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Long QT Syndrome (LQTS)

Cardiology

16 genes now known, most incomplete penetrance. Important in drug induced Torsades too. LQTS probably accounts for many sudden unexpected deaths, some evidence for SUDI too.  Some genes associated with epilepsy. Triggers for cardiac event seem to vary from 1 gene to another eg exercise (LQT1), sudden loud noise (LQT2).

Variable expressivity too, so 1 normal ECG not adequate.

Other ECG clues are bradycardia, T wave alternans or biphasic, abnormal U waves. T wave changes with posture or exercise may also be seen. Allow at least 3 consecutive beats to measure, to allow for sinus arrhythmia.

Consensus diagnostic criteria

Any of:

  1. LQTS risk score >=3.5 (in the absence of an alternative cause) – score is complex, but involves QTc, Torsades, T wave abnormalities, syncope, cong deafness, FH.
  2. Pathogenic mutation in a LQTS gene
  3. QTc >500 on repeated ECG
  4. QTc 480-499 (repeated) PLUS unexplained syncope.

Treatment is with beta blockers, avoidance of triggers.

[Current Opinion in Pediatrics. 26(6):727-33, 2014 PMID: 25313972].

Attention Deficit & Hyperactivity Disorder

Community, OPD, Psychology

ADHD defined as at least 6 months of

  • Inattention,
  • Hyperactivity,
  • Impulsivity.

ICD requires all 3, DSM requires just 1.

Plus,

  • social and/or academic difficulties not explained by anxiety or depression,
  • child should be under 7 yrs.

DSM does not give guidance on assessing severity. UK guidelines do not mention mild ADHD.

Commonly associated with peer rejection, increased risk of injury. Long term, less likely to enter higher education or find employment, more likely to have delinquent/criminal behaviour, more likely to smoke, use alcohol and illegal drugs.

There is high concordance for monozygotic twins, which supports a genetic cause. There are also MRI/PET lesions, which support a physical cause (cortical abnormalities in the frontal, temporal, and parietal lobes, Lancet 2003). It is 3 times more common in boys. It may be related to traumatic experience in infancy.

There are rating scales eg Conner’s ADHD index, which is 94% sensitive.

Examples of inattention:

  • Careless mistakes
  • Does not seem to listen when spoken to directly
  • Does not follow through instructions (NOT simply oppositional)
  • Avoids sustained mental effort
  • Loses things necessary for tasks/activites

Examples of hyperactivity/impulsivity:

  • Fidgets, squirms, leaves seat when expected to remain
  • Runs about, climbs in appropriate situations
  • Acts as if “driven by a motor”
  • Blurts out answers before question finished
  • Interrupts, intrudes on others

There should be impairments in at least 2 settings eg school and home.

Management

Parent training programmes are effective for preschool children.

Methylphenidate, a dopamine agonist, is effective, esp for concentration, hyperkinesis and impulsiveness. Clonidine has been suggested.

Behaviour modification (NOT cognitive behavioural) is effective for age 6yr+ only when combined with medication.

Hyperactivity tends to improve over time, but there are associated antisocial behaviours and learning difficulties long term. The longest trial showed better performance up to 8yrs after entry (compared with baseline), but still underperforming compared with peers.

A diagnosis can help parents but also carries stigma: children with ADHD are perceived as lazier and less clever by peers, and teachers/parents have lower academic expectations.

BMJ 2013;347:18a

Sepsis

Emergency medicine, Infectious disease

See also Sepsis6.

In reviews of child deaths, most significant recurrent avoidable factor is failure to recognize severe illness, most often at point of first contact with health services (Why children die, Pearson Arch Dis Child doi:10.1136/adc.2009.177071)

American College of critical care medicine 2007 shock update – central venous and arterial monitoring, dopamine within 15 mins, then warm vs cold shock, etc.  2009 Paed intensive care society audit in UK found majority of children (62%) targets were not met, for reasons that remain unclear. OR for death 3.8 where shock still present at time of PICU admission.

In 2011 goal directed therapy study, less intubations and inotropes, half the number of deaths. (But less severe group?) [Andrea Cruz, Pediatrics 2011;127;e758; DOI: 10.1542/peds.2010-2895]

Chinese study of antibiotic timing found reduced time to reversal of shock where given within 1 hour.

Definition of risk group – Paed CCM international consensus conference – at least 2 of the following 4, 1 must be abnormal temp (reported within 4 hours of admission if afebrile at presentation)

  • Core temp <36 or > 38.5
  • Tachycardia
  • Bradycardia
  • Tachypnoea
  • Leucocyte count elevated for age or >10% immature neutrophils

(Not clear why different criteria used for sepsis6)

Def of inappropriate tachycardia?

Studies continue to be done looking for predictive factors esp young infants.

Management

  • Give high flow O2, regardless of sats!
  • Titrate fluids over 5-10 mins, repeat if necessary. Aim to reverse shock.
  • Early inotropic support viz adrenaline (make up during 3rd bolus). 0.3mg/kg in 50ml 5% dextrose, 1ml/hr (0.1mcg/kg/min)
  • 15 mins ideal, within 60mins acceptable.

Headaches and exertion/sport

Neurology, OPD

Not uncommon. Tension headaches tend to get better with exertion, in any case mild by definition so unlikely to be a problem. Some specific exertion-related headaches eg Primary headache with raised cardiac output – pulsating in quality, can last just a few minutes but up to 48 hours! Primary headache with raised venous pressure is related to valsalva manoeuvre eg weight lifting, can last just seconds, rarely more than 30 minutes.

Do MRI, ECG to exclude underlying cause.

Could try more gentle aerobic warm up, NSAID prophylactically, Else triptan/NSAID treatment as required. Beta blockers (esp Non-selective eg propanolol) appear to have some negative effects on aerobic exercise capacity (except when used for treating cardiac failure). They are also banned in competitive sports (due to their use by precision sports athletes eg archery). [Sports Med. 1988 Apr;5(4):209-25. PMID   2897710]

Beckwith Wiedemann Syndrome

Genetics, Metabolic, Neonatology

Chromosome 11p problem, where IGF2 gene lies. Hemihypertrophy, macroglossia, ear creases/pits, exomphalos, umbilical hernia, visceromegaly, macrosomy, hyperinsulinism.

Focal disease is associated with uniparental disomy in chromosome 11 (“upd(11)pat”), whereas diffuse disease can be familial or sporadic.

Focal disease can be managed by limited surgery, whereas diffuse disease needs near total pancreatectomy for any benefit. DOPA-PET scans can differentiate focal disease with a sensitivity of 88-94%, and are 100% accurate in localizing the focal lesion (Aberdeen does).

At increased risk of tumours esp nephroblastoma, adrenal carcinoma, hepatoblastoma. Screening recommendations depend on mutation viz IC2 LOM, IC1 GOM, upd(11)pat etc. For all but the first, every 3 months until age 7yrs.

OMIM link.

Support group https://www.bwssupport.com/

Congenital Hyperinsulinism

Congenital, Genetics, Metabolic, Neonatology

Hyperinsulinaemic hypoglycaemia is a common cause of persistent severe hypoglycaemia, and is associated with long term neurodisability and epilepsy. Can be congenital, due to unregulated beta cell function (used to be called nesidioblastosis), else secondary to various other conditions eg:

  • Maternal diabetes mellitus
  • Birth asphyxia
  • IUGR
  • Beckwith Wiedemann Syndrome – about 50% are affected, usually transiently
  • Inborn error of metabolism eg glycosylation disorder

Can present with severe hypoglycaemia in the newborn period despite good oral intakes, else more insidiously in infancy and childhood. No ketones of course – cf ketotic hypoglycaemia.  Macrosomia (+/- hypertrophic cardiomyopathy and hepatomegaly) is a feature of fetal hyperinsulinism but is not always present, otherwise typical features of hypoglycaemia may be seen, including seizures.

Cases secondary to IUGR/asphyxia tend to be transient, settling within a few days, but some have persistent symptoms for months before suddenly resolving!

Recessive defects in sulphonylurea receptor probably most common cause.  Fasting or exertion are the usual triggers, but postprandial symptoms may reflect dumping syndrome (usually secondary to gastro-oesophageal surgery) or else hyperammonaemic hyperinsulinism (glutamate dehydrogenase disorder – the high ammonia of 100-200 is persistent but asymptomatic). A form of exercise induced hyperinsulinism exists that requires exercise testing to diagnose.

Insulinoma is more likely in later childhood. Can be part of a multiple endocrine neoplasia syndrome type 1 (ask family history).

Raised plasma hydroxybutyrylcarnitine and urinary 3-hydroxyglutarate are diagnostic of Hydroxy AcylCoA Dehydrogenase (HADH) deficiency.

Management aims to achieve normal glucose levels, using Carbohydrate supplemented oral feeds plus IV fluids. A central line may be needed to give concentrated dextrose solutions, esp if chubby. Glucagon can be given IM in an emergency but may lead to paradoxical insulin release. Glucagon and/or octreotide can be given as infusions in resistant cases.

For ongoing treatment, diazoxide acts on K-ATP channels in beta cells. Chlorthiazide is synergistic in the neonatal period. Hypertrichosis is the main side effect of diazoxide. Some rare gene defects are resistant to Diazoxide! Feeding probs esp GORD common, partly due to all the NG/IV feeding.

[Kapoor, Arch Dis Child 2009 PMID 19193661]

Hypoglycaemia

Endocrinology, General paediatrics, Metabolic, Neonatology

Glucose levels are maintained after a meal by release from glycogen stores in liver (glycogenolysis), driven by Glucagon. When glycogen stores are low, then glucose can be produced from fat stores by fatty acid oxidation (via ketones) and from protein by gluconeogenesis. The switching over is moderated by cortisol, and growth hormone (reduces insulin resistance) also important.  Insulin is the only hormone that lowers blood sugar levels.

Cortisol increases gluconeogenesis, adrenaline increases lipolysis. Hypoglycaemia makes you grumpy, sweaty, pale. You can feel sick with it, and it can give you palpitations.  It can cause a wide range of acute, transient neurological symptoms including tremor, confusion, ataxia, weakness, visual disturbance.  If severe, it causes seizures, which causes release of glucose from muscles. Some cases of sudden unexpected death are thought to be due to inborn errors of metabolism causing hypoglycaemia.

Recurrent severe episodes in infancy can lead to permanent neurodisability.

There is debate about what level of blood sugar is abnormal, or whether it is only symptomatic low blood sugar that is important.  What the level in the blood is, is not the same as levels in the brain, of course.  Less than 2.6mmol/l is uncontroversial (note that near patient tests are not very accurate at low levels, which they are not really designed for, so lab confirmation is always required).  Generally <3.3 used in practice, but clinical signs important.

Usual cause is acute viral illness with reduced oral intake and vomiting.  But this can also be a trigger that reveals an underlying metabolic disorder…

  • Neonate? If big liver, remember Galactosaemia and Fructosaemia (reducing sugars in urine). Else Beckwith Wiedemann Syndrome.
  • High glucose requirement (see below)? =Hyperinsulinism
  • High ammonia? If encephalopathic, metabolic. Else Hyperammonaemia hyperinsulinaemia –  second most common congenital cause of hyperinsulinism. Gain of function mutations in the mitochondrial enzyme glutamate dehydrogenase (GDH). Can treat with diazoxide.
  • Signs of adrenal insufficiency? Abdominal/back pain, low Na, high K/Ca! Hyperpigmentation.
  • Signs of hypopituitarism? Growth failure, midline defects, micropenis.
  • Encephalopathy (esp vomiting)? Consider organic aciduria
  • Odour? Consider Maple syrup urine disease etc
  • Ketones should be present. If not then Fatty acid oxidation disorder eg MCAD.
  • Hepatomegaly? Glycogen storage disorders, also galactosaemia, acute liver failure eg Reyes syndrome (this may also be the mechanism in respiratory chain disorders).
  • With sepsis and shock consider galactosaemia – usually big liver too
  • Overdose? Propranolol, alcohol, salicylates in particular.
  • Consanguinity?
  • Time of last meal? Endocrine problems can cause symptoms at any time, as can hyperinsulinism. Glycogen storage/synthase problems cause early hypoglycaemia (ie within 3-8 hours).

Investigations

Get 1 ml lactate & 6 ml lithium heparin, bloodspots on neonatal screening card during hypo, and first urine (freeze).

Glucose requirement (mg/kg/minute) can be calculated from the following formula:

  • from IV fluids = Infusion rate (ml/hr) x % of glucose infusion x 0.1677/weight.
  • from oral feed: glucose content of standard infant formula is 7.2g/ 100ml, and of LBW formula is 8.6g/ 100ml.

Normal is 4-6 mg/kg/min, over 8 is suspicious of hyperinsulinism.

  • Insulin and C-peptide. Insulin should be undetectable, C-peptide 0.3-1.12 if hypoglycaemic with appropriate insulin response. Else hyperinsulinism (exogenous, or congenital)
  • Blood Glucose – below 2.6 considered true hypoglycaemia.  Note that BM sticks are not really designed for low sugars, and are not reliable.
  • Lactate – should be normal, otherwise high (with ketones) suggests glycogen storage disorder (with notable exception of Glycogen synthase defect)
  • TFTs – hypopituitarism
  • Cortisol – hypoadrenalism (cortisol should be high as part of stress response – else consider hypoadrenalism (Addison’s). Infants under 6 months should go over 800, older should be over 500. If low cortisol but GH >15 unlikely to be pituitary problem.
  • LFTs – beware primary liver problem
  • U&Es, Calcium – Low sodium, high potassium/Ca seen in hypoadrenalism
  • Ammonia – for organic acidaemias etc, or primary liver problem
  • Amino acids – for Maple Syrup Urine Disease etc
  • Carnitine, hydroxybutyrate – for Fatty Acid Oxidation (FAO) disorders
  • Acylcarnitines (blood spot) – for FAO disorders
  • Free Fatty acids – for FAO disorders, esp FFA/3OH-butyrate ratio (ketones are made from FFA so should be higher or not much lower, else block)
  • Blood gas – ?Acidosis
  • Urine for reducing sugars (Galactosaemia etc),
  • Urine/blood for organic acids

Prognosis

Mostly ketotic hypoglycaemia, due to starvation/vomiting. Adequate history?  Beware encephalopathy, raised ammonia, hepatomegaly.

75 LGA newborns with hypoglycaemia followed up to age 4 – no late effects. [Archives of Disease in Childhood 2005;90]

Precocity and Sex hormones

Endocrinology, General paediatrics

From US data, by age 7 10% of white girls and 23% of black girls have started puberty.  Rates are probably lower in Europe.  Likely that dietary changes (in particular, increasing adiposity) have driven this change over time to earlier puberty in girls.

Red flags:

  • boys (much more likely to be a serious underlying issue) with changes before age 9.
  • Unilateral testicular enlargement.
  • clitoromegaly (ie virilizing, so excess androgens)
  • Rapidly increasing height (increase across 1 space typical for precocious puberty)
  • Vaginal bleeding before age 8 (consider tumours etc)
  • Polydipsia, polyuria incl bed wetting (pituitary pathology)
  • Headaches, visual disturbance similarly
  • History of CNS disease eg head trauma, meningitis

For a girl, pubertal developmental that follows the normal pattern before the age of 8 is considered abnormal. Where no serious cause suspected, usually idiopathic gonadotrophin dependent – common, slow to progress, no treatment required usually.  Often mothers had the same.

Obesity contributes as a result of raised oestrogen levels, and increased aromatisation of androgens.  But obesity can also give appearance of breast development.

Note puberty lines on RCPCH growth charts, for starting puberty (girls 8), delayed beginning (girls 13, boys 14) and completing (girls 16, boys 17).  Delayed completion (especially menses) also needs investigation.  Also a shaded triangle for short boys and girls during this time, to remind that probably ok if puberty not yet started, but potentially a problem if nearly completing.

Differential is:

  • Central precocious puberty – therefore pubertal development associated with growth spurt, behaviour changes (“moods like a teenager”), acne, odour, vaginal discharge/bleed. LH/FSH should be raised (less than 3.5iU/L in prepubertal) but unless random levels very high needs GnRH testing (shows high responses viz 2-3x baseline). The majority are idiopathic but MRI brain should be done to rule out central lesion.
  • Thelarche=breast bud development. Usually the first sign of puberty, but premature thelarche often seen. Due to high oestradiol or rising sensitivity. Common in babies, then another peak in infants/preschool. Breast only, often just one: clinical diagnosis if normal growth, most regress within 1-2 yrs. Older girls less likely to regress. Sometimes fluctuating.
  • Variant thelarche – a significant minority of girls with premature thelarche will progress to precocious puberty, another group show advanced bone age and accelerated height velocity but these do not seem to be the ones who get precocious puberty.
  • Peripheral precocity ie hormone secreting tumours – tend to produce asynchronous pubertal milestones (eg virilization, penile enlargement without testicular enlargement, extensive pubic hair, or menarche without breast buds).
  • Premature adrenarche – ie adrenal hormones moderately raised but normal pre-pubertal FSH/LH with low oestrogens. Due to increased sensitivity to ACTH, zona reticularis in adrenal gland develops, producing steroid enzymes.
    • Best thought of as extreme end of normal.  But slight risk of obesity and insulin resistance, and possibly mood disorder and PCOS.
    • Principally androgen effects viz pubic/axillary hair development, +/- acne/sweating/odour. In girls, true puberty (ie with gonadal oestrogens) follows soon after, but the two can be distinct (Turners get one but not the other, Addisons may get more of the other). Bone age should not be advanced, although the child may be taller than expected. Androstenedione, precursor of both oestrogen and testosterone, is most sensitive (but can be adrenal OR ovarian), DHEA and DHEAS will also go up as precursors to androstenedione.  Do urinary steroid profile for completeness and to exclude congenital adrenal hyperplasia (CAH) – might need ACTH stimulation test to exclude late onset CAH. If progresses, then might be true precocious puberty after all. Some suggestion that premature adrenarche is related to intrauterine environment (eg SGA) and obesity, and may lead on to polycystic ovarian syndrome.
  • Premature menarche – usually benign! Not well understood, ?transient upregulation of ovarian activity, ?exogenous steroids. Observe.
  • Else Mccune Albright – sporadic genetic disease.  Unilateral cafe au lait spots, facial asymmetry, fibrous dysplasia of bones (?nerve compression). Periods appear early, even before development of breasts and pubic hair! May cause premature puberty in boys but less of a feature. Thyroid, adrenal abnormalities (Cushings) and acromegaly sometimes seen too.

So do:

  • Pubertal assessment – Tanner scale.  For obese children, lipomastia can look like breast development but will not be firm tissue under areola (lying child supine may help).  In boys, pubertal development with small (<4cm) testes means gonadotrophin independent.
  • FSH/LH, prolactin (normal is 0-500)
  • Oestradiol (not great sensitivity in girls, v high levels suggest tumour), testosterone (good sensitivity in boys)
  • DHEAS, Androstenedione, 17-OH progesterone, urinary steroid profile
  • Bone age – advanced by obesity, CAH.

Can be hard for parents to discuss! Check if they are worried about social issues (ie sexualisation).  Then pelvic USS, MRI adrenals, brain, LHRH test as appropriate. Else monitor progression and growth.

GnRH treatment can be discussed to prevent premature fusion of epiphyses and thus to preserve adult height potential.  Some families are concerned about the psychosocial impact of early puberty.  If untreated, menarche commences at mean 4.5 years, so not much different from mean age (12.3) in population.  And actually untreated children have similar height to those treated (but selection bias).  GnRH treatment is monthly or 3 monthly injections to postpone periods.

Virilizing in girls(clitoromegaly) can be due to –

  • CAH (mild needs no rx, leads to polycystic)
  • exaggerated adrenarche (“adrenal puberty”- tall, no breast/menarche, ?pubic hair)
  • tumour (v rapid changes)

Virilising in boys: true precocious (v rarely brain tumour), adrenarche, adrenal/testic tumour.

Functional ovarian hyperandrogenism (FOH), with obesity, hirsutism, acne, LH:FSH >3, irregular menses in perimenarcheal girls. Pelvic ultrasound exams are usually normal.

[BMJ 2020;368:l6597]

Mycoplasma pneumonia

Infectious disease, Respiratory

Most common bacterial cause of pneumonia in children requiring hospitalisation (Clin Infect Dis 2019) – relatively older children (5+ yrs), more likely to have had recent antibiotics but otherwise clinically indistinguishable.

Studies have indicated that the prevalence of M. pneumoniae in the upper respiratory tract (PCR) is similar among asymptomatic, healthy children and children with a symptomatic respiratory tract infection!  Current diagnostic procedures for M. pneumoniae are unable to differentiate between bacterial carriage and infection!

Note rapid worldwide emergence of macrolide-resistant (MRMP) isolates.

Meyer Sauteur PM; van Rossum AM; Vink C.  Current Opinion in Infectious Diseases. 27(3):220-7, 2014 Jun. PMID UI: 24751894

Macrolide allergy

Allergy

The majority of cases reported are non immediate reactions eg maculopapular rash, urticaria. The incidence of anaphylactic reactions is extremely low.

Less than 15% of those suspected of having macrolide allergy are finally confirmed as allergic, mainly by direct provocation testing.

Cross-reactivity between the different macrolides is variable and little information is available.

Current Opinion in Allergy and Clinical Immunology 14(4), August 2014, p 278–285. DOI: 10.1097/ACI.0000000000000069