Paediatric endocrinology for adult endocrinologists
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Paediatric endocrinology for adult endocrinologists Presentation Transcript

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