Short Stature

UMH_L_ShortStature@1x_0.pnghttps://labblog.uofmhealth.org/rounds/should-growth-hormone-be-used-for-short-stature-kids

Introduction

Short stature is defined as a height ≥2 standard deviations below mean for the age and sex of a child (or less than 3rd percentile). Short stature can either be a normal variant of growth or pathologic. Pediatricians should monitor for short stature with serial height measurements. 

 

Definitions

  • Growth velocity is the rate at which a child grows. It progressively declines after birth until it rises during puberty.
    • Average for the 1st year of life      - 24 cm / year
    • Average for the 2nd year of life     - 12 cm / year
    • Average for the 3rd year of life      - 8 cm / year
    • Average years 4 until puberty        - 4 - 7 cm / year
    • Average pubertal growth spurt  - 8.3 cm / year for girls and 9.5 cm / year for boys     
  • Midparental "target" height – a calculation to approximate a child’s genetic target height range. Most children achieve an adult stature within 4 inches of their midparental height.
    • For boys:   [father’s height (in) + mother’s height (in) +5] / 2
    • For girls:   [mother’s height (in) + father’s height (in) – 5] / 2
                   
  • Bone age – skeletal maturation, most commonly assessed by examining the epiphyseal maturation of the hand and wrist via plain radiography - which is then compared to a child's chronologic age. Can be used to predict adult height using the Bayley-Pinneau method or another method.

bone age.jpg

https://en.wikipedia.org/wiki/Bone_age             

  • Height age – the age at which the child’s height is the 50th percentile
                      

Growth Determinants        

Genetics is believed to account for 80% of height variation within a population. Other important determinants include:

  • Uterine function and size, maternal nutrition, and insulin/IGF levels are most important for fetal growth.
           
  • Growth hormone and thyroid hormone are the most important hormones for normal growth in childhood (postnatally).
                 
  • Sex steroids (testosterone, estrogen) and nutrition, in addition to growth hormone and thyroid hormone, are also important for the pubertal growth spurt                 

 

Comparing the causes for short stature

table_0.png

 

“Normal” growth variants

  • These children are otherwise healthy and typically have a family history suggesting short stature or delayed puberty and a normal linear growth rate parallel to the lower percentiles on the growth curve. These are the most common causes of short stature.
    • Familial short stature
                                    
      • Associated with family history of short stature (i.e. short midparental height)
      • Most are normal weight and length at birth but decelerate during the first 3 years of life until they reach their genetic-appropriate linear growth percentile
      • Normal onset of puberty
                     
    • Constitutional delay of growth and puberty
                       
      • Often associated with family history of relative being a “late bloomer
      • Slowed growth velocity during the first 3-5 years of life, but normal or near-normal growth velocity during the rest of childhood.
      • Delayed bone age, often corresponding to height age. Delayed onset of puberty.
      • Adult height usually within normal range
                  
    • Small for gestational age
      • Risk for short stature 
      • Approximately 15% do not catch up to normal growth by age 2
    • Idiopathic short stature
      • ​Diagnosis of exclusion, when patient is born normal size for gestational age, does not have any known pathologic causes (e.g. chronic disease, endocrinopathy, chromosomal abnormality), and has normal nutritional status 

 

Endocrinopathies

  • These children are typically well-nourished or obese with a deceleration in linear growth and increased weight-to-height ratio. Endocrine etiologies account for <5% of cases.
    • Growth hormone deficiency
                            
      • Causes: 1) perinatal asphyxia 2) prenatal embryologic malformation (e.g. abnormal CNS anatomy), 3) acquired secondary to intracranial tumor, trauma or nosocomial injury  or 4) idiopathic (most common)
      • Incidence of 1 in 3,500 children
      • Clinical findings include slow growth velocity, crossing height percentiles, delayed bone age, and facial phenotype resembling a younger child
      • Biochemically defined by peak stimulated GH concentration of <10 ng/mL (as stimulated by two GH stimulation tests using arginine, insulin, clonidine and/or glucagon)2 and low IGF-1 and IGFBP3 levels
                         
    • Growth hormone insensitivity
                             
      • Autosomal recessive disorder due to defect in growth hormone receptor
      • Similar to patients with growth hormone deficiency except elevated growth hormone levels on GH stimulation tests (and AR inheritance)
                       
    • Hypothyroidism
                   
      • Causes: 1) thyroid agenesis/dysgenesis 2) maternal anti-thyroid antibodies 3) autoimmune condition acquired during childhood (e.g. Hashimoto thyroiditis) 4) inborn error of thyroid metabolism 5) iodine deficiency
      • Congenital hypothyroidism is often detected on newborn screening (due to low levels of T4 at birth) 
      • Acquired hypothyroidism is more common and often diagnosed based solely on growth failure. Pediatric patients are less likely to display classical clinical symptoms like constipation, dry skin, decreased stamina, etc.                  
    • Glucocorticoid excess
                      
      • Causes: 1) iatrogenic (most common) 2) adrenal adenoma 3) ACTH-secreting pituitary adenoma
      • Typically associated with weight gain and elevated blood pressure

 

Chronic Systemic Disease

  • These children are often thin with decreased weight gain or increased weight loss.
  • Virtually any chronic disease can attenuate growth depending on how severe or poorly managed the disease is.
  • Common causes to consider are malnutrition or gastrointestinal disease (e.g. malabsorption, inflammatory bowel disease).
  • Poor growth may also be caused by treatment of systemic disease.

 

Genetic and Syndromic Causes of Short Stature

  • These children often have other abnormalities and are found to have disproportionate short stature and/or dysmorphic features
                            
  • Skeletal Dysplasia (e.g. achondroplasia)
    • Associated with higher upper to lower body ratios for age
    • Diagnosis is usually radiological and/or based on serology for specific genetic markers associated with the condition
                   
  • Turner Syndrome
                           
    • Sometimes associated with other dysmorphic features (e.g. webbed neck, shield chest) but may only manifest as short stature or “late-onset” puberty
    • Consider karyotyping  any girl with short stature and delayed puberty
      Turner_syndrome.jpeg
      Eleven-year-old with typical appearance of 45,X gonadal dysgenesis, including short stature, lack of breast development, and shield chest with widely spaced nipples. Additional features may include webbed neck, cubitus valgus, and shortened fourth metatarsals. Reproduced with permission from: Rebar RW, Paupoo AAV. Puberty. In: Berek and Novak's Gynecology, Berek, JS (Ed), Philadelphia: Lippincott Williams & Wilkins, 2012. Copyright © 2012 Lippincott Williams & Wilkins. www.lww.com.
  • SHOX (Short Stature Homeobox) mutations
    • X-linked disorder that manifests primarily with short stature. Other skeletal abnormalities may resemble Turner syndrome
    • More severe in females 
  • Other Syndromes
    • E.g. Down syndrome, Prader-Willi syndrome, Fetal alcohol syndrome, Cornelia deLange syndrome, Russell-Silver syndrome
    • Often defined or diagnosed based on the presence of other dysmorphic and developmental features

Growth Curves of Various Conditions Associated with Short Stature

Graphs_0.jpgRose, S.R., et. al. (2005) 

 

Evaluation

  1. Is the child short?
             
  2. Does the child have dysmorphic features or disproportionate short stature?
                   
  3. If the child is short, is his or her growth velocity normal or impaired?

Pediatricians should also inquire about the following: 

  • Birth and pregnancy history: size for gestational age and neonatal complications
  • Past medical history
  • Family history: height and timing of puberty in relatives as well as chronic and autoimmune conditions 
  • Medications
  • Dietary patterns
  • Developmental issues and learning disabilities

Further workup includes:

  • Screening labs including TSH, free T4, anti-tissue transglutaminase, IGF-1, IGF-BP3 and inflammation markers 
  • Left hand radiograph 

 

Treatment

When possible, treatment should be directed towards the underlying cause (e.g. providing thyroid hormone for a hypothyroid child), but due to the common availability of recombinant growth hormone, it is now being widely used.

pros-and-cons-of-hgh-replacement_0.jpghttps://www.kingsbergmedical.com/pros-and-cons-of-human-growth-hormone-therapy/

The FDA has approved growth hormone for:         

  • Chronic renal insufficiency (up to time of transplantation)
  • Growth hormone deficiency (as diagnosed based on a growth hormone stimulation test)
  • Idiopathic short stature (defined as <1st percentile)
  • Noonan syndrome
  • Prader-Willi syndrome
  • SHOX gene haploinsufficiency
  • Small for gestational age children (with no evidence of catchup growth before age 2-4)
  • Turner syndrome

 

In general, growth hormone is recommended to be started as soon as the diagnosis is made for these conditions (as soon as 6-9 months for Prader-Willi and Turner syndrome) to enable appropriate growth as soon as possible.

Patients must be monitored at least every 3 months (sooner at the initiation of therapy) to ensured continued efficacy of the treatment and lack of unwanted and sometimes serious side-effects such as hyperglycemia, slipped capital femoral epiphysis, leukemia and increased intracranial pressure.  In these situations, the benefit of additional height gain must be weighed carefully against the potentialy serious risks and side effects that can occur.         

Growth hormone administration is generally continued until linear growth decreases to less than 1 in/yr (i.e. after puberty), though for some growth hormone deficiencies, the treatment may continue into adulthood.

 

Footnotes

1 Variability exists between the different algorithms for predicting a child’s expected height. For a comparison of a few algorithms based on target height and/or bone age, click on this link to Topor, et al.’s article in Pediatrics on “Variation in methods of predicting adult height for children with idiopathic short stature.

2 Growth hormone stimulation tests are notably limited by arbitrary cutoffs, inaccurate assays, poor documentation of test reproducibility and a poor sense of how the nonphysiological test corresponds with true physiology.

 

References

  1. Allen, D.B. (2010). rhGH treatment for short stature: panacea, or Pandora's box? AAP News, 31(3), 16. 
  2. Lee, P.A., et. al. (2005). Persistent short stature, other outcomes, and the effect of growth hormone treatment in children who are born small for gestational age. Pediatrics, 112(1), 150-162.
  3. Rose, S.R., et. al. (2005). A general pediatric approach to evaluating a short child. Pediatrics in Review, 26(11), 410-420. 
  4. Silvers, J.B., et. al. (2010). A national study of physician recommendations to initiate and discontinue growth hormone for short stature. Pediatrics, 126(3), 468-476.
  5. Topor, L.S., et. al. (2010). Variation in methods predicting adult height for children with idiopathic short stature. Pediatrics, 126(5), 938-944.
  6. Wudy, S.A., et. al. (2005). Children with idiopathic short stature are poor eaters and have decreased body mass index. Pediatrics, 116(1), 52-57. 
  7. Braun, L.R. and Marino, R. (2017). Disorders of growth and stature. Pediatrics in Review, 38 (7) 293-304; DOI: https://doi.org/10.1542/pir.2016-0178.