Characteristics of probands and relatives with IRS4 mutations
| Case | Sex | Nucleotide alteration | Amino acid alteration | Age at diagnosis of CeH (years) | Age at confirmation IRS4 mutation (years) | TSH (mU/L) without treatment RI: 0.5–5.0 | FT4 (pmol/L) without treatment RI: 10–23 | T4 (nmol/L) without treatment RI: 70–150 | T3 (nmol/L) without treatment RI: 1.3–2.7 | TBG (nmol/L) RI: 200–650 | Thyroid volume on ultrasound (RI) |
| A.II.6 | F | c.643G>T | p.(Gly215*) | – | 50 | 4.6 | 12.9 | 115 | 2.75* | 450 | 5.0 mL (4.9–19.1) |
| A.III.4 | M | c.643G>T | p.(Gly215*) | 2 weeks† | 18 | 2.9 | 6.7* | 85 | 3.05 (0.7–4.9) | 310 | 0.2 mL* (4.9–19.1) |
| A.III.5 | M | c.643G>T | p.(Gly215*) | 2 weeks† | 14 | 4.6 (1.7–7.9) | 11.7* (12–30) | 110 | × | 290 | 1.1 mL* (p50: 9.1) |
| B.II.2 | F | c.1772dup | p.(Lys592Glnfs*12) | – | 52 | 1.6 | 16.2 | 90 | 1.95 | 340 | 11 mL (4.9–19.1) |
| B.III.2 | F | c.1772dup | p.(Lys592Glnfs*12) | – | 25 | 3.8 | 14.5 | 85 | 1.65 | 330 | 10 mL (4.9–19.1) |
| B.III.3 | M | c.1772dup | p.(Lys592Glnfs*12) | 12 | 22 | 3.4 | 9.4* | × | 1.90 | 310 | 2 mL* (4.9–19.1) |
| B.III.4 | M | c.1772dup | p.(Lys592Glnfs*12) | 2 weeks† | 12 | 4.8 | 7.9* | × | × | 350 | 1.1 mL* (p50: 7.4) |
| C.I.2 | F | c.3161_3165del | p.(Cys1054Tyrfs*12) | – | 53 | 4.9 | 14.2 | 95 | 2.55 | 350 | 7.8 mL (4.9–19.1) |
| C.II.2 | F | c.3161_3165del | p.(Cys1054Tyrfs*12) | – | 31 | 1.4 | 13.2 | 100 | 2.20 | 340 | 23.5 mL* (4.9–19.1) |
| C.III.2 | M | c.3161_3165del | p.(Cys1054Tyrfs*12) | 2 weeks† | 5 | 7.7* | 7.5* | 70 | 2.80 (0.9–4.5) | 420 | 1.5 mL* (p50: 3.3) |
| D.II.4 | F | c.1587_1588insT | p.(Arg530Serfs*18) | – | 37 | 2.7 | 13.4 | 85 | 1.90 | 300 | 6.4 mL (4.9–19.1) |
| D.II.6 | F | c.1587_1588insT | p.(Arg530Serfs*18) | – | 35 | 0.6 | 16.5 | 120 | 2.40 | 360 | 9 mL (4.9–19.1) |
| D.III.6 | M | c.1587_1588insT | p.(Arg530Serfs*18) | 2 weeks† | 10 months | 1.4 (1.7–7.9) | 9.4* (12–30) | × | × | 520 | ׇ (p50: 1.6) |
| E.II.4 | F | c.1772dup | p.(Lys592Glnfs*12) | – | 35 | 0.8 | 11.2 | 90 | 1.85 | 360 | 7.1 mL (4.9–19.1) |
| E.III.4 | M | c.1772dup | p.(Lys592Glnfs*12) | 2 weeks† | 5 | 4.0 | 10.3 | 85 | 2.00 (0.9–4.5) | 450 | 0.8 mL* (p50: 3.3) |
| E.III.5 | M | c.1772dup | p.(Lys592Glnfs*12) | 3 | 3 | 3.2 | 9.2* | 100 | 2.65 (1.4–4.4) | 440 | 1.1 mL* (p50: 2.9) |
| E.III.6 | F | c.1772dup | p.(Lys592Glnfs*12) | – | 4 months | 1.4 | 11.9 | 160* | 4.40 (0.5–4.9) | 550 | x§ (p50: 1.6) |
Note: the FT4 concentrations included in the table are either (A) neonatal values before treatment (A.III.5 and D.III.6), or (B) values beyond the neonatal period without treatment (before start treatment, A.III.4, B.III.3 and E.III.5; or off-treatment to confirm the diagnosis, B.III.4, C.III.2 and E.III.4).
Neonatal FT4 value (or range) per patient (if available; RI: 12.0–30.0): A.III.4: 11.5 pmol/L; A.III.5: 11.7–12.1 pmol/L; B.III.4: 10.0–13.0 pmol/L; C.III.2: 14.0 pmol/L; D.III.6: 9.4–12.0 pmol/L; and E.III.4: 11.2–11.6 pmol/L.
×, missing value; not applicable; CeH, central hypothyroidism; F, female; FT4, free thyroxine; L, left; M, male; R, right; RI, reference interval; SDS, SD score; TSH, thyroid stimulating hormone; T3, triiodothyronine; T4, thyroxine. RI for FT4: 10–23 pmol/L (adults and children) and 12–30 pmol/L (neonates). RI for TSH: 0.5–5 mU/L (adults and children) and 1.7–7.9 mU/L (neonates). RI for T3 for age.49 RI for thyroid size for age.19 20
*Abnormal values.
†Detected by neonatal screening.
‡Volume could not be measured reliably, though visually smaller than average.
§Volume could not be measured reliably, though visually normal volume.