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Hereditary spherocytosis

General paediatrics, Genetics, Haem/Oncology

One of the genetic red blood cell abnormalities that protects against malaria (cf sickle cell), as haemolysis shortens life span and potential for parasite reproduction.

Phenotype (severity) consistent within family, but very different between families. FH may be vague eg splenectomy, jaundice rather than awareness of underlying diagnosis…

Presentation

Anaemia, jaundice and splenomegaly classically. Splenomegaly is usually mild and there is no increased risk of rupture. Neonatal jaundice can be severe but does not predict severe disease! Severe cases (assessed when well, not during crises, only about 5%) can be transfusion dependent in first years of life (erythropoietin helpful) but not usually afterwards.

May present with parvovirus aplastic crisis (not just red cells; white cells and platelets often drop too) – only happens once.

Diagnosis by spherocytes on film, reduced MCV, high reticulocytes (but retics do not go up during aplastic crisis), unconj hyperbilirubinaemia, splenomegaly. There are other causes of spherocytes, and they can be seen in normal neonatal blood films.

Differential is autoimmune haemolytic anaemia, which is associated with acute viral infection (direct Coombs test usually positive). Osmotic fragility test does not distinguish, can be false negative in iron deficiency, and is unreliable in the first few months of life. New EMA dye binding test takes 2 hours and is 92% sensitive. Gene tests don’t add much.

Other problem is gallstones. High reticulocyte count predicts.

Folate probably only necessary for severe cases.

Splenectomy

Most children are asymptomatic, but severe cases can have growth failure, lethargy, heart failure and leg ulcers. Should be delayed until at least 5 yrs, potentially laparascopic and/or partial. Do cholecystectomy at same time if symptomatic. Platelets rise to abnormally high levels after splenectomy, but no apparent increase in thrombosis.

[Arch Dis Child PMID 15321852]

Haemolysis

General paediatrics, Haem/Oncology

ie red cell breakdown.

Intravascular (eg disseminated intravascular coagulation) or Extravascular (eg hypersplenism)?

Immune or non-immune? Do Indirect Coombs (anti-globulin) test.

Differential:

  • disseminated intravascular coagulation – eg sepsis.  Sick! Low platelets, low Hb, abnormal clotting, high inflammatory markers.
  • Hypersplenism eg G6PD deficiency, storage disorders
  • autoimmune haemolysis (see below)
  • Hereditary spherocytosis

Autoimmune

Type of AHA is usually revealed by antibody screen as part of Direct Antiglobulin Test (DAT) – pattern of anti IgG plus anti C3. 

Basically, warm, cold or paroxysmal cold haemoglobinuria.

Can be primary, or associated with autoimmune disease (eg SLE), lymphoproliferative disorder, infection (EBV, mycoplasma), drugs. Big spleen usually suggests secondary.

Warm means haemolysis at body temperature. Cold means triggered by cold exposure – acrocyanosis (even ischaemia) can be a feature.

Titre less important than threshold temperature for activation!

Paroxysmal cold haemoglobinuria – most common autoimmune haemolytic anaemia in under 3 yrs. Post viral. NB normal platelets, no fragments on film cf HUS. It is intravascular however, unlike warm/cold, so no liver/spleen. Donath-Landsteiner antibody. Can be with localised cold exposure eg hands in cold water, even just drinking cold water!  IgG vs P antigen on RBC.  Can be associated with syphilis. Renal failure. Plasma exchange helps.

Osteoporosis

General paediatrics, Medical, Orthopaedic

Various causes of secondary osteoporosis: coeliac disease,  hyperthyroidism, hypogonadism, IBD, chronic liver disease, JIA, chronic renal, immobility.

Consider calculating fracture risk if secondary osteoporosis or previous fragility fracture, frequent use of systemic steroids, FH hip fracture, low BMI, smoking/alcohol etc.

Use online tools FRAX or QFracture to estimate 10yr predicted fracture risk (FRAX includes previous bone mineral density value if DXA done, not necessary).  If risk is in the region of “intervention threshold” for proposed treatment, consider doing DXA and recalculate FRAX.  Tools may underestimate risk if history of multiple fractures, previous vertebral fracture, high dose steroids, other causes of secondary osteoporosis. These tools are meant for adults over 30-40yrs however.

“Intervention thresholds” are NOT covered in guideline, it says see local guidance!

For WOS, no Dexa for coeliac until in 20s.

[NICE osteoporosis guideline ]

MRSA

General paediatrics, Infectious disease, Microbiology

=methicillin resistant staphylococcus aureus.  Cf methicillin sensitive staph, MSSA.

Methicillin resistance equates with flucloxacillin resistance. mecA is the methicillin resistance gene, which codes for a low affinity PBP (penicillin binding protein) – ie penicillin can’t bind easily. The gene has probably crossed from coag neg staph on at least 5 occasions to create MRSA strains. As with MSSA, different strains exist, carrying a range of different pathogenic genes.

Traditionally MRSA was found in institutions and the elderly, but now can be seen frequently in the young and healthy, causing the same infections that MSSA causes eg skin/soft tissue. It can also be responsible for rarer, more severe diseases eg necrotizing fasciitis. The US Center for Disease Control details criteria for distinguishing hospital acquired and community acquired MRSA infections – community acquired strains are typically SCCmec type IV (this is the cassette that contains mecA), which are sensitive to most non-beta lactam antibiotics, but on the other hand is associated with Panton Valentine Leucocidin (PVL, a cytotoxin associated with necrotizing disease). But again, this distinction is becoming less clear with strains associated with community acquired infection becoming more frequent in hospital acquired cases, and having variable levels of non-beta lactam antibiotic resistance.

In itself, antibiotic resistance may not translate to increased virulence and pathogenicity – it may just make it harder to treat. Studies have shown that after correcting for other factors eg age and co-morbidity, mortality is not significantly different. However, one important factor is use of inappropriate antibiotics, which of course is more likely with MRSA. Furthermore, in the US many MRSA outbreaks are caused by the USA300 clone, which carries a number of genes (in common with Methicillin sensitive staphylococcus aureus) eg PVL, ACME which are associated with enhanced pathogenicity.

PVL seen in 50% of symptomatic (skin) community MRSA in the US. Now also being reported in hospital acquired MRSA. Prevalence much lower in Europe, but risk of spread. Geographical areas tend to have their own clones (eg type 80 in Europe), with occasional pandemic.

Epidemiology

  • MRSA has been shown to survive on sterile packaging for at least 6 months.Journal of hospital infection 2001;49(4):255-61.
  • Basic simple infection control like hand washing works.
  • MRSA prevalence in hospitals is associated with macrolide and 3rd generation cephalosporin use.Clinical microbiology and infection 2007;13(3):269-76.
  • Alcohol hand rub reduces its transmission and hospitals which have introduced a policy of using this between patient contacts reduce their MRSA rate.
  • Isolation and screening work but may be impracticable in emergency admissions or in hospitals with near 100% occupancy.

In the UK, most MRSA are resistant to quinolones and macrolides. Even if sensitive to quinolones, treatment is not recommended as resistance evolves rapidly. Most MRSAs are sensitive to tetracyclines (but not for use under 12yrs), rifampicin, co-trimoxazole, and linezolid, all of which can be given orally. Clindamycin can be effective but beware inducible resistance – see below. No evidence for trimethoprim alone (cf septrin); use in combination with rifampicin? Probably best not to give rifampicin or fusidic acid monotherapy anyway as resistance frequently induced.  See antibiotic classes.

In MRSA skin infections (cellulitis/abscesses), most will get better anyway, esp after I&D, but using the wrong antibiotic increases risk of treatment failure by odds ratio of 2.80 (87% success cf 95% of patients who received an active antibiotic). Topical agents will induce resistance if used for high load infections eg wounds, catheter sites so should be combined with systemic therapy.  About 12% are resistant to topical mupirocin.

For intravenous therapy, gentamicin, vancomycin and teicoplanin are effective, although vancomycin resistance has been described since 2002. Teicoplanin levels can be unpredictable, and treatment failure associated with low levels has been seen; checking levels would make sense (aiming for trough of at least 10, 20 in endocarditis) but is rarely done. In line infections, vancomycin or linezolid should be used if the infection is severe; if milder, then removal of the line and oral therapy may be sufficient.

In bone infection, linezolid is good but should be given for a maximum of 28 days. Fusidic acid and Rifampicin are good adjuncts (rifampicin has in vitro activity against biofilms). Clindamycin and co-trimoxazole have also been used for bone infections. Early surgery (eg within 2/7 of onset of symptoms) is important esp where a prosthesis is present.

Necrotising pneumonia with MRSA post-influenza has mortality up to 75%.

For bacteraemia/endocarditis, vancomycin is the drug of choice, as treatment failures have been described with teicoplanin. Rifampicin or fusidic acid can be considered as adjuncts; there is no evidence for adding an aminoglycoside. A minimum of 14 days treatment is required (although oral treatment may be appropriate for maintenance) but should be extended if vegetations seen on trans-oesophageal echo. Infected pacemakers should be considered the same as orthopaedic prostheses.

Clindamycin resistance is sometimes only 1 mutation away from erythromycin resistance. If the bug is erythromycin sensitive, then there is no issue, and clindamycin is a good choice (and can be given orally). On the other hand, if erythromycin resistance is seen, then the D test should be done: if a D-shaped zone appears around the clindamycin disk when an erythromycin disk is placed nearby, then you have induced resistance and clindamycin should be avoided. The erm gene is responsible for erythromycin-inducible resistance; the mrsA gene also confers resistance to erythromycin but does not affect clindamycin.

Eradication

Once colonized, about 40% of patients develop persistence – commoner where skin breaks present. Vancomycin does not clear nose, throat or gut.

Eradication of S. aureus nasal colonization eg with 72 hour mupirocin has been successful. However, recolonization usually occurs within a relatively short time, and the Cochrane review did not find much evidence in favour. Use of mupirocin to prevent infection in endemic settings eg dialysis centers have shown conflicting results although metanalysis suggests benefit (but fear of mupirocin resistance). Neomycin is even less effective, but is an alternative where mupirocin resistance is seen.

Combined treatment seems sensible, and recent RCT of 2% chlorhexidine gluconate washes, 2% mupirocin ointment intranasally, oral rifampin and doxycycline for 7 days vs no treatment confirms. At 3 months of follow-up, 74% cf 32% had cleared. Still significant benefit at 8 months (54% of those treated culture negative). On multivariable analysis, having a mupirocin-resistant isolate increased the risk of treatment failure nearly 10 fold. Mupirocin resistance emerged in only 5% of follow-up isolates. Clin Infect Dis. 2007 Jan 15;44(2):178-85.

Other control measures include a combination of active surveillance cultures of high risk patients, improved health care worker hand hygiene, consistent use of contact precautions for colonized/infected patients, and directed treatment of health care workers implicated in transmission. PIDJ January 2005 pp 79-80

Screening patients seems to reduce hospital acquired infection in the Netherlands, but not in Switzerland. UK guidelines say do for high risk only eg previous carriers, transfers, ICU. Standard infection control procedures alone seem to have worked in UK although what do you compare with? Rapid test (PCR) did not help (in crossover trial) except in reducing inappropriate isolation. 3-4x as expensive.

[UK guidelines, J antimicro chemo 2006 PMID 16507559]

 

 

Benign transient hyperphosphatasaemia

Common, General paediatrics

Common, typically young children with minor infections.

Due to decreased clearance, probably, carbohydrate side chains changed, affecting recognition – characteristic iso enzyme pattern on electrophoresis (ie not usual bone/liver forms).

Can be as high as 50x normal upper limit viz 10 000+!  Can last up to 6 months.

Just show that other liver function tests normal, normal calcium/phosphate and no suspicion of myositis, rickets.

Asthma

Common, General paediatrics, OPD, Respiratory

See BTS/SIGN/NICE 2025 guidance on asthma,  asthma prevention, asthma and obesity

FeNO is expensive and available in only a minority of GP practices and hospital services.  Requiring it means GPs can no longer make diagnosis themselves.

Spirometry results in most primary care patients with asthma are normal!

Spacer best for everyone! Orange aerochamber is small mask, up to 18 months, yellow is 1-5yrs. Green is 5+, blue is adult. You can get blue with mask, not green.

200 doses in an MDI.   2 puffs BD exhausts an MDI in 50 days. Multidosing 5 puffs 4hrly will exhaust it in 6 days.

Growth Restriction

Children who use inhaled steroids for asthma grow slower than their peers in the first year of taking the medication, by about half a centimetre per year. Metanalysis of 25 trials, various types of steroid.  Seems to be most obvious in initial year of treatment.  Only 1 study followed children into adulthood – budesonide, used for average of 4 years – reduction in final height of  1.2cm (Kelly, PMID 22938716).

Should therefore be prescribed at the lowest effective dose. Cochrane 2014 found significant difference between low dosing (50-100 Clenil equivalent) and medium dosing  of 0.2cm per year but noted that the  majority of trials did not report height data.

However, the small effect on growth needs to be weighed against the proven benefits of these drugs in controlling asthma, and ensuring children’s lungs grow to their full capacity.   Undertreated asthma is much more likely to have a harmful effect on a child’s development than a small reduction in growth.

Newer Therapies

Xolair=Omalizumab, monoclonal vs IgE. Subcut, 2-4 weekly, for age 6+ where conventional therapy not working.  Other criteria are total igE >30, positive tests for aeroallergens, FEV1<80%.

Airsonett is evidence based, temperature controlled laminar flow system for bedroom. Noisy!

Management

See National review of asthma deaths.  Recommendations include:

  • Refer specialist if >=2 courses oral steroids within 12 month period
  • Follow up after every ED/OOH attendance
  • Hospital follow up after every hospital attendance
  • Annual inhaler technique check
  • Personal asthma plan for everyone

See MyLungsMyLife.org website for self management.

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.