A mother with a mitochondrial DNA gene mutation will pass this abnormal gene to all of her children. The children will all be affected, but with different degrees of severity.
As it is not possible to predict how the children will be affected, this is immensely difficult for planning a family.
Infantile subacute necrotizing encephalopathy.
Clinically heterogenous, lots of different genes. Can be X-linked, mitochondrial or recessive!!! Main genetic problem is mitochondrial complex defect, but same disease can be caused by pyruvate dehydrogenase defect (actually a complex of enzymes).
Baby’s initial development may appear normal, although there may be failure to thrive. Lactate can be raised in serum. Progressive, often rapid, neurological deterioration including hypotonia, dystonia, seizures.
Lesions (necrotic, gliosis, spongiosis) seen in basal ganglia, brainstem, cerebellum, spinal chord. CSF lactate and pyruvate may be raised, even if serum normal.
See mitochondrial inheritance.
Legumes, pulses, beans… Some terminology first: legumes are plants in family Fabaceae (or Leguminosae). Pulses are (strictly) those cultivated for DRY seed, as opposed to green beans, broad beans etc that are eaten fresh. Lentil simply describes shape (“like lens”). So other examples of legumes are peanut, lupin, tamarind, carob, alfalfa!
Very common cause of food allergy, even excluding peanut! And varies across different cultures, depending on typical pulses used. Fifth most common cause of food allergy in Spain. In India, often a trigger of asthma/rhinitis when being boiled. Cross sensitivity is seen, but not automatic, and hard to predict.
Soya allergy is sometimes seen in highly atopic babies, but otherwise actually pretty rare (except in Japan) – lucky, cause gets into lots of different things eg many breads. Soya lecithin is a common additive, used to make texture more smooth, but usually only in very small amounts. Fermentation eg soy sauce appears to significantly reduce allergenicity, soya flour also seems less allergenic than soya milk, even though most of the allergens are cupins eg 2s albumin and would therefore be considered heat stable.
Lupin is used in some continental baked goods, for example packaged waffles. A good proportion of peanut allergic children will be allergic to it too, but as lupin is not found very commonly most will never know or have a problem with it. A few restaurants (in UK and abroad) have lupin in their allergy menus.
A couple of lentil allergens have been identified including a vicilin and a lipid transfer protein. In my experience pappadoms can often be tolerated – there is certainly evidence that autoclaving for 30 mins can affect binding, but these are only deep fried for a few seconds.
Both the known pea allergens are vicilins, hence cross reactivity with lentil. Chickpea allergens however are not (one a prolamin, the other a cupin) – still, cross reactivity fairly common.
French beans have an LTP so potentially severe, and potentially fruit allergies too. Green (mung bean) and red gram are cupins, black gram appears to be something else.
[Clin Rev Allergy Immunol. 45(1):30-46, 2013 Aug]Usually develops over a few weeks, not an acute drug allergy!
Rash is maculo-papular, not specific. Apart from eosinophilia, other blood abnormalities occur eg atypical lymphocytosis or lympho/thrombocytopenia.
The systemic features are fever and lymphadenopathy, but generally 1 or more organs, typically liver, kidney and lung involvement.
Thyroid issues can be congenital, neonatal, autoimmune, or related to syndromes eg Downs, Digeorge.
Note that thyroid function tests can be affected by intercurrent illness, there is also viral thyroiditis where you might get transient (usually mild) abnormalities. So borderline results (especially if asymptomatic or other medical issues) usually just need repeated. If results confusing, do T3. If normal then abnormal T4 likely to be transient. If suspicion of evolving problem, do autoantibodies (TPO antibody, Thyroid Receptor Ab (TRab)). If progressive decline then likely to be emerging autoimmune condition.
All kinds of unusual clinical presentations in thyroid disease, for example:
Isolated TSH elevation >20 is usually treated.
True congenital hypothyroidism mostly dysgenesis, ie poorly formed gland, of which <2% have identified mutations (mostly thyroid peroxidise, thyroglobulin and TSH receptor proteins – EDTA sample, Dr Therese Bradley at SGH Genetics). May be due to dyshormonogenesis (10%, autosomal dominant, gland looks normal on scan), TSH Receptor defect. Do a Family History.
Mostly found on newborn screening now. Life long.
Placental thyroxine important, iodine too, on neonatal thyroid function. In the first 14/7 of life, high TSH/T4/T3 seen. Transient neonatal hypothyroidism seen, 25% of +ve guthrie tests!
If missed or untreated, classic signs are umbilical hernia, goitre, hoarse cry, coarse facies, Developmental Dysplasia of Hip!
SPEG recommend that all families should be given the opportunity for imaging, subject to availability, because more informative than blood tests alone, will aid in genetic counselling, likelihood of lifelong treatment if proven permanent CH, provides a useful guide as to thyroxine dose.
Combined isotope and ultrasound imaging (dual scanning) is preferred. Isotope scans should be performed by day 5 of start of treatment to ensure avoidance of false negatives due to TSH suppression (advisable to take thyroid function sample on day of scans to confirm reliability of results). Ultrasound may show an abnormal gland (dyshormonogenesis) or else agenesis (no gland). But in agenesis may be remnants of embryonic structural elements which can be mistaken for a gland – can persist into teenage years but max 5mm x 5mm! Hence importance of supporting radio-isotope imaging. Experience of ultrasonographer important.
Some concern that thyroxine liquid not as consistent levels? Automatic script request from pharmacy, patient then notified when ready.
Repeat TGTs at 10-12 weeks. Aim to keep TSH in lower half of reference range (room to spare as child grows).
Aim for fT4 > 15 pmol/l and TSH <5.0 mU/l
| Age | LT4 dose (ug daily) | LT4 dose (ug/kg/day) | ||
| Female | Male | Female | Male | |
| 3 months | 41.3 | 43.3 | 7.2 | 6.9 |
| 6 months | 45.8 | 50.0 | 6.1 | 6.2 |
| 9 months | 47.9 | 53.1 | 5.6 | 5.7 |
| 12 months | 55.0 | 53.1 | 5.8 | 5.2 |
| 18 months | 62.5 | 61.1 | 5.8 | 5.3 |
| 24 months | 70.3 | 58.3 | 5.9 | 4.6 |
| 36 months | 75.0 | 62.5 | 5.3 | 4.25 |
The clinical severity of a patient’s hemophilia is gauged by the baseline clotting factor level, a value that remains fairly constant throughout that person’s life, and is pretty consistent through a family. Around 5% of normal is moderate.
Intramuscular injections should be avoided if at all possible. If they must be given, factor replacement therapy should precede the injection. Parenteral agents should be given intravenously or subcutaneously. Immunizations are administered subcutaneously.
Aspirin is contraindicated due to antiplatelet effect. Avoid NSAIDs if possible, and contraindicated if actively bleeding or being treated for a recent bleeding problem.
The treatment of choice for individuals with factor VIII deficiency is recombinant factor VIII. There are different brands, with different combinations of additives which may or may not be antigenic. Cryoprecipate and fresh frozen plasma are used only if factor cannot be obtained.
For individuals with Christmas disease (factor IX deficiency), recombinant factor IX is the treatment of choice. Fresh frozen plasma is only used if factor is unavailable.
Ideally let patients/parents reconstitute and administer their own factor. Families should have an emergency dose of factor concentrate or DDAVP in their home and to take it with them when they travel, esp if they do not live close to a hospital. Factor replacement should be offered within 1 hour of the patient’s arrival: it should be readily available, the patient should not be left waiting, and treatment should not be deferred pending x-rays or other results. The most experienced IV therapist or phlebotomist available should perform venipuncture – misses and tourniquets may cause painful hematomas which then limit further IV access – use the smallest needle possible unless volume replacement is needed..
Factor replacement must be administered intravenously by IV push over 1-2 minutes. Round the dose up to the closest full vial ie don’t throw away any left overs (excess factor does not create a hypercoaguable state but will prolong the therapeutic half-life of the product administered).
For individuals with inhibitors (antibodies to factor VIII or IX), treatment decisions may be more complicated. The care of inhibitor patients should be urgently discussed with the patient’s hematologist. If an individual with an inhibitor presents in a life- or limb-threatening scenario, the safest immediate action is to prescribe recombinant factor VIIa (rFVIIa, Novoseven) at a dose of 90 mcg/kg or activated prothrombin complex concentrates (FEIBA, Autoplex) at 75-100 units/kg (contraindicated in factor IX patients with a history of inhibitors and anaphylaxis). Hopefully the patient/family can provide information on response to second line therapeutic agents.
[Medical and Scientific Advisory Council (MASAC) of the US National Hemophilia Foundation 2003]
In a study of 342 kids with asymptomatic microscopic haematuria, no cause was found in the large majority of patients. The most common cause discovered was hypercalciuria (16% of patients) followed by post–streptococcal glomerulonephritis (1%). No evidence for value of early detection of hypercalciuria (may be at long-term risk for nephrolithiasis and bone demineralization). The children with asymptomatic post–streptococcal glomerulonephritis all improved spontaneously and without complication. None had evidence of urinary tract infection! Clinically insignificant abnormalities in the upper urinary tracts of 5 children and grade 3 reflux in 1 [Arch Pediatr Adolesc Med. 2005;159(4):353-355. doi:10.1001/archpedi.159.4.353]
Asympt recurrent can be monitored for 5yr!
Beware:
Haematuria defined as persistent dipstick positive on at least 3 occasions for at least 3 months. Else as >2rbc per HPF (not same as flow cytometry). Then consider:
If spot urine abnormal, repeat on early morning urine and then proceed to 12-14hr collection. Urine calcium/creatinine has age specific normals, high at birth (up to 1.5 in toddlers) falling to adult max of 0.7 at age 7. High levels especially significant in the presence of a normal plasma calcium
Investigations – only do bloods if macroscopic or nephritis suspected:
Differential is:
Biopsy if persistent high grade microscopic, or microscopic with proteinuria (>150 mg/24 hr)/hypertension/impaired renal function, or 2 episodes of gross haematuria. Cystoscopy for bladder problem.
DSM-5 has “illness anxiety disorder”, defined as preoccupation with the idea that you’re seriously ill, based on normal body sensations (such as a noisy stomach) or minor symptoms (such as a minor rash), to the degree that it gets in the way of normal life. Other features are persistence of such ideas over 6 months, finding little or no reassurance from negative test results or a doctor’s reassurance, repeatedly checking body, avoiding people, places or activities for fear of health risks.
In other words, hypochondriasis. Which gets its name from the idea that such feelings came from liver/spleen/gall bladder (“melancholy” – black bile). William Cullen, in Edinburgh in the 1790s, appeared to take a particular interest in this.
For the sake of diagnosis, this disorder requires the absence of symptoms, which excludes the large group of people who have similar preoccupation and fears about non-specific or unexplained signs and symptoms.
Health anxiety is therefore a broader concept, and can include anyone who is more desperate for relief from worry, than for relief from actual symptoms.
Cyberchondria = combination of increased pathologisation of society, and ability to browse the internet. Because provides the opportunity to find very serious, extremely unlikely explanation for problems.
Diagnosis of health anxiety is well accepted by patients if explained respectfully!
[BMJ 2016;353:i2250]
Proliferation of mast cells. Can be restricted to skin or be systemic, with infiltration of bone marrow, spleen, liver and lymph nodes. Systemic involvement not always obvious in the skin! Messy though, since mast cell mediators might act systemically even if mast cells themselves not widespread.
Systemic mastocytosis can present with episodic symptoms of dyspnoea, collapse (hypotension), reflux, diarrhoea. Rather non-specific, so easily missed. May also have hepatosplenomegaly, lymphadenopathy, osteoporosis, bone abnormalities.
Skin lesions may be present but not always dramatic (might just look like freckles). May be history of dermatographism, recurrent itching, flushing and/or urticaria. Different skin patterns seen, but overlapping:
So look at skin, try Darier’s sign (not v sensitive). Feel for liver and spleen. Check Tryptase level (rarely normal even in systemic – compare baseline to peak, rather than just absolute level). Consider bone marrow biopsy to look for mast cells. Consider bone scan to look for abnormalities. PCR for the D816V mutation in KIT gene?
Control triggers (very individual):
60% of kids resolve during puberty!
In later life there is a slightly higher risk of haematological disorders including cancer. There is also an increased risk of osteoporosis.
Stabilize mast cells:
Emergency treatment: Adrenaline auto-injectors for –
UK support group at www.ukmasto.org [Jess Hobart]
[Am Fam Physician. 1999 Jun 1;59(11):3047-3054.]