abnormalities of growth and development in puberty · from puberty onset in boys to adult ......

CM E Adolescent medicine ndash I I

Disorders of grow th and pubertaldevelopment in the teenage yearspresent as a spectrum of abnormalitiesembracing common normal variantsless common disease states and raredisorders increasingly recognised andunderstood as genetic in origin Thisbrief review is intended to provide aguide to the diagnosis of problemspresenting most commonly inadolescentteenage children to helpwith initial assessment and manage-ment and to stress the need for referralto appropriate endocrine or otherspecialist services Long-term manage-ment of individual diagnoses is beyondthe scope of this article (references areprovided for further reading) In order tofocus on the teenage child precociouspuberty (by definition before the age of8 years in girls and 9 years in boys) isnot discussed but readers can seekguidance from a recent review1

Delayed grow th and puberty

Pubertal delay is the commonestproblem seen It is usually associatedwith apparent poor growth ndash but notnecessarily with short stature as growthrate is intimately related to pubertaldevelopment What may seem to begrowth failure is an inevitable conse-quence if a child is later than averagewith timing of onset of puberty (as are50 of children) The clinical problemis to decide whether development isabnormal in terms of being late withthe onset of puberty or of failing toprogress to completion of puberty at anormal rate (arrested puberty) Growthdelay is common and usually there is nounderlying pathology (boys in particular

may none the less benefit from treat-ment) whereas arrested pubertaldevelopment is a major cause for con-cern By convention delayed puberty isdefined as lack of puberty at an age +2standard deviations (SD) above thepopulation mean (boys 14 years girls13 years)2 The mean time to progressfrom puberty onset in boys to adulttesticular volume is 32plusmn18 years (meanplusmnSD) and in girls from onset of breastdevelopment to menarche is 2411(mean plusmnSD) years Thus if 4ndash5 yearshave elapsed from puberty onset with-out completion investigations shouldbe made

Delayed puberty may be classified asprimary delay (constitutional) orsecondary delay (underlying chronic ill-ness) Children with failure to enterpuberty because of a disorder of thehypothalamo-pituitary-gonadal axismay also be divided into two groupshaving either hypogonadotrophic orhypergonadotrophic hypogonadism

depending on whether the defect lies athypothalamo-pituitary or gonadal level(Table 1) Suggested plans of assessmentand investigation are given in Figs 1and 234

Pubertal delay

Constitutional (primary) delay of growthand puberty

A normal variant of grow th morefrequently seen in clinical practice inboys than girls is constitutional primarydelay of growth and puberty This pre-ponderance of males vs females partlyreflects social values in respect of thesignificance and disadvantages of bothshort stature and delayed pubertyThere is often a family history ofdelayed puberty Children will havesustained a normal growth rate throughthe prepubertal years but the delayedonset of puberty (usually by an age of13ndash15 years at presentation) and lack ofattendant growth spurt lead to aprogressive fall in height centilePhysical examination should be normalbut it is important to note whether signsof pubertal development are presentand delayed rather than absent Allendocrine investigations (Table 2)

Journal of the Royal College of Physicians of London Vol 34 No 2 MarchApril 2000 141

Charles R Buchanan BSc MRCP FRCPCHConsultant Paediatric EndocrinologistKingrsquos College Hospital London

J R Coll Physicians Lond 200034141ndash6

Abnormalities of growth and

development in puberty

Hypogonadotrophic (low LH FSH) disorder s

No underlying disease Constitutiona l delay of growth and puberty

Hypothalamic-pituitary disorder Congenital or acquired multiple pituitary hormone deficienciesIsolated gonadotroph in deficiency (eg Kallmannsyndrome)

Dysmorphic syndromes eg Noonan syndrome Prader-Willi syndrome

Chronic illness Systemic disease (eg asthma cystic fibrosis Crohnrsquos disease primary hypothyroidism)Long-term glucocorticoid therapyAnorexia nervosa

Hypergonadotrophic (high LH FSH) disorders

Sex chromosome anomalies Turner syndrome Klinefelter syndrome

Other causes of gonadal failure Gonadal dysgenesisagenesisSurgery radiotherapy chemotherapyGalactosaemia (girls)Autoimmune gonadal failurePrimary ovarian failure

LH = luteinising hormone FSH = follicle-stimulating hormone

Table 1 Summary of main causes of delayedarrested puberty

CM E Adolescent m edicine ndash I I

should be normal for a pre- or earlypubertal child with some delay in boneage of perhaps 2ndash3 years

Dysmorphic features may suggestNoonan syndrome (perhaps as com-mon as 1 in 2000 with autosomaldominant inheritance5) in which severepubertal delay is common Girls mayshare many similar physical featureswith Turner syndrome with short staturefrom infancy but unlike Turner syn-drome impaired intellectual develop-

ment is often a major feature Boys havea high incidence of cryptorchidism Thediagnosis is made on clinical groundsalthough the gene defect may soon bedetermined Other syndromes withpubertal delay (such as Prader-Willi syndrome) are nowadays likely to havebeen recognised before the adolescentyears

Unfortunately there is no endocrinetest which will reliably distinguishconstitutionally delayed puberty from

isola ted hypogonadotrophic hypogo-nadism (see below) time observationand spontaneous pubertal developmentare the critical factors Management istherefore focused on exclusion of thosedisorders which may be associated withpubertal delay through chronic illnessor with multiple pituitary hormone defi-ciencies By the age of 13ndash14 yearsraised serum gonadotrophin levels arelikely to identify patients with hyper-gonadotrophic hypogonadism

142 Journal of the Royal College of Physicians of London Vol 34 No 2 MarchApril 2000

zz z

zz z z

z

Fig 1 Algor ithm for the investigation of delayed puberty when there are signs of pubertal development Reproduced with permissionfrom Ref 3 CDGP = Constitutional delay of growth and puberty


Secondary pubertal delay

Most chronic illnesses will affect growthandor pubertal development withincreasing effect in relation to theirseverity and duration through under-nutrition chronic inflammation andcertain drug treatments (eg gluco-corticoids for asthma or renal disease)6Mechanisms underlying these effects ongrow th are becoming better under-stood78 For many children the

management of a long-standing illnesswill include anticipation of the need forhelp or adjustment of treatmentthroughout puberty (eg cystic fibrosisasthma renal failure diabetes mellitus)whereas other children may first presentonly with impaired growth andorimpaired pubertal development (eganorexia nervosa) possibly even withminimal other signs or symptoms ofchronic disease (especially inflam-matory bowel disease) Thus from a

diagnostic approach all patients withdelayed growth and puberty should beassessed clinically and investigated toexclude such chronic diseases (Table 2)Specific endocrine causes of delayedpuberty in this category include primaryhypothyroidism hypercortiso lismhyperprolactinaemia (prolactinoma)thalassaemia major and sickle celldisease (in which pituitary or gonadaldamage may also occur) As with consti-tutional delay the bone age is likely to


z

z

zz

z z z

Fig 2 Algor ithm for the assessment of delayed puberty w hen there are no signs of puber ty Reproduced with permission from Ref 3CDGP = Constitutional delay of growth and puberty


be delayed in keeping with the physicalmaturity of the child

Pubertal failure

Hypogonadotrophic hypogonadism

Patients with hypogonadotrophichypogonadism may have congenital oracquired disorders It is important todistinguish iso lated gonadotrophindeficiency disorders from those withmultiple pituitary hormone deficiencies

Multiple pituitary hormone deficienciesThese are more readily diagnosed byhistory or demonstration of coexistingabnormalities of growth hormone thy-roid or adrenal function on pituitaryhormone tests and abnormal magneticresonance imaging (MRI) The mostcommon acquired causes includetumours in the hypothalamo-pituitaryregion and the sequelae of surgery andradiotherapy The possibility of a previ-ously unrecognised craniopharyngiomaor for example suprasellar germinomafocuses the need for adequate investi-gation without delay before impairedvision or devastating tumour progres-sion occurs The serum prolactin levelmay be modestly elevated (2ndash3 fold) inthe presence of a mass lesion com-pressing the pituitary stalk and reducingthe dopaminergic constraint on pro-lactin release A prolactinoma may be

the commonest pituitary tumour inadults but is very rare under 18 years9It may present with delayed puberty(more often in girls) but is more likely topresent with headache or secondaryamenorrhoea

Kallmann syndrome Isolated gonado-trophin deficiency (Kallmann syndrome)is uncommon but four times moreprevalent in boys than girls with X-linked abnormalities of the KAL gene (atXp223) commoner than other autoso-mal defects yet to be characterisedThese patients are of normal statureuntil they fail to undergo a normalpubertal growth spurt Anosmiaimpaired olfaction and mirror move-ment of upper limbs are important diag-nostic features while family historyichthyosis cafeacute au lait pigmentation andstructural renal abnormalities maysupport the diagnosis until definitiveconfirmation of a gene defect can beobtained through a supportivelaboratory MR I imaging of theolfactory10 bulbs may be helpful

Hypergonadotrophic hypogonadism

Gonadotrophin levels are raised inresponse to primary gonadal failurewhich results most frequently from sexchromosome anomalies causinggonadal dysfunction

Turner syndrome This syndrome iscaused by the absence or structuralabnormality of one X chromosome(45XO or variant) and occurs inapproximately one in 3000 women11Most are diagnosed in early childhoodon account of dysmorphic featuresassociated medical problems (eg con-genital cardiac or renal abnormalities)or short stature However a proportionof girls in particular those with a mosaicsex chromosome constitution have fewor only subtle features They maypresent with short stature only at aboutthe age of 12ndash13 years old when theirprogressive early childhood decline inheight centile together with lack of anormal pubertal growth spurt leads toa height deficit of about 15 cm fromtheir expected genetic potential ndashsufficient to arouse concern

It is estimated that perhaps only 20of Turner girls will have spontaneousonset of puberty while nearer to90ndash95 will require sex hormonetreatment to allow them to completepuberty and establish menses Thusmost will present with failure to enterpuberty Almost all (except for the fewwith tall parents) will by then be belowthe 2 height centile and a proportionwill present with arrested pubertyprimary amenorrhoea The diagnosis isconfirmed in most cases by lymphocytekaryotype analysis but in girls with lowgrade mosaicism the diagnosis mayoccasiona lly prove difficult withoutanalysis of a different cell source (egfibroblasts from skin biopsy)Psychological support may be morecrucial for these girls with lsquolatersquo diag-nosed Turner syndrome to come toterms with the rather sudden recog-nition of implications for their futurefertility rather than short stature asmost will achieve a final height close toor in the low but lsquonormalrsquo centilechannels

Klinefelter syndrome (47XXY) Thissyndrome occurs in approximately onein 600 men but few are diagnosedbefore puberty and many not even inadult life Pubertal onset is notnecessarily delayed but inadequatevirilisation results from impaired Leydigcell synthesis of testosterone semin-iferous tubule dysgenesis results ininfertility and the characteristic inappro-priate smallness of the testes (lt6 ml) inrelation to the degree of virilisation inlater puberty The assoc iation offeatures such as eunuchoid bodyproportions gynaecomastia a smallishpenis in some relatively tall stature forparental heights and behavioura lproblems in earlier childhood shouldsuggest the diagnosis in a boy in earlypuberty before the diagnosis is morereadily apparent from the small testesTreatment requires careful counsellingwith long-term testosterone replace-ment treatment to support completionof pubertal development and epiphy-seal fusion and through adulthood tomeet the physical and psychologicalneeds of the individual


Blood ThyroxineTSHLH FSHTestosterone oestradiolProlactinFull blood count platelets ESR or CRPCreatinineelectrolytesLiver function tests

Karyotype (all females males according to phenotype)

Bone age

Ultrasound Uterusovaries (females)

CRP = C-reactive protein ESR = erythrocytesedimentation rate FSH = folliclestimulating hormone LH = luteinisinghormone TSH = thyroid stimulatinghormone

Table 2 Baseline invest igations fordelayedarrested puberty


Noonan syndrome and Prader-Willisyndrome These two syndromes arecommonly associated with delayedpuberty in both sexes (see above) Themen may have undescended testeswhich may be hypoplasticdysgeneticand manifest as a hypergonadotrophichypogonadism requiring long-termtestosterone replacement This needs tobe distinguished from the relativelyhypogonadotrophic state if puberty issimply delayed

Primary gonadal failure Primary gonadalfailure may uncommonly arise in theteenage years through autoimmune dis-ease or there may be recognisedantecedent factors such as orchidopexyfor undescended testes orchitis orexposure of the gonads to irradiation orgonadotoxic chemotherapy for child-hood malignancy Ovarian failure iscommon in women with galactosaemianow surviving to adulthood althoughthe mechanism for this is unclear menseem to have normal testicular function

Resistance to luteinising hormoneand follicle-stimulating hormone areautosomal recessive genetic disorderscaused by mutations in their respectivereceptors Together with other singlegene disorders they may prove to becommoner than previously suspectedcauses of delayed puberty or gonadalfailure12ndash15

Gynaecomastia

Another problem is gynaecomastiawhich is extremely common duringmale puberty (30ndash50 of all healthyboys) and may persist for a few monthsor 1ndash2 years before resolution It isthought to result from oestrogen(derived in men by aromatisation of asmall proportion of testosterone) beingable to exert more biological effect inearly puberty before higher sustainedtestosterone levels are achieved Inobese boys it may be particularlymarked and in slimmer boys moreobvious Provided that grow th andpubertal development are otherwiseprogressing appropriately it does notnormally require investigation unlessthere are particular features of concern

Increased incidence severity andlikelihood of persistence are associatedwith Klinefelter syndrome (see above)but testes greater than 6 ml volumewould generally exclude Klinefeltersyndrome and the need to check akaryotype

Galactorrhoea with gynaecomastiashould raise susp icion of a prolac-tinoma8 There are extremely rare casesof severe progressive gynaecomastiaassociated with an oestrogen secretinggonadal tumour with acceleratedgrowth and bone age and lack ofnormal pubertal virilisation

Management of gynaecomastiarequires reassurance that it is acommon normal occurrence andshould regress with time with advicethat no effective medical treatmentexists ndash but weight reduction is helpfulin the obese boys Surgical removal ofthe breast tissue through a circum-areolar incision if indicated for psycho-logical reasons can have excellentresults particularly in non-obeseindividuals

References

1 Merke DP Cutler GB Jr Evaluation andmanagement of precocious puberty ArchDis Child 199675269ndash71

2 Tanner JM Growth at adolescence 2ndedn Oxford Blackwell ScientificPublications 1962

3 Albanese A Stanhope R Investigation ofdelayed puberty Clin Endocrinol 199543105ndash10

4 Argente J Diagnosis of late pubertyHormone Res 199951(Suppl)95ndash100

5 Ranke MB Heidemann P Knupfer CEnders H et al Noonan syndromegrowth and clinical manifestations in144 cases Eur J Pediatr 1988148220ndash7

6 Preece MA Law CM Davies PSW Thegrowth of children with chronic paedi-atric diseases Clin Endocrinol Metab198615453ndash77

7 Brain CE Savage MO Growth andpuberty in chronic inflammatory boweldisease Baillieres Clin Gastroenterol1994883ndash100

8 Handelsman DJ Dong Q Hypothalamic-pituitary-gonadal axis in chronic renalfailure Endocrinol Metab Clin North Am199322145ndash61

9 Colao A Loche S Cappa M DiSarno Aet al Prolactinomas in children andadolescents Clinical presentation andlong-term follow-up J Clin EndocrinolMetab 1998832777ndash80

10 Quinton R Duke VM de Zoysa PA PlattsAD et al The neuroradiology ofKallmannrsquos syndrome a genotypic andphenotypic analysis J Clin EndocrinolMetab 1996813010ndash7

11 Ranke MB Optimizing the managementof Turner syndrome Baillieres ClinPaediatrics 19964295ndash307

12 Aittomaki K Herva R Stenman UHJuntunen K et al Clinical features ofprimary ovarian failure caused by a pointmutation in the follicle-stimulatinghormone receptor gene J Clin EndocrinolMetab 1996813722ndash6

13 Allingham-Hawkins DJ Babul-Hirji RChitayat D Holden IJ et al Fragile X premutation is a significant risk factor forpremature ovarian failure theInternational Collaborative POF in Fragile


copy Short stature presenting in the early teenage years most commonly results from

pubertal delay

copy Pubertal delay is usually lsquoconstitutionalrsquo but systemic disorder s and Turner

syndrom e in girls should be excluded

copy Gonadotrophin deficiency cannot be easily distinguished from constitu tional

delay unless associated features (eg anosm ia) make the diagnosis likely

copy Elevated basal gonadotrophin (LH FSH) levels are helpful to identify patients

with primary hypogonadism

copy After identif iable causes of delayed puberty have been excluded treatment w ith

sex steroids may proceed and observation over time will distinguish delay from

gonadotrophin deficiency

copy Gynaecomastia is very common in boys clinical assessment and reassurance

are usually sufficient

Key Points

This review discusses the problemsfacing adolescents with juven ileidiopathic arthritis (JIA) and how theyare managed Similar problems faceadolescents with juven ile dermato-myositis systemic lupus erythematosusrarer connective tissue diseases andother musculoskeletal conditions but adetailed discussion concerning thesediseases is beyond the scope of thisarticle

The size and scope of the problem

JIA has a prevalence of approximately130 per 100000 children The classific-ation has recently been changed (Table1) Although principally a disease ofyounger children JIA presents betweenthe ages of 10 and 16 years in 25 ofpatients Those who develop systemicor polyarticular disease at a youngerage have a higher incidence ofdestructive joint disease The commonbelief is that JIA lsquoburns outrsquo before orduring adolescence so the ensuingproblems improve or remain static butin fact in one-third of these childreninflammatory activity continues intoadult life12

Approximately 20 of children withJIA will be unable to perform someaspect of self-care1 the longer thefollow-up the greater both the dis-ability3 and the deterioration inpsychosocial function1 Unemploymentis common and significantly does notcorrelate with educational achieve-ment24 While many people with majordisabilities enjoy happy fulfilled livesothers with much milder functionalimpairment lead seriously restric tedlives limited by factors often simplethat may be avoided

Now that 90 of children withchronic disabilities reach their 20thyear5 attention has been focused ontheir successful transition to adulthoodThe key elements have been identifiedfor an effective transition programmefor adolescents with various chronic ill-nesses leaving the paediatric service6ndash8While the key elements also apply toadolescents with JIA the details of theideal transition programme for thisgroup are far from established Only20 of the paediatric rheumatologydepartments in the UK provide atransition service6 and their standardsare variable To appreciate the late


X study mdash preliminary data Am J MedGenet 199983322ndash5

14 Davison RM Davis CJ Conway GS The Xchromosome and ovarian failure ClinEndocrinol 199951673ndash9

15 Latronico AC Anasti J Arnhold IJRapaport R et al Brief report testicularand ovarian resistance to luteinizinghormone caused by inactivatingmutations of the luteinizing hormonereceptor-gene N Engl J Med 1996334507ndash12

Address for correspondence Dr C RBuchanan Consultant PaediatricEndocrinologist Kingrsquos College HospitalDenmark Hill London SE5 9RS


Musculoskeletal diseases

in adolescence

copy 25 of children w ith juvenile arthr itis present between 10 and 16 years of age

copy A significant number of children with juvenile idiopathic arthr itis (J IA) develop

progressive destructive joint disease

copy New treatments such as methotr exate have revolutionised outcom e measures

in J IA

copy An ongoing multidisciplinary transit ion programme is important both to allow

the adolescent independence and to ensure a smooth transfer to the adult

service

Key Points

Jacqueline Clinch MRCP Senior Registrar in Paediatric Rheumatology

Peter Hollingworth FRCP Consultant Adult and Paediatric Rheumatologist

Department of Paediatric Rheumatology Southmead Hospital Westbury on Trym Bristol



should be normal for a pre- or earlypubertal child with some delay in boneage of perhaps 2ndash3 years

Dysmorphic features may suggestNoonan syndrome (perhaps as com-mon as 1 in 2000 with autosomaldominant inheritance5) in which severepubertal delay is common Girls mayshare many similar physical featureswith Turner syndrome with short staturefrom infancy but unlike Turner syn-drome impaired intellectual develop-

ment is often a major feature Boys havea high incidence of cryptorchidism Thediagnosis is made on clinical groundsalthough the gene defect may soon bedetermined Other syndromes withpubertal delay (such as Prader-Willi syndrome) are nowadays likely to havebeen recognised before the adolescentyears

Unfortunately there is no endocrinetest which will reliably distinguishconstitutionally delayed puberty from

isola ted hypogonadotrophic hypogo-nadism (see below) time observationand spontaneous pubertal developmentare the critical factors Management istherefore focused on exclusion of thosedisorders which may be associated withpubertal delay through chronic illnessor with multiple pituitary hormone defi-ciencies By the age of 13ndash14 yearsraised serum gonadotrophin levels arelikely to identify patients with hyper-gonadotrophic hypogonadism


zz z

zz z z

z

Fig 1 Algor ithm for the investigation of delayed puberty when there are signs of pubertal development Reproduced with permissionfrom Ref 3 CDGP = Constitutional delay of growth and puberty







z

z

zz

z z z




Pubertal failure














Bone age








Gynaecomastia





References
















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Key Points













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abnormalities of growth and development in puberty · from puberty onset in boys to adult ......

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