Multimodal phenotyping of foveal hypoplasia in albinism and albino-like conditions: a pediatric case series with adaptive optics insights.

Aim of the present study is to evaluate the relationship between genetic and phenotypic data in a series of patients affected by grade I and II of foveal hypoplasia with stable fixation and good visual acuity using multimodal imaging techniques. All patients underwent complete clinical and instrumental assessment including structural Optical Coherence Tomography (OCT), OCT Angiography and Adaptive Optics (AO) imaging. Central macular thickness (CMT), inner nuclear layer (INL), vessel density in superficial capillary plexus were the main variables evaluated with OCT technology. Cone density, cone spacing, cone regularity, cone dispersion and angular density were the parameters evaluated with AO. Genetic evaluation and trio exome sequencing were performed in all affected individuals. Eight patients (3 males and 5 females) with a mean age of 12.62 years (range 8-18) were enrolled. The mean best corrected visual acuity (BCVA) was 0.18 ± 0.13 logMAR, mean CMT was 291.9 ± 16.6 µm and INL was 26.2 ± 4.6 µm. The absence of a foveal avascular zone (FAZ) was documented by examination of OCT-A in seven patients in the superficial capillary plexus. However, there was a partial FAZ in the deep plexus in patients P5 and P8. Of note, all the patients presented with major retinal vessels clearly crossing the foveal center. All individuals exhibited a grade I or II of foveal hypoplasia. In 5 patients molecular analyses showed an extremely mild form of albinism caused by compound heterozygosity of a TYR pathogenic variant and the hypomorphic p.[Ser192Tyr;Arg402Gln] haplotype. One patient had Waardenburg syndrome type 2A caused by a de novo variant in MITF. Two patients had inconclusive molecular analyses. All the patients displayed abnormalities on OCT-A. Photoreceptor count did not differ from normal subjects according to the current literature, but qualitative analysis of AO imaging showed distinctive features likely related to an abnormal pigment distribution in this subset of individuals. In patients with foveal hypoplasia, genetic and multimodal imaging data, including AO findings, can help understand the physiopathology of the foveal hypoplasia phenotype. This study confirms that cone density and visual function can both be preserved despite the absence of a pit.

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.

Continuous spike-wave of slow sleep in a patient with KCNB1-related epilepsy responsive to highly purified cannabidiol: a case report and comparison with literature.

KCNB1-associated encephalopathy is characterized by intellectual disability (ID), autism spectrum disorder and epilepsy. Specific treatments are still lacking. We describe a 12-year-old boy with severe ID and treatment-resistant seizures due to a pathogenic KCNB1 variant. His EEG showed a CSWS pattern. Aged 11, he started treatment with highly purified cannabidiol (CBD) and has been seizure free for 18 months, with significant EEG and social skills improvements. This suggests CBD may benefit CSWS, likely due to its anti-inflammatory properties. Some preclinical studies also indicate CBDs interact with voltage-gated channels, leading us to speculate its possible role for treating KCNB1 related encephalopathy.

MSL2 variants lead to a neurodevelopmental syndrome with lack of coordination, epilepsy, specific dysmorphisms, and a distinct episignature.

Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotemporal gene expression during neurodevelopment. The male-specific lethal (MSL) complex is a prominent multi-subunit epigenetic regulator of gene expression and is responsible for histone 4 lysine 16 acetylation (H4K16ac). Using exome sequencing, here we identify a cohort of 25 individuals with heterozygous de novo variants in MSL complex member MSL2. MSL2 variants were associated with NDD phenotypes including global developmental delay, intellectual disability, hypotonia, and motor issues such as coordination problems, feeding difficulties, and gait disturbance. Dysmorphisms and behavioral and/or psychiatric conditions, including autism spectrum disorder, and to a lesser extent, seizures, connective tissue disease signs, sleep disturbance, vision problems, and other organ anomalies, were observed in affected individuals. As a molecular biomarker, a sensitive and specific DNA methylation episignature has been established. Induced pluripotent stem cells (iPSCs) derived from three members of our cohort exhibited reduced MSL2 levels. Remarkably, while NDD-associated variants in two other members of the MSL complex (MOF and MSL3) result in reduced H4K16ac, global H4K16ac levels are unchanged in iPSCs with MSL2 variants. Regardless, MSL2 variants altered the expression of MSL2 targets in iPSCs and upon their differentiation to early germ layers. Our study defines an MSL2-related disorder as an NDD with distinguishable clinical features, a specific blood DNA episignature, and a distinct, MSL2-specific molecular etiology compared to other MSL complex-related disorders.

Natural history of adults with KBG syndrome: A physician-reported experience.

PURPOSE: KBG syndrome (KBGS) is a rare neurodevelopmental syndrome caused by haploinsufficiency of ANKRD11. The childhood phenotype is extensively reported but limited for adults. Thus, we aimed to delineate the clinical features of KBGS. METHODS: We collected physician-reported data of adults with molecularly confirmed KBGS through an international collaboration. Moreover, we undertook a systematic literature review to determine the scope of previously reported data. RESULTS: The international collaboration identified 36 adults from 31 unrelated families with KBGS. Symptoms included mild/borderline intellectual disability (n = 22); gross and/or fine motor difficulties (n = 15); psychiatric and behavioral comorbidities including aggression, anxiety, reduced attention span, and autistic features (n = 26); nonverbal (n = 3), seizures with various seizure types and treatment responses (n = 10); ophthalmological comorbidities (n = 20). Cognitive regression during adulthood was reported once. Infrequent features included dilatation of the ascending aorta (n = 2) and autoimmune conditions (n = 4). Education, work, and residence varied, and the diversity of professional and personal roles highlighted the range of abilities seen. The literature review identified 154 adults reported across the literature, and we have summarized the features across both data sets. CONCLUSION: Our study sheds light on the long-term neurodevelopmental outcomes, seizures, behavioral and psychiatric features, and education, work, and living arrangements for adults with KBGS.

Genetic Epilepsies and Developmental Epileptic Encephalopathies with Early Onset: A Multicenter Study.

The genetic causes of epilepsies and developmental and epileptic encephalopathies (DEE) with onset in early childhood are increasingly recognized. Their outcomes vary from benign to severe disability. In this paper, we wished to retrospectively review the clinical, genetic, EEG, neuroimaging, and outcome data of patients experiencing the onset of epilepsy in the first three years of life, diagnosed and followed up in four Italian epilepsy centres (Epilepsy Centre of San Paolo University Hospital in Milan, Child Neurology and Psychiatry Unit of AUSL-IRCCS di Reggio Emilia, Pediatric Neurology Unit of Vittore Buzzi Children's Hospital, Milan, and Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia). We included 168 patients (104 with monogenic conditions, 45 with copy number variations (CNVs) or chromosomal abnormalities, and 19 with variants of unknown significance), who had been followed up for a mean of 14.75 years. We found a high occurrence of generalized seizures at onset, drug resistance, abnormal neurological examination, global developmental delay and intellectual disability, and behavioural and psychiatric comorbidities. We also documented differing presentations between monogenic issues versus CNVs and chromosomal conditions, as well as atypical/rare phenotypes. Genetic early-childhood-onset epilepsies and DEE show a very wide phenotypic and genotypic spectrum, with a high risk of complex neurological and neuropsychiatric phenotypes.

Characterization of the prenatal renal phenotype associated with 17q12, HNF1B, microdeletions.

OBJECTIVE: Recurrent deletions involving 17q12 are associated with a variety of clinical phenotypes, including congenital abnormalities of the kidney and urinary tract (CAKUT), maturity onset diabetes of the young, type 5, and neurodevelopmental disorders. Structural and/or functional renal disease is the most common phenotypic feature, although the prenatal renal phenotypes and the postnatal correlates have not been well characterized. METHOD: We reviewed pre- and postnatal medical records of 26 cases with prenatally or postnatally identified 17q12/HNF1B microdeletions (by chromosomal microarray or targeted gene sequencing), obtained through a multicenter collaboration. We specifically evaluated 17 of these cases (65%) with reported prenatal renal ultrasound findings. RESULTS: Heterogeneous prenatal renal phenotypes were noted, most commonly renal cysts (41%, n = 7/17) and echogenic kidneys (41%), although nonspecific dysplasia, enlarged kidneys, hydronephrosis, pelvic kidney with hydroureter, and lower urinary tract obstruction were also reported. Postnatally, most individuals developed renal cysts (73%, 11/15 live births), and there were no cases of end-stage renal disease during childhood or the follow-up period. CONCLUSION: Our findings demonstrate that copy number variant analysis to assess for 17q12 microdeletion should be considered for a variety of prenatally detected renal anomalies. It is important to distinguish 17q12 microdeletion from other etiologies of CAKUT as the prognosis for renal function and presence of associated findings are distinct and may influence pregnancy and postnatal management.

Heterozygous rare variants in NR2F2 cause a recognizable multiple congenital anomaly syndrome with developmental delays.

Nuclear receptor subfamily 2 group F member 2 (NR2F2 or COUP-TF2) encodes a transcription factor which is expressed at high levels during mammalian development. Rare heterozygous Mendelian variants in NR2F2 were initially identified in individuals with congenital heart disease (CHD), then subsequently in cohorts of congenital diaphragmatic hernia (CDH) and 46,XX ovotesticular disorders/differences of sexual development (DSD); however, the phenotypic spectrum associated with pathogenic variants in NR2F2 remains poorly characterized. Currently, less than 40 individuals with heterozygous pathogenic variants in NR2F2 have been reported. Here, we review the clinical and molecular details of 17 previously unreported individuals with rare heterozygous NR2F2 variants, the majority of which were de novo. Clinical features were variable, including intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, and vascular malformations, thus expanding the phenotypic spectrum associated with NR2F2 variants. The variants seen were predicted loss of function, including a nonsense variant inherited from a mildly affected mosaic mother, missense and a large deletion including the NR2F2 gene. Our study presents evidence for rare, heterozygous NR2F2 variants causing a highly variable syndrome of congenital anomalies, commonly associated with heart defects, developmental delays/intellectual disability, dysmorphic features, feeding difficulties, hypotonia, and genital anomalies. Based on the new and previous cases, we provide clinical recommendations for evaluating individuals diagnosed with an NR2F2-associated disorder.

Delineation of the clinical profile of CNOT2 haploinsufficiency and overview of the IDNADFS phenotype.

CNOT2 haploinsufficiency underlies a rare neurodevelopmental disorder named Intellectual Developmental disorder with NAsal speech, Dysmorphic Facies, and variable Skeletal anomalies (IDNADFS, OMIM 618608). The condition clinically overlaps with chromosome 12q15 deletion syndrome, suggesting a major contribution of CNOT2 haploinsufficiency to the latter. CNOT2 is a member of the CCR4-NOT complex, which is a master regulator of multiple cellular processes, including gene expression, RNA deadenylation, and protein ubiquitination. To date, less than 20 pathogenic 12q15 microdeletions encompassing CNOT2, together with a single truncating variant of the gene, and two large intragenic deletions have been reported. Due to the small number of affected subjects described so far, the clinical profile of IDNADFS has not been fully delineated. Here we report five unrelated individuals, three of which carrying de novo intragenic CNOT2 variants, one presenting with a multiexon intragenic deletion, and an additional case of 12q15 microdeletion syndrome. Finally, we assess the features of IDNADFS by reviewing published and present affected individuals and reevaluate the clinical phenotype of this neurodevelopmental disorder.

Modeling RTT Syndrome by iPSC-Derived Neurons from Male and Female Patients with Heterogeneously Severe Hot-Spot MECP2 Variants.

Rett syndrome caused by MECP2 variants is characterized by a heterogenous clinical spectrum accounted for in 60% of cases by hot-spot variants. Focusing on the most frequent variants, we generated in vitro iPSC-neurons from the blood of RTT girls with p.Arg133Cys and p.Arg255*, associated to mild and severe phenotype, respectively, and of an RTT male harboring the close to p.Arg255*, p.Gly252Argfs*7 variant. Truncated MeCP2 proteins were revealed by Western blot and immunofluorescence analysis. We compared the mutant versus control neurons at 42 days for morphological parameters and at 120 days for electrophysiology recordings, including girls' isogenic clones. A precocious reduced morphological complexity was evident in neurons with truncating variants, while in p.Arg133Cys neurons any significant differences were observed in comparison with the isogenic wild-type clones. Reduced nuclear size and branch number show up as the most robust biomarkers. Patch clamp recordings on mature neurons allowed the assessment of cell biophysical properties, V-gated currents, and spiking pattern in the mutant and control cells. Immature spiking, altered cell capacitance, and membrane resistance of RTT neurons, were particularly pronounced in the Arg255* and Gly252Argfs*7 mutants. The overall results indicate that the specific markers of in vitro cellular phenotype mirror the clinical severity and may be amenable to drug testing for translational purposes.

Expanding the Molecular Spectrum of ANKRD11 Gene Defects in 33 Patients with a Clinical Presentation of KBG Syndrome.

KBG syndrome (KBGS) is a neurodevelopmental disorder caused by the Ankyrin Repeat Domain 11 (ANKRD11) haploinsufficiency. Here, we report the molecular investigations performed on a cohort of 33 individuals with KBGS clinical suspicion. By using a multi-testing genomic approach, including gene sequencing, Chromosome Microarray Analysis (CMA), and RT-qPCR gene expression assay, we searched for pathogenic alterations in ANKRD11. A molecular diagnosis was obtained in 22 out of 33 patients (67%). ANKRD11 sequencing disclosed pathogenic or likely pathogenic variants in 18 out of 33 patients. CMA identified one full and one terminal ANKRD11 pathogenic deletions, and one partial duplication and one intronic microdeletion, with both possibly being pathogenic. The pathogenic effect was established by RT-qPCR, which confirmed ANKRD11 haploinsufficiency only for the three deletions. Moreover, RT-qPCR applied to six molecularly unsolved KBGS patients identified gene downregulation in a clinically typical patient with previous negative tests, and further molecular investigations revealed a cryptic deletion involving the gene promoter. In conclusion, ANKRD11 pathogenic variants could also involve the regulatory regions of the gene. Moreover, the application of a multi-test approach along with the innovative use of RT-qPCR improved the diagnostic yield in KBGS suspected patients.

Phenotypes in adult patients with Rett syndrome: results of a 13-year experience and insights into healthcare transition.

BACKGROUND: Rett syndrome is a complex genetic disorder with age-specific manifestations and over half of the patients surviving into middle age. However, little information about the phenotype of adult individuals with Rett syndrome is available, and mainly relies on questionnaires completed by caregivers. Here, we assess the clinical manifestations and management of adult patients with Rett syndrome and present our experience in transitioning from the paediatric to the adult clinic. METHODS: We analysed the medical records and molecular data of women aged ≥18 years with a diagnosis of classic Rett syndrome and/or pathogenic variants in MECP2, CDKL5 and FOXG1, who were in charge of our clinic. RESULTS: Of the 50 women with classic Rett syndrome, 94% had epilepsy (26% drug-resistant), 20% showed extrapyramidal signs, 40% sleep problems and 36% behavioural disorders. Eighty-six % patients exhibited gastrointestinal problems; 70% had scoliosis and 90% low bone density. Breathing irregularities were diagnosed in 60%. None of the patients had cardiac issues. CDKL5 patients experienced fewer breathing abnormalities than women with classic Rett syndrome. CONCLUSION: The delineation of an adult phenotype in Rett syndrome demonstrates the importance of a transitional programme and the need of a dedicated multidisciplinary team to optimise the clinical management of these patients.

Beyond the Guidelines: How We Can Improve Healthcare for People With Tuberous Sclerosis Complex Around the World.

BACKGROUND: Tuberous Sclerosis Complex International (TSCi) is a consortium of organizations that supports individuals with tuberous sclerosis complex (TSC) around the world. To improve care for TSC on a global level, TSCi identified the need to expand understanding about existing resources available in other countries, what individuals and caregivers value in TSC care, key gaps between needs and reality in each country, and ways these gaps can be addressed by advocacy organizations around the world. METHODS: An iterative, mixed methods approach (the Improving Care project) was adopted to incorporate views from diverse members of TSCi. Through idea generation, a collection of qualitative open-ended responses and concept elicitation, we were able to build consensus where shared experiences and opinions were identified. RESULTS: The research performed as a part of the Improving Care project revealed a significant gap between the guidelines and what is actually available to people with TSC worldwide. Three key priority areas of action to improve this gap were identified: (1) implementation of the guidelines; (2) access to TSC expertise, and (3) coordinated and integrated health care. CONCLUSIONS: There are significant opportunities for key stakeholders, including organizations, clinicians, and researchers to improve care for individuals with TSC on both local and global levels. Working across stakeholder groups and utilizing TSC organizations are essential to ensure that the advances in TSC research benefit people living with TSC around the world.

Chromatin Imbalance as the Vertex Between Fetal Valproate Syndrome and Chromatinopathies.

Prenatal exposure to valproate (VPA), an antiepileptic drug, has been associated with fetal valproate spectrum disorders (FVSD), a clinical condition including congenital malformations, developmental delay, intellectual disability as well as autism spectrum disorder, together with a distinctive facial appearance. VPA is a known inhibitor of histone deacetylase which regulates the chromatin state. Interestingly, perturbations of this epigenetic balance are associated with chromatinopathies, a heterogeneous group of Mendelian disorders arising from mutations in components of the epigenetic machinery. Patients affected from these disorders display a plethora of clinical signs, mainly neurological deficits and intellectual disability, together with distinctive craniofacial dysmorphisms. Remarkably, critically examining the phenotype of FVSD and chromatinopathies, they shared several overlapping features that can be observed despite the different etiologies of these disorders, suggesting the possible existence of a common perturbed mechanism(s) during embryonic development.

Exploring the Role of Matrix Metalloproteinases as Biomarkers in Sporadic Lymphangioleiomyomatosis and Tuberous Sclerosis Complex. A Pilot Study.

Background: Lymphangioleiomyomatosis can develop in a sporadic form (S-LAM) or in women with tuberous sclerosis complex (TSC). The matrix metalloproteinases (MMPs) are extracellular matrix-degrading enzymes potentially involved in cystic lung destruction, and in the process of migration of LAM cells. The aim of the study was to explore the role of MMP-2 and MMP-7, such as vascular endothelial growth factor (VEGF) -C and -D in women with LAM, including patients with minor pulmonary disease (i.e., <10 lung cysts), and TSC with or without LAM. Methods: We evaluated 50 patients: 13 individuals affected by S-LAM, 20 with TSC-LAM, of whom six with minor pulmonary disease, and 17 with TSC without pulmonary involvement. Sixteen healthy women were used as controls. Results: MMP-2 resulted higher in LAM compared to healthy volunteers, and TSC patients (p = 0.040). MMP-7 was higher in TSC-LAM patient, with even greater values in patients with TSC-LAM minor pulmonary disease, than in S-LAM patients, and in controls (p = 0.001). VEGF-D level was lower than 800 pg/mL in all healthy controls and resulted higher in S-LAM and TSC-LAM than in TSC patients and controls (p < 0.001). VEGF-C values were not statistically different in the study population (p = 0.354). The area under ROC curves (AUCs) of MMP-2, and MMP-7 for predicting LAM diagnosis were of 0.756 ± 0.079 (p = 0.004), and 0.828 ± 0.060 (p < 0.001), respectively. Considering only patients with TSC, the AUCs for MMP-2, and MMP-7 in predicting LAM were 0.694 ± 0.088 (p = 0.044), and 0.713 ± 0.090 (p = 0.027), respectively. Conclusions: Our data suggest that MMP-2 and MMP-7 could be promising biomarkers for LAM diagnosis.

8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature.

To date only five patients with 8p23.2-pter microdeletions manifesting a mild-to-moderate cognitive impairment and/or developmental delay, dysmorphisms and neurobehavioral issues were reported. The smallest microdeletion described by Wu in 2010 suggested a critical region (CR) of 2.1 Mb including several genes, out of which FBXO25, DLGAP2, CLN8, ARHGEF10 and MYOM2 are the main candidates. Here we present seven additional patients with 8p23.2-pter microdeletions, ranging from 71.79 kb to 4.55 Mb. The review of five previously reported and nine Decipher patients confirmed the association of the CR with a variable clinical phenotype characterized by intellectual disability/developmental delay, including language and speech delay and/or motor impairment, behavioral anomalies, autism spectrum disorder, dysmorphisms, microcephaly, fingers/toes anomalies and epilepsy. Genotype analysis allowed to narrow down the 8p23.3 candidate region which includes only DLGAP2, CLN8 and ARHGEF10 genes, accounting for the main signs of the broad clinical phenotype associated to 8p23.2-pter microdeletions. This region is more restricted compared to the previously proposed CR. Overall, our data favor the hypothesis that DLGAP2 is the actual strongest candidate for neurodevelopmental/behavioral phenotypes. Additional patients will be necessary to validate the pathogenic role of DLGAP2 and better define how the two contiguous genes, ARHGEF10 and CLN8, might contribute to the clinical phenotype.

Epilepsy in adult patients with tuberous sclerosis complex.

OBJECTIVES: Little is known about the evolution of epilepsy in individuals with tuberous sclerosis complex (TSC) in adulthood. This study aims at describing the characteristics of epilepsy in adult TSC patients attending a single multidisciplinary clinic. MATERIALS AND METHODS: We collected data about epilepsy (age at onset, seizure types, history of infantile spasms (IS), epilepsy diagnosis and outcome), genetic and neuroradiological findings, cognitive outcome and psychiatric comorbidities. RESULTS: Out of 257 adults with TSC, 183 (71.2%) had epilepsy: 121 (67.2%) were drug-resistant; 59 (32.8%) seizure-free, at a median age of 18 years. 22% of the seizure-free patients (13/59) discontinued medication. Median age at seizure onset was 9 months. Seventy-six patients (41.5%) had a history of IS. TSC2 pathogenic variants (p = 0.018), cortical tubers (p < 0.001) and subependymal nodules (SENs) (p < 0.001) were more frequent in those who developed epilepsy. Cognitive functioning was lower (p < 0.001) and psychiatric disorders more frequent (p = 0.001). We did not find significant differences regarding age, gender, mutation and tubers/SENs in seizure-free vs drug-resistant individuals. Intellectual disability (p < 0.001) and psychiatric disorders (p = 0.004) were more common among drug-resistant patients. CONCLUSIONS: Epilepsy in TSC can be a lifelong disorder, but one-third of individuals reach seizure freedom by early adulthood. In the long term, age at epilepsy onset has a crucial role in drug resistance and in developing intellectual disability, both in drug-resistant and drug-sensible patients. Patients with drug-refractory seizures tend to develop psychiatric issues, which should be recognized and adequately treated.

Detailed Clinical and Psychological Phenotype of the X-linked HNRNPH2-Related Neurodevelopmental Disorder.

OBJECTIVE: To expand the clinical phenotype of the X-linked HNRNPH2-related neurodevelopmental disorder in 33 individuals. METHODS: Participants were diagnosed with pathogenic or likely pathogenic variants in HNRNPH2 using American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria, largely identified via clinical exome sequencing. Genetic reports were reviewed. Clinical data were collected by retrospective chart review and caregiver report including standardized parent report measures. RESULTS: We expand our clinical characterization of HNRNPH2-related disorders to include 33 individuals, aged 2-38 years, both females and males, with 11 different de novo missense variants, most within the nuclear localization signal. The major features of the phenotype include developmental delay/intellectual disability, severe language impairment, motor problems, growth, and musculoskeletal disturbances. Minor features include dysmorphic features, epilepsy, neuropsychiatric diagnoses such as autism spectrum disorder, and cortical visual impairment. Although rare, we report early stroke and premature death with this condition. CONCLUSIONS: The spectrum of X-linked HNRNPH2-related disorders continues to expand as the allelic spectrum and identification of affected males increases.

Sleep and behavior in children and adolescents with tuberous sclerosis complex.

Sleep disorders are frequent in tuberous sclerosis complex (TSC) during the developmental age but are not well characterized. Forty-six TSC patients and 46 healthy age- and sex-matched controls were enrolled. Their parents completed the Sleep Disturbances Scale for Children (SDSC) and the Child Behavior Checklist (CBCL). A total of 17.4% of the TSC patients obtained a total pathologic score at the SDSC versus 4.4% in the control group (p = 0.024). 45.7% of individuals with TSC reported a pathologic score in at least one of the factors. We found a statistically significant difference between the TSC cohort and healthy controls for most of the CBCL scales scores. A significant relationship was found between the Total SDSC score and the Total CBCL score (R-square = 0.387, p < 0.0001), between the Total SDSC score and the Internalizing and Externalizing areas scores (R-square = 0.291, p < 0.0001 and R-square = 0.350, p < 0.0001, respectively) of the CBCL. Sleep disorders are more frequent in TSC than in the general population and correlate with behavior. The use of SDSC and CBCL is proposed as part of the surveillance of TSC patients in the developmental age.