Endocrinology · Deficiency in anterior pituitary function with variable immunodeficiency syndrome

Diagnosis, Lab Tests, and Understanding Reports

At a Glance

Doctors evaluate DAVID syndrome by combining pituitary hormone tests, immune studies, and NFKB2 genetic results. No single test is definitive: a normal cortisol stimulation test or brain scan may not exclude the condition, so the care team should interpret the findings together.

The diagnostic path for DAVID syndrome often feels like solving a puzzle with pieces from two different boxes. Because it is so rare, doctors must look beyond the “standard” tests to see the link between the immune system and the pituitary gland.

The Pitfall of the “Single Diagnosis”

Some children are first diagnosed with Common Variable Immunodeficiency (CVID) because they have frequent infections ^[1]. However, if a child with CVID also has severe fatigue, low blood sugar, or autoimmune issues, it is critical to screen them for hormone deficiencies ^[2]^[3].

Conversely, if a child is diagnosed with unexplained ACTH deficiency or unexplained hypoglycemia, doctors should check their immunoglobulin (antibody) levels, even if the child hasn’t had many infections yet.

Key Hormone (Endocrine) Tests

To see if the pituitary gland is sending the right signals, your doctor will look at several levels. The endocrinologist must interpret the whole pattern; you must never stop or alter hydrocortisone before testing unless specifically instructed.

Morning Cortisol and ACTH: These blood tests are usually done early in the morning. In DAVID syndrome, cortisol is often low, and ACTH is also low or “inappropriately normal” ^[3].
ACTH Stimulation Test (Cosyntropin Test): Doctors give a small injection of a synthetic hormone to see if the adrenal glands produce cortisol. A failed response confirms the deficiency, but importantly, early or partial central ACTH deficiency can sometimes pass this test, so a normal result doesn’t entirely rule out a central deficiency ^[3].
Thyroid Testing: This should include both TSH and Free T4. In central hypothyroidism, TSH can be misleadingly normal or low ^[1]. Crucially, adrenal insufficiency must be assessed and treated before starting any thyroid replacement, because thyroid treatment can worsen an unrecognized cortisol deficiency and precipitate a crisis.
Pituitary MRI: A scan of the brain may show pituitary hypoplasia (a smaller gland), but a normal MRI does not rule out NFKB2-related disease ^[3].

Key Immune (Immunology) Tests

Testing the immune system looks at how many antibodies the body is making and how well they work. Results must be compared to age-adjusted laboratory ranges:

Quantitative Immunoglobulins: Measures IgG, IgA, and IgM. While many children with this syndrome have low levels of all three, findings are variable, and some classes may be normal ^[1]^[4].
B-Cell Phenotyping: Looks at different types of B cells. The test may show abnormalities in “switched-memory B cells,” though again, the pattern varies between patients ^[4]^[5].
Vaccine Response (Titers): Doctors check if your child’s body “remembers” vaccines like the pneumococcal shot. Poor response can indicate immune dysfunction ^[2]. Note that if your child is on immunoglobulin replacement, it can make vaccine titers difficult to interpret.

Genetic Testing

Genetic testing of the NFKB2 gene is a critical piece of the puzzle, but it is not a simple “yes or no” binary.

Variant Classification: Finding a pathogenic or likely pathogenic variant in the NFKB2 gene strongly supports the diagnosis. However, finding a “Variant of Uncertain Significance” (VUS) does not establish the diagnosis, and a negative result does not completely exclude another genetic or acquired cause ^[1].
Family Testing: Testing parents and siblings should be arranged with a genetic counselor, tailored to the family’s specific variant, age, and clinical context ^[6].

Completeness Checklist for Your Records

Use this checklist to ensure you have a complete picture from your medical team:

Category	Essential Test/Finding	What to Discuss with Your Doctor
Pituitary	Morning Cortisol & ACTH	Do these levels, based on the lab’s specific assay cutoffs, indicate deficiency? ^[3]
	ACTH Stimulation	Was the peak cortisol adequate? ^[3]
	Other Pituitary Axes	Have TSH, Free T4, and Growth Hormone been evaluated based on growth and symptoms? ^[1]
Immune	IgG, IgA, IgM Levels	How do these compare to age-adjusted normal ranges? ^[1]
	B-Cell Subsets	Are there any abnormalities in the memory B cells? ^[4]
	Vaccine Titers	Was the response to vaccines adequate? ^[2]
Genetics	NFKB2 Sequencing	What is the classification (Pathogenic, VUS) of the variant found? ^[1]

Common questions in this guide

How is DAVID syndrome diagnosed?

Doctors combine pituitary hormone testing, immune-system testing, and NFKB2 genetic testing rather than relying on one result. The evaluation may include morning cortisol and ACTH, an ACTH stimulation test, thyroid tests, immunoglobulins, B-cell testing, vaccine antibody levels, and sometimes a pituitary MRI.

What does low cortisol with low or normal ACTH suggest?

Low cortisol with low or inappropriately normal ACTH can suggest central ACTH deficiency, meaning the pituitary is not sending enough signal to the adrenal glands. An endocrinologist must interpret the pattern using the collection time, medication history, symptoms, and laboratory cutoffs.

Can a normal ACTH stimulation test rule out DAVID syndrome?

No. Early or partial central ACTH deficiency can sometimes produce a normal response, so this test does not completely exclude the condition. The result should be considered with morning cortisol and ACTH levels and the rest of the clinical evaluation.

Which immune tests are used when DAVID syndrome is suspected?

Common tests include IgG, IgA, and IgM levels; B-cell subtype testing; and antibody responses to vaccines such as pneumococcal vaccine. Results should be compared with age-adjusted ranges, and immunoglobulin replacement can make vaccine antibody results harder to interpret.

How should an NFKB2 genetic test result be interpreted?

A pathogenic or likely pathogenic NFKB2 variant strongly supports DAVID syndrome when it matches the clinical findings. A variant of uncertain significance does not establish the diagnosis, and a negative result does not rule out every genetic or acquired cause. A genetic counselor can help explain family testing.

Can a normal pituitary MRI rule out DAVID syndrome?

No. Some people with DAVID syndrome have a small pituitary gland on MRI, but a normal scan does not exclude NFKB2-related disease. Hormone, immune, and genetic findings are still important.

Why must cortisol problems be addressed before thyroid treatment?

Untreated cortisol deficiency can become dangerous when thyroid hormone is started and may lead to an adrenal crisis. Doctors should assess and treat suspected adrenal insufficiency before thyroid replacement unless the treating team gives different instructions.

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Key takeaways

DAVID syndrome is evaluated with both pituitary hormone tests and immune-system tests, rather than a single diagnostic result.
Low morning cortisol with low or inappropriately normal ACTH can indicate central ACTH deficiency, but an ACTH stimulation test may be normal early or in partial disease.
Quantitative immunoglobulins, B-cell subsets, and vaccine antibody titers help assess immune function, with age-adjusted ranges and treatment effects considered.
A pathogenic or likely pathogenic NFKB2 variant supports the diagnosis, while a variant of uncertain significance does not establish it and a negative result does not exclude every cause.
Adrenal insufficiency should be assessed and treated before thyroid replacement, and a normal pituitary MRI does not rule out NFKB2-related disease.

References (6)

1
Deficient anterior pituitary with common variable immune deficiency (DAVID syndrome): a new case and literature reports.
Mac TT, Castinetti F, Bar C, et al.
Journal of neuroendocrinology 2023; (35(6)):e13287 doi:10.1111/jne.13287.
PMID: 37322808
2
A Case Report of Hypoglycemia and Hypogammaglobulinemia: DAVID Syndrome in a Patient With a Novel NFKB2 Mutation.
Lal RA, Bachrach LK, Hoffman AR, et al.
The Journal of clinical endocrinology and metabolism 2017; (102(7)):2127-2130 doi:10.1210/jc.2017-00341.
PMID: 28472507
3
Symptomatic hypoglycemia in a child with common variable immunodeficiency: Deficient anterior pituitary with variable immune deficiency (DAVID) syndrome.
Nogueira M, Pinheiro M, Maia R, et al.
Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 2020; (29(3)):111-113 doi:10.1297/cpe.29.111.
PMID: 32694887
4
[De novo NFκB2 gene mutation associated common variable immunodeficiency].
Luo MZ, Xu T, Xue XH, et al.
Zhonghua er ke za zhi = Chinese journal of pediatrics 2018; (56(8)):628-632 doi:10.3760/cma.j.issn.0578-1310.2018.08.014.
PMID: 30078247
5
Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2.
Klemann C, Camacho-Ordonez N, Yang L, et al.
Frontiers in immunology 2019; (10()):297 doi:10.3389/fimmu.2019.00297.
PMID: 30941118
6
A Novel Heterozygous NFKB2 Variant in a Multiplex Family with Common Variable Immune Deficiency and Autoantibodies Against Type I IFNs.
Baran A, Atılgan Lülecioğlu A, Gao L, et al.
Journal of clinical immunology 2024; (45(1)):48.
PMID: 39579251

This page explains DAVID syndrome testing for informational purposes only and does not constitute medical advice. Your child’s endocrinologist, immunology team, and genetic counselor should interpret the results and guide medication decisions.

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