Growth hormone deficiency in megalencephaly-capillary malformation syndrome: An association with activating mutations in PIK3CA

Megalencephaly-capillary malformation syndrome (MCAP) is a brain overgrowth disorder characterized by cortical malformations (specifically polymicrogyria), vascular anomalies, and segmental overgrowth secondary to somatic activating mutations in the PI3K-AKT-MTOR pathway (PIK3CA). Cases of growth failure and hypoglycemia have been reported in patients with MCAP, raising the suspicion for unappreciated growth hormone (GH) deficiency. Here we report an observational multicenter study of children with MCAP and GH deficiency. Eleven participants were confirmed to have GH deficiency, all with very low or undetectable circulating concentrations of insulin-like growth factor-1 and insulin-like growth factor binding protein-3. Seven underwent GH stimulation testing and all had insufficient responses with a median GH peak of 3.7 ng/ml (range 1.1-8.6). Growth patterns revealed a drastic decline in length z-scores within the first year of life but then stabilized afterward. Five were treated with GH; one discontinued due to inconsolability. The other four participants continued on GH with improvement in linear growth velocity. Other endocrinopathies were identified in 7 of the 11 participants in this cohort. This study indicates that GH deficiency is associated with MCAP and that children with MCAP and hypoglycemia and/or postnatal growth failure should be evaluated for GH deficiency and other endocrinopathies

Minipuberty in Klinefelter syndrome:Current status and future directions

Klinefelter syndrome is highly underdiagnosed and diagnosis is often delayed. With the introduction of non-invasive prenatal screening, the diagnostic pattern will require an updated description of the clinical and biochemical presentation of infants with Klinefelter syndrome. In the first months of life, the hypothalamic-pituitary-gonadal (HPG)-axis is transiently activated in healthy males during the so-called minipuberty. This period represents a “window of opportunity” for evaluation of the HPG-axis before puberty and without stimulation tests. Infants with Klinefelter syndrome present with a hormonal surge during the minipuberty. However, only a limited number of studies exist, and the results are contradictory. Further studies are needed to clarify whether infants with Klinefelter syndrome present with impaired testosterone production during the minipuberty. The aim of this review is to describe the clinical and biochemical characteristics of the neonate and infant with Klinefelter syndrome with special focus on the minipuberty and to update the clinical recommendations for Klinefelter syndrome during infancy

Autism Spectrum Disorder in Males with Sex Chromosome Aneuploidy

ObjectiveNeurodevelopmental concerns in males with sex chromosome aneuploidy (SCA) (XXY/Klinefelter syndrome, XYY, XXYY) include symptoms seen in autism spectrum disorder (ASD), such as language impairments and social difficulties. We aimed to: (1) evaluate ASD characteristics in research cohorts of SCA males under DSM-IV compared to DSM-5 criteria, and (2) analyze factors associated with ASD diagnoses in SCA.MethodsEvaluation of participants with XXY/KS (n=20), XYY (n=57) and XXYY (n=21) included medical history, cognitive/adaptive testing, Social Communication Questionnaire, Social Responsiveness Scale, Autism Diagnostic Observation Schedule, Autism Diagnostic Interview-Revised, and DSM ASD criteria. Clinical impressions of ASD diagnostic category using the ADOS and DSM-IV criteria were compared to ADOS-2 and DSM-5 criteria. T-tests compared cognitive, adaptive, SES and prenatal vs. postnatal diagnoses between ASD and no ASD groups.ResultsASD rates in these research cohorts were 10% in XXY/KS, 38% in XYY, and 52% in XXYY using ADOS-2/DSM-5, and were not statistically different compared to DSM-IV criteria. In XYY and XXYY, the ASD group had lower verbal IQ and adaptive functioning compared to those without ASD. Many children without ASD still showed some social difficulties.ConclusionASD rates in males with SCA are higher than reported for the general population. Males with Y chromosome aneuploidy (XYY and XXYY) were 4.8 times more likely to have a diagnosis of ASD than the XXY/KS group, and 20 times more likely than males in the general population (1 in 42 males, CDC 2010). ASD should be considered when evaluating social difficulties in SCA. Studies of SCA and Y-chromosome genes may provide insight into male predominance in idiopathic ASD

Cell-Free DNA Screening Positive for Monosomy X: Clinical Evaluation and Management of Suspected Maternal or Fetal Turner Syndrome

Initially provided as an alternate to evaluation of serum analytes and nuchal translucency for the evaluation of pregnancies at high-risk of Trisomy 21, cell-free DNA (cfDNA) screening for fetal aneuploidy, also referred to as non-invasive prenatal screening (NIPS), can now also screen for fetal sex chromosome anomalies (SCAs) such as monosomy X as early as 9 to 10 weeks of gestation. Early identification of Turner syndrome, a SCA resulting from the complete or partial absence of the second X chromosome, allows for medical interventions such as optimizing obstetrical outcomes, hormone replacement therapy, fertility protection and support as well improved neurocognitive outcomes. However, cfDNA screening for SCAs and monosomy X in particular is associated with high false positive rates and low positive predictive value. A cfDNA result positive for monosomy X may represent fetal TS, maternal TS, or confined placental mosaicism. A positive screen for monosomy X with discordant results of diagnostic fetal karyotype presents unique interpretation and management challenges due to potential implications for previously unrecognized maternal Turner syndrome (TS). . The current international consensus clinical practice guidelines for the care of individuals with TS throughout the lifespan do not specifically address management of individuals with a cfDNA screen positive for monosomy X. The objective of this manuscript is to provide context and expert-driven recommendations for maternal and/or fetal evaluation and management when cfDNA screening is positive for monosomy X. We highlight unique challenges of cfDNA screening that is incidentally positive for monosomy X, present recommendations for determining if the result is a true positive and discuss when diagnosis of TS is applicable to the fetus or the mother. While we defer the subsequent management of confirmed TS to the clinical practice guidelines, we highlight unique considerations for these individuals initially identified through cfDNA screening

Behavioral Health Diagnoses in Youth with Differences of Sex Development or Congenital Adrenal Hyperplasia Compared with Controls: A PEDSnet Study

Objective: To evaluate the odds of a behavioral health diagnosis among youth with differences of sex development (DSD) or congenital adrenal hyperplasia (CAH) compared with matched controls in the PEDSnet database. Study design: All youth with a diagnosis of DSD (n = 1216) or CAH (n = 1647) and at least 1 outpatient encounter were extracted from the PEDSnet database and propensity-score matched on 8 variables (1:4) with controls (n = 4864 and 6588, respectively) using multivariable logistic regression. The likelihood of having behavioral health diagnoses was examined using generalized estimating equations. Results: Youth with DSD had higher odds of a behavioral health diagnosis (OR, 1.7; 95% CI, 1.4-2.1; P \u3c.0001) and neurodevelopmental diagnosis (OR, 1.7; 95% CI, 1.4, 2.0; P \u3c.0001) compared with matched controls. Youth with CAH did not have an increased odds of a behavioral health diagnosis (OR, 1.0; 95% CI, 0.9, 1.1; P =.9) compared with matched controls but did have higher odds of developmental delay (OR, 1.8; 95% CI, 1.4, 2.4; P \u3c.0001). Conclusions: Youth with DSD diagnosis have higher odds of a behavioral health or neurodevelopmental diagnosis compared with matched controls. Youth with CAH have higher odds of developmental delay, highlighting the need for screening in both groups

The human inactive X chromosome modulates expression of the active X chromosome

The inactive X chromosome (Xi) has been assumed to have little impact, in , on the active X (Xa). To test this, we quantified Xi and Xa gene expression in individuals with one Xa and zero to three Xis. Our linear modeling revealed modular Xi and Xa transcriptomes and significant Xi-driven expression changes for 38% (162/423) of expressed X chromosome genes. By integrating allele-specific analyses, we found that modulation of Xa transcript levels by Xi contributes to many of these Xi-driven changes (≥121 genes). By incorporating metrics of evolutionary constraint, we identified 10 X chromosome genes most likely to drive sex differences in common disease and sex chromosome aneuploidy syndromes. We conclude that human X chromosomes are regulated both in , through Xi-wide transcriptional attenuation, and in , through positive or negative modulation of individual Xa genes by Xi. The sum of these and effects differs widely among genes

Automated syndrome diagnosis by three-dimensional facial imaging.

PurposeDeep phenotyping is an emerging trend in precision medicine for genetic disease. The shape of the face is affected in 30-40% of known genetic syndromes. Here, we determine whether syndromes can be diagnosed from 3D images of human faces.MethodsWe analyzed variation in three-dimensional (3D) facial images of 7057 subjects: 3327 with 396 different syndromes, 727 of their relatives, and 3003 unrelated, unaffected subjects. We developed and tested machine learning and parametric approaches to automated syndrome diagnosis using 3D facial images.ResultsUnrelated, unaffected subjects were correctly classified with 96% accuracy. Considering both syndromic and unrelated, unaffected subjects together, balanced accuracy was 73% and mean sensitivity 49%. Excluding unrelated, unaffected subjects substantially improved both balanced accuracy (78.1%) and sensitivity (56.9%) of syndrome diagnosis. The best predictors of classification accuracy were phenotypic severity and facial distinctiveness of syndromes. Surprisingly, unaffected relatives of syndromic subjects were frequently classified as syndromic, often to the syndrome of their affected relative.ConclusionDeep phenotyping by quantitative 3D facial imaging has considerable potential to facilitate syndrome diagnosis. Furthermore, 3D facial imaging of "unaffected" relatives may identify unrecognized cases or may reveal novel examples of semidominant inheritance