dromlakhani CAH Newborn Subtype Differentiator
Source: Balsamo A, Baronio F, Ortolano R, et al. Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant. Frontiers in Pediatrics 2020;8:593315. doi:10.3389/fped.2020.593315.
Scope: any newborn or young infant (< 6 months) with confirmed/suspected CAH where the specific enzyme defect has not yet been identified. 21-hydroxylase deficiency (CYP21A2-D) accounts for ≥ 90% — but the remaining ~10% (11β-OHD up to 8%, plus the rare forms) must be considered when the phenotype does not fit, NBS misses the diagnosis, or hypertension/low renin features appear.
STEP 1 — Phenotype the newborn (3 quick axes)
Collect these data points before reaching for the table:
- Karyotype (46,XX vs 46,XY) and external genitalia (Prader / EMS / EGS staging).
- Mineralocorticoid axis: Na, K, BP, plasma renin activity (PRA).
- Glucocorticoid axis: clinical adrenal insufficiency (AI) — hypoglycaemia, lethargy, poor feeding, hyperpigmentation? Serum cortisol, ACTH.
- Androgen axis: 17-OHP, androstenedione, testosterone, DHEA, DOC, 11-deoxycortisol, 11-oxygenated androgens if available.
- Imaging: adrenal size on US (enlarged in StAR-D, CYP21A2-D; reduced in CYP11A1-D).
STEP 2 — First-pass triage by 3 questions
Use this branching logic before opening Table 1.
Q1. Is there salt wasting (SW) + adrenal insufficiency?
- YES → think StAR-D, CYP11A1-D, HSD3B2-D, CYP21A2-D (most common).
- NO → consider CYP17A1-D, CYP11B1-D, or POR-D (these do NOT cause SW; CYP17A1-D and CYP11B1-D cause low-renin hypertension from DOC excess).
Q2. What is the genitalia phenotype for the karyotype?
- 46,XX virilised (DSD) → CYP21A2-D, CYP11B1-D, POR-D (most common), HSD3B2-D (mild in ~25%).
- 46,XY undervirilised (DSD) → StAR-D, CYP11A1-D, HSD3B2-D, CYP17A1-D, POR-D.
- 46,XX normal female genitalia → CYP17A1-D (no virilization at birth; manifests at puberty as absent secondary sexual characteristics + hypertension).
- 46,XY normal male genitalia → CYP21A2-D (males look normal at birth — picked up by SW crisis or NBS), CYP11B1-D.
Q3. Renin and BP direction:
- High renin + low BP → StAR, CYP11A1, HSD3B2, CYP21A2 (all GC and MC deficient).
- Low renin + high BP → CYP17A1, CYP11B1 (DOC excess drives sodium retention).
- Variable / low–normal renin → POR-D.
STEP 3 — Pattern-match to Table 1
| Defect | Karyotype → genitalia | Renin | Na / K | BP | Neonatal SW | AI | Hypoglycaemia | Adrenal size on US | Key biochemical clue |
|---|---|---|---|---|---|---|---|---|---|
| StAR-D (lipoid CAH) | 46,XY DSD (female-appearing); 46,XX normal | ↑↑ | ↓ / ↑ | ↓ | +++ | +++ | ++ | ↑↑ (markedly enlarged) | All steroids ↓↓; very low cortisol, aldo, androgens |
| CYP11A1-D (P450scc) | 46,XY DSD; 46,XX normal | ↑↑ | ↓ / ↑ | ↓ | +++ | +++ | ++ | ↓↓ (small) | All steroids ↓↓ (mimics StAR but adrenals are small) |
| HSD3B2-D (3β-HSD) | 46,XY DSD; 46,XX mild virilization (~25%) | ↑↑ | ↓ / ↑ | ↓ | +++ | +++ | ++ | ↔ | ↑ Δ5/Δ4 steroid ratio; ↑ 17-OH-pregnenolone, DHEA |
| CYP17A1-D (17α-OH / 17,20-lyase) | 46,XX normal at birth; 46,XY DSD; absence of 2° sex characteristics in both sexes at puberty | ↓ | ↔ | ↑ (no in partial defects) | – | ± | – | ↔ | ↑ DOC, ↑ corticosterone, ↓↓ androgens; serum B↑ |
| CYP21A2-D (classic 21-OHD) | 46,XX DSD; 46,XY normal at birth | ↑↑ | ↓ / ↑ | ↓ | +++ | +++ | ± | ↑↑ | ↑↑ 17-OHP (often > 300 nmol/L), ↑ 11-K-Δ4A, ↑ 11-KT |
| CYP11B1-D (11β-OHD) | 46,XX DSD; 46,XY normal | ↓ | ↔ / ↑ | ↑ | – | – | – | ↑ ↔ | ↑↑ 11-deoxycortisol (S) and ↑ DOC; ↑ THS, THDOC in urine |
| POR-D (P450 oxidoreductase) | 46,XX DSD; 46,XY DSD (~75%); maternal virilization in pregnancy; skeletal anomalies (Antley-Bixler) | ↓ ↑ (variable) | ↔ | ↑ | – | ++ (latent / mild) | – | ↔ | Combined CYP17A1 + CYP21A2 pattern; ↑ pregnanetriolone (PTONE); urine: ↑ Pregn, Prog, 17-OHP metabolites |
Legend: + present, ± variable, – absent; ↑ increased, ↓ decreased, ↔ normal.
STEP 4 — Use the cardinal clues (when in doubt)
| Cardinal feature | Best fit |
|---|---|
| Massively enlarged adrenals + zero steroid output + 46,XY phenotypic female | StAR-D (lipoid CAH) |
| Small adrenals + zero steroid output + 46,XY phenotypic female | CYP11A1-D |
| ↑ Δ5/Δ4 ratio (17-OH-pregnenolone, DHEA dominating) | HSD3B2-D |
| Hypertension + low renin + 46,XX virilised + ↑ 11-deoxycortisol | CYP11B1-D |
| Hypertension + low renin + no virilization + delayed puberty | CYP17A1-D |
| Skeletal malformations (craniosynostosis, midface hypoplasia, radio-humeral synostosis) + maternal virilization during pregnancy + DSD | POR-D (Antley-Bixler phenotype) |
| ↑↑ 17-OHP on NBS + virilised 46,XX or SW 46,XY | CYP21A2-D |
STEP 5 — Confirm with the right test
| Suspected defect | First-line confirmatory test |
|---|---|
| CYP21A2-D | Serum 17-OHP (basal, or post-ACTH); LC-MS/MS multi-steroid profile; CYP21A2 sequencing |
| CYP11B1-D | Serum 11-deoxycortisol + DOC; urine THS, THDOC; CYP11B1 sequencing |
| CYP17A1-D | Serum DOC ↑, corticosterone ↑, low androgens; CYP17A1 sequencing |
| HSD3B2-D | Serum Δ5 : Δ4 steroid ratio post-ACTH; urine steroid profile (caution — neonatal 3βOH5ene physiologically high); HSD3B2 sequencing |
| StAR-D | Markedly enlarged adrenals on US/MRI + flat steroid panel; StAR sequencing |
| CYP11A1-D | Small adrenals + flat steroid panel; CYP11A1 sequencing |
| POR-D | Combined urinary steroid profile (mass-spec); skeletal X-rays; POR sequencing |
Send a single serum and a 24-h urine (or random spot urine) for LC-MS/MS multi-steroid profiling before glucocorticoid is started where feasible — post-treatment samples lose diagnostic power.
STEP 6 — Don't miss these traps
- NBS only detects CYP21A2-D reliably. Rare forms (StAR, CYP11A1, CYP17A1) escape NBS — clinical suspicion is essential.
- HSD3B2-D can falsely raise NBS 17-OHP (cross-reactivity) → don't anchor on CYP21A2-D if the phenotype doesn't fit (e.g. undervirilised 46,XY).
- POR-D gives a mild ↑ 17-OHP — looks like a "mild 21-OHD" but pregnanetriolone in urine and skeletal exam settle it.
- CYP17A1-D and CYP11B1-D do NOT cause salt wasting — they cause hypertension. A hypertensive newborn with adrenal disease is NOT classic 21-OHD.
- In any newborn with bilateral non-palpable gonads and "male" external genitalia + SW → karyotype urgently. This is often a virilised 46,XX with CAH, not a male.
Quick reference
- 90%+ of CAH = CYP21A2-D. Confirm with 17-OHP.
- Hypertension + CAH → CYP11B1-D or CYP17A1-D.
- Severe undervirilization + flat steroids in 46,XY → StAR / CYP11A1 / HSD3B2.
- Skeletal malformations + DSD + maternal virilization → POR-D.
- NBS is a screen for CYP21A2 only — don't be falsely reassured by a negative NBS in a sick newborn.
Related skills
- [[cah-nbs-17ohp-interpretation]] — interpret newborn screening 17-OHP results.
- [[cah-infant-hydrocortisone-dosing]] — start replacement once subtype is confirmed.
- [[cah-adrenal-crisis-protocol]] — for the acutely decompensating newborn.