Auditory neuropathy is a rare form of deafness characterized by an absent or abnormal auditory brainstem response with preservation of outer hair cell function. We have identified Diaphanous homolog 3 (DIAPH3) as the gene responsible for autosomal dominant nonsyndromic auditory neuropathy (AUNA1), which we previously mapped to chromosome 13q21-q24. Genotyping of additional family members narrowed the interval to an 11-Mb, 3.28-cM gene-poor region containing only four genes, including DIAPH3. DNA sequencing of DIAPH3 revealed a c.-172G > A, g. 48G > A mutation in a highly conserved region of the 5′ UTR. The c.-172G > A mutation occurs within a GC box sequence element and was not found in 379 controls. Using genome-wide expression arrays and quantitative RT-PCR, we demonstrate a 2-to 3-fold overexpression of DIAPH3 mRNA in lymphoblastoid cell lines from affected individuals. Likewise, a significant increase (≈1.5-fold) in DIAPH3 protein was found by quantitative immunoblotting of lysates from lymphoblastoid cell lines derived from affected individuals in comparison with controls. In addition, the c.-172G > A mutation is sufficient to drive overexpression of a luciferase reporter. Finally, the expression of a constitutively active form of diaphanous protein in the auditory organ of Drosophila melanogaster recapitulates the phenotype of impaired response to sound. To date, only two genes, the otoferlin gene OTOF and the pejvakin gene PJVK, are known to underlie nonsyndromic auditory neuropathy. Genetic testing for DIAPH3 may be useful for individuals with recessive as well as dominant inheritance of nonsyndromic auditory neuropathy.

Introduction: Germ cell tumors normally occur in the gonads but may be found in extragonadal sites (due to abnormal migration of germ cells during embryogenesis). Metastatic choriocarcionomas are non-seminomatous germ cell tumors which overproduce beta Human Chorionic Gonadotropin (hCG). Rarely, thyrotoxicosis can be driven by germ cell tumor-mediated hCG excess. This hormone binds to the TSH receptor with reduced potency compared to intact TSH. Paraneoplastic thyrotoxicosis, driven by extremely high levels of hCG, is a rare condition which can be associated with choriocarcinomas. Case Presentation: We present a case of 29-year-old man with metastatic extragonadal choriocarcinoma under active treatment with oxaliplatin, paclitaxel, gemcitabine (2 cycles completed), right upper lobe resection and whole brain radiation. He was admitted for small bowel obstruction and persistent tachycardia which prompted evaluation of thyroid function. His initial labs were remarkable for TSH <0.01 mclU/mL (0.27-4.20 mclU/mL), FT4 of 6.38 ng/dL (0.93-1.70 ng/dL), total T3 261 ng/dL (75-170 ng/dL), and beta hCG 578,259 mlU/ML (0-2 mlU/ML). His most recent round of chemotherapy was 7 days prior to admission. He was started on atenolol and methimazole but his FT4 rapidly declined, hence methimazole was stopped after one dose of 40 mg. Sevenfold decrease in FT4 to 0.93 ng/dL correlated with fivefold decrease in beta hCG levels to 98,921 mlU/ML. A week later his FT4 increased to 2.42 ng/dL along with increase of beta hCG to 448,116 mlU/ML. At this point he developed multiple complications due to progressive metastatic disease including acute urinary retention, shortness of breath, abdominal pain, tachycardia, acute anemia and thrombocytopenia, anxiety and was started on methimazole as part of palliative treatment for symptom relief. Unfortunately, he passed away three weeks after initial presentation of thyrotoxicosis due to widespread disease. Discussion: Choriocarcinoma is very rare and aggressive germ cell tumor especially in males. Unfortunately, the widespread nature of choriocarcinomas at the time of diagnosis is a major main reason for poor prognosis. Clinical manifestations of thyrotoxicosis associated with choriocarcinoma such as tachycardia, anxiety, tachypnea are variable and often can overlap with constitutive symptoms in widespread malignancy. Even if a definitive cure of choriocarcinoma is not attainable, recognizing an associated paraneoplastic thyrotoxicosis can provide an important pathway to provide palliative symptom relief.

Background: Thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome is a variant of Castleman Disease, which is a rare lymphoproliferative disease that can be life threatening. Diagnosis is often delayed because of its nonspecific presentation. Bilateral adrenal hyperplasia has been a reported complication, however the majority of cases reported have been in Asian patients. Prior accounts of elevated ACTH in TAFRO have been in the context of adrenal insufficiency. Clinical Case: A 28-year-old Caucasian male with a history of multiple sclerosis was seen in the ED with abdominal pain. On presentation, he was afebrile and normotensive. Physical exam was notable for cervical lymphadenopathy and abdominal tenderness. There was no facial rounding/plethora, bruising, abnormal striae, or proximal muscle weakness. He had normal blood counts, serum chemistry and liver function. An abdominal CT scan showed marked bilateral adrenal hyperplasia with pre-aortic, peri-aortic and retroperitoneal lymphadenopathy. An 8AM serum cortisol was 14.1 mcg/dl (4.8–19.6 mcg/dl) and adrenocorticotrophic hormone (ACTH) was elevated at 152 pg/ml (7.2–63 pg/ml). A repeat serum 8AM cortisol following low dose dexamethasone suppression test (LDDST) was 14.7 mcg/dl, however at that point the patient had developed new fevers and thrombocytopenia. Blood pressure, blood glucose and potassium remained normal. An MRI of the brain showed a normal appearing pituitary gland. An extensive infectious and rheumatologic evaluation was negative, and he underwent an inguinal lymph node biopsy which showed nodal expansion with histiocytes, consistent with TAFRO. High dose methylprednisolone and Siltuximab (an IL-6 inhibitor) were started, and his fever and abdominal pain resolved. He was discharged home on oral prednisone. Conclusion: We describe a case of bilateral adrenal hyperplasia with elevated ACTH and non-suppressed cortisol on LDDST suggestive of ACTH-driven cortisol excess. However, interpretation of his LDDST is made difficult in the context of persistent fevers. Although we cannot definitively exclude pathologic hypercortisolism at this time, given his lack of suggestive features such as proximal muscle weakness, abnormal striae or hypokalemic alkalosis, his over-all presentation was more consistent with hyperplasia secondary to TAFRO rather than an underlying pathologic hypercortisolism. Adrenal hyperplasia has been noted in TAFRO, however its pathogenesis remains poorly understood. TAFRO should be added among the differentials for bilateral adrenal hyperplasia to facilitate early diagnosis and treatment. References: Ducoux G, et al. Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis/Renal Failure, and Organomegaly (TAFRO) Syndrome with Bilateral Adrenal Hemorrhage in Two Caucasian Patients. Am J Case Rep. 2020;21:e919536.

Background: Iodine is essential for the formation of thyroid hormones. Therefore, the thyroid gland is generally able to maintain normal hormone synthesis despite changes in iodine availability. When there is an increase in iodide load, the thyroid gland is able to inhibit the formation of organic iodide via the Wolff-Chaikoff effect (WCE). This prevents the formation of large quantities of thyroid hormones, thus preventing hyperthyroidism1. Continued exposure to excess iodine is also overcome by the “escape” phenomenon and hormone synthesis resumes in a normal fashion2. However, some patients may lack this autoregulation and develop hypothyroidism. Clinical Case: An 86-year-old male with a history of subclinical hypothyroidism initially presented to his PCP for evaluation of cognitive decline. Workup revealed a TSH of 10 mcIU/mL (0.34 – 5.6 mcIU/mL), a normal FT4 and a negative TPOAb. It was subsequently revealed that the patient was started on Iodoral 12.5 mg daily, an iodine/potassium iodide supplement, 1 month prior to presentation by a naturopathic doctor. Prior to all this, his TSH had always ranged between 4 – 6 mcIU/mL for many years. It was recommended that he discontinue Iodoral and repeat thyroid labs in the future. Despite this, the patient continued on varying doses of Iodoral supplementation. Repeat labs obtained 8 months later revealed an elevated TSH of 99 mcIU/mL and a low FT4 of 0.43 ng/mL (0.6 – 2.6 ng/mL). Despite these numbers, he was asymptomatic and did not exhibit any overt signs of hypothyroidism. He was referred to Endocrinology and finally stopped taking Iodoral.7 weeks post-discontinuation, his repeat labs showed a resolution of hypothyroidism and return to his baseline subclinical disease with a TSH of 8.2 mcIU/mL and a normal FT4. A urine iodine/creatinine was normal at 244.2 ug/g (35 – 540 ug/g) indicating that there was no residual iodine excess from the Iodoral. Conclusion: As far as we are aware, we present the first reported case of Iodoral-induced iatrogenic hypothyroidism. As with past cases of iodine-induced hypothyroidism, our patient had underlying thyroid disease in subclinical hypothyroidism which could explain why he was unable to escape from the WCE. The half-life of Iodoral is unknown but it is generally understood that the effects of iodide are reversed between 2 to 4 weeks after withdrawal. Our patient did not repeat his thyroid function tests until 7 weeks post-discontinuation but did demonstrate a return to baseline with no other intervention. Reference: 1. Markou K, Georgopoulos N, Kyriazopoulou V, Vagenakis AG. Iodine-Induced hypothyroidism. Thyroid. 2001 May;11(5):501-10. doi: 10.1089/105072501300176462. PMID: 11396709.2. Torti JF, Correa R. Potassium Iodide. 2020 Oct 12. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan–. PMID: 31194460.

ObjectiveManaging type 1 diabetes is stressful. Stress physiology influences glucose metabolism. Continuous glucose monitors allow us to track glucose variability in the real-world environment. Managing stress and cultivating resiliency should improve diabetes management and reduce glucose variability.Research Design and MethodsThe study was designed as a randomized prospective cohort pre-post study with wait time control. Participants were adult type 1 diabetes patients who used a continuous glucose monitor and recruited from an academic endocrinology practice. The intervention was the Stress Management and Resiliency Training (SMART) program conducted over 8 sessions over web-based video conference software. The main outcome measures were Glucose variability, the Diabetes Self-Management questionnaire (DSMQ),Short-Form Six-Dimension (SF-6D), and the Connor-Davidson Resiliency (CD-RSIC) instrument.ResultsThere was statistically significant improvement in participants DSMQ and CD RISC scores though the SF-6D did not change. Participants under age 50 years-old showed a statistically significant reduction in average glucose (p = .03) and Glucose Management Index (GMI) (p = .02). Participants also had reduced percentage of time high and increased time in range though this did not reach statistical significance. The participants found doing the intervention online acceptable if not always ideal.ConclusionsAn 8-session stress management and resiliency training program reduced diabetes related stress and improved resiliency and reduced average blood glucose and GMI in those under 50 years-old.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT04944264.