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Pediatric Growth Hormone Deficiency: Identification, Diagnosis, & Management

Kent Reifschneider, MDCHKD / EVMS

Norfolk, VA

Conflict of Interest• Speaker bureau and advisor for Pfizer• Board member of The Human Growth

Foundation

• THANK YOU!

Objectives• Review the literature regarding

measurement accuracy• Discuss accurate measurement techniques• Identify normal verse abnormal growth

patterns• Review differential diagnosis for poor growth• Case studies

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Importance of Accurate Growth Measurement

• Incorrect measurements = Inaccurate assessment

• A 2004 study showed growth to be measured accurately in only 30% of children1

1. Lipman TH et al. Arch Dis Child. 2004; 89: 342-346.

Accurate Height Measurement Technique

• No shoes, hair ornaments, braids, etc1

• Heels together, legs straight, arms at sides, shoulders relaxed1

• Patient should inhale deeply and stand fully erect1

• Height should be potted on patient’s chart at each visit

1. Lipman TH et al. Arch Dis Child. 2004; 89: 342-346.

Accurate Length Measurement Technique

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Evaluating Growth (cont’d)• Normal growth velocity:

– Most rapid in first year of life (up to 22 cm/yr)1

– Slows to 7-9 cm/yr, ages 2-4 years2

– Declines further to ~ 5-7 cm/yr, mid-childhood1

– Increases to 10-12 cm/yr, during pubertal growth spurt1

• Serials measurements over at least 6 months are required for growth velocity calculation

• Velocity standards are required for correct evaluation of data1

1. Lipman TH et al. Arch Dis Child. 2004; 89: 342-346.2. CDC growth chart. 2000. www.cdc.gov/growthcharts

Causes of Abnormal Growth• Normal Variants

- Familial Short Stature- Constitutional Delay

• Prenatal Factors Postnatal Growth- Low Birth Weight (SGA)- Congenital Anomalies

• Nutritional Deficiency- GER, FTT, Eating Disorders

• Chronic Disease- Common - GI, Renal, Neurologic- Less Common - Cardiac, Pulmonary

• Medications-Steroids, Stimulant medications

• Endocrine- Hypothyroidism- GH deficiency- Cushing Syndrome- Early or late puberty

• Genetic Syndromes- Down- Turner- Prader-Willi- Pseudohypoparathroidism- Russell-Silver

• Bone Disorders- Achondroplasia, etc

Normal VariantsShort Stature with normal growth rate• Familial Short Stature

• Short stature with normal onset of puberty• FH of short stature• BA = CA• Final height short but within target range

• Constitutional Delay• Short stature with delayed puberty (late bloomer)• FH of slow growth and delayed puberty in ~50-75%• BA < CA• Final height normal or low normal

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Auxological Signs of Pediatric GHD1

• Short stature1

• Low growth velocity for age (<25th% for bone age)2

• Crossing centiles in a downward direction• Auxology is helpful as an indication for

evaluation for pediatric GHD; however it doesn’t differentiate children with pediatric GHD from other causes of growth problems1– Screening tests can help differentiate endocrine

from non-endocrine causes of growth failure

1. Growth Hormone Research Society. J Clin Endocrinol Metab. 2000;85:3990-39932. Wilson TA et al. J Pediatr. 2003;143:415-421.

Etiologies of Pediatric GHD -Congenital• Multiple genetic causes of pediatric GHD have

been identified1,2

– Examples include abnormalities of the GH gene, the GHRHR gene, or the Pit-1 gene (POI1F1 gene)

• May be associated with structure defects3:– Agenesis of corpus callosum– Hydrocephalus– Sept-optic dysplasia

• May be associated with midline facial defects3:– Cleft lip/palate– Single central incisor

1. AACE Growth Hormone Task Force. Endocr Pract. 2003;9:64-762. Camocho-Hübner C et al. Pediatric Endocrinology.3. Cowell CT. Clinical Paediatric Endocriniology. 1995:136-172.

Etiologies of Pediatric GHD -Acquired• Trauma1

• CNS infection1

• Hypophysitis2

• Primary or secondary CNS tumors, particularly of the hypothalamus or pituitary (eg, craniopharyngioma, glioma, germinoma, histiocytosis)2

• Cranial irradation3,4

1. Ronsenfeld RG et al. Pediatric Endocrinology.2. Cowell CT. Clinical Paediatric Endocriniology.3. Rappaport R et al. Pediatric Res. 1989;25:561-5674. Shalet SM et al. Ballieres Clin Endocrinol Metab. 1992;6:513-526.

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Idiopathic Pediatric GHD• Majority of pediatric GHD cases• Presentation may be in early childhood with severe

growth failure and other clinical features of GHD• Affected infants usually have a normal weight and

length at birth, but impairment of linear growth may occur within the first 2 years of life1

– This growth pattern2 suggest that GH may not be an essential growth factor in utero

• History may include difficult deliver, recurrent hypoglycemia, and/or prolonged jaundice1,3

1. Camocho-Hübner C et al. Pediatric Endocrinology.2. Goossens M. J Clin Endocrinol Metab. 1986;62:712-716.3. Craft WH et al. J Pediatr. 1980;96:397-402.

Auxological Criteria for GHD Evaluation

• Investigation should be initiated if a child exhibits one or more of these features:

• Severe short stature1

• Height >2.25 SD below the mean for age or >2 SD below the midparental height percentile2

• Midparental height = (father’s height + mother’s height)/2;+ 6.5 cm for boys, - 6.5 cm for girls3

• Growth velocity <25th% for bone age3

1. AACE Growth Hormone Task Force. Endocr Pract. 2003;9:64-762. Wilson TA et al. J Pediatr. 2003;143:415-421.3. Rosenfeld RG et al. Pediatric Endocrinology.

Conclusions• Pediatric GHD is defined as short stature or slow

growth caused by the absence or inadequate production of GH in children

• Multiple etiologies have been identified; may also be idiopathic

• Diagnosis is complex1

– Based on clinical, auxological, biochemical, and radiological evaluations

• GH therapy is proven to improve growth in children with pediatric GHD2

• Routine follow-up of patients receiving GH therapy should be performed by a pediatric endocrinologist3

1. Growth Hormone Research Society. J Clin Endocrinol Metab. 2000;85:3990-3993.2. Bierich JR. Acta Paediatr Scan. 1987;337(suppl):135-140.3. Wilson TA et al. J Pedatr. 2003;143:415-421.

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Management of Short Stature in Children Born Small for Gestational Age

Objectives of Presentation

• Define small for gestational age (SGA)• Review the etiology of SGA• Discuss methods of identifying children who are

born SGA• Review evidence for the use of growth hormone

(GH) in children who are born SGA and fail to manifest catch-up growth by 2 years of age

• Discuss assessment and monitoring of children who are candidates for GH therapy

Etiology of SGA

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SGA: Pathophysiology (Hypothesis)• Fetal response to prolonged nutrient

deficiency late in gestation may be permanently reset to a slow growth rate, with a degree of resistance to GH, insulin-like growth factor (IGF-I), and insulin

• Therefore, a subset of children born SHA may have:

• Slow growth rate as a manifestation of a degree of GH or IGF-I resistance

• Increased risk of cardiovascular and metabolic diseases in later life

Gluckman PD, Harding JE. Hom Res. 1997;48(suppl 1):11-16.

Identifying Children Born SGA• For correct diagnosis of SGA, birth length must

be measured precisely• 2 people required for accuracy• Infant on back, centered on board, lying straight with

shoulders and buttocks flat against surface• Infant’s eyes looking straight up and toes pointing

upward with feet flat against footpiece, both legs fully extended

Pomerance JJ. Pediatrics. 2003; 112(1 pt 1):180-182.

Catch-up Growth in Children Born SGA

• ~90% of children who are born SGA experience catch-up growth by age 2 years and will achieve a height greater than -2 SDS (~3rd percentile)1,2

• 80% or more of infants caught up in the first 6 months of life1,2

1. Albertsson-Wikland K, Karlber J. Acta Paediatr Suppl. 1997;423:193-195.2. Karlberg JPE et al. Hom Res. 1997;48(suppl 1):17-24.

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Growth Failure in Children Born SGA

• In some children born SGA, the growth pattern falls away from age- and gender-specific growth curves

National Center for Health Statistics and National Center for Chronic Disease Prevention and Health Promotion (2000).

Rationale for GH Evaluation• Children who have

not experienced catch-up growth by age 2 years have higher risk of short stature (less than -2SDA) as adults, especially those with low birth weight.

Albertsson-Wikland K, Karlberg J. Acta Paediatr Suppl. 1997; 423:193-195.

Age (mo)

Conclusions: Management of Short Stature in Children Born SGA

• Children born SGA who fail to exhibit catch-up growth by 2 years of age are unlikely to catch up, and may be candidates for GH therapy1

• Treatment of children with GH for up to 6 years has been effective and well tolerated in clinical trials2

• Early initiation of therapy may result in better growth response3

1. Albertsson-Wikland K, Karlberg J. Acta Paediatr Suppl. 1997; 423:193-1952. De Zegher F et al. J Clin Endocrinol Metab. 2000; 85:2816-28213. Bogusewski M et al. iActa Paediatr. 1998; 87:257-263.

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What is Normal Growth?

…It depends!

Accuracy of measurement

Reference point (gender, MPH)

Hx:Birth, PMH (trauma, meningitis) & FH

Medications

Activities

ROS:Hass, vision, hearing or signs of

hypothyroidism

P.E:arm span, tanner, skeletal exam, &

growth velocity

Important Questions

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What if this was a girl?

Turner SyndromeClinical Features

%• Short Stature ~100• Gonadal failure >95• Characteristic facies 60

micrognathia, high-arched palate, low-set ears • Cardiovascular anomalies 30-50 • Renal abnormalities 40• Skeletal abnormalities 40-50

short metacarpalscubitus valgus, scoliosis

• Endocrine abnormalities 30-40autoimmune thyroiditisType 2 diabetes

• Webbed neck 25 • Edema of hands/feet 25

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Evaluation

• Confirm accurate measurements• Compare to genetic potential and Hx• Follow growth velocity• Similar to FTT plus hormones & Bone age

• CBC - CMP• UA - ESR• TSH/T4 - IGF-1/IGF-BP3*• IgA with TTG abs - Bone age*

Nutrition

• ALL JUICE IS BAD!

• LOW FAT MILK IS GOOD!

• Diet soda?

• N.E.A.T. vs Exercise

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References1. Lipman TH et al. Arch Dis Child. 2004; 89: 342-

346.

2. Growth Hormone Research Society. J ClinEndocrinol Metab. 2000;85:3990-3993

3. Wilson TA et al. J Pediatr. 2003;143:415-421.

4. AACE Growth Hormone Task Force. EndocrPract. 2003;9:64-76

5. Camocho-Hübner C et al. Pediatric Endocrinology.

6. Cowell CT. Clinical Paediatric Endocriniology. 1995:136-172.

7. Ronsenfeld RG et al. Pediatric Endocrinology.

8. Rappaport R et al. Pediatric Res. 1989;25:561-567

9. Shalet SM et al. Ballieres Clin Endocrinol Metab.1992;6:513-526.

10. Goossens M. J Clin Endocrinol Metab. 1986;62:712-716

11. Craft WH et al. J Pediatr. 1980;96:397-402

12. AACE Growth Hormone Task Force. Endocr Pract. 2003;9:64-76

13. Bierich JR. Acta Paediatr Scan. 1987;337(suppl):135-140.

14.Wollmann HA. Horm Res. 1998;49(suppl 2) 1-6.

15. Neerhof MG. Clin Perinatol. 1995;22:375-385.

16. Gluckman PD, Harding JE. Hom Res. 1997;48(suppl 1):11-16.

17. Pomerance JJ. Pediatrics. 2003; 112(1 pt1):180-182.

18. Albertsson-Wikland K, Karlber J. Acta PaediatrSuppl. 1997;423:193-195.

19. Karlberg JPE et al. Hom Res. 1997;48(suppl1):17-24.

20. Albertsson-Wikland K, Karlberg J. Acta PaediatrSuppl. 1997; 423:193-195.

21. De Zegher F et al. J Clin Endocrinol Metab. 2000; 85:2816-2821

22.Bogusewski M et al. iActa Paediatr. 1998; 87:257-263.