Swedish family and cancer data constitute the largest source on familial cancer in the world. We analyze here familial risks in prostate cancer (PC) with focus on multiple affected brothers and comparation of full-brothers to maternal and paternal half-brothers. Age-specific incidence and standardized incidence ratios (SIRs) were calculated for PC in brothers. Curves for relative risk (RR) by diagnostic age were plotted for risk distributions. A total of 115,066 PCs were diagnosed in 1.2 million men. Familial SIR for full brothers was 2.23, for maternal half-brothers it was 1.92 and paternal half-brothers was 1.34. Considering SIRs with least possible detection bias (7+ years after first brother's diagnosis) the above SIRs were 2.06, 1.66 and 1.41. SIRs in full brothers increased stepwise by the number of affected brothers reaching 21.33 when 6 brothers were affected. Age-RR curves for two affected brothers declined evenly from RR 2.8 at age 45 to below 2.0 at age 80. When four or more brothers were affected, a discrete high-risk peak (RR 4-7) was detected between ages 60 and 69. Data on full-brothers and half-brothers indicate that familial risk in PC is largely genetic which is also supported by discrete RR peaks in high-risk families at ages matching preferential penetrance age for known predisposition genes of PC. Familial risk increased already when two brothers were affected calling for clinical vigilance concerning family history. Family history should deserve a place as an inclusion criterium in schemes for PC screening.
Advances in genetic testing have allowed for refined phenotypic categorization of pediatric-onset genetic movement disorders. ADCY5-related movement disorder is among this group of conditions for which we have begun to better understand a genotype-phenotype correlation. This case series details the clinical course of three biological brothers with autosomal recessively inherited biallelic variants in the ADCY5 gene. Each brother demonstrates a varied severity and combination of mixed movement disorder phenomenology, including parkinsonism, dystonia, and myoclonus exemplified in videos. The phenotype classically associated with ADCY5-related movement disorders, particularly when inherited recessively, should be expanded to include a wider spectrum of severity as well as early-onset parkinsonism. Adjusting the classically recognized phenotype in this way will help to prevent delays to genetic testing, diagnosis, and treatment while informing prognostic counseling.
Research examining family relationships in families with autistic members remains limited, and integrative frameworks that translate evidence into family focused practice are scarce. Existing interventions often prioritise individual symptom management rather than strengthening family relationships and connectedness. This article presents an evidence informed practice model designed to enhance relationships and connectedness in families of autistic adolescents, grounded in systems theory. The model draws on qualitative research with 44 participants from 18 families, including autistic adolescents, parents and siblings. Family relationship experiences and dynamics were explored, with seven key findings informing the conceptual framework and practice model. Disruptive factors such as stress, conflict, caregiver burden and challenges in relating contributed to withdrawal and disconnection, while connective factors including communication, teamwork, routines and shared positive experiences supported bonding. The practice model comprises six elements and is guided by ten principles across family structure, roles, communication and adaptive patterns. This model addresses gaps in holistic family support and offers practitioners evidence informed, family centred strategies that build on strengths while addressing relational challenges.
Research examining Deaf older adults' needs or experiences of old age care is scarce. This study aims to describe how Deaf older adults, supported by Swedish old age care, experience interactions and participation in everyday life and in social care situations. This study gives voice to Deaf older adults whose perspectives are rarely represented in research. To minimize misunderstandings, the qualitative individual interviews with Deaf older adults were conducted by Deaf signing research assistants. The results show that Deaf older adults face communication barriers due to a lack of shared language with their old age care staff, which may also pose health risks. Yet, despite the absence of sign language communication, participants described communication with those who help them as sufficient for basic needs, albeit limited. Furthermore, restricted community mobility contributed to sparse social contacts with Deaf peers, leading to social isolation and reduced social well-being.
We report the case of an 82-year-old male acalabrutinib-treated patient with chronic lymphocytic leukemia (CLL) who was admitted to hospital because of a crural ulceration. Examination of a peripheral blood smear revealed 81% of the neutrophils as hypolobulated in addition to the leukemic lymphoma- and smudge cells. The nuclei of the abnormal neutrophils showed a markedly clumped chromatin and appeared as unilobular (round or oval) in 51%, bilobular in 13% and peanut- and band-shaped in 17%, respectively. A suspected diagnosis of a drug-induced acquired Pseudo-Pelger-Huet anomaly (PPHA) was made, because the morphological anomaly was not apparent in several blood smears prior to the initiation of acalabrutinib. Retrospectively, the presence of hypolobulation was first mentioned in a medical report two weeks after starting acalabrutinib. PPHA has been reported in a few patients with CLL, associated with different therapy regimens such as bendamustin- and fludarabine-containing chemotherapy protocols, venetoclax as well as the Bruton tyrosine kinase inhibitors ibrutinib and zanubrutinib. To our knowledge, an association of PPHA with acalabrutinib has not been previously described. The prevalence, the underlying pathomechanism as well as a potential clinical implication of this phenomenon have not been elucidated so far.
X-linked intellectual disability (XLID) is a well-recognized group of neurodevelopmental disorders, with pathogenic variants in X-chromosomal genes accounting for approximately 16% of intellectual disability cases in males. Clinical expression in females is variable and depends on patterns of X-chromosome inactivation. We describe three affected individuals from a single family with XLID caused by a confirmed duplication of the Xq28 region, including the genes SLC6A8, L1CAM, MECP2, TKTL1, FLNA, and GDI1. Two male siblings presented with severe phenotypes, including profound intellectual disability, severe speech impairment, behavioral issues, facial dysmorphism, spastic cerebral palsy, epilepsy, and cutaneous abnormalities. Their mother showed mild intellectual disability and skin manifestations. Family history suggested additional affected male relatives with a similar or even more severe clinical presentation. The duplication of multiple dosage-sensitive genes within the Xq28 region likely explains the multisystem involvement and the marked phenotypic variability observed between male and female family members. This report highlights the importance of considering Xq28 duplication, the most common X-linked copy number variation associated with intellectual disability, in the differential diagnosis of families with X-linked intellectual disability, especially if it is accompanied by additional neurological impairment.
A childhood cancer diagnosis creates a profound crisis for the entire family. While the psychological distress of this journey is well-documented globally, the lived experiences of families within the specific socio-political and economic context of Iran remain underexplored. This study aimed to explore the lived experiences of Iranian families caring for a child with cancer. A hermeneutic phenomenological study was conducted in Urmia, Iran. Through purposive sampling, 19 family members (parents and siblings) of children with cancer were recruited. Data were collected over an 8-month period (November 2023-June 2024) via in-depth, semi-structured interviews. The data were analyzed using the Van Manen approach and managed using MAXQDA software. Trustworthiness was ensured through strategies such as peer debriefing with an external qualitative researcher and maintaining a detailed audit trail of all analytical decisions. The analysis yielded 2433 codes, categorized into 14 sub-themes and 5 main themes: (1) psychological and emotional concerns, (2) physical and medical concerns, (3) family challenges, (4) support systems as an important asset, and (5) spiritual experiences. These findings were experienced under the pervasive shadow of sanctions and the threat of war. The experience of caring for a child with cancer in Iran is deeply shaped by the interplay of intense emotional suffering and significant structural challenges, including economic pressure and limited support systems. The findings underscore the critical need for culturally sensitive psychosocial support and policy interventions that address the unique socio-economic vulnerabilities of these families.
Sepiapterin reductase deficiency (SPD) is an extremely rare autosomal recessive neurotransmitter disorder caused by mutations in the sepiapterin reductase gene. Clinical features include motor and cognitive manifestations, and L-DOPA/Carbidopa is the main therapy available. To date, it is not known if prenatal diagnosis of SPD may improve the motor and cognitive outcomes by prompt correction of dopamine and serotonin deficiency after birth. We describe the motor and cognitive profiles of 2 siblings with SPD with a follow-up of 9 and 6 years, respectively. The diagnosis of the second patient was prenatally performed and the patient was treated by the neonatal age. Conversely, the first patient was treated by 10 months of age. Early treatment with L-DOPA/Carbidopa seems to be effective in improving motor outcomes but had no impact on cognitive impairment. Protocols for further treatment attempts, potentially also started before birth, are needed to provide conclusive results.
The present study aims to assess the incidence of causes of cardiac arrest and sequelae after resuscitation from OHCA (out-of-hospital cardiac arrest) identified on early, post-arrest Computed Tomography (CT). This is an observational, registry study of adult OHCA patients admitted to three hospitals at the University of Pennsylvania Health System who achieved sustained return of spontaneous circulation between January 2019 and October 2020. Data collected encompassed demographics, arrest characteristics, basic metabolic profiles, CT imaging data, and clinical care notes. Primary outcome is survival to hospital discharge and secondary outcomes included neurologic outcome, CT findings and interventions, and IV contrast and kidney injury rates. Out of 161 patients, 117 received at least one CT in the ED after return of spontaneous circulation. The most common pathologies identified by post-arrest CT scans include cerebral oedema (30/117); pulmonary embolism (8/87); sternal fractures (9/87); pulmonary infiltrates (69/87) that included aspiration, pneumonia, or pneumonitis; deep venous thrombosis (4/64); pulmonary contusions (4/87); hematomas (2/87); flail chest (1/87). Early CT imaging after ROSC from OHCA regularly identified potential causes of cardiac arrest and important sequelae of resuscitation efforts. Implementing larger scale prospective studies comparing such protocols and standard-of-care is important to determine impact on OHCA outcomes.
Severe combined immunodeficiency (SCID) is a life-threatening primary immunodeficiency disorder. This study aimed to identify novel recombination activating gene 1 (RAG1) variants in a Chinese pedigree and characterize their impact on protein structure and function, providing a genetic basis for preimplantation genetic testing for monogenic (PGT-M) cycle. Potential RAG1 mutations of the probands were screened by whole-exome sequencing (WES) and confirmed by Sanger sequencing. Configuration predictions of the variants were achieved using SWISS-MODEL. PROVEAN, PolyPhen-2, and MutationTaster were used to predict their pathogenicity. Isogenic pre-B cell lines carrying the mutations were established via CRISPR-Cas9 RNP editing. Functional impacts were assessed through western blotting, proliferation ability, and apoptosis analysis. We identified novel compound heterozygous RAG1 variants c.946T > G (p.C316G) and c.1197_1199del (p.L400del) in two affected siblings with typical SCID. Familial genotyping confirmed autosomal recessive inheritance, with each parent as an asymptomatic carrier of one variant. Both mutations were highly conserved and predicted to be pathogenic. Structural modeling revealed disruption of RAG1 secondary and tertiary structure, affecting zinc-binding (p.C316G) and hydrogen-bonding (p.L400del) interactions. Functional studies demonstrated markedly reduced RAG1 protein expression, synergistic impairment of RAG2 expression, and significantly elevated apoptosis in double-mutant pre‑B cells. Further investigation indicated dysregulation of the PI3K/AKT1/FOXO1 pathway, evidenced by increased phosphorylation of AKT1 and FOXO1. Our study provides genetic and functional evidence that biallelic RAG1 p.C316G and p.L400del mutations act synergistically to cause SCID through protein destabilization, disruption of RAG1/RAG2 complex integrity, and induction of pre‑B cell apoptosis likely mediated by PI3K/AKT1/FOXO1 signaling dysregulation. These findings expand the mutational spectrum of RAG1 and support the clinical application of PGT-M for affected families.
The epidemiology of sporotrichosis, a neglected mycosis caused by Sporothrix species, has shifted in South America from classic sapronosis to urban zoonosis driven by feline transmission of the hypervirulent Sporothrix brasiliensis. However, the fine-scale transmission dynamics of this epidemic, particularly within households, remain poorly understood. Here, we dissect an intrafamilial outbreak in Brazil involving a cat (the index case), a dog, and three humans. High-resolution genotyping using 15 microsatellite markers revealed a clonal transmission event, with isolates from the index cat and human patients being genetically indistinguishable (100% similarity). Multiple bioinformatic analyses, including principal component analysis, minimum spanning tree, and self-organizing maps, corroborated these findings. Strikingly, this outbreak strain produced markedly divergent clinical phenotypes, including Parinaud's oculoglandular syndrome in an 8-year-old girl, a fixed cutaneous lesion in her 5-year-old brother, and a disseminated maculopapular exanthem in her 28-year-old mother. This clinical pleomorphism from a genetically invariant pathogen unequivocally demonstrates the pivotal role of host factors, such as age, immune response, and inoculation site, in dictating disease manifestation. Furthermore, all outbreak isolates belonged to the MAT1-1 idiomorph, a finding that challenges the paradigm of a monolithic epidemic dominated by MAT1-2 strains and suggests a more complex, polycentric expansion of S. brasiliensis. Overall, this study provides strong evidence of zoonotic transmission and highlights how host determinants, not pathogen variability, shape the clinical diversity of sporotrichosis.
After participating in this CME activity, the psychiatrist should be better able to:• Describe the mental, physical, and social health risks experienced by individuals bereaved by suicide across different kinship groups.• Identify key gaps in the current suicide bereavement research literature and explain their implications for clinical postvention strategies.• Differentiate suicide bereavement-related risks by kinship group (offspring, parents, spouses, siblings) and age at the time of loss.• Recognize populations with the highest suicide bereavement-related vulnerabilities. Suicide bereavement is a global public health problem associated with adverse physical and mental health outcomes. While population-based registry studies offer a promising avenue to understand the impacts of suicide bereavement, there has been no systematic review of results from such studies. This systematic review examines mental, physical, and social health outcomes among suicide-bereaved individuals in global population-based registry studies, with a focus on differences in findings by outcome, kinship, and comparison group. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for studies registered in PubMed and PsycInfo. The review was conducted in April 2025. The initial search revealed 404 unique records. After screening and full-text review, 36 studies published between 2005-2024 were included. Most frequently, studies examined bereaved offspring (n = 20), followed by bereaved parents (n = 8), spouses (n = 5), siblings (n = 5), and unspecified familial relations (n = 5). Overall, suicide loss was frequently associated with adverse health outcomes, including mortality, particularly due to suicide, and mental health (e.g., major depression, self-harm), and some physical health concerns. Associations meaningfully differed by kinship and comparison group. This is the first systematic review on population-based registry research concerning relationships between suicide loss and adverse mental, physical, and social health outcomes. Future studies should examine patterns of disease comorbidity, expand types of kinship examined (e.g., roommates), and probe how risk varies by time since loss.
To what extent do individual cognitive biases in anticipating position stability reflect and reproduce structural socioeconomic inequalities? The Korean Longitudinal Survey on Aging 2006-2020 allows estimating the probability of keeping one's position six years ahead at each wave. Respondents are also asked to anticipate their probability of remaining in position five years ahead. The gap between these two underlying log-hazard rates quantifies agents' error regarding their professional future. With age, both anticipated hazards and underestimation increase. Underestimation increases over anticipation time. Unpaid family workers are influenced by family environment and residence; self-employed workers by housing, siblings and the suitability of their education for the position held; daily wage earners by children, consumption, savings and sector of activity; temporary wage earners by variables linked to extended family; regular wage earners by personal success variables. A recommendation is to provide tables for position retention by covariate built from a representative longitudinal survey, such as the one used.
Combined dyslipidemia of overweight/obesity (CDO) is prevalent in youth and is associated with an increased risk of early cardiovascular disease. We sought to determine the impact and safety of statin therapy for CDO in adolescents. A double-blind, randomized trial was performed across 18 North American sites. Participants aged 10 to 19 years with body mass index ≥85th %ile and CDO defined as non-high-density lipoprotein cholesterol (HDL-C) ≥120 mg/dL (3.10 mmol/L) and either low HDL-C or high triglyceride:HDL-C ratio were randomized centrally to receive either pitavastatin calcium 4 mg/d or placebo for 2 years. The primary outcome was change in carotid-femoral pulse wave velocity (PWV), assessed at baseline, 6, 12, 18, and 24 months. Secondary outcomes included safety and lipid measures. The intention-to-treat analysis included 59 participants (33 males) who received pitavastatin calcium and 60 who received placebo (32 males), enrolled from June 2018 to April 2021. There were no significant changes or trends for PWV in either group. Compared with placebo, at 24 months, pitavastatin was associated with significantly reduced low-density lipoprotein cholesterol (from 134 ± 23 mg/dL [3.47 ± 0.60 mmol/L] to 105 ± 25 mg/dL [2.72 ± 0.65] pitavastatin vs 130 ± 25 mg/dL [3.37 ± 0.65] to 126 ± 27 mg/dL [3.26 ± 0.70] placebo; P < .001). There was 1 serious adverse event (placebo), and no significant differences in liver enzymes, muscle toxicity, glucose homeostasis, or linear growth. Over 2 years, treatment with pitavastatin calcium of CDO for adolescents resulted in no changes in vascular measures. Statin therapy safely lowered atherogenic lipid particles, potentially reducing cardiovascular risk.
This study investigated factors associated with socioemotional outcomes in preschool-aged siblings of children and adolescents/youth with chronic conditions and special care needs (CYSHCN) and examined whether parenting influences these outcomes. This cross-sectional study included 123 healthy preschool-aged siblings of CYSHCN receiving care in Brazil. Socioemotional outcomes were assessed using the Strengths and Difficulties Questionnaire (SDQ), and parenting was measured using the Parenting Sense of Competence Scale (PSOC). Data analysis included bivariate tests to explore associations between predictors and socioemotional outcomes followed by structural equation modeling (SEM) to examine direct and mediated pathways via parental sense of competence. Final model demonstrated satisfactory fit (χ2/df = 2.24, CFI = 0.969, TLI = 0.950, SRMR = 0.073, RMSEA = 0.082). Half of the preschoolers scored in the "abnormal" range (according to SDQ classification) for socioemotional difficulties, with conduct problems most prevalent. Socioemotional problems were associated with greater clinical severity of the CYSHCN. The analysis using SEM showed that parental competence mediated the relationship between CYSHCN clinical severity and healthy sibling's socioemotional outcomes (indirect effect a*b = 0.075, p = .046; 21.3% mediation). This study focused on preschool-aged children, a sensitive period for socioemotional development that remains underexplored in research on siblings of CYSHCN, and demonstrated that they are at an increased risk for socioemotional difficulties, especially when the condition of the CYSHCN is more severe. Parental competence plays a mediating role and may buffer this association, highlighting the need for interventions that strengthen parenting to promote better child outcomes.
Face processing is fundamental to social communication and has been a major focus of autism research. While event-related potential (ERPs) studies of face processing have produced mixed results, little work has examined neuro-oscillatory dynamics, which may better capture the integrity of underlying networks. To address this gap, EEG was recorded from children aged 8-13 across three groups: autistic (n = 50), non-autistic (n = 38) and siblings of autistic children (n = 26), during a visual oddball task. In a blocked design, participants viewed faces and objects, presented upright and inverted (non-targets), to assess the face inversion effect (the FIE; a larger or delayed N170 to inverted than upright faces), and responded to infrequent shadow versions (targets). Analyses using permutation statistics and linear mixed models focused on non-target stimuli, quantifying face-related ERPs (P1, N170) and oscillatory activity associated with sensory and attentional processing (theta, alpha, gamma). Across groups, faces elicited earlier P1 and larger N170 amplitudes than objects, and showed a FIE. Furthermore, the rightward lateralization of the FIE was reduced for autistic participants. Analyses in the frequency domain revealed greater induced theta for inverted versus upright stimuli and for faces versus objects, revealing face specific effects, and stronger theta for inverted faces for the autistic and sibling groups, suggesting greater cognitive effort in processing these social stimuli. Gamma-band inter-trial phase coherence exhibited face selectivity only in the non-autistic group, pointing to differences in early network synchronization in autistic children relative to their non-autistic peers, whereas alpha event-related desynchronization did not vary by group or category. Altogether, these findings support altered neural synchronization/efficiency for autistic participants and siblings of autistic children, that is specific to face stimuli and seen despite largely typical sensory driven encoding. These data suggest that neural oscillatory assays are more sensitive to face processing differences in autism than broadband ERPs and that these oscillatory assays may be endophenotypic.
This study explored socio-demographic associations and physical activity (PA) participation of autistic adolescents reported by parents. Parents also reported the patterns and frequencies of PA participation, as there is a limited understanding of the activities they engage in Ontario, Canada. There is a need for this research as autistic adolescents are less likely to participate in PA. Studying socio-demographic characteristics and understanding the activities adolescents engage in can inform policies and practice to support participation. A cross-sectional survey was mailed to parents of 525 autistic adolescents aged 12-19 years about PA participation for the preceding year. Parents provided data about free play and organized PA activities of adolescents (n = 306; 63.7% male; Mage = 15.1 years), and demographic information. Multiple linear regression was used to evaluate the relationships between PA scores, activities reported and the six demographic variables. The relationship between the sedentary scores, tallied frequency scores and number of activities was also assessed using linear regression. Overall, 85% of autistic adolescents participated in at least one of the 18 free play activities. Sex, number of siblings, and income were associated with PA participation. Sedentary behaviour was negatively associated with activity frequency and parental education level. Sedentary behaviour was positively associated with income level. Ensuring PA reflects socio-demographic characteristics and local priorities is critical to support participation and well-being. Tailoring programs and policies for autistic females, siblings and parent mediated interventions are areas in need of further development to support autistic adolescents in PA.
We propose in this paper a hybrid approach to regression estimation under censoring combines the practical effectiveness of neural networks and the theoretical strength of the least squares method. The censoring weights are incorporated as pre-specified weighting variables in the neural network's training loss function, enabling the model to effectively account for censored observations during the learning process. Construction on this, a least squares estimator is introduced within a well-defined neural network function space to estimate the network parameters. This combination allows the method to benefit from the empirical performance of neural networks while solidifying it with strong theoretical guarantees. In particular, the paper establishes an almost sure convergence theorem for the L2 estimation error, demonstrating the robustness of the approach. A simulation study is conducted to evaluate the performance of the estimator, and the methodology is then validated using an example on real data.
Family-centered care, including open visitation and effective communication, is increasingly recognized as essential in pediatric intensive care. Despite growing international evidence supporting open visitation policies and family involvement, significant variation exists in implementation across different healthcare systems and cultural contexts. This study aimed to evaluate the current visitation policies and family information practices in pediatric intensive care units (PICUs) in Turkey. A web-based survey was conducted among 59 PICUs across Turkey, focusing on ICU characteristics, visitation policies, and the provision of family information. The survey was distributed through the Turkish Pediatric Intensive Care Society network, and responses were obtained from one designated representative per unit. The majority of the units (78%) allowed a parent to remain at the bedside for 24 h for non-intubated patients, adopting family-centered care. However, 91.5% of the units had at least one restrictive visitation policy. Sibling visitation was prohibited in 67.8% of units. Visitation restrictions were eased under certain circumstances, such as after a diagnosis of brain death (83.1%) or in end-stage illness (76.3%). Family information was provided regularly by physicians in 57.6% of the units, and 49.2% had a dedicated family meeting room. Statistically significant differences were observed between isolation room-only units and mixed-room units regarding 24-h bedside family presence, visit duration, and the location of family information provision (p = 0.012, p = 0.031, p = 0.023, respectively). None of the units permitted family presence during invasive procedures or cardiopulmonary resuscitation. While a substantial proportion of Turkish PICUs allow 24-h family presence for non-intubated patients, restrictive policies remain common for visitors and siblings. The prohibition on family presence during procedures represents an important gap in the implementation of family-centered care. These findings highlight opportunities for policy development and staff education. • Restrictive visitation policies in pediatric ICUs increase family stress and may prolong patient recovery. • Family-centered care with 24-hour family presence improves patient and family outcomes. • Visitation and family information practices vary widely between countries and institutions. • This is the first national survey evaluating visitation policies and family information practices in Turkish pediatric ICUs. • Most Turkish PICUs allow 24-hour family presence but maintain some visitation restrictions. • Significant differences exist between isolation-room-only and mixed-room units regarding visitation and family information provision.
Allgrove syndrome, also known as Triple-A syndrome, is a rare autosomal recessive disorder characterized by the triad of alacrima, achalasia, and adrenal insufficiency, alongside a broad spectrum of neurological and autonomic dysfunctions. We present a compound heterozygosity for the pathogenic NM_015665.6:c.787T > C, p.(Ser263Pro) and the not previously described in the literature NM_015665.6:c.1442 A > G, p.(His481Arg), as a possible cause for Allgrove syndrome. Exome sequencing was performed in a female patient with achalasia, alacrima, optic atrophy, asymmetrical axonal sensorimotor polyneuropathy, segmental demyelination, and chronic denervation, revealing the above-mentioned compound heterozygosity. Segregation analysis was performed in three siblings of the proband and in the mother. The affected brother of the proband (presenting with achalasia, alacrimia, motor neuropathy, autonomic dysfunction, optic atrophy and osteoporosis), was found to be compound heterozygotes for the same variants. Although the paternal genotype was not available, the absence of the p.(His481Arg) variant in the mother indicates paternal inheritance of this variant, providing indirect evidence that the two AAAS variants are located on different alleles (in trans). The proband and her affected sibling were found to carry compound heterozygosity for the known pathogenic AAAS variant p.(Ser263Pro) and the novel p.(His481Arg) variant. Segregation analysis in available family members supports a contributory role of p.(His481Arg) in the context of autosomal recessive inheritance, however, phase could not be directly confirmed due to the unavailability of the paternal sample. Functional validation and/or identification of the variant in unrelated affected individuals would be required to further clarify its pathogenic significance. We also provide a comprehensive review of reported Allgrove syndrome cases in the literature carrying compound heterozygosity for the NM_015665.6:c.787T > C, p.(Ser263Pro) variant and the respective wide spectrum of this syndrome.