Management of short stature

A 12-year-old girl is brought in by her mother, who is concerned becauseher daughter is short even compared with other family members. She estimatesthat her daughter has grown less than 3 cm (∼1 in) in the past year andasks if she should receive growth hormone—a treatment that was recentlymentioned in a newspaper article. The girl has no significant past medicalillness or family history of disease that might be associated with shortstature and is free of symptoms. She is a good student and has not beensubjected to physical or verbal bullying at school. Her father is 170 cm (5 ft10 in) tall (10th percentile for a man), and her mother is 160 cm (5 ft 3 in)tall (25th percentile for a woman). Neither was a “late bloomer.”On physical examination, the prepubertal girl has no signs of disease. Herheight is 133 cm (4 ft 4 in) (<5th percentile for age), and her weight is35 kg (77 lb) (25th percentile).

BACKGROUND

Short stature is not a disease but a statistically defined heightthreshold. Some children with short stature are healthy, some have a medicalcondition known to be associated with short stature, and in some, shortstature is the result of an undiagnosed illness. Parents and children whoconsult a physician about short stature may be concerned about either thepossibility of an underlying disease or perceived social discriminationbecause of short stature, including teasing or bullying in school or decreasedfuture socioeconomicsuccess.¹ In thepast 15 years, the manipulation of human stature has become an area of intensebiologic and psychological research, controversial clinical practice,substantial commercial interest, and important ethicaldebate.^2,3

Growth assessment requires accurate measurements of height and weight overtime, the measurement of parental height, pubertal staging, and the selectionof appropriate group referencestandards.^4,5,6The definition of short stature has varied with time and place. On some growthcharts, short stature is defined as a height of less than the fifth percentilefor age. On others, it is defined as the lower limit of normal for height atthe 3rd and even the 0.4th percentile forage.^7,8To measure height, it is essential to use a stable wall-mounted device thathas been accurately installed and is regularly calibrated and to ensure thattrained personnel correctly position the patient. Repeating the measurementreduces error. The height should be recorded and plotted on a growth chart.Height velocity is obtained by taking two accurate height measurements atleast 6 months apart and comparing with standard height-velocity data.Parental heights may be used to estimate a target height percentile. The finalheight range can be estimated by taking the average of the heights of thebiologic parents, adding 6.5 cm (2.5 in) if the patient is male or subtracting6.5 cm if the patient is female, and drawing a target range around this pointon the growth chart to represent plus or minus 10 cm (4 in). When needed,radiographic bone age should be determined by a specialist in thetechnique.

FORMULATING CLINICAL QUESTIONS

Several questions need to be answered before the appropriate diagnosticworkup and the need for interventions to increase height are chosen. You frameyour questions to help structure a search of the literature.

• In children (population) presenting with short stature (exposure), what isthe frequency of an underlying medical disorder (outcome)? [baseline risk]

• Is short stature (exposure) during childhood (population) associated withpsychological disability (outcome)? [harm]

• In children (population) with short stature but without underlying disease(exposure), does growth hormone supplementation (intervention) increase adultheight (outcome)? [therapy]

General approach to searching for evidence

You first look for summarized evidence, such as high-quality systematicreviews and evidence-based guidelines, to answer your questions. Issue 5 ofthe British publication, Clinical Evidence, has nothing on shortstature. The Cochrane Library's Database of Systematic Reviewscontains a recent review of the use of growth hormone in children with chronicrenal failure but no reviews of its use in otherconditions.⁹ TheCochrane Clinical Trials Register lists numerous studies of the useof growth hormone in various conditions associated with short stature,including Turner syndrome, idiopathic short stature, growth hormonedeficiency, Prader-Willi syndrome, and intrauterine growth retardation. Youalso search MEDLINE through WinSPIRS and PubMed's Clinical Queries feature(box 1).

Box 1.

Search strategy: MEDLINE

Question 1

MEDLINE, using WinSPIRS 4.0: Body-height, all subheadings AND mass screening,all subheadings

Question 2

PubMed Clinical Query, search term: short stature; category:prognosis; emphasis: specificity PubMed Clinical Query, search term: short stature ANDpsychol*; category: etiology; emphasis: specificity

Question 3

PubMed Clinical Query, search term: short stature AND growthhormone; category: therapy; emphasis: specificity MEDLINE search term: exp [expand] growth hormone/allsubheadings AND randomized controlled trials (textword)

CRITICAL REVIEW OF THE EVIDENCE

Frequency of underlying medical disorder in short stature

Between 1985 and 1987, the Wessex Growth Study investigators attempted tomeasure all children at 5 years of age (school entry) in two adjacent healthdistricts in Wessex,England.¹⁰ Thosedetected by the nurses to have short stature (height <3rd percentileaccording to the Tanner-Whitehouse standards) had thyroid function and bloodchemistry tests and bone age estimates, with referral to a specialistpediatrician if the results were abnormal. This cross-sectional study fulfillsthe validity criteria for a study of disease probability, as reviewed byRichardson andcolleagues.¹¹ Thestudy patients are representative of the full spectrum of those who would beseen in primary care, the diagnostic workup was fairly comprehensive andconsistently applied, and undiagnosed patients were observed for an additionalyear. Thus, the data from this study should be applicable to groups indeveloped countries even 15 years later.

In total, 14,346 children were screened, and 180 (1.3%) were found to haveshort stature. Of these 180 children, 25 were known to have a known diagnosisconsistent with short stature, such as trisomy 21, hypochondroplasia, Turnersyndrome, Russell-Silver syndrome, celiac disease, or conditions with severeskeletal malformation. Five children belonged to ethnic groups for which thegrowth standards were deemed inappropriate, and three families declined toparticipate in the study. Eight children were diagnosed with an underlyingdisease as a result of the screening program, including Noonan syndrome,hypothyroidism, celiac disease, lead poisoning, neurofibromatosis, and growthhormone deficiency. The remaining 139 healthy children with short stature wereobserved for 1 year to confirm that they had normal height velocity. In thislarge study, about 18% of children identified to have short stature at schoolentry were found to have an underlying medical condition that was previouslyundiagnosed in about 5% (95% confidence interval [CI], 0%-14%).

Growth hormone deficiency was not well studied in the Wessex study, so youlook at the study of the prevalence of growth hormone deficiency by Xiu-lanand associates.¹²This study also fulfills the validity criteria of Richardson etal.¹¹ Schoolphysicians measured all 103,753 students aged 6 to 15 years in two districtsof Beijing. The 202 children confirmed to have short stature (<3rdpercentile for age by northern Chinese standards but less than the 0.2percentile for the Beijing population) were comprehensively evaluated. Ofthese children, only 13 (6% of those with short stature) were diagnosed ashaving medical conditions other than growth hormone deficiency. Using a strictdefinition of growth hormone deficiency, seven children with height below the0.2 percentile were found to have “total” growth hormonedeficiency—a prevalence of 1 per 15,000, or 3.5% (95% CI,1.0%-6.4%).¹³

Finally, you create a list of conditions, including rare diseases, that maycause short stature and are important to diagnose because of their severeprognosis or potential for treatment (seebox 2), using your textbook asa second source. Common variants of normal that may present with short statureare clinically defined by normal height velocities in mid-childhood and eitherdelayed bone age (for constitutional delay) or short parents (for familialshort stature), or a combination of both. Sensitive and specific tests areavailable to diagnose some of the rarer causes of short stature: for example,thyrotropin level for primary hypothyroidism and karyotype for Turnersyndrome. For other conditions (such as gastrointestinal diseases), thespecific tests are invasive. You find no concise summary of evidence on thediagnostic properties of tests for disorders that cause short stature.

Box 2.

Causes of short stature

Commoncauses*

Familial short stature Constitutional delay of growth and puberty A combination of the 2

Rarer causes

Genetic syndromes Turner syndrome Hypochondroplasia Russell-Silver syndrome Intrauterine growth retardation with failure to “catch up” Gastrointestinal disease Celiac disease Inflammatory bowel disease Endocrine disease Acquired primary hypothyroidism Growth hormone deficiency Steroid-induced growth failure Pseudohypoparathyroidism Renal disease Renal failure Renal tubular acidosis

^*No underlying disease is found in >95% of short children.

Short stature in childhood and psychological disability

The first search through PubMed (prognosis of short stature)yields one review article that concludes that “short stature is notassociated with clinically significant psychologicmorbidity.”¹⁴The second search (on short stature as a cause of psychological problems)yields only one primaryarticle.¹⁵ Theauthors tested the hypothesis that referral bias had influenced an earlierstudy finding that children with short stature were academically and sociallyhandicapped. Random samples of children with and without short stature wererecruited in parallel from the public school system and from pediatricendocrinology specialty clinics. The average age of each group was between 9and 10 years. A battery of psychosocial tests was used, including tests forintelligence and educational achievement (completed by the children), familycohesion and adaptability (completed by the parents), and adaptive problematicbehavior (completed by the teacher). Comparison groups were clearly definedand measured for height and psychosocial state independently and consistentlyand at a relevant age. The community-based participants were randomly selectedfrom the group, and there were no obvious confounders. However, the groupnumbers were small (about 30 per group), and issues of sample size, power, andproperties of the measurement scales were not addressed in the article. Theauthors found that the short children who were referred to specialists hadmore externalizing behavioral problems and poorer social skills than thosewith normal stature. No differences were found between community participantswith and without short stature, so the criteria for assessing harm (causation)could not beapplied.¹⁶

Role of growth hormone in short children with no underlyingdisease

The search through PubMed finds only one article that describes a recentrandomized trial on the use of growth hormone, but with no results on finalheight available.¹⁷The other search of MEDLINE yields one systematic review, performed 10 yearsafter the introduction of biosynthetic human growth hormone, which identifiesrandomized controlled trials (RCTs) and theirlimitations.¹⁸ Onlyfive RCTs on the use of interventions in healthy children were listed: fourstudies of human growth hormone and one study of gonadotropin-releasinghormone. Of these five, only one has published adult heightresults.¹⁹ Twotrials have examined the use of human growth hormone in patients with Turnersyndrome, one of which published results in abstract form only. No publishedtrials to adult height in patients with any other diagnosis are available.

The article by McCaughey and colleagues is the only RCT of the use ofgrowth hormone to increase adult height in healthy shortchildren.¹⁹ Thisstudy recruited 18 girls (mean age, 8.0 years) of 40 eligible from the WessexGrowth Study. Of these 18, data were available on the 13 who completed thetrial (7 treated subjects and 6 control subjects). The mean duration oftreatment was 6.2 years. The trial initially used randomization to create twogroups; however, the loss of 5 (28%) of the 18 subjects could have influencedresults. The adult height difference between groups was 7.5 cm (3 in). Allseven treated subjects had heights within their target range, but only 3 of 6control subjects had heights within the target range. Hence, two patientswould need to be treated (number needed to treat = 2) to result in oneadditional child reaching the target height (95% CI, 1-10). There are threestatistical concerns with adopting this evidence: this is the only publishedRCT of its kind; the sample size is small, leading to large CIs; and theoriginal study recruited both boys and girls, who may have different responsesto therapy. The study needs to be replicated to confirm its results.

From the history taking and findings of the physical examination, you areable to reassure the child and her mother that nothing suggests that the childhas an underlying disease that might be associated with short stature. She hasno evidence of psychological difficulties associated with her short stature,and you reassure them that such difficulties are uncommon in otherwise healthychildren. The child is shorter than expected, based on the parents' heights,and because the mother reports poor linear growth, you obtain bone ageradiographs. You do some screening tests to exclude rare causes of shortstature that would be important to treat—hypothyroidism, Turnersyndrome, inflammatory bowel disease, renal failure or renal tubular acidosis,and hypoparathyroidism. The bone age is delayed, but the blood test values arenormal. You explain that constitutional growth delay is the most likely causeof the girl's short stature and make an appointment for 6 months later tomeasure height, calculate height velocity, and assess pubertal status. If thepatient has an abnormal height velocity, specialist referral will be necessaryto assess for acquired growth hormone deficiency and, if growth hormonedeficiency is present, to arrange imaging to exclude a central nervous systemtumor. You explain to the family that there is insufficient evidence tojustify the use of growth hormone in healthy children who do not have growthhormone deficiency or another underlying medical condition.

Figure 1.