# Cah Newborn Subtype Differentiator

> CAH Newborn Subtype Differentiator

- Skill: `dromlakhani/cah-newborn-subtype-differentiator` (Agent Skill)
- Install (CLI): `npx skillmds@latest add dromlakhani/cah-newborn-subtype-differentiator`
- Raw SKILL.md: https://api.skillmd.com/api/skills/dromlakhani/cah-newborn-subtype-differentiator/raw
- Safety review: pending (external: skill-scanner PASS, skillspector PASS)
- Works with: Claude Code, Claude.ai, OpenAI Codex
- Category: Coding & Dev Tools
- Author: dromlakhani (https://skillmd.com/u/dromlakhani)
- Updated: 2026-09-21
- Page: https://skillmd.com/skills/dromlakhani/cah-newborn-subtype-differentiator

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# 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.

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## STEP 1 — Phenotype the newborn (3 quick axes)

Collect these data points before reaching for the table:

1. **Karyotype** (46,XX vs 46,XY) and external genitalia (Prader / EMS / EGS staging).
2. **Mineralocorticoid axis:** Na, K, BP, plasma renin activity (PRA).
3. **Glucocorticoid axis:** clinical adrenal insufficiency (AI) — hypoglycaemia, lethargy, poor feeding, hyperpigmentation? Serum cortisol, ACTH.
4. **Androgen axis:** 17-OHP, androstenedione, testosterone, DHEA, DOC, 11-deoxycortisol, 11-oxygenated androgens if available.
5. **Imaging:** adrenal size on US (enlarged in StAR-D, CYP21A2-D; reduced in CYP11A1-D).

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## 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.

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## 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.

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## 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.

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## 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.

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## 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.

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## 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.