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

    • Paediatric Endocrinology for Adult Endocrinologists: an introduction Paul Ward Consultant Paediatrician
    • Endocrinology & age
      • Perinatal endocrinology
      • Paediatric endocrinology
      • Adolescent endocrinology
      • Transition to adult services
    • 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
    • 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
    • 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
    • What do I see in the paediatric growth & endocrinology clinic?
    • Common
      • Physiological short stature
      • Delayed onset of puberty (boys)
      • Early adrenarche (girls)
      • Congenital hypothyroidism
    • Less common
      • Thyrotoxicosis
      • Turner syndrome
      • Juvenile acquired hypothyroidism
      • Turner syndrome
      • Premature thelarche
      • Girls with tall stature
      • Labial adhesions in young girls
    • Uncommon
      • Growth hormone deficiency
      • Congenital adrenal hyperplasia
      • Diabetes insipidus
      • Gonadotropin-dependent precocious puberty
      • Hypophosphataemic rickets
      • Klinefelter syndrome
      • Gonadotropin dependent precocious puberty
    • Rocking horse t…s
      • Complete androgen insensitivity syndrome
      • Late-presenting congenital adrenal hyperplasia
      • Hypoparathyroidism
      • Cushing’s disease
      • Spontaneous hypoglycaemic episodes
      • Hyperparathyroidism
    • 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)
    • GROWTH
    • 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
    • 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 disproportionate short stature.
    •  
    • 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
    • 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
    • Plot child’s height
    • 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
    • Plot serial heights. Analyse chart.
    •  
    • 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.
    • 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.
    • 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
    • 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
    • “ Tempo of Growth” A B A B
    • 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”.
    • 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.
    • 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
    • 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”.
    • 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.
    • 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.
    • 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)
    • Relatively short, falling through centiles in late childhood / early adolescence, delayed bone age, predicted height consistent with family TCR. Constitutional delay of growth & adolescence.
    •  
    • 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?
    • Examination
      • Very small
      • Absent upper 2 nd incisors
      • High arched palate
      • Normally proportioned
      • Nil else
      Age 3 ½
    • 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
    • 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
    • Clonidine & TRH stimulation test
    • Diagnosis?
    • Diagnosis
      • Growth hormone deficiency
      • Possible evolving secondary hypothyroidism
    • Treatment
      • Growth hormone replacement therapy
      • Subsequently also started on thyroxine
      Age 4 ½, one year after starting GH
    • Growth hormone deficiency, response to treatment
    •  
    • 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
    • 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
      • 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)
    • 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
    • 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
    • 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
    • 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
    • Molly (1)
      • Presented April 2002, aged 8 months
        • Abdominal distension
        • Vaginal bleeding
      • Examination:
        • Bilateral breast buds
        • Distended abdomen
        • Enlargement of labia
    • 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
      • 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)
    • 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
    • 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
    • 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
    • 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
    •  
    • 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
    • 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
    •  
    • 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
    • Helen: growth chart
    • 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
    • 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
      • 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)
      • 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)
      • 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)
    • 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
      • 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)
      • 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)
      • 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)
    • 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
    • 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 %
    • Additional Neurological Problems: Spasticity Gait disorders Incoordination Awkwardness Tremor & jerky movements Cerebellar ataxia & nystagmus Sensorineural hearing loss
    • Congenital Hypothyroidism : “textbook” appearances
    • 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
    • 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 % detected within 3 to 4 years Clinical Detection Rate before universal screening
    • 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.
    • Treatment
      • l-Thyroxine, 100 mcgs/m 2 .day p.o.
      • Monitor:
        • Serum Free T4, TSH
        • Growth
        • Bone age
        • Neurodevelopment
    • 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
    • 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
    • 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
    • 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
    • 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/l Conclusion?
    • 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
    • 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.
    • 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.
    • 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
    •  
    • 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