45 X

**Genetics/Pathophysiology** - Karyotype 45,X (also written 45,XO). About 50% of cases are pure 45,X. The rest are mosaics (e.g., 45,X/46,XX) or have structural X abnormalities (isochromosome Xq, ring X, partial deletions). - Cause: usually meiotic nondisjunction or loss of the sex chromosome. The missing X is most often paternal. It is NOT associated with advanced maternal age. - Most 45,X conceptuses are lost as spontaneous abortions. Survivors are often mosaic. - Haploinsufficiency of the SHOX gene (on the pseudoautosomal region of X) causes short stature. Loss of genes that escape X inactivation causes the ovarian dysgenesis. - Barr body: absent in pure 45,X, because there is only one X.

**Clinical features** - Short stature, the most common finding. Growth hormone therapy is used. - Gonadal dysgenesis: streak ovaries, primary amenorrhea, and absent breast development. Labs show ↑FSH and LH and ↓estrogen (hypergonadotropic hypogonadism). Infertility follows, though pregnancy is possible with donor oocytes. - Lymphatic: cystic hygroma and webbed neck in utero or at birth. Lymphedema of the hands and feet at birth. Low hairline, "shield" chest with widely spaced nipples. - Cardiac: bicuspid aortic valve is most common. Preductal coarctation of the aorta is the next most common. These patients are also at risk for aortic root dilation and dissection. - Renal: horseshoe kidney, which is usually asymptomatic. Check renal ultrasound. - Other: cubitus valgus, short fourth metacarpal, hypothyroidism (Hashimoto), celiac disease, hearing loss, and ↑ risk of autoimmune disease. Intelligence is typically normal. - Gonadoblastoma risk exists only if Y material is present in mosaic forms (e.g., 45,X/46,XY). Prophylactic gonadectomy is recommended in that case.

**Diagnosis** - Prenatal: ↑ nuchal translucency or cystic hygroma on ultrasound. - Karyotype confirms the diagnosis.

**Management** - GH therapy for short stature. - Estrogen replacement (then progestin) to induce puberty and maintain bone health. - Cardiac evaluation (echo/MRI), renal ultrasound, and thyroid and celiac screening.

**High-yield differentials** - Noonan syndrome: normal karyotype (46,XX or XY), PTPN11 mutation (RAS/MAPK pathway), and **right-sided** heart lesions (pulmonic stenosis, hypertrophic cardiomyopathy). Both sexes are affected and gonadal function is usually normal. - Klinefelter syndrome (47,XXY): male with hypogonadism and tall stature. - Pure 46,XX gonadal dysgenesis (Swyer syndrome is 46,XY).

**Mnemonic**: Turner = "Lymphatic + left-sided heart lesions + streak ovaries" (Noonan = right-sided lesions).