bluuebunny/crossref_metadata_2025 huggingface dataset:
7196 Variants in the Neurodevelopmental Gene BRINP2 are Associated with Severe Delayed Puberty
Authors: Al-Sayed Yasmin , Oleari Roberto , Cariboni Anna , He Wen , Chan Yee-ming , Howard Sasha R
Published: October 2024

Disclosure: Y. Al-Sayed: None. R. Oleari: None. A. Cariboni: None. W. He: None. Y. Chan: None. S.R. Howard: None.

Gonadotropin-releasing hormone (GnRH) is the master hormone regulating the reproductive axis and its pulsatile secretion is crucial for puberty onset and fertility. Disruption in GnRH neuron development or hypothalamic function can lead to absent or delayed puberty (DP) due to GnRH deficiency, with a phenotypic spectrum from severe delayed puberty to partial or complete Hypogonadotropic Hypogonadism (HH). HH can also be present as a shared trait with other neurodevelopmental disorders (NDDs). The aim of our study was to identify novel genetic etiology of severe DP by identifying variants in associated genes in our patient cohort; and ascertain the functional effects of identified variants of interest. Whole exome sequencing (WES) was performed on DNA samples from 180 probands with DP to identify potentially pathogenic rare coding variants in relevant gene pathways. Integrative analysis was performed on genomic data from human patients combined with transcriptomics analysis of rodent immortalized and primary GnRH neurons to determine novel regulators of GnRH neuronal development and function. Bone morphogenetic protein/retinoic acid inducible neural-specific 2 (BRINP2) was identified as a candidate gene of interest as it was found to be significantly upregulated during GnRH neuronal development in these single cell transcriptomics analyses. Mutations in this gene have been previously associated with NDDs such as autistic spectrum disorder (ASD). BRINP2 is localised to the olfactory bulb, a key site during GnRH neuron migration. Copy number variation in this gene is seen in multiple individuals from the Deciphering Developmental Disorders study with a phenotype including cryptorchidism and intellectual disability (https://www.deciphergenomics.org/gene/BRINP2/patient-overlap/cnvs). WES analysis identified four variants in BRINP2 (p.R726W, p.R649Q, p.I629V and p.D729N) in four unrelated probands with severely DP or partial HH, in combination with ASD or other NDD features. These four variants are all rare or ultra-rare and are predicted to be pathogenic by in silico tools including CADD, REVEL and SIFT. Protein expression of the four mutants was comparable to the reference protein. BRINP2 has been shown to inhibit neuronal cell proliferation by negative regulation of cell cycle transition and Brinp2 knockout mice show hyperactive behaviour representative of human attention-deficit hyperactivity disorder, but pubertal timing has not been assessed. Thus, BRINP2 is a novel candidate for GnRH deficiency with NDD and we have investigated the role of BRINP2 in GnRH biology via wildtype and mutant protein sub-cellular localization, as well as tissue expression in mouse hypothalamic tissue across development.

Presentation: 6/2/2024
6606 Connshing Syndrome: An Uncommon Presentation Of Bilateral Adrenal Mass
Authors: Suarez C S Botero , Meda N , Lamar K , Suryanarayanan S K
Published: October 2024

Disclosure: C.S. Botero Suarez: None. N. Meda: None. K. Lamar: None. S.K. Suryanarayanan: None.

Introduction: Mild autonomous hypersecretion of cortisol in the underlying setting of hyperaldosteronism has been described before and coined the term Connshing Syndrome. Even though it was described in 1979, recently W. Arlt et al in 2017 revived interest in the topic of Connshing Syndrome represents a distinct entity among PA (primary hyperaldosteronisms). We present a case of bilateral adrenal mass associated with mild autonomous hypersecretion of cortisol as well as the development of primary aldosteronism. Case Description: A 62-year-old male with a medical history of hyperlipidemia, hypertension, spontaneous hypokalemia, and T2DM was referred to the clinic due to concerns for hyperaldosteronism. Exam was unremarkable for signs of hypercortisolism. Blood pressure in the clinic was 143/88 mmHg, pulse 81 bpm, weight 105.4 Kg (231.8 lbs.), and a BMI of 28 kg/m2. A non-contrast abdominal CT performed, showed a 2.9 x.1.4 cm right adrenal lipid-rich adenoma with -3.7 HU, as well as a left adrenal lipid-rich adenoma of 1.8 x 1.3 x cm and -7.7 HU. A hormonal workup showed normal plasma metanephrines, an aldosterone of 39 ng/dL, plasma renin activity 0.16 ng/mL/h, and aldosterone/PRA ratio of 243. The patient underwent 1 mg dexamethasone suppression test which resulted in an ACTH <5 pg/mL, dexamethasone level of 288 ng/dL, and cortisol of 1.9 mcg/dL. AVS with Cosyntropin was performed (see Table 1). Right sided adrenalectomy is being considered but the identification of possible lateralization of cortisol is being considered. Discussion: Surgical management is usually preferred treatment modality for both unilateral PA and MACS, but identification of lateralization of both cortisol and aldosterone can be difficult. Although identifying lateralization of aldosterone with Cosyntropin-stimulated AVS is well understood, lateralization of cortisol production is not well understood. Johnson et. all have suggested the use of adrenal venous sampling with dexamethasone suppression as well as measurement of epinephrine levels to identify the source of hypercortisolism. They demonstrated identification of cortisol lateralization with adrenal vein sampling with specificity of 95 – 100% for unilateral disease utilizing a AV/IVC cortisol ratio > 9 and a cortisol lateralization ratio (CLR) of > 2.3. Although our case had a Cosyntropin-stimulated AVS showing clear lateralization of aldosterone production to the right adrenal, the lateralization of cortisol production is yet unknown and AVS with dexamethasone suppression is being considered. Although the treatment considerations are traditionally utilizing the guidelines for both PA and Cushing Syndrome guidelines respectively, very little is known when there are divergence of autonomous secretion amongst the bilateral adrenal masses and more studies are needed to clarify the long-term treatment considerations. 1

Presentation: 6/3/2024
7096 Variants in WASHC3, a component of the WASH complex, cause distinctive facial dysmorphism, short stature, and variable neurodevelopmental abnormalities
Authors: Jee Y , Lui J , Marafi D , Xia Z J , Bhatia R , Zhou E , Herman I , Temnycky A G , Whalen P , Elliot G , Leschek E , Wijngaard R , Beek R , Vreugd A , De Vries M , Karnebeek C , Oud M , Markello T , Barnes K , Alrohaif H , Freeze H H , Gahl W , Malicdan M , Posey J , Lupski J , Baron J
Published: October 2024

Disclosure: Y. Jee: None. J. Lui: None. D. Marafi: None. Z. Xia: None. R. Bhatia: None. E. Zhou: None. I. Herman: None. A.G. Temnycky: None. P. Whalen: None. G. Elliot: None. E. Leschek: None. R. Wijngaard: None. R. Beek: None. A. Vreugd: None. M. De Vries: None. C. Karnebeek: None. M. Oud: None. T. Markello: None. K. Barnes: None. H. Alrohaif: None. H.H. Freeze: None. W. Gahl: None. M. Malicdan: None. J. Posey: None. J. Lupski: None. J. Baron: None.

Genetic defects that impair growth plate chondrogenesis can result in a spectrum of phenotypes, ranging from skeletal dysplasia to mild short stature, sometimes accompanied by syndromic features. However, the genetic underpinnings of impaired skeletal growth often remain elusive. In our study, we investigated three unrelated families with short stature (height standard deviation score z < -2), distinctive facies (down-slanting eyes, low set ears, high arched palate, and short neck), and various neurodevelopmental abnormalities (from leaning difficulties to low intelligence quotient). In these families, exome sequencing (ES) identified rare, predicted-pathogenic variant alleles in WASHC3 that segregated with the phenotype. WASHC3 is a component of the WASH complex, which is involved in endosome receptor recycling. In the first family, a de novo-dominant missense variant (p.L69F) impaired WASHC3 participation in the WASH complex. This variant led to altered PTH1R endosomal trafficking, resulting in diminished PTH1R signaling and impairing growth plate chondrocyte hypertrophic differentiation, providing a likely explanation for the short stature. Knockdown of other WASH complex components (WASH1, SWIP, Strumpellin) also diminished PTH1R signaling, confirming the importance of an intact WASH complex. In the second and third families, a homozygous variant in the start codon (p.M1?) markedly reduced WASHC3 protein expression by approximately 75%. In conclusion, our findings strongly suggest that the WASH complex is required for normal skeletal growth and that, consequently, genetic abnormalities impairing the function of the WASH complex (WASHopathy) cause short stature as well as distinctive facies and variable neurodevelopmental abnormalities. These effects are likely mediated through disruptions in endosomal receptor trafficking. This new pathological information sheds light on the molecular basis of impaired longitudinal bone growth.

Presentation: 6/3/2024
6369 Weiss-Kruszka Syndrome and Growth Hormone Deficiency, Adrenal Insufficiency, and Morbid Obesity
Authors: Falcon-Rodriguez Taimy , Solano Natalia , Diaz Alejandro
Published: October 2024

Disclosure: T. Falcon-Rodriguez: None. N. Solano: None. A. Diaz: None.

Background: Weiss-Kruszka syndrome (WKSA) is a rare autosomal dominant genetic disorder caused by heterozygous loss-of-function variants in the ZNF462 gene. Individuals affected by this condition exhibit distinctive craniofacial features, ptosis, dysgenesis of the corpus callosum, hearing loss, intellectual disability, and hypotonia. There is one other case report that described a boy with empty sella syndrome with growth hormone deficiency and delayed puberty. Case Presentation: We present the case of a 15-year-old boy who initially came under the care of endocrinology at age 9 due to severe obesity and short stature. Past medical history included ADHD (for which he was on stimulants since age 5), microcephaly, VUR, asthma, and developmental delay. He grew along the 2nd percentile for height from the ages of 6 and 13, after which his growth velocity notably decelerated. His initial bone age at 9 years old was advanced by 3 years. His BMI had exceeded the 99th percentile since age 3. His family history was relevant for maternal type 1 diabetes mellitus, paternal height of 165 cm, and maternal height of 160 cm. Upon physical examination, notable findings included short stature, severe obesity, a low anterior hairline, arched eyebrows, upslanted palpebral fissures, low-set ears, a tubular and short nasal bridge, and an exaggerated cupid's bow. At age 9, the patient was diagnosed with growth hormone (GH) deficiency following a clonidine and glucagon stimulation test, with a GH peak of 1.9 ng/mL (normal >7 ng/mL). Additionally, he was diagnosed with adrenal insufficiency (cortisol peak of 5 ug/dL, after 250 mcg of cosyntropin). A brain/sella MRI revealed a hypoplastic pituitary gland. Subsequently, hydrocortisone replacement was initiated at a dose of 6 mg/m2/day, and GH treatment at a weekly dose of 0.3 mg/kg. Despite treatment with growth hormone and IGF-1 levels on the upper side of the normal range, his growth velocity did not improve significantly. He reached his peak adult height of 150 cm at age 15. His BMI had consistently been at the 99th percentile. According to his mother, he did not have issues with satiety, and his portion sizes were considered normal. He did not consume fast foods or sugary drinks, and his level of physical activity was suboptimal. Whole Exome Sequencing identified a heterozygous de novo pathogenic variant in the ZNF462 gene, specificallyc.2664 C>A, p.(C888*) (NM_021224.4), consistent with the diagnosis of Weiss-Kruszka syndrome (OMIM # 618619). Conclusion: We present, to our knowledge, the first report of morbid obesity and central adrenal insufficiency in a child with WSKA. GH deficiency had been previously reported in 1 patient with WSKA. The finding of a hypoplastic pituitary gland supports the diagnosis of GH deficiency and central adrenal insufficiency.

Presentation: 6/3/2024
6987 Whole exome sequencing for permanent congenital hypothyroidism
Authors: Ahn J , Jeong H
Published: October 2024

Disclosure: J. Ahn: None. H. Jeong: None.

Background: Guidelines on congenital hypothyroidism (CH) recommend that genetic testing should aim to improve diagnosis, treatment or prognosis. Little information is available regarding the genetic heterogeneity of CH in Koreans. We aimed to investigate the genetic etiology of permanent CH to increase the genetic diagnosis rate and find associated diseases by whole exome sequencing (WES). Methods: A total of 32 patients with permanent CH were enrolled from Endocrinology Clinic at Jeju National University Hospital and Soonchunhyang University Cheonan Hospital. WES was performed on 3billion extracted through the patient's buccal swab. Variant classification is based on the guidelines presented by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP). Results: A total of 30 variants were identified in 20 patients. (62%). WES identified 22 variants in 6 genes (DUOX2, DUOXA2, TPO, PAX8, TG, TSHR). We detected 20 Pathogenic /Likely pathogenic of 5 genes in 15 patients (50%). The most frequently affected genes were DUOX2 (n = 10), TPO(n=4) DUOXA2 (n=3), TSHR(n=3)and PAX8 (n=2). 16 patients are monogenic and 4 patients have oligo-genic mutations. The test results of patients (n=6) with thyroid agenesis or ectopic thyroid gland were all negative. Conclusions: In patients with permanent congenital hypothyroidism, the mutation rate through the WES method is quite high. Genetic testing is useful for medication dose adjustment and genetic counseling through correlation of genotype and phenotype.

Presentation: 6/1/2024
6694 A Case of an Extraneous Organ: A Uterus Found in a Genotypic and Phenotypic Male
Authors: Zielinski Rachel A , Shteyman Sara , Samat Aashish G
Published: October 2024

Disclosure: R.A. Zielinski: None. S. Shteyman: None. A.G. Samat: None.

Background: Persistent Mullerian Duct Syndrome (PMDS) is a rare entity that occurs when a phenotypic male is found to have female reproductive organs. In our case we describe an XY male who was found to have an abdominal mass consistent with a uterus on pathology. Clinical Case: Our patient is a 58-year-old male with hypertension, obesity, and obstructive sleep apnea who presented to the ED with 3 weeks of left upper quadrant pain. Abdominal CT showed two homogeneous enhancing oval lesions in the pelvis superior to the urinary bladder; 8.3 x 4.6 cm on the right and 3.6 x 3 cm on the left. Exploratory laparotomy was performed, and intraoperatively the mass was firm with a left satellite lesion and two fibrous bands that appeared similar in structure to round ligaments. Microscopically the tissue contained mullerian-type epithelium and smooth muscle with cystic degeneration. It was CK7 positive, estrogen receptor variable positive, and CK20 negative. Genetic testing confirmed the patient’s karyotype to be XY without genetic mosaicism. Our patient had two children spontaneously, regular spontaneous erections, and occasional hot flashes. Physical exam revealed an obese male (BMI 51) with bilateral gynecomastia and normal testicular size. He had no history of intra-abdominal or undescended testes requiring surgery. Labs showed increased total estrogen (283.7 pg/mL, n 60-190 pg/mL) and estradiol (39 pg/mL, n <= 29 pg/mL), decreased total testosterone (86 ng/dL, n 250-1,100 ng/dL), and normal free testosterone when corrected for SHBG (140 ng/dL, n 110-574 ng/dL). Testicular ultrasound was unrevealing. 3 years postoperatively his estradiol level normalized (34 pg/mL) and his total testosterone improved from 86 ng/dL to 223 ng/dL after losing 40 pounds on semaglutide. Discussion and Conclusion: Although the exact incidence of PMDS is unknown, it is a rare phenomenon. Only 200 cases between 1964 and 2000 and 34 cases between 2013 and 2017 have been reported. Mullerian ducts are embryologic structures present in both XY and XX fetuses until week 8 of life, when XY fetuses produce anti-mullerian hormone (AMH). In PMDS, the XY fetus either fails to produce AMH, or there is a defect in the AMH receptors, leading to the persistence of mullerian ducts. These ducts can then differentiate into a uterus, fallopian tubes, and/or the upper vagina. Our patient is a genotypical and phenotypical male with a uterus-like organ. The mild elevation in his estrogen level is likely secondary to his obesity. The estrogen could have increased the size of the uterus, causing the patient’s initial symptoms of abdominal pain which prompted his presentation to the hospital. References: Picard, Jean-Yves, et al. “The Persistent Müllerian Duct Syndrome: An Update Based UponPersonal Experience of 157 Cases.” Sexual Development, vol. 11, no. 3, 2017, pp. 109-125, https://doi.org/10.1159/000475516.

Presentation: 6/3/2024
8661 A case of post-menopausal female with virilization due to Sertoli-Leydig cell ovarian tumor recurring in contralateral ovary 8 years later
Authors: Maharaul M S , Miller J L
Published: October 2024

Disclosure: M.S. Maharaul: None. J.L. Miller: None.

Introduction: Sertoli-Leydig cell tumors (SLCTs) are rare androgen-secreting tumors of the ovaries, accounting for less than 0.5% of all ovarian tumors. Their incidence peaks in the second to third decade of life. New onset of severe hyperandrogenism with virilization in postmenopausal women is exceedingly rare, and the three most frequent causes are ovarian tumors, ovarian hyperthecosis and adrenal androgen producing tumors. We report one such case of ovarian androgen producing tumor which was further complicated by recurrence in the contralateral ovary. Case: A 66-year-old woman presented for evaluation of hyperandrogenism. Physical examination revealed evidence of virilization and clitoromegaly. Laboratory workup was remarkable for total serum testosterone level of 367 ng/dL with normal dehydroepiandrosterone sulfate and cortisol levels. A computerized scan of abdomen did not show any adrenal masses. Transvaginal ultrasound revealed uterine myomas but did not show any ovarian pathology. She underwent selective vein catheterization of her adrenal glands as well as ovaries and was noted to have right ovary secreting 3,982 ng/dL of testosterone whereas all other samples had total testosterone levels < 200 ng/dL. She underwent right salpingo-oophorectomy. Histopathologic examination revealed a 2.2 cm well differentiated Sertoli-Leydig cell tumor confined to the ovary; the fallopian tube was negative for tumor. Six weeks later, her serum total testosterone level was 18 ng/dL. 8 years later, she returns with recurrent symptoms of hyperandrogenism. Repeat workup revealed a total testosterone level of 662 ng/dL. A computerized scan of abdomen and transvaginal ultrasound revealed an unremarkable uterus and left ovary. Magnetic resonance imaging of the pelvis was done that showed a 1.2 cm enhancing mass in the left ovary. She then underwent left salpingo-oophorectomy and supracervical hysterectomy. Histopathologic examination revealed a 1.5 cm Sertoli-Leydig-cell tumor of the left ovary, the fallopian tube was negative for tumor. Six weeks later, her serum total testosterone level was 24 ng/dL and she felt significant improvement in her symptoms. Conclusion: We present an interesting case of virilization in a post-menopausal female due to Sertoli-Leydig cell tumor that resolved after unilateral oophorectomy but recurred 8 years later in the contralateral ovary with resolution after completion oophorectomy.

Presentation: 6/2/2024
7452 A Diagnostically Challenging Case of Hyperandrogenism in Postmenopausal Woman
Authors: Hossain Md Shajjad , Hossain Sadaf , Gautam Bharat , Liao Huijuan , Kumar Salini Chellappan , Rosenthal David S
Published: October 2024

Disclosure: M.S. Hossain: None. S. Hossain: None. B. Gautam: None. H. liao: None. S.C. Kumar: None. D.S. Rosenthal: None.

Background: The diagnosis of new-onset severe hyperandrogenism in postmenopausal women is rarely encountered, posing a unique challenge for clinicians. Ovarian hyperthecosis and androgen-secreting tumors are the usual suspects in post menopause. In our case ovarian hyperthecosis is the primary consideration but elevated 17-OH Progesterone (17-OHP) introduces the potential co-existence of Non classical congenial adrenal hyperplasia (NCCAH) or rare instances of Sertoli-Leydig Cell Tumor (SLCT). Case Presentation: A 70 years old female, with no past medical history, referred to the Endocrinology clinic for significantly elevated testosterone level. She reported excessive hair growth in various areas of her body since 2022, which required shaving almost every day. She also reported male pattern hair loss and weight loss of 15 lbs over the last three months. She denied headache, vision changes, deepening of voice, history of fertility problems and use of exogenous testosterone. Her vital sign were normal. On examination, she had clitoromegaly, terminal hair growth on her upper lip and chin, breast atrophy, male pattern baldness, but no cushingoid or acromegaly features. Blood tests showed significantly elevated total testosterone: 1422 ng/dl (2-45); free testosterone: 147.9 pg/ml (0.2-3.7) and Estradiol: 64 pg/ml (Postmenopausal <31) with low LH: 7.6 mIU/ml (Postmenopausal 10.0-54.7) and FSH: 22.2 mIU/mL (Postmenopausal 23-116). Her serum ACTH, DHEA Sulfate, 11-deoxycortisol, 17 OH pregnenolone, TSH, Free T4, prolactin, IGF-1 were normal while her 17-OHP: 396 ng/dl (<45 ng/dl) was significantly elevated. An ACTH stimulation test showed 17-OHP level of 734 ng/dl at 30 minutes and 901 ng/dl at 1 hour. Pelvic ultrasonography: right ovary of 2.3 x 1.6 x 1.9 cm and the left ovary of 3.1 x 1.8 x 3.0 cm. MRI showed normal adrenal glands but a prominent left ovary. Patient was referred to the Obstetrics department to undergo bilateral oophorectomy for the definitive diagnosis and treatment. Discussion: The current ACTH stimulation test for non-classical congenital adrenal hyperplasia is validated for premenopausal women but lacks standardization in post-menopausal state. In our case, distinguishing the source of elevated 17-OHP between adrenal (NCCAH) and ovarian (SLCT) was difficult. Unexpected asymmetry in ovarian size observed in our case further complicates the scenario, contrasting with the typical symmetrical enlargement seen in ovarian hyperthecosis. Pending surgical pathology will further guide the management. This case highlights the complexity of diagnosing hyperandrogenism in postmenopausal women, emphasizing the significance of thoroughly exploring differential diagnoses and meticulously analyzing laboratory results.

Presentation: 6/2/2024
8281 Continuous Low-Dose Etomidate Infusion For The Management Of Severe Hypercortisolism In Metastatic Adrenocortical Carcinoma
Authors: Jamil Abid , Mohammad Nazar , Narayana Shyam
Published: October 2024

Disclosure: A. Jamil: None. N. Mohammad: None. S. Narayana: None.

Background: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy of the adrenal glands with a poor prognosis that often presents with excess hormone secretion. Approximately, 45% of cases present with hypercortisolism.1 A key component of management is achieving control of hypercortisolism. Though there are multiple enteral therapies that can inhibit cortisol production, few treatment options are available for use in critically ill patients who are not surgical candidates and cannot take oral medications. Though primarily known as a short-acting intravenous anesthetic agent used for sedation, etomidate also inhibits 11-β-hydroxylase, a key enzyme involved in corticosteroid biosynthesis.2 Clinical Case: A 28-year-old woman with metastatic adrenocortical carcinoma with associated hypercortisolism was initially admitted for anemia and thrombocytopenia, with an initial cortisol on admission of 29.3 μg/dl (normal range: 2.3-19.4 ug/dl). Due to her large tumor burden with metastasis to the liver and invasion into the inferior vena cava, she was deemed a poor surgical candidate with a poor overall prognosis. Her hospital course was complicated by acute hypoxemic respiratory failure requiring intubation, and thus her enteral steroidogenesis inhibitors (mitotane, ketoconazole, and metyrapone) were discontinued as none were administrable via nasogastric tube. Consequently, her hypercortisolism worsened rapidly with a cortisol level of 351.3 μg/dl , prompting initiation of continuous low-dose etomidate infusion, which resulted in significant improvements in her cortisol levels. After eight days of etomidate treatment, her cortisol levels reached a goal value of 25.0 μg/dl. However, she then suffered an ischemic cerebrovascular event and multiorgan failure, and was subsequently transitioned to hospice care. Conclusion: Low-dose etomidate infusion is an effective therapeutic agent for hypercortisolism in patients with ACC that are unable to take oral medications. References: 1. Ng L, Libertino JM. Adrenocortical carcinoma: diagnosis, evaluation and treatment. J Urol. 2003;169(1):5-11. doi:10.1016/S0022-5347(05)64023-2 2. Carroll TB, Peppard WJ, Herrmann DJ, et al. Continuous Etomidate Infusion for the Management of Severe Cushing Syndrome: Validation of a Standard Protocol. J Endocr Soc. 2018;3(1):1-12. Published 2018 Oct 26. doi:10.1210/js.2018-00269

Presentation: 6/2/2024
5048 A Rare Cause of Hyperandrogenism in Postmenopausal Women: Ovarian Stromal Hyperplasia
Authors: Mark Shemrine , Shanik Michael Howard , Romao Isabela J
Published: October 2024

Disclosure: S. Mark: None. M.H. Shanik: None. I.J. Romao: None.

Ovarian stromal hyperplasia (OSH) is a rare cause of hyperandrogenism. It is a non-neoplastic proliferation of ovarian stromal cells that leads to the overproduction of testosterone. This case report highlights that OSH should be considered in patients who present with hyperandrogenism.A 49-year-old postmenopausal woman with a past medical history of polycystic ovary syndrome, type 2 diabetes and obesity complained of unwanted hair growth. On the physical exam her BMI was 51. She had an obese body habitus, hirsutism of her chin, chest and back and acanthosis nigricans on her neck. Blood work showed a total testosterone of 203 (2-45 ng/dL) and free testosterone 29 (0.1-6.pg/dL). FSH, LH, DHEAS, estradiol, SHBG and 17 hydroxyprogesterone (17 OHP) were in the normal range. She completed a 1 mg dexamethasone suppression test that was normal. She took spironolactone for hirsutism with minimal relief. Pelvic ultrasound was limited due to body habitus. CT of the abdomen and pelvis showed no adrenal or ovarian masses. The patient had a family history of pancreatic, ovarian, and breast cancer. Given her symptoms and her family history, the patient underwent genetic testing that was negative. She underwent bilateral salpingo-oophorectomy. Pathology revealed bilateral ovarian stromal hyperplasia. After surgery, her total testosterone normalized to 18 ng/dL and free testosterone was 1.6ng/dL with improvement in hair distribution. The patient continued to struggle with her weight and diabetes management.OSH is a non-malignant proliferation of ovarian stromal cells which leads to overproduction of testosterone. It occurs more in postmenopausal women and rarely in women of reproductive age. There is approximately 1 case of OSH in every 1000 cases of hirsutism. Clinical features include obesity, insulin resistance, acanthosis nigricans, acne, and hirsutism. Testosterone levels are usually greater than 150 ng/dL. Differential diagnosis includes PCOS, Cushing’s disease, adrenal or ovarian tumor and non-classic adrenal hyperplasia. Transvaginal ultrasound can be used to assess the ovaries for tumors or increase in size. If negative a pelvic MRI or CT can be done for further assessment. The gold standard for diagnosis would be histological evaluation following bilateral oophorectomy which is curative. Pathology usually shows stromal hyperplasia that is nodular or diffuse. Alternative treatment options include GNRH agonist therapy in patients who are not surgical candidates. Complications of this condition include insulin resistance, acanthosis nigricans and diabetes mellitus. After treatment hyperandrogenism skin changes improve. It is important that clinicians consider OSH as a cause of hyperandrogenism to ensure timely diagnosis and treatment.

Presentation: 6/2/2024
7802 A Review of 21 Cases of Kallmann Syndrome
Authors: Kashima Takemoto , Ishimaru Masanori , Tanimoto Eri , Fukui Sadahiro , Nakamura Chiduko , Ujita Nagisa , Miyagi Hajime , Igarashi Mizuho , Doi Hibiki , Yoshii Keisuke , Naiki Yasuhiro , Horikawa Reiko
Published: October 2024

Disclosure: T. Kashima: None. M. Ishimaru: None. E. Tanimoto: None. S. Fukui: None. C. Nakamura: None. N. Ujita: None. H. Miyagi: None. M. Igarashi: None. H. Doi: None. K. Yoshii: None. Y. Naiki: None. R. Horikawa: None.

Kallmann syndrome is the most common form of hypogonadotropic hypogonadism. The incidence is estimated to be 1 in 10,000 birth boys and 1 in 50,000 birth girls. The goals of treatment for childhood puberty are to induce the progression of secondary sexual characteristics close to physiological sexual maturity, to improve psychosocial problems caused by delayed puberty, and to achieve fertility. Methods.Twenty-one patients (fifteen males and six females) with a diagnosis of Kallmann syndrome who visited our Department between August 2004 and November 2023 were included in the study. The electronic medical records were reviewed retrospectively. Results.The median age at first visit was 15 years and 11 months (13 years and 3 months to 17 years and 7 months). The chief complained were secondary sexual characteristics not yet developed, olfactory disturbance, amenorrhea, decreased growth rate, and micropenis. Three adults had symptoms of Kallmann's syndrome and were seen for close examination. 6 had a history of hearing loss. Family history included 2 cases of hypogonadotropic hypogonadism and a sibling with Sjogren-Larsson syndrome. 9 cases had genetic testing, including KAL1, KAL2, FGF8, IL17D, 1 case each, and 2 gene variants of CHD2.At the time of initial examination, the median testicular volume in males was 1.0 mL (1.0-3.0 ml). Five of the six female patients had no breast enlargement.Endocrine examination revealed that the mean basic LH and LHRH test peak values were 0.25 and 3.40 mIU/mL, respectively; the mean basic FSH and peak FSH values were 0.91 and 4.47 mIU/m, respectively; the mean testosterone level in males was 0.09 ng/mL; and the mean estradiol level in females was 5.58 pg/mL.For the 20 patients, excluding children, gonadotropins (HCG+rFSH) for men and estrogen patches for women were both started at low doses and titrated up to Kaufman therapy in women. Median age at initiation of treatment was 16 years and 5 months (14 years and 1 month to 18 years and 6 months). Bone density increased after the start of treatment. One patient diagnosed with micropenis in infancy was treated with testosterone for micropenis at 2 years and 5 months. Two male patients had a baby with their partners. Discussion.The age of diagnosis (age of first examination) is considerably older than the average age of onset of secondary sexual characteristics, so it is necessary to educate the public so that patients can be examined earlier. The patient's fertility was partially confirmed, and a smooth transition to adult/reproductive medical care can be expected through earlier intervention.

Presentation: 6/1/2024
12270 Adolescent PCOS With Unexpected, Sudden-onset GAD And MDD: A Call For Vigilance In Longitudinal PCOS Care
Authors: Sarkisian K I , Aliabadi T , Stanczyk F Z
Published: October 2024

Disclosure: K.I. Sarkisian: None. T. Aliabadi: None. F.Z. Stanczyk: None.

Background: Polycystic Ovary Syndrome (PCOS) is a multifaceted endocrine disorder often associated with psychiatric disorders, yet the integration of psychiatric monitoring and multidisciplinary care following diagnosis remains understated as a guideline of clinical management of PCOS post-diagnosis. Historically, psychiatric comorbidities in PCOS have been attributed to social and personal factors such as self-image and self-esteem. However, the present patient’s denial of thoughts of disordered eating and lack of self-esteem related to acne or hirsutism challenges these assumptions.Clinical Case: A 13-year-old girl presented with classic symptoms of PCOS, including hirsutism, irregular and painful periods, and premature adrenarche. Laboratory investigations revealed an elevated total testosterone level (58 ng/dL, normal<38 ng/dL), consistent with PCOS. Previously, the patient had not expressed any concerns about mood. However psychological symptoms emerged alongside the physical symptoms. A psychological assessment performed by a licensed therapist revealed moderate-to-severe generalized anxiety disorder (GAD), which had rapidly worsened in a matter of weeks. Both the patient and the patient’s parents denied prior symptoms of moderate-to-severe anxiety before the onset of PCOS symptoms. Over the course of follow-up spanning 47 months, the patient documented symptoms, tracking both mood and PCOS fluctuations. During the follow-up period, the patient’s mood worsened, leading to the formal diagnosis of Major Depressive Disorder (MDD), despite a low assessed risk, no family history, and no symptoms prior to her PCOS development. The diagnoses of GAD and MDD were later confirmed through neuropsychiatric testing by a licensed psychologist.Clinical Lessons: While this presentation may not be considered novel in the context of PCOS, its overwhelming prevalence underscores the need for heightened awareness and research on the topic. The patient, previously considered low-risk for psychiatric conditions, experienced an unexpected onset of GAD and MDD concurrently with the diagnosis of PCOS. It is imperative to recognize that PCOS patients defy the conventional categorization of ‘healthy’ individuals concerning psychiatric care. This notion holds significance not only in clinical practice but also in research endeavors. Merely attributing psychiatric comorbidities in PCOS patients to social factors overlooks the unforeseen presentations of psychiatric disorders, as demonstrated in this patient. These manifestations cannot be solely attributed to social aspects of identity-insecurity, emphasizing the need for a more nuanced, proactive approach to psychiatric care in PCOS. This is crucial for achieving the best long-term prognosis and quality of life in affected individuals.

Presentation: 6/1/2024
6597 An Unusual Case of Klinefelter Syndrome with Both Primary and Superimposed Secondary Hypogonadism
Authors: Krueger Abigail , Pelley Elaine
Published: October 2024

Disclosure: A. Krueger: None. E. Pelley: None.

Introduction: Klinefelter syndrome (KS) (47, XXY) is a sex-chromosome disorder that is a common cause of infertility and hypogonadism in men. Clinical phenotype includes tall stature, delayed or incomplete puberty, small testes (<4ml), gynecomastia, and oligo or azoospermia. The extra X chromosome leads to fibrosis and hyalinization of seminiferous tubules resulting in impaired sperm production. Leydig cells also function abnormally and fail to stimulate with LH. Common biochemical evaluation results in low serum testosterone, elevated FSH and LH concentrations, and azoospermia. Case Report: 37-year-old male presented with long standing history of low libido and a perception that he had never fully progressed through puberty. Physical exam was notable for a height of 6’ 4”, obesity, fine pubic and axillary hair, and testes <4mL bilaterally. Initial biochemical work up revealed low serum total testosterone 43 (ref 300-1080 ng/dL), low free testosterone 8.1 (ref 47-244 pg/mL), inappropriately normal LH 10.8 (ref 0.6-12.1 mlU/mL), and elevated FSH 28.3 (ref 1.0-12.0 mlU/mL). Patient was referred to Endocrinology. Labs were repeated with consistent results in addition to chromosome analysis which confirmed diagnosis of Klinefelter syndrome with (47, XXY) karyotype. Due to inappropriately normal LH and mixed picture of primary and superimposed secondary hypogonadism, an MRI of the pituitary was obtained and revealed an 8mm x7mm x 14mm pituitary macroadenoma. Evaluation for pituitary hypersecretion and other deficiencies was unremarkable. Conclusion: Data from the Danish National registry shows that only 25% of Klinefelter patients are correctly diagnosed. Klinefelter syndrome should be considered in the differential for the evaluation of hypogonadism and infertility. Diagnosis can be made by karyotyping. The degree of impaired spermatogenesis and testosterone production in Klinefelter syndrome can be variable. Biochemical evaluation should be interpreted in conjunction with clinical context. Patients with known causes of primary hypogonadism who demonstrate an inappropriate gonadotropin response require evaluation for causes of secondary hypogonadism. In this case, the inappropriately normal LH was the sole clue leading to the identification of his pituitary macroadenoma.

Presentation: 6/1/2024
12581 Association Between AMH And Psychological Symptoms Across The BMI Spectrum In Peri-menarcheal Adolescents: Preliminary Findings
Authors: Brink Heidi Vanden , McCormick Kathleen C , Lujan Marla E , Chang Jane , Ipp Lisa , Alladeen Anisah , Mendle Jane
Published: October 2024

Disclosure: H. Vanden Brink: None. K.C. McCormick: None. M.E. Lujan: None. J. Chang: None. L. Ipp: None. A. Alladeen: None. J. Mendle: None.

Introduction: Depression, anxiety, and disordered eating are associated with Polycystic Ovary Syndrome in adults and adolescents with PCOS, and significantly impact quality of life as well as intervention and PCOS management success. Elevated AMH and obesity are known risk factors for future PCOS risk. Thus, the objective was to determine whether AMH was associated with the degree of psychological symptoms in the peri-menarcheal years across the adiposity spectrum. Methods: 40 females (n=12 pre-menarcheal, n=28 <2 years post-menarche) underwent a non-fasting blood draw, anthropometry, menstrual history, and a series of surveys to evaluate depression (CES-DC), anxiety (MASC), perceptions of pubertal-related change (POPS), and transdiagnostic psychological processes (rumination, emotional clarity) which can contribute to, and are risk factors for, psychopathology. Anti-mullerian hormone was measured using picoAMH assay (Motive Biosciences Inc). Linear regression analyses were conducted to determine whether AMH, body habitus (lean [n=26], overweight [n=7], obesity [n=7]) were associated with psychological symptoms. A BMI category-by-AMH interaction was included to test the hypothesis that relationship between psychological symptoms and AMH was greater among those living with obesity, who are at an increased risk of progression to PCOS. Results: In the full model, depression scores were positively associated with AMH (p=0.035), and an AMH*BMIcat interaction was trending (p=0.059), such that the association between AMH and depression scores among those with obesity was greater (p=0.026). POPS was positively associated with AMH, only after inclusion of BMI (p=0.029). Lower body appreciation scores and a higher drive for thinness were associated with higher AMH only among those with obesity (BAS: interaction term p=0.087; parameter estimate AMH*OB p=0.045; EDI: interaction term: 0.061, AMH*OB parameter estimate, p=0.019). Rumination and anxiety also demonstrated a BMI-dependent association with AMH; both were positively associated with AMH among participants with obesity (rumination, interaction p=0.014, AMH*OB parameter estimate p=0.007; anxiety interaction p=0.0009, AMH*OB parameter estimate p=0.0002), but the inverse was detected in lean participants (rumination AMH*Lean parameter estimate p=0.014; anxiety AMH*Lean parameter estimate p=0.009). Conclusion: While preliminary, these findings suggest that obesity and elevated AMH in the pre- and early post-menarcheal years is associated with increased symptoms that could affect psychological well-being symptoms. Research is ongoing to validate these findings in a larger, more diverse cohort and to assess subsequent PCOS risk.

Presentation: 6/3/2024
6669 Association Between Serum Levels of Thyroid Function and Per- and Polyfluoroalkyl Compounds Concentrations in Central Precocious Puberty in Girls
Authors: Li Y , Xing Y , Yin X , Yang J , Zang S , Dong T , Pan Y , Dai J , Li P
Published: October 2024

Disclosure: Y. Li: None. Y. Xing: None. X. Yin: None. J. Yang: None. S. Zang: None. T. Dong: None. Y. Pan: None. J. Dai: None. P. Li: None.

Background: Exposure to per- and polyfluoroalkyl substances (PFASs) may interfere with thyroid function in the general population and disturb the timing of puberty onset. Objectives: We investigated the possible relationship between PFASs and thyroid hormone (THs) exposure in girls with central precocious puberty (CPP). Methods: In a prospective study initially established for assessing CPP, 627 serum samples were collected with (n = 226) and without (n = 401) CPP. The concentrations of 25 PFASs, thyroxin (T4), 3,5,3’-triiodothyronine (T3), and 3,3’,5’-triiodothyronine (rT3) were measured. We used logistic regression to examine the association of THs with the odds of having CPP and multiple linear regression to analyze the associations between THs and various PFASs in the CPP and control groups. Results: The levels of T4 in the CPP group were significantly lower than those in the control group, and the levels of T3 and rT3 were significantly higher than those in the control group. After adjusting for confounders, T3 concentrations were associated with 1.526-fold increased odds of having CPP [odds ratio (OR) = 1.526, 95% confidence interval (CI):1.216-1.914]. In the CPP cohort, perfluoroheptanoic acid (PFHpA), perfluoro (2-ethoxyethane) sulphonic acid (PFEESA), and fluorotelomer phosphate diester (6:2/8:2 diPAP) were inversely associated with T3; perfluorobutanoic acid (PFBA) was inversely associated with T4, and PFEESA and 6:2/8:2 diPAP positively associated with T4; PFBA was positively associated with rT3, and perfluorooctane sulfonic acid (PFOS) was inversely associated with rT. In the control cohort, perfluorobutanesulfonic acid (PFBS) was positively associated with T3, and PFEESA and 6:2/8:2 diPAP were inversely associated with T3, and these PFASs had an adverse association with T4. Perfluorohexanoic acid (PFHxA) was positively associated with rT3, and 6:2/8:2 diPAP was negatively associated with rT3. Conclusion: In this study, different measurements of PFASs and THs were observed in the CPP and control groups. Discrepancies in exposure to PFASs were associated with THs in the CPP cohort and healthy girls. Further research is necessary to investigate the mechanism by which PFASs affect the timing of puberty onset and thyroid function.

Presentation: 6/1/2024
12546 Association Of Quality Of Life And Age At Diagnosis In Women With Turner Syndrome
Authors: Julian G , Folsom L J
Published: October 2024

Disclosure: G. Julian: None. L.J. Folsom: None.

Background: There is a well-documented association between chronic disease and decreased quality of life (QoL), including in women with Turner syndrome (TS). Much of the existing research exploring QoL in women with Turner syndrome primarily establishes the finding of decreased QoL; fewer studies seek to explore potential etiologies for this finding. Health-related QoL (HRQoL) has been evaluated using the HRQOL 14, a validated measure of QoL, since 1995, and in individuals >12 years of age as part of National Health and Nutrition Examination Survey (NHANES). The primary objective of our study was to investigate the relationship between HRQoL in women with TS and age of TS diagnosis (AoD). A secondary aim included identification of correlations between medical treatment history and HRQoL. Methods: After obtaining IRB approval, the electronic medical record (EMR) was queried using the “slicer-dicer” feature using search and limiting criteria based on desired and specified variables. Inclusion criteria encompassed a documented diagnosis of TS, a recorded office visit within the past 2 years, and participant age of at least 18 years at time of study initiation. Exclusion criteria included lack of a confirmed diagnosis of TS, presence of other diseases known to influence stature or pubertal development, inability to understand the survey, lack of ability to read or speak English, and diagnosis of TS within the past year. QoL was assessed using the HRQOL 14. After review for exclusion criteria an opt-out letter was mailed via USPS. Results: Thirty participants completed the study out of 84 qualifying individuals. Early AoD was defined as younger than 13 years; late AoD was defined as >12 years. Twenty-four participants met criteria for early AoD; six met criteria for late AoD. The mean age for early diagnosis was 6 years and the mean age for late diagnosis was 23 years. The early AoD group reported fewer medical problems (3.6 vs. 6.2 other medical problems, p=0.009), was less likely to state days of lack of sufficient sleep (4.5 vs. 30 days, p=0.001), and was less likely to note days of limited physical activity due to pain (1 vs. 15 days, p=0.007). Conclusions: The novel finding of association of earlier AoD of TS and fewer medical problems invites the possibility that other health conditions may be more effectively managed if TS is diagnosed earlier. This finding highlights the opportunity for enhanced care with earlier AoD.

Presentation: 6/1/2024