Approach to a Short Child & Diagnosis of Growth Hormone Deficiency in Childhood and Adolescence Dr. Huen Kwai Fun COS & Con (Paed & Adol Med), TKOH President,

Approach to a Short Child & Diagnosis of Growth Hormone Deficiency

in Childhood and Adolescence

Dr. Huen Kwai FunCOS & Con (Paed & Adol Med), TKOH

President, The Hong Kong Society of Paediatric Endocrinology & Metabolism

Prevalence of IGHD

UK, Germany, France – 18-24 per million Sweden – 62 per million US – 287 per million Guyda HJ. TEM. 5(8):334-40

Differences in diagnostic criteria – inclusion for Rx of less severe forms of IGHD

Worldwide Indications for GH Px Canada – Only approved for classical GHD

Dx with strict criteria Ht and GV < -2SDS and peak GH <5 ug/L

(before 1983) or <8 ug/L (after 1983) after ITT, arginine, or combined L-dopa-propanolol testing on 2 separate occasions

Japan, Sweden, France - Approved for Turner Syndrome also

USA - Approved for CRF also

Australia – approved use of GH for all short children who meet only auxological criteria without regard to GH secretory status

1988 – Ht < 3% and GV < 25% 1994 – Ht < 1% and GV < 25%

(OZGROW study) (comprehensive national database + small

no prescribers + tight audit system)

FDA approved indications: GHD, CRI, Turner syndrome, SGA, Prader-Willi syndrome, idiopathic short

History Birth weight

– SGA baby may remain small with no catch up

Neonatal history– Hypoglycaemia, micropenis, prolonged jaundice,

craniofacial midline abn, cong nystagmus may indicate congenital GHD and panhypopituitarism

– Maternal drug exposure

Parents’ height– Calculate mid-parental height:

(mother’s ht + father’s ht 13cm) 2 5cm

– Genetic short stature / hereditary skeletal dysplasia as causes

Heights of siblings Pubertal history of parents:

– Age of menarche of mother

– History of late bloomers for father

– +ve FHx of pubertal delay may indicate Constitutional growth delay

Past growth history, growth velocity and when falling off is first noticed– Normal GV usually ~5cm/yr (4-10yrs)

– Children with constitutional growth delay may demonstrate fall off growth between 3m to 2yrs and then grow along that percentile until puberty

Detail nutritional history

– Poor dietary intake may indicate nutritional dwarfism as

cause

Detail psycho-social history

– May indicate emotional deprivation as cause

Past health

– Any chronic illnesses may result in poor growth

Dental history

– Late teeth eruption may suggest pubertal delay

Drug history: especially glucocorticoids

Physical Examination Height, weight and HC Weight to height ratio Arm span

– Increased vs body height in patients with short axial skeleton (skeletal dysplasia) or long extremities (Marfan’s syndrome)

Sitting height– Measured using sitting height table / stool,

with upper surface of thighs horizontal, feet supported and back of knee just clear of stool

– Lower segment can also be measured by length between public symphysis to heel

Upper segment / lower segment ratio– Sitting ht (standing ht – sitting ht)– Normal ratio: ~1.4 under 4yr, ~1.2 at 10yr,

~1.1 during puberty– Short limbs: achondroplasia,

hypochondroplasia, multiple epiphyseal dysplasia

– Short trunk: mucopolysaccharidoses, spondyloepiphyseal dysplasia

Dysmorphic features– Turner’s syndrome

• Must be considered in any girls with short stature, may have no obvious features in Mosaic Turner’s

• Dysmorphic features: cubitus valgus, low hair line, shield like chest, hypoplastic nails

• Hints: raised baseline FSH and LH in girls after 9-10yr

– Russell-Silver syndrome• Clinical features: IUGR, hemihypertrophy, triangular

facies and clinodactyly

– Other syndromes: Seckal, Noonan, Prader-Willi

Pubertal development Systemic examination of all systems

– To exclude chronic illness and hypothyroidism

Genetic Short Stature

One or both parents and often grandparents short

Ht after age 2 correlated well with final ht Short throughout childhood GV normal, grow // to and often just < 3% BA ~ CA PAH short normal Final ht near target ht

Constitutional Growth Delay

Parental ht normal Hx of delay maturation of parents Slow GV, ht gradually deviate from normal

curve until puberty Delay BA and sexual development PAH in normal range

Evaluation of short stature

Ht just < -2 SDS, GV > 5 cm/yr (age 3 -10) – just monitor growth

Ht -2 SDS to -3 SDS, GV normal – FBC,ESR, urinalysis, R/LFT, TFT, BA

Ht < -3 SDS or abn GV – further endocrine and systemic work up

Indications for further investigations

Current height percentiles not compatible with

genetic potential

Demonstration of deceleration of growth by

crossing one percentile (> 2 yrs)

>3 SD below the mean height for age

Subnormal growth velocity for age

(Refer endocrinologists for further evaluation and work up)

Further investigations GH assay: considered normal GH reserve if peak

GH response to stimulation 15mIU/L in any 1 test

For IGF-1, IGF-BP3 and genetic study if

– Persistent subnormal growth velocity

– Significantly short children (>3SD below mean

height for age)

– High baseline GH suggestive of GH resistance

X ray long bones and genetic study for

disproportionate short stature due to skeletal

dysplasia

Follow up and Management

Follow up once every 4-6 months if a firm diagnosis is

made with a normal GH response

Improve dietary intake if inadequate diet

Explain height potential if genetic short stature and

constitutional growth delay and reassure parents

Prepared by Dr. Elaine Kwan References:

Short stature and GHD. Clin Endo 1995; 43:133-42Pediatric decision making. Berman

Clinical Paediatric Endocrinology. Kaplan

Importance of Diagnosis of GHD1. Identify children most likely to benefit from many

years of GH Rx before initiation Children uniformly benefitted most in all published series - those

identified to have GHD utilizing classical criteria Use of inadequate Dx criteria for GHD in childhoood resulted in

a significant no (40-67 %) having a normal GH result upon retesting after discontinuation of GH Rx in adults (Longobardi S et al. JCEM 81:1244-7; Tillmann V et al. JCEM 82: 531-5; Tauber M et al. JCEM 82:352-6; Maghnie M et al. JCEM 84: 1324-8)

Canada – strict Dx criteria - retested – high true +ve rate of 95% in childhood onset due to organic causes and 91% in idiopathic GHD (Reyes L et al.)

2. Identify children w profound GHD – frequently ass w MPHD that must be Dx and Rx

3. Identify GHD ass w CNS tumors4. The ethics, economics, and potential Cxs related to

use of GH Rx esp w high dosages

Consensus Guidelines for the Dx and Rx of GHD in Childhood and Adolescence

Summary Statement of the GH Research Society Endorsed by:

European Society for Pediatric Endocrinology Lawson Wilkins Pediatric Endocrine Society Australasian Pediatric Endocrinology Group Japanese Society for Pediatric Endocrinology Sociedad Latinoamericana de Endocrinologia

Pediatrica GH Research Society JCEM 2000; 85 (11) : 3990-3

Consensus

In absence of a clearly defined benefit (auxological or psychological), use of GH for children w normal GH secretion is not supported.

Despite limitations, it is indeed possible to accurately assess GH-IGF axis in majority of short children, and, further, to make a Dx of ‘classical’ GHD, using a combination of auxological criteria and biochemical assessments.

GH Research Society. JCEM 2000; 85 (11) : 3990-3

Entry into this evaluation process should be reserved for the slowly growing child w a significantly decreased GV. Rosenfeld RG JCEM 1995; 80(5):1532-40

Diagnosis of GHD GHD part of a spectrum of growth disorders,

continuum in all parameters No observations or tests absolutely reliable

Clinical and Auxological evaluation Biochemical assessment Radiological evaluation Genetic work-up Best judgement of an experienced clinician

Stress on considering all available information in reaching a conclusion. The appropriate focus is on the pt and not on any particular set of nos.

Clinical & Auxological Criteria Short stature is defined as ht < -2 SDS or < 3% 2.5% – 3% at extreme end of distribution – normal GV < 25 % ( <5 cm/yr age 3-10) Require updated population standard and longitudinal

velocity standards ? Expressed in SDS rather than in percentiles -3 SDS or 0.1 % should be included Use of Ht % and GV in cm/yr – ?deserve a place in def Body composition, bone density and bone markers –

presently not discriminatory for Dx of GHD Advantages - Noninvasive and inexpensive Probably defines the population at risk Pitfalls - Not distinguish pts w GHD and those w ISS Does not predict response to GH Rx

Criteria for immediate Ix1. Severe short stature – ht < -3 SDS

2. Ht < -1.5 SDS mid-parental ht

3. Ht < -2 SDS and GV over 1 yr < -1 SD, or decrease in Ht SDS >0.5 over 1 yr (>2 yr old)

4. In absence of short stature, GV < -2 SDS over 1 yr or < -1.5 SDS sustained over 2 yr

5. Signs indicative of intracranial lesions

6. Signs of MPHD

7. Neonatal S/S of GHD

Consensus Guidelines by GH Research Society. JCEM 85(11):3990-3

Radiological Evaluation Bone age Lateral SXR MRI Up to 80% pts labeled as IGHD has defined

diagnostic markers >50% isolated GHD have PSIS Pituitary Stalk Interruption Syndrome (PSIS) –

lack of a visible or an interrupted pit stalk, ant pit hypoplasia, and lack of normal post lobe hypersignal in sella turcica, w an ectopic hyperintense post pit

Evaluation for genetic disorders Tests for genetic mutations (e. g. PROP1 and

POU1F1) only available in research lab

Pointers to genetic disorders:

1. Early onset of growth failure

2. +ve FHx and possible consanguinity

3. Ht > 3SD below the mean

4. Extremely low GH response to provocation tests

5. Very low IGF-1 and IGFBP-3 levels

Biochemical assessment Limitations of conventional methodologies:1. GHD and normal short stature not cleanly

demarcated entities. Evidence of overlap of all auxological and biochemical parameters

2. GH secretion is a continuous spectrum. Criteria for abnormal response is only arbitrary. Loosening of Dx cut-off from 5-7 to 10 ng/ml, based on no physiological data

3. No satisfactory mechanism to resolve conflicting data from 2 or more tests. The commonly employed paradigm of requiring failure on 2 provocative tests does not address the simple question of 2 out of how many?

4. Lack of age- and puberty-related (? sex steroid priming) normal data to define threshold for subnormal IGF-1 and IGFBP-3 levels and GH responses to provocative test

5. Application of a single fixed cut-off level for GHD independent of the provocative test in use

6. Poor reproducibility of GH provocative tests or spontaneous GH profiles

7. Provocative testing is nonphysiological. Such tests clearly do not replicate normal secretory dynamics

8. Great interassay variations in GH radioimmunoassays. Presumably reflecting variability in molecular forms of GH among pts, use of polyclonal vs monoclonal Ab, and employment of different diluents and standards.

9. Provocative GH testing ass w significant cost, discomfort to pt, and some risk. Deaths occurred during ITT and arginine stimulation tests

10. Impact of obesity and depression on GH provocative testing not properly addressed

11. Demonstration of normal response does not exclude various forms of GH insensitivity

Practical assessment of GH status1. 24-h spontaneous GH profiles –

impractical. Not more reliable (both sensitivity & specificity) than standard provocative tests

2. GHRH tests + arginine or pyridostigmine (suppress somatostatin) – best GH stimulation but unable to detect GH insufficiency ass w hypothalamic dysfunction(most common cause of GHD)

3. Urinary GH estimation – not useful, great inter- and intra- variability

4. Growth factor measurements IGF-1 & IGFBP-3 More reproducible, longer half-lives, little diurnal

variation. Acceptable sensitivity and specificity No age- , sex- and puberty - related standards Unreliable <5 yrs. Discriminate better >8 yrs Higher levels in CNS tumors and radiation-

induced GHD Hintz: Paed 102(2) Aug 1998:524-6

IGF-1 or IGFBP-3 > -1 SDS essentially rules out classic GHD. Practical application – exclude pts unlikely GHD and identify pts further work up should be performed JCEM 1996;81:1927-32

Pitfalls – cannot discriminate completely GHD and short normal; cannot predict long-term response to GH

DDx of IGF deficiency1. GHD due to hypothalamic dysfunction2. GHD due to pit dysfunction3. GH insensitivity (GHI) A. Primary GHI a. GH receptor def –mutations/deletions b. Abn GH signal transduction – post-receptor B. Secondary GHI a. malnutrition b. hypothyroidism c. chronic ds – liver ds, DM, infection d. drugs- chemoPx, steroids, psychotropic drug4. Primary defects of IGF synthesis5. Primary defects of IGF transport/clearance6. IGF resistance

5. Most information gained by single IGF-1 and IGFBP-3 estimation + single dynamic provocative test

(N) IGF-1 + IGFBP-3 + (subN) peak GH response – 2nd test help to distinguish GHI and normal short

GH Provocation tests Age- and sex-defined N data Standardized GH assay -An assay that measures 22-

kDa hGH, using monoclonal Ab recommended Appropriate GH cut-off w recent lab advances Limit no. of provocative agents w well

standardized protocol Great care exercised in using insulin or

glucagon in a young child Sex steroid priming indicated in immediate

peripubertal period 2 tests in suspected GHD (sequential or on

separate days). One test w defined pathology New approaches to improve Dx accuracy of GH

testing by both endogenous GHRH stimulation and somatostatin inhibition -> augmented and more reproducible peak GH response

GH provocation tests IH – 0.1 IU/kg IV; GHRH stimulation; hypoG

Sxs; GH 0-120 min ARG – 0.5 g/kg infusion; somatostatin

inhibition; vomiting 2%; GH 0-120 min CLO – 2 mcg/kg po; GHRH stimulation;

mild somnolence 35%; GH 0-180 min L-DOPA – 125mg, 250mg, 500mg po for

BW <15, 15-30, >30 kg; GHRH stimulation; vomiting 25%; GH 0-180 min

GLU – 15 mcg/kg, max 1 mg IM; GHRH stimulation; vomiting 15%; GH 0-180 min

GHRH – 1 mcg/kg IV; facial flushing 30%; GH 0-90 min

Pyridostigmine – 60 mg po; somatostatin inhibition; mild abd pain; GH 0-180 min

GHRH + ARG/ PD – max somatotrope stimulation

Propanolol – 0.5 mg/kg, max 40 mg; 1h before test to augment primary stimulus response

Dx of GHD

Ht < - 3 SDS GV < 25 % Delayed bone age (< -2 SDS) PAH substantially < mean parental Ht

(< -1.5 SDS) IGF1 and IGFBP3 < -1 SDS Impaired peak GH response to 2

provocation tests +/- MRI or genetic abnormalities

Thank You