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 yrs124 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 7½ 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 2nd

incisors• High arched palate• Normally proportioned• Nil else

Age 3½

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

GH & TSH responses to clonidine & TRH

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0 30 60 90 120Time (mins)

GH

(m

u/l)

, TS

H (

mIU

/l) GH

TSH

Clonidine & TRH stimulation test

Diagnosis?

Diagnosis

• Growth hormone deficiency• Possible evolving secondary

hypothyroidism

Treatment

• Growth hormone replacement therapy

• Subsequently also started on thyroxine

Age 4½, 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

Girls Boys

GDPP:

idiopathic 66 1

secondary 18 7

GIDPPP 4 5

exagerated adrenarche 79 18

thelarche 45

thelarche variant 31

prem menarche 15

Aetiology of GDPPRHSC Glasgow 1989-99

Girls Boys

Idiopathic 66 1

Cranial irradiation 4 0

Tumour 7 4

Neurological disorder 8 3

“priming” 0 4

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 (>>99.6th centile), weight 26.31

kgs (98th – 99.6th 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

Pretreatment LH & FSH responses to LHRH

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time (mins)

IU/l

LH

FSH

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

LH & FSH responses to LHRH after 3 weeks treatment with goserelin

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10

20

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0 30 60 90 120

Time (mins)

IU/L

LH

FSH

Helen (7)

Current situation:

• Age 10 yrs

• Height 148.8 cms (91st 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”

• 1st tooth erupted @ age 10 months, only just started losing primary dentition

• General health excellent• Normal sense of smell

• Examination:– Height 146.5 cms (2nd centile), weight 52.4 kgs

(50-75th 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 agenesis60 % ectopic thyroid gland10 % 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:

SpasticityGait disordersIncoordinationAwkwardnessTremor & jerky movementsCerebellar ataxia & nystagmusSensorineural 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/m2.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/lTSH 29.2 mIU/lL-Thyroxine to 50 mcg o.d

1/8/94 Total thyroxine 114 nmol/lTSH 0.16 mIU/l

7/11/94 Well, growing normallyFree 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.dDose equivalent to 180 mcg/m2.day

Date Thyroxine Free T4 TSH(mcgs od) (pmol/l) (mU/l)

24/4/95 75 22.0 99.212/9/95 75 24.3 23.825/9/95 75 9.6 91.8

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/lTSH 0.7 mU/l

Conclusion?

7/11/95 l-thyroxine reduced to 50 mcgs

28/11/95 Free T4 41.4 pmol/lTSH 7.2 mU/l

4/12/95 D.N.A.

22/1/96 Brought to clinic by fatherFree T4 44 pmol/lTSH 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/lTSH 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/lTSH 4.17 mU/l

3/10/96 Free T4 22.5 pmol/lTSH 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