Table 1.
Representative Syndromes with Which Spontaneous 46,XX Primary Ovarian Insufficiency Has Been Associated.*
| Syndrome | Gene | OMIM Number | Prominent Associated Findings |
|---|---|---|---|
| Fragile X–associated disorders | FMR1 (fragile X mental retardation 1) | 309550 | Family history of intellectual disability due to fragile X syndrome or tremor–ataxia disorder |
| Autoimmune polyendocrine syndrome, type 1 | AIRE (autoimmune regulator) | 240300 | Adrenal insufficiency, hypoparathyroidism, chronic mucocutaneous candidiasis |
| Autoimmune polyendocrine syndrome, type 2 | Unknown | 269200 | Adrenal insufficiency, type 1 diabetes mellitus, autoimmune thyroid disease |
| Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency | CYP17A1 (cytochrome P450, family 17, subfamily A, polypeptide 1) | 202110 | Hypertension, hypokalemic alkalosis |
| Lipoid congenital adrenal hyperplasia | STAR (steroidogenic acute regulatory protein) | 600617 | Congenital adrenal insufficiency; testicular function in men more severely affected than ovarian function in women |
| Aromatase deficiency | CYP19A1 (cytochrome P450, family 19, subfamily A, polypeptide 1) | 107910 | Maternal virilization during pregnancy due to absence of placental aromatase |
| Blepharophimosis, ptosis, epicanthus inversus syndrome | FOXL2 (forkhead box L2) | 110100 | Dysmorphic eyelids |
| Progressive external ophthalmoplegia with mitochondrial DNA deletions | POLG (polymerase [DNA directed], gamma) | 157640 | Adult-onset weakness of external eye muscles and exercise intolerance |
| Galactosemia | GALT (galactose-1-phosphate uridylyltransferase) | 230400 | Hepatomegaly, cataracts, intellectual disability |
| Congenital disorder of glycosylation, type 1A | PMM2 (phosphomannomutase 2) | 212065 | Neonatal encephalopathy, hypotonia, psychomotor retardation, cerebellar hypoplasia, retinitis pigmentosa |
| Fanconi’s anemia | FA (Fanconi anemia complementation groups) | 227650 | Anemia, leukopenia, thrombocytopenia; cardiac, renal and limb malformations; dermal pigment changes |
| Ataxia–telangiectasia | ATM (ataxia–telangiectasia mutated) | 208900 | Cerebellar ataxia, telangiectases, immune defects, predisposition to cancer, premature aging, genome instability |
| Bloom’s syndrome | BLM (Bloom syndrome) | 210900 | Premature aging, predisposition to cancer, genome instability |
| Werner’s syndrome | WRN (Werner syndrome) | 277700 | Premature aging, predisposition to cancer, genome instability |
*
For a complete list of syndromes with which spontaneous 46,XX primary ovarian insufficiency has been associated, see the Supplementary Appendix, available with the full text of this article at NEJM.org. OMIM denotes Online Mendelian Inheritance in Man.