11

Precocious PubertyPrecocious Pubertycase reviewscase reviews

Nadia Muhi IddinNadia Muhi Iddin

Endocrinology PLEATEndocrinology PLEAT

Conquest hospital 8/7/2011Conquest hospital 8/7/2011

22

Case 1Case 1

• Term baby. Born locally. 2.8KgTerm baby. Born locally. 2.8Kg

• Primigaravida 18 year old mother.Primigaravida 18 year old mother.

• Uneventful pregnancy and delivery.Uneventful pregnancy and delivery.

• No significant medical history.No significant medical history.

• Family now had a 4 month old baby at Family now had a 4 month old baby at time of child referral to paediatric time of child referral to paediatric services.services.

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3/2008 3/2008

• GP referral at 3.5 year with 2 month history of GP referral at 3.5 year with 2 month history of breast development and rapid growth.breast development and rapid growth.

• Seen with in a month. Had single episode of Seen with in a month. Had single episode of vaginal bleeding & abdominal pain.vaginal bleeding & abdominal pain.

• No headache or visual symptoms. No headache or visual symptoms. • Past history of mild eczema.Past history of mild eczema.• Breast stage B3 bilateral. No pubic or axillary Breast stage B3 bilateral. No pubic or axillary

hair growth. Family thought is was ( puppy fat)hair growth. Family thought is was ( puppy fat)• Height & weight 98Height & weight 98thth centile (2002 growth chart) centile (2002 growth chart) • Child now had 2 younger siblings 2 year old sister Child now had 2 younger siblings 2 year old sister

and 7 month old brother.and 7 month old brother.

44

InvestigationsInvestigations

• TFT,FSH, LH, 17B oestardiol.TFT,FSH, LH, 17B oestardiol.• Urgent MRI Head/Pituitary with Urgent MRI Head/Pituitary with

gadolinium under GA.gadolinium under GA.• Urine steroid profile.Urine steroid profile.• FBC, LFT, Ca Profile, U&E, creatinine, FBC, LFT, Ca Profile, U&E, creatinine,

Bicarbonate, Iron levels.Bicarbonate, Iron levels.• Bone age ( left hand & wrist)Bone age ( left hand & wrist)• Pelvic and renal US.Pelvic and renal US.

55

Blood test results.Blood test results.

DateDate LHLH FSHFSH

10/03/010/03/088

5.15.1 7.97.9

02/06/002/06/088

0.40.4 1.21.2

08/09/008/09/099

1.61.6 4.24.2

18/01/118/01/100

2.42.4 3.33.3

15/03/115/03/100

3.73.7 6.36.3

66

Bone age reportBone age report

DateDate Chronological Chronological ageage

Bone ageBone age

10/3/200810/3/2008 3y 6 months3y 6 months 8.9 years8.9 years

02/02/201002/02/2010 5y 5 months5y 5 months 9.1 years9.1 years

77

88

managementmanagement

• Diagnosis of Gonadotropin dependant central precocious Diagnosis of Gonadotropin dependant central precocious puberty.puberty.

• Discussion with paediatric endocrinologist & parents and Discussion with paediatric endocrinologist & parents and maternal grandfather.maternal grandfather.

• Discussion with pharmacy for medication. Discussion with pharmacy for medication. • Managements included Cryptoterone acetate 50mg tablet. Managements included Cryptoterone acetate 50mg tablet. • IM injections at hospital. Gonapeptyl depot 3.75mg IM injections at hospital. Gonapeptyl depot 3.75mg

( Triptorelin) 6/5/2008.( Triptorelin) 6/5/2008.• Further vaginal bleed.Further vaginal bleed.• 4 weeks interval. Commenced on Decapeptyl SR 11.25mg 4 weeks interval. Commenced on Decapeptyl SR 11.25mg

Tritorelin IM injection on 12 week interval.Tritorelin IM injection on 12 week interval.• Local appointment with paediatric endocrinologist 1/7/2008.Local appointment with paediatric endocrinologist 1/7/2008.• Offer of referral to CAHMS.Offer of referral to CAHMS.• Home care nursing team for the injections.Home care nursing team for the injections.

99

Follow upFollow up

• 1/2009. Injection interval reduced to 11 weeks. 1/2009. Injection interval reduced to 11 weeks. Becomes moody before injections.Becomes moody before injections.

• Illness 9/2009 reduced energy .Illness 9/2009 reduced energy .• Mother coping with appointments and 3 young Mother coping with appointments and 3 young

children.children.• Started reception year and school support at Started reception year and school support at

home. ( play therapy)home. ( play therapy)• 7/2009 reduced to 9 weeks interval. LH.FSH not 7/2009 reduced to 9 weeks interval. LH.FSH not

completely suppressed.completely suppressed.• 2/2010 reduced to 8 week interval. Mother & child 2/2010 reduced to 8 week interval. Mother & child

happy.happy.

1010

ContinuedContinued

• 4/2010 family disruption and lost 4/2010 family disruption and lost appointment. Moved with appointment. Moved with grandparentsgrandparents

• 3/2010 product change needles.3/2010 product change needles.• 2/2010 repeat bone age.2/2010 repeat bone age.• Follow up 6 monthly and annual with Follow up 6 monthly and annual with

endocrinologist.endocrinologist.• No concerns started ballet. Went on No concerns started ballet. Went on

holiday. holiday.

1111

Case 2Case 2

• Term female baby Born at the Conquest.Term female baby Born at the Conquest.• 3425 gm birth weight. 11/20053425 gm birth weight. 11/2005• Admitted at 5 weeks for RSV Bronchiolitis.Admitted at 5 weeks for RSV Bronchiolitis.• Admitted at 10 weeks with croup.Admitted at 10 weeks with croup.• Admitted at 11 moths swallowed a Admitted at 11 moths swallowed a

dishwasher calgon tablet.dishwasher calgon tablet.• Presented at 2years 5months because of Presented at 2years 5months because of

rapid Growth in the last year. HV referral.rapid Growth in the last year. HV referral.

1212

HistoryHistory

• Always big baby with length near 91 centile.Always big baby with length near 91 centile.

• Parents tall mid parental height 91Parents tall mid parental height 91stst centile-98 centile-98thth..

• Currently in 5-6 year old cloths.Currently in 5-6 year old cloths.

• Older brother of 7 years and a shorter 5 year Older brother of 7 years and a shorter 5 year old brother.old brother.

• Current height and weight above 99.8Current height and weight above 99.8thth centile. centile.

• Grown 4.8cm in 4 months.Grown 4.8cm in 4 months.

• HV referral.HV referral.

1313

ExaminationExamination

• Pubic hair stage 2Pubic hair stage 2

• Breast stage 3Breast stage 3

• Body odourBody odour

• White vaginal discharge.White vaginal discharge.

• No headaches, visual symptoms, No headaches, visual symptoms, faints or fits.faints or fits.

1414

InvestigationsInvestigations

• FBC,LFT,U&E, Creatinine. Bicarbonate.FBC,LFT,U&E, Creatinine. Bicarbonate.

• Ca profile and proteinCa profile and protein

• TFT,LH,FSH,IGF1,oestardiol. ProlactineTFT,LH,FSH,IGF1,oestardiol. Prolactine

• Tumour markers AFP, Serum B HCG Tumour markers AFP, Serum B HCG

• Bone ageBone age

• MRI head under GAMRI head under GA

• Pelvic & renal US.Pelvic & renal US.

1515

ManagementManagement

• At age 2 years and 9 months. 8/2008At age 2 years and 9 months. 8/2008

• Treptoreline ( Gonapeptyl) IM injection.Treptoreline ( Gonapeptyl) IM injection.

• Oral Crypriterone acetate.Oral Crypriterone acetate.

• Followed in 4 weeks . Followed in 4 weeks .

• Meetings with family and printed Meetings with family and printed information. Contact with nurse team.information. Contact with nurse team.

• Blood stained discharge 9/2008. Blood stained discharge 9/2008.

1616

Bone ageBone age

DateDate Chronological Chronological ageage

Bone ageBone age

2/6/20082/6/2008 2 y 6 months2 y 6 months 7.3 y7.3 y

12/08/201012/08/2010 4y 9 months4y 9 months 7.4 y7.4 y

1717

Hormonal testsHormonal tests

DateDate 17.beta 17.beta oestradioloestradiol

LHLH FSHFSH

12/08/0812/08/08 184pmol/l184pmol/l 3.53.5 8.98.9

05/11/0905/11/09 9797 3.03.0 1.61.6

14/10/1014/10/10 <73<73 0.60.6 0.90.9

1818

Other investigationsOther investigations

• Presenting IGF1:47.3 (4-20)Presenting IGF1:47.3 (4-20)

• Presenting IGFBP3: 3.4 (0.4-2.9)Presenting IGFBP3: 3.4 (0.4-2.9)

• Prolactin:1842mU/L. Repeat test Prolactin:1842mU/L. Repeat test 190mU/L190mU/L

• Urine steroid profile qualitatively normal.Urine steroid profile qualitatively normal.

• Pelvic US was difficult but reported both Pelvic US was difficult but reported both ovaries mature with follicles. Left ovaries mature with follicles. Left 22mmX15mmUterus mature.22mmX15mmUterus mature.

1919

ProgressProgress

• 10/2008 Blood stained vaginal discharge.10/2008 Blood stained vaginal discharge.• Mother concern about appetite.Mother concern about appetite.• 3/2009 Reduced injections to every 10 3/2009 Reduced injections to every 10

weeks.weeks.• 11/2009 Mood changes 1 week before 11/2009 Mood changes 1 week before

medication.medication.• 1/2010 technical difficulties revert to 4 1/2010 technical difficulties revert to 4

weekly medication. Stress.weekly medication. Stress.• 1/2011 Unwell for 3 weeks unrelated illness.1/2011 Unwell for 3 weeks unrelated illness.• 6 monthly and annual follow up. Growth 6 monthly and annual follow up. Growth

and endocrine. and endocrine.

2020

2121

Precocious PubertyPrecocious Puberty

• True precocity refers to an abnormally True precocity refers to an abnormally early puberty in which physical early puberty in which physical changes follow a normal progression changes follow a normal progression and lead to full sexual maturity.and lead to full sexual maturity.

• Age below 8 years in girls and 9 in Age below 8 years in girls and 9 in boys.boys.

• Variant under age 6 in girls and under Variant under age 6 in girls and under 8 for menarche.8 for menarche.

• Partial forms of precocious puberty. Partial forms of precocious puberty.

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Cause of precocious pubertyCause of precocious puberty

Complete/true(Gonadortopin)

LHRH dependent

Constitutional (idiopathic)

Organic brain disease:Tumours, hydrocephalus

Sever head trauma post infections

irradiation

2323

Incomplete/ false/LHRH Incomplete/ false/LHRH independent/ pseudo pubertyindependent/ pseudo puberty

Girls/ feminising

Ovarian cyst or tumour:Granulosa theca

cell tumours

Adrenal oestrogen producing tumour

2424

Incomplete continuedIncomplete continued

Boys. Isosexual/ Masculinising

hCG secreting tumours Adrenal tumours

Lydig cell tumours ,teratoma

Congenital adrenal hyperplasia21 hydroxylase deficiency

11beta hydroxylase deficiency

Familial testotoxicosis. Familial male precocious puberty

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Incomplete/LHRL in both Incomplete/LHRL in both sexes sexes • McCune-Albright McCune-Albright

syndromesyndrome

• Primary Primary hypothyroidism. hypothyroidism. Long standingLong standing

• Exogenous sex Exogenous sex steroid exposure. steroid exposure.

Partial forms of Partial forms of Precocious PubertyPrecocious Puberty

• Premature thelarchePremature thelarche

• Premature Premature adrenarcheadrenarche

• Premature isolated Premature isolated menarche.menarche.

The 1The 1stst 2 are much 2 are much more common.more common.

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McCune –Albright syndromeMcCune –Albright syndrome

• Irregular skin pigmentationIrregular skin pigmentation• Fibrous bone dysplasiaFibrous bone dysplasia• Endocrine autonomy of glands notably ovaries.Endocrine autonomy of glands notably ovaries.• Very enlarged ovaries with solitary cystsVery enlarged ovaries with solitary cysts• Precocious puberty with early vaginal bleeding. Precocious puberty with early vaginal bleeding. • *Gene map locus 20q13.2*Gene map locus 20q13.2• Bone fracturesBone fracturesRef: Geneva foundation for Ref: Geneva foundation for medical education& research.medical education& research.

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Premature thelarchePremature thelarche

• Infant or young girlInfant or young girl

• Transient/ CyclicalTransient/ Cyclical

• Often asymmetricalOften asymmetrical

• No growth acceleration or other pubertal No growth acceleration or other pubertal features.features.

• Parallel follicular development but uterus Parallel follicular development but uterus remains small.remains small.

• Self limiting but may progress to early Self limiting but may progress to early puberty.puberty.

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Premature adrenache Premature adrenache /Pubarche/Pubarche• Normal mid childhood 6-8 years increase Normal mid childhood 6-8 years increase

in adrenal androgens due to maturation of in adrenal androgens due to maturation of Zona reticularis.Zona reticularis.

• Modest growth spurt.Modest growth spurt.• Early pubic hairEarly pubic hair• Advanced bone age.Advanced bone age.• More common in girlsMore common in girls• If before age 6 or increasing exclude CAH If before age 6 or increasing exclude CAH

and adrenal tumours.and adrenal tumours.

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Guide to examinationGuide to examination

• Detailed examination Detailed examination in girls under 6 yearsin girls under 6 years

• Abnormal sequence or Abnormal sequence or virilisation in girls.virilisation in girls.

• Neurological Neurological symptoms, symptoms, hypertension or hypertension or abnormal growth.abnormal growth.

• Testicular palpation in Testicular palpation in boys.boys.

Boys

Infantile testesRapid growth

Adrenal

Symmetrical enlargedTestes

Intracranial

Single large testesGonadal tumour

3030

Issues to considerIssues to consider

• Explanation. 90% Ideopathic in girls.Explanation. 90% Ideopathic in girls.

• Support. Child. Family and schoolSupport. Child. Family and school

• Suppressing medications. GnRh analoguesSuppressing medications. GnRh analogues

• Monitoring of growth. Rate and puberty.Monitoring of growth. Rate and puberty.

• Bone age.Bone age.

• Monitoring of hormonal levels.Monitoring of hormonal levels.

• Final height.Final height.

• Side effects of medication.Side effects of medication.

3131

Treatment requires specialist Treatment requires specialist managementmanagement• Gonadotropin depend precocious Gonadotropin depend precocious

puberty :Gonadorelin analoguespuberty :Gonadorelin analoguesAim: Aim: 1.1. Delay development of secondary sex Delay development of secondary sex

characteristics characteristics 2.2. Reduce growth velocityReduce growth velocityGonadotropin Independent precocious puberty.Gonadotropin Independent precocious puberty.1.1. Crypterone is a progesterone with anti-Crypterone is a progesterone with anti-

androgen activity used in gonodotropine androgen activity used in gonodotropine independent Precocious Puberty/independent Precocious Puberty/

2.2. TestolactoneTestolactone3.3. Spironolactone.Spironolactone.

3232

Gonadorelin analoguesGonadorelin analogues

• Goserelin. Not licensed for use in children.Goserelin. Not licensed for use in children.Implant 2 manufacturers.Implant 2 manufacturers.• Leuprorelin acetate.Not licensed for use in Leuprorelin acetate.Not licensed for use in

children. 1 manufacturer. ( 4 & 12 week)children. 1 manufacturer. ( 4 & 12 week)Subcutaneous or IM injection. Subcutaneous or IM injection. • Triptorelin: Triptorelin: Sub cut or im 3-4 weekly. ( Gonapeptyl)Sub cut or im 3-4 weekly. ( Gonapeptyl)IM every 3 months ( Decapeptyl SR).IM every 3 months ( Decapeptyl SR).Side effects: Local, GI, asthenia, arthralgia .Side effects: Local, GI, asthenia, arthralgia .• Other products licensed in USA. Products under Other products licensed in USA. Products under

trial.trial.

3333

Behavioural interventionsBehavioural interventions

• Peer relationships in school/tall stature.Peer relationships in school/tall stature.• Adults raised expectations.Adults raised expectations.• No evidence of long term psychological No evidence of long term psychological

sequel.sequel.• Protection from inappropriate relationshipsProtection from inappropriate relationships• Patient education.Patient education.• Play therapy & or psychology referral for Play therapy & or psychology referral for

child and family with significant issues. child and family with significant issues.

3434

ReferencesReferences

• Hospital paediatrics: A.Milner/D.HullHospital paediatrics: A.Milner/D.Hull

• Nelson text book of pediatrics:18Nelson text book of pediatrics:18thth EditionEdition

• BNF for children2010-2011.BNF for children2010-2011.

• Paediatrics. Clinical guide for nurse Paediatrics. Clinical guide for nurse practitioners.practitioners.

• Essential paediatrics: David HullEssential paediatrics: David Hull