Key Clinical Summary: Growth HormoneDeficiency: Diagnosis, Management & Evolving Therapies

This is a micro-learning module summary of the LAGH Education session which you can find here.

Before participating please read our CME and disclosure information which can be found here. This program was supported by an independent medical education grant from Novo Nordisk. This content is intended for US Healthcare Professionals only.

Introduction:

This summary provides a clinical overview of the diagnosis and management of Growth Hormone Deficiency (GHD) in children. Growth is one of the most sensitive indicators of a child's health, and deviations from the normal trajectory, such as short stature, warrant a thorough and systematic evaluation. A stepwise diagnostic approach is essential to differentiate GHD from more common normal variants of short stature and other pathological conditions, ensuring timely and appropriate intervention to optimize growth outcomes.

Initial Evaluation of Short Stature

A comprehensive assessment is the foundation for diagnosing growth disorders. Short stature is typically defined as a height below the 3rd percentile or more than two standard deviations below the mean for age and sex. However, a significant drop across height percentiles is also a major red flag, even if the child's height remains above the 3rd percentile.

• Accurate Measurements are Crucial: Errors in measurement are a common pitfall. Standing height should be measured with a stadiometer in children over three years old, while supine length is used for infants under two.
• Growth Velocity is Key: Monitoring growth rate (velocity) is often more informative than a single height measurement..
• Genetic Potential: Calculating the mid-parental target height helps determine if a child's stature is appropriate for their genetic background.

Differentiating GHD from Normal Variants

Many children evaluated for short stature have normal variants of growth, which must be distinguished from pathological causes like GHD.

• Familial Short Stature: These children exhibit a normal growth velocity, consistently tracking along a lower percentile that is appropriate for their mid-parental height. Their bone age is consistent with their chronological age, and they enter puberty at a normal time.
• Constitutional Growth Delay ("Late Bloomer"): This pattern involves normal birth size followed by a deceleration of growth between 6 months and 2 years of age. Afterward, they grow at a normal velocity but along a lower percentile. The hallmark is a delayed bone age (typically by 2-3 years), which leads to delayed puberty and a later pubertal growth spurt, ultimately allowing them to reach a normal final adult height consistent with their genetic potential.

Diagnosing Growth Hormone Deficiency

When a pathological cause is suspected, a systematic workup is necessary. Initial lab tests should screen for common systemic diseases (e.g., celiac disease, chronic inflammation, renal tubular acidosis) and hypothyroidism, which can mimic GHD.

• Clinical Clues for GHD:
• In infants, look for hypoglycemia, prolonged jaundice, micropenis (in males), and midline facial defects (e.g., single central incisor, cleft palate), which can be associated with pituitary abnormalities.
• In children, signs include significant growth deceleration, a high-pitched voice, delayed tooth eruption.
• Biochemical Testing for GHD:
• Screening: Due to the pulsatile secretion of growth hormone, random GH levels are not useful. The initial screening tests are IGF-1 and IGFBP-3, which are GH-dependent and typically low in GHD.
• Confirmation: The diagnosis is confirmed with a GH stimulation test, using provocative agents like arginine, clonidine, or glucagon. A peak GH level below a defined cutoff confirms GHD.
• Neuroimaging:
• An MRI of the brain is mandatory in any child diagnosed with GHD. This is critical to rule out organic causes such as congenital anomalies (e.g., pituitary hypoplasia, septo-optic dysplasia) or tumors, most commonly a craniopharyngioma.

Management and Evolving Therapies

• Daily Growth Hormone Therapy:
• Daily subcutaneous injections of recombinant human GH (rhGH) have been the standard of care for decades, with a well-established safety and efficacy profile.
• Treatment prompts a robust "catch-up growth" phase, especially in the first year, and is continued until the patient reaches their final adult height.
• Long-Acting Growth Hormone (LAGH):
• Once-weekly LAGH formulations are a major advancement, offering comparable efficacy to daily GH injections.
• The primary advantage is the reduced injection frequency, which can improve treatment adherence and quality of life for patients and families.
• Monitoring is different: Unlike the stable IGF-1 levels with daily GH, levels fluctuate significantly over the week with LAGH. To accurately assess the average weekly IGF-1 exposure, the blood sample timing is critical. Clinicians must use product-specific guidelines, such as drawing blood on day 4 post-injection or using a correction factor based on the draw day, to interpret the results correctly.
• Treatment Selection: The choice between daily and long-acting GH should be individualized, taking into account family preferences, lifestyle, and potential adherence challenges. Early diagnosis and treatment are critical for achieving optimal height and metabolic health outcomes.