Background: Hypergonadotropic hypogonadism(HH) in females results from primary gonadal failure related to genetic defects affecting ovarian development and function or acquired gonadal damage; limited knowledge exist regarding underlying genes involved or potential gene X environment interactions responsible for disease trait manifestations. While pathogenic variants in single genes, chromosomal abnormalities such as Turner syndrome and acquired gonadal damage have been described as etiologies of HH, over 75% of cases do not have a clear molecular diagnosis.
Methods: Twenty-eight females with 46,XX HH from a single pediatric endocrinology center were studied. Patients with gonosomal chromosomal abnormalities and gonadal failure secondary to chemotherapy/surgery were excluded. Ascertainment was based on characteristic clinical and laboratory features. Potential molecular genetic etiologies were investigated by family based genomics as a means to gain insights into disease biology.
Results: Mean age at diagnosis was 15.1±2.3years; clinical presentations included primary amenorrhea(PA) in 19(67.9%), secondary amenorrhea(SA) in 5(17.9%), short stature in 3(10.7%) and breast underdevelopment with irregular menstrual cycles in 1(3.5%). Consanguinity ratio was 71.4% and 25% of the patients had a family member with HH. Height and BMI SDs were -0.8±1.1 and 0.6±1.5, respectively. There was no breast development in 25% of patients, while 43% of them at breast Tanner stage IV-V (BIV-V). Mean LH and FSH levels were 27.1±9.7mIU/ml(Ref:2.4-12.6) and 82.2±30.8mIU/mL(Ref:3.8-8.8), respectively. There were no differences in FSH, LH levels, height or BMD SDs between the PA and SA groups, but length of the uterine long axis differed (34.6±11.8 vs.54.6±13.0mm, p:0.004). Lumbar spine BMD Z-score with DXA was -1.8±1.1, 41.9% of them had Z-score <-2. Final height and MPH SDs were -0.2±1.0 and -0.5±0.9, respectively. Median time from initiation of estrogen to combined hormone replacement therapy was 18.1 and 1.1 months in PA and SA groups, respectively (P=0.012). Likely damaging pathogenic variants were identified in 14 patients (50%); genes included SOHLH1 (n:2), NOBOX, PAD16, MRPS22, GALT (n:2), CYP17A1, MSH5, MCM9, MCM8 and C3. Multi-locus pathogenic variation was detected in 2 cases. Patients with galactosemia (GALT) presented with PA, and their urinary reducing substance levels were normal.
Conclusion: At least 50% of HH cases have a molecular diagnosis in a gene that contributes to gonadal development and maintenance, that participates in estrogen biosynthesis, or that has been implicated in diminished ovarian reserve. Additionally, standard laboratory screening can fail to identify galactosemia.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology