may show GVHD if maternal lymphocytes cross the placenta (usually mild) or via breast-feeding (very mild, not a contraindication). Role in gastrointestinal symptoms? More severe GVHD can follow blood transfusion – hence all lymphopenic patients should get irradiated blood to kill donor white cells. Differential is disseminated CMV, CD40 ligand deficiency, Omenns, ICF. Diagnosis is by finding 2 cell populations by chimerisms.
  • Occasionally SCID can present like Langerhans cell histiocytosis with dramatic erythrodermic or scaly rash, organomegaly (Omenns).

On examination (usually), no lymph nodes; no thymic shadow on chest X-ray (development of thymus requires appropriate signals from bone marrow). Hepatomegaly (?). Investigations usually reveal lymphopenia (<2.8 in first year), and there may or may not be NK cells – the exact pattern helps you work out where the block is. Odd results may reflect presence of maternal lymphocytes! Mitogen responses (proliferation studies) are usually absent. IgG will usually be present from Mum, but gets used up quickly! IgA and IgM may be present if B cells are present, but usually limited clonal diversity so not much function and no specific antibody responses.

Subtypes

B- NK- is ADA. B+ NK+ is IL7R defect. B+ NK- is gamma chain or JAK3 (the two bind to each other). B- NK+ is RAG or Artemis. Bare lymphocytes (T but not CD4) are HLA deficient.

Complex, because the defect can relate to cytokine signalling, T-cell receptor signalling, receptor gene recombination etc.

The biggest group are T- B+ NK-: the main cause is Gamma chain deficiency, which is X-linked. About 50% of all SCID. The Gamma chain is found in numerous cytokines (IL-2, 4, 7, 9 and 15), hence why it causes severe problems. JAK3 binds to gamma chain so causes an identical syndrome.

The next main group are T- B- NK-: Adenosine deaminase (ADA) deficiency is the main cause. Accumulation of toxic deoxyadenosine triphosphate (d-ATP) in lymphocytes leads to cell death. All cell lines are reduced. Additional features are:

  • Skeletal abnormalities (cupping deformities of the ends of the ribs, abnormalities of the transverse vertebral processes and the scapulae) are seen in up to 50% of cases and can be correlated with histological changes.
  • Neurodevelopmental problems may also occur in some patients.

Occasional cases of ADA deficiency have been described, where inexplicably, immune function is normal. The diagnosis is confirmed by assay of red cell ADA activity (Purine lab, Guy’s). First trimester antenatal diagnosis is possible. Gene therapy is done in London and Paris.

Purine nucleoside phosphorylase (PNP) deficiency is initially less severe than ADA deficiency but progresses with age. It is autosomal recessive (gene is on chromosome 9). The toxic metabolite is deoxyguanosine triphosphate. Immunoglobulin levels and antibody responses are initially normal but in the late stages levels fall.

PNP vs ADA

  • Onset of symptoms is usually later, can be delayed for several years.
  • Predominantly cell-mediated defect (viruses, fungi, GVHD).
  • Marked tendency to autoimmune disease, esp hemolytic anemia (even red cell aplasia).
  • No skeletal abnormalities, but more neurodevelopmental probs.
  • Partial, asymptomatic, forms of the deficiency have not been reported.

Reticular dysgenesis (autosomal recessive) is characterized by an absence of myeloid as well as lymphoid precursors, so no neutrophils or macrophages. Platelets and red cells are usually OK but can be low too! Even more severe than other forms of SCID, tends to present very early. Often GVHD rash. Hard to transplant…

The T- B- NK+ group are to do with VDJ recombination. The main one here is RAGs (recombination activating genes, 1 and 2) defect. If you can’t recombine these variable areas, then you can’t develop the necessary diversity in antigen receptors on T and B cells. Artemis and Ligase 4 similarly. NK don’t use them so they’re fine. Diagnose by looking at Ig gene rearrangements.

Ommen’s syndrome is a leaky B- SCID, usually a RAG defect, but characterised by:

  • infiltrative skin rash resembling seborrheic dermatitis (scaling, erythroderma): histologically, proliferation of CD8/CD4 double negative cells and histiocytes.
  • hepatomegaly and lymphadenopathy
  • lymphocytosis but with marked eosinophilia and raised IgE levels

Diagnosis is confirmed by showing limited TCR Vbeta clonal populations (the few clones leaking past the block expand in the periphery to cause the signs). Differential is GVHD (usually milder, not lymph nodes usually), congenital ichthyosis and Nethertons syndrome (autosomal recessive ichthyosis with immunodeficiency and growth failure). Interferon gamma may produce some clinical improvement but definitive treatment is with bone marrow transplantation.

The final group, T- B+ NK+, is a mixed bag of different problems, all to do with signal transduction:

  • ZAP-70 defect (CD8 deficiency, AR) – defective kinase, part of the CD3/TCR complex. Whereas CD8s are absent, CD4 and other cells are present.
  • JAK-3 defect – Janus kinase 3, a tyrosine kinase, interacts with the STAT (signal transduction and activators of transcription) family (AR).
  • IL7R defect

Defects in cytokine production are not really SCID:

  • IL-1, IL-2 and interferon gamma deficiency described, result in a spectrum of clinical problems including failure to thrive and opportunistic infections. Humoral immunity is relatively preserved.
  • Interferon gamma receptor defects predispose to disseminated atypical mycobacterial infection (see above).
  • IRAK (IL1R Associated Kinase) defect – like NEMO, broad range of cytokines affected. Typical infections are Pseudomonas, pneumococci, salmonella. NOT candida, viruses, mycobacteria, fungi. 50% die within first 3 years, thereafter survival improves markedly.The following have normal cell populations but abnormal surface molecules:
    • Bare lymphocyte syndrome (AR). You have T cells, but they don’t differentiate into CD4 and CD8 cells. Usually due to defective HLA expression. T and B cell numbers are normal! CD4 count is low in Class II and the CD8 count in Class I deficiency. Confirmation of the diagnosis depends on demonstration of the absence of the HLA antigens on the cells. Other weird features:
      • lymph nodes are palpable and the thymus is normal size (not histologically normal, mind you).
      • Mitogen responses are normal but antigen specific responses and delayed hypersensitivity tests are negative.
    • CD3 deficiency – also gives normal numbers of circulating T and B cells, so thymus and lymph nodes present. CD3 actually made up of several different chains, so In delta chain defect, the T cells make it to the thymus but don’t progress into the circulation.
    • Fas (CD95) deficiency = Autoimmune Lymphoproliferative Syndrome (30% have unknown mutations). This is a cell surface molecule important in apoptosis, hence lymphoproliferation ie massive lymphadenopathy, hepatosplenomegaly (but variable). It is expressed on thymocytes and activated T cells. Most obvious manifestation of autoimmunity is cytopenias. CD4 cells are low but lymphocyte count is normal by virtue of a proliferation of CD4/CD8 double negative cells (eg 30-60% of total). LNs have characteristic histology. Rx immunosuppression, usually pred and high dose IVIG are sufficient although may need extended treatment. MMF and rituximab have been used.
    • OKT4 deficiency is a defect in an epitope on the CD4 molecule recognized by a monoclonal antibody of that name. There is a mild immunodeficiency and a tendency to autoimmune disease.
    • Idiopathic CD4 lymphocytopenia. Usually adults, but can be seen in children. Affected individuals are highly susceptible to opportunistic infections, obviously; immunoglobulin levels and antibody responses are generally normal. The CD4 cell count seems to remain stable for a prolonged period cf HIV infection. Prophylaxis against Pneumocystis carinii infection should be given.

    Management of SCID

    Flow cubicle, sterile handling, Septrin, Itraconazole, IVIG prophylaxis. If unable to get flow, discharge from general paeds ward!

    PEG-ADA available for ADA deficiency. Use d-ATP levels to guide dosing. Treat while looking for transplant match.

    BMT or PBSC if match available. Haploidentical (ie parent) BMT have poor results in Europe but currently 80% success rates in UK (cf 97% success for full HLA match). No big breakthrough in BMT science, just incremental improvements in conditioning regimens, supportive care, graft manipulation. Non SCID success rate is currently 69%; the rate is actually falling as more risky cases are now taken on. MUD for Wiskot Aldrich has 85% 10yr survival rate; a good MUD, using genomic rather than serological matching, is probably just as good as a sibling transplant. Other issues:

    • Cord transplants: new cord bank in Newcastle. Better engraftment cf regular BMT but you still need a good match to avoid GVHD. Above 15kg, 1 cord is unlikely to yield enough cells – use 2?
    • If CMV infected, then using a CMV pos donor may be a good thing!
    • Busulphan usually makes you infertile.
    • Fludarabine/melphalan and Campath looks like a good conditioning regimen but historical controls of limited meaningfulness in BMT work. With lower intensity regimens, poor engraftment can always be boosted with more stem cells…
    • 20 CGDs done in Newcastle – 1 death after conditioning, 1 chronic GVHD else all successful!
    • Note strong age effect – older kids do worse. Psychological? More established organ damage?
    • Some “unnecessary” transplants may need to be done, to avoid missing an opportunity to cure 1 case that might go on to do badly in later life.
    • GVHD is rarely a long term problem in kids. Long term complications are infertility, hypothyroidism, prior organ damage.

    Gene therapy: T cell count starts to rise from 12 weeks onwards. GVHD may present at that point, but resolves spontaneously. 8 patients done so far in UK, only 1 non-responder who was an adult (not surprising, too old for thymic reconstitution), 2 have stopped IVIG treatment. More done in Paris, but 2 cases of malignancy; risk associated with number of cells returned. New gene therapy trials for CGD and ADA-type SCID.