Table 1.
Phenotypes, genotypes, and investigation of gonadal function in 13 children with pathogenic variants in the DHX37 gene
| Variable | Patient 1 | Patient 2 | Patient 3 | Patient 4 | Patient 5 | Patient 6 | Patient 7 | Patient 8 | Patient 9 | Patient 10 | Patient 11 | Patient 12 | Patient 13 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Sex of rearing | Female | Female | Female | Female | Female | Female | Female | Female | Female | Male | Male | Male | Male |
| Karyotype | XY | XY | XY | XY | XY | XY | XY | XY | XY | XY | XY | XY | XY |
| Age at presentation | 20 years | 3 years | 16 years | 15 years | 15.5 years | Birth | NA | Birth | Birth | Birth | Birth | Birth | Birth |
| Diagnosis | Gonadal dysgenesis | Gonadal dysgenesis | Gonadal dysgenesis | Gonadal dysgenesis | Gonadal dysgenesis | Gonadal dysgenesis | 46,XY DSD | 46,XY DSD | Gonadal dysgenesis | TRS | TRS | TRS | TRS |
| Phenotype, external genitalia | Female, primary amenorrhea | Female | Female, primary amenorrhea | Female, discrete fusion of labia minora | Female, absence of puberty, discrete fusion of labia minora | Female, partial fusion of labia minora | Female, poorly developed labia | Virilized female, ambiguous genitalia | Ambiguous genitalia | Male, micropenis and bilateral cryptorchidism | Male, micropenis, hypospadias; unilateral cryptorchidism (L); small palpable testis (R) | Male, severe micropenis; cryptorchidism | Male, bilateral cryptorchidism |
| Internal genitalia | No Müllerian structures, Wolffian structures present | Urogenital sinus | No Müllerian structures, Wolffian structures present | Fallopian tube-like structures and epididymis on each side | Vagina present, absent uterus, Wolffian structures present (both sides) | Vagina 16–17 mm long and 6–7 mm wide not opened, absent uterus; no gonads present | Absent uterus and vagina | Vagina present, absent uterus, Wolffian structures present | Vaginal septum and uterus didelphys | No Müllerian structures | Vagina present | Absent vagina and uterus; bilateral epididymal-like structures | Absent gonads with vas deferens present (12 years) |
| Gonadal position | - | Abdominal cavity | - | - | - | - | - | - | - | L: Inguinal canal, R: abdominal cavity | - | - | - |
| Gonadal histology | Homogeneous fibrous tissues associated with a rete testis on both sides | Bilateral fibrous gonads, duct-like structures, fragments of uterine tube | R: Small nodule of fibrous tissue; L: fibrous tissue with rare tubule-like structures | No gonadal tissue present | Homogeneous fibrous tissue | L: No gonad tissue, remnants of ductus deferens; R: no gonad tissue, remnants of epididymis tissue | NA | NA | NA | No gonadal tissue; remnants of epididymis, ductus deferens | NA | L: Homogeneous fibrous tissue; R: no gonadal tissue | NA |
| LH (U/liter) | - | ||||||||||||
| Value | 23.1 | 7.2 (4 years) | 18 | 17 | 20 | 0.7 (1 week) 3.3 (5 months) | NA | NA | NA | 0.6 (1 week) | 0.5 (28 days) | <0.4 (10 days) | NA |
| Reference range | 2.4–13 | Tanner 1: 0.03–0.55 | 2.4–13 | 2.4–13 | 2.4–13 | 0.2–0.5 | 0.2–0.5 | 0.2–0.5 | 0.2–0.5 | ||||
| FSH (U/liter) | |||||||||||||
| Value | 61.5 | 90.9 (4 years) | 56 | 45 | 50 | 1.2 (1 week) 54.4 (5 months) | NA | NA | NA | 10.7 (1 week) | 8.9 (28 days) | 26.7 (5 years) | 100 (2 years) |
| Reference range | ND–13.5 | 0.7–3.39 | ND–13.5 | ND–13.5 | ND–13.5 | ND–2.0 | ND–2.0 | ND–2 | ND–2 | 0.22–1.92 | |||
| T (ng/ml) | |||||||||||||
| Value | 0.29 | <0.025 (4 years) | <0.25 | <0.25 | <0.25 | 0.25 (1 weeks) <0.19 (5 months) | NA | NA | NA | 0.16 (1 weeks) 2 (9 weeks) | 0.1 (Basal and after HCG 1500 ui x3) | 0.2 (10 days) | 0.7 (11 years) |
| Reference range | 2.70–9.00 | 0.02–0.23 | 2.70–9.00 | 2.70–9.00 | 2.70–9.00 | 0.1–0.5 0.02–0.2 | 0.1–0.5 0–8–3.3 | 0.2–0.5 | 0.7–1.7 | (0.4–19) | |||
| AMH (ng/ml) | |||||||||||||
| Value | 0.29 | 0.06 (4 years) | NA | 0.65 | NA | 0.01 (5 months) | NA | NA | NA | NA | NA | 0.0 | <0.01 (11 years) |
| Reference range | 32.77–262.69 | 105–270 | 7.4–243 | ||||||||||
| Ancestry | European | European | European | European | European | European | European | European | European | European | European | European | European |
| DHX37 pathogenic variant and inheritance | c.G2021A p.R674Q unknown | c.G2021A p.R674Q de novo | c.G923A p.R308Q de novo | c.C911T p.T304M maternal | c.C911T p.T304M de novo, absent in unaffected XY sib | c.G1001T p.R334L de novo | c.G923A p.R308Q unknown | c.G923A p.R308Q unknown | c.G923A p.R308Q unknown | c.C1877T p.S626L unknown | c.C1000T p.R334W unknown | c.G923A p.R308Q de novo | c.G3089A p.G1030E unknown |
Reference range refers to the range of basal levels in control subjects matched according to age and chromosomal sex with the case subjects. To convert the values for testosterone to nanomoles per liter, multiply by 3.467. To convert the values for estradiol to picomoles per liter, multiply by 3.671.
AMH anti-Müllerian hormone, DSD disorders/differences of sex development, FSH follicle stimulating hormone, L left, LH luteinizing hormone, NA not available, R right, T testosterone, TRS testicular regression syndrome.