short stature Dr. Azad A Haleem

MBChB, DCH, FIBMS Pediatrics Lecturer

Pediatric department

Medical college/ Duhok university

Heevi Pediatrics Teaching Hospital

azad82d@gmail.com

General Objective:

• Define short stature.• our guideline • another guideline • Bone age by RUS• some point on provocation test • Outlines about Managements. • I may use Kurdish language some times for

clarification and discussion ???

Definition HSDS < -2SD Ht velocity < 3rd percentile .

Males

Age (y)

30

34

38

42

46

50

54

58

62

66

70

74

78

Hei

ght (

in)

Hei

ght (

cm)

2 4 6 8 10 12 14 16 18 2070

80

90

100

110

120

130

140

150

160

170

180

190

200

0

+2

+1

-1

-2 -2.0 SD (2.3 percentile)

Generally accepted definition of normal range

Stadiometers: relative costs

Harpenden $3000

Leicester $60

Growth charts• The normal range for height is generally considered to be

between about the 3rd and the 97th percentiles

• Normal height range differs from one country to another.

• As we don't have Iraqi growth charts so we depend on CDC growth charts.

Guidelines for referral

UK guidelines, depend on single measurement on school entrance, at 5years of age , no data on sensitivity and specificity

Important definitions • Chronological age – Actual age of the child.• Height age – it’s the age at which the height of the

child is at 50th centile.• Bone age - is an indicator of skeletal maturation. • Target MPH: F+M/2 +6.5 for boys and -6.5 for girls.• Then plot the result on Growth Chart at Age 20 to

form Family chart For boys ±10 & Girls ± 8.5

• Example: 10 Y male,HT=115

• HT< 3RD • HA= 6 Y

MPH• Example: 3 Y – girl • Ht=85 cm • Father Ht= 165 cm• Mother Ht= 155 cm• MPH= 160-6.5=• 153.5 • Plot on age 20 • 153.5 ±8.5 • 145 – 162

3rd

MPH= 153.5±10

Approach to short stature (now in Heevi Hospital)

1- Height (CDC) ↓ 3rd centile 2- Family Chart: HT ↓ MPH 3- Bone age evaluation by greulich and pyle method.4- BA < HA<CA (Pathological Short Stature)5- Investigations: level 1 general then Level 2 TFT6- Provocative tests (GH stimulation tests)&IGF

Familial Short Stature Constitutional Short Stature Pathological Short Stature

↓3rd Centile ↓3rd Centile ↓3rd Centile

↔ MPH ↓ MPH ↓ MPH

BA = CA Normal BA = Height Age < CA BA < HA<CA

approach to short stature (new)

1- Height SDS =(height observed – mean height reference) SD reference 2- MPH (SDS )= Target mph – MHR (From 19 years refrences)

SDR

3- Calculate the difference between the height SDS of the

child and the midparental height SDS

4- Bone age evaluation by TW2(RUS) method.

5- Investigations: level 1 general then Level 2 TFT

6- Provocative tests (GH stimulation tests)&IGF

Calculation of standard deviation scores

• Height SDS = (height observed – mean height reference) SD reference

Example calculation:A 9-year-old boy is 116 cm tall

• Mean height reference for his age = 134.7 cm• Standard deviation reference = 6.2 cm

Height SDS = (116–134.7) = –3 SDS 6.2

Calculation of midparental height SDS

Target MPH: F+M/2 +6.5 for boys and -6.5 for girls. MPH (SDS )= Target MPH -MHR

SDRExample calculation:Target midparental height for a 9-year-old boy is 170 cm

• (MHR)Mean height reference for maximum age (adult height) for boys = 176 cm

• (SDR)Standard deviation reference for maximum age (adult height) for boys = 6 cm

Midparental height SDS = (170–176) = –1 SDS 6

Does growth of a child correspond to the genetic potential?

Calculate the difference between the height SDS of the child and the midparental height SDS

Example of calculation:

Height SDS of the child: –3 SDSMidparental height SDS: –1 SDS

Difference: –2 SDS

• As the boy’s height SDS is more than 1.5 SDS below the midparental height SDS, he is short for his genetic potential

Bone Age evaluation

Bone age evaluation

• Bone age estimated from an x-ray of the left wrist and hand should be undertaken as part of the routine evaluation of children with growth failure over 1 year of age.

• It is important investigation in evaluation of patient with short stature and diagnosis of GHD in which it is usually delayed.

The two most widely used systems are:

1) the Greulich-Pyle Atlas method (GP method) in which a left-hand wrist radiograph is compared by means of a sequence of radiographs grouped in the atlas according to age and gender.

2) The Tanner-Whitehouse 2 Bones method (TW2 method). In which a maturity score is awarded to individual epiphyses, the sum of which is then converted to a bone age which is plotted on the growth chart as height for bone age.

G & P Method

Patient’s film is compared with the standard of the same sex and nearest age

It is next compared with adjacent standard, both older and younger to get the closest match

The Greulich-Pyle Atlas method

In the UK, most centers use the radius, ulna and small bone method devised by Tanner and Whitehouse 2 {RUS(TW2)}.

RUS

12

344

5

6

6

8

87

9

9

1-Radus2-Ulna3- 1MCB4-3&5MCB5-P1P6-P3&5P7-M3&5P8-D1P9-D3&5P

12

344

5

6

6

8

87

9

9

each scored from B to I ( 8)Each have corresponding Number.Collect all Then get correct age in chart.

BENEFITS Bone age assessment provides precious information, but if not properly used, can be

misleading and it should always be considered ancillary to the clinical and auxological examination.

Bone age is necessary: - in the diagnosis of FSS and CGD; - for interpreting hormone levels in pubertal age; - for diagnosis of precocious puberty or hyperandrogenism; - for deciding whether to treat or not the above mentioned conditions; - for predicting adult height in normal children.

Bone age is useful : - in evaluating any child with growth and/or puberty disorders;- in deciding the time to start replacement therapy in hypogonadism.- in monitoring children on growth hormone therapy.

Bone age can be misleading:- in evaluating children with disorders of bone mineralization;

(osteochondrodysplasias). - in predicting adult height in pathological conditions; such as in

pp & SGA. - if considered an absolute diagnostic marker; such as in FSS and

CGD. - if, during the follow-up of a patient or in comparing groups of

patients, different readers are involved or different methods are employed.

Provocative tests

Growth hormone secretion

• GH secretion occurs in discrete irregular pulses

• Between the pulses, circulating GH falls to levels that are undetectable with current assays

• Greatest GH levels at night, generally correlating with the onset of sleep

• GH secretion is influenced by other physiological stimuli such as nutrition and exercise

Provocative tests (GH stimulation tests)

• Random sampling of serum GH is insufficient to diagnose GH deficiency; GH stimulation tests are required

• A limited number of provocative agents should be used after an overnight fast in a well standardized protocol.

• Insulin tolerance test (ITT)• Glucagon test (100 microgrammes/kg BW IM(max.1 mg)• L-dopa test• Arginine test(0.5g/kg BW , slow IV infusion (max,30g) ,• Clonidine test (0.1- 0.15 mg/kg BW orally).

Priming with sex steroidA majority of normal pre pubertal children fail to achieve GH values >10 ng/mL with 2 pharmacological tests, so

•Sex Steroid Priming Performed in pre-pubertal male and female patients with a bone age greater than 10 years. •Stilboestrol 1 mg bd for 48 hours prior to test in both sexes •or ethinyl-oestradiol 10 mg od for 3 days before Glucagon test in girls, •or testosterone 100 mg IM start 72 hrs before test in boys.

The drugs are usually prescribed in advance, when the child is assessed in out-patient. 

Provocative tests•In healthy volunteers peak GH levels are 10 ng/ml (20 mU/ml).

•If peak GH level of 10 ng/ml (20 mU/ml) is detected , it exclude classical GHD

•In a classical GHD case a GH peak is not detected or GH peak is less than 3 ng/ml (6 mU/ml) in all these tests.

•In partial GHD cases GH peak of 8-10 ng/ml (16-20 mU/ml) may be seen.

•A strong clinical suspicion is important in establishing the diagnosis because laboratory measures of GH sufficiency lack specificity.•In chronic GH deficiency, the demonstration of poor linear growth, delayed skeletal age, and peak levels of GH (<10 ng/mL) in each of 2 provocative tests, are compatible with GH deficiency. •Acquired GH deficiency can occur at any age; when it is of acute onset, height may be within the normal range with normal bone age but growth velocity decline, so• In acute GH deficiency, a high clinical suspicion of GH deficiency and low peak levels of GH (<10 ng/mL) in each of 2 provocative tests are compatible with GH deficiency.

In addition to establishing the diagnosis of GH deficiency, it is necessary to examine other pituitary functions, which includes TSH, thyroxin (T4), ACTH, cortisol, gonadotropins, and gonadal steroids •If the thyroid functions tests are abnormal ,treat 1st & then do the provocative test for growth hormone.

•If cortisol and ACTH were low give hydrocortisone tab as replacement therapy before GH replacement.

IGF-1 and IFGBP-3 measurement

• IGFBP-3 and IGF-1 serum levels represent a stable and integrated measurement of GH production and tissue effects

• The combination of IGF-1 and IGFBP-3 measurements appears superior to determining either analyte alone in the diagnosis of growth hormone (GH) related disorders

Interpretation of results• If IGF-1 and IGBP-3 level are normal then it

shows that GH level is also normal (no need for GH testing)

• If IGF-1 and IGBP-3 level are low then it may be due to GH def or GH resistance-----

• Go for GH basal level and after stimulation• If GH also low then GH def,• if GH normal or high then GH resistance

( Primary IGF-1 def), (Laron syndrome).

Growth Hormone Therapy

Growth hormone is used for short stature in the following

conditions:• Growth hormone deficiency .(The prevalence

between 1 in 3500 and 1 in 4000 children)

• Turner syndrome. PWS

• Chronic renal insufficiency (pretransplantation)

• SGA: Growth failure at 4 years or older in those born small for gestational age. (Approximately 10% of SGA do not reach the normal height range)

Dosage & administration:The dosage of somatropin should be tailored to the needs of each individual child& varies according to the condition being treated:

• 23–39 microgram/kg daily or 0.7–1.0 mg/m² daily for growth hormone deficiency.

• 45–50 microgram/kg daily or 1.4 mg/m² daily for Turner syndrome and CRI.

• 35 microgram/kg daily or 1.0 mg/m² daily for growth disturbance in children born small for gestational age.

• Somatropin is self-administered or given to the child by an adult, at home, usually as a subcutaneous injection, 6–7 times a week.The maximum recommended daily dose should not be exceeded.

Predicted treatment outcome

• Gains in final height for children treated with somatropin compared with untreated children ranged from approximately 3 to 11 cm

• for growth hormone deficiency 8–11 cm.

• Turner syndrome 5 cm.

• Chronic renal insufficiency 3–9 cm.

• Long-term continuous GH treatment in short children born SGA without signs of persistent catch-up growth leads to a normalization of adult height.

Discontinuation of treatment:Treatment with somatropin should be discontinued if any of the following apply:

• final height is attained.

• Decision by patient that he/she is tall enough.

• growth velocity increases less than 50% from baseline in the first year of treatment

• final height is approached and growth velocity is less than 2 cm total growth in 1 year.

• BA >14years in girls & 16years in boys.

• there are insurmountable problems with adherence

• FOLLOWUP: required as there is risk of :primary hypo

thyroidism/adrenal insuffiency so periodic follow up needed.

• SIDE EFFECTS:Pseudotumour cerebri, hyperglycemia, acute

pancreatitis, liver abnormalities, gynaecomastia,

Special warnings and precautions for use

• In Turner syndrome and SGA children it is recommended to measure the IGF-I level before start of treatment and twice a year thereafter.

• If on repeated measurements IGF-I levels exceed +2 SD compared to references for age and pubertal status, the dose should be reduced to achieve an IGF-I level within the normal range.

• Scoliosis may progress in any child during rapid growth. Signs of scoliosis should be monitored during treatment. However, somatropin treatment has not been shown to increase the incidence or severity of scoliosis.

• Because somatropin may reduce insulin sensitivity, patients should be monitored for evidence of glucose intolerance. Patients with glucose intolerance should be monitored closely during somatropin therapy.

Special warnings and precautions for use

References:• 1.NICE technology appraisals [TA188] Published

date: May 2010• 2.Van Pareren Y et al. Adult height after long-

term, continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose-response GH trial. J Clin Endocrinol Metab. 2003Aug;88(8):3584-90.

Thank You !!