First description of co-occurrence of 49,XXXXY and X-linked Cornelia de Lange syndrome: case report

49,XXXXY is a rare sex chromosome aneuploidy with an estimated incidence of 1 in 85,000–100,000 newborn males. Individuals with this syndrome exhibit variable clinical manifestations, typically including developmental delay, intellectual deficits, hypogonadism, and distinctive facial features such as ocular hypertelorism, epicanthic folds, a flat nasal bridge, prognathism, folded-over ears, and a short neck. Unlike patients with Klinefelter syndrome, they are often short in stature. Cornelia de Lange syndrome (CdLS) is an unrelated rare disorder with an incidence of 1 in 10,000–30,000 live births, affecting both sexes. CdLS shares overlapping features with 49,XXXXY, including intellectual deficits and hypogonadism. However, it also presents with unique facial characteristics, such as synophrys, thick or highly arched eyebrows, low-set ears, upturned nasal tips, long eyelashes, and microcephaly. CdLS is a clinically and genetically heterogeneous condition, with severe cases involving congenital malformations including limb anomalies, and milder cases showing only subtle facial dysmorphism. Both syndromes may also involve cardiac and renal anomalies. We report the first documented concurrence of 49,XXXXY and X-linked CdLS, emphasizing the challenges in diagnosis and the phenotypic overlap between these two rare syndromes, and propose a theoretical mechanism for the co-occurrence

International investigation of neurocognitive and behavioral phenotype in 47,XXY (Klinefelter syndrome): Predicting individual differences

47,XXY (KS) occurs in 1:650 male births, though less than 25% are ever identified. We assessed stability of neurocognitive features across diverse populations and quantified factors mediating outcome. Forty‐four boys from the Netherlands (NL) and 54 boys from the United States (US) participated. The Wechsler Intelligence Scales assessed intellectual functioning; the ANT program evaluated cognitive function; and the CBCL assessed behavioral functioning. ANOVA was used for group comparisons. Hierarchical regressions assessed variance explained by each independent variable: parental education, timing of diagnosis, testosterone, age, and nationality. Parental education, timing of diagnosis, and hormonal treatment all played an important role in neurocognitive performance. The observed higher IQ and better attention regulation in the US group as compared to the NL group was observed with decreased levels of behavioral problems in the US group. Cognitive measures that were different between the NL and US groups, i.e., attention regulation and IQ scores, were also significantly influenced by external factors including timing of diagnosis, testosterone treatment, and parental education. On the ANT, a cognitive phenotype of 47,XXY was observed, with similar scores on 9 out of the 10 ANT subtests for the NL and US groups. This study lays additional features to the foundation for an algorithm linking external variables to outcome on various neurodevelopmental measures.Development Psychopathology in context: clinical setting

GestaltMatcher Database - A global reference for facial phenotypic variability in rare human diseases

The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.</p

International Investigation of Neurocognitive and Behavioral Phenotype in 47,XXY (Klinefelter syndrome): Predicting Individual Differences.

47,XXY (KS) occurs in 1:650 male births, though less than 25% are ever identified. We assessed stability of neurocognitive features across diverse populations and quantified factors mediating outcome. Forty‐four boys from the Netherlands (NL) and 54 boys from the United States (US) participated. The Wechsler Intelligence Scales assessed intellectual functioning; the ANT program evaluated cognitive function; and the CBCL assessed behavioral functioning. ANOVA was used for group comparisons. Hierarchical regressions assessed variance explained by each independent variable: parental education, timing of diagnosis, testosterone, age, and nationality. Parental education, timing of diagnosis, and hormonal treatment all played an important role in neurocognitive performance. The observed higher IQ and better attention regulation in the US group as compared to the NL group was observed with decreased levels of behavioral problems in the US group. Cognitive measures that were different between the NL and US groups, i.e., attention regulation and IQ scores, were also significantly influenced by external factors including timing of diagnosis, testosterone treatment, and parental education. On the ANT, a cognitive phenotype of 47,XXY was observed, with similar scores on 9 out of the 10 ANT subtests for the NL and US groups. This study lays additional features to the foundation for an algorithm linking external variables to outcome on various neurodevelopmental measures.Development Psychopathology in context: clinical setting