The Diagnostic Journey: Understanding Your Child's Test Results

The diagnostic journey for GHSR deficiency is often paradoxical. Because this condition affects how the body naturally “times” its growth signals rather than the body’s physical ability to make growth hormone, standard tests often come back looking “normal,” which can lead to years of uncertainty for families ^[1][2].

The Standard Short Stature Workup

A confirmed diagnosis requires looking at the full clinical picture, appropriate endocrine evaluation, and molecular findings that fit the phenotype. Your child’s workup likely included:

• Clinical Exam and Auxology: Doctors track your child’s height and weight over time to calculate their growth velocity (how fast they are growing) and their SDS (Standard Deviation Score), which compares them to millions of other children ^[3].
• Bone Age X-ray: A simple X-ray of the left hand and wrist to see how “mature” your child’s skeleton is ^[4][5].
• Systemic Screening: Blood tests to rule out other “hidden” causes of short stature, such as celiac disease, thyroid problems, or kidney issues ^[6][7].

The Hormone Profile: Why Tests Are “Normal”

In many cases of short stature, doctors look for a lack of growth hormone. However, children with GHSR variants often present a unique hormone profile:

IGF-1: The Growth Messenger

IGF-1 (Insulin-like Growth Factor 1) is a hormone made in response to growth hormone. In children with GHSR variants, IGF-1 levels are often low or low-normal for their age ^[1][2]. However, an IGF-1 result can be affected by age, puberty, nutrition, thyroid/liver health, and the laboratory assay, so a low value is not by itself diagnostic.

The Growth Hormone (GH) Stimulation Test

Most children with this condition have a normal response to GH stimulation tests ^[1].

• How it works: During the test, medicine is used to force the pituitary gland to release stored growth hormone ^[8].
• The Result: Because the pituitary gland itself is healthy and the medicine uses different pathways to stimulate it, the gland can still fire a large burst when forced. In a study of 26 children with this condition, all “passed” their stimulation test ^[1].
• The Problem: The test is an artificial measure of GH reserve, not a direct measurement of everyday spontaneous 24-hour secretion. A normal response does not rule out a problem with natural pulsatility ^[2].

Genetic Testing: Finding the Molecular Cause

Because hormone tests can be misleading, genetic testing (like a targeted short-stature panel or whole exome sequencing) is used to look for molecular causes ^[9][10]. However, a genetic test alone is not the only way to diagnose the condition, nor does finding a variant automatically confirm a disease. A pathogenic finding must be interpreted alongside the clinical symptoms.

Understanding the Genetic Report (ACMG Classifications)

Genetic labs use an evidence-based five-tier system from the ACMG (American College of Medical Genetics and Genomics) to classify what they found ^[11]. These classifications can be revised over time as new research emerges:

1. Pathogenic: Strong evidence that the variant causes the condition.
2. Likely Pathogenic: Evidence strongly suggests it is pathogenic, though it is not a fixed statistical guarantee.
3. Variant of Uncertain Significance (VUS): The lab sees a change but there is not enough evidence to know if it is harmful or a harmless natural variation ^[12]. A VUS should not be used by itself to justify treatment or reproductive decisions.
4. Likely Benign: Probably harmless.
5. Benign: Definitely harmless.

When it’s a VUS: Segregation Analysis

If your child’s report shows a VUS, your doctor may suggest segregation analysis—testing the parents for the same variant ^[12]. This can add evidence (e.g., if a parent with the variant is also very short), but it cannot by itself prove causality or rule it out.

What Tests Can and Cannot Tell You

Your Diagnostic Completeness Checklist

When you review your child’s genetic report, locate these critical data points for your records and any future consultations:

• [ ] Gene Name: Should clearly state GHSR.
• [ ] Specific Variant: Listed as a “c.” (DNA change) and “p.” (protein change) code (e.g., c.611C>A, p.Ala204Glu).
• [ ] Reference Transcript: The specific genetic map the lab used (e.g., NM_198407.2).
• [ ] ACMG Classification: (e.g., Pathogenic, Likely Pathogenic, or VUS).
• [ ] Zygosity: Usually Heterozygous (one copy), Homozygous (two identical copies), or Compound Heterozygous (two different mutations). ^[1]
• [ ] Report Date: Important in case the lab reanalyzes the data in the future.