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Abstract Context The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in humans led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed. Objective The objective of this work is to determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures. Methods We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients. Results All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to 2 GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male patient. Conclusions Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with but may not depend on olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.

Congenital arhinia (absent external nose) is an extremely rare mendelian disorder (<100 case reports in the past century) caused by heterozygous missense mutations in the gene SMCHD1. Arhinia is frequently accompanied by ocular and reproductive defects, a clinical triad which defines the Bosma arhinia microphthalmia syndrome (BAMS). The etiology and spectrum of reproductive defects in BAMS is unknown. We studied eleven subjects with arhinia or nasal hypoplasia (aged 18-53 yrs; 5 males) to assess endogenous luteinizing hormone (LH) secretion (n=11), a validated marker of GnRH, responsiveness to pulsatile GnRH (n=2), and non-reproductive phenotypes (n=11). Clinical data abstracted from questionnaires were analyzed in 33 additional international patients. Nearly every male demonstrated clinical and biochemical signs of severe congenital GnRH deficiency (CGD) including a history of microphallus and/or cryptorchidism, testicular volumes < 3 ml, hypogonadotropic hypogonadism (HH), low inhibin B levels, and apulsatile LH profiles; two young boys (studied from afar) had normal genitals but an absent mini-puberty of infancy was confirmed biochemically in one case. Pulsatile GnRH administered to one adult male and hCG to two others also revealed testicular resistance. Several females reported spontaneous breast bud development, but all had primary amenorrhea, small ovaries on pelvic ultrasound, HH, and apulsatile LH profiles. Pulsatile GnRH administered to one female induced ovulation on treatment day 21. Two females (studied from afar) reported normal thelarche and menstrual cycles. The 11 subjects studied in detail were completely anosmic with absent internal olfactory structures on brain MRI but normal hypothalamic-pituitary anatomy. Subjects with arhinia demonstrated some, but not all, non-reproductive phenotypes characteristic of Kallmann syndrome (KS) and/or CHARGE syndrome including dental agenesis (56%) and congenital mirror movements (CMMs; 50%); none had renal agenesis, severe congenital heart defects, or deafness. This study demonstrates for the first time that the hypogonadotropism observed in BAMS is indeed secondary to GnRH deficiency. In contrast to the male predominance (3-5:1) in KS, there is no sex bias in the incidence of BAMS. However, females may demonstrate partial or complete pubertal development whereas males are severely affected with some showing both hypothalamic and testicular defects. The combination of defects in the nasal skeleton, olfactory structures, and GnRH ontogeny point to aberrant development of the nasal placode in BAMS, yet the high prevalence of CMMs, a sign of misrouted commissural axons, suggests insults may occur even earlier in neurogenesis, at the neural plate border.