A Novel Mutation Causing Pseudohypoparathyroidism 1A with Congenital Hypothyroidism and Osteoma Cutis

Various inactivating mutations in guanine nucleotide−binding protein, alpha−stimulating activity polypeptide1 (GNAS1) gene have been described with poor phenotype correlation. Pseudohypoparathyroidism type 1a (PHP1a) results from an inactivating mutation in the GNAS1 gene. Hormone resistance occurs not only to parathyroid hormone (PTH), but typically also to other hormones which signal via G protein coupled receptors including thyroid stimulating hormone (TSH), gonadotropins, and growth hormone releasing hormone. In addition, the phenotype of Albright hereditary osteodystrophy (AHO) is observed, which may include short stature, round facies, brachydactyly, obesity, ectopic soft tissue or dermal ossification (osteoma cutis) and psychomotor retardation with variable expression

Bohring–Opitz syndrome (BOS) with a new ASXL1 pathogenic variant: Review of the most prevalent molecular and phenotypic features of the syndrome

Bohring–Opitz syndrome (BOS) was first described by Bohring et al. [1999]. The authors reported four cases which had several features in common, including a prominent metopic suture, hypertelorism, exophthalmos, cleft lip and palate, limb anomalies, as well as difficulty feeding with severe developmental delays. In almost 50% of cases that meet the clinical criteria for BOS, de novo frameshift and nonsense mutations in the ASXL1 gene have been detected, suggesting that loss of function of this gene is a major cause. We report on the clinical characterization of one young female patient who was evaluated because of severe developmental delays, failure to thrive, and multiple minor anomalies and was clinically diagnosed with BOS. Whole exome sequencing analysis detected one novel disruptive frameshift mutation in the ASXL1 gene and we were also able to confirm the presence of two CFTR mutations associated with her chronic pancreatitis with acute severe breakthrough attacks requiring multiple ICU admissions. This latter complication of pancreatitis further contributed to the complexity of the clinical presentation and represents an independent genetic finding. Our case report emphasizes the importance of highly specific phenotypic characterization of patients with complex phenotypes before proceeding with molecular studies. That approach will lead to more accurate molecular data interpretation and better clinical genetic diagnosis, particularly for those patients with rare, difficult-to-diagnose disorders

Rare inheritance of Leri-Weill Syndrome due to crossover of short stature Homeobox Gene (SHOX) Deletions between X and Y Chromosomes: a case report

Background: Leri-Weill syndrome (LWS) is a genetic disorder caused by deletions or mutations in the SHOX gene or by deletions downstream of the gene and is classically characterized by short stature, mesomelic shortening of forearms and legs, and Madelung deformity. Correct identification of short stature homeobox-containing gene (SHOX) deficiency in children with growth problems is vital for appropriate initiation of growth hormone therapy. Method: We report a phenotypically normal 23 day old male infant born to a father diagnosed with Leri-Weill syndrome at age 12 years with a documented SHOX deletion on his X chromosome. The patient’s fetal long bones had been found to be about three weeks delayed in growth on prenatal ultrasound during the second trimester. Results: The infant underwent genetic evaluation at 23 days of life and was found to have a SHOX deletion on Yp11.32 identified using single nucleotide polymorphism microarray (SNP) analysis and confirmed by FISH using a SHOX gene probe. Conclusion: We report the case of a male infant diagnosed with Leri-Weill syndrome with an unusual documented inheritance between father and son due to crossover between X and Y chromosomes during paternal meiosis. Our case is the youngest patient in literature documented by FISH analysis to have an X to Y chromosome transfer and the first of these patients diagnosed prior to onset of short stature or Madelung deformity. Our patient was identified prior to growth failure and can now be monitored for growth abnormalities with the ability to implement growth augmentation therapy without delay. Our case highlights the importance of advising affected SHOX patients of risks to future offspring and supports screening off-spring of parents carrying SHOX abnormalities regardless of sex

De novo mutations in PURA are associated with hypotonia and developmental delay

PURA is the leading candidate gene responsible for the developmental phenotype in the 5q31.3 microdeletion syndrome. De novo mutations in PURA were recently reported in 15 individuals with developmental features similar to the 5q31.3 microdeletion syndrome. Here we describe six unrelated children who were identified by clinical whole-exome sequencing (WES) to have novel de novo variants in PURA with a similar phenotype of hypotonia and developmental delay and frequently associated with seizures. The protein Puralpha (encoded by PURA) is involved in neuronal proliferation, dendrite maturation, and the transport of mRNA to translation sites during neuronal development. Mutations in PURA may alter normal brain development and impair neuronal function, leading to developmental delay and the seizures observed in patients with mutations in PURA

Lack of difference in treatment patterns and clinical outcomes between black and white patients with inflammatory bowel disease

Background: Previous reports have shown differences in phenotypes among black patients with inflammatory bowel disease (IBD) compared with other racial groups, but prior studies were limited by small numbers of black patients and cross-sectional analyses. We used data from the Sinai-Helmsley Alliance for Research Excellence cohort to compare phenotypes and treatment patterns of black and white patients with IBD in a prospective study. Methods: We compared phenotypes, IBD-specific therapies, and health care utilization among black and white patients with IBD. For all analyses, we performed bivariate analyses and multivariable logistic regression to adjust for potential confounders. Results: Among 5537 patients with IBD, 314 (6%) reported black race. Black patients were more likely to report a Crohn's disease (CD)-related complication at baseline (adjusted odds ratio [aOR], 1.44; 95% confidence interval [CI], 1.06-1.95). Black patients with CD were more likely to develop a new abscess (aOR, 2.27; 95% CI, 1.31-3.93) and initiate an anti-tumor necrosis factor therapy during follow-up (aOR, 1.85; 95% CI, 1.09-3.14). Black patients with ulcerative colitis were more likely to have proctitis (24% vs 13%, P = 0.033) at baseline. There were no differences in surgery or hospitalization rates during the follow-up period. Conclusions: Black patients with CD demonstrated increased complications at baseline and during follow-up in this cohort. Despite more complicated disease, black and white patients with IBD were generally given the same medications and experienced similar rates of hospitalization and surgery during the study period. In our multicenter cohort, clinical outcomes among black and white patients with IBD were similar

Mutations in the Cholesterol Transporter Gene ABCA5 Are Associated with Excessive Hair Overgrowth

Inherited hypertrichoses are rare syndromes characterized by excessive hair growth that does not result from androgen stimulation, and are often associated with additional congenital abnormalities. In this study, we investigated the genetic defect in a case of autosomal recessive congenital generalized hypertrichosis terminalis (CGHT) (OMIM135400) using whole-exome sequencing. We identified a single base pair substitution in the 5′ donor splice site of intron 32 in the ABC lipid transporter gene ABCA5 that leads to aberrant splicing of the transcript and a decrease in protein levels throughout patient hair follicles. The homozygous recessive disruption of ABCA5 leads to reduced lysosome function, which results in an accumulation of autophagosomes, autophagosomal cargos as well as increased endolysosomal cholesterol in CGHT keratinocytes. In an unrelated sporadic case of CGHT, we identified a 1.3 Mb cryptic deletion of chr17q24.2-q24.3 encompassing ABCA5 and found that ABCA5 levels are dramatically reduced throughout patient hair follicles. Collectively, our findings support ABCA5 as a gene underlying the CGHT phenotype and suggest a novel, previously unrecognized role for this gene in regulating hair growth

The mental health burden of racial and ethnic minorities during the COVID-19 pandemic

Racial/ethnic minorities have been disproportionately impacted by COVID-19. The effects of COVID-19 on the long-term mental health of minorities remains unclear. To evaluate differences in odds of screening positive for depression and anxiety among various racial and ethnic groups during the latter phase of the COVID-19 pandemic, we performed a crosssectional analysis of 691,473 participants nested within the prospective smartphone-based COVID Symptom Study in the United States (U.S.) and United Kingdom (U.K). from February 23, 2021 to June 9, 2021. In the U.S. (n=57,187), compared to White participants, the multivariable odds ratios (ORs) for screening positive for depression were 1 16 (95% CI: 1 02 to 1 31) for Black, 1 23 (1 11 to 1 36) for Hispanic, and 1 15 (1 02 to 1 30) for Asian participants, and 1 34 (1 13 to 1 59) for participants reporting more than one race/other even after accounting for personal factors such as prior history of a mental health disorder, COVID-19 infection status, and surrounding lockdown stringency. Rates of screening positive for anxiety were comparable. In the U.K. (n=643,286), racial/ethnic minorities had similarly elevated rates of positive screening for depression and anxiety. These disparities were not fully explained by changes in leisure time activities. Racial/ethnic minorities bore a disproportionate mental health burden during the COVID-19 pandemic. These differences will need to be considered as health care systems transition from prioritizing infection control to mitigating long-term consequences

Brain Abnormalities in Patients with Germline Variants in H3F3: Novel Imaging Findings and Neurologic Symptoms Beyond Somatic Variants and Brain Tumors

BACKGROUND AND PURPOSE: Pathogenic somatic variants affecting the genes Histone 3 Family 3A and 3B (H3F3) are extensively linked to the process of oncogenesis, in particular related to central nervous system tumors in children. Recently, H3F3 germline missense variants were described as the cause of a novel pediatric neurodevelopmental disorder. We aimed to investigate patterns of brain MR imaging of individuals carrying H3F3 germline variants. MATERIALS AND METHODS: In this retrospective study, we included individuals with proved H3F3 causative genetic variants and available brain MR imaging scans. Clinical and demographic data were retrieved from available medical records. Molecular genetic testing results were classified using the American College of Medical Genetics criteria for variant curation. Brain MR imaging abnormalities were analyzed according to their location, signal intensity, and associated clinical symptoms. Numeric variables were described according to their distribution, with median and interquartile range. RESULTS: Eighteen individuals (10 males, 56%) with H3F3 germline variants were included. Thirteen of 18 individuals (72%) presented with a small posterior fossa. Six individuals (33%) presented with reduced size and an internal rotational appearance of the heads of the caudate nuclei along with an enlarged and squared appearance of the frontal horns of the lateral ventricles. Five individuals (28%) presented with dysgenesis of the splenium of the corpus callosum. Cortical developmental abnormalities were noted in 8 individuals (44%), with dysgyria and hypoplastic temporal poles being the most frequent presentation. CONCLUSIONS: Imaging phenotypes in germline H3F3-affected individuals are related to brain features, including a small posterior fossa as well as dysgenesis of the corpus callosum, cortical developmental abnormalities, and deformity of lateral ventricles