Early Diagnosis of 46,XX Testicular Difference of Sexual Development: Unusual Presentation with Increased Nuchal Translucency.

INTRODUCTION: 46,XX testicular disorder of sexual development (DSD) may present prenatally as a mismatch between phenotype and karyotype. Enlarged nuchal translucency is an abnormal sign of many disorders. We present a first trimester fetus with increased nuchal translucency that was later determined to be a 46,XX testicular DSD. CASE PRESENTATION: A first-trimester pregnancy ultrasound revealed enlarged nuchal translucency. Chorionic villous sampling documented a 46,XX karyotype. Subsequent ultrasounds identified male external genitalia. FISH analysis documented a SRY gene translocation. At birth, the infant had normal male internal and external genitalia. CONCLUSIONS: 46,XX testicular DSD may present in the first trimester with an enlarged nuchal translucency.

Simpson-Golabi-Behmel syndrome: One family, same mutation, different outcome.

Simpson-Golabi-Behmel syndrome (SGBS) is a rare X-linked condition characterized by pre and postnatal overgrowth with visceral and skeletal abnormalities. The syndrome is caused mainly by mutations in the X-linked gene GPC3. Clinical presentation of SGBS in affected males is well defined, but there is a lack of knowledge about affected females, with very few reported cases. In total, eight female carriers with clinical expression of SGBS have been reported to date. In the present report, we describe the ninth patient and her family history. The interesting features of our female patient are the Wilms' tumor and the transfontanelar ultrasound findings. The patient's older sister, carrier of the same mutation, has minor facial dysmorphisms but no congenital anomalies and so far, no further clinical findings, as well as her mother and grandmother. There is a lesson to be learned from these rare cases, namely that SGBS may have a significant clinical expression in females, and therefore, screening should be considered in all patients with SGBS regardless of the sex or phenotypic severity.

Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome.

Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families. A homozygous splice site mutation was identified by Sanger sequencing of SNX14 in a third family, selected purely by phenotypic similarity. This discovery confirms that these characteristic features represent a distinct and recognizable syndrome. SNX14 encodes a cellular protein containing Phox (PX) and regulator of G protein signaling (RGS) domains. Weighted gene coexpression network analysis predicts that SNX14 is highly coexpressed with genes involved in cellular protein metabolism and vesicle-mediated transport. All three mutations either directly affected the PX domain or diminished SNX14 levels, implicating a loss of normal cellular function. This manifested as increased cytoplasmic vacuolation as observed in cultured fibroblasts. Our findings indicate an essential role for SNX14 in neural development and function, particularly in development and maturation of the cerebellum.

Intellectual disability, coarse face, relative macrocephaly, and cerebellar hypotrophy in two sisters.

We report on two Portuguese sisters with a very similar phenotype characterized by severe intellectual disability, absent speech, relative macrocephaly, coarse face, cerebellar hypotrophy, and severe ataxia. Additional common features include increased thickness of the cranial vault, delayed dental eruption, talipes equino-varus, clinodactyly, and camptodactyly of the fifth finger. The older sister has retinal dystrophy and the younger sister has short stature. Their parents are consanguineous. We suggest this condition constitutes a previously unreported autosomal recessive entity.

Ophthalmic Manifestations of Heimler Syndrome in Two Siblings With PEX1 Variants.

PURPOSE: To report two new cases with confirmed diagnosis of Heimler syndrome and describe their systemic and ophthalmic phenotype and visual rehabilitation. METHODS: Retrospective review of medical records. RESULTS: Both siblings were diagnosed as having sensori-neural hearing loss and retinal dystrophy with exuberant intraretinal cystoid spaces and cone-rod dysfunction. The older sibling also had amelogenesis imperfecta and neither had nail abnormalities. Genetic analysis identified homozygosity for the pathogenic variant c.2528G>A p.(Gly843Asp) in the PEX1 gene in both siblings. The parents were heterozygous carriers of the variant. CONCLUSIONS: The authors report a familial case of Heimler syndrome due to biallelic PEX1 pathogenic variants that manifested as macular dystrophy characterized by cone-rod dysfunction and complicated by intraretinal cystoid spaces. Review of the literature shows that ocular phenotype is variable in patients with Heimler syndrome. [J Pediatr Ophthalmol Strabismus. 2024;61(1):59-66.].

Phenotypic spectrum of Simpson-Golabi-Behmel syndrome in a series of 42 cases with a mutation in GPC3 and review of the literature.

Simpson-Golabi-Behmel syndrome (SGBS) is a rare X-linked multiple congenital abnormality/intellectual disability syndrome characterized by pre- and post-natal overgrowth, distinctive craniofacial features, macrocephaly, variable congenital malformations, organomegaly, increased risk of tumor and mild/moderate intellectual deficiency. In 1996, Glypican 3 (GPC3) was identified as the major gene causing SGBS but the mutation detection rate was only 28-70%, suggesting either genetic heterogeneity or that some patients could have alternative diagnoses. This was particularly suggested by some reports of atypical cases with more severe prognoses. In the family reported by Golabi and Rosen, a duplication of GPC4 was recently identified, suggesting that GPC4 could be the second gene for SGBS but no point mutations within GPC4 have yet been reported. In the genetics laboratory in Tours Hospital, GPC3 molecular testing over more than a decade has detected pathogenic mutations in only 8.7% of individuals with SGBS. In addition, GPC4 mutations have not been identified thus raising the question of frequent misdiagnosis. In order to better delineate the phenotypic spectrum of SGBS caused by GPC3 mutations, and to try to define specific clinical criteria for GPC3 molecular testing, we reviewed the clinical features of all male cases with a GPC3 mutation identified in the two molecular laboratories providing this test in France (Tours and Paris). We present here the results of the analysis of 42 patients belonging to 31 families and including five fetuses and three deceased neonates.

Advantages of current fetal neuroimaging and genomic technologies in prenatal diagnosis: A clinical case.

The diagnosis of prenatal microcephaly, as well as the possibility of underlining a genetic cause, is becoming more frequent thanks to advances in prenatal imaging and parallel massive sequencing. One case of primary microcephaly in three sibs demonstrates how complementary diagnostic exams can help to diagnose and establish the etiology.

Combined Oxidative Phosphorylation Deficiency Type-13 with Perinatal Presentation: A Case Report.

INTRODUCTION: Polynucleotide phosphorylase is involved in RNA processing in mitochondria. Biallelic variants in PNPT1 cause mitochondrial RNA import protein deficiency and heterogeneous clinical manifestations. CASE REPORT: The patiest was the first child of remote consanguineous parents, born at 35 weeks by caesarean section due to fetal growth restriction. Apgar index was 9/10/10. Birth weight, length and head circumference were at 3rd, <3rd and 10th percentiles, respectively. In the first hours of life, respiratory distress, hypoglycaemia and seizures ensued. She started invasive mechanic ventilation, phenobarbital and was transferred to ICU. Physical examination showed minor facial dysmorphisms, brief eye-opening, hypotonia and hyporeflexia. Electroencephalogram showed immature pattern and multifocal paroxysmal activity. MRI at D8 of life showed severe reduced brain volume. Normal aminoacid screen was also observed. Expanded newborn screening was negative. Mitochondrial organic aciduria was seen. WES showed a homozygotic likely pathogenic variant in the PNPT1 gene. MRI at 6-months showed brain atrophy, thin corpus callosum, reduced brainstem volume. Bilateral and symmetrical lesions in globi pallidi, compatible with Leigh síndrome were observed. Currently, at 14 months, no neurodevelopment progress, dystonia, visual deficit, sensorineural deafness, hypertrophic cardiomyopathy and microcephaly are observed. CONCLUSION: The early and severe Leigh-like presentation of our patient expands the phenotype spectrum of this disease. As far as we know, this is the first reported case of PNPT1 mutation with onset in the perinatal period. Moreover, hypertrophic cardiomyopathy has not yet been described in association with mutation of the PNPT1 gene. WES was the key for early diagnosis in this patient. It should be done in all children with severe clinical presentation of unknown origin.

Ultrasound and molecular prenatal diagnosis of Beckwith-Wiedemann syndrome: Two case reports.

Beckwith-Wiedemann syndrome (BWS) is a rare genetic disease, characterized by macrosomia, congenital malformations and tumor predisposition, associated with genetic and epigenetic alterations in the 11p15 region. Most cases are diagnosed after birth, with prenatal diagnosis being difficult and depending on the identification of specific ultrasound anomalies, namely macrosomia, macroglossia, omphalocele and renal dysplasia. Case 1: Ultrasound diagnosis at 13 weeks of isolated omphalocele with normal array. At 20 weeks, there were shortened fetal long bones, foot deformity, macroglossia, corpus callosum hypoplasia and bilateral nephromegaly. Due to the polymalformative syndrome, a termination of pregnancy (TOP) was performed. The anatomopathological study of the placenta identified mesenchymal dysplasia. The search for the methylation pattern of the 11p15 region by MS-MLPA was normal and the molecular study of the CDKN1C gene identified a likely pathogenic variant, inherited from the mother. Case 2: Morphological ultrasound at 21 weeks revealed macrosomia, macroglossia, omphalocele, bilateral renal dysplasia, and hydramnios. The cytogenetic study, after amniocentesis, was normal (46,XX karyotype). TOP was performed. The anatomopathological study of the fetus confirmed the described malformations and the one concerning the placenta identified placentomegaly. The search for the methylation pattern of the 11p15 region by MS-MLPA revealed abnormal methylation. These results confirmed the diagnosis of BWS in both cases. Prenatal ultrasound suspicion of this pathology is extremely important to guide the conduct in pregnancy and/or the prevention of perinatal complications. Shortened fetal long bones and foot deformity complement the broad spectrum of this syndrome. Positive molecular tests allow confirming the diagnosis, assessing the risk of recurrence and guiding the surveillance of future pregnancy.

A serious and unusual presentation of congenital isolated ACTH deficiency due to TBX19 mutation, beyond the neonatal period.

Summary: Congenital isolated adrenocorticotrophic hormone (ACTH) deficiency due to T-box transcription factor-19 (TBX19 mutation) (MIM 201400; ORPHA 199296) usually presents in the neonatal period with severe hypoglycemia, seizures, and sometimes prolonged cholestatic jaundice. We report a case with an unusual presentation that delayed the diagnosis. A 9-month-old female patient with no relevant personal history was admitted to the emergency department due to a hypoglycemic seizure in the context of acute gastroenteritis. There was rapid recovery after glucose administration. At age 4, she presented with tonic-clonic seizures, fever, and gastrointestinal symptoms and came to need support in an intensive care unit. Low serum cortisol was documented and hydrocortisone was initiated. After normalization of inflammatory parameters, the patient was discharged with hydrocortisone. The genetic investigation was requested and compound heterozygous mutations in TBX19 were detected. This is a rare case of presentation of TBX19 mutation outside the neonatal period and in the setting of acute disease, which presented a diagnostic challenge. Learning points: Congenital isolated adrenocorticotrophic hormone deficiency due to TBX19 mutation usually presents with neonatal hypoglycemia and prolonged cholestatic jaundice. An uneventful neonatal period, however, does not exclude the diagnosis as the disease may be asymptomatic at this stage. In the context of idiopathic hypoglycemia, even in the context of acute disease, hypocortisolism must always be excluded. Genetic evaluation should be performed in cases of congenital central hypocortisolism to allow proper counselling.

Association between the orientation received during hospitalization and the occurrence of wound healing.

OBJECTIVES: to assess whether there is an association between the orientation received during hospitalization and the occurrence of wound healing from the patient's perspective after hospital discharge. METHODS: concurrent cohort, with 180-day follow-up, held in Dermatology Ward. A total of 62 patients with wounds requiring care after discharge were evaluated between July 2015 and November 2016. Information about the orientation was obtained by phone call between 7 and 10, 60, 120 and 180 days after discharge. RESULTS: the older the patient, the lower the chance of healing in up to ten days; and the longer the hospitalization, the lower the chance of healing. They received orientation in the high 90.3%, while 87% understood the orientations. CONCLUSIONS: there was no association between the orientation received during hospitalization and the occurrence of wound healing from the patient's perspective after hospital discharge.

DEPDC5 variant in focal cortical dysplasia: a case report and review of the literature.

Germline and 2-hit brain somatic variants in DEPDC5 gene, a negative regulator of the mammalian target of rapamycin (mTOR) pathway, are increasingly recognized in patients with focal cortical dysplasia (FCD). Next-generation targeted sequencing identified a heterozygous germline variant in DEPDC5 gene (c.3241A>C, p.Thr1081Pro), classified as of unknown significance, in a patient with clinical features compatible with DEPDC5 phenotype (FCD, focal epilepsy, attention-deficit/hyperactivity disorder and borderline intellectual functioning). This missense variant has previously been reported in two other epileptic patients. Although interpretation of missense variants remains a challenge, DEPDC5 variants in patients with FCD and epilepsy cannot be neglected. Null variants were the most frequently reported in FCD patients, but missense variants have been described as well. The recognition of DEPDC5 phenotype and the appropriate interpretation of the detected variants are essential, since it may have important treatment implications in the near future, namely the use of mTOR inhibitors.

Helping Couples Connect during the COVID-19 Pandemic: A Pilot Randomised Controlled Trial of an Awareness, Courage, and Love Intervention.

BACKGROUND: A second pandemic of mental health problems due to COVID-19 is predicted, suggesting a demand for interventions to mitigate its impacts. This study evaluated the effectiveness of an online psychological intervention based on the Awareness, Courage, and Love (ACL) model from Functional Analytic Psychotherapy to promote closeness between couples during the pandemic. METHOD: Thirty-one couples were randomised into either the intervention or control group for a 2-hour online group session. The intervention was designed to increase closeness between couples, whereas control group members watched a movie. In both groups, participants responded to two instruments that assessed the couple's relationship. Generalised linear mixed modeling was used to compare the change scores over time between the groups, with random effects used to control for the correlation within a couple and the correlation within the individual. RESULTS: The intervention group's closeness increased by 23 per cent while the control group's closeness increased only 2 per cent. A week later, a significant difference between the two groups emerged on closeness. CONCLUSION: Online ACL protocols requiring minimal training offer a promising intervention to quickly buffer against stress for large numbers of individuals during pandemic times.

Aspects that influence the self-care of patients living with human immunodeficiency virus.

OBJECTIVE: to analyze aspects related to the increase or decrease of self-care in patients living with human immunodeficiency virus treated in a specialized outpatient service. METHOD: analytical cross-sectional study with 135 patients aged 18 and over, of both sexes, who are followed up on the service. The independent variables and outcomes were collected from the nursing consultation instrument, whose theoretical reference is the Orem's Theory. The data were analyzed by parametric approach. Relationships or differences were considered significant if p <0.05. The analysis was done with SPSS v21.0 software. RESULTS: most participants were male (56.3%), with a mean age of 42.1 years. Patients who needed to conceal the diagnosis had less self-care (ß = -0.72 (-1.38, -0.06), p <0.031). The chance of performing self-care decreased with increasing age (OR = 0.93 (0.89, 0.97), p <0.003). On the other hand, patients with a permanent partner had a higher chance of performing self-care (OR = 3.46 (1.27, 9.46), p <0.015). CONCLUSION: aspects related to the increase or decrease of self-care in patients living with human immunodeficiency virus were evidenced. However, further studies are necessary to emphasize the analytical character of the self-care of these patients.

Gastric emptying before and after cholecystectomy in patients with cholecystolithiasis.

BACKGROUND/AIMS: The objective of the present study was to measure gastric emptying time of solids and semisolids in dyspeptic individuals with cholecystolithiasis before and 6 months after cholecystectomy in order to determine whether cholecystectomy interferes with gastric emptying. METHODOLOGY: A prospective, self-pairing study was conducted on 29 patients selected according to appropriate inclusion and exclusion criteria. Gastric emptying time of solids and semisolids was determined before and six months after laparoscopic cholecystectomy by the 13C-octanoic acid and 13C-acetate breath tests, respectively. The samples were analyzed by infrared spectrometry. The gastric retention time (lag phase) and gastric emptying half-time of solid and semisolid were determined and the results obtained before and after surgery were compared in the same patient. In addition, the effects of surgery on dyspeptic symptoms were assessed. RESULTS: No significant differences (p>0.05) in gastric retention time and gastric emptying half-time of solid and semisolid test meals were observed before and after cholecystectomy. Dyspeptic symptoms (pain, upper abdominal gases, early satiety, nausea and vomiting) improved after surgery. CONCLUSIONS: Laparoscopic cholecystectomy does not interfere with the gastric emptying time of solids or semisolids in dyspeptic individuals with cholecystolithiasis.

Intervención psicológica corta para promoción del enfrentamiento de los estresores en la enseñanza universitaria / Intervenção psicológica breve para promoção do enfrentamento dos estressores no ensino superior / Brief psychologycal intervention for the promotion of ways to cope with stressors in higher education

O ingresso no Ensino Superior inclui estressores variados para o estudante e a literatura aponta a necessidade de intervenções para facilitar a adaptação à universidade. A oficina de vivências acadêmicas, uma intervenção psicológica breve (8 sessões) de base analítico-comportamental, buscou desenvolver repertórios para o enfrentamento dos estressores presentes no Ensino Superior. Participaram 9 acadêmicas de enfermagem, que após consentimento, responderam antes e após a participação na oficina: 1) o Self-Reporting Questionnaire, versão brasileira, um instrumento de triagem de sintomas relacionados a transtornos mentais comuns (TMC); e 2) a Escala de Bem-estar Psicológico (EBEP). Inicialmente, 88,9% das participantes apresentavam sintomas de TMC, e a média da EBEP foi 24,97 (DP=1,22). Após a intervenção, somente 22,2% das estudantes continuaram apresentando sintomas de TMC, e a média da EBEP aumentou para 29,34 (DP=1,17). As implicações dessa intervenção são discutidas tendo em vista os desafios enfrentados pela Psicologia Escolar e Educacional no Ensino Superior.

La entrada en la enseñanza universitaria incluye estresores variados para el estudiante y la literatura apunta la necesidad de intervenciones para facilitar la adaptación a la universidad. El taller de vivencias académicas, una intervención psicológica corta (8 sesiones) de base analítico-comportamental, buscó desarrollar repertorios para el enfrentamiento de los estresores presentes en la enseñanza universitaria. Participaron 9 académicas de enfermería que, tras consentimiento, respondieron antes y después la participación en el taller: 1) el Self-Reporting Questionnaire, versión brasileña, un instrumento de selección de síntomas relacionados a trastornos mentales comunes (TMC); y 2) la Escala de Buen-estar Psicológico (EBEP). Inicialmente, el 88,9% de las participantes presentaban síntomas de TMC, y el promedio de la EBEP fue 24,97 (DP=1,22). Tras la intervención, solamente el 22,2% de las estudiantes continuaron presentando síntomas de TMC, y el promedio de la EBEP aumentó para 29,34 (DP=1,17). Las implicaciones de esta intervención son discutidas teniendo en vista los desafíos enfrentados por la Psicología Escolar y Educacional en la enseñanza universitaria.

Enrolling in Higher Education includes various stressors for the student and the literature points to the need for interventions to facilitate adaptation to university. The academic experiences workshop, a brief psychological intervention (8 sessions) based on behavioral analysis, sought to develop repertoires for coping with the stressors present in higher education. Nine nursing students participated after signing consent terms. They provide answers before and after participating in the workshop: 1) the Self-Reporting Questionnaire, Brazilian version, an instrument for screening symptoms related to common mental disorders (CMD); and 2) the Psychological Well-Being Scale (PBS). Initially, 88.9% of participants had symptoms of CMD, and the mean EBEP was 24.97 (SD=1.22). After the intervention, only 22.2% of the students continued to present symptoms of CMD, and the mean EBEP increased to 29.34 (SD=1.17). The implications of this intervention are discussed in view of the challenges faced by School and Educational Psychology in Higher Education.

Stressors and maternal Coping in Congenital Zika virus Syndrome / Estressores e Coping materno no contexto da Síndrome Congênita do vírus Zika

Objective: Congenital Zika virus Syndrome is characterized by a series of neurological changes bearing consequences for child development. In view of the large number of children born with microcephaly and other neurological disorders, this qualitative study sought to understand and review the coping strategies used by 10 mothers of children affected by the syndrome. Methods: A semi-structured interview was applied, which identified four main maternal stressors: diagnosis; childcare routine; child treatment; and development and access to health services. Results: The most used coping strategies with regard to these stressors were: information-seeking, problem-solving, and delegation. Conclusion: The implications of such results for the care of this population are discussed within the perspective of expanding the adaptive coping to these stressors and ensuring the necessary support for those families in the long and difficult process of taking care of a child with this syndrome.

Objetivo: A síndrome congênita do vírus Zika é caracterizada por uma série de alterações neurológicas com consequências para o desenvolvimento da criança. Diante do elevado número de crianças afetadas pela síndrome, nascidas com microcefalia e outros distúrbios neurológico, este estudo qualitativo buscou compreender e analisar as estratégias de coping utilizadas por 10 mães de crianças afetadas nessa situação. Método: Foi utilizada uma entrevista semiestruturada, que identificou quatro principais estressores maternos: o diagnóstico; a rotina e os cuidados com a criança; o tratamento e desenvolvimento da criança e a dificuldade de acesso aos serviços de saúde. Resultados: As estratégias de enfrentamento mais utilizadas para lidar com esses estressores foram: busca de informações, resolução de problemas e delegação. Conclusão: Discutem-se as implicações desses resultados para o cuidado das mães na perspectiva de ampliar o enfrentamento adaptativo aos estressores e garantir o suporte necessário às famílias no longo e difícil processo de cuidar de uma criança com a Síndrome Congênita do Vírus Zika.

Why could a woman have three Trisomy 21 pregnancies? - a case report.

Mosaicism, an important cause for recurrent T21, should be suspected in families with more than one affected child wishing to receive prenatal counseling. Fluorescence in-situ hybridization analysis in a large number of cells and in different tissue samples is critical for detecting low-level mosaicism and is a key prognostic factor.

Validation of a Next-Generation Sequencing Pipeline for the Molecular Diagnosis of Multiple Inherited Cancer Predisposing Syndromes.

Despite the growing knowledge of the genetic background behind the cancers that occur in a context of hereditary predisposition, personal or family cancer history may not be clear enough to support directional gene testing. Defined targeted next-generation sequencing gene panels allow identification of the causative disease mutations of multigene syndromes and differential diagnosis for syndromes with phenotypically overlapping characteristics. Herein, we established a next-generation sequencing analysis pipeline for the molecular diagnosis of multiple inherited cancer predisposing syndromes using the commercially available target sequencing panel TruSight Cancer. To establish the analysis pipeline, we included 22 control samples with deleterious mutations covering all genes currently analyzed at our institution by standard Sanger sequencing. We tested the pipeline using 51 samples from patients with a clinical diagnosis of neurofibromatosis type 1 (NF1), 10 of which without previous molecular characterization of the causative NF1 mutations. We propose a thoroughly validated analysis pipeline that combines Isaac Enrichment, Burrows-Wheeler Aligner Enrichment, and NextGENe for the alignment and variant calling, and GeneticistAssistant for variant annotation and prioritization. This pipeline allowed the identification of disease-causing mutations in all 73 patients, including a large duplication of 37 bp in NF1. We show that high sensitivity and specificity can be achieved by using multiple bioinformatic tools for alignment and variant calling and careful variant filtering, having in mind the clinical question.