The Massachusetts General Hospital IHH cohort consisted of a total of 1,453 IHH (KS and nIHH) patients enrolled in a research study within the Massachusetts General Hospital (MGH) Harvard Center for Reproductive Medicine. This cohort was clinically defined by (i) absent or incomplete puberty by age 18 years, (ii) serum testosterone < 100 ng/dL in men or estradiol < 20 pg/mL in women with low or normal levels of serum gonadotropins, (iii) otherwise normal anterior pituitary function, (iv) normal serum ferritin concentrations, and (v) normal MRI of the hypothalamic-pituitary region (4 (link)). These stringent clinical criteria allowed us to infer a hypothalamic site defect in these patients. In addition, since hypothalamic GnRH deficiency is often intertwined with olfactory dysfunction (KS form of IHH), both self-reported olfaction as well as University of Pennsylvania Smell Identification Test scores were used to classify patients as either KS (when olfaction was abnormal: anosmia/hyposmia) or nIHH (normal smell) (48 (link), 49 (link)). For male patients who were evaluated at prepubertal age, other signs of neonatal hypogonadism were evaluated, including hypospadias, micropenis, and cryptorchidism. Clinical charts and patient questionnaires were reviewed for phenotypic evaluation for both reproductive and nonreproductive phenotypes.
The diagnosis of SOX2 disorder was established in IHH probands in whom molecular genetic testing identified a heterozygous intragenic SOX2 pathogenic variant, a deletion that is intragenic, or a deletion of 3q26.33 involving SOX2 (1 ). Eye defects were classified as severe or mild as previously described (3 (link)). Severe eye defects were defined as bilateral ocular malformations including anophthalmia and microphthalmia. Mild eye defects were defined as unilateral anophthalmia or microphthalmia, coloboma, optic nerve hypoplasia/aplasia, strabismus, hypertelorism, nystagmus, small palpebral fissures, and myopia. Patients were evaluated for other nonocular features that have been associated with the syndrome, including neurocognitive developmental delay, seizures, hearing loss, and esophageal abnormalities, as well as genital anomalies including hypospadias, micropenis, and cryptorchidism. Patients’ pituitary function was assessed by detailed laboratory evaluation of all pituitary hormones, including thyroid-stimulating hormone, free thyroxine, prolactin, IGF1, adrenocorticotropic hormone, and morning cortisol, and pituitary anatomy was evaluated with pituitary MRIs.
The diagnosis of SOX2 disorder was established in IHH probands in whom molecular genetic testing identified a heterozygous intragenic SOX2 pathogenic variant, a deletion that is intragenic, or a deletion of 3q26.33 involving SOX2 (1 ). Eye defects were classified as severe or mild as previously described (3 (link)). Severe eye defects were defined as bilateral ocular malformations including anophthalmia and microphthalmia. Mild eye defects were defined as unilateral anophthalmia or microphthalmia, coloboma, optic nerve hypoplasia/aplasia, strabismus, hypertelorism, nystagmus, small palpebral fissures, and myopia. Patients were evaluated for other nonocular features that have been associated with the syndrome, including neurocognitive developmental delay, seizures, hearing loss, and esophageal abnormalities, as well as genital anomalies including hypospadias, micropenis, and cryptorchidism. Patients’ pituitary function was assessed by detailed laboratory evaluation of all pituitary hormones, including thyroid-stimulating hormone, free thyroxine, prolactin, IGF1, adrenocorticotropic hormone, and morning cortisol, and pituitary anatomy was evaluated with pituitary MRIs.
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