Dr Craig Jefferies 1. Diabetes 1. Diabetes Paediatric 2

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PAEDIATRICS

Paediatric EndocrinologyCommon problems

Dr Craig Jefferies

Teaching Content

1. Diabetes 1. Diabetes

2. Vitamin D2. Vitamin D

3. Thyroid3. Thyroid

4. Puberty and Growth 4. Puberty and Growth

Diabetes definition

Before Insulin After Insulin

PAEDIATRICSCase-1

12 yr old Caucasian girl Mild weight loss, polyuria, polydipsia. Random glucose 20 mmol/l, Trace ketonuria.Father diabetic

From 24 yrs age & Rx insulin, no complications as yet.

BMI SDS +1, No acanthosis nigricansHbA1c always around 6.5% (N= 4-6%)Remains with HbA1c <7% for next 2 years

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PAEDIATRICSCase-1

What is the differential diagnosis and what (if any) investigations are required?

Pre-Diabetes antibody screeningICA, GAD, IAA and IA2 antibody (negative)Presentation insulin 27 mU/l (BG 20 mmol/l).DNA for ?MODY

Diagnosis: MODY 3.HNF1α mutation in exon 4.

PAEDIATRICS

MODY: Glucokinase underfunction (AD) or transcription factor disease

Influences expression of many other genes in several organs.

Failure of β cell development ± ↓insulin gene transcriptionHattersley. J Paed Endocrinol Metab. 2000; 13(S6):1411-7.

PAEDIATRICSMODY Prevalence

Monogenic DM, more to come.Freq of MODY and forms varies with

country, ethnicity, policy.

In the UK Paediatric Clinics MODY is >10x more prevalent than type 2 DM.Hattersley. J Paed Endocrinol Metab. (2000)

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PAEDIATRICSMODY 3

Reputedly commonest form of MODY (65%).

Progressive β cell failure, usually presents with symptomatic hyperglycaemia in 20’s sometimes in adolescence.

Those at risk of developing MODY 3 have normal insulin secretion however fail to increase insulin secretion with increased plasma glucose.

PAEDIATRICSCase-2

A 110 kg 13 yr old Pacific Island female presents with polyuria and polydipsia. Mother has type 2 DM. BG = 30 mmol/lKetonuria =TraceWeight loss 20 KG

PAEDIATRICSCase-2

Cervical and axillary acanthosis nigricans.Tanner 5 breast/pubic hair.BP=140/85 Renal function normalInvestigations:

ICA, GAD negativeDyslipidaemicMicroalbuminuria

PAEDIATRICSCase-2

What sort of Diabetes does she have?Symptomatic Type 2 Diabetes Mellitus

1) Ketonuria Can be present2) “diabetes” autoantibodies negative3) Family history First degree relative4) Pubertal5) Acanthosis nigricans

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Obesity Trends* Among U.S. AdultsBRFSS, 1985

No Data <10% 10%–14%

(*BMI ≥30, or ~ 30 lbs overweight for 5’ 4” person)


No Data <10% 10%–14%



No Data <10% 10%–14% 15%–19%



No Data <10% 10%–14% 15%–19%


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No Data <10% 10%–14% 15%–19% ≥20



No Data <10% 10%–14% 15%–19% ≥20



No Data <10% 10%–14% 15%–19% 20%–24% ≥25%


Obesity* Trends Among U.S. AdultsBRFSS, 2003


No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

T2DM and obesityGuidelines for type 2 diabetes (Starship)

Who should be tested for diabetes?ANY young person with SYMPTOMS of diabetes

ANDObese* children (normally BMI SDS >3-4 SDS)

WITH acanthosis nigricansAND one of the following additional risks for type 2 diabetes

>10 years of ageHigh risk diabetes ethnic group: Maori, Pacific Island or AsianFirst degree relative with type 2 diabetes Their mother had gestational diabetesPresence of polycystic ovarian syndrome (PCOS)Being known to be hypertensive or dyslipidaemic

Test: Preferably the formal OGTT

Vitamin D

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Bowed legs Somalian Boy, 18 months old presents with delayed motor milestones, weakness and bowed legs.

Breast fed till 16/12sMother pregnant, wears strict religious coveringsNormal diet, hates milk and drinks ribena

Examination reveals flared epiphyses, hypotonia, and frontal bossing. Rickets confirmed on X-ray

Case: Lab investigations

FBC Mild anaemiaALP 1000 U/LCalcium 2.10 mmol/lPhosphate 0.9 mmol/lAlbumin 40Normal renal function PTH 20 pmol/l (1-5) 25 OH25 OH Vitamin D Low (<25)

Cholecalciferol (D3)

Skin

7 dehydrocholesterol Diet VitD3

UV light

1:25 (OH)2 VitD3 (calcitriol)

25(OH) VitD3 (calcidiol)25α Hydroxlyase

1α Hydroxylase

LIVER

Kidney

Vitamin D intake

“man” received most Vitamin D by sunlight

Diet has only become more important since sunlight exposure and skin area reduced (~5%).Recommended intake

in infants of 10µg/day (400 IU)in the elderly 15µg/day (600 IU) is conservative.

Total body sun exposure provides ~ 250 µg/day (10,000 IU) – consider this the ‘physiological limit’Hypervitaminosis D all caused with doses > 1000 µg/day (40,000 IU)

CausesVitamin D deficiency/ resistance

Nutritional↓ 1α hydroxylase functionVit D receptor mutation

Calcium DeficiencyDietary (no milk, allergies etc)Preterm TPN

Phosphate DeficiencyRenal disease (cystinosis, Fanconi’s etc)Renal loss (X-linked, Autosomal dominant, tumour induced).Preterm TPN

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Clinical ManifestationsOsseous

CraniotabesFrontal Bossing in early infancyLarge fontanelle with delayed closureHypotonia and delayed walkingRickety rosary, big wristsSkeletal deformities (bow legs, narrowed pelvic outlet, scoliosis)Limb painSeizures

PAEDIATRICS

Thyroid

Thyroid Physiology -1 Thyroid physiology-2

Thyroid Physiology -3PAEDIATRICS

Thyroid

5 day old neonate has an elevated TSH on neonatal screening >100 mIU/LFT4 2.1pmol/l (15-35)FT3 1.2pmol/l (3.9-9.0)TSH 145 mIU/L (0.5-6.0)

Mildly jaundiced quiet baby. No dysmorphicfeatures.

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PAEDIATRICS

Thyroid scintiscanIncreased unptake into a normal sized, appropriately sited gland.

Dyshormogenesis

Initial treatment with L-thyroxine 10 mcg/kg

Normalization of FT4 and FT3 by day 14

Trial off thyroxine at 3 years of age

PAEDIATRICSCase

6 day old neonate has an elevated TSH on neonatal screening >100 mIU/LFT4 3.8pmol/l (15-35)TSH 135 mIU/L (0.5-6.0)

No features of hypothyroidism or hx or examination.

PAEDIATRICSCase

Thyroid scintiscan – athyreosis

Treated with L-Thyroxine 15mcg/day

TFTs over the first 12 months were normal and minimal increase in her L-Thyroxine was required.

At 13 months of age the mother ran out of L-thyroxine and failed to fill further prescriptions!

PAEDIATRICSCase

But she continued with monthly TFTs.

4 months after stopping L thyroxineFT4 18 pmol/l (15-35)FT3 6 pmol/l (3.9-9.0)TSH 2.5 mIU/l (0.5-6.0)

PAEDIATRICSCase

What is the likely cause for this presentation?A normally formed gland can be missed on thyroid scintiscan in the presence of blocking antibodies. TSH receptor needed for I/technecium uptakeTransient hypothyroidism secondary to TSH blocking antibodies.

A normally formed gland can be missed on thyroid scintiscan in the presence of blocking antibodies. TSH receptor needed for I/technecium uptake

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PAEDIATRICSGROWTH PAEDIATRICSGrowth regulated by:

Adequate NUTRITIONCaring ENVIRONMENTNormal CHROMOSOMESGood HEALTHAppropriate functioning HORMONES

PAEDIATRICSGrowth Hormone secretion:

Pulsatile with low baseline.Primarily at night (stages III - IV sleep).Increased by: sleep, exercise stress hypoglycaemia, amino acids, malnutrition, sex steroids.Decreased by: obesity, psychosocial deprivation.

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PAEDIATRICSGH actions PAEDIATRICSSex steroids

Greatest effect on skeleton maturation.Estrogen or TestosteroneESTROGEN

Responsible for epiphyseal maturation/closure in both sexes.

ESTROGEN

PAEDIATRICSThyroid hormones

Facilitatory role in growth.Necessary for normal GH secretion and growth plate development (and body proportions).

PAEDIATRICSInsulin

Facilitatory role in growth.Provides substrate for growth (amino acid uptake, glycogenesis and lipogenesis).

Normal GrowthThe infant/child/puberty model of growth: (Karlberg)•Infant - Birth to 2 years. Rapid growth at birth declining rapidly over the first 2 years of life – less growth hormone dependent.

•Childhood - 2 years until puberty. Relatively constant annual growth - growth hormone

•Puberty - growth primarily dependent on sex steroids and increased growth hormone release.

Sex steroids cause fusion of skeletal epiphyses and growth arrest.

PAEDIATRICSHeight velocity (HV)

HV differentiates normal variant short stature from pathologicalshort stature.

HV calculated over 6-12 month interval because of errors in measurement .Normal height velocity 25-75 PC.

Note HV curve for children with delayed puberty.

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PAEDIATRICS

Short Stature

PAEDIATRICS

A common clinical problem.A symptom and not a disease.May represent a variant of normal growth.May indicate pathology.One of the commonest manifestations of

chronic illness; recognised or unrecognised.

PAEDIATRICSShort Stature History

Mother and fathers heights.MPH = M (cm) + F (cm) ±13 cm /2.MPH range ±8 cm.FH short stature: males <165 cm

females <152 cmFH delayed puberty: menarche >14 yrs in females and continued

growth after high school in males.

Look at other sibs child development records.

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PAEDIATRICSGrowth Disorders

Normal height velocity:Familial short statureConstitutional delay in growth and

development

Poor height velocity:Usually pathologicalDisproportionate

Bone Age

Greulich and Pyle standards.Imprecise picture matching.1 yr intervals.Tables of Bayley & Pinneau for final Ht prediction.

PAEDIATRICSNormal Variant Short Stature

Familial short stature.Constitutional delay of growth and development.Account for >95% of children who present with

short stature.HALLMARK IS NORMAL HEIGHT VELOCITY.

PAEDIATRICS

PAEDIATRICSIUGR/SGA

Intrauterine growth retardation or small for gestational age: very common.Birth weight <10th PC for gestation.Catch-up growth above 3rd PC usually occurs by 6/12 but

may drag on to 2 yrs.Short stature by 2 yrs usually associated with short final

height.Approx 10% become short adults.

PAEDIATRICSTurner Syndrome

Consider in ALL girls with unexplained short stature or Ht below MPH range.Commonest feature is short for MPH (100%).50% will only have short stature as clinical feature.Present with short stature, poor HV or delayed puberty.

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Precocious Puberty

The three puberties of lifeDefinitions- Normal Puberty

Normal Puberty (All in tempo)Central activation of the H-P-Gonadal axis Progressive sequential changesAppropriate rate (over 3-4 years)

Girls (First Sign)Breast development before Growth Spurt

Boys (First Sign)Increased testicular enlargement>4ml (orchidometer)Growth spurt later

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Precocious Puberty -Definition

Pathological processToo earlyToo fastPathological hormonal milieu

ArbitraryFemales <8 years (menarche <9 years)

This will be 2% of healthy girlsMales <9 years

Clinical confirmationClinical signs (and USS in females)Hormonal evaluationBone age advancementRate of acceleration

Clinical signs of sustained sex steroids exposure

Growth height velocityheight compared to mid parental height

Breasts progressive developmentAndrogen Pimples/acne/body odour

Introitus pink-red epithelium pre oestrogenwhite-pink with sustained oestrogen exposure(cornification of epithelium)

Investigation (First line)Bone Age (X-ray L hand and wrist)

USS pelvis Uterine size, sometimes useful info on ovaries.+/- TFT

Unhelpful/ Useless/ Un-interpretable testsFSH and LHTestosteroneOestradiol

Differential Diagnosis

Endogenous Exogenous

CentralGnRH dependent

PeripheralGnRH independent

O/CHRTE2 creamsSoy?‘Natural remedies’

GnRH (LHRH) stimulation testPubertal response LH dominantPrepubertal FSH dominant

Aetiology of Central PPIdiopathic

Structural AbnormalityHypothalamic HamartomaMeningomyleocoeleHydrocephalusNF-1

CNS insultNeonatal EncephalopathyCranial IrradiationTrauma/Surgery

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Aetiology of peripheral PP

OvariesCyst (benign/malignant)McCune-Albright

TestesTumourLH receptor+

Liver (beta HCG)Adrenal

TumourEnzyme defect

OtherExogenous (dad’s Androgel®)

CPP treatment

GnRH analoguesDepot GnRH analogues first line

Monitoring and FollowupRegular bone age (yearly)Some advocate regular USSGnRH stim tests

Treatment cessation

PAEDIATRICS

Paediatric EndocrinologyCommon problems

Documents

Dr Craig Jefferies 1. Diabetes 1. Diabetes Paediatric 2