Introduction

Growth hormone deficiency can lead to disabling short stature (requiring modifications to home, modifications to vehicle, custom clothing, inability to perform man jobs, etc.). Human growth hormone was first used more than 30 years ago to help a child with hypopituitarism grow. A limited supply came from purifying the extract of human cadavers, which was laborious and costly in production. In the 1980’s, the first cases of Creutzfeld-Jakob disease (CJD) was discovered in patients who had received these growth hormone extracts. Biosynthetic growth hormone became available around the same time, eliminated the risk for CJD and made available the opportunity to treat children with growth hormone deficiency, as well as other conditions associated with short stature and found to benefit from growth hormone therapy. Advantages bestowed by increased height include medical, social, psychological, economic as well as professional success. Growth hormone therapy remains costly (up to $30,000 per year), and controversy remains on who and by what criteria should a patient qualify for medication.

Short Stature Evaluation

1. Short stature is defined as height that is less than 2 SD for average height for child’s age and sex. Important factors determining clinical significance include genetic potential, growth velocity and pubertal staging.
2. Growth velocity (change of linear growth over time) most rapid during infancy, with overall growth about 30 to 35 cm. Infants may cross growth percentiles lines depending on their genetic potential in the first two years of life.  Growth velocity stays relatively constant at 5 to 7 cm per year during pre-pubertal years, and then accelerates to 8 to 14 cm per year during pubertal years.
3. Adult height potential based on calculation of mid-parental height:
   1. For females, add together mother and father’s heights and subtract 13 cm (or 5 inches) and divide by 2.
   2. For males, add together mother and father’s heights and add 13 cm (or 5 inches) and divide by 2.
   3. Target height range is mid-parental height +/- 8.5 cm (or 2.4 inches).
4. Short stature evaluation requires accurate measurements of height and weight, with periodic measurements to assess growth velocity, clinical history for chronic/systemic diseases, nutritional history, physical exam for dysmorphisms, cardiac and pulmonary anomalies, pubertal tanner staging.
5. Physiological causes are most common causes of short stature: (1) familial short stature and (2) constitutional delay in growth and development. Differential diagnosis is listed in table below.
6. Laboratory evaluation depends on clinical suspicion, includes CBC and comprehensive metabolic panel, urinanalysis, ESR, tissue transglutaminase IGA, vitamin D studies, thyroid function tests, growth hormone studies, chromosome/karyotype (for females).
7. Bone age to assess skeletal maturation.

Diagnosis of Growth Hormone Deficiency

1. Based largely on clinical diagnosis, auxological features, and biochemical tests
2. Suspected in marked short stature (< 2.5 SD below mean for age/sex), and/or growth failure (growth velocity < 25th % for age/sex), without alternative explanation.
3. History of other co-morbidities, including CNS malformation or intracranial tumor, history of cranial radiation, other hypothalamic- pituitary deficits.
4. Congenital growth hormone deficiency presents with severe growth failure in infancy, along with hypoglycemia, prolonged jaundice, microphallus or  microclitoris. These children have very low serum levels of growth hormone, IGF-1, and IGF-BP3.
5. GH deficiency unlikely if IGF-1 and IGF-BP3 levels at or above 50% for normal range, and have normal growth velocity and bone age.
6. Provocative growth hormone testing if  IGF-1 and IGF-BP3 levels are less than 10% for normal range, poor growth velocity, delay in bone age
7. Provocative growth hormone testing includes use of 2 of the following stimulants: Arginine, insulin, clonidine, L-Dopa or glucagon.  Limitations to testing include non-physiological, arbitrary cut-off, non-reproducibility, risk and cost.
8. MRI of hypothalamic-pituitary sella to rule out tumors and structural defects, such as pituitary hypoplasia or agenesis.

Growth Hormone Treatment in Children

1. Growth hormone increases bone mass, reduces fat mass, and increases lean body mass, increases plasma and liver lipid content.
2. Growth hormone stimulates cartilage growth which promotes for linear growth.
3. FDA indication for growth hormone deficiency, chronic renal insufficiency, Turner syndrome, Prader-Willi syndrome, small for gestational age, idiopathic short stature.
4. Recombinant Growth hormone treatment typically with starting doses ∼ 40 mcg/kg/day SQ daily. Dose titrated based on growth velocity and IGF-1 levels. Once weekly subcutaneous injectable growth hormone was approved in 2021.
5. Side effects are rare, but may include pseudotumor cerebri, slipped capital femoral epiphysis, glucose intolerance, increase nevi, (?) neoplasm.
6. Predictors of good response to growth hormone include starting in pre-pubertal age, deviation from target height based on genetic potential, degree of delay skeletal maturation, dose of medication.
7. Growth hormone therapy continued until linear growth near complete (GV less than <2 cm/year) and bone age shows near fusion of epiphysis.
8. Should patient be retested for GH deficiency as adults? Most have normal GH secretion during adulthood, because of priming of hypothalamic-pituitary axis from sex steroid hormones
9. Long term risks are unknown, and follow up studies are needed, including metabolic effects of the therapy: children on GH therapy are usually lean and muscular. Also controversial whether therapy is associated with increased risk of malignancies: leukemia, lymphoma, and tumors.