monosomy X

**Genetics / Pathophysiology** - Karyotype 45,X (often written 45,XO). It is the only viable human monosomy. About 99% of 45,X conceptuses are lost as spontaneous abortions, and 45,X is a common chromosomal cause of first-trimester loss. - Cause: meiotic nondisjunction or sex-chromosome loss. The missing X is usually paternal, so there is no Barr body. Risk does NOT increase with maternal age. - Mosaicism (e.g., 45,X/46,XX) gives a milder phenotype and can allow some ovarian function or even spontaneous pregnancy. Structural variants (e.g., isochromosome Xq, X deletions) also occur. - Haploinsufficiency of SHOX (on the pseudoautosomal region of X) causes short stature and skeletal abnormalities. Loss of the second X causes ovarian follicle atresia, leading to streak gonads (gonadal dysgenesis). - Mosaics with Y-chromosome material (e.g., 45,X/46,XY) have increased risk of gonadoblastoma, so prophylactic gonadectomy is recommended.

**Clinical features** - Short stature, the most common finding. Height is normal at birth, then growth falls off. - Primary amenorrhea, lack of secondary sexual characteristics, and infertility (streak ovaries, "hypergonadotropic hypogonadism" with ↑FSH/LH and ↓estrogen). - Lymphatic: cystic hygroma (prenatal), webbed neck (pterygium colli), lymphedema of hands and feet at birth, low posterior hairline. - Skeletal: shield chest with widely spaced nipples, cubitus valgus, short 4th metacarpal, Madelung deformity. - Cardiac: bicuspid aortic valve (most common), coarctation of the aorta (preductal), aortic root dilation and dissection risk. - Renal: horseshoe kidney (also a classic association), other renal anomalies. - Endocrine/autoimmune: Hashimoto thyroiditis and hypothyroidism, celiac disease, type 2 diabetes, obesity, and dyslipidemia. - Neurocognitive: normal intelligence usually, but with specific visuospatial and math deficits. - Other: recurrent otitis media and hearing loss, and pigmented nevi.

**Diagnosis** - Karyotype is confirmatory. - Prenatal: increased nuchal translucency, cystic hygroma, and hydrops on ultrasound. Quad screen shows ↓AFP, ↓estriol, ↓hCG, and normal or ↓inhibin A. Cell-free DNA can screen for it. - Workup after diagnosis: echocardiogram or cardiac MRI, renal ultrasound, TSH, audiology, and screening for celiac disease and glucose and lipid abnormalities.

**Management** - Growth hormone in childhood. - Estrogen replacement to induce puberty, then estrogen plus progestin to maintain secondary sexual characteristics and bone health. - Fertility: donor oocyte IVF, with careful cardiovascular screening before pregnancy. - Lifelong cardiology surveillance.

**High-yield comparisons** - Turner: ↓estrogen, ↑FSH/LH, streak ovaries, no Barr body, normal-appearing female. - Klinefelter (47,XXY): 1 Barr body, tall male with testicular atrophy. - Noonan syndrome: similar phenotype (webbing, short stature) but in males and females with a normal karyotype (PTPN11 mutation), pulmonary stenosis (right-sided lesions), and normal fertility and gonadal function. - Coarctation in Turner: associated with a "notching" of the ribs and a BP differential between upper and lower extremities.