Growth & Endocrine

Growth & Endocrine Primary V Secondary 1o failure = at production site 2o failure = at controlling hormone e.g. 1o hypothyroid = problem at thyroid à high TSH e.g. 2o = deficiency in TSH Hormone Production Hypothalamus = above pituitary DRH TRH GnRH Somatostatin Dopamine Pituitary = within sella turcica = 2 lobes GH TSH ACTH LH FSH Prolactin ADH Oxytocin e.g. 1o hypoadrenalism = Addison’s e.g. 2o hypoadrenalism = pituitary problem } } } } } All pass to pituitary via portal blood system } } } } } } Anterior pituitary (adenohypophysis) - from oral ectoderm ] ] posterior pituitary = neurohypophysis – from neural ectoderm Hall-Pallister syndrome Congenital absence of pituitary Hypothalamic hamartoblastoma Polydactly Nail dysplasia, bifid epiglottis, imperforate anus and heart/lung/renal anomalies Growth Prenatal Growth rate varies little in the 1st & 2nd trimester Rate varies greatly in 3rd trimester USS @ 20/40 can give early indication of IUGR (symmetrical or head sparing) Postnatal growth Is affected by nutrition, GH, TH, Steroids & genetics Somatic Growth Head circumference – Measure of brain growth At term is ¾ of adult value Usually complete by 2 yrs AF palpable until 6m, but often patent until 18m Wt 1.1, 2.2, 3.3 kgs at 28/40, 34/40 and 40/40. 7, 10 and 12 kgs at 6, 12 and 24 months Ht 0-2yrs – independent of GH & T4. Dep. on nutrition, placental function and IGF I & II 2-12yrs – depends of GH & T4 12 yrs + final height – increase in GH stimulated by sex steroids. Fusion of epiphysis by oestrogen PEAK height velocity At birth is 18-25cm / yr During puberty – 6-11cm/y in girls, 7-13cm/y in boys Mid parental height = (mum + dad) / 2 then +/- 12.5cm XYY > XY > XX > XO Faltering Growth / Short stature Faltering growth = Failure to Thrive = below 2nd centile or fallen 2 centiles after 6 weeks Short stature = < 3rd centile (= 2 SD below mean) 7 Dwarfs Happy = Normal small Familial Short Stature Normal genetics - short parents, well child, normal bone age Constitutional delay Looks young, parents had late growth spurts, delayed bone age, late puberty Persisting IUGR Most will catch up by 2 years, but 10% remain small SGA = < 3rd centile for gestation Asymmetrical = head sparing, likely to catch up Symmetrical = remains small Causes include Fetal Alcohol syn and Russell-Silver Syn – see above Grumpy = GI (e.g. coeliac) Sneezy = Chronic illness (e.g. CF) Dopey = Syndromes (e.g. downs, turners) E.g. Downs, Turners, Noonan syndrome E.g. Fetal Alcohol Syndrome – VSD, remain short with small head, short concentration span & learning difficulties, malar hypoplasia, short palpebral fissures, short philtrum E.g. Russel Silver Syndrome (right) – triangular face, expanded skull vault (appearance of hydrocephalus), down turned mouth, clinodactyl, can have asymmetry of limbs. Sleepy = Endocrine (e.g. hypothyroid, GH deficiency, Cushing’s) Hypopituiratism Congenital GH deficiency – due to error in genes OR pituitary aplasia / hypoplasia. Can be isolated / with other deficiencies. Can cause low BMs / jaundice in neonate Acquired –due to damage from tumour, trauma, surgery or radiation Septo-optic dysplasia Midline defect – can have other midline defects e.g. cleft lip / palate Absent / partial absence of septum pellucidum Optic nerve aplasia / hypoplasia (nystagmus, decreased visual acuity) Pituitary hypoplasia / dysfunction à hypoglycaemia, hypogonadism & growth failure GH insensitivity syndrome (Laron’s syndrome) = VERY RARE Genetic defect of GH receptor High GH levels & short stature Final height = 120-130cm Skeletal Dysplasia (see rheum notes) Long bones – achondroplasia, hypochronroplasia, metaphyseal dysplasia à short limbs, normal spine Spine & long bones – spondyolmetaphyseal dysplasia à short everything Bashful Doc = Neglect (e.g. lack of / wrong food) – will catch up in new environment = Iatrogenic Investigations Routine - Fe, FBC, ESR, UE, LFT, Ca & Bone Immune – thyroid & celiac Abs Karyotype – turners, downs, Klinefelters Endocrine – TFTs, Dynamic GH secretion tests, LHRH, TRH tests X-ray – bone age, skeletal survey (if ? achondroplasia) US – renal & ovaries Echo CT/MRI brain + scan adrenals Treatment Recombiant GH treatment – only licenced for: GH deficiency, Turners, CRF, Prader Willi, IUGR Tall Stature Ht > 97% centile Normal Normal – looks normal, tall parents, normal bone age Constitutional advance – looks old, advanced bone age Obesity Overweight = BMI > 85th Centile, Obese = > 95th, Severe obese > 98th Increased calorie intake à increased height velocity Dysmorphic Kleinfelters – 47XXY Normal – tall stature Small testes Mild – moderate mental retardation Marfans – AD, mitral valve prolapsed & dilated aortic root Homocysteinuria – high myopia with lens dislocation Sotos Syndrome (right) – relatively common. Tall, macrocephaly, prominent forehead, large hands & feet, poor co-ordination, advanced bone age so end height is not too excessive Beckwith Weidemann – overgrowth (see baby check notes) Endocrine Sexual precocity, thyrotoxicosis, GH excess à gigantism (see below) Growth Hormone GHRH (hypothalamus) (decreased by somatostatin) à Ant pituitary à GH (pulsatile, mainly during sleep) à increased protein synthesis, lipolysis & glucose release and à liver à IGF1 à Skeletal growth (Stimulates prochondrocytes in germinal layer of epiphyses) Ix – difficult to measure levels (overnight fasting required but can à hypoglycaemia Can do a stimulation test - give GnRH + TRH + ACTH (should be > 20mU/l, partial insuff = 1020, severe = 5-10, total <5, If suspect excess à glucose tolerance test – should à suppression to < 5 Deficiency Congenital Breech delivery can à traction (RARE) Genetic error (malfunctioning form) Development (septo-optic dysplasia = hypothalamic hypo-pituitarism, optic nerve hypoplasia & absent septum pellucidum. Variable degree of effect based on extent of defect) Acquired Tumours e.g. craniopharyngioma (remnants of rathke’s pouch)à pressure effects – can present with low GH, DI, bitemporal field loss or hydrocephalus. Rx: shunt fb surgery & radiotherapy Can also be caused by cranial surgery / radiotherapy or Langerhans cell histiocytosis Growth Hormone resistance Receptors don’t respond – e.g. Laron Dwarfism (right - seen in African pygmies) Rx of deficiency – single nightly injection of GH Most children, even treated, don’t reach normal height (stop at 3rd centile) Can have central obesity, delayed puberty & small penis with delayed bone age Some forms are X-linked Excess Obesity Adenoma – excess GH à gigantism McCune-Albright Syn Endocrine hyperfunction e.g. gonadotropin-independent precocious puberty = due to autonomous ovarian / testicular function. Can à advanced bone age e.g. ACTH independent Cushing’s can à growth failure e.g. excess GH from somatotroph adenomas of pituitary Poly-osteolytic fibrous dysplasia à fractures Unilateral cafe-au-lait patches (right) Multiple endocrine neoplasia type I (aka Werner’s Syn) 1 in 30,000 AR Increased risk of benign & malignant tumours of glands e.g. parathyroid, pituitary & pancreas (MEN1 requires 2 of the 3) Problems include: Hyperparathyroidism = 90% (à stones, weakness & fatigue) Insulinomas = 60-70% à excess insulin àlow BMs Excess gastrin = >50% à excess acid àmultiple ulcers (atypical, often bleed / perforate / obstruct (20-60% of Zollinger-Ellison have MEN1) Pituitary tumours = 15-40%. Of which most are Prolactinomas à suppresses testosterone & causes gynaecomastia Or GH secreting à Gigantism Or ACTH secreting à Cushing’s If in pituitary can à pressure effect MEN2 – most commonly à medullary thyroid Ca & phaeochromocytoma & is due to different genes Rx: surgery f.b. radiotherapy. Octreotide = somatostatin analogue 4 main factors Food intake Signals from adipose (à increased leptin à decreased appetite) Central control Satiety signals (CCK from bowel) Causes Nutrition, hypothyroidism, Cushing’s, hypothalamus damage (tumour / irradiation), syndromes (downs, Prader-Willi) Puberty Centrally initiated by pulsatile GnRH (approx. 7-8yrs) à anterior pituitary à LH & FSH By 10-11 yrs LH pulses are sufficient to à stimulates oestrogen / testosterone production à secondary sexual characteristics Girls Oestrogen à breast & uterine enlargement with endometrial thickening Breast budding = 1st sign Periods occur around breast stage 3 Peak growth = 12 yrs = before menarche Adrenal hormones à acne, body odour, pubic & axillary hair Ovarian Physiology By 6 months have reached the max no of primordial follicles Gonadotrophin à 10 – 20 follicles develop FSH à androstenedione into theca cells à granulose cells à oestradiol (by aromatase) Ovulation triggered by LH surge = end of 1st meiotic phase 2nd phase ends just before fertilisation Oestrogens Low doses stimulate growth In large doses inhibits growth & fuses epiphyses Girls Boys – growth, breasts, hair, menarche – testicular enlargement, hair, growth, strength Boys 9-13 (menarche 11-13) 9-14yrs Testosterone à enlarges testes 1st sign = enlarging testes Peak height velocity = mid puberty (approx. 14 yrs) Adrenal hormones à acne, body odour, pubic & axillary hair Testicular physiology Seminiferous tubules = germ cells (haploid & diploid cells) & sertoli cells (have paracrine action of germ cells and secrete inhibin B à inhibits FSH) Interstitial tissue = leydig cells à secrete testosterone Testosterone Anabolic = promotes growth Gives boys pre-pubertal growth spurt In large doses advances bone age and closes epiphyses Spermatogenesis from 11y but not adult numbers & morphology until 17y Boys end up taller because pubertal growth spurt is 2 yrs later, more intense spurt & slightly taller to start with Bone age – L wrist XR, based on ossification of carpals Tanners Staging G1 – testes < 4mls, pre-pubertal = approx 11 yrs G2 – testes 4+ mls, penis pre-pubertal, laxity of scrotal skin G3 – enlarging penis = approx 14 yrs (+ growth spurt) G4 – testes > 12 mls, further penile lengthening & widening G5 – adult development, 15-25mls B1 – no breast tissue B2 – budding = 11 yrs B3 – mound = 12 yrs B4 – projection of areolus = menarche B5 – adult P1 – none P2 – wispy, fine P3 – adult type, limited to symphysis & labia P4 – near adult P5 – adult, extension to thighs & lower abdo Gynaecomastia XXY Drugs (e.g. digoxin, spironolactone, anti-prostate) Liver disease Teratoma Puberty (40%) A1 – none (axilliary hair) A2 – some A3 – adult Precocious / Early Puberty g x5 more common than boys Girls – < 10 yrs. common esp if FH, investigate if <6yrs or neuro symptoms Boys - < 11 yrs. <9yrs is always pathological, check for adrenal, intracranial or gonad tumour O/E – advanced bone age & height Optic nerve atrophy (pressure from pituitary lesion) Cafe-au-lait spots (neurofibromatosis + McCune Albright syn) Hx - Review for hydrocephalus, head trauma, CP or meningitis True Precocity (Gonadotropin dependent) Idiopathic – common in girls, rare in boys <8yrs girls = usually idiopathic , < 9yrs boys = usually pathological (à full Ix) Causes Hypothalamus tumour CNS disorder (CP, hydrocephalus) Low dose cranial radiation (e.g. leukaemia) cranial radiotherapy affects HPA axis, à early puberty, GH deficiency à short once grown Rapid growth & skeletal maturation LH/FSH/Oestrogen & Testosterone all raised Pseudopuberty: outside of hypothalamic/pituitary control Normal gonadotrophin levels Causes – tumour (adrenals/gonads), CAH, hypothyroid, McCune-Albright Syndrome (usually girls, often 2o to ovarian cysts, bony dysplasia on XR, patchy hyperpigmentation) Premature Thelarche Breast only (US = ovarian maturation but small uterus), usually self-limiting & non pathological Benign transient condition with isolated breast development occurs in 1st 2 years of life Can be unilateral / symmetrical Regresses after 2 years (can persist 3-5 years) Check bone age but no other Ix usually required Follow up regularly to ensure not precocious puberty Premature adrenarche / pubarche ↑ adrenal androgen (6-8yrs) à growth spurt, adrenarche = hair everywhere, pubarche = pubic hair only, can also à advancement of bone age. Most likely in IUGR children RX: GnRH analoges à down regulation of gonadotrophins à delay full puberty (e.g. goserelin = Zoladex) Delayed Puberty Absence of early stages by 13 (F), or 14 (M – most likely constitutional delay) or failure to complete within 4-5 yrs Ask ages of parent’s puberty (constitutional delay of growth & puberty - CDGP) Low gonadotropin (low LH / FSH) • Constitutional – familial / sporadic • Systemic – CF, severe asthma, crohns, excess exercise • Hypothalamic / pituitary disorders o Acquired hypothyroidism o Panhypopituitarism o Isolated gonadotropin / GH deficiency o Intracranial tumour (e.g. craniopharyngioma) o Kallman’s syndrome (+anosmia) Midline defects (e.g. cleft palate) Congenital deafness Anosmia (can also have colour blindness) Icthyosis Pubertal delay (due to hypogonadotropic hypogonadism) Increased gonadotrophin (high LH / FSH) • Gonadal dysgenesis (Chromosomal) – Klienfelters, Turners o Klienfelters (Hypergonadotrophic hypogonadism) Most common male hypogonadism High LH & FSH, Low Testosterone 1/300 – 1/1000 Usually XXY 1st sign may be delayed puberty At puberty pubic hair may be normal but small testes Often tall with gynaecomastia Infertile o Turners 1/2500 live births Can have mosaic (45X/46XY or 45x/47XXX) Short stature – increased carrying angle, hypertelorism, low set eats & low posterior hair line. Multiple naevi, lymphoedema, dysplastic nails, broad chest, inverted nipples, webbed neck, high arched palate Gonadal dysgenesis Assoc with – HTN, horse-shoe kidney, Coarctation, recurrent ear infections, autoimmune thyroiditis GH improves final height Oestrogen will help initiate puberty If Y chromosome then need gonadectomy as risk of blastomas • Steroid hormone enzyme deficiency • Acquired gonadal disease e.g. post surgery, chemo / radiotherapy, trauma, torsion, autoimmune Amennorrhoea 1o – anatomical absence, turners, androgen insensitivity (XY females) 2o – anorexia, systemic disease, pregnancy Sexual differentiation Gonads develop from 5/40 Y à testis à testosterone + anti-mullerian hormone à wolfian ducts à epididymis, vas and seminal vesicles Without Y à ovary à wolfian involutes & mullerian system develops à fallopian tubes, uterus & upper 1/3 of vagina & urogenital sinus à lower 2/3 vagina & urethra Androgen Insensitivity Syndromes Failure of cells to respond to androgens (testosterone) Prevents masculinisation of males But not effect on development of females Generally XL Recessive with 30% spontaneous mutations (can be the result of parental germ cell mosaicism) Gonads are ALWAYS male Divided into 3 categories Complete androgen insensitivity – externally female XY, functioning testes, absent external genitalia Short vagina, absent uterus & fallopian ducts Breast development occurs due to testosterone (which is peripherally converted to oestrogen) Can present with lump in groin (testis) or primary amenorrhoea, or absent pubic hair Partial Androgen insensitivity – ambiguous XY with micropenis, hypospadia & bifid scrotum Difficult to decide if to raise as male or female as response to testosterone at puberty is difficult to predict Mild androgen insensitivity – externally male Testosterone insensitivity doesn’t impair physical early development But is sufficient to prevent 2o sexual characteristics (pubic hair etc) & prevents spermatogenesis Can be assoc with hypospadia, infertility, decreased testicular volumes Usually undiagnosed until problems with fertility Masculinised Females Usually due to excess androgens from CAH (see later) Hermaphrodites Usually 46XX (can be mosaic with 46XY) Have BOTH ovarian & testicular tissue (primordial follicles + seminiferous tubules) PCOS Obesity & Hirsuitism 2o amenorrhoea Bilateral enlarged polycystic ovaries Increased LH:FSH ratio with abnormal high levels of morning LH & exaggerated response to GnRH 10% have markedly raised prolactin (less than 1000) NORMAL oestrodiol Assoc with insulin resistance & acanthosis nigricans Hirsuitism PCOS à Raised LH/FSH, Normal Oestrodiol Minoxidil treatment Increased testosterone (à low LH & FSH à Low Oestrodiol) Can be assoc with early use of valproate Adrenal Axis Inner medulla = 10% From neural crest (ectoderm) Makes catecholamines Outer Cortex = 90% Formed from mesoderm of urogenital ridge Makes steroid hormones = 90% of gland Split into 3 sections Zona glomerulosa = outer Controlled by RAA system à aldosterone Zona fasiculata = middle Controlled by HPA à CRH à ACTH à Cortisol Zone reticularis = inner Inactive until puberty à androgens Mineralocorticoids (mainly aldosterone) Aldosterone increases Na+ reabsorption in the distal tubule (Na+/K+ transport channel) à Na+ reabsorption at cost of K+ loss Deficiency à low Na, high K = fluid loss = low BP à high Renin Excess à HTN, low K, low Renin Glucocorticoid (cortisol) Cortisol (iatrogenic) Large dose à inhibits growth à decreased GH & IGF1 à slows bone maturation à osteoporosis Fasting and sleeping cortisol (loss of diurnal rhythm) Urine free cortisol, 24 hr collection If excess cortisol à dexamethasone suppression test If low cortisol à raised ACTH = 1o, low = 2o à synacthen test Adrenal insufficiency Primary Adrenal Insufficiency Sx of weakness, N&V, abdo pain, hypotension & fever Ix of low Na, high K, acidosis & low BM (due to low cortisol) Adrenal hypoplasia congenita X-linked, Dax 1 gene Presentation similar to CAH but low/normal levels of 17 OHP History of early deaths in male infants on maternal side à Salt wasting, dehydration, FTT, low Na, low Glucose, Increased pigmentation (increased ACTH) Little response to standard dose synacthen test (minimal adrenal tissue) Low cortisol levels NOT virilising Rx – same as CAH Familial glucocorticoid deficiency (AR) No response from cortex in response to ACTH but NOT salt wasting as reninangiotensin-aldosterone system unaffected Congenital Adrenal Hyperplasia (AR, Chr 6) 1/10,000 Decreased cortisol à increased ACTH à Hyperplasia of adrenals à overproduction of intermediate metabolites (androgenic steroids) & deceased gluco- and mineralocorticoids AR inheritance 21-hydroxylase deficiency = most common = 95% 1/15,000 = AR Chr 6 Approx ½ are salt loosers and half not Tends to be Female à virilised / ambiguous genitalia, Males à salt losers/adrenal crisis Females with less severe forms of 21-hydroxylase def identified later in childhood due to precocious pubic hair / clitoromegally. Often also oligomenorrhoea, hirsuitism or infertility due to excess androgen. Low Na & High K 11-beta-hydroxylase = next most common increased incidence in jews of north African origin (Israel) NON-salt loosing Other types inc 3-beta-hydroxysteroid dehydrogenase à slight virilsation in girls & undervirilsed boys with hypospadias Lipoid adrenal hyperplasia à accumulation of cholesterol & lipds within adrenal cortex & failure of any steroid production à externally normal females and phenotypically female boys AND salt losing 17 hydroxylase deficiency à hypokalaemic alkalosis and hypertension. Boys with ambigious genetalia and girls fail to develop 2o sex characteristics If untreated can à infertility due to increased androgens Salt loosing –70-80% - more common in males. Due to effect of excessive aldosterone on renal tubes Hyponatraemia with high K in 2nd weeks of life Vomiting, poor feeding & shock à increased renin Increased scrotal pigmentation (excess ACTH), low Na, high K (due to low aldosterone), acidosis & low glucose Untreated have high mortality. Virilising – 20-30% most easily recognised in male infants as hypertrophic, pigmented genitalia. In girls can be missed àenlarged clitoris, narrowed vagina, urogenital sinus, fusion of labia. If very severe appear as boy with un-descended testes & hypospadias. Prove with karyotype If missed then as child ages à increasing virilisation due to increased androgens with pubic hair etc AND advanced bone age à decreased adult height Investigations Day 1 of age - karyotype & USS Day 3 onwards = Low Na, High K, Low aldosterone Low BM due to low cortisol Buccal smear chromatin +ve à increased risk of salt loosing crisis GOLD STANDARD = Raised 17-alpha-hydroxyprogesterone Monitor response to treatment with 17-OH progesterone & androstendione levels Rx : Emergency - IV saline, glucose and glucocorticoid à suppression of ACTH. Long term - Mineralocorticoid to replace aldosterone. Females may require vaginoplasty. Prenatal treatment – if antenatally diagnosed. Give mum dexamethasone from 10 weeks to inhibit ACTH à reduces virilisation of females Long term problems – short stature, virilisation, precocious puberty, subfertility (increased risk of all if decreased compliance) ** antenatal diagnosis possible à give dexamethasone in future pregnancy to reduce virilisation Acquired adrenal insufficiency Addison’s No cortisol = can’t respond to stress No aldosterone = Na+ not reabsorbed in distal tubule à high K+ & high H+ (metabolic acidosis due to K+/H+ co-transport), Low Na+, fluid loss in urine Causes – autoimmune (assoc. with hashimoto’s and DM), TB, drugs (metyrapone), Xlinked adrenolecodystrophy. APECED – Autoimmune polyendocrinopathy with cutaneous ectodermal dysplasia = Ch21 – Addison’s + hypoparathyroid + mucocutaenous candidasis Sx – initial lethargy, increased illness frequency with slow recovery, pigmentation to scars, skin creases and buccal mucosa (ACTH). Wt loss, Late sign is vomiting from low aldosterone Addisonian crisis Low BP, circulatory collapse, coma, Hyponatraemic dehydration with high K+ & low BM, Metabolic acidosis, low bicarb, High urea, Low Chloride Normochromic, normocytic anaemia with neutropenia, eosinophilia & lymphocytosis 10-20% will have high Ca2+ Diagnosis – high ACTH & renin Low Na, low Cl, high K, low cortisol Rx: urgent IV glucose, saline & hydrocortisone 2o and 3o adrenal insufficiency Idiopathic congenital panhypopituitarism Septo-optic dysplasia Secondary to stopping low term steroids Adrenal Excess Excess mineralocortiocoid is rare in children Would be Conn’s Syndrome = 1o hyperaldosteronism due to adenoma Excess glucocorticoid = CUSHINGS 1o Cushing’s = Cushing’s disease = ACTH secreting pituitary adenoma Cushing’s syndrome = more common = due to steroid use / adrenal adenoma NB: exogenous obesity à increased growth. Normal height unlikely in Cushing’s Most commonly seen in Rheum/Resp/Renal clinics due to patients on high dose steroid treatments Increased cortisol at night with loss of diurnal variation. F:M = 3:1 Causes Adrenal cortex tumour – usually malignancy, 85% in under 7s 1o pigmented nodular adrenocorticoid disease ACTH independent (due to circulating Ig to ACTH receptor) Occurs as part of Carnii complex (AD inheritance) or McCune Albright (see earlier) Bilateral Adrenal Hyperplasia e.g. due to tumour Ectopic ACTH e.g. Islet cell Tumour, neuroblastoma etc Sx - Obesity, moon face, buffalo hump, truncal obesity with thin arms, hirsuitism, acne, short stature, muscle wasting, bruising, striae, osteoporosis, mood change Ix – high dose dexamethasone suppression test à decrease cortisol if from pituitary, but not if adrenal / ectopic ACTH production Iatrogenic Cushing’s – eczema / asthma treatment Excess androgen = virilisation Before Rx After Rx Anabolic steroid abuse Paranoid delusions & aggression Acne Gynaecomastia with increased breast cancer risk HTN & raised cholesterol Hepatic tumours Posterior Pituitary Diabetes Insipidus Arginine Vasopressin = ADH, Acts on tubule à water retention, Released in response to low volume or high osmolarity Deficiency / affected receptors à DI Sx – polydipsia, polyuria, Causes – tumour, AD mutations in ADH gene, langerhans cell histiocytosis, trauma (inc neurosurgery) Ix – Normal – High Na Water deprivation test Normal à Final urine osmo > 6-800mOsmo/kg AND response to DDAVP >6-800 AND high final plasma ADH level Cranial DI à Final urine osmo <300 BUT response to DDAVP >600 AND Low plasma ADH Nephrogenic DI à Final urine osmo <300 AND no response to DDAVP AND High plasma ADH Rx cranial – oral / intranasal DDAVP Rx renal – indomethacin. Usually XL/AR SiADH Causes Cranial – surgery / trauma, encephalitis / abscess / meningitis, tumour, GuillaineBarre, bulbar poliomyelitis, CVA, subdural, tumours of 4th ventricle, neonatal hypoxia, hydrocephalus Pulmonary – pneumonia, TB, tumour, asthma Excess ADH à retention of water à LOW serum sodium (dilutional hyponatraemia) – can à cerebral oedema, convulsions etc LOW plasma osmolarity (<270) HIGH urine sodium (>20) High urine osmolarity (>300) as excess concentrating LOW Renin, Angiotensin, Aldosterone Rx – e.g. fluid restriction. Can consider demeclocycline to reduce SiADH sensitivity at renal tubule AND seek cause Hyperprolactinaemia Caused by proloactinoma & hypothyroid (increased TRH) Assoc. with galactorrhoea & amenorrhoea Also if non-functional tumour with stalk compression e.g. craniopharyngioma Can be due to drugs such as fluoxetine, chlorpromazine, haloperidol & domperidone (dopamine antagonists) Rx with bromocriptine / cabergoline / surgery (if resistant to drug therapy Assoc. with acromegaly & PCOS Pregnancy Raised Prolactin (>1000) and Oestrogen at 12/40 Anorexia Low BMI, increased exercise Amenorrhoea (hypogonadotrophic hypogonadism) Mildly raised prolactin PCOS 10% get mildly raised prolactin Satiety System Satiety - Leptin from adipose binds to hypothalamus à inhibits secretion of neuropeptide Y à satiety Hyperphagia - à overeating à obesity à hyperinsulinaemia with acanthosis nigricans à DMII Prader-Willi Syndrome Loss of paternal genes at 11-13q of Ch15 (or maternal disomy) Loss of proteins à hypothalamic dysfunction à hyperphagia, hypogonadism, temper tantrums, hypotonia, learning disability (IQ approx 70) Presentation – decreased fetal movements, floppy baby with poor suck, delay in gross motor milestones, hyperphagia starts approx 2-3 yrs, moderate short stature (low GH) Males - bilateral cryptorchidism with absent or incomplete puberty Females – delayed but complete development but oliogomenorrhoea Rx – diet, physio, SALT, GH to increase height, testosterone for males NB: increased risk of sleep apnoea, respiratory failure and DM II Thyroid Hormone Thyroid develops from buccal endoderm (d16-17) & 4th pharyngeal pouches Descends into neck by day 50 Accumulates iodine from 10-12/40 Failed development can be hypoplasia or mal-descent (along throglossal tract). Fetus depends on maternal T4 until wk 10, then starts making own. Low I2 or T4 à delayed neuronal development Minimal transplacental T3 / T4 Stimulates synthesis & secretion of GH TRH(from hypothalamus) à TSH (from ant pit) à T3/T4 (thyroid) Carried bound to thyroid binding globulin Hypothyroid Primary Hypothryoid = High TSH in compensation, 2o will have low levels Assoc with macrocytic anaemia, alopecia, Addison’s (autoimmune) & effusions (e.g. pericardial) Neonatal hypothyroid – low levels during neonatal illness = cause for 10-20% of +ve screening tests Congenital hypothyroidism 1/ 35-40,000 Causes 1o (affecting thyroid gland) = 90% Dysgenesis 75% = Ectopic 30%, Absent 30%, Hypoplastic 15% Dyshormonogenesis = 20% - multiple causes, assoc with goitre at birth. AR inheritance Isoimmune 5% = transplacental Ab can be temporary or permanent 2o = pituitary / hypothalamus = 10% Incidence 1/3-4000 births (less common in black infants 1/30,000) Sporadic (not familial), can à mental handicap Presents on Guthrie (raised TSH detected) or with prolonged jaundice NB: guthrie wont detect 2o causes (i.e. due to pituitary / hypothalamus failure & deficiency of thyroid-binding globulin) Test has high sensitivity & specificity and cost effective treatment is available Clinical features None at birth à Coarse facies, large tongue, hoarse cry, umbilical hernia, dry skin, hypothermia, lethargy, prolonged jaundice Transient +ve screen but no treatment required e.g. maternal hypothyroid, anti-thyroid drugs / Ab, I2 containing antiseptics used on baby Investigations TSH on Guthrie = screening T4 & TSH (low T4, raised TSH) Ab for mum & baby Radioisotope scan to detect ectopic / hypoplasia US thyroid Xray for bone age (delayed if low) Enzyme assays for metabolic screen Treatment Rx by 2/52 to prevent development delay L-thyroxine 7-10microg/kg/day Lifelong treatment Need increased doses in infancy and puberty Prognosis Good prognosis if diagnosed early Depends on treatment delay If treated by 3m = 75% have IQ > 90 If no treatment at 6m = 50% have IQ < 90 Acquired (autoimmune / hashimoto’s) Worldwide most common cause is iodine deficiency UK most common cause is autoimmune (hashimoto’s) More common in girls & usually presents in teens (but can be any age) Often +ve FH of autoimmune conditions (DM etc.) Goitre, pallor, tired, cold etc Also menorrhagia, ataxia, “peaches & cream” appearance to skin due to hyperbetacarotinaemia +ve TPO Ab, Rx with replacement Rx – thyroxine Endemic goitre I2 deficiency, à cretinism, deaf-mutism, myxoedema, dwarfism Rx depot I2 in pregnancy Goitrous Hypothyroidism Inborn error of thyroid metabolism, presents in childhood with goitre Juvenile hypothyroidism Autoimmune, usually F>M S&S: goitre, FTT, bone age delay, lethargy, constipation, can à epiphyseal dysgenesis à slipped femoral epiphysis. Usually no effect on intelligence as brain already developed Rx: thyroxine Hyperthyroidism F>M at all ages delayed sexual maturation & accelerated skeletal growth Should have decreased TSH Neonatal thyrotoxicosis Occurs in 1-10% of mothers with graves TSH receptor Ab of graves cross placenta Self-limiting as Ab clear (by 3/12) Resolves by 2-5 months Features - fetal ↑HR (by 48 hours, can à cardiac failure), irritability, fever, diarrhoea, poor weight gain, small baby with small goitre at birth. Rx: usually transient, Treat HR with propranolol. if required give iodine & carbimazole Paediatric Graves >90% of hyperthyroidism in children Genetic link = Familial G:b = 7:1 Can occur at any age but teens most common Rarer but more severe than adult form. Insidious onset TSH receptor antibodies à High T3 & T4 with low TSH Sx – diffusely enlarged thyroid with bruits & raised HR, opthalmopathy, moist hands & fine tremor, restless, heat intolerance, anxiety and palpitations, wt loss despite increased appetite, poor school performance, menstrual irregularity, rapid growth Rx – Carbimazole / propylthiouracil for 2-3 yrs (NB can à marrow suppression). High relapse rate Iodine ablation - ? increased malignancy risk = permanent therefore lifelong thyroxine required Surgery – risk to recurrent laryngeal nerve. Total thyroidectomy = risk of hypoparathyroidism Rx propranolol Hashimoto’s 5% have hyperthyroid phase Drug induced Amiodarone is thyroid analogue Juvenile hyperthyroidism Excess growth, abnormal chorieform movements, manage with carbimazole (50% will relapse within 2yrs of stopping treatment) Anti-thyroid treatments Carbamazepine & propylthiouracil à inhibit iodination of tyrosine à block T3 & T4 production in thyroid cells Steroids & PTU block peripheral T4 à T3 B-blockers don’t act on thyroid – but counteract excess catecholamines Radio-Iodine à beta radiation Goitres Simple colloid – pubertal – usually euthyroid Hashimoto’s – low T4 Graves – high T4 Viral thyroiditis Congenital (dyshormonogenesis) Calcium Regulation Calcium Normal serum Ca = 2.2 – 2.6 Most of Ca = in bone When in blood = ionised (=active) / bound to albumin / citrate complex Vital to nerve conduction & muscle contractility AND blood clotting ½ is ionised & ½ protein bound. Ionised is more physiologically active Fetal Ca levels are higher than maternal, then drop to minimum at 18-24 hours (due to calcitonin) Fall à parathormone à bone reabsorption à increase serum Ca Parathyroid hormone Parathyroid glands form from 3rd & 4th branchial pouches à behind thyroid Secreted from parathyroid glands in response to low Ca Causes increased Ca & decreased PO4 By increasing reabsorption from bone & increasing tubular reabsorption of Ca in kidney (with decreased PO4 reabsorption) & stimulating Vit D production Vitamin D From diet / sunlight Requires skin, liver & renal metabolism Metabolised in liver à 25 hydroxy Vit D Hydroxylated in kidneys à 1,25 dihydroxy Vit D Acts on intestinal epithelium à increases calcium absorption & PO4 absorption, increases skeletal mineralisation & increased bone formation Calcitonin Peptide hormone produced by parafolicular C cells of thyroid Secreted in response to high ionised Ca à reduced Ca & PO4 Acts by inhibiting osteoclasts à decreased reabsorption Hypocalcaemia Neonatal Hypocalcaemia Serum Ca < 1.8mmol/L Ionised fraction is regulator of symptoms (obtain from gas machine) Acidosis à causes ionisation of more Ca (alkalosis à decreased ionisation) Early neonatal hypocalaemia (<72hrs) Risk factors – prem, RDS, birth asphyxia, IDM, neonatal sepsis If persistent then due to hypoparathyroidism (XL or AR) OR Di-George Syn Hypocalcaemia is assoc. with Hyperphosphataemia & needs Vit D Late neonatal hypocalcaemia (aka neonatal tetany) Occurs after a few weeks Now rare (due to giving infants unmodified cows milk) Rarely due to maternal hyperparathyroidism à fetal high Ca à suppression of PTH à latent low Ca Causes – prem, maternal vitamin D def, maternal hyperparathyroidism, low Mg, increased PO4 in milk, congenital hypoparathyroidism Clinical features – (low ionised) Irritability, tremors, jittery, convulsions Diagnosis – lab levels, ECG à prolonged QTC Management If asymptomatic à oral supplements If symptomatic à calcium gluconate IV May need vitamin D supplements Prognosis – most recover completely Childhood hypocalcaemia Serum Ca < 2.2 (sx at <2.0) Causes – vit D deficiency, hypoparathyroidism, renal disease Sx – paraesthesia in mouth & hands, muscle cramps, carpo-pedal spasm, mood changes, diarrhoea, convulsions Signs – dry skin, coarse hair, brittle nails, enamel hypoplasia of teeth Tapping over facial nerve à facial twitch (Chovstek sign) Inflation of BP cuff à wrist & finger flexion (Trousseau sign) Ix – Bone profile + Mg & vit D levels Hypoparathyroidism è low Ca Sx – headaches, vomiting, photophobia, cataracts, poor dental enamel, diarrhoea Ix – low Ca, high PO4, low PTH Congenital – aplasia of glands = 22q11 Acquired – isolated / assoc. with other autoimmune / surgical Transient Hypoparathyroidism Usually in prems / sick newborns, ↓Ca à convulsions / apnoea Hypoparathyroidism Low PTH & Low Ca, can occur in isolation or with Di-George syn (CATCH22) Assoc with Addison’s, DM & hypothyroidism & short 4th& 5th MCs Pseudohypoparathyroidism Low Ca, high PO4 à should cause low PTH but in pseudo à high PTH levels due to insensitivity (receptor error) AD Short stature, stocky, obese with round face Dev delay Dental hypoplasia Brachymetacarpals/tarsals Soft tissue calcification Assoc with SUFE Rx Iv Ca infusion Supraphysiological doses of Vit D analogues à promote Ca absorption, and mobilise bone Ca Titrate dose to maintain low-normal Ca2+ PseudoPseudoHypoparathyroidism Phenotypic appearance of pseudohypoparathyroidism but normal biochemically Rickets Defect in mineralisation of osteoid tissue More common if prolonged breast feeding / certain ethnic groups – therefore if high risk à supplement Vit D Also give supplements to pregnant women – especially Asians Most commonly due to Vit D Def – inadequate sunlight, dietary insufficiency, malabsorption (fat soluble e.g. coeliac/CF), liver/kidney disease Features Craniotabes – soft skull with delayed closure of fontanelles & sutures Rachitic rosary – enlarged costochondral junctions Delayed dentition Bowing of the legs (if wt bearing) Tetany (teens) Ix High ALP & PTH Low Ca, PO4 & Vit D X-rays – widened growth plates with cupping/splaying of metaphysis Hypercalcaemia Neonatal hypercalcaemia Serum Ca > 2.75mmol/L Often iatrogenic due to use of calcium gluconate Rare causes inc renal failure, SIADH, Vit D overdose & Williams Syndrome (elfin facies, supra-valvular aortic stenosis) Childhood Hypercalcaemia >2.65mmol/L Anorexia, polyuria, polydipsia, mood change, abdo pain & constipation Rx – low Ca diet Glucose Regulation Before birth - fetus has continual supply via placenta. Mum BM = Baby BM At birth – supply is cut à transient hypoglycaemia due to excess fetal insulin taking time to adapt Glycogen Glycogen production and glycogenolysis occur in liver and muscles. Glucose can’t be produced if no glycogen stores Gluconeogenesis Using amino acids (esp alanine) also lactate, pyruvate and glycerol Lipolysis Glycerol metabolised from adipose à gluconeogenesis Fatty acids & triglycerides à ketone bodies (used directly by brain) Endocrine pancreas = 70% Beta cells à insulin others are alpha cells à glucagon Delta à somatostatin & PP-cells à pancreatic polypeptide Insulin = anabolic hormone from B cells of islets of Langerhans Insulin à lowers blood sugar, converts glucose à glycogen and inhibits breakdown on glycogen, protein and fat Neonatal Hypoglycaemia Because babies often use alternative energy substrate (e.g. ketones) it is difficult to rely on lab sugars Generally <2.6 = requires treatment Risk factors Infants of diabetic mothers Worse if maternal vascular disease (à HTN & poor placenta) or poor glycaemic control (aim to keep BM < 8 at all times) Complications include Congenital malformations – CHD (VSD / TGA / Coarc), renal vein thrombosis, sacral / coccygeal agenesis, left microcolon or hypertrophic cardiomyopathy Stilbirth (increased risk) SGA if vascular disease Macrosomia (if hyperinsulinaemia infant). Increased length & wt but normal head. Plethoric, obese & cushingoid with organomegally à increased risk of birth trauma & asphyxia Neonatal hypoglycaemia – can be transient or prolonged Increased risk of RDS Growth restricted Prems Birth asphyxia Rewarming after hypothermia Infection Polycythaemia Beckwith-Weidemann (1/3 will get low BMs) Congenital hyperinsulinism B cells upregulat insulin secretion Consider if requiring > 15% & high insulin from lab Symptoms Major – apnoea, convulsion, coma, PPHTN Minor – jitteriness, irritability, tremors, apathy, cyanotic spells, temperature instability Causes Decreased substrate – SGA, Prems Increased requirement – hyperinsulinism, polycythaemia Inability to utilise glucose – storage disorders, galactosaemia, fructose intolerance, inborn errors of amino acid metabolism Iatrogenic – inappropriate IVI Misc – birth asphyxia, other endocrine problems, hypopituitarism Management Bolus 100mg/kg over 10mins (= 1ml/kg of 10% dextrose) Followed by infusion of 10% May need 12.5% or 15% via central access If resistant then try hydrocortisone, glucagon (if adequate stores), diazoxide, somatostatin or in extreme cases subtotal pancreatectomy Investigations Serum insulin Screen for causes e.g. metabolic errors Prognosis If severe symptomatic then ½ will die & ½ survivors will have neurodevelopmental problems General hypoglycaemia BM < 2.6 Sx – jittery, fits, neurodevelopmental delay, cognitive defects Causes – (in non diabetics) Hyperinsulinism Persisting hyperinsulinism of infancy (neisidioblastosis) Beckwith-Wiedermann Syndrome Insulinoma – collapse preceded by raise in adrenalin, prevented by increased carbs, assoc. with increased wt. Hormone deficiency – isolated/combined ACTH or Cortisol deficiency Metabolic – glycogen storage disorders, fatty acid oxidation defects (MCADD) Misc – aspirin, liver failure, Reyes syndrome Metabolic Hormonal • • • • Ketotic hypoglycaemia Liver disease – e.g. Reyes Inborn errors of metabolism e.g. MCAD, Organicacidaemia, tyrosinaemia Poisoning – alcohol, aspirin • Growth hormone • • Decreased ACTH (panyhypopituitarism) à Cortisol (addisons, CAH) Hyperinsulinaemia – e.g. neisidioblastosis, Beckwith-Weiderman, Insulinoma, Exogenous (Overdose / Munchausens) Ketotic Hypoglycaemia Usually presents between 18m & 5y Improved spontaneously by 9y Low BMs with illness / starvation à ketones in blood & urine Tend to be small children with limited reserves Low insulin levels & low alanine levels (major gluconeogenic precursors) Beckwith Wiedermann Syndrome Classical features (don’t always have them all) Macroglossia Macrosomia (>90th centile) Midline abdominal wall defects Ear creases / pits Neonatal hypoglycaemia – beta-cell hyperplasia(1/3 of cases) Other features Naevus flammeus Prominent occiput Midface hypoplasia Hemihypertrophy Enlarged kidneys Cardiac & MSK anomalies Hearing loss Increased risk of cancer = approx 10% by age 4 years, then tails off. (esp. Wilms & hepatoblastoma) Investigations – to be taken BEFORE treatment Lactate, ammonia Insulin & C-peptide GH, Cortisol FFA:B hydroxybutyrate ratio Organic acids & acylcarnitines Hyperglycaemia Neonatal Hyperglycaemia BM > 9, not usually problem unless glycosuria Common if getting 10% dextrose / TPN ALWAYS consider sepsis as a cause If insulin is required = 0.1U/kg IV Glucose intolerance Assoc with Ataxia telangectasia Werner & cockayne syndromes Prader-willi syndrome (insulin resistance) Familial hypertriglycerideaemia / hyperlipidaemia Diabetes Mellitus Hyperglycaemia Glycosuria + osmotic diuresis à increased thirst + dehydration Wt loss secondary to uninhibited breakdown of fat à ketones à N&V à further dehydration = DKA Types of DM I. B cell destruction à insulin deficiency. Either immune / idiopathic II. Insulin resistance Increasing with childhood obesity High prevalence in native Americans & Hispanics III. Genetic defect of insulin or of B cell function • Mature onset DM of young = MODY) o AD with high penetrance – due to glucokinase / hepatocyte nuclear factor mutations o Strong FH of early onset (<25yrs) o Rare – only 1-2% of childhood DM o Mild presentation, Insidious onset • Treatable without insulin for 5+ yrs • No islet cell antibodies • Not HLA DR3/DR4 linked • Not prone to episodes of ketosis • exocrine problem (CF DM = 3b) o Due to CF/pancreatectomy/trauma/haemochromatosis • endocrinopathy (cushings) • drug induced (steroids) • infection (congenital rubella) • genetic syndromes (Prader Willi) • DIDMOAD (Wolfram Syndrome) o Diabetes insipidus (2nd decade) o Diabetes Mellitus (1st decade) o Optic Atrophy (1st decade) o Deafness (2nd decade) - sensorienural o Mitochondrial dysfunction o Usually AR inheritance o Dilated renal outflow tracts in 3rd decade o Assoc with neurology & psych problems in 4th decade o Death usually in 4th decade from resp failure due to brainstem atrophy IV. Gestational DM Type 1 diabetes T cell mediated B cell destruction due to environmental triggers in a susceptible individual presentation usually 10-14 yrs (when B cell function = 10-20%) Usually HLA DR3/4 (95% will have one or both, but having both doesn’t mean you’ll get DM) Virus e.g. coxsackie/rubella à modifies immune system Autoantibodies often +ve at diagnosis Can have honeymoon remission period where insulin is not required. Sub-acute Presentation Majority of cases present before decompensation with polyuria, polydipsia & wt loss. Demonstrate glycosuria +/- ketonuria + hyperglycaemia 85-90% have antibodies at presentation Ketoacidosis presentation Delay à prolonger hyperglycaemia à “paralyses” remaining B cells à complete insulin deficiency à ketones à abdo pain with rigidity of wall, vomiting and dehydration. Polyuria continues despite shock. Kussmaul breathing to blow off CO2 from acidosis Rx: Fluid bolus to correct shock (0.9% saline) Fluid replacement (IV maintainence – with K+ regardless of level as will drop) IV insulin – to start 1 hour AFTER fluids If delayed rx à cerebral oedema à death. Subcut insulin once stable with 30 minute overlap Non-ketototic hyperglycaemia Is usually asymptomatic Can be due to untreated hypo à regulatory hormones (e.g. catecholamines & GH) Assoc with furuncles Somogyi Phenomenon Hypoglycaemia followed by hyperglycaemia due to stress response Seen in those with difficult control High cortisol at start of Synacthen test Glycaemic control will improve with reduced dose of insulin Type 2 diabetes Insulin resistance and B cell secretory failure Increases with obesity and often strong FH Increased in girls & Asian/Arabic ppn Diagnosis Fasting BM > 7 OR 2hrs post GTT BM > 11.1 +/- typical history Treatment Initial insulin at 0.5-0.7 units/kg Vary site to avoid lipohypertrophy (à poor control with unpredictable absorption & unsightly skin changes) Remission – Sx usually when 90% + are destroyed Insulin regimes INCLUDE checking BMs min 4x per day – ideally 6-8 BD insulin Twice daily mixtard (30% short, 70% long acting) Pre breakfast (2/3 of daily total) & pre dinner (1/3) à Poor postprandial control with hyperglycaemia pre breakfast (worsened by am cortisol surge) & mid-morning snack needed to avoid hypo Multiple daily injections (basal-bolus) Long acting (glargine / levemir) OD at night + boluses (novorapid) for meals based on carb-counting New DM = ½ unit / kg / d } ½ basal Established child = 1unit / kg / d } & Established teen = 2unit / kg / d } ½ meals Insulin pump Only for those with good compliance and willing to do regular monitoring Types of insulin Short/ rapid Peak 1-2hrs Med Peak 4-6hrs Standard Actrapid Insultard Analogue (longer duration) Novorapid Humalog S Active in 10 mins, lasts 1 hr Long Dur 16-18hr Mixed Insultard Humalin M3 Mixtard 30 (withdrawn) Levomir Glargine Novomix 30 (novo + insultard) Humalog mix 25 “Sick day rules” – increased metabolic rate à increased requirement. GI sx à decreased carb absorption. ALWAYS need low level insulin even if not eating. Continue to give carbs (liquid if req) Diet Should be >50% carbs 30-35% fat 10-15% protein Appropriate snacks (e.g. pre bed) encouraged Regular exercise Education – including sick-day rules Aim for HbA1c of < 7.5 Hypos BM<4.0 Recurrent hypos can à intellectual impairment Autonomic symptoms – hunger, shaking, sweating, pallor Neuroglycopenia – disorientation, aggression, speech problems, poor concentration, vision changes, decreased level of consciousness Screening Every clinic - Ht, Wt & HbA1c + check injection sites Annual review – retinopathy, microalbuminuria, BP, thyroid disease, foot care Every 3 yrs – coeliac screen DKA 1-10% per pt per yr 15-60% of 1st presentation 0.15-0.3% mortality Risk of low K & cerebral oedema (accounts for 57-87% of DKA deaths) Treatment of DKA Normal Saline Insulin Potassium replacement Rx cause Consider bicarb if pH < 7.0 NB: initial BM = poor indicator of severity Teenagers Poor compliance Increased insulin requirements Alcohol can à nocturnal hypos Can drive IF well controlled and no unexpected hypos Complications of DM Hypogylcaemia Most well controlled patients report hypo Sx at least 1/wk. Most commonly after unexpected exercise / late for meals Toddlers lack awareness, some children with very tight control can lose awareness Move to new injection site (hypertrophy at site delays uptake) Hypos can be due to excess insulin (some children give extra to hide sweet eating) +ve rhomberg sign – due to peripheral neuropathy Snowflake cateracts