Short stature Dr Olcay Evliyaoğlu

Definition Height lower than 3 % in growth charts(<-2sd) Severe short stature: Height lower than 1% (< -3sd)

Etiologic classification of short stature Normal Constitutional growth retardation Familial short stature Both

Etiologic classification of short stature Pathologic Nutritional Malnutrition Malabsorption Celiac disease Zinc deficiency Enflamatuary bowel disease

Etiologic classification of short stature İntrauterine growth retardation Sporadic Dysmorphic syndrome Chromosomal abnormalities ( Silver-Russel, Down, Seckel etc) Skeletal dysplasias Metabolic disease Mucopolysaccharidosis Other storage disease

Etiologic classification of short stature Chronic diseases Chr renal disease Chr liver disease Congenital heart disease Pulmonary diseases ( cystic fibrosis, branchial asthma) Chr infections Psychosocial dwarfism

Etiologic classification of short stature Drugs Glucocorticoids Estradiol ve androgens Endocrine short stature Hypothyroidism GH deficiency Hypopituitarism Excess cortisol Pseudohypoparathyroidism

Etiologic classification of short stature Dysmorphic syndromes with short stature Turner Noonan Aarskog Disproportional short stature Skeletal dysplasias Congenital abnormalities

İdiopathic normal variant short stature (familial short stature) Genetics determine Target height is short Bone age is not delayed, and is appropriate for chronologhical age Growth is parellal to curves but is lower than 3% . HA<BA=CA

İdiopathic normal variant short stature (nonfamilial short stature) Bone is not delayed, is appropriate for chronologhical age Growth is parellal to curves but is lower than 3% . Target height is not short

Constitutional growth and pubertal delay Most common short sature Mostyly in boys Family history Can be associated with familial short stature Growth velocity is slow in the first 3 years of life, they loss centile gradually untill 2-3 years. After they grow normal untill adolescent period. Their weight gain is also slow HA=BA< CA Puberty develops later then expected normals, growth continues for a longer time than peers and their final height reaches their target height. If pubertal delays beyond 16 years organic reasons should also be thought

Pathologic short stature The most seldom and severe form After 6 years GV< 4,5cm/ year The first sign of chronic systemic disease in the cessation of growth. One third of the patients admitting with short stature have systemic disease.

İdiopathic normal variant short stature Nonfamilial Const growth and pub delay Familial

Differential diagnosis of normal and pathological short stature İdiopathic normal variant <3% Height sds between -2SD , -3SD GV is normal ( >6 years >4,5 cm/ year) Parallel to growth curves Pathologic <1% Boy sds > -3SD GV is subnormal(<4,5 cm/ year) Growth is not parallel to curves Cessation of growth in any time

Pathological short stature Term, BW<2500gr Term, BW>2500gr Prenatal IUGR Postnatal Proportional Disproportional Systemic dis Skeletal dysplasia Dysmofic synd yes no Endocrine short stature TFT euthyroidism TFT Hypothyroidism Growth hormone axis

Management of a child with short stature Physical examination and anthropometric mesurements Somatic abnormalities, proportion of the body Signs of chronic systemic disease Height , sitting height, upper and lower segments, arm span measurement, weight, bmı Growth velocity Bone age Target height Predicted adult height according to bone age

Height should be given as standart deviation score (SDS) (z-score) SDS = measured height – mean height according to gender and age / SDS

Target height Girls (cm)= (mat height+pat height)-13 2 Boys (cm)=(mat height+pat height)-13

TH + 8-10cm is what expected

In the first 6 months of life knee later left wrist radiography In skeletal dysplasias and in some dysmorphic syndromes despite short stature bone age may not be delayed.

Laboratuary Total blood count Urine density, urine evaluation Kidney and liver function tests Blood gases Electrolytes Calcium, phosphorus, alkaline phosphatase. Celiac, antiendomysial, antigliadin autoantibodies Creatine kinase (CPK) TFT

Proportional short stature No systemic disease Euthyroid Postnatal Proportional short stature No systemic disease Euthyroid Growth velocity < 4,5-5 cm/y Delay in bone age >2 years GH tests

Evaluation of growth hormone axis Bioinactive GH IGF-1 N or low 20 % increase in IGF-1 levels in IGF1 generation test GH resistance GH normal or increased Low IGF-1 levels in IGF-1 generation test No response to 2 pharm stim Disturbed secretion in sleep GH deficiency Neurosecretory dysfunction

Growth hormone Most of the cells in the pituitary are somatotrophs. One chain alpha-helical nonglicolized polipeptid. 191 aminoasits and 2 intramolecular disulfide connection. 22kDa molecular weight 75% 20kDa 10-25% N-asetile and desamine forms or oligomers

Human growth hormone (hGH) Nonpulsatile secretion in infants GH secretion pulses and amplitude is decreased and tonic secretion disappears untill puberty. In puberty GH secretion amplitude increase (gonodal steroids effect on GHRH) Secretion of GH decrease with aging but is secreted in whole life.

Growth homone effects İncrease protein synthesis, positive nitrogen balance Lypolysis in fat tissue Decrease carbonhydrate utilization and insulin sensivity  increase blood glucose

GH effect Binded to GH-binding protein (GHBP) (at least 50%) GHBP,is the extracelluar part of GH-R .

IGF-1 levels are decreased GH deficiency Hypothyroidism Malnutrition Chronic diseases

IGF’s bind to binding proteins (IGFBP). Transport to target tissue Modifiy the relation between IGF and its rec 6 different IGFBP are cloned IGFBP-3 90%, depends on IGF-1

IGF-1 rec Structurally similiar to insulin rec (2 alfa,2beta subunits)

GH IGF’s (somatomedins) Similar to proinsulin Effect on extracellular growth is mediated by IGF-1 (70aa polipeptid)

Factors that increase growth hormone secretion GHRH Arginine, leucin Alpha adrenergic agonistler (alfa 2 adrenargic) Beta adrenergic antagonists Dopamine, acetylcholine Hypoglycemia Sleeping Exercise

Factors that decrease growth hormone secretion Hyperglycemia Obesity İncrease in free fatty acids Glucocorticoid excess Hypothyroidism İncrease in adrenargic tonus Psychosocial deprivition

Growth hormoned stimulation tests Pharmacologic stimulation GH response < 5 ng/ml complete GH def GH response 5-10 ng/ml partial GH def GH response >10ng/ml normal At least no response to 2 stimuli

Growth hormone deficiency Congenital growth hormone deficiency incidence1:4000 -1:10,000 live birth Stunded growth

Growth hormone deficiency Mild deficiency Symptoms after the first 6 months of life . After the disappearence of maternal hormones Normal birth length Growth velocity decrease gradually Bone age delays Periabdominal fat tissue increase Less muscle mass Teeth development is delayed Thin hair, delay in nail growing

Growth hormone deficiency Severe deficiency Newborn period Hypoglycemia Conjugated hyperbilirubinemia Micropenis (multiple pituitary hormone deficiency)

Treatment Konstitutional growth and pubertal delay GH deficiency Boys : Testesterone enantate 50-100mg/ months IM for 3-4 months Girls: Ethynylestradiol 10-20µg/ day for 3-4 months GH deficiency GH 0,2mg/kg/ week, in the management of pediatric endocrinologist