Central Hypogonadism Research Articles

Factors of mineral homeostasis impairment and bone mineral density loss in women with central hypogonadism

Objective The aims of the study were to estimate markers of mineral turnover and bone mineral density (BMD) in young women with central hypogonadism (CH) in comparison with healthy young and postmenopausal women, and to reveal the possible impact of different factors on BMD. Method We examined 73 patients with CH (mean age 25 [21.2; 30.5] years, mean duration of amenorrhea 5 [2.3; 10.1] years), 47 young healthy women (mean age 24 [23.1; 28.0] years) and 50 healthy women in natural postmenopause (mean age 56 [53; 58] years, mean duration of 6 [2; 10] years since last menstrual period). Women with CH were examined before and after 12 months of treatment with 17β-estradiol 2 mg and dydrogesterone 10 mg in continuous sequential fashion. Results Levels of calcium, alkaline phosphatase, and C-terminal telopeptide of type I collagen were statistically higher in women with CH without treatment than in young healthy women but did not differ from those in postmenopausal women. Prevalence of T-score ≤−2.5 standard deviations was higher in CH than in postmenopause both in lumbar vertebrae and total femur. Factors that were responsible for lower BMD in young women with CH included the duration of hypoestrogenism, primary amenorrhea, and hypoandrogenism. Conclusion Central hypogonadism at a young age poses a higher risk of bone metabolism impairment than physiological menopause.

OR15-03 High Prevalence of Gene Variants in Boys of Prepubertal Age with Clinical Suspicion of Central Hypogonadism and Low AMH

Introduction: In boys of prepubertal age, the diagnosis of central hypogonadism may be difficult to ascertain since gonadotropins and testosterone are normally low. Sertoli cell markers, like AMH and inhibin B, may be useful. In recent years, with the development of next generation sequencing (NGS) technology, the number of genes associated with central hypogonadism has had an exponential increase. However, even with these advanced techniques, the gene variants with potential pathogenicity can be found at present in only 30-50% of the patients. Hypothesis of the study: Low serum AMH is an appropriate screening biomarker to select patients for NGS, in order to make a genetic diagnosis in boys of prepubertal age with suspected central hypogonadism. Patients and methods: All patients aged 1-10 yr referred between 2001 and 2018 with clinical suspicion of central hypogonadism (micropenis and cryptorchidism and/or microorchidism), with low serum AMH (<10th centile) were included. Serum AMH was determined by ELISA (Beckman-Coulter), and LH, FSH and testosterone (T) by ECLIA (Roche). NGS was performed with the TruSight™ One Sequencing Panel in a NextSeq® 500 sequencer (Illumina). Results are expressed as medians (range). Results: 13 patients were included. Age at first visit was 4.4 (0.1-9.2) yr. Cryptorchidism was present in all of them, micropenis in 10 and microorchidism in 11. Orchiopexy was required in 11 boys and the other 2 responded to hCG treatment. 4 patients had olfactory disturbances, 1 had sensory deafness and 1 had piebaldism. 2 patients had a family history of olfactory disturbances and/or central hypogonadism. 7 patients could be followed up to pubertal age, and the diagnosis of central hypogonadism was clinically confirmed. At age 6.1 yr (1.2-10), AMH was 159 pmol/L (65-363), LH was <0.1 IU/L in all, FSH was 0.61 IU/L (<0.1-1.9). 17 variants in 9 genes associated with central hypogonadism were found in 10 of 13 patients. 5 boys had 1 gene variant, while 4 had 2 gene variants and 1 had 3 gene variants indicating probable oligogenicity, in the following genes: FGFR1 (n:4), CHD7 (n:3), PROKR2 (n:2), SOX10 (n:2), AXL (n:2), HS6ST1 (n:1), AMHR2 (n:1), NSMF (n:1), DCC (n:1). Conclusion: A high prevalence of gene variants was found in boys of prepubertal age with a suspicion of central hypogonadism based on micropenis and cryptorchidism and/or microorchidism with low serum AMH.

SAT-234 Association Between Hypogonadotrophic Hypogonadism and NARP Due to Mitochondrial Disease

Introduction: Hypogonadotropic hypogonadism is a common disorder encountered in endocrine practice with a prevalence of 1 in 10,000 men (1). We describe a patient with possible mitochondrial mutation causing him to have concurrent central hypogonadism and NARP syndrome (neuropathy, ataxia, retinitis pigmentosa). Case: 65 year old male with central hypogonadism diagnosed at age 17 was on testosterone replacement therapy off and on since then. He was diagnosed with NARP at age 49. On exam, he was OX3, BP 147/83mmHg, HR 63 bpm, wt 185lbs. Pupils were sluggish to light. Unable to assess visual fields as patient is legally blind. No gynecomastia. Cardiac and pulmonary exam were normal. Testicles were soft and the volume was 12mL. Prostate was enlarged, non tender and without nodules. He had ataxic gait, abnormal finger to nose test and strength was normal. LH <0.2 mIU/ml (N 1.2 - 10.6 mIU/ml), FSH < 0.2 mIU/ml (N 0.7 - 10.8mIU), total testosterone as low as 12ng/dL when off and 260ng/dL (N 250-1110ng/dL) while on testosterone IM. CBC, CMP, prolactin, ACTH, cortisol, Igf-I, TSH and PSA wnl. MRI brain showed cerebellar atrophy and normal pituitary. Discussion: NARP is a mitochondrial disorder characterized by neuropathy, ataxia and retinitis pigmentosa primarily affecting the nervous system. NARP results from point mutation at base pair 8993 of the mitochondrial genome in the ATPase 6 gene. Symptoms typically consist of proximal neurogenic muscle weakness, sensory neuropathy, ataxia, and retinitis pigmentosa. According to Al-Gadi et al, hypogonadism has been reported in mitochondrial disease (2). RRM2B is a nuclear-encoded mitochondrial maintenance gene. Mitochondrial DNA depletion due to ar-RRM2B mutations have been reported in association with hypogonadism. A mutation of m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotrophic hypogonadism has also been reported in a case report of two patients (3). Upon literature review, no prior cases of hypogonadotropic hypogonadism in patients with NARP have been reported. The impairment of the hypothalamic-pituitary axis appears to manifest in severe mitochondrial phenotypes. For example, the association of central hypogonadism with Kearns Sayre Syndrome (KSS). Given that both disorders are related to mitochondrial dysfunction, we propose that the hypogonadism may be linked to NARP syndrome. References Rohayem, J.et al. (2016), Causes of hypogonadotropic hypogonadism predict response to gonadotropin substitution in adults. Andrology Al-Gadi.et al. (2018). Endocrine Disorders in Primary Mitochondrial Disease. JES Kytövuori, L. et al. (2016, August 8). A novel mutation m.8561C>G in MT- ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.

OR32-02 Immune Checkpoint Inhibitor-Induced Hypophysitis Is Associated with Improved Overall Survival in Cancer Patients

Context: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies against checkpoints namely CTLA-4, PD-1 and PD-L1. These can cause pituitary dysfunction due to hypophysitis in addition to other endocrinopathies. While the prevalence and course of hypophysitis have been described extensively, the relationship between hypophysitis and cancer prognosis has only been investigated in melanoma patients on ipilimumab. Additionally, the impact of high dose glucocorticoids for hypophysitis treatment on survival has been unclear. Objective: In order to address these important questions, we aimed to characterize the frequency and course of hypophysitis from various ICIs, and to investigate a possible impact on overall survival in cancer patients.Design and Methods: We conducted a single center retrospective cohort study of adult cancer patients that received an ICI from 1/1/2012 - 12/31/2016, followed for a median of 14.8 months. A total of 896 patients were identified that received ipilimumab alone (n=120); ipilimumab and nivolumab (n=50); ipilimumab followed or preceded by pembrolizumab (n=70), pembrolizumab alone (n=406), and nivolumab alone (n=250). Results: Twenty-six patients (2.9%) developed hypophysitis after a median of 2.3 months (range 0.8 to 11.7). Their median age at initiation of ICI was 57.9 years (range 42.4 to 78.5), 54% were males, and the most common malignancy was melanoma (81%). All had hypopituitarism showing secondary adrenal insufficiency (100%), central hypothyroidism (38.5%) and central hypogonadism (28.5% in men, 25% in premenopausal women). Sixty-four percent demonstrated pituitary enlargement on imaging which resolved on follow-up. Mass effects occurred in 50% and were managed by initial high dose glucocorticoids. Thyroiditis occurred in 19.2% of those with hypophysitis. Occurrence of hypophysitis was associated with better overall survival (median 50.7 vs 16.5 months; p value 0.015) and reduced mortality (RR 0.52, 95% CI 0.28 to 0.99; p value 0.036) after adjusting for age, sex and malignancy type. Conclusions: Hypophysitis, usually but not always accompanied by classic MRI features, occurrs within a few weeks in cancer patients most frequently after ipilimumab alone or in combination with a PD-1 inhibitor, rarely after pembrolizumab and never after nivolumab alone. ICI-induced hypophysitis presents as mass effects in half and as hypopituitarism in all patients involving the corticotrophs more commonly than thyrotrophs and gonadotrophs. The improved survival with a 48% lower mortality rate in patients with hypophysitis suggests its possible role as a marker for better efficacy of ICIs against malignancy.

MON-381 Endocrinological Evaluation of Adult Thalassemia Patients

Background: Endocrine disorders are among the most common complications in thalassemia patients. Although cardiac complications are the main cause of mortality, endocrinological disturbances have a significant impact on morbidity and quality of life. Methods: Sixty-eight patients (35 F, 33 M; 60 thalassemia major, 8 thalassemia intermedia) admitted to our outpatient clinic between August 2015 - December 2017 were included in the study. Patients were evaluated for short stature, hypogonadism, glycemic abnormalities, hypoparathyroidism, hypothyroidism and osteoporosis. Results: The average height of thalassemia major patients was 165.67±8.8 cm in men and 155.6±6.6 cm in women. Nine patients had short stature (4 F, 5 E), but 91.5% (54/59) of the whole group had low IGF-1 levels. There were 23 thalassemia major patients (11 F, 12 M) who had a history of hormonal induction therapy for delayed puberty. Overall, 60% (n = 36) of the patients were currently receiving hormone replacement therapy for central hypogonadism (19 F, 17 M). The median age at diagnosis of central hypogonadism was 22.5 years in men (IQR: 16.5-27.5) and 18 years in women (IQR: 16-25). There were five diabetic thalassemia major patients in study group whose median age at diagnosis was 20 (16-36). Of the 47 patients who underwent OGTT, 13 thalassemia major patients had prediabetes (27.7%). None of the thalassemia intermedia patients had glycemic abnormalities. Subclinical hypothyroidism was present in 19.7% (13/66) of the whole group, hypoparathyroidism was found in 8.5% (9/59) of thalassemia major patients, and vitamin D deficiency (25OH D < 20 ng/ml) was found in 70.8% (46/65) of all patients. Of 64 patients who underwent BMD, 25 had osteoporosis (39.1%) while 23 hadosteopenia (35.9%). The incidence of pathological fractures in thalassemia major patients was 20% (11/55). Conclusions: The incidence of endocrine disorders may increase in thalassemia patients due to prolonged duration of lifespan. Regular screening for newly emerging endocrinopathies during adulthood has great value. In our study, the most common endocrine disorders were vitamin D deficiency, hypogonadism, osteoporosis and glycemic abnormalities; respectively. Early diagnosis and treatment would prevent patients from having related morbidities and therefore increase quality of life.

SUN-271 Langerhans Cell Histiocytosis: A Difficult Diagnosis in Cranial Diabetes Insipidus

BackgroundLangerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder that is rare in adults, with a reported incidence of 1-2 cases per million per year. Cranial diabetes insipidus (CDI) is the most common and often the first endocrine manifestation of LCH, when histiocytes infiltrate the pituitary. Anterior pituitary dysfunction, when present, usually develops after onset of CDI. Unlike most other etiologies of CDI, multisystem involvement is frequent in LCH, especially the bones, skin, and lungs.CaseA 23-year-old man of good past health presented with 3 months of polyuria and polydipsia in 2015. CDI was confirmed by water deprivation test, and his symptoms resolved with DDAVP treatment. There were no anterior pituitary hormone deficiencies on presentation. Pituitary MRI showed loss of the posterior bright spot and a contrast enhancing pituitary stalk thickening (PST) of 5 mm, with no compression on the optic chiasm. Lumbar puncture showed no evidence of CNS infection or neoplastic cells. Beta HCG, AFP, IgG4, ANA, and chest Xray were unremarkable. Three months later he developed central hypogonadism, and was treated with testosterone after sperm banking. A repeat MRI showed persistent PST of 5 mm, and biopsy of the pituitary suggested lymphocytic infundibulo-hypophysitis (LIH). Unfortunately the biopsy was complicated with irreversible focal visual field defect.It was then noted that a bone scan had been arranged earlier for intermittent left hip pain, which revealed a 3.5 cm osteolytic lesion over the left ilium. The concomitant pituitary and bone lesions thus make LCH the more likely diagnosis. However bone biopsy showed nonspecific fibrosis only. The pathologist was then contacted for further immunohistochemical analysis. This identifies clusters of Langerhans cells with positive stain for S100, CD1a, and Langerin (LCH cell markers) in the pituitary tissue, and BRAF V600E mutation was detected by PCR, compatible with the diagnosis of LCH. Systemic chemotherapy was proposed due to multisystemic disease, but was declined by patient. At 4 years of follow-up, the PST spontaneously regressed to 2 mm but the CDI and central hypogonadism persisted.ConclusionOur case illustrates the diagnostic challenge in a patient presenting with CDI, given a pituitary biopsy with histological features mimicking LIH and an inconclusive bone biopsy. However, a diagnosis of LIH would not explain for the unusual bone lesion in a young man, and bone biopsies can be prone to crush artifacts limiting analysis. The importance of actively looking for and biopsying extracranial lesions before biopsying the pituitary cannot be understated as the latter entails risks of hypopituitarism and visual defect, as had happened to our patient. When clinical and pathologic findings do not match, communication with the pathologist for histological review had been essential in establishing the diagnosis of LCH.

SUN-295 Prevalence of Self-Reported Endocrine Comorbidities in Hypothalamic Hamartoma Patients: Data from the Hope for Hypothalamic Hamartoma Survey

Background: Hypothalamic hamartoma (HH) are rare, congenital, benign mass lesions in the ventral hypothalamus that can be asymptomatic or associated with gelastic seizures and treatment-resistant epilepsy. Central precocious puberty (CPP) is the main endocrine comorbidity (30-80% of cases). Other endocrine comorbidities have also been described that tends to occur after surgery. However, previous studies reporting its prevalence have shown inconsistent results because of the rarity of the disease, variability of follow-up, and lack of long-term endocrinologic assessment. Aims: To evaluate the self-reported prevalence of demographics and endocrine comorbidities in a large cohort of HH patients. Methods: Hope for HH is a volunteer-based nonprofit organization founded by parents of children with HH. This international survey was initiated, translated into multiple languages and distributed by mail and electronically to families of children with HH in the Hope for HH database after concerns were raised that there have been multiple ongoing comorbidities (including endocrine) that continues to be under-recognized. Results: In total, 257 HH patients (132M/125F, mainly between ages 4-35 years and from the US, Russia, UK, Australia, Canada, Germany and Kazakhstan) participated in the survey. Some patients had a secondary diagnosis of Pallister-Hall (7.0%), Lennox-Gastaut (1.95%), Prader-Willi (0.8%) and West (0.8%) syndromes. The majority of patients (n=163, 63.4%) underwent surgery (MRI-guided stereotactic laser ablation [n=61, 37.4%], endoscopic resection [n=31, 19.0%], transcallosal resection [n=30, 18.4%], stereotactic radiofrequency ablation [n=27, 16.6%], orbitozygomatic resection [n=9, 5.5%]) or gamma knife radiosurgery (n=28, 17.2%). After surgery and/or radiation, ~50% of patients were seizure-free but reported unchanged, poor or very poor quality of life (QoL), with fatigue (56.4%), heat intolerance (46.3%) and adipsia (21.8%) being the more common symptoms. Reported endocrine comorbidities include CPP (42%), hypothalamic obesity (35.0%), abnormal body composition (31.5%), central hypothyroidism (19.8%), osteopenia/osteoporosis with low BMD (12.8%), diabetes insipidus (11.3%), GH deficiency (10.5%), central adrenal insufficiency (10.5%), central hypogonadism (5.1%), and delayed puberty (4.7%), and 26.5% of patients were not seeing an endocrinologist. Conclusion: In contrast to previous studies reporting low prevalence, mild and transient endocrine comorbidities in HH patients (2,3), this survey suggests a greater prevalence of other non-CPP endocrine comorbidities with a substantial number of patients reporting unchanged or impaired QoL. Thus, long-term endocrinologic follow-up with the involvement of a multidiscliplinary team is essential to diagnose early and treat these comorbidities in these patients.

MON-235 Mycobacterium Fortuitum Infection Mimicking Sellar Chondrosarcoma in a Non-Immunosuppressed Patient: An Unusual Cause of Hypopituitarism and Oculomotor Nerve Palsy

A 32-year old male patient of central African origin presented with diplopia and left eyelid ptosis. He described a 2-month history of fatigue, weight loss (8 Kg), headaches, diffuse myalgia and night sweats. Clinical examination revealed cavernous sinus syndrome with left eyelid ptosis and weakness of eye adduction. Magnetic resonance imaging of the brain demonstrated a 36 mm mass centered on the left petroclival suture, infiltrating the sella and the pituitary gland, the ipsilateral orbital apex as well as the cavernous sinus bilaterally. The mass showed heterogenous enhancement after gadolinium injection, with elements of central necrosis and was associated with an extensive bone destruction. These radiologic features raised the hypothesis of chondrosarcoma. Chest computed tomography demonstrated multiple lung micro-nodules suspect of metastasis. Laboratory testing of the anterior pituitary function revealed low free-T4 (11 pmol/l, n = 12-22) with normal TSH (0.4 mUI/l, n=0.3-4.2), low total testosterone (1.5 ugr/l, n = 3.3-8.1) with normal LH and FSH and slight hyperprolactinemia (27 ugr/l, n = 4-15). IGF-1, 24-h urinary free cortisol, as well as morning serum cortisol and cortisol after 250 mcg ACTH stimulation test were normal. There was no evidence of diabetes insipidus. Levothyroxine was prescribed. Craniotomy was performed, for left optic nerve decompression and biopsy of the mass. Pathologic examination revealed granulomatous, giganto-cellular and necrotizing inflammation, but no evidence of malignancy. PCR for Mycobacterium tuberculosis complex was negative but Mycobacterium fortuitum was detected in sputum and also confirmed in cerebral biopsy latter. Other causes of granuloma were excluded (brucellosis, cat scratch disease, histoplasmosis, syphilis, coccidioidomycosis, tropical germs etc.). Different causes of immunosuppression (including HIV) were excluded. The patient was treated with amikacin, isoniazid and ciprofloxacin for several months and improved gradually. MRI performed one year later demonstrated significant decrease on the size of the sellar mass (more than 50% of its initial size). Central hypogonadism regressed spontaneously with decrease in tumor size, and normal testosterone levels were achieved at one-year follow-up (7 ugr/l, n = 3.3-8.1). Mycobacterium fortuitum infections of the sella turcica are poorly described in literature in non-immunosuppressed individuals. Although usually not pathogenic, histopathological examination, identification in the CNS lesion and the lungs and response to treatment are convincing evidence of a causal relationship. Differential diagnosis from malignant lesions is challenging and biopsy is necessary in order to establish the cause and offer adequate treatment.

Etiopathogenetic aspects of central (hypogonadotropic) hypogonadism in female

Central hypogonadism (CH) is a rare endocrine disorder caused by the disfunction of production, secretion and/or biological action of gonadotropin-releasing hormone (GnRH), which is the main hormonal regulator of hypothalamo-pituitarygonadal axis in human. Female CH is important medical and social concern due to large amount of infertile couples. Etiological structure of this condition is heterogeneous and diff ers between congenital and acquired forms. Congenital forms have a genetic predisposition: currently about 50 genes associated with CH have been found. However, genetic basis can be identifi ed just in half of CH cases. Speaking about acquired forms of CH, important to pay attention on hypothalamo-pituitary area condition. In case of intact state the functional form of CH can be diagnosed, the presence of structural disorders in this area speaks in favor of the organic cause of CH. In this review are summarized current knowledge in the fi eld of etiology and pathogenesis of female central hypogonadism.

45,X/46,X,i(Yp): Importance of Assessment and Support during Puberty and Adolescence

The Y-chromosome genes are primarily involved in sex determination, stature control, spermatogenesis, and fertility. Among structural rearrangements of the Y chromosome, the isochromosome of Yp, i(Yp), appears to be the most uncommon. We describe a detailed evolution of puberty in a boy with 45,X/46,X,i(Yp). Array CGH found 2 cell lines, one with i(Yp) and the other with monosomy X. Genetic analysis of currently known genes involved in Kallmann syndrome/normosomic central hypogonadotropic hypogonadism showed no abnormality. The patient presented with a pubertal course suggestive of a delayed puberty with gynecomastia, reduced growth rate, and infertility that need testosterone treatment to induce the appearance of the secondary sex characteristics. This patient shows the potential effects of i(Yp) and emphasizes the importance of appropriate management of puberty in people with 45,X/46,X,i(Yp). Early hormone treatment, concerns regarding fertility, emotional support, and a successful transition to adult care may help improve the physical and psychosocial well-being of affected patients.

Efficacy and safety of fractionated conformal radiation therapy in acromegaly: a long-term follow-up study.

Conformal, fractionated radiation therapy (XRT) is variably used as a treatment alternative for active acromegaly patients, usually, after failed pituitary surgery. Our objective was to evaluate the long-term efficacy and safety of XRT using strict criteria of biochemical control. Retrospective cohort study of 94 patients (73 women, mean age at radiation 53.16 ± 12.9 years) attending a specialized multidisciplinary clinic between 1998 and 2014 with a mean duration of follow-up of 12.9 ± 7.3 years. A basal growth hormone < 1 ng/mL and an IGF-1 < 1.2 × the upper limit of normal was achieved by 41% and 50.8%, respectively, at 5 years of follow-up, and by 44% and 66%, respectively, 10 years after XRT. Median tumor volume decreased significantly from 904 mm3 at baseline to 424 mm3 upon last follow-up (p = 0.01). The prevalence of central hypogonadism, central hypocortisolism, and central hypothyroidism increased from 18%, 35%, and 35% at baseline, to 38%, 53%, and 64%, respectively, after 10 years of follow-up. One patient was diagnosed with a meningioma and another one developed optic neuritis. No cerebrovascular events were recorded, and all patients are currently alive. XRT is an effective and reasonably safe means of controlling acromegalic activity. Its main disadvantages are the time required to achieve biochemical control and the development of anterior pituitary hormone deficiencies.

Prader- Willi syndrome: An uptodate on endocrine and metabolic complications.

Prader-Willi syndrome (PWS) is a genetic disorder characterized by short stature, low lean body mass, muscular hypotonia, mental retardation, behavioral abnormalities, dysmorphic features, and excessive appetite with progressive obesity. It is caused by lack of expression of genes on the paternally inherited chromosome 15q11.2-q13. This genetic disorder has an estimated prevalence that ranges between 1/10,000-1/30,000. Hypothalamic dysfunction is a common finding in PWS and it has been implicated in several manifestations of this syndrome such as hyperphagia, temperature instability, high pain threshold, sleep disordered breathing, and multiple endocrine abnormalities. These include growth hormone deficiency, central adrenal insufficiency, hypogonadism, hypothyroidism, and obesity often complicated by type 2 diabetes. The aim of this manuscript is to overview the current literature on metabolic and endocrine complications of PWS, focusing on human studies and providing insights on the physio pathological mechanisms. A careful management of metabolic and endocrine complications can contribute to improve quality of life, prevent complications, and prolong life expectancy of PW patients.

Familial GATA6 mutation causing variably expressed diabetes mellitus and cardiac and renal abnormalities.

SummaryA 26-year-old man presented with a combination of permanent neonatal diabetes due to pancreatic aplasia, complex congenital heart disease, central hypogonadism and growth hormone deficiency, structural renal abnormalities with proteinuria, umbilical hernia, neurocognitive impairment and dysmorphic features. His older brother had diabetes mellitus due to pancreatic hypoplasia, complex congenital heart disease, hypospadias and umbilical hernia. Their father had an atrial septal defect, umbilical hernia and diabetes mellitus diagnosed incidentally in adulthood on employment screening. The proband’s paternal grandmother had a congenital heart defect. Genetic testing of the proband revealed a novel heterozygous missense variant (Chr18:g.19761441T>C, c.1330T>C, p.Cys444Arg) in exon 4 of GATA6, which is class 5 (pathogenic) using American College of Medical Genetics and Genomics guidelines and is likely to account for his multisystem disorder. The same variant was detected in his brother and father, but not his paternal grandmother. This novel variant of GATA6 likely occurred de novo in the father with autosomal dominant inheritance in the proband and his brother. The case is exceptional as very few families with monogenic diabetes due to GATA6 mutations have been reported to date and we describe a new link between GATA6 and renal pathology.Learning points:Monogenic diabetes should be suspected in patients presenting with syndromic features, multisystem congenital disease, neonatal-onset diabetes and/or a suggestive family history.Recognition and identification of genetic diabetes may improve patient understanding and empowerment and allow for better tailored management.Identification of a genetic disorder may have important implications for family planning.

OR32-1 Endocrine Manifestations of Erdheim-Chester Disease: The Mayo Clinic Experience

Objective: Erdheim- Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis characterized by multisystem tissue infiltration of foamy histiocytes. Very few studies have investigated the prevalence of endocrine abnormalities in patients with ECD. Based on limited data, it is known that endocrine manifestations are not uncommon. The objective of this study was to characterize the extent of endocrine gland involvement and hormonal function abnormalities in the largest reported endocrine cohort of patients with ECD. Design: Retrospective chart review study of patients with ECD evaluated at the Mayo Clinic from January 1990 to June 2018. A tissue biopsy confirming the diagnosis of ECD was necessary for inclusion in this study. In all cases, the diagnosis of ECD was confirmed using clinical criteria in conjunction with histopathologic findings. Clinical, laboratory, and imaging data were collected. Results: Eighty-three patients with confirmed ECD were included in our study (71.1% women, 83.1% Caucasian, median age at time of diagnosis 55.2[46.3-66.1]). Symptom onset preceded the diagnosis by a median time of 2.7[1.0-6.9] years. Forty-eight patients (57.8%) had at least one hormonal deficiency. Central diabetes insipidus (25.3%) was the most common endocrine manifestation at initial presentation. Fifty percent of patients with central diabetes insipidus had at least one co-existent anterior pituitary deficiency at presentation, most commonly hypogonadism (40%). Among patients that had further endocrine evaluation, 16/64 (25.0%) had primary hypothyroidism and 7/64 (10.9%) had central hypothyroidism. 7/34 (20.3%) had central secondary adrenal insufficiency and 2/34 (5.8%) had primary adrenal insufficiency. Central hypogonadism was found in 18/31 (58.1%) of patients, whereas 6/31 (19.4%) had primary hypogonadism. Growth hormone deficiency was found in 7/59 (29.7%) patients and 4/27 (14.8%) patients had hyperprolactinemia. Imaging revealed involvement of the pituitary/hypothalamus in 18 (21.7%) patients, adrenal glands in 18 (21.7%) patients and testicles in 5 (6.0%) patients. Thirty-five patients (42.2%) had at least one gland involved seen on imaging, Visible gland infiltration did not correlate with hormonal deficiencies. New hormonal deficits appeared during follow-up. Conclusions: This is the largest case series of endocrine manifestations in patients with ECD. Endocrine involvement is frequent in these patients, 57.8% have at least one hormonal deficiency. Because endocrine abnormalities can evolve throughout the course of the disease, patients should have endocrine evaluation periodically.

SAT-470 A Case of Acromegaly with Concomitant Hypercortisolism Presenting with Diabetic Ketoacidosis

Background: Acromegaly is a rare disorder with an annual incidence of 4-6 new cases per 1 million population.1 Impairment in glucose metabolism has been previously described in such disorder, but diabetic ketoacidosis is rare. Case: A 25 year old, male, presented at our emergency room with seizures. Laboratory data showed hyperglycemia (blood glucose 418 mg/dl), ketonuria (urine ketone +2), and pure high anion gap metabolic acidosis consistent with severe Diabetic Ketoacidosis. Hba1c was 12%. A normal fasting C-peptide 1.68 ng/ml (1.10-4.40 ng/ml) indicate residual insulin secretion, or maybe an inappropriately normal response in the presence of severe hyperglycaemia hyperglycemia. Features of acromegaly were noted and hormonal evaluation showed elevated IGF-1 level at 484.50 ng/ml (83-344 ng/ml), supporting the diagnosis. Random growth hormone was elevated at 5.7 ng/ml (<3 ng/ml). GH suppression testing with oral glucose load was not done due to unstable glucose levels. An elevated 24 hour urine cortisol 6208.0 nmol (100.0-379.0 nmol/24h) may be associated with uncontrolled diabetes, or an underlying subclinical Cushing’s disease contributing to further insulin resistance. Other hormones of the anterior pituitary reveal normal thyroid function, central hypogonadism and hyperprolactinemia at 828.50 uIU/ml (58.0-475.0 uIU/ml) likely due to hypophyseal stalk compression by the tumor. Cranial MRI with contrast showed an enhancing sellar mass measuring 23.7 x 22.3 x 18.0 mm (AP x T x CC) which extends inferiorly to the upper portion of the prepontine cistern. Resolution of ketoacidosis required 360 units of regular insulin per day, without achieving target blood glucose levels. Blood glucose level was successfully controlled with insulin and oral hypoglycemic agents. There was incomplete resection of the mass following transphenoidal surgery. Conclusion: This case highlights the concomitant presence of increased counter regulatory hormones (GH and cortisol) and IGF-l levels in Acromegaly leading to increased insulin resistance, which are uncommon, but important causes of Diabetic Ketoacidosis. Reference: Melmed, S. (2016). Williams textbook of endocrinology. Elsevier Health Sciences.

MON-453 Endocrine, Bone, and Metabolic Disorders in Adults after Allogeneic Stem-Cell Transplant

Introduction Allogeneic hematopoietic stem cell transplantations (allo-HSCT) is often indicated in malignant hematologic diseases. Conditioning regimens, used to reduce the tumor burden and to prevent transplant rejection, are based on chemotherapy alone or combined with total body irradiation (TBI). Endocrine complications are frequent transplant-related side effects. They have been well described in children studies but less in adulthood. Objective To assess retrospectively endocrine, bone and metabolic disorders in adult patients, 12 months after allo-HSCT. Patients & Methods Inclusion criteria were : patients treated with allo-HSCT from 2006 to 2016 for a malignant hematologic disease; adult and in complete remission at exploration. Exclusion criteria were : anteriority of brain radiotherapy and prior HSCT. Twelve months after HSCT, each patient underwent fasting measurement of IGF1, TSH, fT4, FSH, LH, sex steroids, glycemia, insulin level, and lipid profile. Unless contraindication, adrenal and growth hormone functions were assessed with insulin hypoglycemia test. A dual X-ray absorptiometry was also performed. Results During the inclusion period, 249 patients received allo-HSCT at our institution. Among them, 148 stayed in complete remission 12 months after HSCT and 63 have been explored in our department. The study sample consisted of the 45 patients meeting the inclusion/exclusion criteria. 40 patients had insulin hypoglycemia test. Hypopituitarism was observed in 20 patients (44%) (14 GH deficiency, 8 central adrenal deficiency, 2 central hypothyroidism and 1 central hypogonadism). No predictive factor was found. One patient had central adrenal deficiency after 12 Gy TBI regimen without any corticotherapy. Hypothyroidism was observed in 6 patients (13,6 %), evenly distributed in subclinical, overt and central hypothyroidism. The risk of developing hypothyroidism was higher in patients aged less than 30 y/o at transplantation (OR = 8,5). All premenopausal women (n = 16) had premature ovarian failure. Half of the 18 men were suspected to have spermatogenesis disorder (elevated FSH). Five men had elevated LH with normal testosterone, and one had central hypogonadism possibly attributed to his obesity. Bone mineral density (BMD) was decreased in 33 patients (77 %). Twelve (28 %) had osteoporosis. Conditioning regimen with busulfan was protective of BMD decrease (OR = 0,66 [0,5-0,85], P = 0,02). Obesity was more frequent (20 %) than our national prevalence (14 %). There were no increase in insulino-resistance and diabetes prevalences. Twenty patients (45 %) had dyslipidemia, 14 of them hypertriglyceridemia. Conclusion Our study shows a high frequency of endocrine, bone and metabolic disorders 12 months after allo-HSCT during adulthood. Hypopituitarism is more frequent that previously described, using the gold standard of the GH and adrenal function exploration.

SAT-LB082 Neurosarcoidosis Presenting as Panhypopituitarism, Diabetes Insipidus and Sellar Mass

Introduction: Granulomatous hypophysitis is a rare entity with an annual incidence of 1 in 10 million. It may be primary or secondary to tuberculosis, sarcoidosis, Wegener’s disease, syphilis or mycotic infections. It accounts for <1 % of cases of panhypopituitarism or visual field defects. Isolated Neurosarcoidosis without systemic involvement is extremely rare. It can rarely present as an isolated granuloma of the sella mimicking pituitary adenoma. Case: A 47-year-old-male was admitted with generalized weakness of 1 month and headache with loss of peripheral vision of 1 week duration. MRI brain revealed a sellar mass with suprasellar extension involving the pituitary stalk and hypothalamus representing pituitary macroadenoma. Biochemical tests were evident for central hypoadrenalism, secondary hypothyroidism and hypogonadism with mild hyperprolactinemia. He had low urine specific gravity on admission and provided history of increased thirst, polyuria and nocturia from past 3 weeks. CSF analysis showed elevated CSF protein and ACE levels. Visual field testing revealed bitemporal hemianopsia. Patient underwent transsphenoidal biopsy and partial resection of pituitary mass with significant improvement in visual field defects post operatively. Pituitary biopsy showed non-necrotizing granulomatous hypophysitis. CT chest revealed hilar and mediastinal lymphadenopathy suspicious of sarcoidosis. He had positive Quantiferon and PPD testing but hilar lymph node biopsy was negative for granuloma or malignancy. CSF analysis, pituitary and lymph node biopsy were negative for bacterial, AFB and fungal culture/stain. Tests for HIV, hepatitis, syphilis, lymphoma panel and sputum AFB culture x3 were negative. He was discharged on levothyroxine, hydrocortisone, testosterone and desmopressin. He completed treatment for latent TB and was monitored as outpatient. After 8 months, his visual field defects had completely recovered. Patient was asymptomatic with unchanged hilar and mediastinal lymphadenopathy. Repeat MRI brain showed avidly enhancing thickened pituitary stalk with complete resolution of pituitary mass lesion. He was diagnosed with probable Neurosarcoidosis and referred to rheumatology. Discussion: Hypothalamic-pituitary sarcoidosis occurs in less than 10% of patients with Neurosarcoidosis. Polyuria, polydipsia and signs and symptoms of hyperprolactinemia are the most common presenting manifestations. Earlier, the endocrine dysfunction was attributed to a destructive process affecting pituitary, but pituitary responsiveness to synthetic hypothalamic releasing factors indicates that hypothalamic insufficiency is the major cause for panhypopituitarism. Diabetes Insipidus can be masked by secondary adrenal deficiency on presentation. Clinicians should be cautious of unmasking diabetes insipidus while replacing glucocorticoids in such cases. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

SUN-437 Central Adrenal Insufficiency Unmasked by Pregnancy

Recognition and prompt treatment of adrenal insufficiency (AI) during pregnancy are important to prevent maternal adrenal crisis and/or fetal intrauterine growth retardation, death, and low birth weight. The diagnosis may be difficult to establish in pregnancy because of estrogen-induced increases in cortisol-binding globulin (CBG) production, which lead to increased serum cortisol (sF) levels. Placental-derived ACTH levels also increase, confounding the diagnosis of secondary AI [1]. We report a case of a 36-year-old woman who was followed at the NIH for 10 years for partial hypopituitarism secondary to presumed lymphocytic hypophysitis. She initially presented with central diabetes insipidus followed by central hypogonadotropic hypogonadism, growth hormone deficiency and central hypothyroidism; she received physiologic doses of replacement hormones. Prolactin, albumin, CBG, ACTH (9.1-18 pg/ml; nl: 0-46), and the response to annual 250 mcg Cosyntropin stimulation tests were normal, with stimulated sF levels of 18-24 mcg/dl (nl: >18 mcg/dl). In 2017, in anticipation of a planned pregnancy, a Cosyntropin stimulation test was performed off estrogen supplementation; baseline ACTH (26 pg/ml) and CBG were normal, and sF was 9.3, 18.2 and 20 mcg/dl at baseline, 30, and 60 min of the test, respectively. Pregnancy was successfully induced with gonadotropins, progesterone and timed intercourse. Patient had nausea beginning in the first trimester. This worsened at week 36, when she also complained of increased fatigue and vomiting. At that time, morning sF was 12-14 mcg/dl, with corresponding ACTH of 25-33 pg/ml. These values were subnormal for the third trimester of pregnancy, confirming secondary AI [1]. Hydrocortisone replacement was started at a dose of 12mg x 1.6 body surface area (BSA), with improvement in symptoms. At 40 weeks she received stress doses of hydrocortisone during an elective C-section, and delivered a 7-lbs healthy boy without complications. At 40 days postpartum a Cosyntropin stimulation test showed continued evidence of central AI: sF by immunoassay was 6.5 mcg/dl, 13.6 and 16.7 at baseline, 30 and 60 min after Cosyntropin; at the same times, aldosterone was 16.3, 31, and 23 ng/dl (nl:>6). Baseline ACTH was 11.9 pg/ml, DHEAs was 30 (n:45-295 mcg/dl) and CBG was 2.9 mg/dl (nl: 1.7-3.1). She continues to receive physiological hydrocortisone replacement, currently at 10 mg x BSA, without symptoms of AI. This case illustrates that pregnancy may unmask central adrenal insufficiency, in this case, presumably because the adrenal glands could not produce sufficient cortisol to saturate the increased levels of CBG. The persistent post-partum abnormality in our patient suggests also that pituitary function may continue to decline over time, and that women with partial hypopituitarism should be monitored closely during pregnancy for further deficits.

MON-129 An Unusual LMNA Mutation Causing a Complex Phenotype: When the Genetic Diagnosis Uncovers Novel Features

Background: Lipodystrophy syndromes are characterized by loss of body fat. Although classical Familial Partial Lipodystrophy (FPLD) and Congenital Generalized Lipodystrophy (CGL) have different clinical presentations, we have encountered a unique case where the distinction was quite challenging. Clinical Case: Our patient first presented to an endocrinologist at age 19 with secondary amenorrhea and hypothyroidism. After normalization of TSH, further investigation revealed central hypogonadism, hypertriglyceridemia (>3,000 mg/dL, normal<150mg/dL), xanthomas and fatty liver disease. By that time, she had adiposity changes such as lack of subcutaneous fat in the limbs and abdomen and prominent muscles. She believed she had those traits since early childhood. After puberty, she developed generalized muscle pain and was noted to have elevated CK. At 59 years old, she developed diabetes as well as liver fibrosis. These led to the diagnosis of lipodystrophy (initially classified as FPLD due to inheritance pattern). However, physical examination revealed acromegaloid features, BMI of 23.2 kg/m2, minimal fat palpable around the neck and minimal fullness of the supraclavicular fossa. The rest of the body was virtually devoid of subcutaneous fat tissue, consistent more with the CGL phenotype and inspection of older photos demonstrated progressive fat loss. She displayed prominent and hypertrophic muscles, phlebomegaly on limbs and trunk, umbilical hernia and acanthosis nigricans around the neck and armpits. Enlarged spleen and liver were also noted. There was labial hypertrophy with no cliteromegaly. Dual-Energy X-ray Absorptiometry (DEXA) showed total fat percentage of 22% and a "fat shadow” was obtained highlighting the generalized pattern of fat loss. Genetic analysis revealed a pathogenic variant (p. Arg541Pro) at exon 8 of the LMNA gene. Upon identification of the variant, her previously obtained muscle biopsy was reevaluated as muscular dystrophy. Cardiovascular investigations demonstrated first-degree atrioventricular block and non-sustained ventricular tachycardia on the ECG and fibrosis on cardiac MRI. Given her family history of sudden death, a dual-chamber implantable cardioverter-defibrillator was placed. When her HbA1c rose to 7.2% on Metformin monotherapy and her triglycerides exceeded 250 mg/dL on fibrates, we presented her case to her insurance company. She was approved for Metreleptin therapy even though she does not meet the consensus definition of generalized lipodystrophy. Conclusion: We present a unique case with lipodystrophy who had progressive fat loss from partial to generalized. Making the correct classification is important in the US where treatment with Metreleptin is approved only for generalized lipodystrophy. We also highlight a complex genotype-phenotype association of laminopathy that challenges the distinction between FPLD and CGL.

SAT-446 No Central Adrenal Insufficiency Found in Adults with Prader-Willi Syndrome Tested by Multiple-Dose Metyrapone Test

Introduction Individuals with Prader-Willi syndrome (PWS) have hypothalamic dysfunction, with deficiencies of several hypothalamic-pituitary axes. Prevalence of central hypogonadism, hypothyroidism and growth hormone deficiency are increased in comparison with non-PWS individuals. Central adrenal insufficiency (CAI) has also been reported in PWS. Several studies, using different testing modalities, have reported strikingly differing prevalences of CAI in PWS, ranging from 0% to 60%. It is speculated that CAI may be responsible, in part, for high mortality (3%) in patients with PWS. If CAI is present, timely diagnosis and treatment is needed in order to prevent avoidable mortality. Due to the lack of consensus, there are no guidelines or recommendations on the appropriate evaluation and management of CAI in the adult PWS population. Many adults patients with PWS receive standard hydrocortisone (HC) stress dose during physical and/or psychological stress. Frequent administration of HC increases the risk of obesity, hypertension, osteoporosis and diabetes, already a major problem in adults with PWS. It is therefore of utmost importance to assess the prevalence of CAI in order to prevent overtreatment with HC. Methods We screened medical histories of all patients for symptoms of CAI. We performed multiple dose metyrapone (MTP) test in 45 adults with genetically confirmed PWS. At day one, oral MTP 750 mg (Laboratoire HRA Pharma, Paris, France) was administered orally six times (every 4 hours, starting from 8h00). At 0800 h on day two, blood was drawn for determining 11-deoxycortisol (11-DOC) levels. At both days, blood was drawn after 8 hours fasting. Levels of 11-DOC greater than 7.6 g/dL (230 nmol/L) were classified as adrenal sufficiency. Results Mean age of participants was 30.9. Seventeen were using GH treatment since childhood. Male/female ratio was 28/17. Revision of medical histories revealed that a substantial part of patients had undergone operations or had infections without receiving HC stress dose, without any negative consequences. All 45 patients had 11-DOC greater than 7.6 g/dL during MTP test and therefore CAI was excluded in all patients. MTP test was tolerated well by all individuals. Conclusion Central adrenal insufficiency was absent in 45 adults with Prader-Willi syndrome assessed by a multiple dose metyrapone test. This indicates that CAI is rare, or even absent, in adults with PWS. Based on these results, we recommend to perform MTP test instead of routinely prescribing HC stress dose in adults with PWS.