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, The Hong Kong Society of Paediatric Endocrinology & Metabolism

Prevalence of IGHD  UK, Germany, France – per million  Sweden – 62 per million  US – 287 per million Guyda HJ. TEM. 5(8):  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 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: Pediatric decision making. Berman Clinical Paediatric Endocrinology. Kaplan

Importance of Diagnosis of GHD 1. 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: )  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 tumors 4. 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) :

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

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 Ix 1. Severe short stature – ht < -3 SDS 2. Ht < -1.5 SDS mid-parental ht 3. Ht 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 status 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 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:  Pitfalls – cannot discriminate completely GHD and short normal; cannot predict long-term response to GH

DDx of IGF deficiency 1. GHD due to hypothalamic dysfunction 2. GHD due to pit dysfunction 3. 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 drug 4. Primary defects of IGF synthesis 5. Primary defects of IGF transport/clearance 6. 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 – 2 nd 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 min  ARG – 0.5 g/kg infusion; somatostatin inhibition; vomiting 2%; GH min  CLO – 2 mcg/kg po; GHRH stimulation; mild somnolence 35%; GH min  L-DOPA – 125mg, 250mg, 500mg po for BW 30 kg; GHRH stimulation; vomiting 25%; GH min

 GLU – 15 mcg/kg, max 1 mg IM; GHRH stimulation; vomiting 15%; GH min  GHRH – 1 mcg/kg IV; facial flushing 30%; GH 0-90 min  Pyridostigmine – 60 mg po; somatostatin inhibition; mild abd pain; GH 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

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