Phenotypic Presentation Research Articles

FRI446 A Case Of 46 XX Testicular Disorder Of Sex Development Presenting As Hypogonadism And Infertility

Abstract Disclosure: N. Balachandar: None. S. Agarwal: None. K.K. Soe: None. Introduction: Hypergonadotropic hypogonadism in males can be due to genetic, acquired or developmental causes. Common etiologies of testicular failure include trauma, systemic illnesses, radiotherapy, gonadotoxic drugs, and viral orchitis; in addition, genetic causes should be considered. Here, we present a case of primary hypogonadism and infertility due to 46 XX testicular disorder of sex development (DSD). Case Report: A male in his early fifties with history of obesity presented with fatigue to his PCP. A total testosterone level was 1.8 ng/mL (normal: 1.7 - 7.6 ng/mL) with a repeat value confirming the finding. Bioavailable testosterone was low at 85.1 ng/dL (normal: 110-575 ng/dL). FSH was elevated at 39.9 mIU/mL (normal: 1.3 - 19.3 mIU/mL), and LH was elevated at 16.6 mIU/mL (normal: 1.2 - 8.6 mIU/mL). In endocrinology clinic, he reported a year of fatigue, erectile dysfunction despite normal libido, and an inability to conceive despite three years of regular unprotected intercourse. He noted loss of muscle mass, bilateral breast tissue development, and reduction in testicular size. Physical exam revealed normal phallus, diffusely sparse body hair with atypical male distribution, bilateral gynecomastia, and bilateral reduction in testicular volume (right: 5 mL; left: 8 mL). Chromosomal analysis showed a mosaic pattern of 45 XO in 6% of cells and 46 XX in 94% of cells. Fluorescence in situ hybridization (FISH) analysis confirmed the presence of the sex-determining region (SRY) gene in 96% of cells. Metaphase FISH showed cryptic insertion of the SRY gene into the p arm of the X chromosome. Semen analysis showed azoospermia. He was diagnosed with 46 XX testicular DSD with abnormal mosaicism. He was prescribed testosterone gel and counseled on fertility options resulting in improvement of testosterone levels, sexual function, and subjective well-being. Discussion: The SRY gene, normally located on the p arm of the Y Chromosome, is responsible for development of primitive gonads into testicles during embryogenesis. Homologous recombination occurs between chromosomes during gametogenesis. It is hypothesized that in patients with 46 XX DSD, the SRY gene is translocated to the X chromosome, as demonstrated in this case. Its expression helps with selection of male sex in a growing fetus. Thus, in a 46 XX SRY positive male, the phenotypic presentation is male. Since the AZF gene on the q arm of the Y chromosome which is essential for spermatogenesis is not translocated, 46 XX males are infertile and undiagnosed until adulthood when azoospermia is noted during infertility workup. 46 XX SRY negative males develop ambiguous genitalia leading to earlier diagnosis. Eighty-percent of 46 XX males are SRY positive and twenty-percent are SRY negative. Thus, in adult males presenting with infertility and hypogonadism, genetic causes such as 46 XX DSD with SRY translocation should be considered. Presentation: Friday, June 16, 2023

THU533 Cowden Syndrome: A Rare Disease With A Lasting Impact

Abstract Disclosure: C.S. Hastings: None. S.A. Patrick: None. D. James: None. Introduction: Cowden Syndrome (CS) is a genetic condition caused by an autosomal dominant mutation in the phosphatase and tensin homolog (PTEN) tumor suppressor gene. The prevalence of CS is approximately one in 200,000 and onset is typically in the second decade of life. It is characterized by multiple benign or malignant skin tumors, non-medullary thyroid cancer, breast carcinoma, endometrial carcinoma, gastrointestinal hamartomas, renal cell carcinoma, and/or developmental delay. CS is typically underdiagnosed due to the variety of phenotypic presentations. Case Description: We present a case series of Cowden Syndrome. The first patient was a 51-year-old male with follicular thyroid cancer status post radiation and thyroidectomy, multiple gastrointestinal polyps, trichilemmomas, and an extensive family history of cancer. These factors led to an increased suspicion for CS. The patient underwent genetic testing for PTEN mutations in 2022 and was heterozygous for the c.723dupT pathogenic PTEN mutation as well as p.S598L mutation. The second patient was an 18-year-old female with developmental delay, autoimmune hypothyroidism, multinodular goiter who presented with an increasing number of thyroid nodules on annual thyroid ultrasounds. Her thyroid nodule biopsy revealed follicular and papillary thyroid carcinoma requiring total thyroidectomy. Her mother had a known history of CS. Genetic testing revealed she was heterozygous for the p.S1701 pathogenic mutation in the PTEN gene. Diagnosis of CS involves a combination of family history, presence of mucocutaneous lesions, and either thyroid, breast, or endometrial carcinoma. Given the higher likelihood of cancers in these patients, routine screening for thyroid, breast, kidney, and colon cancers should begin at an earlier age. Treatment includes topical agents such as fluorouracil or excision surgery for skin lesions. Treatment of malignancy is similar to sporadic counterparts and involves systemic immunosuppressants, chemotherapy, or surgery. Conclusion: Cowden Syndrome is a rare genetic condition resulting in tumors in a variety of organ systems, placing patients at a higher risk of malignancy. A strong family history of malignancy, as well as skin, breast, GI, or thyroid findings should prompt further investigation. Collaboration between dermatology, oncology, gastroenterology, endocrinology, and neurology is essential for successful treatment. Routine screening for these patients includes thyroid studies every 3-4 months, thyroid ultrasound yearly, colonoscopy every two years, and renal CT or MRI yearly. Early diagnosis of the condition is pivotal for close cancer surveillance and management. Presentation: Thursday, June 15, 2023

SAT139 Non-insulinoma Pancreatogenous Hypoglycemia Syndrome In A Patient With 1p36 Deletion Syndrome

Abstract Disclosure: E.D. Auckley: None. M.A. Arosemena: None. L. Philipson: None. Background: 1p36 deletion syndrome comprises a phenotypic presentation that includes central nervous system, cardiac, and craniofacial anomalies. There has been no report of associated hypoglycemia with this syndrome. Nesidioblastosis, also known as non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS), is understood as a rare condition defined by diffuse pancreatic hypertrophy with subsequent hyperinsulinemic hypoglycemia. Diagnosis requires serologic workup consistent with endogenous hyperinsulinemic hypoglycemia, intraarterial calcium stimulation positive for inappropriately elevated insulin secretion, and imaging studies without identified masses. Clinical Case: A 21-year-old female with 1p36 deletion syndrome (seizure disorder, cerebral palsy, vision loss and heart failure) was admitted to the hospital due to persistent falls. On admission vital signs were within normal limits, and physical exam revealed a thin non-verbal patient without significant other findings. During hospitalization and prolonged fasting periods of approximately 14-18 hours related to poor appetite she developed several episodes of hypoglycemia with serum glucose as low as 57 mg/dl. As patient was non-verbal at baseline, symptoms of hypoglycemia such as sweating, lightheadedness or shakiness were not confirmed. Even when she started to eat, hypoglycemic events continued to occur. Dextrose containing fluids (Dextrose 5% and later 10%) were added to try to maintain blood sugars within the normal range. Nevertheless, she continued to develop hypoglycemia. Endocrinology service was consulted and recommended to obtain a critical sample. A critical sample revealed serum glucose of 59 mg/dl, insulin level of 20.6 mcU/mL, proinsulin of 33 pmol/L, and beta-hydroxybutyrate of <0.10 mmol/L. Insulin antibodies was negative. Adrenal insufficiency was unlikely due to a normal 9 am cortisol level of 13.7 ug/dl. Due to the presence of hyperinsulinemic hypoglycemia further workup was conducted. A CT of the abdomen with a pancreatic protocol and 68Ga-DOTATATE PET/CT scan was negative for a pancreatic mass. Endoscopic ultrasound did not reveal a clear pancreatic mass either. This was followed by a calcium stimulation test which showed a two-fold increase in insulin levels in all 3 catheterized pancreatic territories. In the absence of a discrete mass, non-surgical management was recommended. For hypoglycemia management patient was started on octreotide injections with resolution of hypoglycemia. Prior to discharge she was switched to lanreotide and was discharged to continue monthly lanreotide injections. Conclusion: To our knowledge, this is the first case reported of NIPHS in a patient with a mutation in 1p36 deletion. Hyperinsulinism in the setting of diabetes has been reported in this syndrome1 but to our knowledge no cases of hypoglycemia with NIPHS have been reported. Presentation: Saturday, June 17, 2023

FRI452 A Rare Case of Klinefelter Syndrome, 48XXYY

Abstract Disclosure: P. Kachhadia: None. S. Khan: None. S. Aldasouqi: None. A. Abu Limon: None. Introduction: Klinefelter Syndrome (KS), 47XXY, is the most commonly seen chromosomal abnormality causing infertility, or primary hypogonadism. Other chromosomal variants are rare. We present a very rare case of nondisjunction of the sex chromosome resulting in a 48XXYY KS variant. Case Presentation: The patient is a 45-year-old male was referred to our clinic for evaluation of early onset osteoporosis. The patient was accompanied by his sister, given his cognitive delay. On initial physical exam, there was a concern about acromegaly with signs of frontal bossing, increased hand size, increased ring size and increased shoe size. More recent pictures of the patient showed significant changes in his facial appearance from few years prior. Other symptoms included night sweats. Physical exam revealed decreased testicular volume (less than 3mL bilaterally). Pituitary labs showed elevated prolactin, elevated LH, FSH and low free and total testosterone. GH, IGF-1 levels were within normal range. Chromosomal analysis showed an unexpected pattern of 48XXYY. In addition, MRI of the pituitary was done which showed increased infundibular stalk and increase in size of the pituitary gland which was thought to be secondary to pituitary microadenoma. DEXA scan confirmed osteoporosis. Patient was treated with testosterone injections and alendronate. The rationale for alendronate therapy was considered as a bridge to prevent fractures while the bone density would expectedly improve with androgen therapy, over time. Discussion: Although KS is commonly seen at a frequency of 1:500-1:1000 males, less common and variable phenotypical presentations can occur and can lead to a delayed diagnosis. The reason for the delay of diagnosis in these rare KS variants is the cognitive impairment which leads to delayed evaluation of fertility or hypogonadism, as contrasted to patients with the common variant, KS 47XXY. Additionally, unlike the classic KS variant, these rare variants are often associated with learning disabilities and gross bony features. Conclusion: Clinicians should be familiar with different clinical presentations of the less common KS genetic variants, in contrast to classical KS variants. Patients with classical KS typically present early in view of recognizable complaints of infertility, while patients with the less common KS variants may not present early on due to cognitive delay. Thus, familiarity with the additional manifestations of the less common KS variants (e.g., gross bony features) can help clinicians to suspect the possibility of these variants, prompting chromosomal analysis for further evaluation in such patients. Presentation Date: Friday, June 16, 2023

FRI198 Acute Pancreatitis And Diabetic Ketoacidosis As A Presentation Of Subclinical Cushing Syndrome

Abstract Disclosure: W.H. Alkhidady: None. N. Almefgaie: None. A. Ekhzaimy: None. Case Report: A 43-year-old Saudi woman, presented to the emergency department with two days history of right upper quadrant pain, radiating to the back. Associated with nausea and vomiting with no history of diarrhea, constipation, or constitutional symptoms. She has a 4-year history of hypertension on 5 mg amlodipine with no history of endocrine or malignant tumors. On Examination she was alert, severely dehydrated with temperature of 37 °C, pulse of 124 per minute, blood pressure of 147/61 mmHg. The abdomen was tender in the right upper quadrant area. A laboratory examination showed lipemic sample with high triglycerides level 11mmol/L (0.4-1.48), high amylase 763nu/l (25-115), lipase 5773 u/l (73-393), low potassium level 2.6 mmol/l (3.50-5.10) and low calcium level 1.25 mmol/l (2.10-2.55). The urine analysis showed 4+ glucosuria and ketonuria. Her venous blood gas showed pH of 7.18 and bicarbonate of 10 mmol/L, random blood glucose was 16 mmol/L and anion gap could not be calculated at that time. A diagnosis of DKA secondary to acute pancreatitis secondary to high triglycerides level was made and management was started along with plasmapheresis. A CT pancreatitis protocol was done which showing a 4.2 x 3.5 cm well-circumscribed left adrenal lesion. An MRCP showed 4.3 cm well defined collision tumor in left adrenal gland, its peripheral part is suggestive of adenoma. further work up showed negative 24-hours urine metanephrins, normal Aldosterone Renin ratio, High 24-hour urine cortisol level 644 nmol/l, low ACTH 0.6 pmol/l and morning cortisol level post 1 mg DST was not suppressed on two different occasions. Since the patient had no phenotypical presentation of Cushing’s a diagnosis of SCS was made. She underwent left robotic assisted adrenalectomy, with pathological diagnosis of adrenocortical adenoma. 2 days later, AM cortisol level reduced to 230 nmol/L. while blood pressure and serum potassium remained normal with no signs of adrenal insufficiency. Her Diabetes mellitus and Hypertriglyceridemia resolved after left adrenalectomy. Conclusion: This case report demonstrates the uncommon association of subclinical Cushing syndrome and acute pancreatitis as a first presentation therefore it highlights the significant role of endocrine evaluation of any young patient with unexplained acute metabolic presentations. Presentation: Friday, June 16, 2023

Autosomal dominant neovascular inflammatory vitreoretinopathy with CAPN5 c.731T > C gene mutation; clinical management of a family cohort and review of the literature

ABSTRACT Background To report a cohort of patients with clinically and genetically diagnosed autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) and showcase the spectrum of the disease utilizing multimodal imaging and genetic testing. Additionally, the utility of multimodal imaging in guiding treatment will also be illustrated. Materials/Methods Five patients from a single-family pedigree in Ohio with clinical signs of ADNIV were evaluated. Medical history, family history, and complete ocular examinations were obtained during regular clinic visits. Multimodal imaging including ocular coherence tomography, fluorescein angiography, wide-field fundus photographs, and Humphrey visual field testing was obtained for all five patients. Additionally, genetic testing for the Calpain-5 (CAPN5) gene was conducted on all patients. Results All five patients were noted to have a CAPN5 c.731T > C (p.L244P) mutation on genetic testing. Using multimodal imaging to supplement the clinical examination, pathologic changes such as retinal vascular inflammation, macular edema, and tractional retinal membranes were well illustrated and monitored over time. This allowed for earlier intervention when appropriate such as with intraocular steroid or systemic anti-inflammatory treatments. Conclusion Phenotypic presentation varied among patients in this series, but is consistent with the spectrum of pathologic changes previously described in patients with other CAPN5 gene mutations. Monitoring of patients with ADNIV utilizing multimodal imaging can help better assess progression of this disease and guide treatment decisions. Additionally, increased genetic testing in patients with inherited retinal diseases may reveal novel gene mutations that could serve as potential targets for future genetic treatment regimens.

Measurement invariance of Child Behavior Checklist internalizing and externalizing factors between non-speaking/partially verbal and speaking autistic children

BackgroundThe Child Behavior Checklist (CBCL) is commonly used to screen for emotional and behavioral concerns (EBC) in autistic children; however, few studies have tested the measurement invariance across language groups. MethodThe current study conducted a multi-group confirmatory factor analysis to examine the factorial invariance of the broadband internalizing and externalizing factor structure between 311 speaking and 1778 non-speaking/partially verbal (NSPV) autistic children using the Simons Simplex Collection (N = 2089), which represents a specific phenotypic presentation of autism. ResultsThe two-factor structure achieved configural and metric but not scalar invariance, suggesting that, while the CBCL appears useful as a measure of EBC in autistic youth within language groups in our sample, the Internalizing and Externalizing domain scores might not be comparable between language groups due to measurement bias. ConclusionsWhile EBC in autistic children can be measured using the CBCL, comparisons between NSPV and speaking children should be approached with caution. Measures that demonstrate invariance across language groups are a critical research priority in understanding how EBC manifest across ability levels, particularly in the development of appropriate mental health interventions. Considerations for practical implications of scalar non-invariance are discussed.

Novel method for prediction of combinatorial phase-variable gene expression states

Short sequence repeat mediated phase variation results in diverse phenotype presentation in many bacteria including Campylobacter and Neisseria species. Current methods for identifying the expression states of phase-variable genes involve taking a high number of single colonies. This approach is subject to bias, sampling effects and high workloads that reduce the ability to perform intermediary sampling. The use of high concentration colony sweeps provides a work around but reduces the resolution of combinatorial expression profiles (termed phasotypes). A parsimonious approach combining both single colony and sweep data was developed to overcome these limitations. The critical methodological advance is the use of an algorithm that utilises the experimental data from the two sample types and a parsimonious, iterative mathematical analysis that outputs the phasotype distribution with the highest likelihood of underpinning the experimental data sets. The advantages of this unified method are increased resolution and accuracy of gene expression state combinations as compared to conventional single colony sampling, reduced requirement for sampling large numbers of colonies leading to reduced costs, and a higher capacity for collecting samples and replicates.•Inputting of sweep and single colony data into an algorithm for a rapid determination of the combinatorial phase variation states (phasotypes) for repeat-mediated phase-variable bacterial genes•This method reduces the number of single colony samples required to produce accurate estimates of phasotypes•This method will reduce the costs of phasotype analyses and increase potential to analyse more time points or sample sites leading to an improved understanding of how phase variation contributes to bacterial host persistence and the ability to cause disease

Emotional dysregulation as a part of the autism spectrum continuum: a literature review from late childhood to adulthood.

The concept of emotional dysregulation (ED) has recently gained interest in the scientific literature and is commonly defined as the inability to use the modulatory mechanisms involved in emotion regulation, resulting in a functioning meaningfully below the baseline. Even though the data available are still limited, an increasing number of studies have hypothesized a promoting role for some of the core features of autism spectrum disorder (ASD) in the development of ED, in particular being repetitive behaviors, social difficulties and alexythimia. In this framework, the purpose of this study was to review the literature that is currently available about presence and correlates of ED in young adults with autism spectrum conditions as well as to offer some insights about possible implications for illness trajectories. The data reported seems to point to a shared etiology between ED and repetitive/restricted ASD symptoms, with perseveration features serving as the foundation for the inability to control one's emotions. In this context, a neurodevelopmental basis for ED could be consistent with the transnosographic conceptualization of ASD, which hypothesizes a potential neurodevelopmental basis for several psychiatric disorders, whose autistic traits would be the phenotypical presentation.

Glutaric Acidemia Type 1: Diagnosis, Clinical features, and Outcome in a Portuguese Cohort.

Glutaric acidemia type 1 (GA1) is a rare autosomal recessive disorder characterized by a deficiency of glutaryl-CoA dehydrogenase, resulting in the accumulation of glutaric acid (GA), 3-hydroxyglutaric acid, and glutarylcarnitine, especially in the brain. GA1-affected children are clinically characterized by macrocephaly. Neurological abnormalities usually appear between 6 and 18 months of age, often triggered by a catabolic event. On the other hand, several biochemically affected individuals may remain asymptomatic or experience an insidious onset of mild neurological abnormalities. Retrospective study of GA1 patients followed at a Portuguese Hereditary Metabolic Disease Center, to characterize the phenotypic and genotypic variations associated with GA1. Therefore, we analyzed the clinical, neuroradiological, biochemical, and genetic information from 14 patients. 14 patients (four months-27 years old) were identified in the last 26 years, 9 were male, 1 was from a consanguineous family. 11 were diagnosed by newborn screening (NBS), and 3 identified following clinical symptoms (later diagnosed, LD). There were 3 phenotypic presentations: 6 asymptomatic, 3 with a motor disability after encephalopathic crisis (EC), and 5 with insidious onset. Acute EC occurred in 1/3 of the LD patients and in 2/11 NBS-identified patients. About urinary GA concentrations: 5 were low excretors (LE), 9 were high excretors (HE). All LE showed symptoms, and 2 had EC. Concerning HE, 3 showed symptoms and 1 had EC. GCDH analysis showed: 6 compound heterozygotes and 8 homozygotes. most frequent variant was c.1204C>T (p.R402W). All of them received appropriate therapy from the time of diagnosis, with a mean age of 23.3 months in LD patients and 13.3 days in NBS-identified patients. The outcomes were different between the two groups: all the LD patients presented motor dysfunction however in the NBS-identified patients only 5 developed this symptom. Patients identified by NBS had better outcomes showing that NBS enables an early diagnosis, and treatment, and consequently improves the clinical outcomes for these patients. No correlation was observed with clinical phenotype between LE and HE, as both groups can suffer the most severe neurological manifestations. These conclusions are in agreement with previous cohorts described in the literature.

The natural history, clinical outcomes, and genotype-phenotype relationship of otoferlin-related hearing loss: a systematic, quantitative literature review.

Congenital hearing loss affects one in 500 newborns. Sequence variations in OTOF, which encodes the calcium-binding protein otoferlin, are responsible for 1-8% of congenital, nonsyndromic hearing loss and are the leading cause of auditory neuropathy spectrum disorders. The natural history of otoferlin-related hearing loss, the relationship between OTOF genotype and hearing loss phenotype, and the outcomes of clinical practices in patients with this genetic disorder are incompletely understood because most analyses have reported on small numbers of cases with homogeneous OTOF genotypes. Here, we present the first systematic, quantitative literature review of otoferlin-related hearing loss, which analyzes patient-specific data from 422 individuals across 61 publications. While most patients display a typical phenotype of severe-to-profound hearing loss with prelingual onset, 10-15% of patients display atypical phenotypes, including mild-to-moderate, progressive, and temperature-sensitive hearing loss. Patients' phenotypic presentations appear to depend on their specific genotypes. For example, non-truncating variants located in and immediately downstream of the C2E calcium-binding domain are more likely to produce atypical phenotypes. Additionally, the prevalence of certain sequence variants and their associated phenotypes varies between populations due to evolutionary founder effects. Our analyses also suggest otoacoustic emissions are less common in older patients and those with two truncating OTOF variants. Critically, our review has implications for the application and limitations of clinical practices, including newborn hearing screenings, hearing aid trials, cochlear implants, and upcoming gene therapy clinical trials. We conclude by discussing the limitations of available research and recommendations for future studies on this genetic cause of hearing loss.

Rare variant modifier analysis identifies variants in SEC24D associated with orofacial cleft subtypes.

As one of the most common structural birth defects, orofacial clefts (OFCs) have been studied for decades, and recent studies have demonstrated that there are genetic differences between the different phenotypic presentations of OFCs. However, the contribution of rare genetic variation genome-wide to different subtypes of OFCs has been understudied, with most studies focusing on common genetic variation or rare variation within targeted regions of the genome. Therefore, we used whole-genome sequencing data from the Gabriella Miller Kids First Pediatric Research Program to conduct a gene-based burden analysis to test for genetic modifiers of cleft lip (CL) vs cleft lip and palate (CLP). We found that there was a significantly increased burden of rare variants in SEC24D in CL cases compared to CLP cases (p = 6.86 [Formula: see text] 10-7). Of the 15 variants within SEC24D, 53.3% were synonymous, but overlapped a known craniofacial enhancer. We then tested whether these variants could alter predicted transcription factor binding sites (TFBS), and found that the rare alleles destroyed binding sites for 9 transcription factors (TFs), including Pax1 (p = 0.0009), and created binding sites for 23 TFs, including Pax6 (p = 6.12 [Formula: see text] 10-5) and Pax9 (p = 0.0001), which are known to be involved in normal craniofacial development, suggesting a potential mechanism by which these synonymous variants could have a functional impact. Overall, this study indicates that rare genetic variation may contribute to the phenotypic heterogeneity of OFCs and suggests that regulatory variation may also contribute and warrant further investigation in future studies of genetic variants controlling risk to OFC.

Contiguous Gene Deletion of Chromosome 15q25.2q25.3 in Biallelic ALPK3-Related Cardiomyopathy: Novel Insights Into Phenotypic Presentation and Variant Spectrum.

Contiguous Gene Deletion of Chromosome 15q25.2q25.3 in Biallelic ALPK3-Related Cardiomyopathy: Novel Insights Into Phenotypic Presentation and Variant Spectrum.

“Fifth‐day fits” revisited: A literature review of benign idiopathic neonatal seizures and comparison with KCNQ2‐ and KCNQ3‐associated benign familial epilepsy syndromes

AbstractBenign idiopathic neonatal seizures (BINS), colloquially referred to as the “fifth‐day fits,” is a clinical neonatal epilepsy syndrome associated with early, spontaneous resolution of seizures and favorable developmental outcome. Although this disease entity was first described over four decades ago, the etiopathogenesis remains unknown, and it is unclear if the syndrome represents a single, cohesive disorder or a common manifestation of various unrelated neonatal neurological disturbances. As such, there are no standardized approaches to diagnostic workup and management. Benign familial neonatal seizures (BFNS) is a well‐characterized genetic syndrome associated with KCNQ2 and KCNQ3 pathogenic variants, which also manifests clinically with self‐resolving seizures in the neonatal period. While it remains unclear if there is any shared pathogenesis between these two disorders, the exceedingly similar phenotypic presentations and natural history raise the question of whether consensus management approaches used in genetic BFNS can also be applied to BINS. Here, we present a topical and historical review of BINS and BFNS literature and propose specific treatment recommendations based on extrapolation of limited existing clinical data.

Urologic manifestations of hypotonia, ataxia, and delayed development syndrome (HADDS), a rare neurodevelopmental disorder

Early B-cell factor 3 (EBF3) is a transcription factor involved in neuronal differentiation and maturation. Pathogenic variants are associated with hypotonia, ataxia, and delayed development syndrome (HADDS) (MIM#617330). Urologic manifestations are common and may have implications regarding long term renal function. To review all known patients with pathogenic variants of the EBF3 gene resulting in HADDS with urologic manifestations. We hypothesize a high rate of bladder dysfunction secondary to the EBF3 variant's impact on relaxation of the urinary sphincter leading to detrusor sphincter dyssynergia (DSD). The PubMed database was queried for publications of the EBF3 mutation between January 2017 and January 2023. Search terms were "EBF3 mutation OR HADDS AND urology OR phenotype". Retrospective analysis of HADDS patients cared for in our institution was performed. Demographic and clinical information was collected. We identified 52 patients (33F:19M) through literature (28F:18M) and retrospective review (5F:1M). There was a high prevalence of genitourinary physical exam abnormalities, history of urinary tract infection, vesicoureteral reflux (VUR), and diagnosis of neurogenic bladder. Within the literature review cohort, 67% had a urologic diagnosis. Females were disproportionately affected with urologic manifestations. In our cohort, four of six children were diagnosed with VUR and severe voiding dysfunction consistent with neurogenic bladder (67%). These children were managed with a vesicostomy. Five children had bowel dysfunction requiring therapy. Urodynamics suggested a high prevalence of external sphincter dyssynergia. Less severe forms of DSD were felt to be implicated in the abnormal voiding parameters in children who presented later in life based on non-invasive flow studies. There is significant variability in the phenotypic presentation of patients with HADDS. While EBF3 plays a clear role in neurodevelopment, it also impacts muscle development and may impact muscle relaxation. The location of the genetic variant may impact the degree of DSD, with more severe forms leading to earlier presentations. Initial work-up should include a renal ultrasound (RUS) and post void residual (PVR). Consideration can be given to obtaining a VCUG, DMSA scan or urodynamic studies. Yearly screening should be pursued with an RUS and PVR in those with an initial unremarkable work-up given the variable timing and severity of presentation. Urologic manifestations of HADDS include high rates of bladder dysfunction secondary to DSD, vesicoureteral reflux, urinary tract infection, and cryptorchidism. These patients are at risk of renal deterioration if urinary abnormalities are not properly diagnosed and managed.

Easily Applicable Predictive Score for Differential Diagnosis of Prefibrotic Primary Myelofibrosis from Essential Thrombocythemia.

Essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (prePMF) initially have a similar phenotypic presentation with thrombocytosis. The aim of our study was to determine significant clinical-laboratory parameters at presentation to differentiate prePMF from ET as well as to develop and validate a predictive diagnostic prePMF model. This retrospective study included 464 patients divided into ET (289 pts) and prePMF (175 pts) groups. The model was built using data from a development cohort (229 pts; 143 ET, 86 prePMF), which was then tested in an internal validation cohort (235 pts; 146 ET, 89 prePMF). The most important prePMF predictors in the multivariate logistic model were age ≥ 60 years (RR = 2.2), splenomegaly (RR = 13.2), and increased lactat-dehidrogenase (RR = 2.8). Risk scores were assigned according to derived relative risk (RR) for age ≥ 60 years (1 point), splenomegaly (2 points), and increased lactat-dehidrogenase (1 point). Positive predictive value (PPV) for pre-PMF diagnosis with a score of ≥points was 69.8%, while for a score of ≥3 it was 88.2%. Diagnostic performance had similar values in the validation cohort. In MPN patients with thrombocytosis at presentation, the application of the new model enables differentiation of pre-PMF from ET, which is clinically relevant considering that these diseases have different prognoses and treatments.

The phenotypic presentation of adult individuals with SLC6A1-related neurodevelopmental disorders.

SLC6A1 is one of the most common monogenic causes of epilepsy and is a well-established cause of neurodevelopmental disorders. SLC6A1-neurodevelopmental disorders have a consistent phenotype of mild to severe intellectual disability (ID), epilepsy, language delay and behavioral disorders. This phenotypic description is mainly based on knowledge from the pediatric population. Here, we sought to describe patients with SLC6A1 variants and age above 18 years through the ascertainment of published and unpublished patients. Unpublished patients were ascertained through international collaborations, while previously published patients were collected through a literature search. A total of 15 adult patients with SLC6A1 variants were included. 9/13 patients had moderate to severe ID (data not available in two). Epilepsy was prevalent (11/15) with seizure types such as absence, myoclonic, atonic, and tonic-clonic seizures. Epilepsy was refractory in 7/11, while four patients were seizure free with lamotrigine, valproate, or lamotrigine in combination with valproate. Language development was severely impaired in five patients. Behavioral disorders were reported in and mainly consisted of autism spectrum disorders and aggressive behavior. Schizophrenia was not reported in any of the patients. The phenotype displayed in the adult patients presented here resembled that of the pediatric cohort with ID, epilepsy, and behavioral disturbances, indicating that the phenotype of SLC6A1-NDD is consistent over time. Seizures were refractory in >60% of the patients with epilepsy, indicating the lack of targeted treatment in SLC6A1-NDDs. With increased focus on repurposing drugs and on the development of new treatments, hope is that the outlook reflected here will change over time. ID appeared to be more severe in the adult patients, albeit this might reflect a recruitment bias, where only patients seen in specialized centers were included or it might be a feature of the natural history of SLC6A1-NDDs. This issue warrants to be explored in further studies in larger cohorts.

The onchocerciasis hypothesis of nodding syndrome.

Nodding syndrome (NS) is a phenotypic presentation of onchocerciasis-associated epilepsy (OAE). OAE is an important public health problem in areas with high ongoing Onchocerca volvulus transmission. OAE, including NS, is preventable by strengthening onchocerciasis elimination programs. The presence of tau in OAE postmortem brains could be the consequence of neuroinflammation directly or indirectly induced by O. volvulus. Omics research is needed to investigate whether O. volvulus worms contain a neurotropic virus.

Sex difference contributes to phenotypic diversity in individuals with neurodevelopmental disorders.

Gain a better understanding of sex-specific differences in individuals with global developmental delay (GDD), with a focus on phenotypes and genotypes. Using the Deciphering Developmental Disorders (DDD) dataset, we extracted phenotypic information from 6,588 individuals with GDD and then identified statistically significant variations in phenotypes and genotypes based on sex. We compared genes with pathogenic variants between sex and then performed gene network and molecular function enrichment analysis and gene expression profiling between sex. Finally, we contrasted individuals with autism as an associated condition. We identified significantly differentially expressed phenotypes in males vs. females individuals with GDD. Autism and macrocephaly were significantly more common in males whereas microcephaly and stereotypies were more common in females. Importantly, 66% of GDD genes with pathogenic variants overlapped between both sexes. In the cohort, males presented with only slightly increased X-linked genes (9% vs. 8%, respectively). Individuals from both sexes harbored a similar number of pathogenic variants overall (3) but females presented with a significantly higher load for GDD genes with high intolerance to loss of function. Sex difference in gene expression correlated with genes identified in a sex specific manner. While we identified sex-specific GDD gene mutations, their pathways overlapped. Interestingly, individuals with GDD but also co-morbid autism phenotypes, we observed distinct mutation load, pathways and phenotypic presentation. Our study shows for the first time that males and females with GDD present with significantly different phenotypes. Moreover, while most GDD genes overlapped, some genes were found uniquely in each sex. Surprisingly they shared similar molecular functions. Sorting genes by predicted tolerance to loss of function (pLI) led to identifying an increased mutation load in females with GDD, suggesting potentially a tolerance to GDD genes of higher pLI compared to overall GDD genes. Finally, we show that considering associated conditions (for instance autism) may influence the genomic underpinning found in individuals with GDD and highlight the importance of comprehensive phenotyping.

Parvovirus in dermatology: A review

AbstractParvovirus B19 is a small nonenveloped single‐stranded DNA virus belonging to the parvoviridae family. The dermatological manifestations are varied ranging from infective to inflammatory, but the most common among infective etiologies is erythema infectiosum, also known as the fifth disease or ‘slapped cheek’ disease, which is mildly contagious. Clinical corroboration of symptoms and signs with serum antibody levels has been seen in acute and persistent parvoviral infections. Other dermatological manifestations of parvovirus B19 infections include erythema multiforme, vasculitis, reticular erythema, maculopapular eruptions, pustular eruptions, papular‐purpuric gloves and socks syndrome (PPGSS) and Gianotti‐Crosti syndrome. Skin lesions are quite characteristic and begin with oedema and erythema symmetrically localized to the hands and feet. Subsequently, petechial and purpuric changes appear varying from a few millimetres in diameter to larger, confluent patches. The primary target of parvovirus B19 is the hematopoietic‐erythroid cell line, specifically near the pronormoblast stage and the vulnerability to cellular damage increases along the differentiation lineage. There's multimodal clinical phenotypic presentation seen in parvoviral infections. Among the clinical expression of HPV B19 infections, the most common is dermatologic, however other manifestations such as rheumatologic and hematologic are not uncommon. However, some infections can be asymptomatic, especially in immunocompetent hosts, whereas in others with haematological abnormalities, these can lead to aplastic cellular crises.