Expanding the PRAAS spectrum: De novo mutations of immunoproteasome subunit ß-type 10 in six infants with SCID-Omenn syndrome.

Mutations in proteasome ß-subunits or their chaperone and regulatory proteins are associated with proteasome-associated autoinflammatory disorders (PRAAS). We studied six unrelated infants with three de novo heterozygous missense variants in PSMB10, encoding the proteasome ß2i-subunit. Individuals presented with T-B-NK± severe combined immunodeficiency (SCID) and clinical features suggestive of Omenn syndrome, including diarrhea, alopecia, and desquamating erythematous rash. Remaining T cells had limited T cell receptor repertoires, a skewed memory phenotype, and an elevated CD4/CD8 ratio. Bone marrow examination indicated severely impaired B cell maturation with limited V(D)J recombination. All infants received an allogeneic stem cell transplant and exhibited a variety of severe inflammatory complications thereafter, with 2 peri-transplant and 2 delayed deaths. The single long-term transplant survivor showed evidence for genetic rescue through revertant mosaicism overlapping the affected PSMB10 locus. The identified variants (c.166G>C [p.Asp56His] and c.601G>A/c.601G>C [p.Gly201Arg]) were predicted in silico to profoundly disrupt 20S immunoproteasome structure through impaired ß-ring/ß-ring interaction. Our identification of PSMB10 mutations as a cause of SCID-Omenn syndrome reinforces the connection between PRAAS-related diseases and SCID.

Intra-observer variability of Doppler measurements in umbilical artery (UA) and middle cerebral artery (MCA) in uncomplicated term pregnancies.

OBJECTIVE: To evaluate the intra-observer variability of the middle cerebral artery (MCA) and umbilical artery (UA) Doppler measurement taken under optimal conditions in term, uncomplicated pregnancies. METHODS: A prospective study on uncomplicated singleton term pregnancies was performed. Multiple Doppler measurements were taken in the MCA and the UA by one examiner. Intra-rater agreement was calculated. Doppler indices were correlated to fetal biometric parameters and to gestational age. RESULTS: One hundred patients were recruited. MCA indices were found to have the highest strength of intra-rater/observer agreement (K = 0.888) versus only a "good" agreement for UA pulsatility index (PI) (K = 0.755).The MCA-PI was significantly correlated with BPD (r = -0.198, p = .047), EFW (r = -0.241, p = .01) and birthweight (r = -0.208, p = .03). A statistically significant decrease was found in the MCA PI (r = -.422, p < .001) and in the CPR (r = -0.444, p < .001) with advancing pregnancy, between 37 and 42 weeks gestation. The UA PI did not change significantly (p = .099) during this period. CONCLUSIONS: MCA PI measured at term is reproducible with a high ICC. MCA PI significantly decreases with advancing gestation at term. No correlation was found between Doppler measurements and time to delivery.

A single center experience with publicly funded clinical exome sequencing for neurodevelopmental disorders or multiple congenital anomalies.

Exome sequencing (ES) is an important diagnostic tool for individuals with neurodevelopmental disorders (NDD) and/or multiple congenital anomalies (MCA). However, the cost of ES limits the test's accessibility for many patients. We evaluated the yield of publicly funded clinical ES, performed at a tertiary center in Israel, over a 3-year period (2018-2020). Probands presented with (1) moderate-to-profound global developmental delay (GDD)/intellectual disability (ID); or (2) mild GDD/ID with epilepsy or congenital anomaly; and/or (3) MCA. Subjects with normal chromosomal microarray analysis who met inclusion criteria were included, totaling 280 consecutive cases. Trio ES (proband and parents) was the default option. In 252 cases (90.0%), indication of NDD was noted. Most probands were males (62.9%), and their mean age at ES submission was 9.3 years (range 1 month to 51 years). Molecular diagnosis was reached in 109 probands (38.9%), mainly due to de novo variants (91/109, 83.5%). Disease-causing variants were identified in 92 genes, 15 of which were implicated in more than a single case. Male sex, families with multiple-affected members and premature birth were significantly associated with lower ES yield (p < 0.05). Other factors, including MCA and coexistence of epilepsy, autism spectrum disorder, microcephaly or abnormal brain magnetic resonance imaging findings, were not associated with the yield. To conclude, our findings support the utility of clinical ES in a real-world setting, as part of a publicly funded genetic workup for individuals with GDD/ID and/or MCA.

Simple Hysterectomy for Residual Cervical Intraepithelial Neoplasm.

OBJECTIVE: Many patients undergo hysterectomy for the treatment of cervical dysplasia. Factors that correlate with residual high-grade squamous intraepithelial lesions (HGSIL) at hysterectomy are not clear. We set out to determine preoperative features that may predict residual disease for patients treated for cervical dysplasia. MATERIALS AND METHODS: A retrospective database was reviewed for women who underwent simple hysterectomy for HGSIL between 1990 and 2013. Clinical data included age, history of dysplasia, initial treatment, follow-up colposcopy, indications for surgery, time elapsed between initial treatments, and pathology findings after hysterectomy. Significant residual disease was defined as HGSIL or cervical carcinoma. Statistical analyses were performed with the SPSS, independent Student t test, and Pearson χ test. Significance was set at p < .05. RESULTS: Eighty-three women met the study criteria. The indication for hysterectomy was residual histological finding at conization pathology in 30 women and patients' request in 53 women. Residual disease was found in 42 hysterectomy specimens: in 16 of 30 with residual histological finding and in 26 of the 53 patients' request. Reason for the hysterectomy was not statistically significant for residual disease (p = .708). Median age of patients with residual disease was 46.5 years versus 44.1 years for those without residua (p = .02). Postmenopausal patients had a higher rate of residual disease, 12 (32.4%) of the 28 premenopausal patients and 25 (67.6%) of the 54 postmenopausal patients (p = .04). Conization margin status was not associated with residual disease (p = .878). CONCLUSIONS: Older women and those in menopause are at significantly higher risk of residual disease at hysterectomy.

Outcome of trial of labor after cesarean section in women with past failed operative vaginal delivery.

OBJECTIVE: The objective of the study was to assess the outcome of trial of labor after cesarean (TOLAC) in women with past failed operative vaginal delivery (OVD). STUDY DESIGN: A retrospective study of all women who underwent cesarean section (CS) because of a failed OVD in a tertiary medical center between 1996 and 2011. Women who had a subsequent delivery were identified, and the outcome of subsequent delivery was analyzed. RESULTS: Overall, 533 women underwent CS because of failed OVD during the study period. A total of 204 women (38.3%) had a subsequent delivery, of whom 93 (45.6%) had a TOLAC and 111 (54.4%) had a repeat elective CS. The success rate in the TOLAC group was 61.3% (n = 57). The most common indication for repeat CS was lack of progress (72.3%) among the 36 women in whom TOLAC failed (38.7%). The rate of postpartum hemorrhage and prolonged maternal hospitalization was lower in the TOLAC group than in the repeat CS group (2.2% vs 10.8%, P = .02, and 0% vs 8.1%, P = .005). There were no cases of rupture or dehiscence of the uterine scar. Factors associated with failed TOLAC were the occiput-posterior position and prolonged the second stage as the indication for OVD in the index pregnancy, maternal age older than 30 years at the time of subsequent delivery, and a birthweight in the subsequent pregnancy that is higher than the birthweight in the index pregnancy. CONCLUSION: TOLAC in women who underwent a previous CS because of a failed OVD is associated with a relatively high success rate compared with the reported success rates among women with past CS during the second stage of labor. This information and the risk factors for TOLAC failure can be used when counseling these women regarding mode of delivery in subsequent pregnancy.