Differential Diagnosis of the Short IGF-I-Deficient Child with Apparently Normal Growth Hormone Secretion

Area of Science:

• Pediatric Endocrinology
• Genetics
• Growth Hormone Disorders

Background:

• Short stature in children with low IGF-I and normal GH stimulation tests presents a diagnostic challenge.
• Differential diagnoses include GH neurosecretory dysfunction (GHND), genetic GH sensitivity defects, and GH insensitivity (GHI).
• Accurate diagnosis is crucial for appropriate growth hormone (GH) therapy selection.

Purpose of the Study:

• To critically appraise the concept of GH neurosecretory dysfunction (GHND).
• To evaluate the role of 12- or 24-hour GH profiles in selecting children for GH treatment.
• To review genetic causes of GH deficiency and insensitivity.

Main Methods:

• Critical appraisal of existing literature on GHND and GH profiles.
• Analysis of 24-hour GH concentrations in healthy children versus those with GH deficiency.
• Review of genetic variants associated with GH disorders (GH1, GHSR, GHR, STAT5B, STAT3, IGF1, IGFALS) and related syndromes (Noonan, 3M).

Main Results:

• Mean 24-h GH concentration overlaps between healthy children and those with GH deficiency, suggesting current GHST cutoffs may be too high.
• GH profiles can prevent ~20% of false-positive GHST results and identify low spontaneous GH secretion.
• Evidence supports Kowarski syndrome (GH1 variants); the role of GHSR variants is less clear. Several genetic causes of GHI exist, some responsive to GH therapy.

Conclusions:

• GH profiles offer diagnostic advantages over GHST alone but are limited by patient burden and cost.
• Genetic testing is important for diagnosing GH1 and GHI-related disorders.
• Further research into hypothetical causes of short stature with normal GHST is warranted.