| Gene or subtype | Core molecular defect | Typical clinical clues / extra-adrenal features | Key quantitative evidence |
|---|---|---|---|
| **MC2R / FGD type 1** | ACTH receptor defect causing adrenal ACTH resistance; many variants are missense with residual receptor function (pqac-00000000, pqac-00000002) | Isolated glucocorticoid deficiency with high ACTH, low/undetectable cortisol, usually preserved mineralocorticoid function; hyperpigmentation, hypoglycemia/seizures; later presentation and tall stature are characteristic clues (pqac-00000000, pqac-00000002) | In the 62-patient FGD cohort, **40/62** had MC2R variants; type 1 accounted for ~**25%** of all FGD, with median presentation age **2.0 y** (range **0.02–16**) and height SDS **+1.75** (pqac-00000000). In the UK pediatric PAI cohort, MC2R was **30/155 (19.4%)**; p.S74I occurred in **20/30** cases, consistent with an Irish/Scottish founder effect (pqac-00000011, pqac-00000014). |
| **MRAP / FGD type 2** | Defect of melanocortin 2 receptor accessory protein, impairing MC2R trafficking/function; variants often abolish protein (nonsense/splice) (pqac-00000000) | Similar biochemical picture to FGD1, but typically **earlier neonatal/infant presentation**; not associated with the tall-stature tendency seen in FGD1 (pqac-00000000, pqac-00000003) | In the 62-patient FGD cohort, **22/62** had MRAP variants; type 2 accounted for ~**20%** of all FGD, with median presentation age **0.08 y** (birth to **1.6 y**) and height SDS **+0.12** (pqac-00000000). In the Turkish nationwide pediatric PAI cohort, MRAP variants were found in **9/95** children; recurrent **c.IVS3ds±1delG** suggested a regional founder effect (pqac-00000008, pqac-00000010). |
| **NNT** | Mitochondrial inner-membrane defect impairing **NADPH** generation and antioxidant defense, increasing **ROS**-mediated cellular injury (pqac-00000001, pqac-00000015, pqac-00000016) | Primary adrenal insufficiency/FGD-like disease; extra-adrenal clues can include progressive gonadal dysfunction. Reported manifestations include testicular adrenal rest tumor, Sertoli cell-only syndrome, hypergonadotropic hypogonadism, and azoospermia (pqac-00000015, pqac-00000016) | NNT variants were found in **7/95** children in the Turkish cohort and **6.5%** of the UK pediatric PAI cohort (pqac-00000008, pqac-00000013, pqac-00000014). UK data note presentation usually between **6 months and 4 years** (pqac-00000012). A 2023 case described a **35-year-old** man whose intensified glucocorticoids for **8 months** did **not** improve TART volume or sperm production (pqac-00000015). |
| **TXNRD2** | Mitochondrial thioredoxin reductase defect affecting redox homeostasis/ROS detoxification, mechanistically related to NNT-dependent antioxidant pathways (pqac-00000005) | FGD-like/PAI presentation is reported, but specific phenotype details were limited in the gathered evidence; consider potential extra-adrenal oxidative-stress vulnerability (pqac-00000005) | In the UK pediatric PAI cohort, TXNRD2 accounted for **4.5%** of genetically solved cases overall (**7/155**) (pqac-00000014). The gathered evidence supports mechanism and cohort frequency, but detailed FGD-specific clinical quantitation was not retrieved (pqac-00000005, pqac-00000014). |
| **Partial STAR / partial CYP11A1 deficiency** | Partial loss of early steroidogenesis steps can mimic isolated glucocorticoid deficiency; CYP11A1 can be disrupted by missplicing, including variants initially predicted benign/synonymous (pqac-00000009, pqac-00000010, pqac-00000012) | Can present as FGD-like pediatric adrenal insufficiency; clinical clue in UK cohort was **childhood ketotic hypoglycemia**; some cases require mineralocorticoid replacement or show genital findings, so these are not always purely isolated FGD (pqac-00000008, pqac-00000010, pqac-00000012) | In the Turkish cohort, CYP11A1 variants occurred in **9/95** children, all **9** carrying recurrent **p.R451W** from **8 unrelated families**; **6/9 (66%)** had salt-wasting and **8/9 (89%)** had consanguinity (pqac-00000007, pqac-00000010). In the UK cohort, CYP11A1 accounted for **7.7%** and STAR for **3.9%** of **155** cases (pqac-00000014). |
| **MCM4** | DNA replication/repair-related defect associated with adrenal insufficiency rather than classic ACTH-receptor pathway failure (pqac-00000001) | Important syndromic clue set includes **growth retardation** and **natural killer cell deficiency**; not classic isolated FGD, but may enter the differential in childhood adrenal insufficiency (pqac-00000012) | Gathered evidence identifies MCM4 as reported in an Irish travelling community and as a cause of progressive PAI (pqac-00000001). No robust frequency figures specific to MCM4 were retrieved in the gathered FGD-focused evidence. |
| **AAAS (Triple A syndrome) — differential / phenocopy** | Nuclear pore protein defect (ALADIN), causing ACTH-insensitive adrenal insufficiency but typically **syndromic**, not classic isolated FGD (pqac-00000014) | Key differentiating clues are **alacrima** and **achalasia**, often with neurologic features; useful differential when ACTH-resistant adrenal insufficiency is suspected (pqac-00000004) | In the UK pediatric PAI cohort, AAAS accounted for **7.1%** (**11/155**) of genetically diagnosed cases (pqac-00000014). Case-based differential guidance emphasizes excluding Triple A when alacrima/achalasia are present (pqac-00000004). |


*Table: This table summarizes the main familial glucocorticoid deficiency genes and closely related differentials, highlighting mechanism, clinical clues, and quantitative cohort evidence. It is useful for linking genotype to phenotype and for prioritizing diagnostic testing.*