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EDUCATIONAL OBJECTIVE

145. ApproprIate understandingof the role of measurements ofgrowth hormone In the evaluationof the child with short stature (81/82).

pediatrics in review #{149} vol. 3 no. 6 december 1981 PIR 171

Short Stature in ChildrenS. Douglas Frasier, MD*

A consideration of all of thecauses of short stature would ap-proach the scope of a general pedi-atric textbook. Therefore, this dis-cussion will focus on the most corn-mon endocrine abnormalities thatcause growth failure and their differ-ential diagnosis.

GENERAL CONSIDERATIONS

Growth Standards

Accurate serial measurements ofheight and weight and an accuraterecord of growth are essential corn-ponents of the clinical evaluation ofall children. Maintenance of agrowth chart allows comparison ofan individual child with a large pop-ulation in terms of both percentileranking and the determination of‘ ‘ height age’ ‘ : the chronologic ageat which the patient’s height falls onthe 50th percentile. The growthchart also facilitates observations ofthe pattern of growth and providesthe basis for calculation of growthvelocity.

Until recently, growth standardsused in the United States werebased on data accumulated morethan 30 years ago. Newer stan-dards, compiled by the NationalCenter for Health Statistics of theUnited States Public Health Service,and growth charts based on thesedata are now generally available.

The pattern of growth is of greathelp in the assignment of a patientto a general diagnostic category. Asshown in Fig 1, children with a con-genital condition interfering withgrowth show persistent deviationaway from the normal curve from avery early age. At times this occursbefore 3 to 6 months of age, and itis almost always apparent within thefirst 12 to 18 months of life. Childrenwith an acquired abnormality affect-ing growth follow a normal curve fora variable period of time and thenbegin to deviate away from the norm.

#{149}Professor of Pediatrics and Physiology!Biophysics, University of Southern CaliforniaSchool of Medicine, and Chief, Division ofPediatric Endocrinology, Los Angeles Count y-USC Medical Center, Los Angeles.

In contrast, the child with constitu-tional delay in growth and adoles-cence may show transient deceler-ation of growth from late infancythrough the third year of life, butsubsequently will grow at a normalrate. Although the height of childrenwith familial short stature is well be-low average, their growth curve par-allels the standard curve.

The growth rate or height velocitycan also be calculated from serialmeasurements plotted on the growthcurve. In general, an abnormalgrowth rate suggests that a signifi-cant problem may be present and isan indication for carrying out diag-nostic studies. On the other hand, anormal growth rate is reassuring tothe patient, parents, and physicianand suggests that extensive diag-nostic studies can be postponed orneed not be pursued.

The definition of normal growthvelocity varies with age and sex. Forpractical purposes, a growth ratebelow 5 cm/yr in both boys and girlsbetween 5 years of age and the be-ginning of rapid adolescent growthis subnormal. Because younger chil-dren normally grow more rapidly, thelower limit of normal for height veloc-ity must be raised with decreasingage. A growth rate between birthand 6 months of age below 16 cm ingirls and 17 cm in boys should beevaluated. Between 6 to 12 months,both boys and girls should grow atleast 8 cm. A growth rate between 1and 2 years of age below 11 cm forgirls and 10 cm for boys is less thanexpected for this age. Between 2 to5 years of age both boys and girlsshould grow 6 cm/yr.

The determination of body propor-tions provides additional useful clin-ical information. The proportionsthat have been most widely used arethe ratio of upper body segment tolower body segment and the rela-tionship between arm span andheight. The average measurementsfor these two proportions as a func-tion of age and sex are shown inTable 1. The lower segment is thedistance from the top of the sym-physis pubis to the heel, with theankle at 90 degrees. In practice, theupper segment measurement is ob-

tamed by subtracting the lower seg-ment measurement from the totalheight. Arm span is measured withthe arms fully extended. Short pa-tients with primary disorders of boneand cartilage, or with long standinghypothyroidism, have relativelyshort extremities. Their arm span isshorter than their height, and theirupper/lower segment ratio isgreater than expected. Other shortchildren are normally proportioned.

Bone Age Determination

Determination of the level of epi-physeal maturation is often helpful inevaluating children with abnormalgrowth. The standards published byGreulich and Pyle, which are basedon the left hand and wrist, havefound the most general use in theUnited States. These standards arenot useful before 6 months of agebecause normal infants may nothave calcified carpal centers untilthat time.

A delayed bone age does not pro-vide specific diagnostic informationinasmuch as epiphyseal maturationis delayed in all of the disorders thatcause short stature and in constitu-tional delay in growth and adoles-cence as well. The bone age tendsto be normal in genetic or familialshort stature.

The major value of determiningbone age is prognostic. Short chil-dren whose bone age is delayedhave a much better prognosis forfurther growth and ultimate heightthan do children whose level of epi-

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‘CONSTITUTIONAL DELAY

IN GROWTH

1810

AGE (years)

Birth 1.70 1.70 -2.5 -2.56 mo 1.60 1.62 -3.0 -2.512 mo 1.52 1.54 -3.3 -2.518 mo 1.46 1.50 -3.3 -2.724 mo 1.41 1.42 -3.5 -3.03yr 1.30 1.35 -4.0 -2.74 yr 1.22 1.24 -3.8 -3.0Syr 1.15 1.19 -3.5 -3.36yr 1.10 1.12 -3.3 -2.57 yr 1.06 1.07 -2.0 -2.58yr 1.02 1.03 -1.8 -1.29yr 1.01 1.02 -1.2 0lOyr 1.00 0.99 -1.0 0llyr 0.99 0.98 0 0l2yr 0.99 0.98 0 +2.013 yr 1.00 0.97 0 +3.314 yr 1.01 0.97 0 +3.3lSyr 1.01 0.98 +1.2 +4.3

Short Stature

PIR 172 pediatrics in review #{149}vol. 3 no. 6 december 1981

Fig 1. Characteristic growth patterns plotted against growth curve based on current National

Center for Health Statistics Standards. (Reprinted with permission from Frasier SD: Abnor-malities of growth, in Pediatric Endocrinology. New York, Grune & Stratton, 1980.)

TABLESegmen

1. Bt Ratio

ody Proportions: 50th Percentile Stanand Arm Span Compared to Height

dards for Upper/Lower

Age

Upper/Lower SegmentRatio

Arm Span Minus Height(cm)

Female MaleFemale Male

physeal maturation is consistentwith their chronologic age. The sim-plest method of height prediction isthe use of the Bailey-Pinneau tablesas published in the Greulich andPyle’s Radiographic Atlas of Skele-tal Development of the Hand andWrist. This predication is based onthe patient’s chronologic age, boneage, and current height. The accu-racy is relatively poor when the boneage is less than 1 0 years. At best,the Bailey-Pinneau predication is re-liable to ±4 to 6 cm (±1.5 to 2inches). The equation of Roche,Wainer, and Thissen (RWT method)is more complicated to apply thanthe Bailey-Pinneau tables and uti-lizes the patient’s chronologic age,recumbent length, weight, and pa-rental heights in arriving at a predic-ation. This method is gaining in pop-ularity because of its somewhatgreater accuracy. It must be bornein mind that the accuracy of bothmethods depends on the validity ofthe bone age determination.

CAUSES OF SHORT STATURE

Chronic Disease of aNonendocrine Organ System

Chronic disease of any major or-gan system may interfere withgrowth and lead to short stature. Thehistory, physical examination , androutine laboratory evaluation will un-cover the clues that allow the diag-nostic search to be narrowed to aparticular system and eventually toa specific disorder. The growth pat-tern in children with nonendocrinechronic illness is that of acquiredgrowth failure. Body proportions arenormal except in disorders primarilyaffecting bone and cartilage; in suchdisorders the limbs are shorter thanexpected.

Short patients growing at a sub-normal rate for their age should havea screening hematologic evaluationand routine urinalysis with particularattention to the presence of reducingsubstances and protein, as well asurine specific gravity and pH. Ascreening chemistry panel should beperformed to evaluate electrolyteand acid-base status, as well as kid-ney and liver function.



TABLE 2. Common

Nonendocrine conditions

I. Constitutional delay in growthand adolescence

II. Familial (genetic) short statureIII. Intrauterine growth retardation

ENDOCRINOLOGY


Common NonendocrineConditions

In Table 2 are listed several non-endocrine conditions that requireconsideration in a differential diag-nosis of short stature. These are notreally disorders, but rather are van-ations of normal which show moreor less characteristic clinical pic-tunes and patterns of growth.

Children with constitutional delayin growth and adolescence are non-mal in height and length at birth.They grow normally for severalmonths or longer and usually deviateaway from a normal growth patternfor some period of time between 6and 36 months of age. After thattime, the growth rate is normal andtheir growth pattern parallels thenormal growth curve. When seen forevaluation, these children are usu-ally growing at a normal rate for age.Puberty is delayed, and there is alater than average adolescent accel-eration of growth. However, normaladult height is attained and normalsexual development occurs. Thereis usually a family history of a similarpattern of childhood and adolescentgrowth in one parent or other firstdegree relative. The great majorityof children who fall into this categoryare short, but otherwise normal,boys.

The general screening studiespreviously described are not neces-sary in short children who are grow-ing at a normal rate. However, abone age x-ray should be obtainedfor prognostic purposes. Their boneage is delayed and is more consist-ent with height age than with chron-ologic age. Tests of thyroid functionare often performed but only some-times indicated, and the diagnosis ofhypothyroidism can usually be elim-inated by history and physical ex-amination. The short child who isactive, alert, and clearly euthyroid inthe examining room, does not needlaboratory confirmation of his nor-mality.

The question of treatment is con-troversial as ultimate height is nor-mal without therapy. There is verylittle evidence that children who aretreated are any taller than theywould have been without treatment.Normal short children do not re-

spond with any consistency to thy-roxine or physiologic amounts of hu-man growth hormone. Potent andro-gens or human chonionic gonadotro-pin should not be administered be-cause these agents cause vinilizationand accelerate epiphyseal develop-ment. A large number of syntheticsteroids, designed to have an in-creased anabolic/androgenic ratio,have been used to accelerate thegrowth of normal short children, andsuch agents do increase the rate oflinear growth in the short run. How-ever, in no instance has there beena complete separation of anabolicfrom androgenic activity, and the ef-

fect of these agents on epiphysealmaturation cannot be predicted inan individual child.

If possible, it is preferable to helpthese patients and their familieswork through the problems of shortstature rather than to alter growthand development with a phanmaco-logic agent. The cautious adminis-tration of an anabolic agent is mdi-cated only when short stature cne-ates psychologic problems that can-not be solved in other ways. I nec-ommend treating only prepubertalpatients who are at least 1 2 yearsold and whose bone age is at least2 years behind their chnonologicage. This recommendation is basedon the observation that bone age ismore likely to be unduly acceleratedby treatment in younger children.Because the aim of treatment at thisage is acceleration of growth andnot the induction of sexual matura-tion, an agent with a maximum ana-bolic/androgenic ratio is preferable.I use oxandnolone in a dose of 0.1to 0.25 mg/kg of body weight in oneor two doses each day. Treated pa-tients must be seen at frequent in-tervals to monitor the clinical effectsof therapy. Bone age x-rays shouldbe obtained every six months. Ther-apy should be discontinued if epi-physeal maturation advances out ofproportion to the change in chrono-logic age on if unacceptable viniliza-tion is induced.

Anabolic/androgenic steroids areoccasionally hepatotoxic and baseline tests of liver function, as well asperiodic follow-up evaluation, mustbe carried out. High-dose androgentherapy has been associated with

the development of hepatic tumorsand, although such tumors have notdeveloped in patients receiving an-abolic/androgenic therapy for theacceleration of growth, the physi-cian who treats short children withthese agents must be aware of thispotential complication.

Patients with familial or geneticshort stature tend to be short atbirth. They grow parallel to the nor-mal curve but below the fifth pencen-tile from early infancy. Adolescentdevelopment and the adolescent ac-celeration of growth occurs at theusual time. Ultimate height is shortfor the patient’s racial and ethnicbackground but is consistent withfamily height. All laboratory studiesare normal, including bone age.There is no therapy to modify eithergrowth rate or ultimate height.

Intrauterine growth retardation(IUGR), which occurs as both an iso-lated abnormality and in a number ofconditions in which short stature isassociated with multiple congenitalmalformations, is usually sporadic.There is no family history of a similarpattern of growth. As this conditionhas multiple causes, the clinicalcourse is highly variable. Many af-fected children rapidly catch up to alength that is within the range ofnormal for their age. A subgroup ofchildren with IUGR remain small dur-ing infancy and early childhood, butshow later catch-up growth and ul-timately reach a normal height. How-ever, a significant number of chil-dren with IUGR remain small and donot experience a period of acceler-ated growth in infancy or later child-hood.

The diagnosis of IUGR dependson the history of the length of ges-tation and the measurement ofweight and length at birth. As thedetermination of birth length and thehistory of the length of the preg-nancy are notoriously inaccurate,



TABLE 3. Endocrine Disorders

I. HypothyroidismII. Abnormalities of the X chro-

mosomeIII. Growth hormone deficiencyIV. Deprivation (psychosocial)

dwarfismV. Cortisol excess

Short Stature

PIR 174 pediatrics in review #{149} vol. 3 no. 6 december 1981

the diagnosis is frequently based onbirth weight and the best estimate ofthe length of pregnancy. All labora-tory studies of endocrine functionare normal. The bone age of patientswith IUGR is variable when corn-pared to both height age and chron-ologic age. In general, the bone ageof patients who catch up to normalheight is normal. Patients who re-main short generally have delayedepiphyseal maturation.

The same considerations apply tothe treatment of short children witha history of IUGR as those discussedfor children with constitutional delayin growth and adolescence. Ana-bolic/androgenic steroid therapymay benefit children with IUGR whoare significantly below averageheight and whose bone age is de-layed. The possibility of side effectsincluding undue acceleration of epi-physeal maturation and abnormali-ties in liver function, must be kept inmind.

General statements cannot bemade regarding the long-term prog-nosis for ultimate height in IUGR.Although many patients who aresmall at birth achieve a normal adultheight, there are a significant num-ber who may be short at maturity.Unfortunately, there is no satisfac-tory way of predicting which childrenfall into the group with an unfavora-ble prognosis.

Endocrine Disorders

The major endocrine disordersthat must be considered in the dif-ferential diagnosis of short statureare listed in Table 3.

Hypothyroidism. Children withcongenital or acquired primary hy-pothyroidism often are first seen withthe complaint of growth failure. Asthe diagnosis of congenital hypothy-roidism should be made by neonatal

screening, this discussion will focuson acquired disease.

By far the most common cause ofacquired hypothyroidism is autoim-mune or Hashimoto’s thyroiditis. Fe-males are affected four or five timesmore often than are males, and oftenthere is a strong family history ofthyroid disease.

If short stature is due to hypothy-roidism, associated symptoms canusually be elicited. These includecold intolerance, increased need forsleep, constipation, muscle achesand weakness, decreased activity,and mental dullness. Hypothyroidchildren are both short and growingat a subnormal rate. Their growthcurve is that of acquired growth fail-ure. If growth is impaired from anearly age, body proportions may berelatively infantile with a greater thanexpected upper/lower segment ra-tio and short arm span in relation toheight.

When hypothyroidism has beenpresent for more than 6 to 12months, patients may appear paleand puffy. Speech may be slow andthe voice may be hoarse and low-pitched. The skin is usually thick-ened, dry, coarse, and cool. Scalphair may be dry and brittle. Somepatients show an unusual type ofhirsutism in which there is an in-crease in fine, dark lanugo-like hairover the back, shoulders, and upperarms. Dental development is fre-quently delayed. There may bebradycardia and an elevation in dia-stolic blood pressure. Althoughthere is muscle weakness, the mus-cles of the extremities may be hy-pertrophied. There is characteristicdelay in the relaxation phase of thedeep tendon reflexes which is mosteasily demonstrated at the ankle.Goiter is frequently present, and thethyroid is two or three times the nor-mal size. The surface is generallyirregular but not nodular, and theconsistency of the gland is firm andrubbery.

The diagnosis of acquired primaryhypothyroidism is confirmed by thedemonstration of a decreased serumconcentration of thyroxine and anelevated serum concentration of thy-roid-stimulating hormone (TSH).After chronic disease of a nonendo-crine organ system has been elimi-

nated from consideration, these twotests of thyroid function should beperformed in all short children whoare growing at a subnormal rate.Antibodies to thyroglobulin and thy-roid microsomes should be soughtin all hypothyroid patients.

Epiphyseal maturation is usuallysignificantly delayed in acquired hy-pothyroidism. At times characteristicepiphyseal stipling (epiphyseal dys-genesis) is seen. This abnormalitymay not become evident until then-apy is begun, but it is frequentlypresent during the resolving phaseof hypothyroidism.

The therapy for acquired hypothy-roidism is sodium-L-thyroxine. Thedose is 4 to 6 pg/kg/day between1 and 5 years of age, and 3 to 5 �g/kg/day, up to a maximum of 1 50 ��tgin older patients. Therapy should bemonitored with determinations of Se-rum thyroxine and TSH, and treat-ment should lead to normalization ofboth serum thyroxine and TSH con-centrations.

All abnormalities associated withacquired hypothyroidism, includinggrowth failure, should resolve corn-pletely with appropriate replacementtherapy.

Abnormalities of X Chromosome(Gonadal Dysgenesis). It is nowclear that there are a wide variety ofx chromosome abnormalities thatmay be associated with a broadspectrum of phenotypic abnormali-ties (Table 4). The unifying expres-sions are short stature and gonadaldysgenesis, but even these featuresare not uniformly present. Abnor-malities of the X chromosome occurwith an incidence of 1 to 1.5/2,000term births, and they must be con-sidered in the evaluation of any shortgirl whether or not associated ab-normalities and/or sexual immatu-rity are present.

The pathogenesis of the shortstature seen with X chromosome ab-normalities is not well understood.Linear growth in females depends,at least in part, on homozygosity forgenes that are carried on the X chro-mosome. When these height-deter-mining genes are not present in thehomozygous state, growth failureand ultimate short stature result. De-ficient hormone production or re-sponsiveness has not been demon-



TABLE 4. AbnormalitiesFound in Patients with XChromosome Disorder

Short stature 95-100Gonadal failure 95-100Skin: pigmented nevi 60-70Face:

Prominent ears 60-90Small mandible 60-90Narrow, arched 60-90

palatePtosis 30-60Epicanthal folds 20-50

Neck:Short ne�k 60-90Low hairlIne 50-80Webbed neck 40-60

Chest:Shield chest 80-90Pectus excavatum 40-50Abnormal nipples 30-80

Extremities:Congenital lymph- 50-80

edemaAbnormal nails 80-90Puffiness of toes 30-50Clinodactyly 20-40Cubitus valgus 60-80

Heart:Coarctation of 10-30

aortaOther anomalies 5-15

Kidney: renal anom- 50-70alies

TABLE 5. Growth HormoneDeficiency Due to IntracranialLesion

I. CongenitalA. Midline defectB. Pituitary dysgenesis

II. AcquiredA. NeoplasmsB. ReticuloendotheliosisC. TraumaD. InfectionE. Radiation therapy

ENDOCRINOLOGY


strated. Growth hormone secretionand somatomedin generation arenormal. Although the incidence ofautoimmune thyroiditis is increased,hypothyroidism does not account forthe growth failure.

Short stature is present from birthin up to half of the patients. In almostall patients height is below that ex-pected by age 4 or 5 years. Thegrowth rate is subnormal and thereis no pubertal acceleration ofgrowth.

Patients with gonadal failure usu-ally show no estrogen effect at thetime of expected puberty. However,the increase in adrenal androgenproduction, which is part of normalpubertal development, does occur,and girls with gonadal failure de-velop pubic and axillary hair. In afew patients in whom sufficient go-nadal tissue is present, pubertal de-velopment may advance and men-arche may occur. Regular menstrua-tion and pregnancy are possible butextremely rare.

If no chronic illness is present, alleuthyroid girls being evaluated forshort stature should have chromo-some analysis of peripheral lympho-cytes. As no more than half of thepatients with abnormalities of the Xchromosome are chromatin-nega-tive, the buccal smear is not a sat-isfactory method of diagnosis. Thepresence of primary gonadal failurecan be confirmed by demonstratingelevated concentrations of follicle-stimulating hormone (FSH) and lu-teinizing hormone (LH). Because ofthe association between abnormali-ties of the X chromosome and au-toimmune thyroiditis, thyroid func-tion should be evaluated and antithy-roid antibodies should be measuredat regular intervals. Epiphyseal de-velopment is delayed in most pa-tients with short stature due to anabnormality of the X chromosome.

The treatment of girls with an ab-normality of the X chromosome isdirected at promoting linear growth,inducing secondary sexual matura-tion, and, when necessary, correct-ing associated anomalies. Only themanagement of short stature will beconsidered here. Therapy with an-drogen/anabolic steroids acceler-ates linear growth in the majority ofpatients. There is some, but still only

minimal, evidence that such treat-ment increases ultimate height inthis group of children. It has beensuggested that the combination ofhuman growth hormone and an an-abolic agent is preferable to an an-abolic steroid used alone. Growthhormone alone is without effect as isthyroxine.

Patients should be treated with an-abolic steroid therapy at age 8 to 10years with 0.1 to 0.2 mg of oxandro-lone per kilogram of body weight perday given in two doses. Patients arechecked for their response and thepresence of side effects at three-month intervals, and bone age ismonitored every six months. Ther-apy is continued as long as there isan increase in growth rate withoutan undue advance in bone age or

unacceptable vinilizing side effects.When older patients wish to be fern-inized, anabolic steroid therapy iscontinued if it is still having a positiveeffect.

The ultimate height of girls withabnormalities of the X chromosomeis much less than that of normal adultwomen. The average adult height ofpatients treated with estrogensalone is 1 42 to 1 45 cm (56 to 58inches), and the range extends from1 32 to 1 63 cm (52 to 65 inches).

Growth Hormone Deficiency. Al-though growth hormone (GH) defi-ciency is a relatively rare cause ofshort stature, it should be looked forafter chronic nonendocnine disease,hypothyroidism, and abnormalitiesof the X chromosome have beeneliminated as diagnostic possibili-ties.

GH deficiency may result from anintracranial lesion or may occur inthe absence of any anatomic abnor-mality. Table 5 shows the major cat-egories of intracranial lesion thatmay lead to a deficiency of GH. Con-genital midline defects range fromanencephaly at one extreme throughsepto-optic dysplasia, to cleft lipand/or palate, and the single uppercentral incisor syndrome at theother. There may be defects in pitui-tary development; these include pi-tuitary agenesis, pituitary hypopla-sia, and ectopic pituitary. By farthe most common associated neo-plasm is craniopharyngioma. Hand-Schuller-Chnistian disease, basilar

PatientsAbnormality (%)

skull fracture, and several infec-tions, particularly tuberculous men-ingitis may lead to abnormalities inGH synthesis and/or secretion. In-tracranial radiation of patients withneoplasms or leukemia may lead toGH deficiency, which complicatestheir prolonged survival.



TABLE 6. Pathogenesis ofIdiopathic Growth hormoneDeficiency

I. Neurotransmitter defectII. Releasing hormone deficiency

III. Pituitary growth hormone defi-ciency

IV. Biologically inactive growthhormone

V. Unresponsiveness to growthhormone

VI. Unresponsiveness to somato-medin

Fig 2. Eight-year-old girl with growth hor-mone deficiency. Height age is 3�/i 2 years,and weight age is 3 �/2 years. Note normal

body proportions and missing deciduous sin-gle central incisor. (Reprinted with permissionfrom Frasier SD: Growth disorders in children.Ped Clin North Am 26:1, 1979.)

Short Stature


The physiologic system that is re-sponsible for GH secretion and ac-tion involves several different levels.These include the central nervoussystem outside of the hypothalamus,the hypothalamus itself, the pituitarygonadotroph, and the mechanismsthrough which GH generates its end-organ hormones, the sornatomedins.As shown in Table 6, functional de-

fects may exist at any of these levelsand lead to the clinical syndrome ofGH deficiency. Defective neuro-transmitter metabolism mediating in-put to the hypothalamus may be in-volved in the transient GH deficiency

[ of psychosocial dwarfism. GrowthI hormone releasing factor deficiency� may exist as part of a syndrome of

multiple hypothalamic releasing hor-mone deficiencies or may occur asan isolated abnormality. Pituitary GHdeficiency may also occur as an iso-lated problem or in association withdeficiencies of other pituitary hor-mones. Recently a syndrome inwhich growth hormone is detectableby standard immunologic tech-niques but is biologically inactivehas been described. Patients withthis syndrome have low levels of so-matomedin which can be increasedby the administration of exogenousgrowth hormone. Patients may havea biologically active growth hormonewhich fails to generate somatomedinbecause of a defect in the GH recep-ton mechanism. This syndrome, de-scnibed by Laron, is a recessivelyinherited genetic abnormality. Pa-tients with peripheral unresponsive-ness to somatomedin have also beendescribed.

If growth hormone deficiency iscongenital, growth failure is usuallynoted by 12 to 18 months of age.

Children with acquired GH defi-ciency have the growth curve of ac-quired growth failure. GH deficientchildren are normally proportionedand their upper/lower segment ratioand the relationship between armspan and height are normal. Manypatients share a number of physical

features regardless of the underly-ing etiology which, when taken to-gether, produce a common appear-ance (Fig 2). Patients tend to beoverweight for their height, and theirheight age is less than their weightage. Although the excess fat depo-sition does not spare the extremities,it is frequently concentrated over thechest and abdomen. Head size mayalso be more consistent with chron-ologic age than height. This overallappearance has been described as“doll-like” or “cherubic.” The voicemay be high-pitched and squeakydue to immaturity of the facial bones.Congenital GH deficiency may first

become manifest in early infancy ashypoglycemia with convulsions, cy-anosis, and shock. In the male, as-sociated congenital gonadotropindeficiency may lead to micropenis,and the combination of microgeni-talia and hypoglycemia is usuallydue to multiple pituitary hormone de-ficiencies which include growth hor-mone.

Associated endocrine abnormali-ties are also frequently present inacquired GH deficiency. The mostcommon of these is diabetes insip-idus in patients with chronic reticu-loendotheliosis. Intracranial lesionsmay also lead to impaired gonado-tropin secretion and failure of ado-lescent development to begin or toprogress may be an associated pre-senting problem. Hypoglycemia isalso commonly seen in GH deficientchildren with organic pituitary dys-function.

As growth hormone is often un-

detectable in the serum of healthypersons, a random determination ofthe concentration of growth hor-mone is of no value. Children inwhom the diagnosis is suspected onclinical grounds should be screenedfor GH deficiency and, if the child isold enough to cooperate, an exer-cise test should be performed. Pa-tients are instructed to have nothingby mouth for three or four hours andto rest quietly for 30 minutes aftercoming to the office or are studiedbetween 8 and 9 AM after an over-night fast without a rest period. Acontrol blood sample is drawn andthe patient either walks on a levelsurface for 15 minutes and then runsup and down one flight of stairs forfive minutes or performs 20 minutesof parent-supervised vigorous exer-cise consisting of jumping jacks,running, or whatever is preferablefor the patient. A postexercise bloodsample is then obtained. Between80% and 90% of normal children willrespond to exercise with an increasein the serum concentration of growthhormone to �6 ng/ml. Pretreatmentwith propranolol (20 mg to childrenweighing less than 20 kg and 40 mgto heavier children) enhances theresponse. A propranolol-pnimed testshould be performed in children whofail to respond to exercise aloneprior to proceeding to definitive test-



ENDOCRINOLOGY

pediatrics in review #{149}vol. 3 no. 6 december 1981 PIR 177

ing. Children who are too young to

perform standardized exerciseshould be given L-dopa, as de-scnibed for definitive testing, withsamples obtained at 0, 30, and 60minutes.

Children who fail to respond to ascreening test need definitive testingwith two stimuli. The tests that havebeen standardized for this purposeare insulin-induced hypoglycemia,intravenous arginine, oral L-dopa,and intramuscular or subcutaneousglucagon.

Hypoglycemia is induced by theintravenous injection of regular in-sulin in a dose of 0.05 to 0.1 unit/kg of body weight. Blood samplesare obtained for the determination ofboth blood glucose and growth hor-mone concentrations at 1 0- or 15-minute intervals over an initial hour,and at 20- or 30-minute intervalsover a second hour. A 50% de-crease in the concentration of bloodglucose results in an increase in theconcentration of growth hormone inserum to �8 ng/ml in more than85% to 90% of normal children. Thepeak serum concentration of growthhormone is usually observed at 30

to 60 minutes after the administra-tion of insulin. Symptoms of hypogly-cemia may be seen between 15 and45 minutes. The person performingthe test must be prepared to admin-ister 50% glucose intravenouslyand/or 1 mg of glucagon intramus-cularly if termination of the test isindicated.

Arginine HCI, which is available asa 10% solution for use as a diagnos-tic reagent, is administered as anintravenous infusion over 30 min-utes. The dose is 0.5 gm/kg of bodyweight up to a maximum of 30 gm.

Blood samples are obtained every15 minutes for the first hour and at

30-minute intervals over a secondhour. Between 80% and 85% of

healthy children will respond with apeak serum growth hormone level�8 ng/ml, usually at 30 to 60 min-utes. Girls are somewhat more likelyto respond than are boys. The intra-venous infusion of arginine is essen-tially without side effects.

When L-dopa is administered bymouth there is a prompt release of

GH from the pituitary. The dose ofL-dopa is 25 mg for children weigh-

ing less than 1 5 kg, 250 mg forchildren weighing 1 5 to 30 kg, and500 mg for children weighing morethan 30 kg. Blood samples are ob-tamed every 30 minutes over a two-hour period. A peak serum growthconcentration of �8 mg/mI is seenin 85% to 90% of healthy children inthe 30- or 60-minute sample. Un-pleasant side effects, particularlynausea and/or vomiting, are in-duced by L-dOpa in a significantnumber of children.

The intramuscular or subcuta-neous administration of glucagon ina dose of 0.03 zg/kg up to 1 .0 mgresults in a significant increase inthe serum concentration of GH as arelatively late response. Blood sam-pIes are obtained at 30-minute inter-vals over a three-hour period follow-ing glucagon injection, and a maxi-mum GH concentration of �8 ng/mIis observed between 120 and 150

minutes in 75% to 80% of normalchildren. No significant side effectshave been reported following glu-cagon administration.

Patients with growth hormone de-ficiency respond dramatically to theadministration of human growth hor-mone (hGH). At present, the sourceof hGH, available from the NationalPituitary Association (NPA) or com-mercial sources, is human pituitaryglands. Recombinant DNA technol-ogy should provide another sourceof hGH in the near future. Humangrowth hormone is administered in-tramuscularly in an initial dose of0.05 to 0.1 unit/kg of body weight,three times a week. Catch-upgrowth, without an undue accelera-tion of bone age, is seen in about80% to 90% of patients. The re-sponse is greatest during the first 6to 12 months of therapy and subse-quently declines. The dose of hGHmay be increased in increments of0.05 unit/kg at 6- to 12-month in-tervals up to 0.2 to 0.25 unit/kgthree times a week. The concomitantadministration of oxandrolone in a

dose of 0.1 to 0.25 mg/kg/day or

fluoxymesterone, 4 to 10 mg/daymay ameliorate the declining effect.

There are surprisingly few side-ef-fects when hGH is administered togrowth hormone deficient patients.Local tenderness at the site of injec-tion is an occasional complaint. Al-

lergic reactions have not beennoted. A significant proportion oftreated patients have developedantibodies to hGH, but in all but afew patients the antibodies have notinterfered with the biologic activityof hGH.

Because of limitations in the sup-ply of hGH, insufficient numbers ofpatients have been treated from anearly age until maturity to allow anydefinitive statements regarding theeffect on their ultimate height. With-out therapy, affected children wouldnot be expected to reach a height of

1 52 cm (60 inches), and many wouldbe less than 1 37 cm (54 inches)tall. Theoretically, treated patientsshould attain a normal adult height.

Deprivation (Psychosocial)Dwarfism. The syndrome of depri-vation or psychosocial dwarfism ischaracterized by emotional disturb-ances and abnormalities in behaviorthat are associated with reversiblegrowth failure and transient impair-ment of pituitary function.

Although there is no doubt thatenvironmental deprivation can leadto abnormalities in growth, the path-ogenic link between the resultingemotional disturbances and growthhormone deficiency remains ob-scure. Preliminary data suggest thatneurotransmitter function may beimpaired in this syndrome. However,no definite conclusions can bereached regarding the pathogenicsignificance of this finding. Thereare also fragmentary data that sug-gest that the growth retardation ofaffected patients may be related totheir sleep disturbances, but theseobservations also await confirma-tion. The etiologic role of malnutri-tion is controversial. Present dataindicate that although impaired foodintake may contribute to the growthfailure of some patients, it is usuallynot the only causative factor.

The age of onset of growth failureis highly variable. At the time of initialevaluation patients are well belowaverage height for their age and aregrowing at a subnormal rate. Their

growth curve cannot be distin-guished from that seen in acquiredgrowth hormone deficiency. Thegrowth retardation is proportional.

The relationship between span andheight is normal and the upper/



Short Stature


lower segment ratio is appropriatefor the patient’s height. Althoughthere is a tendency for the patientsto be underweight for height, this isa variable finding and some patientsare mildly or even moderately obese.There may be a protuberant abdo-men and thin extremities, both ofwhich suggest the possibility of in-testinal malabsorption.

In most patients, the characteristicbehavior abnormalities begin beforeage 2 years. Disturbed behavior iscentered around drinking, eating,and sleeping. Almost all patientsshow bizarre polydipsia. It is not un-usual for them to drink from toiletbowls, sprinkler heads, gutters, orfish tanks. Water is frequently re-quested throughout the night. Mostaffected children have a voraciousappetite. They frequently eat fromgarbage cans, and they beg or stealfood from friends, neighbors, or foodstores. Rumination and cyclic vom-iting are sometimes seen. Insomniaand roving nighttime behavior arecommon. Many patients have diffi-culty with bladder and bowel train-ing. Apparent retardation of intellec-tual development and speech is fre-quent.

These patients usually have dis-rupted families. The incidence of di-vorce and separation is higher thanexpected, and the father is fre-quently out of the home. One or bothparents are often alcoholic. Theremay be clear evidence of estrange-ment between the parents, particu-larly the mother, and the patient. Apast history or current physical evi-dence of child abuse is often found.The child with psychosocial dwarf-ism tends to be isolated and doesnot participate in family activities.

The diagnosis depends primarilyon past history and subsequent clin-ical course. When tests of pituitaryfunction are performed during thetime that growth is impaired, there isusually evidence of growth hormonedeficiency. Many patients also haveadrenocorticotropin (ACTH) def i-ciency. Thyroid function is normal.If pituitary function is studied duringthe recovery phase when growth isaccelerated, growth hormone andACTH secretion are found to be nor-mal. The bone age is markedly re-tarded during the period of growth

failure, and epiphyseal maturationnormalizes during the phase ofcatch-up growth.

The therapy of deprivation dwarf-ism is modification of the patient’senvironment. This most often takesthe form of hospitalization for initialdiagnostic evaluation and subse-quent placement in a foster home.Removal of the patient from the de-priving environment is usually fol-lowed by remarkable changes inweight gain and linear growth. Whenpatients are removed from theirhome, their abnormal pattern of be-havior is also modified. Appetite be-comes more normal and bizarre eat-ing and drinking habits lessen.There is frequently a marked in-crease in verbal behavior and intel-lectual retardation is no longer ap-parent. It is not unusual for patientsto become much more extrovertedand social. Sleep disturbances de-crease and bowel and bladder con-trol are better established.

The ultimate prognosis for weightgain, growth, and adolescent devel-opment is good, provided the patientcan remain in a supportive environ-ment. The long-term psychologicalprognosis is guarded and very littlehas been written about the ultimatepsychological and social function ofpatients with deprivation dwarfism.

Glucocorticoid Excess. Gluco-corticoid excess in infancy andchildhood almost always leads to asubnormal growth rate, short stat-ure, and delayed epiphyseal matu-ration. Occasionally growth failure isthe primary or only clinical manifes-tation. This diagnosis should be con-sidered, and appropriate tests forcortisol excess should be performedwhenever the cause of growth failureis obscure as well as when there aremore classic symptoms and signs ofincreased glucocorticoid secretion.

SUMMARY

Short stature in childhood hasmany possible causes, only the mi-nority of which are endocrine disor-ders. In addition to a complete his-tory and physical examination, themost important information that canbe brought to bear on the differentialdiagnosis of short stature is accu-rate serial measurements of length

and/or height. When these data areused to calculate growth velocityand are plotted on a standard growthcurve, short children can be quicklyclassified into those growing at asubnormal rate and likely to have asignificant underlying problem andthose whose growth rate is normaland who are very unlikely to haveany problem. In general, diagnosticstudies may be limited to short chil-dren who are growing at a subnor-mal rate. Endocrine disease shouldonly be considered after chronic ill-ness of a nonendocnine organ sys-tern has been eliminated from con-sideration. The possibilities of hy-pothyroidism, an abnormality of thex chromosome in short girls, andgrowth hormone deficiency shouldbe sequentially evaluated. The unu-sual diagnoses of deprivation dwarf-ism and glucocorticoid excess mustbe kept in mind. If a specific diag-nosis is confirmed, appropriate then-apy can be instituted. The vast ma-jonity of short children are growingat a normal rate and are boys withconstitutional delay. A bone age x-ray is extremely helpful in arriving ata prediction of their mature heightwhich is almost always within therange expected in their family. Thereassurance provided by this ma-neuver usually makes any pharma-cologic therapy unnecessary.

ACKNOWLEDGMENT

I wish to acknowledge the expert assist-ance of Mrs Wilda J. Lyons without whomlittle would get done.

REFERENCES

Frasier SD: Abnormalities of growth, in Pedi-atric Endocrinology. New York, Grune &Stratton, 1980

Goodman HG, Grumbach MM, kaplan SL:Growth and growth hormone. II. A compar-ison of isolated growth-hormone deficiencyand multiple pituitary-hormone deficienciesin 35 patients with idiopathic hypopituitarydwarfism. N EngI J Med 278:57, 1968

Hayles AB, Cloutier MD: Clinical hypothyroid-ism in the young: A second look. Med ClinNorth Am 56:871, 1972

Homer JM, Thorsson AV, Hintz RL: Growthdeceleration patterns in children with con-stitutional short stature: An aid to diagnosis.Pediatrics 62:529, 1978

Moore DC, Tattoni OS, Limbeck GA, et al:Studies of anabolic steroids. V. Effect ofprolonged oxandrolone administration ongrowth in children and adolescents with



EDUCATIONAL OBJECTIVE

131. Appropriate famIliarity withthe clinical picture of heatstrokeand of its prevention and treat-ment (81/82).

ENDOCRINOLOGY


uncomplicated short stature. Pediatrics 58: Powell GF, Brasel JA, Blizzard RM: Emotional method for the prediction of adult stature.41 2, 1 976 deprivation and growth retardation simulat- Pediatrics 56:1 026, 1975

Moore DC, Tattoni OS, Ruvalcaba RHA, et al: ing idiopathic hypopituitarism. I. Clinical Root AW, Bongiovanni AM, Eberlein WA: Di-Studies of anabolic steroids. VI. Effect of evaluation of the syndrome. N EngI J Med agnosis and management of growth retar-prolonged administration ofoxandrolone on 276:1 271 , 1 967 dation with Special reference to the problemgrowth in children and adolescents with Powell GF, Brasel JA, Raiti 5, et al: Emotional of hypopituitarism. J Pediatr 78:737, 1971gonadal dysgenesis. J Pediatr 90:462, deprivation and growth retardation simulat- Urban MD, Lee PA, Dorst JP, et al: Oxandro-1 977 ing idiopathic hypopituitarism. II. Endocri- lone therapy in patients with Turners syn-

Post EM, Richman RA: A condensed table for nologic evaluation of the syndrome. N Engl drome. J Pediatr 94:823, 1979predicting adult stature. J Pediatr 98:440, J Med 276: 1 279, 19671 981 Roche AF, Wainer H, Thissen D: The RWT

Short Stature

Short Stature as the Primary Manifestation of Coeliac Disease. Groll A, et al:

Lancet 2:1 097, 1980.

Thirty-four patients aged 2#{189}to 1 7 years with short stature of undetermined causeand no gastrointestinal symptoms underwent jejunal biopsy for exclusion of coeliacdisease. Eight patients had subtotal or severe partial villous atrophy; seven of theseshowed a significant acceleration in growth velocity after the introduction of agluten-free diet. The authors conclude that short stature by itself, in the completeabsence of gastrointestinal symptoms, is an indication for jejunal biopsy, particularlyif bone age is delayed by more than four years and/or there are associatedhematologic abnormalities.

Comment: In this study 21 % of children with short stature, in whom dysmorphic orprimary endocrinopathy had been ruled out, proved to have coeliac disease. It iswell known that some patients with coeliac disease may have only short stature andfailure to thrive; however, most do have gastrointestinal manifestations such asabdominal distention, abdominal distress, or foul-smelling stools. What is surprisingis that such a large percentage of this group of 34 patients had coeliac disease.This may be a reflection of the fact that the study was carried out in England, wherecoeliac disease is probably more common than in the United States. Despite thefact that coeliac disease is less commonly diagnosed in this country than it previouslyhad been, physicians must maintain a high index of suspicion. Screening tests areunreliable and when the diagnosis is suspected, jejunal biopsy should be performed.Blind trials of a gluten-free diet frequently cause confusion and should be avoided.Patients who are true coeliacs should be on a strict gluten-free diet for life. (K.

Nord)

Heatstroke

Exertional Heatstroke in Novice Runners. Hanson PG, et al. JAMA 242:1 54, 1979.

As former President Carter demonstrated, heatstroke can develop in presumablytrained people who are running in hot weather. Heat production in steady-stateexercise in adults can produce 1 ,000 kcal/hr on more, and rectal temperatures canreach 41 #{176} C. A critical thermal maximum of 42#{176}C, when reached, can lead toheatstroke. Runners, especially novices, need data about temperature and humidity

and need to be reminded to drink adequate volumes of hypotonic fluids duringexercise. They also need to recognize the early symptoms of evolving hyperthermiaincluding increasing fatigue, hyperventilation, nausea, disorientation, and eventual

staggering gait. Other clinical features of heatstroke include hyperpyrexia andincoherence of speech with eventual loss of consciousness. Although anhidrosisand tachycardia may be seen, active sweating and relative bradycardia may occurin conditioned athletes. Treatment of heatstroke includes rapid vigorous cooling,rehydration, and maintenance of adequate circulation.

Comment: Heatstroke is the second most common cause of athletic death (CNSinjuries is the number 1 cause of death). It is preventable by avoidance of excessiveexercise in hot weather, acclimatization, and education. During hot weather theathlete needs frequent rest and adequate intake of hypotonic fluids. (R.H.R.)



DOI: 10.1542/pir.3-6-1711981;3;171Pediatrics in Review

S. Douglas FrasierShort Stature in Children

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