Paediatric endocrinology for adult endocrinologists

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
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
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
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
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
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

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Paediatric endocrinology for adult endocrinologists

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Paediatric endocrinology for adult endocrinologists — Presentation Transcript