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Paediatric Endocrinology for Adult Endocrinologists: an introduction Paul Ward Consultant Paediatrician
Endocrinology & age <ul><li>Perinatal endocrinology </li></ul><ul><li>Paediatric endocrinology </li></ul><ul><li>Adolescen...
Perinatal endocrinology <ul><li>Neonatal consequences of maternal endocrine disease e.g. thyrotoxicosis </li></ul><ul><li>...
Paediatric endocrinology <ul><li>Short stature / tall stature, faltering growth </li></ul><ul><li>Juvenile acquired hypoth...
Adolescent endocrinology <ul><li>Delayed onset of puberty </li></ul><ul><li>Obesity & its metabolic consequences </li></ul...
What do I see in the paediatric growth & endocrinology clinic?
Common <ul><li>Physiological short stature </li></ul><ul><li>Delayed onset of puberty (boys) </li></ul><ul><li>Early adren...
Less common <ul><li>Thyrotoxicosis </li></ul><ul><li>Turner syndrome </li></ul><ul><li>Juvenile acquired hypothyroidism </...
Uncommon  <ul><li>Growth hormone deficiency </li></ul><ul><li>Congenital adrenal hyperplasia </li></ul><ul><li>Diabetes in...
Rocking horse t…s <ul><li>Complete androgen insensitivity syndrome </li></ul><ul><li>Late-presenting congenital adrenal hy...
What’s becoming more common? <ul><li>Obesity & its complications </li></ul><ul><li>Polycystic ovarian syndrome </li></ul><...
GROWTH
Measuring standing height: note no shoes or socks! Head held in Frankfurt plane. Feet, back and back of head touching the ...
Measuring supine length when not possible to measure standing height e.g. babies, disabled children
Measuring sitting height using Harpenden sitting height stadiometer. Sitting height may be useful in diagnosing disproport...
 
Dealing with growth data <ul><li>Plot child’s height & weight </li></ul><ul><li>Calculate corrected mean parental height a...
Example <ul><li>Boy, age 5 years, height 110 cms </li></ul><ul><li>Father’s height 177 cms </li></ul><ul><li>Mother’s heig...
Plot child’s height
Calculate & plot mean parental height & target centile range: Boys: (Mother’s height plus fathers height)/2  plus  7, +/- ...
Plot serial heights. Analyse chart.
 
Exercise: Case 1 <ul><li>Boy, aged 7 years </li></ul><ul><li>Height 110 cms </li></ul><ul><li>Father’s height 162 cms </li...
Exercise: Case 2 <ul><li>Girl aged 6 yrs </li></ul><ul><li>Height 127 cms </li></ul><ul><li>Father’s height 195 cms </li><...
Exercise: Case 3 <ul><li>Girl aged 5 yrs </li></ul><ul><li>Height 110 cms </li></ul><ul><li>Father’s height 174cms </li></...
Exercise: Case 4 <ul><li>Boy aged 6 yrs </li></ul><ul><li>Height 109 cms </li></ul><ul><li>Father’s height 185 cms </li></...
“ Tempo of Growth” A B A B
Clinical Indicators of Maturity <ul><li>Age at eruption of specific teeth </li></ul><ul><li>Age of appearance of specified...
Concept of skeletal maturity <ul><li>skeletal maturation is a continuous biological process from birth to maturity. </li><...
Bone age <ul><li>Standardised x-ray of left hand & wrist </li></ul><ul><li>Comparison of selected bones with atlas of refe...
Tanner & Whitehouse TW2  RUS <ul><li>X-ray of LEFT hand & wrist. </li></ul><ul><li>Radius, ulna, & short bones (metacarpal...
Delayed skeletal maturity <ul><li>Bone age is less than chronological age. </li></ul><ul><li>Child will enter puberty late...
Advanced skeletal maturity <ul><li>Bone age is greater than chronological age. </li></ul><ul><li>Child will enter puberty ...
Clinical Applications of Bone Age <ul><li>DIAGNOSIS </li></ul><ul><ul><li>short stature with delayed growth & adolescence....
Relatively short, falling through centiles in late childhood / early adolescence, delayed bone age, predicted height consi...
 
Clinical case <ul><li>Girl, aged 3 yrs 1 month </li></ul><ul><li>Height 78 cms </li></ul><ul><li>Mother 171 cms, father 18...
Examination <ul><li>Very small </li></ul><ul><li>Absent upper 2 nd  incisors </li></ul><ul><li>High arched palate </li></u...
Previous investigations <ul><li>FBC: Hb 10.9, normal film, ferritin 48 ug/l </li></ul><ul><li>U & Es, creatinine, LFTs nor...
Additional Investigations <ul><li>Bone age 1.5 “yrs” @ age 3 yrs </li></ul><ul><li>09h00 Cortisol 420 nmol/l </li></ul><ul...
Clonidine & TRH stimulation test
Diagnosis?
Diagnosis <ul><li>Growth hormone deficiency </li></ul><ul><li>Possible evolving secondary hypothyroidism </li></ul>
Treatment <ul><li>Growth hormone replacement therapy </li></ul><ul><li>Subsequently also started on thyroxine </li></ul>Ag...
Growth hormone deficiency, response to treatment
 
Timing of puberty <ul><li>“ Normal” puberty does not start before </li></ul><ul><ul><li>age 8 years in girls </li></ul></u...
Sequence of pubertal events in girls
Sequence of pubertal events in boys
Tanner stages of pubic hair development at puberty
Tanner stages of genital development at puberty
Prader orchidometer for measuring testicular volume
Tanner stages of breast development at puberty
Abnormalities of puberty <ul><li>Precocious sexual development (girls <8, boys <9) </li></ul><ul><ul><li>Gonadotropin depe...
Precocious sexual development (1) <ul><li>Gonadotropin dependent (true) precocious puberty : activation of hypothalamo-pit...
Precocious sexual development (2) <ul><li>Thelarche variant : persistent or slowly progressive breast development, moderat...
Sexual precocity: RHSC Glasgow  1989 - 1999 15 prem menarche 31 thelarche variant 45 thelarche 18 79 exagerated adrenarche...
Aetiology of GDPP RHSC Glasgow 1989-99 4 0 “ priming” 3 8 Neurological disorder 4 7 Tumour 0 4 Cranial irradiation 1 66 Id...
Molly (1) <ul><li>Presented April 2002, aged 8 months </li></ul><ul><ul><li>Abdominal distension </li></ul></ul><ul><ul><l...
Molly (2) <ul><li>Abdominal ultrasound: </li></ul><ul><ul><li>Enlarged pubertal shaped uterus, thick myometrium & endometr...
<ul><li>Management: left salpingo-oophorectomy (April 02) </li></ul><ul><li>Histology: juvenile granulosa cell of ovary, c...
Helen (1): <ul><li>Presented March 1998, aged 5 years </li></ul><ul><li>Problem: breast development over preceding 12 mont...
Helen (2) <ul><li>Height 124.6 cms (>>99.6 th  centile), weight 26.31 kgs (98 th  – 99.6 th  centile) </li></ul><ul><li>“ ...
Helen (3) <ul><li>January 1999, age 6  yrs </li></ul><ul><li>Growing rapidly: height 132.5 cms, weight 28.2 kgs </li></ul>...
Helen (4) <ul><li>April 1999: paediatric endocrine clinic </li></ul><ul><li>Breast development & rapid growth </li></ul><u...
 
Helen (5) <ul><li>Bone age 9.9 “yrs” @ CA 5.6 yrs </li></ul><ul><li>Pelvic USS: pubertal development of uterus, 4 mls righ...
Helen (6) <ul><li>Parents chose to accept offer of treatment with goserelin (Prostap) 3.75 mgs three-weekly </li></ul><ul>...
 
Helen (7) <ul><li>Current situation: </li></ul><ul><li>Age 10 yrs </li></ul><ul><li>Height 148.8 cms (91 st  centile) </li...
Helen: growth chart
Delayed puberty & pubertal failure <ul><li>Delayed puberty: no signs of puberty in a girl >13 yrs or boy >14 yrs </li></ul...
Pubertal failure: central (1) <ul><li>Intact HPG axis: </li></ul><ul><ul><li>Constitutional delay of growth & adolescence ...
<ul><li>Impaired HPG axis </li></ul><ul><li>CNS tumours e.g craniopharyngioma, optic glioma </li></ul><ul><li>Congenital a...
<ul><li>Boys : </li></ul><ul><ul><li>Bilateral testicular damage e.g torsion </li></ul></ul><ul><ul><li>Syndromes associat...
<ul><li>Girls : </li></ul><ul><ul><li>Gonadal dysgenesis e.g. Turner syndrome </li></ul></ul><ul><ul><li>Irradiation e.g. ...
Scott (1) <ul><li>Presented May 2002, aged 14 years </li></ul><ul><ul><li>Short stature </li></ul></ul><ul><ul><li>Lack of...
<ul><li>Examination: </li></ul><ul><ul><li>Height 146.5 cms (2 nd  centile), weight 52.4 kgs (50-75 th  centile) </li></ul...
<ul><li>Investigation: </li></ul><ul><ul><li>Bone age 11.7 “yrs” @ chronological age 14.1 yrs </li></ul></ul><ul><li>Clini...
<ul><li>Endocrine clinic July ’03, age 15 years 4 months </li></ul><ul><ul><li>Main concern: growth of penis </li></ul></u...
Congenital Hypothyroidism <ul><li>Incidence 1/3500 - 1/4500 live births </li></ul><ul><li>Majority associated with thyroid...
Consequences of Late Diagnosis: In a series of 651 babies mean IQ was 76% Age at Diagnosis % with IQ > 85 < 3 months 78 % ...
Additional Neurological Problems: Spasticity Gait disorders Incoordination Awkwardness Tremor & jerky movements Cerebellar...
Congenital Hypothyroidism : “textbook” appearances
Pre-screening  <ul><li>Diagnosis on clinical findings: </li></ul><ul><ul><li>growth retardation, delayed bone maturation <...
But …not all babies with congenital hypothyroidism look abnormal!
10 % detected within first 4 months of life 35 % detected within  3 months of birth 70 % detected within first year 100 % ...
Neonatal Screening Filter paper blood spots collected on day 7 Sample analysed for TSH concentration Infants with whole bl...
Treatment <ul><li>l-Thyroxine, 100 mcgs/m 2 .day p.o. </li></ul><ul><li>Monitor: </li></ul><ul><ul><li>Serum Free T4, TSH ...
A.B. Female . Born 26/2/94 Day 1  - Normal birth, birth weight 3.14 kgs @ 38 weeks gestation. Neonatal examination normal ...
Initial Results :  Total thyroxine  40 nmol/l  (n. 60 - 160) T.S.H.  290 mIU/l  (n. 0.17 - 2.9) Diagnosis of congenital hy...
Progress: 25/4/94 D.N.A. 23/5/94 Total thyroxine 90 nmol/l TSH 29.2 mIU/l L-Thyroxine to 50 mcg o.d 1/8/94 Total thyroxine...
7/11/94 Well, growing normally Free Thyroxine 6.0 pmol/l  (n. 11.7-28) TSH 94.2 mU/l Results suggested insufficient dose. ...
Reference Ranges: Free T4 11.7-28 pmol/l   TSH  0.17-2.9 mU/l
October 1995 District Nurses visited daily to administer l-thyroxine 75 mcgs od. Free Thyroxine  41.4 pmol/l TSH    0.7 mU...
7/11/95  l-thyroxine reduced to 50 mcgs 28/11/95 Free T4  41.4 pmol/l TSH   7.2 mU/l 4/12/95 D.N.A. 22/1/96 Brought to cli...
29/4/96 D.N.A. 3/6/96 D.N.A. H.V. discovered that G.P. records showed no prescriptions had been collected since November 1...
14/6/96 Free T4  21.9 pmol/l TSH 19.72 mU/l 24/6/96 Mother insists thyroxine being given regularly. July ‘96 Divorce proce...
Child accommodated with father: . 18/7/96 Free T4 19.1 pmol/l TSH   4.17 mU/l 3/10/96 Free T4 22.5 pmol/l TSH   0.03 mU/l ...
 
Paediatric -v- Adult endocrinology <ul><li>Much of what we see is physiological not pathological </li></ul><ul><li>We have...
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Paediatric endocrinology for adult endocrinologists

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Paediatric endocrinology for adult endocrinologists

  1. 1. Paediatric Endocrinology for Adult Endocrinologists: an introduction Paul Ward Consultant Paediatrician
  2. 2. Endocrinology & age <ul><li>Perinatal endocrinology </li></ul><ul><li>Paediatric endocrinology </li></ul><ul><li>Adolescent endocrinology </li></ul><ul><li>Transition to adult services </li></ul>
  3. 3. Perinatal endocrinology <ul><li>Neonatal consequences of maternal endocrine disease e.g. thyrotoxicosis </li></ul><ul><li>Disordered sexual development presenting with ambiguous genitalia </li></ul><ul><li>Congenital adrenal hyperplasia presenting with ambiguous genitalia &/or salt losing crisis </li></ul><ul><li>Persistent neonatal hyperinsulinaemic hypoglycaemia </li></ul><ul><li>Congenital hypothyroidism detected by neonatal screening programme </li></ul><ul><li>Neonatally-recognised Turner syndrome </li></ul>
  4. 4. Paediatric endocrinology <ul><li>Short stature / tall stature, faltering growth </li></ul><ul><li>Juvenile acquired hypothyroidism </li></ul><ul><li>Thelarche </li></ul><ul><li>Adrenarche </li></ul><ul><li>Early / precocious puberty </li></ul><ul><li>Late presenting congenital adrenal hyperplasia </li></ul><ul><li>Turner syndrome </li></ul><ul><li>Growth hormone deficiency </li></ul><ul><li>Iatrogenic endocrinopathies </li></ul>
  5. 5. Adolescent endocrinology <ul><li>Delayed onset of puberty </li></ul><ul><li>Obesity & its metabolic consequences </li></ul><ul><li>Primary / secondary amenorrhoea </li></ul><ul><li>Polycystic ovarian syndrome (PCOS) </li></ul><ul><li>Late presenting Turner syndrome </li></ul><ul><li>Thyrotoxicosis </li></ul><ul><li>Klinefelter syndrome </li></ul><ul><li>Iatrogenic endocrinopathies </li></ul>
  6. 6. What do I see in the paediatric growth & endocrinology clinic?
  7. 7. Common <ul><li>Physiological short stature </li></ul><ul><li>Delayed onset of puberty (boys) </li></ul><ul><li>Early adrenarche (girls) </li></ul><ul><li>Congenital hypothyroidism </li></ul>
  8. 8. Less common <ul><li>Thyrotoxicosis </li></ul><ul><li>Turner syndrome </li></ul><ul><li>Juvenile acquired hypothyroidism </li></ul><ul><li>Turner syndrome </li></ul><ul><li>Premature thelarche </li></ul><ul><li>Girls with tall stature </li></ul><ul><li>Labial adhesions in young girls </li></ul>
  9. 9. Uncommon <ul><li>Growth hormone deficiency </li></ul><ul><li>Congenital adrenal hyperplasia </li></ul><ul><li>Diabetes insipidus </li></ul><ul><li>Gonadotropin-dependent precocious puberty </li></ul><ul><li>Hypophosphataemic rickets </li></ul><ul><li>Klinefelter syndrome </li></ul><ul><li>Gonadotropin dependent precocious puberty </li></ul>
  10. 10. Rocking horse t…s <ul><li>Complete androgen insensitivity syndrome </li></ul><ul><li>Late-presenting congenital adrenal hyperplasia </li></ul><ul><li>Hypoparathyroidism </li></ul><ul><li>Cushing’s disease </li></ul><ul><li>Spontaneous hypoglycaemic episodes </li></ul><ul><li>Hyperparathyroidism </li></ul>
  11. 11. What’s becoming more common? <ul><li>Obesity & its complications </li></ul><ul><li>Polycystic ovarian syndrome </li></ul><ul><li>Insulin resistance / metabolic syndrome </li></ul><ul><li>Type 2 diabetes mellitus </li></ul><ul><li>Iatrogenic endocrine disorders e.g. </li></ul><ul><ul><li>Anterior pituitary dysfunction (radiotherapy, surgery) </li></ul></ul><ul><ul><li>Gonadal damage (cytotoxic drugs, radioPx) </li></ul></ul>
  12. 12. GROWTH
  13. 13. Measuring standing height: note no shoes or socks! Head held in Frankfurt plane. Feet, back and back of head touching the footplate or back plate. Harpenden stadiometer
  14. 14. Measuring supine length when not possible to measure standing height e.g. babies, disabled children
  15. 15. Measuring sitting height using Harpenden sitting height stadiometer. Sitting height may be useful in diagnosing disproportionate short stature.
  16. 17. Dealing with growth data <ul><li>Plot child’s height & weight </li></ul><ul><li>Calculate corrected mean parental height and target centile range </li></ul><ul><li>Plot serial height measurements </li></ul><ul><li>Factor in bone age (if available) </li></ul><ul><li>Analyse growth curve </li></ul>
  17. 18. Example <ul><li>Boy, age 5 years, height 110 cms </li></ul><ul><li>Father’s height 177 cms </li></ul><ul><li>Mother’s height 163 cms </li></ul><ul><li>Subsequent heights: </li></ul><ul><ul><li>Age 6 116 cms </li></ul></ul><ul><ul><li>Age 7 122 cms </li></ul></ul><ul><ul><li>Age 8 128 cms </li></ul></ul><ul><ul><li>Age 9 133 cms </li></ul></ul>
  18. 19. Plot child’s height
  19. 20. Calculate & plot mean parental height & target centile range: Boys: (Mother’s height plus fathers height)/2 plus 7, +/- 10 cms. Girls: (Mothers height plus fathers height)/2 minus 7, +/- 8.5 cms
  20. 21. Plot serial heights. Analyse chart.
  21. 23. Exercise: Case 1 <ul><li>Boy, aged 7 years </li></ul><ul><li>Height 110 cms </li></ul><ul><li>Father’s height 162 cms </li></ul><ul><li>Mother’s height 150 cms </li></ul><ul><li>Subsequent heights: </li></ul><ul><ul><li>8 yrs 115 cms </li></ul></ul><ul><ul><li>9 yrs 120 cms </li></ul></ul><ul><ul><li>10 yrs 124 cms </li></ul></ul>Plot & analyse the growth curve.
  22. 24. Exercise: Case 2 <ul><li>Girl aged 6 yrs </li></ul><ul><li>Height 127 cms </li></ul><ul><li>Father’s height 195 cms </li></ul><ul><li>Mother’s height 175 cms </li></ul><ul><li>Subsequent heights </li></ul><ul><ul><li>Age 7 ½ 136 cms </li></ul></ul><ul><ul><li>Age 9 146 cms </li></ul></ul><ul><ul><li>Age 10 153 cms </li></ul></ul>Plot & analyse the growth chart.
  23. 25. Exercise: Case 3 <ul><li>Girl aged 5 yrs </li></ul><ul><li>Height 110 cms </li></ul><ul><li>Father’s height 174cms </li></ul><ul><li>Mother’s height 167cms </li></ul><ul><li>Subsequent heights </li></ul><ul><ul><li>Age 6 117 cms </li></ul></ul><ul><ul><li>Age 7½ 122 cms </li></ul></ul><ul><ul><li>Age 9 124 cms </li></ul></ul><ul><ul><li>Age 10 126 cms </li></ul></ul>Plot and analyse the growth chart
  24. 26. Exercise: Case 4 <ul><li>Boy aged 6 yrs </li></ul><ul><li>Height 109 cms </li></ul><ul><li>Father’s height 185 cms </li></ul><ul><li>Mother’s height 174 cms </li></ul><ul><li>Subsequent heights </li></ul><ul><ul><li>Age 7 115 cms </li></ul></ul><ul><ul><li>Age 8½ 123 cms </li></ul></ul><ul><ul><li>Age 10 130 cms </li></ul></ul>Plot and analyse the growth chart
  25. 27. “ Tempo of Growth” A B A B
  26. 28. Clinical Indicators of Maturity <ul><li>Age at eruption of specific teeth </li></ul><ul><li>Age of appearance of specified secondary sexual characteristics e.g. onset of breast development, testicular enlargement. </li></ul><ul><li>Age at onset of menstruation (menarche) </li></ul><ul><li>Radiological appearance of specified bones - skeletal maturity or bone “age”. </li></ul>
  27. 29. Concept of skeletal maturity <ul><li>skeletal maturation is a continuous biological process from birth to maturity. </li></ul><ul><li>ossification centres appear in a specific order & change shape as they develop. </li></ul><ul><li>appearance can be arbitrarily divided up in to a number of recognisable stages. </li></ul><ul><li>Patients bones can be compared with an atlas of “standard” bones. </li></ul>
  28. 30. Bone age <ul><li>Standardised x-ray of left hand & wrist </li></ul><ul><li>Comparison of selected bones with atlas of reference standards (Tanner & Whitehouse 2, RUS) </li></ul><ul><li>Comparison of bone “age” with chronological age </li></ul><ul><li>Delayed bone age implies delayed maturation and improves height prognosis </li></ul><ul><li>Advanced bone age implies accelerated maturation and predicts earlier cessation of growth </li></ul><ul><li>Adult height can be predicted from bone age and measured height </li></ul>
  29. 31. Tanner & Whitehouse TW2 RUS <ul><li>X-ray of LEFT hand & wrist. </li></ul><ul><li>Radius, ulna, & short bones (metacarpals & phalanges) compared with reference standards & scored (A-H). </li></ul><ul><li>Each stage is assigned a score, maturity score (0-1000) obtained by adding individual scores. </li></ul><ul><li>Maturity score converted to Bone “Age”. </li></ul>
  30. 32. Delayed skeletal maturity <ul><li>Bone age is less than chronological age. </li></ul><ul><li>Child will enter puberty later than peers and have a delayed growth spurt. </li></ul><ul><li>Growth will continue beyond the age at which the average child of the same sex stops growing. </li></ul><ul><li>Final height centile may be greater than height centile in childhood. </li></ul>
  31. 33. Advanced skeletal maturity <ul><li>Bone age is greater than chronological age. </li></ul><ul><li>Child will enter puberty earlier than peers and have an early growth spurt. </li></ul><ul><li>Growth will cease before the age at which the average child of the same sex stops growing. </li></ul><ul><li>Final height centile may be less than height centile in childhood. </li></ul>
  32. 34. Clinical Applications of Bone Age <ul><li>DIAGNOSIS </li></ul><ul><ul><li>short stature with delayed growth & adolescence. </li></ul></ul><ul><ul><li>Precocious puberty </li></ul></ul><ul><li>MONITORING </li></ul><ul><ul><li>hypothyroidism </li></ul></ul><ul><ul><li>congenital adrenal hyperplasia </li></ul></ul><ul><ul><li>treatment of delayed growth </li></ul></ul><ul><li>PREDICTION OF ADULT HEIGHT </li></ul><ul><ul><li>short stature (usually boys) </li></ul></ul><ul><ul><li>excessive height (usually girls) </li></ul></ul>
  33. 35. Relatively short, falling through centiles in late childhood / early adolescence, delayed bone age, predicted height consistent with family TCR. Constitutional delay of growth & adolescence.
  34. 37. Clinical case <ul><li>Girl, aged 3 yrs 1 month </li></ul><ul><li>Height 78 cms </li></ul><ul><li>Mother 171 cms, father 182.1 </li></ul><ul><li>BW 3.54 kgs @ 38 weeks </li></ul><ul><li>Neonatal course: </li></ul><ul><ul><li>Hypothermia </li></ul></ul><ul><ul><li>Hypoglycaemia </li></ul></ul><ul><ul><li>Prolonged jaundice </li></ul></ul>Plot data. What are you thinking about at this stage?
  35. 38. Examination <ul><li>Very small </li></ul><ul><li>Absent upper 2 nd incisors </li></ul><ul><li>High arched palate </li></ul><ul><li>Normally proportioned </li></ul><ul><li>Nil else </li></ul>Age 3 ½
  36. 39. Previous investigations <ul><li>FBC: Hb 10.9, normal film, ferritin 48 ug/l </li></ul><ul><li>U & Es, creatinine, LFTs normal </li></ul><ul><li>Free T4 11.5 pmol/l, TSH 1.39 mIU/l </li></ul><ul><li>Karyotype 46 XX </li></ul><ul><li>Immunoglobulins normal </li></ul><ul><li>Coeliac screen negative </li></ul>
  37. 40. Additional Investigations <ul><li>Bone age 1.5 “yrs” @ age 3 yrs </li></ul><ul><li>09h00 Cortisol 420 nmol/l </li></ul><ul><li>Repeat TFTs: FT4 10.0, TSH 1.94 </li></ul><ul><li>LH <0.5 IU/l, FSH 1.8 IU/l </li></ul><ul><li>Prolactin 272 IU/l </li></ul>
  38. 41. Clonidine & TRH stimulation test
  39. 42. Diagnosis?
  40. 43. Diagnosis <ul><li>Growth hormone deficiency </li></ul><ul><li>Possible evolving secondary hypothyroidism </li></ul>
  41. 44. Treatment <ul><li>Growth hormone replacement therapy </li></ul><ul><li>Subsequently also started on thyroxine </li></ul>Age 4 ½, one year after starting GH
  42. 45. Growth hormone deficiency, response to treatment
  43. 47. Timing of puberty <ul><li>“ Normal” puberty does not start before </li></ul><ul><ul><li>age 8 years in girls </li></ul></ul><ul><ul><li>age 9 years in boys </li></ul></ul><ul><li>“ Normal” puberty starts before age 13 in girls and 14 in boys </li></ul><ul><li>Early puberty is common in girls </li></ul><ul><li>Late puberty is common in boys </li></ul><ul><li>Duration of puberty varies enormously </li></ul>
  44. 48. Sequence of pubertal events in girls
  45. 49. Sequence of pubertal events in boys
  46. 50. Tanner stages of pubic hair development at puberty
  47. 51. Tanner stages of genital development at puberty
  48. 52. Prader orchidometer for measuring testicular volume
  49. 53. Tanner stages of breast development at puberty
  50. 54. Abnormalities of puberty <ul><li>Precocious sexual development (girls <8, boys <9) </li></ul><ul><ul><li>Gonadotropin dependent precocious puberty </li></ul></ul><ul><ul><li>Gonadotropin independent precocious pseudopuberty </li></ul></ul><ul><li>“ Incomplete” puberty: </li></ul><ul><ul><li>Adrenarche </li></ul></ul><ul><ul><li>Thelarche </li></ul></ul><ul><ul><li>Thelarche variant </li></ul></ul><ul><ul><li>Premature menarche </li></ul></ul><ul><li>Delayed onset of puberty (girls >13, boys >14) </li></ul>
  51. 55. Precocious sexual development (1) <ul><li>Gonadotropin dependent (true) precocious puberty : activation of hypothalamo-pituitary gonadal axis occurring abnormally early (girls <8, boys <9) </li></ul><ul><li>Precocious pseudopuberty : abnormal sex steroid secretion independent of gonadotropin secretion </li></ul><ul><li>Thelarche : isolated breast development, no other signs of puberty </li></ul>
  52. 56. Precocious sexual development (2) <ul><li>Thelarche variant : persistent or slowly progressive breast development, moderate increase in height velocity & advance of bone age but prepubertal LHRH test (FSH predominant) </li></ul><ul><li>Exaggerated adrenarche : pubic hair growth before 6 yrs in absence of other signs of puberty </li></ul><ul><li>Premature menarche : cyclical uterine bleeding, confirmed by endometrial echo, in absence of other signs of puberty </li></ul>
  53. 57. Sexual precocity: RHSC Glasgow 1989 - 1999 15 prem menarche 31 thelarche variant 45 thelarche 18 79 exagerated adrenarche 5 4 GIDPPP 7 18 secondary 1 66 idiopathic GDPP: Boys Girls
  54. 58. Aetiology of GDPP RHSC Glasgow 1989-99 4 0 “ priming” 3 8 Neurological disorder 4 7 Tumour 0 4 Cranial irradiation 1 66 Idiopathic Boys Girls
  55. 59. Molly (1) <ul><li>Presented April 2002, aged 8 months </li></ul><ul><ul><li>Abdominal distension </li></ul></ul><ul><ul><li>Vaginal bleeding </li></ul></ul><ul><li>Examination: </li></ul><ul><ul><li>Bilateral breast buds </li></ul></ul><ul><ul><li>Distended abdomen </li></ul></ul><ul><ul><li>Enlargement of labia </li></ul></ul>
  56. 60. Molly (2) <ul><li>Abdominal ultrasound: </li></ul><ul><ul><li>Enlarged pubertal shaped uterus, thick myometrium & endometrium. </li></ul></ul><ul><ul><li>5.5 cms partly solid, partly cystic mass arising from left ovary </li></ul></ul><ul><ul><li>Ascites </li></ul></ul><ul><li>Bloods: </li></ul><ul><ul><li>LH <0.5, FSH <0.5, oestradiol 456 pmol/l </li></ul></ul>
  57. 61. <ul><li>Management: left salpingo-oophorectomy (April 02) </li></ul><ul><li>Histology: juvenile granulosa cell of ovary, completely resected </li></ul><ul><li>Follow up: </li></ul><ul><ul><li>Serum oestradiol May 2002: <100 pmol/l </li></ul></ul><ul><ul><li>Pelvic ultrasound Dec ’02: “normal” uterus </li></ul></ul><ul><li>Clinical July ’03: No pubertal signs </li></ul>Molly (3)
  58. 62. Helen (1): <ul><li>Presented March 1998, aged 5 years </li></ul><ul><li>Problem: breast development over preceding 12 months </li></ul><ul><li>Small amount of pubic hair </li></ul><ul><li>Taller than most of her peers </li></ul>
  59. 63. Helen (2) <ul><li>Height 124.6 cms (>>99.6 th centile), weight 26.31 kgs (98 th – 99.6 th centile) </li></ul><ul><li>“ marked breast development” </li></ul><ul><li>No pubic hair </li></ul><ul><li>Hairy legs </li></ul><ul><li>CT brain : “Normal” </li></ul><ul><li>Pelvic ultrasound : “enlargement of fundus of uterus, endometrial echo, several lare follicles in left ovary </li></ul>
  60. 64. Helen (3) <ul><li>January 1999, age 6 yrs </li></ul><ul><li>Growing rapidly: height 132.5 cms, weight 28.2 kgs </li></ul><ul><li>Further breast development </li></ul><ul><li>No pubic or axillary hair </li></ul><ul><li>Referred to PSW </li></ul>
  61. 65. Helen (4) <ul><li>April 1999: paediatric endocrine clinic </li></ul><ul><li>Breast development & rapid growth </li></ul><ul><li>Now some pubic & axillary hair </li></ul><ul><li>Moody swings </li></ul><ul><li>Maternal menarche age 17! </li></ul><ul><li>No neurological symptoms </li></ul><ul><li>Puberty P2 B3 </li></ul><ul><li>For LHRH test </li></ul>
  62. 67. Helen (5) <ul><li>Bone age 9.9 “yrs” @ CA 5.6 yrs </li></ul><ul><li>Pelvic USS: pubertal development of uterus, 4 mls right ovary with several large follicles, no other pelvic abnormalities </li></ul><ul><li>Free T4 15.0 pmol/l, TSH 2.74 mIU/l </li></ul>DIAGNOSIS: Gonadotropin-dependent central precocious puberty
  63. 68. Helen (6) <ul><li>Parents chose to accept offer of treatment with goserelin (Prostap) 3.75 mgs three-weekly </li></ul><ul><li>Warned of potential vaginal bleed with first dose (partial agonist effect) </li></ul><ul><li>LHRH test repeated after three doses </li></ul>
  64. 70. Helen (7) <ul><li>Current situation: </li></ul><ul><li>Age 10 yrs </li></ul><ul><li>Height 148.8 cms (91 st centile) </li></ul><ul><li>No further breast development </li></ul><ul><li>Bone age 10.4 “yrs” @ CA 8.9 yrs </li></ul><ul><li>Remains on treatment – very small primary school ill-equipped to deal with menstruating girls </li></ul>
  65. 71. Helen: growth chart
  66. 72. Delayed puberty & pubertal failure <ul><li>Delayed puberty: no signs of puberty in a girl >13 yrs or boy >14 yrs </li></ul><ul><li>Pubertal failure: failure of puberty to begin or to complete having begun </li></ul><ul><li>Delayed menarche: first period aftetr age 15 yrs </li></ul><ul><li>Primary amenorrhoea: failure to start periods </li></ul><ul><li>Secondary amenorrhoea: cessation of menses after having become established </li></ul><ul><li>Oligomenorrhoea: fewer than 6 periods per year </li></ul>
  67. 73. Pubertal failure: central (1) <ul><li>Intact HPG axis: </li></ul><ul><ul><li>Constitutional delay of growth & adolescence </li></ul></ul><ul><ul><li>Chronic illness (e.g. Crohn’s disease) </li></ul></ul><ul><ul><li>Malnutrition including anorexia nervosa </li></ul></ul><ul><ul><li>Psychosocial deprivation </li></ul></ul><ul><ul><li>Corticosteroids </li></ul></ul><ul><ul><li>hypothyroidism </li></ul></ul>
  68. 74. <ul><li>Impaired HPG axis </li></ul><ul><li>CNS tumours e.g craniopharyngioma, optic glioma </li></ul><ul><li>Congenital anomalies e.g SOD </li></ul><ul><li>Cranial irradiation </li></ul><ul><li>Cranial trauma e.g. head injury </li></ul><ul><li>GnRH/LH/FSH deficiency e.g. Kallman’s </li></ul>Pubertal failure: central (2)
  69. 75. <ul><li>Boys : </li></ul><ul><ul><li>Bilateral testicular damage e.g torsion </li></ul></ul><ul><ul><li>Syndromes associated with cryptorchidism e.g. Prader Willi </li></ul></ul><ul><ul><li>Gonadal dysgenesis e.g. Klinefelter’s </li></ul></ul><ul><ul><li>Testicular irradiation </li></ul></ul><ul><ul><li>Chemotherapy esp. alkylating agents </li></ul></ul>Pubertal failure: peripheral (1)
  70. 76. <ul><li>Girls : </li></ul><ul><ul><li>Gonadal dysgenesis e.g. Turner syndrome </li></ul></ul><ul><ul><li>Irradiation e.g. Wilm’s tumour, TBI </li></ul></ul><ul><ul><li>Disorders of sexual differentiation e.g. CAIS </li></ul></ul><ul><ul><li>Polycystic ovary syndrome </li></ul></ul><ul><ul><li>Toxic damage to ovaries e.g. galactosaemia, iron overload </li></ul></ul>Pubertal failure: peripheral (2)
  71. 77. Scott (1) <ul><li>Presented May 2002, aged 14 years </li></ul><ul><ul><li>Short stature </li></ul></ul><ul><ul><li>Lack of genital development </li></ul></ul><ul><li>Mother 5’5”, menarche @14; father 6’0”, sister menarche @ 14, father “late developer” </li></ul><ul><li>1 st tooth erupted @ age 10 months, only just started losing primary dentition </li></ul><ul><li>General health excellent </li></ul><ul><li>Normal sense of smell </li></ul>
  72. 78. <ul><li>Examination: </li></ul><ul><ul><li>Height 146.5 cms (2 nd centile), weight 52.4 kgs (50-75 th centile) </li></ul></ul><ul><ul><li>Prepubertal penis, 4 mls testes, no pubic hair (Tanner P1G2) </li></ul></ul><ul><ul><li>General physical examination normal </li></ul></ul>Scott (2)
  73. 79. <ul><li>Investigation: </li></ul><ul><ul><li>Bone age 11.7 “yrs” @ chronological age 14.1 yrs </li></ul></ul><ul><li>Clinical review 5 months later: </li></ul><ul><ul><li>4ml testes, scrotal laxity, few wisps of pubic hair (Tanner P2G2) </li></ul></ul><ul><ul><li>Growth rate equivalent to 5.2 cms/year </li></ul></ul><ul><li>Referred for paediatric endocrine opinion </li></ul>Scott (3)
  74. 80. <ul><li>Endocrine clinic July ’03, age 15 years 4 months </li></ul><ul><ul><li>Main concern: growth of penis </li></ul></ul><ul><li>Examination: </li></ul><ul><ul><li>Tanner P2 G2-3 </li></ul></ul><ul><ul><li>Testes 8mls (Lt), 6 mls (Rt) </li></ul></ul><ul><li>Assessment: CDGA </li></ul><ul><li>Management: discussed testosterone treatment, patient’s decision pending </li></ul>Scott (4)
  75. 81. Congenital Hypothyroidism <ul><li>Incidence 1/3500 - 1/4500 live births </li></ul><ul><li>Majority associated with thyroid dysgenesis: </li></ul><ul><ul><li>30 % thyroid agenesis </li></ul></ul><ul><ul><li>60 % ectopic thyroid gland </li></ul></ul><ul><ul><li>10 % eutopic gland </li></ul></ul><ul><li>Male : Female ratio approx 1:2 </li></ul>
  76. 82. Consequences of Late Diagnosis: In a series of 651 babies mean IQ was 76% Age at Diagnosis % with IQ > 85 < 3 months 78 % 3 - 6 months 19 % > 7 months 0 %
  77. 83. Additional Neurological Problems: Spasticity Gait disorders Incoordination Awkwardness Tremor & jerky movements Cerebellar ataxia & nystagmus Sensorineural hearing loss
  78. 84. Congenital Hypothyroidism : “textbook” appearances
  79. 85. Pre-screening <ul><li>Diagnosis on clinical findings: </li></ul><ul><ul><li>growth retardation, delayed bone maturation </li></ul></ul><ul><ul><li>flat nose, sunken nasal bridge, macroglossia </li></ul></ul><ul><ul><li>abdominal distension, umbilical hernia </li></ul></ul><ul><ul><li>cold, dry mottled skin </li></ul></ul><ul><ul><li>persistent neonatal jaundice </li></ul></ul><ul><ul><li>poor feeding, constipation </li></ul></ul><ul><ul><li>lethargy, hypothermia </li></ul></ul><ul><li>Diagnosis often delayed </li></ul>
  80. 86. But …not all babies with congenital hypothyroidism look abnormal!
  81. 87. 10 % detected within first 4 months of life 35 % detected within 3 months of birth 70 % detected within first year 100 % detected within 3 to 4 years Clinical Detection Rate before universal screening
  82. 88. Neonatal Screening Filter paper blood spots collected on day 7 Sample analysed for TSH concentration Infants with whole blood TSH > 20 - 30 mU/l notified to G.P. & designated paediatrician. Infant seen, serum sample collected, treatment commenced.
  83. 89. Treatment <ul><li>l-Thyroxine, 100 mcgs/m 2 .day p.o. </li></ul><ul><li>Monitor: </li></ul><ul><ul><li>Serum Free T4, TSH </li></ul></ul><ul><ul><li>Growth </li></ul></ul><ul><ul><li>Bone age </li></ul></ul><ul><ul><li>Neurodevelopment </li></ul></ul>
  84. 90. A.B. Female . Born 26/2/94 Day 1 - Normal birth, birth weight 3.14 kgs @ 38 weeks gestation. Neonatal examination normal Day 7 - Neonatal Biochemical Screening Test: Day 12 - Whole Blood TSH 250 mU/l, result notified to G.P. & PSW. Day 13 - Seen in Children’s Day Bed Unit: Quiet baby, fading jaundice, dry skin. Serum sample taken. Thyroxine 25 mcg o.d prescribed
  85. 91. Initial Results : Total thyroxine 40 nmol/l (n. 60 - 160) T.S.H. 290 mIU/l (n. 0.17 - 2.9) Diagnosis of congenital hypothyroidism confirmed
  86. 92. Progress: 25/4/94 D.N.A. 23/5/94 Total thyroxine 90 nmol/l TSH 29.2 mIU/l L-Thyroxine to 50 mcg o.d 1/8/94 Total thyroxine 114 nmol/l TSH 0.16 mIU/l
  87. 93. 7/11/94 Well, growing normally Free Thyroxine 6.0 pmol/l (n. 11.7-28) TSH 94.2 mU/l Results suggested insufficient dose. L-thyroxine increased to 75 mcg o.d Dose equivalent to 180 mcg/m 2 .day
  88. 94. Reference Ranges: Free T4 11.7-28 pmol/l TSH 0.17-2.9 mU/l
  89. 95. October 1995 District Nurses visited daily to administer l-thyroxine 75 mcgs od. Free Thyroxine 41.4 pmol/l TSH 0.7 mU/l Conclusion?
  90. 96. 7/11/95 l-thyroxine reduced to 50 mcgs 28/11/95 Free T4 41.4 pmol/l TSH 7.2 mU/l 4/12/95 D.N.A. 22/1/96 Brought to clinic by father Free T4 44 pmol/l TSH 1.4 mU/l
  91. 97. 29/4/96 D.N.A. 3/6/96 D.N.A. H.V. discovered that G.P. records showed no prescriptions had been collected since November 1995 Concerns discussed with Child Care Social Work Dept. & N.S.P.C.C. Child Protection Officer.
  92. 98. 14/6/96 Free T4 21.9 pmol/l TSH 19.72 mU/l 24/6/96 Mother insists thyroxine being given regularly. July ‘96 Divorce proceedings. Request from mother’s solicitors for medical information.
  93. 99. Child accommodated with father: . 18/7/96 Free T4 19.1 pmol/l TSH 4.17 mU/l 3/10/96 Free T4 22.5 pmol/l TSH 0.03 mU/l Legal proceedings continue
  94. 101. Paediatric -v- Adult endocrinology <ul><li>Much of what we see is physiological not pathological </li></ul><ul><li>We have a developmental approach taking in to account growth & pubert </li></ul><ul><li>The spectrum of disease is different e.g: </li></ul><ul><ul><li>developmental anomalies </li></ul></ul><ul><ul><li>inborn errors of metabolism </li></ul></ul><ul><li>We always have to remember child protection issues </li></ul>

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