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.

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.

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.

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.