Kallmann Syndrome Research Articles

Синдром Кальмана (гипогонадотропный гипогонадизм): клинический случай у мальчика 12 лет

Синдром Кальмана (гипогонадотропный гипогонадизм): клинический случай у мальчика 12 лет

Neuron-Derived Neurotrophic Factor Is Mutated in Congenital Hypogonadotropic Hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by infertility and the absence of puberty. Defects in GnRH neuron migration or altered GnRH secretion and/or action lead to a severe gonadotropin-releasing hormone (GnRH) deficiency. Given the close developmental association of GnRH neurons with the olfactory primary axons, CHH is often associated with anosmia or hyposmia, in which case it is defined as Kallmann syndrome (KS). The genetics of CHH are heterogeneous, and >40 genes are involved either alone or in combination. Several CHH-related genes controlling GnRH ontogeny encode proteins containing fibronectin-3 (FN3) domains, which are important for brain and neural development. Therefore, we hypothesized that defects in other FN3-superfamily genes would underlie CHH. Next-generation sequencing was performed for 240 CHH unrelated probands and filtered for rare, protein-truncating variants (PTVs) in FN3-superfamily genes. Compared to gnomAD controls the CHH cohort was statistically enriched for PTVs in neuron-derived neurotrophic factor (NDNF) (p = 1.40× 10-6). Three heterozygous PTVs (p.Lys62∗, p.Tyr128Thrfs∗55, and p.Trp469∗, all absent from the gnomAD database) and an additional heterozygous missense mutation (p.Thr201Ser) were found in four KS probands. Notably, NDNF is expressed along the GnRH neuron migratory route in both mouse embryos and human fetuses and enhances GnRH neuron migration. Further, knock down of the zebrafish ortholog of NDNF resulted in altered GnRH migration. Finally, mice lacking Ndnf showed delayed GnRH neuron migration and altered olfactory axonal projections to the olfactory bulb; both results are consistent with a role of NDNF in GnRH neuron development. Altogether, our results highlight NDNF as a gene involved in the GnRH neuron migration implicated in KS.

Gli3 Regulates Vomeronasal Neurogenesis, Olfactory Ensheathing Cell Formation, and GnRH-1 Neuronal Migration.

During mammalian development, gonadotropin-releasing-hormone-1 neurons (GnRH-1ns) migrate from the developing vomeronasal organ (VNO) into the brain asserting control of pubertal onset and fertility. Recent data suggest that correct development of the olfactory ensheathing cells (OEC) is imperative for normal GnRH-1 neuronal migration. However, the full ensemble of molecular pathways that regulate OEC development remains to be fully deciphered. Loss-of-function of the transcription factor Gli3 is known to disrupt olfactory development, however, if Gli3 plays a role in GnRH-1 neuronal development is unclear. By analyzing Gli3 extra-toe mutants (Gli3Xt/Xt), we found that Gli3 loss-of-function compromises the onset of achaete-scute family bHLH transcription factor 1 (Ascl-1)+ vomeronasal progenitors and the formation of OEC in the nasal mucosa. Surprisingly, GnRH-1 neurogenesis was intact in Gli3Xt/Xt mice but they displayed significant defects in GnRH-1 neuronal migration. In contrast, Ascl-1null mutants showed reduced neurogenesis for both vomeronasal and GnRH-1ns but less severe defects in OEC development. These observations suggest that Gli3 is critical for OEC development in the nasal mucosa and subsequent GnRH-1 neuronal migration. However, the nonoverlapping phenotypes between Ascl-1 and Gli3 mutants indicate that Ascl-1, while crucial for GnRH-1 neurogenesis, is not required for normal OEC development. Because Kallmann syndrome (KS) is characterized by abnormal GnRH-1ns migration, we examined whole-exome sequencing data from KS subjects. We identified and validated a GLI3 loss-of-function variant in a KS individual. These findings provide new insights into GnRH-1 and OECs development and demonstrate that human GLI3 mutations contribute to KS etiology.SIGNIFICANCE STATEMENT The transcription factor Gli3 is necessary for correct development of the olfactory system. However, if Gli3 plays a role in controlling GnRH-1 neuronal development has not been addressed. We found that Gli3 loss-of-function compromises the onset of Ascl-1+ vomeronasal progenitors, formation of olfactory ensheathing cells in the nasal mucosa, and impairs GnRH-1 neuronal migration to the brain. By analyzing Ascl-1null mutants we dissociated the neurogenic defects observed in Gli3 mutants from lack of olfactory ensheathing cells in the nasal mucosa, moreover, we discovered that Ascl-1 is necessary for GnRH-1 ontogeny. Analyzing human whole-exome sequencing data, we identified a GLI3 loss-of-function variant in a KS individual. Our data suggest that GLI3 is a candidate gene contributing to KS etiology.

Live birth in male de novo Kallmann syndrome after cross-generational genetic sequencing.

To present the first case proposing the use of preimplantation genetic testing for monogeneic disorders for Kallmann syndrome, providing comprehensive care in the genomic era of precision medicine. Gonadotropin therapy was used for spermatogenesis, followed by in vitro fertilization by intracytoplasmic sperm injection and embryo transfer. Cross-generational targeted next-generation sequencing was then donefor genes known to cause Kallmann syndrome. A heterozygous mutation at codon 102 of the FGFR1 gene was found in the patient, but the father was found to have the same mutation yet is unaffected by Kallmann syndrome. Since no causative mutation was found, a de novo or sporadic mutation was suspected as the cause of Kallmann syndrome in this case. Comprehensive care must be available for male Kallmann syndrome patients, as treatment should not stop at spermatogenesis, but continue with genetic counseling due to possible inheritance.

Rare health conditions 29: serpiginous choroiditis, haemolytic-uraemic syndrome, Kallman syndrome, Fabry disease

The purpose of this series is to highlight a range of rare health conditions: those that affect no more and usually fewer than 1 person in every 2000. Many healthcare assistants and nurses will encounter some of these conditions, given the high number of them. This 29th article will briefly explore four of these rare conditions.

A novel splice site variant in ANOS1 gene leads to Kallmann syndrome in three siblings

Idiopathic hypogonadotropic hypogonadism (IHH) is a rare genetic disease caused by low doses of hypothalamic gonadotropin-releasing hormone (GnRH), leading to absence or delayed sexual development. Kallmann syndrome (KS) is characterized by IHH with anosmia or hyposmia. Here, we identified a novel splice site variant (c. 726+2T>G) of ANOS1 gene in three siblings with KS from a Chinese Han family by whole-exome sequencing (WES). In this family, KS is classified as an X-linked recessive inheritance pattern. This mutation was inherited from the mother by Sanger sequencing. An in vitro functional experiment has identified the deleterious effect of this mutation on the transcriptional level of ANOS1 gene. Importantly, the effectiveness of timely hormone replacement therapy was evaluated on the three siblings. Hence, finding genetic causes could be helpful in the early diagnosis and timely treatment of KS.

New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. Several genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. The advent of next-generation sequencing (NGS) has allowed the simultaneous genotyping of several regions, faster, making possible the extension of the genetic knowledge of CHH. Genetic characterization of a large cohort of Brazilian CHH patients. A cohort of 130 unrelated patients (91 males, 39 females) with CHH (75 normosmic CHH, 55 Kallmann syndrome) was studied using a panel containing 36 CHH-associated genes. Potential pathogenic or probably pathogenic variants were identified in 43 (33%) CHH patients. The genes ANOS1, FGFR1 and GNRHR were the most frequently affected. A novel homozygous splice site mutation was identified in the GNRH1 gene and a deletion of the entire coding sequence was identified in SOX10. Deleterious variants in the IGSF10 gene were identified in two patients with reversible normosmic CHH. Notably, 6.9% of the patients had rare variants in more than one gene. Rare variants were also identified in SPRY4, IL17RD, FGF17, IGSF1 and FLRT3 genes. This is a large study of the molecular genetics of CHH providing new genetic findings for this complex and heterogeneous genetic condition. NGS has been shown to be a fast, reliable and effective tool in the molecular diagnosis of congenital CHH and being able to targeting clinical genetic testing in the future.

TET1 regulates fibroblast growth factor 8 transcription in gonadotropin releasing hormone neurons.

Fibroblast growth factor 8 (FGF8) is a potent morphogen that regulates the ontogenesis of gonadotropin-releasing hormone (GnRH) neurons, which control the hypothalamus-pituitary-gonadal (HPG) axis, and therefore reproductive success. Indeed, FGF8 and FGFR1 deficiency severely compromises vertebrate reproduction in mice and humans and is associated with Kallmann Syndrome (KS), a congenital disease characterized by hypogonadotropic hypogonadism associated with anosmia. Our laboratory demonstrated that FGF8 signaling through FGFR1, both of which are KS-related genes, is necessary for proper GnRH neuron development in mice and humans. Here, we investigated the possibility that non-genetic factors, such as the epigenome, may contribute to KS onset. For this purpose, we developed an embryonic explant model, utilizing the mouse olfactory placode (OP), the birthplace of GnRH neurons. We show that TET1, which converts 5-methylcytosine residues (5mC) to 5-hydroxymethylated cytosines (5hmC), controls transcription of Fgf8 during GnRH neuron ontogenesis. Through MeDIP and ChIP RT-qPCR we found that TET1 bound to specific CpG islands on the Fgf8 promoter. We found that the temporal expression of Fgf8 correlates with not only TET1 binding, but also with 5hmC enrichment. siRNA knockdown of Tet1 reduced Fgf8 and Fgfr1 mRNA expression. During this time period, Fgf8 also switched histone status, most likely via recruitment of EZH2, a major component of the polycomb repressor complex-2 (PRC2) at E13.5. Together, these studies underscore the significance of epigenetics and chromatin modifications to temporally regulated genes involved in KS.

Congenital anosmia: a case report

Abstract Congenital anosmia, isolated or as a symptom of Kallmann or Klinefelter syndrome, is a rare condition found in young patients and children. Anosmia is detected during childhood, being reported by the patient or by his/her family. Besides the clinical examination and olfactometric evaluation, imaging is mandatory for the olfactory pathways investigation. Multidisciplinary approach is needed for these patients in order to determine the etiology of the smell loss. In the current paper, we are presenting the case of an 11-year-old child diagnosed in our ENT Department with congenital anosmia.

Nasal Placode Development, GnRH Neuronal Migration and Kallmann Syndrome.

The development of Gonadotropin releasing hormone-1 (GnRH) neurons is important for a functional reproduction system in vertebrates. Disruption of GnRH results in hypogonadism and if accompanied by anosmia is termed Kallmann Syndrome (KS). From their origin in the nasal placode, GnRH neurons migrate along the olfactory-derived vomeronasal axons to the nasal forebrain junction and then turn caudally into the developing forebrain. Although research on the origin of GnRH neurons, their migration and genes associated with KS has identified multiple factors that influence development of this system, several aspects still remain unclear. This review discusses development of the olfactory system, factors that regulate GnRH neuron formation and development of the olfactory system, migration of the GnRH neurons from the nose into the brain, and mutations in humans with KS that result from disruption of normal GnRH/olfactory systems development.

Defective AMH signaling disrupts GnRH neuron development and function and contributes to hypogonadotropic hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is a condition characterized by absent puberty and infertility due to gonadotropin releasing hormone (GnRH) deficiency, which is often associated with anosmia (Kallmann syndrome, KS). We identified loss-of-function heterozygous mutations in anti-Müllerian hormone (AMH) and its receptor, AMHR2, in 3% of CHH probands using whole-exome sequencing. We showed that during embryonic development, AMH is expressed in migratory GnRH neurons in both mouse and human fetuses and unconvered a novel function of AMH as a pro-motility factor for GnRH neurons. Pathohistological analysis of Amhr2-deficient mice showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in reduced fertility in adults. Our findings highlight a novel role for AMH in the development and function of GnRH neurons and indicate that AMH signaling insufficiency contributes to the pathogenesis of CHH in humans.

Extracellular matrix protein anosmin-1 modulates olfactory ensheathing cell maturation in chick olfactory bulb development.

Olfactory ensheathing cells (OECs) are a specialized class of glia, wrapping around olfactory sensory axons that target the olfactory bulb (OB) and cross the peripheral nervous system/central nervous system boundary during development and continue to do so post-natally. OEC subpopulations perform distinct subtype-specific functions dependent on their maturity status. Disrupted OEC development is thought to be associated with abnormal OB morphogenesis, leading to anosmia, a defining characteristic of Kallmann syndrome. Hence, anosmin-1 encoded by Kallmann syndrome gene (KAL-1) might modulate OEC differentiation/maturation in the OB. We performed in ovo electroporation of shRNA in the olfactory placode to knock-down kal in chick embryos, resulting in abnormal OB morphogenesis and loss of olfactory sensory axonal innervation into OB. BLBP-expressing OECs appeared to form a thinner and poorly organized outmost OB layer where SOX10 expressing OECs were completely absent with emergence of GFAP-expressing OECs. Furthermore, in embryonic day 10 chick OB explant cultures, GFAP expression in OECs accumulating along the OB nerve layers was dramatically reduced by recombinant anosmin-1. We then purified immature OECs from embryonic day 10 chick OB. These cells express GFAP after 7days in vitro, exhibiting a multipolar morphology. Overexpression of chick anosmin, exogenous anosmin-1 or FGF2 could inhibit GFAP expression with cells presenting elongated morphology, which was blocked by the FGF receptor inhibitor Su5402. These data demonstrate that anosmin-1 functions via FGF signalling in regulating OEC maturation, thereby providing a permissive glial environment for axonal innervation into the OB during development.

HORMONAL AND CLINICAL PROFILE OF HYPOGONADISM IN DIABETES PATIENTS

Introduction: Hypogonadism in male is defined as a condition in which there is a clinical characterization of both sign and symptom and biochemical evidence of testosterone deficiency. Male hypogonadism is one kind of recognized medical condition in which these remains under diagnosed by clinicians. A clinical syndrome which consists of with or without signs and associated with biochemical evidence of testosterone deficiency in called Hypogonadism. Over two decades ago, association between the diabetes mellitus (DM) and hypogonadism came to limelight when a high prevalence of low testosterone levels was observed in men with diabetes. Many studies showed that in one‑third of diabetic men there are low free testosterone levels, which are independent of sex hormone‑binding globulin (SHBG). Due to deficiency of testosterone in men is associated with negative consequences. Many research showed that in DM patients there is increasing evidence of hypogonadism is a risk factor for coronary artery disease, the leading cause of mortality. Other adverse effects are also been reported associated with hypogonadism which included as poor quality of life, sexual dysfunction, increased fracture risk, increasing fat mass, cognitive decline, and mortality. Aim: The main aim of this study is to find out the type of hypogonadism as either hypogonadotropic or hypergonadotropic in DM patients. Material and methods: Total 70 patients were include in this study in which patients visiting out patients department (OPD) of medicine and in patients department (IPD). Individuals with chronic systemic illness, abuse drugs or alcohol and undergone cancer chemotherapy or radiotherapy were excluded in this study. Detailed history of the patients was taken from the patients like height, weight and arm span with general and systemic examination to rule out any systemic illness were noted. Estimation of hormonal levels was noted from all patients. Result: Total 80 DM male patients were included in this study. Out of 70 patients 49 (70%) were below 35 years old and remaining 21(30%) were above 36 years old. Out of 70 patients 55 had hypogonadotropic hypogonadism and 15 had hypergonadotropic hypogonadism in male respectively. Out of total patients 55 had hypogonadotropic hypogonadism. Most common etiology was idiopathic hypogonadotropic hypogonadism. Patient with bilateral anorchia or vanishing testis syndrome, two patients had kallmann syndrome, five of them had hypopituitarism and interestingly three patients had features of gigantism and hypogonadism. 15 patients had hypergonadotropic hypogonadism in which 11 had Klinefelter syndrome and 4 had Turner’s syndrome. Conclusion: The most common cause is Idiopathic hypogonadotropic hypogonadism is shown in male. Height, weight and Arm span varied significantly between Males of hypogonadotropic hypogonadism and hypergonadotropic hypogonadism. Maximum number of patients of DM in India, the incidence of hypogonadism is more in diabetic patients as compared to the general population. Hence, implementation of screening programs in diabetic patients is necessary to understand and detect individuals with low serum total testosterone at any early stage and to supplement testosterone accordingly.
 Keywords: diabetes mellitus, hypogonadism, testosterone, Hypogonadotropic hypogonadism

The PROK2/PROKR2 signaling pathway is required for the migration of most olfactory bulb interneurons.

Neural stem cells in the subventricular zone (SVZ) of the lateral ventricle generate new interneurons, which migrate tangentially through the rostral migratory stream (RMS) to the olfactory bulb (OB). The PROK2 (prokineticin 2) and PROKR2 (prokineticin receptor 2) signaling pathway has been identified to cause human Kallmann syndrome, a developmental disease that associates hypogonadism with anosmia (OB developmental defects). However, the identities and properties of PROK2+ and PROKR2+ cells in the SVZ-RMS-OB remain largely unknown. Here we examine the expression patterns of Prok2 and Prokr2 in the SVZ-RMS-OB using Prok2EGFP transgenic and Prokr2LacZ/+ knockin mice. Our results show that Prokr2 is expressed in postmitotic immature interneurons in the SVZ-RMS-OB. Prok2 is not expressed in the SVZ, but a few PROK2+ cells are found in the medial part of the RMS; they are not neural progenitors or migrating neuroblasts. In the OB, Prok2 is expressed in a subset of granule cells and tufted cells, but no coexpression of Prok2 and Prokr2 in the OB cells is observed. In Prok2 and Prokr2 mutant mice, severe tangential and radial migration defects of neuroblasts in the SVZ-RMS-OB result in loss of ~75% of GABAergic interneurons in the OB. These analyses demonstrate that PROK2/PROKR2 signaling is crucial for the tangential and radial migration of OB interneurons.

Final (FH) and target height (TH) in male and female patients with congenital hypogonadotropic hypogonadism (CHH)/Kallmann syndrome (KS): a monocentric study of 216 patients

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

New diagnosis of Kallmann syndrome in an adult Fugitive

New diagnosis of Kallmann syndrome in an adult Fugitive

SUN-438 Spontaneous Recovery of the Hypothalamic-Pituitary-Gonadal (HPG) Axis in a Female with Kallmann Syndrome

Background: Kallmann Syndrome (KS) is characterized by hypogonadotropic hypogonadism (HH) due to isolated GnRH deficiency (IGD) and anosmia. While reversal of KS has been described, predominantly in males, few cases have been described in females. We report a female with KS who demonstrated spontaneous recovery of her HPG axis. Case Report: A 34-year-old woman with a history of KS was referred to the NIH Clinical Center for evaluation. She was evaluated for absent thelarche and primary amenorrhea at age 18 when, due to her history of vigorous exercise and low BMI, she was assumed to have hypothalamic amenorrhea. At age 22, she was first noted to be anosmic by her endocrinologist who diagnosed her with KS. She underwent bilateral breast augmentation, and oral contraceptive pills (OCPs) induced regular menstrual bleeding. OCPs were self-discontinued after 1 year and amenorrhea recurred. By her late 20s, her level of exercise had decreased and her BMI normalized. She reported 3 episodes of spontaneous menstrual spotting in the six months preceding her visit, cyclical but irregular breast tenderness and emotional lability in the absence of hormonal treatment. Her medications included only fluoxetine. Physical examination revealed a BMI of 19.1 kg/m2, bilateral breast implants, a high-arched palate and bilateral fifth digit clinodactyly. Her laboratory evaluation revealed a serum LH of 8 U/L, FSH of 9 U/L and E2 of 19 pg/mL; all other anterior pituitary hormones were normal. Frequent blood sampling revealed a high-frequency pattern of LH pulsatility (24 pulses/24 hrs) with sleep augmentation and mean LH of 6.8 U/L. Formal smell testing confirmed anosmia. Her pelvic ultrasound revealed normal ovaries with follicles and normal uterus with a 4 mm endometrial stripe. A brain MRI was normal except for absent olfactory bulbs. Clinical testing of 14 IGD genes showed a novel heterozygous ANOS1 variant (c.298C>A p.Q100K) of unknown significance that was also present in her unaffected mother. A maternal half-uncle was reportedly anosmic but is now deceased. Discussion: This KS female exhibited spontaneous recovery of her HPG axis, which has been reported in very few cases. Her olfactory bulb aplasia is consistent with a congenital defect in GnRH neuronal development given their common ontogeny, suggesting that her HH and recovery were not simply due to changes in body weight nor exercise. Although females with heterozygous ANOS1 variants have been reported to demonstrate features of HH, the role of this novel ANOS1 variant remains unclear due lack of functional data and the presence of the same variant in her asymptomatic mother. Conclusions: Reversal of the reproductive phenotype in women with KS is rare with little known about their genetic abnormalities and long-term outcomes. Further study of such cases is warranted to gain insight into the mechanisms required for activation of the HPG axis.

SAT-295 Low Dose rFSH Prior to HCG-rFSH Therapy in Kallmann Syndrome

[Background] Kallmann syndrome (KS) is known as a disorder characterized by hypogonadotropic hypogonadism and anosmia. Sato et al. reported that approximately 60% of Congenital male hypogonadotropic hypogonadism (CMHH) could not achieve sufficient spermatogenesis with the current hCG-rFSH combination therapy. [Objective] With the aim of improving gonadal function of KS, we treat KS patient with new methods proposed by Sato et al. and the effectiveness of low dose of rFSH mono-therapy followed by hCG-rFSH in an adolescent patient is discussed.[Case report] At the age of 14 years, he was diagnosed as KS because of cryptorchidism and micropenis in infancy and delayed puberty and hyposmia in adolescence, and identified with KAL1 mutation. The responses of LHRH stimulation were low levels (peak LH 0.85 mIU/mL, peak FSH 2.05 mIU/mL). The levels of testosterone responded for HCG stimulation test were 0.29 ng/mL before stimulation and 0.81 ng/mL after stimulation.From the age of 15 years, low dose rFSH (75 IU) was administered daily for 10 weeks, then switched to hCG-rFSH. Every six months, replacement doses of hCG and rFSH were increased. His height gain was 10.8 cm after treatment. Testicular volume was 2 mL when treatment began and increased to 6 mL in two years.Then, testosterone reached adult level. [Conclusion] Low dose rFSH therapy prior to hCG-rFSH to treat adolescent patients with KS seems to gain pubertal development slowly but improve testosterone secretion sufficiently.

SAT-212 62-Year-Old Woman with Undiagnosed Kallman Syndrome: A Case of Missed Opportunities

Background: Kallman Syndrome (Isolated gonadotropin-releasing hormone (GnRH) deficiency with anosmia/hyposmia) affects both sexes but has male preponderance. The sex difference likely relates to genetics and possible early diagnosis in males because of microphallus and cryptorchidism. The presentation of Kallman syndrome in females may be very subtle and may lead to a delay in the diagnosis and management. Clinical Case A 62-year-old Caucasian female with a history of hypertension, hyperlipidemia, seizure disorder, COPD, multiple fractures and peripheral vascular disease was referred for evaluation of chronic hyponatremia that was diagnosed 6 years ago. The patient was euvolemic on the exam, and laboratory evaluation was consistent with SIADH. Labs showed Na 122-130 mmol/L, normal thyroid function and cortisol levels, serum Osm 259 mOsm/kg (Normal 280-300 mOsm/kg), urine Osm 565mOsm/kg (Normal 50-1200 mOsm/kg). Hyponatremia had been managed with fluid restriction and salt tablets. Other work-up was negative for malignancy. Unrelated to hyponatremia, the patient had striking virilization and hirsutism. On further history, she reported primary amenorrhea, infertility, lack of secondary sexual characteristics and anosmia. Physical exam was notable for absent secondary female sexual characteristics. Additional family history revealed a brother with anosmia and incomplete secondary sexual development and multiple females who never achieved puberty or fertility. Further workup included a normal pituitary MRI, and inappropriately low FSH of 1.0mIU/ml and LH of 0.3 m IU/ml (expected post-menopausal levels > 51 and 14, respectively). Other pituitary axis evaluation was normal. The patient also had a history of low trauma fractures of the hip and forearm. Bone density scan showed severe osteoporosis with a T-Score of -4.80 at the right femoral neck and -4.90 at the spine. Secondary osteoporosis work-up was negative. She was started on anabolic therapy with Teriparatide with plans to follow with antiresorptive therapy. Conclusion: This patient was diagnosed with hypogonadotropic hypogonadism due to Kallman Syndrome with severe osteoporosis. This case illustrates the value of physical exam and considering diagnoses and work up beyond the initial reason for consultation. A timely diagnosis in her case could have improved her quality of life, helped her achieve fertility and possibly may have prevented severe osteoporosis. The literature review also suggests a significant percentage of patients do not receive treatment for osteoporosis after hip fracture. (1) References 1-Solomon DH, Johnston SS, Boytsov NN, McMorrow D, Lane JM, Krohn KD. Osteoporosis Medication Use After Hip Fracture in U.S. Patients Between 2002 and 2011, J Bone Miner Res. 2014 Sep;29(9):1929-37.

SUN-219 Human Congenital Arhinia Is Associated with GnRH Deficiency and Primary Testicular Defects

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.