Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.

and Royal Victoria Infirmary (R.Q.), Newcastle-upon Tyne NE1 4LP, United Kingdom Context:The complexity of genetic testing in Kallmann syndrome (KS) is growing and costly. Thus, it is important to leverage the clinical evaluations of KS patients to prioritize genetic screening.Objective: The objective of the study was to determine which reproductive and nonreproductive phenotypes of KS subjects have implications for specific gene mutations. Subjects:Two hundred nineteen KS patients were studied: 151 with identified rare sequence variants (RSVs) in 8 genes known to cause KS (KAL1, NELF, CHD7, HS6ST1, FGF8/FGFR1, or PROK2/ PROKR2) and 68 KS subjects who remain RSV negative for all 8 genes. Main Outcome Measures:Reproductive and nonreproductive phenotypes within each genetic group were measured. Results:Male KS subjects with KAL1 RSVs displayed the most severe reproductive phenotype with testicular volumes (TVs) at presentation of 1.5 Ϯ 0.1 mL vs 3.7 Ϯ 0.3 mL, P Ͻ .05 vs all non-KAL1 probands. In both sexes, synkinesia was enriched but not unique to patients with KAL1 RSVs compared with KAL1-negative probands (43% vs 12%; P Ͻ .05). Similarly, dental agenesis and digital bone abnormalities were enriched in patients with RSVs in the FGF8/FGFR1 signaling pathway compared with all other gene groups combined (39% vs 4% and 23% vs 0%; P Ͻ .05, respectively). Hearing loss marked the probands with CHD7 RSVs (40% vs 13% in non-CHD7 probands; P Ͻ .05). Renal agenesis and cleft lip/palate did not emerge as statistically significant phenotypic predictors. Conclusions:Certain clinical features in men and women are highly associated with genetic causes of KS. Synkinesia (KAL1), dental agenesis (FGF8/FGFR1), digital bony abnormalities (FGF8/FGFR1), and hearing loss (CHD7) can be useful for prioritizing genetic screening. (J Clin Endocrinol Metab 98: E943-E953, 2013)

The clinical presentation of female GnRH deficiency varies from primary amenorrhea and absence of any secondary sexual characteristics to spontaneous breast development and occasional menses. In this cohort, rare sequence variants were present in all of the known genes associated with GnRH deficiency, including the novel identification of GnRH-deficient women with KAL1 variants. The pathogenic mechanism through which KAL1 variants disrupt female reproductive development requires further investigation.

Estradiol is higher in AAW compared with CW across the menstrual cycle. Higher estradiol in the face of similar androstenedione and FSH levels suggests enhanced aromatase activity in AAW. Such differences may contribute to racial disparities in bone mineral density, breast cancer, and uterine leiomyomas.

In the majority of this predominantly non-Hispanic white referred sample of obese children, overweight started in the preschool years. The referral to the endocrinologist, occurring after a prolonged interval from the obesity onset, was ineffective in treating obesity. Hyperinsulinemia and hypercholesterolemia are often present also at a young age. These obesity comorbidities in association with high prevalence of parental obesity and type 2 diabetes expose these youths to high risk for developing type 2 diabetes and coronary heart disease. Our data underscore the need for early family-based behavioral-lifestyle intervention programs to be made available to pediatricians, enabling them to target the "at risk for overweight" preschool children and their likely overweight parents.

Studies that control for endogenous GnRH and estradiol demonstrate a direct pituitary site of estrogen negative feedback on LH and FSH responsiveness to GnRH in women. The effect of estrogen on FSH responsiveness is greater than on LH and is attenuated with aging. These studies indicate that estrogen negative feedback occurs directly at the pituitary and contributes to the differential regulation of FSH and LH secretion.

Irregular menstrual cycles due to anovulation are well-described in the first few years after menarche, but the normal developmental trajectory from anovulatory to mature ovulatory cycles during adolescence remains undefined. This paper presents our very limited understanding of this final stage of female reproductive axis development and why additional research in this area is critical to the health of women. Long and irregular menstrual cycles are common in the first 1-2 years after menarche, but the majority of girls settle into a regular pattern of cycles (24-38-day interval) by late adolescence 1. The achievement of the mature ovulatory cycle of a fertile woman is arguably one of the most critical milestones of adolescence, yet the physiological mechanisms underlying this developmental transition are not well understood. This knowledge gap has hampered our ability to distinguish abnormal (e.g. polycystic ovarian syndrome [PCOS]) from normal developmental trajectories. The observation that most adult women with oligomenorrhea of unknown etiology report symptoms dating back to early adolescence 2,3 suggests further that the early post-menarchal period may represent a critical window when preventative measures must be instituted to safeguard reproductive health in adulthood. The purpose of this article is to review what little we do know about reproductive physiology in the early post-menarchal years and to highlight major knowledge gaps to inform future research into adolescent menstruation. The early post-menarchal years: when do girls first achieve ovulatory cycles? There is a general consensus that in the first 1-2 gynecologic years, the majority of menstrual cycles are anovulatory. The gynecologic age at which ovulatory cycles are first achieved, however, is less clear. There is a small, and relatively old, body of literature on this topic, and the estimates encompass a broad range of gynecologic ages (Fig 1) 4-16. This

In studies that isolated the pituitary from endogenous GnRH stimulation, aging attenuated the LH and FSH responses to exogenous GnRH in PMW. These studies indicate that the pituitary plays a role in the decline in gonadotropin levels with aging, further supporting the potential contribution of age-associated changes in both hypothalamic and pituitary function to reproductive senescence.