Endocrine
for disorders of sex development; >90% for congenital adrenal hyperplasia with targeted genetic testing
System Profile
Yield Comparison
Clinical Dimensions
- Recurrent hypoglycemia
- Adrenal crisis
- Abnormal puberty timing
- Congenital hypothyroidism
- Growth failure
- Congenital adrenal hyperplasia
- Congenital hypothyroidism
- Hypopituitarism
- Kallmann
- Disorders of sexual development
- Syndromic obesity (Prader-Willi)
- Delayed or precocious puberty on exam
- Abnormal genitalia
- Small or enlarged thyroid
- Obesity with hypotonia
- Eunuchoid body proportions
- Growth deviation
- Polyuria
- Polydipsia
- Unexplained weight gain or loss
- Heat/cold intolerance
- Excessive hunger
- Delayed or precocious puberty symptoms
- Salt craving
- Abnormal TSH/T4
- ACTH/cortisol dysregulation
- Abnormal glucose/insulin
- Electrolyte derangements from salt wasting
- Abnormal androgen profile
- Abnormal IGF-1 or GH
- Pituitary MRI abnormalities
- Adrenal calcifications
- Thyroid dysgenesis on ultrasound
- Enlarged or streak gonads
- Abnormal reproductive structures
- ACTH stimulation test abnormal
- GnRH stimulation showing abnormal pubertal axis
- Thyroid US showing dysgenesis
- Glucose tolerance tests showing syndromic diabetes
- Chronic steroids for adrenal insufficiency
- Long-term levothyroxine
- Puberty induction agents
- Ongoing metabolic/endocrine medications
- Abnormal steroid response
- Adrenal crisis under stress or rapid steroid taper
- Paradoxical reaction to hormone treatments
- Adrenalectomy
- Thyroidectomy for congenital disease
- Gonadectomy for DSD
- Pituitary surgery
- Nutritional and endocrine counseling for growth
- Metabolic crisis prevention
- Education for steroid stress dosing and hormone therapy
- Insulin pumps
- CGMs
- Hormone infusion pumps where endocrine disease is genetic
- Endocrinology for congenital or complex endocrine disease
- Multiple hormone axes involved
- Endocrine recommending genetic testing for DSD/growth/puberty
- Thyroid disease clustering
- Early-onset diabetes
- Adrenal disorders
- Abnormal puberty patterns in relatives
- Multiple endocrine tumors or autoimmune endocrinopathies
- No severe psychosocial deprivation or eating disorder explaining growth or pubertal issues
- Endocrine abnormalities persist despite good care
- Neonatal hypoglycemia (persistent)
- Ambiguous genitalia
- Salt-wasting crisis
- Abnormal newborn screen for CAH or thyroid
- Significant electrolyte disturbances
Red Flag Combinations
Clinical patterns that should prompt consideration of genetic testing
Hypoglycemia + hypotonia
Adrenal insufficiency + ambiguous genitalia
Thyroid disease + hearing loss
Abnormal puberty + skeletal issues
Screening Decision Pathway
When to consider genetic testing for endocrine presentations
graph TD
START["Patient Presents with\nEndocrine Concerns"] --> SCREEN{"Screen for\nRed Flags"}
SCREEN --> RF1["Abnormal newborn thyroid or CAH screen"]
SCREEN --> RF2["Growth chart red flags"]
SCREEN --> RF3["Screening showing short stature or obesity disprop..."]
RF1 --> EVAL{"Multiple\nFlags Present?"}
RF2 --> EVAL{"Multiple\nFlags Present?"}
RF3 --> EVAL{"Multiple\nFlags Present?"}
EVAL -->|Yes| TEST["Order Genetic Testing\n(ES/GS)"]
EVAL -->|No| MONITOR["Continue Monitoring\nRe-evaluate if New Findings"]
TEST --> DX["Molecular Diagnosis\n28-59% yield"]
style TEST fill:#dcfce7,stroke:#16a34a,color:#14532d
style DX fill:#bbf7d0,stroke:#16a34a,color:#14532d
style MONITOR fill:#fef3c7,stroke:#d97706,color:#92400e
Screening Red Flags
Findings on routine screening that may indicate genetic etiology
- Abnormal newborn thyroid or CAH screen
- Growth chart red flags
- Screening showing short stature or obesity disproportionate to environment
Exome / Genome Sequencing Indications
Clinical scenarios supporting ES/GS as a diagnostic approach
- Endocrine abnormalities in multiple axes without clear acquired cause
- DSD
- Early-onset diabetes or POI with family history
Key Evidence
Published studies supporting genetic testing for endocrine conditions
| Study | Year | Type | Sample | Yield | Key Finding |
|---|---|---|---|---|---|
| Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase... | 2018 | Guideline | None | None | Endocrine Society guidelines recommend CYP21A2 genotyping when hormonal testing ... |
| Exome sequencing for the diagnosis of 46,XY disorders of sex... | 2015 | Cohort | 40 | 35% | Exome sequencing achieved 35% likely genetic diagnosis in 46,XY DSD patients (22... |
| Diagnostic Application of Targeted Next-Generation Sequencin... | 2017 | Cohort | None | 28.1% | 28.1% diagnostic yield with targeted NGS panel for DSD (vs 10% with single gene ... |
| Next-generation sequencing in endocrine diseases | 2018 | Review | None | None | NGS panels and ES increasingly applied across endocrine disorders including thyr... |
| PPP2R3C Variants Cause Syndromic 46,XY Gonadal Dysgenesis | 2019 | Case Report | 4 | None | PPP2R3C biallelic variants cause novel syndromic 46,XY gonadal dysgenesis in 4 g... |
| Translating genomics to the clinical diagnosis of disorders/... | 2019 | Review | None | None | Comprehensive review of genomic tools for DSD diagnosis including CMA, ES, GS an... |
| Cis-Regulatory Control of Mammalian Sex Determination | 2021 | Review | None | None | Comprehensive review of non-coding regulatory elements in mammalian sex determin... |
| Contribution of Clinical and Genetic Approaches for Diagnosi... | 2022 | Cohort | None | 59.3% | 59.3% molecular diagnosis for 46,XY DSD; 78.9% overall when combined with clinic... |
Updated: 2026-02-24
Curated by: human
Status: human reviewed