TRPV6 Variants Interfere with Maternal-Fetal Calcium Transport through the Placenta and Cause Transient Neonatal Hyperparathyroidism.

Transient neonatal hyperparathyroidism (TNHP) is etiologically a heterogeneous condition. One of the etiologies is an insufficient maternal-fetal calcium transport through the placenta. We report six subjects with homozygous and/or compound-heterozygous mutations in the gene encoding the transient receptor potential cation channel, subfamily V, member 6 (TRPV6), an epithelial Ca2+-selective channel associated with this condition. Exome sequencing on two neonates with skeletal findings consistent with neonatal hyperparathyroidism identified homozygous frameshift mutations before the first transmembrane domain in a subject born to first-cousins parents of Pakistani descent as well as compound-heterozygous mutations (a combination of a frameshift mutation and an intronic mutation that alters mRNA splicing) in an individual born to a non-consanguineous couple of African descent. Subsequently, targeted mutation analysis of TRPV6 performed on four other individuals (born to non-consanguineous Japanese parents) with similar X-rays findings identified compound-heterozygous mutations. The skeletal findings improved or resolved in most subjects during the first few months of life. We identified three missense variants (at the outer edges of the second and third transmembrane domains) that alter the localization of the TRPV6: one recurrent variant at the S2-S3 loop and two recurrent variants (in the fourth ankyrin repeat domain) that impair TRPV6 stability. Compound heterozygous loss-of-function mutations for the pathogenic frameshift allele and the allele with an intronic c.607+5G>A mutation resulted in the most severe phenotype. These results suggest that TNHP is an autosomal-recessive disease caused by TRPV6 mutations that affect maternal-fetal calcium transport.

De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features.

TRAF7 is a multi-functional protein involved in diverse signaling pathways and cellular processes. The phenotypic consequence of germline TRAF7 variants remains unclear. Here we report missense variants in TRAF7 in seven unrelated individuals referred for clinical exome sequencing. The seven individuals share substantial phenotypic overlap, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features emerging as key unifying features. The identified variants are de novo in six individuals and comprise four distinct missense changes, including a c.1964G>A (p.Arg655Gln) variant that is recurrent in four individuals. These variants affect evolutionarily conserved amino acids and are located in key functional domains. Gene-specific mutation rate analysis showed that the occurrence of the de novo variants in TRAF7 (p = 2.6 × 10-3) and the recurrent de novo c.1964G>A (p.Arg655Gln) variant (p = 1.9 × 10-8) in our exome cohort was unlikely to have occurred by chance. In vitro analyses of the observed TRAF7 mutations showed reduced ERK1/2 phosphorylation. Our findings suggest that missense mutations in TRAF7 are associated with a multisystem disorder and provide evidence of a role for TRAF7 in human development.

Homozygous/compound heterozygote RYR1 gene variants: Expanding the clinical spectrum.

The ryanodine receptor 1 (RYR1) is a calcium release channel essential for excitation-contraction coupling in the sarcoplasmic reticulum of skeletal muscles. Dominant variants in the RYR1 have been well associated with the known pharmacogenetic ryanodinopathy and malignant hyperthermia. With the era of next-generation gene sequencing and growing number of causative variants, the spectrum of ryanodinopathies has been evolving with dominant and recessive variants presenting with RYR1-related congenital myopathies such as central core disease, minicore myopathy with external ophthalmoplegia, core-rod myopathy, and congenital neuromuscular disease. Lately, the spectrum was broadened to include fetal manifestations, causing a rare recessive and lethal form of fetal akinesia deformation sequence syndrome (FADS)/arthrogryposis multiplex congenita (AMC) and lethal multiple pterygium syndrome. Here we broaden the spectrum of clinical manifestations associated with homozygous/compound heterozygous RYR1 gene variants to include a wide range of manifestations from FADS through neonatal hypotonia to a 35-year-old male with AMC and PhD degree. We report five unrelated families in which three presented with FADS. One of these families was consanguineous and had three affected fetuses with FADS, one patient with neonatal hypotonia who is alive, and one individual with AMC who is 35 years old with normal intellectual development and uses a wheelchair. Muscle biopsies on these cases demonstrated a variety of histopathological abnormalities, which did not assist with the diagnostic process. Neither the affected living individuals nor the parents who are obligate heterozygotes had history of malignant hyperthermia.

Prenatal detection of isolated bilateral hyperechogenic kidneys: Etiologies and outcomes.

OBJECTIVES: To delineate the etiology and outcome of prenatally diagnosed isolated bilateral hyperechogenic kidneys (IBHK). STUDY DESIGN: Pregnancies with IBHK on prenatal ultrasound identified and followed by us between January 1, 2000 and January 1, 2015 were evaluated regarding the etiology and outcome by evaluation of family history, targeted AR-PKD and AD-PKD DNA analysis, and microarray analysis, according to renal size and amniotic fluid volume. RESULTS: Of the 52 identified cases, there were 34 cases with enlarged kidneys, 16 with normal size kidneys, and two with small kidneys. There were seven cases with AD-PKD, six inherited, and one with de novo causative variants in the PKD1 gene. Fifteen had AR-PKD, and microarray analysis showed two inherited findings: one with 17q12 deletion including the HNF1B/TCF2 gene inherited from asymptomatic mother and a duplication at 3p26.1 inherited from a healthy father. Of the remaining four cases, three cases had bilateral multicystic dysplastic kidneys, and one had unilateral renal agenesis. CONCLUSION: Microarray analysis and mutation analysis for PKD1 and PKHD1 have an important contribution to the diagnostic investigation of IBHK and to the management of affected and future pregnancies. Poor outcome was associated with large hyperechoic kidneys with oligohydramnios.

The Use of Ovarian Vein Sampling to Lateralize a Virilizing Leydig Cell Ovarian Tumor.

Background/Objective: Leydig cell tumors are a rare androgen-secreting ovarian tumor. We present a patient with virilization symptoms secondary to a Leydig cell tumor, with nonrevealing imaging studies, that was localized using ovarian vein sampling (OVS). Case Report: A 56-year-old postmenopausal woman was referred by her gynecologist to the endocrinology clinic for voice-deepening, clitoral enlargement, scalp hair loss, and excessive body hair growth. Her total testosterone was 11.5 (0.3-1.3 nmol/L), bioavailable testosterone was 7.19 (0.1-0.6 nmol/L), and dehydroepiandrosterone sulfate was 4.0 (0.8-4.9 µmol/L). Transvaginal ultrasound and abdominal magnetic resonance imaging showed no adrenal or ovarian masses bilaterally. On adrenal vein sampling (AVS) and OVS, total testosterone from the left gonadal vein was 780.0 (0.3-1.3 nmol/L) and right gonadal vein was 18.6 (0.3-1.3 nmol/L), with a left-to-right ovarian testosterone ratio of 41.94. A bilateral salpingo-oophorectomy was performed, and a 1.0 cm Leydig cell tumor in the left ovary was noted on histopathology. One month after surgery, her total and bioavailable testosterone were <0.4 (0.3-1.3 nmol/L and 0.1-0.6 nmol/L, respectively). At 6 months, she had normalization of her voice to baseline, decreased clitoral size, decreased hair growth on her back, and improvement in her male-pattern baldness. Discussion: OVS and AVS are useful diagnostic investigation tools in cases of virilization, in which imaging is nonrevealing. Our case supports previously suggested left-to-right ovarian vein testosterone ratio of ≥15 being associated with a left-sided tumor. Conclusion: Few cases have been published on the interpretation of AVS and OVS in the setting of virilization. Previously suggested ratios for lateralization were valid for this patient.

Use of Sodium-Glucose Cotransporter-2 Inhibitors in Renal Transplant Patients With Diabetes: A Brief Review of the Current Literature.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of oral hypoglycemic agents commonly prescribed in type 2 diabetes (T2D). They have been shown to slow the progression of diabetic nephropathy and improve cardiovascular outcomes in high-risk individuals, although major cardiovascular and renal outcome clinical trials have excluded renal transplant patients. The aim of this review was to determine the outcomes and safety with use of SGLT2 inhibitors in renal transplant patients with diabetes. We conducted a review of randomized controlled trials, cohort studies, case series and case reports that assessed use of SGLT2 inhibitors in patients post-renal transplant with either pre-existing T2D or new-onset diabetes after transplant. The outcomes assessed included blood pressure, renal allograft function (estimated glomerular filtration rate), proteinuria (urinary albumin-to-creatinine ratio), glycemic control, body weight and adverse effects. A total of 9 studies, which included 144 patients, were reviewed. SGLT2 inhibitor use in renal transplant patients demonstrates either a small or nonsignificant reduction in blood pressure and results in overall stable renal allograft function. It also results in modest improvement in glycemic control as well as weight reduction. The incidence of adverse effects is low and reversible, as reported in previous nontransplant clinical trials. Overall, our findings suggest beneficial outcomes with no significant adverse effects or complications with the use of SGLT2 inhibitors in renal transplant patients with diabetes; however, these findings are based on small trials, and thus well-designed trials in this population are warranted.

Lactation Induction in a Transgender Woman Wanting to Breastfeed: Case Report.

CONTEXT: Breastfeeding is known to have many health and wellness benefits to the mother and infant; however, breastfeeding in trans women has been greatly under-researched. OBJECTIVE: To review potential methods of lactation induction in trans women wishing to breastfeed and to review the embryological basis for breastfeeding in trans women. DESIGN: This article summarizes a case of successful lactation in a trans woman, in which milk production was achieved in just over 1 month. SETTING: This patient was followed in an outpatient endocrinology clinic. PARTICIPANT: A single trans woman was followed in our endocrinology clinic for a period of 9 months while she took hormone therapy to help with lactation. INTERVENTIONS: Readily available lactation induction protocols for nonpuerpural mothers were reviewed and used to guide hormone therapy selection. Daily dose of progesterone was increased from 100 mg to 200 mg daily. The galactogogue domperidone was started at 10 mg 3 times daily and titrated up to effect. She was encouraged to use an electric pump and to increase her frequency of pumping. MAIN OUTCOME MEASURE: Lactation induction. RESULTS: At one month, she had noticed a significant increase in her breast size and fullness. Her milk supply had increased rapidly, and she was producing up to 3 to 5 ounces of milk per day with manual expression alone. CONCLUSIONS: We report the second case in the medical literature to demonstrate successful breastfeeding in a trans woman through use of hormonal augmentation.

Seven ways to get a grip on facilitating bedside team rounding.

Although classically considered a cornerstone of inpatient care, rounding at patients' bedsides is increasingly being replaced by rounding in workrooms. Workroom rounds may provide a sense of efficiency and comfort, however bedside rounds have multiple benefits for patients, trainees, and staff physicians. Alongside its benefits, there are human and institutional challenges when incorporating bedside rounding. This article aims to draw on our own experience of implementing bedside rounding at Kingston Health Sciences Centre, to guide staff physicians and institutions on how to implement bedside rounding effectively while overcoming its challenges. The following seven tips provide a framework to avoid pitfalls when implementing bedside team rounding on inpatient services.

Bien que classiquement considéré comme la pierre angulaire des soins aux patients hospitalisés, les tournées médicales au chevet des patients sont de plus en plus remplacées par les tournées dans les salles d'enseignement. Bien que Les tournées en salle de travail puissent procurer un sentiment d'efficacité et de confort, les tournées au chevet présentent de multiples avantages pour les patients, les apprenants et les médecins superviseurs. Parallèlement à ses avantages, il existe des défis humains et institutionnels lors de l'intégration des tournéesau chevet du patient. Cet article vise à tirer parti de notre propre expérience de la mise en œuvre des tournéesau chevet au Kingston Health Sciences Centre, pour guider les médecins superviseurs et les institutions sur la façon de mettre en œuvre efficacement les tournées au chevet tout en surmontant ses défis. Les sept conseils suivants fournissent un cadre pour éviter les pièges lors de la mise en œuvre des tournées en équipes au chevet des patients hospitalisés.

A RARE CASE OF STATIN-INDUCED NECROTIZING AUTOIMMUNE MYOPATHY.

OBJECTIVE: Necrotizing autoimmune myopathy (NAM) is a rare side-effect of statin therapy. We report the case of a patient who developed statin-induced NAM with a review of the clinical presentation and management of this rare entity. The case illustrates the importance of including NAM in the differential diagnosis of persistent myopathy in a statin-exposed individual. METHODS: A 74-year-old male was referred to endocrinology for hypercholesterolemia management in the context of a statin contraindication. He previously developed myositis and rhabdomyolysis secondary to statin therapy, but continued to have persistent proximal lower limb muscle weakness despite statin discontinuation. Rheumatologic and metabolic work-up were negative and neurologic work-up was negative except for a myopathic pattern in the glutei found on electromyography. RESULTS: Due to the persistence of proximal myopathy despite statin discontinuation and myopathic pattern seen on electromyography, NAM was suspected and antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase were sent and came back positive. The patient was treated with the immunosuppressant azathioprine, which resulted in clinical improvement. The patient was started on a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolucumab for hypercholesterolemia, which resulted in significant improvement in his lipid panel. CONCLUSION: The case illustrates the presentation and management of statin-induced NAM. We demonstrate the necessity for prompt diagnosis and timely management, as statin therapy is contraindicated and immunosuppressive therapy is warranted. Statin-induced NAM is rare however, it should be included in the differential diagnosis of persistent myopathy despite statin discontinuation. PCSK9 inhibitors are the only alternative therapy for hypercholesterolemia management in patients with statin-induced NAM.

RAPID DESENSITIZATION WITH INTRAVENOUS INSULIN IN A PATIENT WITH DIABETIC KETOACIDOSIS AND INSULIN ALLERGY.

OBJECTIVE: We report a case of insulin desensitization in a patient with known allergy to multiple insulin preparations who presented with diabetic ketoacidosis (DKA). METHODS: Clinical and laboratory data, and desensitization protocols are presented. RESULTS: A 65-year-old woman with type 2 diabetes and a documented insulin allergy presented with severe DKA. She was managed initially with intravenous (IV) fluids, sodium bicarbonate, and hemodialysis. An intradermal skin test was positive for 0.01 units/mL of human regular insulin. A rapid desensitization protocol for IV human regular insulin was initiated after pretreatment with methylprednisolone, ranitidine, montelukast, and cetirizine. An initial dilution of 1 unit of insulin in 100,000 mL of 0.9% sodium chloride was started at 5 mL/hour IV. The dilution was increased at 60-minute intervals to 1 unit/10,000 mL, 1 unit/1,000 mL, 1 unit/100 mL, 1 unit/10 mL, then 1 unit/1 mL. The dose was then increased from 1 to 7 units/hour (0.1 units/kg body weight/hour). The anion gap closed after 24 hours, and overlapping desensitization was started for subcutaneous (SC) human regular insulin starting with 0.00001 units with a gradual increase to 7 units before meals and 6 units at bedtime over 5 days. There were no anaphylactic reactions to IV or SC insulin. She was discharged with human regular insulin SC 4 times daily, oral montelukast, cetirizine, diphenhydramine as needed, and an epinephrine pen. No allergic reactions were reported at follow-up visits. CONCLUSION: Rapid insulin desensitization is possible to allow treatment of DKA with human regular insulin IV in patients with known insulin allergy.

Fetal Renal Echogenicity Associated with Maternal Focal Segmental Glomerulosclerosis: The Effect of Transplacental Transmission of Permeability Factor suPAR.

We report a case of a pregnant woman with nephrotic syndrome due to biopsy-proven focal segmental glomerulosclerosis (FSGS) whose fetus developed echogenic kidneys and severe oligohydramnios by 27 weeks of gestation. Maternal treatment with prednisone resulted in normalization of the amniotic fluid indices and resolution of fetal renal echogenicity. The newborn was noted to have transient renal dysfunction and proteinuria, resolving by 6 weeks postpartum. The transplacental passage of permeability factors is postulated to have caused both the fetal and newborn renal presentation, with significantly elevated levels of soluble urokinase-type plasminogen activator receptor (suPAR) noted in the cord blood. This case documents the transplacental maternal-fetal transmission of suPAR, demonstrating the potential for maternal-fetal transmission of deleterious, disease-causing entities, and adds to the differential diagnosis of fetal echogenic kidneys. Further, this is the first documentation of a fetal response to maternal systemic therapy.