Paediatric Endocrinology

Question 1

T1DM

Answer 1

Destruction of pancreatic B-cells by Autoimmune process

Question 2

T2DM

Answer 2

Insulin resistance followed by B-cell failure; Usually older children, associated with Obesity and FMHx; More common Afro-Caribbean and Asian populations

Question 3

Other forms of diabetes

Answer 3

MODY (Genetic defects in B-cell function; Strong FMHx), Drugs (Corticosteroids), Pancreatic Insufficiency (CF, Haemochromatosis), Endocrine Disorders (Cushing’s), Genetic Disorders (Down, Turner Syndromes), Neonatal and Gestational Diabetes

Question 4

Pathophysiology of T1DM

Answer 4

Believed to be interplay of Genetics, Environment and Trigger (e.g. Molecular mimicry with B-cell antigen) leading to destruction
o Auto-Ig against Glutamic Acid Decarboxylase, Islet Cell, Insulin
o Associated with Hypothyroidism, Addisons Disease, Coeliac Disease, RA

Question 5

Presentation of T1DM

Answer 5

Peaks in presentation in Spring and Autumn months (? Enteroviral trigger); Children only present with few weeks of Polyuria, Polydipsia and Weight Loss; Secondary Nocturnal Enuresis in younger children

Question 6

Diagnosing T1DM

Answer 6

Diagnosis crucial to prevent DKA; Referral to specialist once diagnosis suspected
o Diagnosis in Symptomatic (Glycosuria, Ketosis) child by marked, raised Random Blood Glucose (>11.1mmol/L)
▪ If in doubt, Fasting Glucose >7mmol/L or HbA1c
o Should be suspected if FMHx, Severely Obese children with signs of Insulin Resistance (Acanthosis Nigricans, Skin Tags, Polycystic Ovarian phenotype)

Question 7

Management of T1DM

Answer 7

DKA requires urgent admission and treatment
• Education – Basic understanding of Diabetes, Injection Technique and Sites, Blood glucose testing for Glucose and Ketones, Health diet (Fruit and Vegetables, Carb counting), Exercise, ‘Sick day rules’ for Insulin, Recognition of Complications

Question 8

Insulin in T1DM

Answer 8

Insulin – In the UK, all Human Insulin; In 100 units/ml concentration
o Human Analogues (Rapid acting e.g. NovoRapid, Humalog, or Long acting e.g. Levemir, Lantus), Short acting Regular Insulin e.g. Actrapid, Intermediate acting e.g. Insulatard, Humulin
o Injection to anterior/lateral thigh, buttocks and abdomen subcutaneously at 45 deg
▪ Rotation of sites to prevent Lipohypertrophy and Lipoatrophy
o Most children either continuous pump, or multiple daily regimen (basal bolus) of rapid before every meal, and long-lasting insulin in late evening or before breakfast
▪ Basal Bolus has better flexibility to relate more closely to intake and exercise
▪ Aim blood glucose 4 – 7 mmol/L before meals; Extra rapid acting insulin at mealtimes; Best glycaemic outcomes and lowers complications

Question 9

Dietary Control

Answer 9

Healthy diet and Matched-insulin doses to Carbohydrates
• High complex carbohydrates, modest fat content (<30% total calories)
• Rich in fibre (sustained release of glucose) rather than refined carbohydrates

Question 10

Monitoring glycaemic control: Purpose

Answer 10

Regular glucose measurement to adjust insulin regimen, understand how lifestyle, food, exercise affects glycaemic control

Question 11

Monitoring glycaemic control: Target

Answer 11

Aim for 4 – 7mmol/L before meals; If change in routine or illness, more testing

Question 12

Monitoring glycaemic control: Continuous glucose monitoring sensors

Answer 12

Useful for unexpected, asymptomatic nocturnal hypoglycaemia, or poor control

Question 13

Monitoring glycaemic control: Ketone Testing

Answer 13

Blood ketone testing mandatory during illness or poor control to detect DKA

Question 14

Monitoring glycaemic control: HbA1c

Answer 14

Overall Diabetes control over previous 6-12/52; Checked four times a year
o Target <48 mmol/mol (6.5%); Related to risk of complications disproportionately
o Misleading if RBC lifespan reduced (Sickle-Cell) or abnormal HbA (e.g. Thalassaemia)

Question 15

Long term management of Diabetes

Answer 15

Aims for normal growth and development, normalcy at home and school, good diabetic control through knowledge and good technique, encouraging self-reliance, minimising hypoglycaemia and maintaining glycaemic control
• Avoid long term complications – Macrovascular (Coronary, CVA, HTN) and Microvascular (Retinopathy, Nephropathy, Neuropathy); Good control delays onset and progression

Question 16

How is diabetes complicated in children

Answer 16

Sugary food intake, Unreliable blood glucose testing and fabricated glycaemic diaries, Illness (raised insulin requirements, partially due to reduced food intake), exercise, eating disorders, family disruption or motivation et

Question 17

Long term management of Diabetes:School

Answer 17

Individualised care plan covers dietary needs, hypoglycaemic management or loss of consciousness; Operation of diabetic control appliances

Question 18

Diabetes in Puberty

Answer 18

Influenced by Biological, Psychological and Social factors; Rapid growth governed by complex hormonal changes, many involving Insulin and Insulin-like Growth Factors
• GH, Oestrogen and Testosterone antagonise Insulin – Increase requirement to 1 unit/kg/day in early childhood, up to 2 units/kg/day
o Especially crucial in morning – Peak of GH secretion overnight
o Insulin dose needs to be reduced during end of puberty; can lead to weight gain
• Glycosuric anorexia – Omission of insulin

Question 19

Hypoglycaemia Symptoms

Answer 19

Most develop symptoms when below 4mmol/L; Highly individual, changes with age
o Hunger, tummy ache, sweatiness, feeling faint/dizzy, wobbly feeling in legs
o Can progress to Seizures and Coma if unmanaged; Can be identified sometimes by pallor, irritability (e.g. change in behaviour)
• Frequent episodes of Hypoglycaemia can lead to loss of awareness

Question 20

Management of Hypo in Children

Answer 20

Early stage management – Easily absorbed glucose (tablets, drinks, buccal gels)
o IM Glucagon injection kit for Severe Hypoglycaemia when child has reduced LOC
• Food should be given subsequently to prevent further Hypos

Question 21

What can precipitate DKA

Answer 21

Infection or other stressors, or neglected Insulin

Question 22

How does DKA present

Answer 22

Presents with Fruity-breath, Vomiting, Dehydration, Abdominal Pain, Acidosis-driven Hyperventilation (Kussmaul), Hypovolaemia Shock, Coma

Question 23

What will investigation show in DKA presentation

Answer 23

Hyperglycaemia, Ketosis, Dehydration (U/Es, Creatinine), Severe Metabolic Acidosis

Question 24

Management of DKA: Dehydration, Hypovolemia

Answer 24

10ml/kg 0.9% saline if in shock;
o Gradual correction over 48hrs after stabilisation to prevent Cerebral Oedema; Replace KCl with saline; monitor fluid balance, blood glucose (hrly), ketones (1-2hrly), U/Es, Acid-base status (2-4hrly) and Neurological state

Question 25

Management of DKA: Insulin

Answer 25

0.1u/kg/hr after IV fluids running for 1hr (Not bolus); Change fluids to 5% glucose when blood glucose falls to 14mmol/L to prevent hypoglycaemia

Question 26

Management of DKA: Potassium

Answer 26

Initial Hyperkalaemia (due to H/K exchange) will fall following Insulin and Rehydration; Potassium replacement once maintenance fluids started; Cardiac monitoring

Question 27

Management of DKA: Acidosis

Answer 27

Avoid bicarbonate unless shock; Acidosis corrects with DKA management

Question 28

Management of DKA: Other

Answer 28

* IV Insulin infusion should not be stopped until after 1hr after Subcut insulin * Identify any underlying infection (DKA can cause neutrophilia but typically afebrile

Question 29

Importance of thyroxine in foetal development

Answer 29

Only small amounts of maternal thyroxine reach foetus; Severe maternal hypothyroidism can affect foetal brain development o Foetal thyroid produces a largely inactive T3 derivative; After birth, surge in TSH leads to increase in thyroid hormones; Declines to normal adult ranges within week o Preterm infants may have very low T4 for first few weeks of life; TSH typically normal, additional thyroxine not required

Question 30

How common is congenital hypothyroidism

Answer 30

• Relatively common (1 in 4000); Preventable cause of severe learning disabilities

Question 31

How is congenital hypothyroidism detected?

Answer 31

• Detection as part of Neonatal screening (by Guthrie test detecting raised TSH);

Question 32

Cause of congenital hypothyroidism

Answer 32

Common causes include Thyroid maldescent or Athyrosis, Dyshormonogenesis (Inborn error of Thyroid Hormone synthesis), Iodine Deficiency (Most common cause worldwide, rare in the UK), TSH deficiency (Rare; usually associated with Pituitary Dysfunction; GH, GnRH and ACTH deficiencies accompany)

Question 33

How is congenital hypothyroidism treated?

Answer 33

Treatment with Thyroxine within 2-3/52 age to reduce risk to neurodevelopment; Lifelong oral replacement of Thyroxine titrated to normal growth, TSH and T4 levels

Question 34

Causes of Acquired Hypothyroidism

Answer 34

• Most commonly Autoimmune; Increased risk in Down or Turner Syndrome; Associated with other Autoimmune disorders (Vitiligo, RA, DM, Addison’s)

Question 35

How does acquired hypothyroidism present?

Answer 35

• More common in females; Can present as Growth Failure accompanied with delayed bone age; Goitre is often present; Treat with Thyroxine

Question 36

How often are babies weighed?

Answer 36

• Babies weighed at week 1 to assess feeding, then again at 8, 12, 16 and 52 weeks

Question 37

Which babies should be evaluated?

Answer 37

• Any child whose weight crosses two centile-spaces, or is below 0.4th centile, or has BMI less than 2nd centile should be evaluated o If preterm, allow for time during first 1-2yrs of age; some severe IUGR infants remain small but most will exhibit catch-up growth

Question 38

Most common causes of weight faltering

Answer 38

• Inadequate Intake of Food is most common cause; often Multifactorial

Question 39

Causes of inadequate food intake

Answer 39

``` o Feeding problems, Unsuitable feed, Behavioural, Impaired suck/swallow Inadequate retention Malabsorption Failure to utilise nutrients Increase requirements ```

Question 40

Causes of inadequate retention

Answer 40

Vomiting, Severe GOR

Question 41

Causes of malabsorption

Answer 41

Coeliac, CF, Allergy, Bile issues

Question 42

Causes of failure to utilise nutrients

Answer 42

IUGR, Prematurity, Metabolic disorders

Question 43

Causes of increased requirements

Answer 43

Thyrotoxicosis, CF, Infection, Congenital Heart Disease

Question 44

Management of Weight Faltering: Dietary History

Answer 44

History of milk feeding, Age of weaning, Food now taken, Meal time routine and Behaviour, 3-day Food Diary o Prematurity, IUGR, Current child behaviour, FMHx, Development, Psychosocial issues

Question 45

Management of Weight Faltering: Signs of Organic Disease

Answer 45

Dysmorphic features, Malabsorption (Distention, Thin buttocks, Misery), Chronic Respiratory Disease, Heart Failure, Evidence of Nutritional Deficiencies (Koilonychia, Angular Stomatitis)

Question 46

Management of Weight Faltering: Investigations

Answer 46

o FBC and Serum Ferritin to identify IDA; Correcting might lead to improved appetite o U/Es, LFTs, TFTs, Inflammatory markers, Ferritin, Ig, IgA tTG or EMA, MC+S o Sweat test, CXR for Cystic Fibrosis

Question 47

Management of Weight Faltering: Health Visitors

Answer 47

Mealtime Observation, Food Diary to assess and support feeding and caloric intake; Paediatric Dietitian and SALT if required

Question 48

Management of Weight Faltering: Nursery and Progression

Answer 48

* Nursery placement can relieve stress at home and assist feeding * Rise in weight centiles typically occurs 4-8/52 after intervention

Question 49

Management of Weight Faltering: When to admit

Answer 49

• If <6/12 age with Severe Growth Faltering, admission for active refeeding and MDT

Question 50

Foetal Growth

Answer 50

Fastest period, accounting for 30% of eventual height; Size at birth determined by Maternal size and Placental supply, modulating IGF-2, HPL and Insulin

Question 51

Infantile Phase

Answer 51

Characterised by rapid but decelerating growth rate; 15% of eventual height o Growth during infancy to 18/12 largely dependent on adequate nutrition and towards genetic height growth pattern o Good health, normal Thyroid function is necessary

Question 52

Childhood Phase

Answer 52

Slow, steady but prolonged period of growth contributing 40% of height o Pituitary GH secretion to produce IGF-1 at Epiphysis; main determinant of height o Thyroid hormone, Vit D and steroids affect cartilage cell division and bone growth

Question 53

Puberty Growth

Answer 53

Sex hormones, mainly Testosterone and Oestradiol, cause back to lengthen and boost GH secretion o Adds 15% to final height; Sex steroids also cause Epiphyseal plate fusion, ceasing growth; Early puberty leads to reduction in final height

Question 54

Adrenarche

Answer 54

(around 7yrs) – Development of Zona Reticularis; Adrenal Androgens produced

Question 55

Gonadarche

Answer 55

(around 8yrs) – Earliest development of Genitals; Sex steroids produced

Question 56

Pubarche

Answer 56

(around 12yrs) – First appearance of Pubic hair; Linked to Androgen production

Question 57

Which stage of maturation follows pubarche

Answer 57

Menarche and Spermarche

Question 58

Laron Syndrome

Answer 58

Defect GH receptors leading to GH insensitivity; High GH but low IGF-1 produced by the Epiphyseal plates and Liver

Question 59

Female Puberty

Answer 59

Breast development (Thelarche = Palpable breast disc starting 8.5-12.5yrs), Pubic Hair Growth and Rapid Height Growth (Almost immediately after breast development), Menarche (2.5yrs after the start of puberty; Signals around 5cm of height gain remaining)

Question 60

Male Puberty

Answer 60

Testicular enlargement (>4ml volume), Pubic Hair Growth (Usually between 10-14yrs), Rapid Height Growth (About 18/12 after testicular growth to 12-15ml)

Question 61

How can abnormally early or late puberty be assessed?

Answer 61

Bone Age (Head and Wrist XR) and Pelvic Ultrasound in females for Uterine size and Endometrial Thickness

Question 62

Precocious Puberty: Categorisation

Answer 62

Categorised as Gonadotrophin Dependent (True; Consonant Stage s) or Independent, due to Excess Sex Steroids outside Pituitary gland (False; Dissonant Stages

Question 63

Precocious puberty in females

Answer 63

Ovaries are very sensitive to GnRH; Precocious puberty common in girls o Can be pathological and secondary to Excess Androgens (e.g. CAH, Adrenal tumours); presents as Pubic hair and virilisation before Thelarche o Gonadotrophic dependent causes such as Pituitary Adenoma o Ultrasound Ovaries and Uterus

Question 64

Precocious Puberty in males

Answer 64

Testes relatively insensitive to GnRH; Gonadotrophin-dependent Precocious Puberty is rare; Important to exclude pathological cause o Bilateral Testicular enlargement suggests Gonadotrophin dependent; Intracranial tumours or rarely Beta-HCG secretion from Liver Tumours o No testicular development suggests Gonadotrophin independent causes e.g. Adrenal Tumour, CAH o Unilateral enlarged testis suggests Testicular tumour

Question 65

Management of Precocious Puberty

Answer 65

* Detection and treatment of underlying pathology – Intracranial MRI, particularly in males * Reducing the rate of skeletal maturation and Addressing psychological and behavioural issues * GnRH analogues can delay onset of Menarche in Gonadotrophin-dependent PP * Sources of Excess Sex Steroids identified; Inhibition of Androgen or Oestrogen production or action can be used (e.g. Cyproterone, Testolactone, Ketoconazole)

Question 66

Delayed Puberty

Answer 66

• Absence of Pubertal Development by 14yrs in females, 15yrs in males; More common in males, due to relatively GnRH-insensitive Testes

Question 67

Commonest cause of delayed puberty

Answer 67

By far most commonly due to Constitutional delay; Variation of normal timing rather than pathological, due to dieting or excessive physical training ▪ Bone age would also show moderate delay ▪ Eventually, target height will be reached

Question 68

Hypogonadotropic Hypogonadism

Answer 68

Systemic disease, Hypothalamo-pituitary

Question 69

Hypergonadotrophic Hypogonadism

Answer 69

Klinefelter, Turner, Steroid Hormone enzyme deficiencies, Acquired damage (Postoperative, Chemotherapy, Radiotherapy, Trauma, Testicular torsion, Autoimmune disease

Question 70

How can delayed puberty be assessed in boys?

Answer 70

Oral Oxandrolone can be used (weakly androgenic anabolic steroid induces catch-up growth, or low-dose IM Testosterone (induces growth plus secondary sexual characteristics)

Question 71

Delayed puberty in girls

Answer 71

Delayed Puberty far less common; need to exclude organic causes o Turner’s syndrome – Karyotype to diagnose o Thyroid and Sex steroid deficiencies, Pituitary disorders o Eating disorders • Oestradiol can be used to induced puberty in girls

Question 72

Inborn Errors of Metabolism

Answer 72

Inborn Errors of Metabolism are disorders of Enzymatic reactions; They are generally separated into disorders of Intoxication, Energy Metabolism, and Complex Organelles

Question 73

Intoxication Disorders

Answer 73

Amino-acidopathies (e.g. Homocystinuria), Urea cycle disorders (e.g. Citrullinaemia), Carbohydrate disorders (e.g. Galactosaemia) and Neurotransmitter disorders (e.g. Pyridoxine-dependent seizures)

Question 74

Energy Metabolism Disorders

Answer 74

Mitochondrial (e.g. MELAS, MERRF), Fatty acid oxidation disorders (e.g. Carnitine transporter deficiency), Glycogen storage disorders (e.g. McArdle disease)

Question 75

Complex Organelles Disorders

Answer 75

Lysosomal Storage Disorders (e.g. Mucopolysaccharidosis), Peroxisomal (Zellweger syndrome)

Question 76

How do inborn errors of metabolism present?

Answer 76

Can present variably and many in early childhood; Considering in all children with unexpectedly severe presentation of otherwise common illness, significant Metabolic Acidosis, unexplained Respiratory Alkalosis, Hypoglycaemia, HF or Cardiomegaly, Hepatomegaly, Splenomegaly or Liver Dysfunction, Altered Mental Status, Early Onset Seizures, Dysmorphic features, Developmental Regression or Sudden Unexplained Death

Question 77

What is important to know in history with inborn errors or metabolism

Answer 77

* FHx is crucial; FHx of IEMs, Sudden Death, Epilepsy, Learning Disabilities, Consanguinity * IEMs are Inherited and display specific Inheritance pattern; Most commonly AR (although Mitochondrial inheritance, and de novo for few) * Infection is a common trigger for IEM presentation; Might confound Metabolic acidosis

Question 78

Investigation of Inborn Errors of Metabolism

Answer 78

• Early discussion with specialist centre is vital; If Metabolic Disease not within differential, unlikely to identify through standard investigations • First line investigations depend on suspected clinical pictures o E.g. Amino acids and acyl-carnitines for suspected Urea Cycle Disorders, Amino-acidopathies or Organic Acidaemia; Ammonia for Urea Cycle Disorders, Beutler screening test for Galactosaemia, etc

Question 79

Management of Inborn Errors of Metabolism: Medical Intervention

Answer 79

Symptom management, Specific therapies, Enzyme replacement therapy; Bone marrow transplantation for a specific few disorders

Question 80

Management of Inborn Errors of Metabolism: Dietary Manipulation

Answer 80

Supplying a deficient product, Prevention of Accumulation of toxic substrate (e.g. by dietary restrictions), Prevention of Catabolism (e.g. through replacing diet with Glucose in times of increased Catabolism) or Ketogenic Diet

Question 81

Newborn Screening

Answer 81

Aims to detect treatable conditions prior to presentation to improve outcome; Offered to newborns at day 5-7, heel-prick • Tests CF, Congenital Hypothyroidism, Haemoglobinopathies, and six IEMs (Phenylketonuria, MCAD Deficiency, Glutaric Aciduria type 1, Isovaleric Acidaemia, Homocystinuria, MSUD)

Question 82

Phenylketonuria (PKU)

Answer 82

• Decreased metabolism of Phenylalanine (Classically, Phenylalanine Hydroxylase mutation) • 1 in 10,000; Can present with Learning difficulties, Seizures and Microcephaly • Management is with Phenylalanine restricted diet o Tyrosine is conditionally essential in patients with PKU

Question 83

Medium-chain Acyl CoA Dehydrogenase (MCAD) Deficiency

Answer 83

• Impaired ability to break down Medium-chain fatty acids into Acetyl-CoA o Fatty acid oxidation is crucial for providing energy when Glucose and Glycogen stores depleted in fasting • 1 in 10,000; Can present with Rapidly Progressive Encephalopathy and Collapse after prolonged fast; Non-Ketotic hypoglycaemia • Management is avoiding fasting/hypoglycaemia, and provision of emergency regimen in times of increased catabolism

Question 84

Glutaric aciduria type 1 (GA1)

Answer 84

• Unable to break down Lysine, Hydroxylysine and Tryptophan, resulting in accumulation of intermediates (Glutaric acid, Glutaryl CoA, 3-Hydroxyglutaric acid and Glutaconic acid o Particularly damaging to Basal Ganglia and other areas of brain o Secondary Carnitine deficiency (Excessive Glutaric acid is detoxified by Carnitine) • 1 in 30,000; Macrocephaly with Encephalic crisis around 1yr resulting in Dystonic-Dyskinetic Movement disorder • Specialist Diet, Avoidance of Fasting and Daily Carnitine

Question 85

Homocystinuria

Answer 85

Cystathionine-Beta-Synthase deficiency classically (=Homocystinuria I); leading to abnormal accumulation of Homocysteine and metabolites; • 1 in 65,000 in Irish ancestry; Marfanoid appearance, Learning Disability, Lens dislocation, Osteoporosis and Thromboembolism • Management with Low Protein Diet, Pyridoxine and Folic Acid Supplementation o Homocysteinaemia associated with higher risk of cerebrovascular events (Increased carotid plaque thickness; vit B supplementation slows progression)

Question 86

- Galactosaemia

Answer 86

o This presents when lactose containing milk feeds are given with vomiting, jaundice, hepatomegaly, chronic liver disease, cataracts and developmental delay o Treatment is lactose free diet

Question 87

Glycogen storage disorders

Answer 87

Glycogen storage disorders come in nine forms, but all prevent mobilisation of glucose from glycogen o Treatment is to give frequent feeds to maintain blood glucose, this may need to be via NG. High protein may be recommended to prevent muscle wasting o Enzyme replacement is important where available