Sunrise Teaching 14th April 2016 Susan knox st1 Anne-Marie McClean st3 Short Stature Sunrise Teaching 14th April 2016 Susan knox st1 Anne-Marie McClean st3

Aims Case: 8 year old boy with short stature Definition History Examination Investigations Aetiology Making the diagnosis

Investigations U+E FBP CRP BP Karotype TFTs Coeliac Disease Antibody Screen Urine Growth Hormone Provocation Testing Serum IGF1 X-ray left hand and wrist Investigations[3]  U+E FBP, CRP (chronic inflammation/disease) BP (bone disorder) Karotype (chromosomal abnormalities, especially Turner’s syndrome) TFTs Serum IGF1 (growth factor deficiency) Coeliac Disease Antibody Screen Urinanalyis X-ray left hand and wrist (Bone age) Growth Hormone Provocation Testing Investigations indicated to confirm or exclude possible underlying causes are based on the clinical assessment. They may include: Blood tests: FBC: anaemia blood dyscrasia and infections. Renal function tests and electrolytes: renal disease and electrolyte abnormalities - eg, Bartter's syndrome, diabetes insipidus and other renal and metabolic disorders. LFTs. TFTs. ESR and CRP: chronic inflammatory conditions. Urinalysis and urine pH level: renal tubular acidosis. Karyotyping may be helpful where examination suggests features of genetic syndromes. It should be performed in all girls with short stature as this may be the only feature of Turner syndrome. Specific tests for suspected underlying or associated diseases - eg, coeliac disease, Cushing's disease, cystic fibrosis, growth hormone deficiency, vitamin D deficiency.

Bone Age Estimation of skeletal maturation from assessment of the ossification of the epiphyseal centres. Comparison of a frontal XR L hand and wrist with Greulich-Pyle atlas standards. Delayed Bone age: 2 SDs below chronological age. Familial short stature- bone age normal CDGP- bone age corresponds with height age and is delayed (up to 2 SDs) Pathological short stature-bone age is severely delayed (>2SDs) Over-emphasis of bone age evaluation can be misleading if not used in the proper settings. The predictions do not apply to children with endocrine or bone pathologies affecting growth. Bone age estimates skeletal maturation from an assessment of the ossification of the epiphyseal centres. The most widely used method is based on comparing a frontal radiograph of the left hand and wrist with standards from the Greulich-Pyle atlas. Bone age is considered delayed if it is two standard deviations below the chronological age. Bone age is usually normal for age in children with familial short stature. In children with CDGP the bone age corresponds with height age and is delayed (up to two standard deviations). In children with pathological short stature, the bone age is severely delayed (more than two standard deviations) Skeletal maturation is assessed by radiography. The appearance of representative epiphyseal centres on the x-ray is compared with age- and gender-appropriate published standards. The most commonly used method is that of Greulich and Pyle, which examines the left wrist and hand, but other methods such as the knee examination maybe more helpful in infants. Bone age may also be used to predict final height, using the tables of Bayley and Pinneau. Many conditions that cause poor linear growth may also cause a delay in skeletal maturation, so the finding of maturation delay is not diagnostic of any particular condition. Delayed bone age does, however, indicate that the short stature is partially reversible, because linear growth will continue until the epiphyses fuse.

Aetiology of Short Stature European Society for Paediatric Endocrinology (ESPE) classification: Primary growth disorders: - condition is intrinsic to the growth plate. 2. Secondary growth disorders: -growth plates change as a consequence of the condition. 3. Idiopathic: -no identifiable cause of short stature. -Familial Short stature -Constitutional Delay of Growth & Maturation The European Society for Paediatric Endocrinology classification system was published in 2007 in the Hormone Research Journal which is the official journal of the ESPE.

Primary growth disorders 1. Clinically defined genetic syndromes 2. IUGR with failure to catch up 3. Congenital bone disorders Clinically defined genetic syndromes, such as: Down's syndrome Prader-Willi syndrome Silver- Russell syndrome Noonan's syndrome Turner syndrome Intrauterine growth restriction with failure to catch up: Fetomaternal factors Prematurity Placental dysfunction Congenital bone disorders such as: Achondroplasia Hypochondroplasia Osteogenesis imperfecta Pics: 1. russell silver syndrome, 2. 3.. acondroplasia,4.. osteogenesis imperfecta.

Secondary growth disorders Chronic Illnesses Metabolic Diabetes mellitus Malnutrition Psychosocial deprivation Medications Endocrine Insufficient nutrient intake , Chronic Illnesses Growth Hormone Deficiency- congenital and acquired Endocrine: Hypothyroidism. Panhypopituitarism. Hypothalamic or pituitary lesions (eg, trauma or tumour). Laron's syndrome (growth hormone insensitivity). Cushing's syndrome. Growth hormone deficiency or insufficiency. Precocious puberty. Disorders of the growth hormone insulin-like growth factor I axis. Metabolic: Mucopolysaccharidoses. Glycogen storage diseases. Diabetes mellitus (poor control). Chronic disease: Cardiovascular disease. Respiratory disease (eg, cystic fibrosis). Haemoglobinopathies. Renal disorders disease. Malignancy. Neurological (eg, hydrocephalus). Juvenile arthritis. Malnutrition: Poverty or neglect. Inflammatory bowel disease. Coeliac disease. Bowel obstruction. Enzyme deficiencies. Chronic bowel infection. Short bowel syndrome. Anorexia nervosa. Rickets. Psychosocial deprivation, including hyperphagic short stature syndrome. Medication: steroid therapy Cardiac disorders Q20–28 1B.2b Pulmonary disorders, e.g. cystic fibrosis J40–99 (E84) 1B.2c Liver disorders K70–77 1B.2d Intestinal disorders, e.g. Crohn’s disease, malabsorption syndromes, short bowel syndrome K50–52 K90–93 1B.2e Renal disorders, e.g. Fanconi syndrome, renal acidosis N10–19 N25–29 1B.2f Chronic anaemia D50–64 1B.2g Multiorgan disordersMuscular and neurological disorders, e.g. Duchenne muscular dystrophy, congenital myotonia G71–73 1B.2i Connective tissue diseases, e.g. juvenile arthritis M08 1B.2y Other specified organ or systemic disorders

Idiopathic Familial Short Stature Constitutional delay of growth and maturation Constitutional delay of growth and maturation is a diagnosis of exclusion essentially

Making the Diagnosis History Family History Systemic Q Diet Examination Blood Tests Bone Age

Genetic Causes History Growth velocity Decreased Diet N Family -   Growth velocity Decreased Diet N Family - General health Specific to syndrome TURNERS CAN BE ASYMPTOMATIC Examination General & systemic Phenotypic features Mid-p centiles N ( most are mutations) Investigations Bone age may be delayed Blood investigations Chromosomes/DNA always check karyotype in a short female Management Multi-disciplinary Including genetics INDICATIONS FOR growth hormone in some cases Adult height potential Short Genetic/chromosomal SHOX gene mutation Turners Trisomies Russel silver microdeletions

Skeletal Dysplasia History Growth velocity Decreased Diet N Family AD   Growth velocity Decreased Diet N Family AD General health delayed dentition General And systemic Examination Short limb Short trunk UPPER LIMB/LOWER LIMB RATIO* Mid-p centiles 1 parent Investigations Bone age Typical limb/trunk abnormaility Blood investigations genetics Management Supportive Adult height potential Short

Endocrine Causes History Growth velocity Decreased Diet N Family   Growth velocity Decreased Diet N Family Known thyroid or other General health Symptoms of hypothyroidism Or growth hormone deficiency Examination General And systemic Hypothyroidism Examine Mid-facial features Mid-p centiles Investigations Bone age Delayed in hypothyroidism Blood investigations TFT IGF-1  Advanced GH stimulation test Management Endocrine referral Thyroxine Growth hormone Adult height potential Variable

Chronic Disease History Growth velocity Decreased Diet N Family -   Growth velocity Decreased Diet N Family - General health Specific to system Examination General And systemic Mid-p centiles N unless strong F/H Investigations Bone age May be delayed Blood investigations  Depend on clinical features Management Referral to appropriate specialty Adult height potential Variable x-ray chest, ecg, echo, esr, urine Coeliac screen, sweat test

Nutritional Causes History Growth velocity Decreased Diet Deficient   Growth velocity Decreased Diet Deficient Family Socioeconomic/neglect General health Macro and micronutrient deficiency symptoms Examination General And systemic Deficiencies-pallor, stomatitis, skin Mid-p centiles N Investigations Bone age Blood investigations FBC-low HB Bone- high ALP or normal VD-low Management Dietetic & Social input Monitor Adult height potential N if well supported

Constitutional Delay of Growth & Maturation History   Growth velocity N Diet Family Delayed puberty General health Examination General And systemic Mid-p centiles Investigations Bone age Delayed Over 2 SD Blood investigations FBC, Bone profile Management Monitor growth Adult height potential Complications[1]  Children with short stature may be teased or bullied, with potential emotional and psychological consequences. This is a source of parental anxiety although, in general, studies are reassuring and suggest long-term complications are infrequent.[11] Because short stature causes anxiety and may prompt consultation it may draw attention to underlying conditions which will then get treated, with consequent improvement in general health.

Familial Short Stature History   Growth velocity N Diet Family Short parent General health Examination General And systemic Mid-p centiles LOW Investigations Bone age Blood investigations FBC, bone profile Management Monitor growth Adult height potential Short

RBHSC Referral Criteria Height <0.4th centile Height below target centile range(TCR) Height >3 centiles below mid parental centile(MPH) Drop of >2 centile lines after 3 years of age Height velocity <4.5cm/year @ 3years to puberty IUGR <2nd centile at 4 years(Fail to show catch-up growth) Turner syndrome Prader-Willi syndrome SHOX mutations Height: fails to progress along the appropriate centile curve. Growth velocity: decreased growth velocity for age. Genetic potential: projected height varies from mid-parental height by more than 5 cm (2 in). Multiple syndromic or dysmorphic features: abnormal facies, midline defects, body disproportions. Bone age: delayed by more than two standard deviations.

NICE Guidelines for GH Use GH- use somatropin- produced using recombinant DNA technology. Indications Have growth hormone deficiency. Have Turner syndrome. Have Prader-Willi syndrome. Have chronic kidney disease. Are born small for gestational age with subsequent growth failure at 4 years of age or later. Have short stature homeobox-containing gene (SHOX) deficiency. Treatment should be discontinued if: Growth velocity increases by 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 one year. Adherence is poor and cannot be improved. Final height is attained. Growth hormone of human origin (somatotrophin) has been replaced by a growth hormone of human sequence (somatropin) which is produced using recombinant DNA technology. The National Institute for Health and Care Excellence (NICE) recommends that somatropin be used for the treatment of growth failure for children with growth failure who:[6] Have growth hormone deficiency. Have Turner syndrome. Have Prader-Willi syndrome. Have chronic kidney disease. Are born small for gestational age with subsequent growth failure at 4 years of age or later. Have short stature homeobox-containing gene (SHOX) deficiency. Treatment should be discontinued if: Growth velocity increases by 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 one year. Adherence is poor and cannot be improved. Final height is attained. Growth hormone therapy in children with idiopathic short stature seems to be effective in partially reducing the deficit in height as adults, although the magnitude of effectiveness is on average less than that achieved in other conditions for which growth hormone is licensed.[7] Treated individuals remain relatively short when compared with peers of normal stature.[8] Mecasermin, a recombinant human insulin-like growth factor-I (rhIGF-I), is licensed to treat growth failure in children and adolescents with severe primary insulin-like growth factor I deficiency.[9][10] 

Summary History and examination together with basic investigations are key for making the diagnosis Constitutional delay of growth and maturation is the most common diagnois but also a diagnosis of exclusion Tertiary centre referral criteria are useful Psychological support

Questions?

Resources BMJ Best Practice Assessment of Short Stature- updated August 2015. Accessible from: http://us.bestpractice.bmj.com/best-practice/monograph/749.html Clinical Dilemmas in Evaluating the Short Child Melissa D. Garganta, MD; Andrew A. Bremer, MD, PhD Pediatric Annals August 2014 - Volume 43 · Issue 8: 321-327 UK Restricted Growth Foundation (www.restrictedgrowth.co.uk)

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