SUNRISE TEACHING 14 TH APRIL 2016 SUSAN KNOX ST1 ANNE-MARIE MCCLEAN ST3 Short Stature

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

Definition Height 2 SD or more below the mean height for the child’s age and sex. On a WHO growth chart this represents a height below 2 nd centile. Or more than 2 SDs below the midparental height.

Assessment Antenatal History Pregnancy, illness, complications Antenatal alcohol, other drugs Perinatal History Gestational age, complications Birth weight, length, head circumference Feeding and weight gain PMHx Chronic illness e.g. asthma, IBD Medication Hx Medications e.g. corticosteroids Growth History Examine previous growth records Neurodevelopmental Developmental delay, school performance, any bullying Family History Short Stature, pubertal delay Endocrine disease Social History

Examination GENERAL  Signs of neglect  Nutritional status  Dysmorphic features CVS Resp Abdo Neuro  Fundoscopy, visual fields MSK  Joint swelling  Skeletal deformities eg, rickets (craniotabes, bulbous wrists and bowing of the extremities), achondroplasia Skin  café-au-lait spots or large haemangiomas Thyroid  ?Goitre  Thyroid status

Dysmorphic features:  Trisomy 21: hypotonia, upward slanting of palpebral fissures, round face, micrognathia, single palmar crease, brachycephaly  Turner's syndrome: webbed neck, low hairline, broad chest, increased carrying angle, hypertelorism, posteriorly rotated ears  Russell-Silver syndrome: triangular face, asymmetry, clinodactyly  Prader-Willi syndrome: obesity, small hands and feet  DiGeorge syndrome: minor facial dysmorphism, cleft palate  Noonan's syndrome: hypertelorism, backward rotated ears  Congenital GH deficiency: associated midline abnormalities such as cleft lip and palate, midfacial hypoplasia, single central incisor

Pubertal  Tanner staging Consider any indications of other possible underlying causes - eg, Cushing's syndrome, chronic kidney disease, hypothyroidism or fetal alcohol syndrome. Look for features of Turners in girls Growth  Measure height, weight, head circumference  Sitting as well as standing height are important in order to consider asymmetry and skeletal disproportion - eg, achondroplasia  Assess growth velocity over minimum of 6 monthly intervals  Measure parents’ heights, calculate MPH and family height target

Calculate expected final height The mid-parental height provides an estimation of the expected final height. If a child's height lies within the target centile range then their height is normal with regard to their genetic potential. A calibrated stadiometer should be used for measuring standing height and the heights of the parents should be accurately measured rather than rely on reported heights. The mid-parental height is unreliable if the parents' heights are very different.

Calculations MPH: Mothers height + Fathers height 2 +7 for boys /- 7cm for girls TCR: Boy = MPH +/- 10cm Girl = MPH +/- 8.5

Baseline Investigations U+E FBP, CRP BP Karotype TFTs Serum IGF1 Coeliac Disease Antibody Screen Urinanalyis X-ray left hand and wrist Growth Hormone Provocation Testing

Bone Age  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)

Causes of Short Stature Familial (genetic) Short Stature Constitutional delay in growth and puberty Intrauterine growth retardation Growth hormone deficiency Other endocrine disorders e.g. hypothyroidism, Cushing’s syndrome Dysmorphic syndromes e.g. turner’s, noonan’s syndromes, T21 Coeliac Disease Chronic renal disease Chronic inflammatory disorders (e.g. inflammatory bowel disease, rheumatic disease) Skeletal Dysplasia (achrondroplasia, hypochondroplasia) Metabolic bone disease (X linked hypophophataemic rickets) Malnutrition

Bone Age Assessment 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. Thefinding 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 The European Society for Paediatric Endocrinology (ESPE) classifies the main causes of short stature into three groups: Primary growth disorders, where the condition is intrinsic to the growth plate. Secondary growth disorders, where the growth plates change as a consequence of the condition. Idiopathic, where there is no identifiable cause of short stature. Most children with short stature will have constitutional delay of growth and puberty (CDGP) or familial short stature, or there will be no identifiable cause.

Primary growth disorders Clinically defined genetic syndromes Intrauterine growth restriction with failure to catch up Congenital bone disorders

Secondary growth disorders Chronic Illnesses Endocrine: Metabolic: Diabetes mellitus (poor control). Chronic disease: Malnutrition: Psychosocial deprivation Medications

Idiopathic Constitutional delay of growth and maturation Familial Short Stature

Referral [4]4 Indications for referral include: Height: 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.

Management of Short Stature Management of any identified underlying cause Growth hormone 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]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] 78910

Secondary growth disorders Endocrine:  Hypothyroidism.  Panhypopituitarism.  Hypothalamic or pituitary lesions (eg, trauma or tumour).  Laron's syndrome (growth hormone insensitivity).  Cushing's syndrome. Cushing's syndrome  Growth hormone deficiency or insufficiency.  Precocious puberty. 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. Short bowel syndrome  Anorexia nervosa.  Rickets. Psychosocial deprivation, including hyperphagic short stature syndrome.hyperphagic short stature syndrome Medication: steroid therapy.

Familial Short Stature Normal growth velocity Normal diet General health good Normal examination Mid-parental height centiles low Bone age normal Normal FBP, BP Management is to monitor growth Adult height potential is short

Constitutional Delay in Growth and Maturation Relative short stature occurring due to a delay in the timing of onset of puberty Variation in timing of normal puberty rather than an abnormal condition Usually presents in early adolescence Often familial history Much more common in males (may represent bias in level of concern) Short Stature and delayed pubertal developmental by 2 SDs Typically there is a shorter back (sitting height percentile) relative to leg length There is invariably delay in bone age maturation which usually remains consistent over time. Height velocity is appropriate for bone age Lab tests are normal including growth hormone provocation testing Management: usually no treatment is required as the onset of puberty and the accompanying growth spurt will occur spontaneously and an appropriate final adult target height is achieved. Treatment is sometimes indicated in those adolescents who have difficulty coping with their short stature or with the delayed physical development. Administration of sex steroids for a period of 3-6 months can be used to induce pubertal changes and accelerate growth rate (boys: testosterone mg IM every 4 weeks). Psychological support

Constitutional Delay in Growth and Maturation Growth velocity normal Diet normal Family history of delayed puberty General health normal Examination normal General And systemic Mid-p centiles normal Investigations normal including GH provocation testing Bone age is delayed over 2 Sds Blood investigations normla Management monitor growth Adult height potential normal

Nutritional Decreased growth velocity Diet deficient in nutrients Socioencomic neglect Macro and micronutrient deficiency symptoms Pallor, stomatitis FBP- low Hb, high Plts (low Fe) BP- ALP can be high/normal Vitamin D level low Check Trace elements Management: dietetic and social input If well supported final adult height can be normal

Endocrine Causes Decreased growth velocity Normal diet Family History- thyroid or other Symptoms of hypothyroidism On Examination Bone age can be delayed in hypothyroidism Send TFTs and IGF1 Do a Growth Hormone Stimulation Test Manange with an endocrine referral, replace the missing hormone- thyroxine or growth hormone Final adult height is variable

Growth Hormone Deficiency GH secreted in bursts Declines with age GH secretion controlled by GHRH and GH inhibiting hormone (somatostatin) GH secretion is regulated by negative feedback by circulating insulin like factor 1 (IGF-1) at the pituitary and hypothalmus

Clinical Features of GH Deficiency Slow growth velocity Short Stature Increased subcutaneous fat, truncal obesity, decreased muscle mass Relative hypoplasia of mid facial bones Delayed dental eruption Delayed closure of anterior fontanelle

Making the Diagnosis and Treatment Baseline/Random serum IGF-1 it is GH dependent and may be low in GH deficiency but normal level of IGF-1 doesn’t exclude GH deficiency GH provocation testing Insulin Tolerance Test (considered gold standard in children >5 yrs) NICE Criteria for diagnosis of GH deficiency rhGH until final adult height achieved

Genetic/chromosomalSHOX gene mutation Turners Trisomies Russel silver microdeletions Decreased growth velcoity Normal diet Turners can be asymptomatic On examination may have phenotypic features- not always apparent with Turners Normal family history as most are mutations Chromosomes, DNA Always check karyotype in short female Management of these children- multidisciplinary including genetics team. There may be an indication for growth hormone Short adult height potential

Skeletal Dysplasia Decreased growth velocity Normal diet Autosomal inheritance therefore one parent may be affected or it may be de-novo mutation Delayed dentition On examination: short limbs, short trunk. Upper to lower limn ratio Refer to genetics Supportive management Short adult height

Resources UK Restricted Growth Foundation ( BMJ Best Practice Assessment of Short Stature- updated August 2015

NICE Guideline-Human growth hormone (somatropin) for the treatment of growth failure in children

Laboratory evaluation Choice of tests should be based on the potential aetiologies after a careful history and physical examination. First-line tests include: FBC Complete metabolic profile (to screen for electrolyte abnormalities in renal and other chronic diseases) including looking for metabolic acidosis, and for hypocalcaemia (e.g., in DiGeorge syndrome, rickets) ESR to rule out underlying undiagnosed chronic inflammatory illness Tissue transglutaminase to rule out coeliac disease Urine analysis to rule out infection, a or proteinuria (with chronic renal disease), and to detect renal tubular acidosis TFTs to screen for hypothyroidism Insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP-3) to screen for GH deficiency Karyotype in girls to rule out Turner's syndrome.

Subsequent Tests Subsequent tests depend on the diagnosis and may include: GH stimulation tests for GH deficiency; patients may also need a MRI brain and full pituitary evaluation to identify co-existing pathology Diurnal cortisol levels, urinary cortisol levels, and a dexamethasone suppression test for Cushing's syndrome X-ray wrist and vitamin D levels for rickets; a skeletal survey in osteogenesis imperfecta, achondroplasia An IGF-1 generation test in patients with a high basal GH and suspected to have GH insensitivity Echocardiogram for congenital heart disease Genetic evaluation with karyotyping for other genetic syndromes Referral to a psychologist for eating disorders Referral to the child protection team if there are concerns regarding abuse or neglect Appropriate investigations for chronic illnesses such as a sweat test for cystic fibrosis, rheumatoid factor in juvenile idiopathic arthritis, HbA1c in diabetes mellitus, endoscopy in inflammatory bowel disease, and a referral to the appropriate specialist if underlying undiagnosed medical condition identified.

References