H syndrome: A histiocytosis-lymphadenopathy plus syndrome. A comprehensive review of the literature.

H syndrome is a rare autosomal recessive genodermatosis that falls under the histiocytosis-lymphadenopathy plus syndrome. The term "H syndrome" includes manifestations such as hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, low height, and occasionally hyperglycemia. The syndrome is associated with mutations in the SLC29A3 gene, which encodes the human equilibrative transporter 3 present in endosomes, lysosomes, and mitochondria. The generalized and ubiquitous presence of affected lysosomes and mitochondria contributes to the systemic and phenotypically heterogeneous manifestations of the syndrome. H syndrome manifestations are cutaneous, systemic, and organ-specific. The pathognomonic signs are hypertrichosis and hyperpigmentation in the inner thighs and shins. However, not all patients present with these symptoms. H syndrome management involves a multidisciplinary approach to address specific symptoms and complications. The prognosis of H syndrome depends on several factors, including the extent and severity of clinical manifestations, the presence of complications, and timely diagnosis and management. Further studies are needed to explore the association between prognosis and the different mutations encountered in H syndrome.

Mitochondrial Ca2+-coupled generation of reactive oxygen species, peroxynitrite formation, and endothelial dysfunction in Cantú syndrome.

Cantú syndrome is a multisystem disorder caused by gain-of-function (GOF) mutations in KCNJ8 and ABCC9, the genes encoding the pore-forming inward rectifier Kir6.1 and regulatory sulfonylurea receptor SUR2B subunits, respectively, of vascular ATP-sensitive K+ (KATP) channels. In this study, we investigated changes in the vascular endothelium in mice in which Cantú syndrome-associated Kcnj8 or Abcc9 mutations were knocked in to the endogenous loci. We found that endothelium-dependent dilation was impaired in small mesenteric arteries from Cantú mice. Loss of endothelium-dependent vasodilation led to increased vasoconstriction in response to intraluminal pressure or treatment with the adrenergic receptor agonist phenylephrine. We also found that either KATP GOF or acute activation of KATP channels with pinacidil increased the amplitude and frequency of wave-like Ca2+ events generated in the endothelium in response to the vasodilator agonist carbachol. Increased cytosolic Ca2+ signaling activity in arterial endothelial cells from Cantú mice was associated with elevated mitochondrial [Ca2+] and enhanced reactive oxygen species (ROS) and peroxynitrite levels. Scavenging intracellular or mitochondrial ROS restored endothelium-dependent vasodilation in the arteries of mice with KATP GOF mutations. We conclude that mitochondrial Ca2+ overload and ROS generation, which subsequently leads to nitric oxide consumption and peroxynitrite formation, cause endothelial dysfunction in mice with Cantú syndrome.

A novel start-loss mutation of the SLC29A3 gene in a consanguineous family with H syndrome: clinical characteristics, in silico analysis and literature review.

BACKGROUND: The SLC29A3 gene, which encodes a nucleoside transporter protein, is primarily located in intracellular membranes. The mutations in this gene can give rise to various clinical manifestations, including H syndrome, dysosteosclerosis, Faisalabad histiocytosis, and pigmented hypertrichosis with insulin-dependent diabetes. The aim of this study is to present two Iranian patients with H syndrome and to describe a novel start-loss mutation in SLC29A3 gene. METHODS: In this study, we employed whole-exome sequencing (WES) as a method to identify genetic variations that contribute to the development of H syndrome in a 16-year-old girl and her 8-year-old brother. These siblings were part of an Iranian family with consanguineous parents. To confirmed the pathogenicity of the identified variant, we utilized in-silico tools and cross-referenced various databases to confirm its novelty. Additionally, we conducted a co-segregation study and verified the presence of the variant in the parents of the affected patients through Sanger sequencing. RESULTS: In our study, we identified a novel start-loss mutation (c.2T > A, p.Met1Lys) in the SLC29A3 gene, which was found in both of two patients. Co-segregation analysis using Sanger sequencing confirmed that this variant was inherited from the parents. To evaluate the potential pathogenicity and novelty of this mutation, we consulted various databases. Additionally, we employed bioinformatics tools to predict the three-dimensional structure of the mutant SLC29A3 protein. These analyses were conducted with the aim of providing valuable insights into the functional implications of the identified mutation on the structure and function of the SLC29A3 protein. CONCLUSION: Our study contributes to the expanding body of evidence supporting the association between mutations in the SLC29A3 gene and H syndrome. The molecular analysis of diseases related to SLC29A3 is crucial in understanding the range of variability and raising awareness of H syndrome, with the ultimate goal of facilitating early diagnosis and appropriate treatment. The discovery of this novel biallelic variant in the probands further underscores the significance of utilizing genetic testing approaches, such as WES, as dependable diagnostic tools for individuals with this particular condition.

Electrophysiology of Human iPSC-derived Vascular Smooth Muscle Cells and Cell-autonomous Consequences of Cantú Syndrome Mutations.

Cantú syndrome (CS), a multisystem disease with a complex cardiovascular phenotype, is caused by gain-of-function (GoF) variants in the Kir6.1/SUR2 subunits of ATP-sensitive potassium (KATP) channels and is characterized by low systemic vascular resistance, as well as tortuous, dilated, vessels, and decreased pulse-wave velocity. Thus, CS vascular dysfunction is multifactorial, with both hypomyotonic and hyperelastic components. To dissect whether such complexities arise cell autonomously within vascular smooth muscle cells (VSMCs) or as secondary responses to the pathophysiological milieu, we assessed electrical properties and gene expression in human induced pluripotent stem cell-derived VSMCs (hiPSC-VSMCs), differentiated from control and CS patient-derived hiPSCs, and in native mouse control and CS VSMCs. Whole-cell voltage clamp of isolated aortic and mesenteric arterial VSMCs isolated from wild-type (WT) and Kir6.1[V65M] (CS) mice revealed no clear differences in voltage-gated K+ (Kv) or Ca2+ currents. Kv and Ca2+ currents were also not different between validated hiPSC-VSMCs differentiated from control and CS patient-derived hiPSCs. While pinacidil-sensitive KATP currents in control hiPSC-VSMCs were similar to those in WT mouse VSMCs, they were considerably larger in CS hiPSC-VSMCs. Under current-clamp conditions, CS hiPSC-VSMCs were also hyperpolarized, consistent with increased basal K conductance and providing an explanation for decreased tone and decreased vascular resistance in CS. Increased compliance was observed in isolated CS mouse aortae and was associated with increased elastin mRNA expression. This was consistent with higher levels of elastin mRNA in CS hiPSC-VSMCs and suggesting that the hyperelastic component of CS vasculopathy is a cell-autonomous consequence of vascular KATP GoF. The results show that hiPSC-VSMCs reiterate expression of the same major ion currents as primary VSMCs, validating the use of these cells to study vascular disease. Results in hiPSC-VSMCs derived from CS patient cells suggest that both the hypomyotonic and hyperelastic components of CS vasculopathy are cell-autonomous phenomena driven by KATP overactivity within VSMCs .

Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes.

Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, ∼15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition.

Cases with the H syndrome presenting with skin and bone findings.

BACKGROUND: The H syndrome is an autosomal recessive disease characterized by hyperpigmentation, hypertrichosis and sensorineural hearing loss. METHODS: A mutation in the coding of the human equilibrative nucleoside transporter 3 (hENT3) within the SLC29A3 gene on chromosome 10q22 leads to the manifestation of this disease. In this report, we present two cases of H syndrome. RESULTS: The first patient exhibits hyperpigmentation, hypogonadism, Type 1 diabetes mellitus, arthritis and osteoporosis. The second patient experiences hyperpigmentation, hypertrichosis, osteopenia and hypogonadism. CONCLUSION: Our objective is to broaden the clinical spectrum of H syndrome, highlighting the involvement of arthritis, hyperinflammation and low bone mineral density in individuals with this disorder.

A recurrent KCNK4 variant in a dominant pedigree with hypertrichosis and gingival fibromatosis syndrome: Variable phenotypic expressivity and insights on patients' dental management.

Abnormal hyperpolarization of the KCNK4 gene, expressed in the nervous system, brain, and periodontal ligament fibroblasts, leads to impaired neurotransmitter sensitivity, cardiac arrhythmias, and endocrine dysfunction, as well as, progressive cell proliferation. De novo gain of function variants in the KCNK4 gene were reported to cause a recognizable syndrome characterized by facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth (FHEIG, OMIM# 618381). FHEIG is extremely rare with only three reported cases in the literature. Herein, we describe the first inherited KCNK4 variant (c.730G>C, p.Ala244Pro) in an Egyptian boy and his mother. Variable phenotypic expressivity was noted as the patient presented with the full-blown picture of the syndrome while the mother presented only with hypertrichosis and gingival overgrowth without any neurological manifestations. The c.730G>C (p.Ala244Pro) variant was described before in a single patient and when comparing the phenotype with our patient, a phenotype-genotype correlation seems likely. Atrial fibrillation and joint laxity are new associated findings noted in our patient extending the clinical phenotype of the syndrome. Dental management was offered to the affected boy and a dramatic improvement was noted as the patient regained his smile, restored the mastication function, and resumed his psychological stability.

Multiple rhabdomyomatous mesenchymal hamartomas in a patient with mosaic Barber-Say syndrome.

Barber-Say syndrome (BSS) is a rare congenital ectodermal dysplasia with few cases reported in the literature. We describe a 9-year-old boy with congenital generalized hypertrichosis and multiple rhabdomyomatous mesenchymal hamartomas (RMHs) on his nose and periocular region. Next-generation sequencing, performed in DNA from a blood sample, and RMH tissue, revealed a pathogenic variant in the TWIST2 gene, which was not detected in a salivary sample of the patient, nor in his parents. Therefore, we consider this variant as de novo mosaicism. To our knowledge, this is the first case of multiple RMHs associated with BSS.

Multiple vascular anomalies and refractory pericardial effusion in a young patient with Cantu syndrome: a case report and review of the literature.

BACKGROUND: Cantu syndrome is a rare and complex multisystem disorder characterized by hypertrichosis, facial dysmorphism, osteochondroplasia and cardiac abnormalities. With only 150 cases reported worldwide, Cantu syndrome is now gaining wider recognition due to molecular testing and a growing body of literature that further characterizes the syndrome and some of its most important features. Cardiovascular pathology previously described in the literature include cardiomegaly, pericardial effusion, vascular dilation and tortuosity, and other congenital heart defects. However, cardiovascular involvement is highly variable amongst individuals with Cantu syndrome. In some instances, it can be extensive and severe requiring surgical management and long term follow up. CASE PRESENTATION: Herein we report a case of a fourteen-year-old female who presented with worsening pericardial effusion of unknown etiology, and echocardiographic findings of concentric left ventricular hypertrophy, a mildly dilated aortic root and ascending aorta. Her medical history was notable for hemoptysis and an episode of pulmonary hemorrhage secondary to multiple aortopulmonary collaterals that were subsequently embolized in early childhood. She was initially managed with Ibuprofen and Colchicine but continued to worsen, and ultimately required a pericardial window for the management of refractory pericardial effusion. Imaging studies obtained on subsequent visits revealed multiple dilated and tortuous blood vessels in the head, neck, chest, and pelvis. A cardiomyopathy molecular studies panel was sent, and a pathogenic variant was identified in the ABCC9 gene, confirming the molecular diagnosis of autosomal dominant Cantu syndrome. CONCLUSIONS: Vascular anomalies and significant cardiac involvement are often present in Cantu syndrome, however there are currently no established screening recommendations or surveillance protocols in place. The triad of hypertrichosis, facial dysmorphism, and unexplained cardiovascular involvement in any patient should raise suspicion for Cantu syndrome and warrant further investigation. Initial cardiac evaluation and follow up should be indicated in any patient with a clinical and/or molecular diagnosis of Cantu syndrome. Furthermore, whole body imaging should be utilized to evaluate the extent of vascular involvement and dictate long term monitoring and care.

[A case of Oliver-McFarlane syndrome caused by PNPLA6 gene mutation].

Oliver-McFarlane syndrome is a rare genetic disorder characterized by long eyelashes, choroidoretinal atrophy, and multiple pituitary hormone deficiencies. The patient in this case is a 29-year-old female who has suffered from night blindness, low vision, and long eyelashes since childhood. Through genetic sequencing, she was diagnosed with compound heterozygous variaton in the PNPLA6 gene, indicating Oliver-McFarlane syndrome based on her comprehensive clinical presentation.

Dental anomalies in syndromes displaying hypertrichosis in the clinical spectrum.

Hypertrichosis and dental anomalies may occur alone or in combination in the spectrum of many syndromes. To identify genetic entities characterized by hypertrichosis and dental anomalies, a search was performed in the Mendelian Inheritance in Man database with the terms "hypertrichosis" or "hirsutism" and "tooth" or "dental abnormalities." Nondependent androgen metabolism disturbances were classified as hypertrichosis. Genetic entities with hypertrichosis and dental anomalies were included in the study. Additional searches were performed in the PubMed and Orphanet databases, when necessary, in order to include data from scientific articles. An integrative analysis of the genes associated with the identified syndromes was conducted using STRING to characterize biological processes, pathways, and interactive networks. The p-values were subjected to the false discovery rate for the correction of multiple tests. Thirty-nine syndromes were identified, and dental agenesis was the most frequent dental anomaly present in 41.02% (n = 16) of the syndromes. Causative genes were identified in 33 out of 39 genetic syndromes. Among them, 39 genes were identified, and 38 were analyzed by STRING, which showed 148 biological processes and three pathways that were statistically significant. The most significant biological processes were the disassembly of the nucleosome (GO:0006337, p = 1.09e-06), chromosomal organization (GO:0051276, p = 1.09e-06) and remodeling of the chromatin (GO: 0006338, p = 7.86e-06), and the pathways were hepatocellular carcinoma (hsa05225, p = 5.77e-05), thermogenesis (hsa04714, p = 0.00019), and cell cycle (hsa04110, p = 0.0433). Our results showed that the identification of hypertrichosis and dental anomalies may raise the suspicion of one of the thirty-nine syndromes with both phenotypes.

Patients with DeSanto-Shinawi syndrome: Further extension of phenotype from Italy.

Here we describe three patients with neurodevelopmental disorders characterized by mild-to-moderate intellectual disability, mildly dysmorphic features, and hirsutism, all of which carry de novo sequence variants in the WW domain-containing adaptor of the coiled-coil (WAC) gene; two of these-c.167delA, p.(Asn56I1efs*136) and c.1746G>C, p.(Gln582His)-are novel pathogenic variants, and the third-c.1837C>T, p(Arg613*)-has been previously described. Diseases associated with WAC include DeSanto-Shinawi syndrome; to date, de novo heterozygous constitutional pathogenic WAC variants have caused a syndromic form of intellectual disability and mild dysmorphic features in 33 patients, yet potential associations with other clinical manifestations, such as oligomenorrhea and hyperandrogenism, remain unknown, because the phenotypic spectrum of the condition has not yet been delineated. The patient bearing the novel c.167delA WAC gene variant presented a normal psychomotor development, oligomenorrhea, hyperandrogenism, and hirsutism, and hirsutism was also observed in the patient with the c.1746G>C WAC gene variant. Hypertrichosis and hirsutism have been described in nine DeSanto-Shinawi patients, only in 17 of the 33 aforementioned patients thus far reported this aspect, and no hormonal-pattern data are available. In conclusion, we note that the pathogenic c.167delA WAC variant may be associated with a mild phenotype; and in addition to the neurodevelopmental problems nearly all DeSanto-Shinawi patients experience (i.e., intellectual disability and/or developmental delay), we recommend the addition of mild dysmorphic features, hirsutism, and hypertrichosis to this clinical presentation.

Lymphedema as first clinical presentation of Cantu Syndrome: reversed phenotyping after identification of gain-of-function variant in ABCC9.

Cantu Syndrome (CS), [OMIM #239850] is characterized by hypertrichosis, osteochondrodysplasia, and cardiomegaly. CS is caused by gain-of-function (GOF) variants in the KCNJ8 or ABCC9 genes that encode pore-forming Kir6.1 and regulatory SUR2 subunits of ATP-sensitive potassium (KATP) channels. Many subjects with CS also present with the complication of lymphedema. A previously uncharacterized, heterozygous ABCC9 variant, p.(Leu1055_Glu1058delinsPro), termed indel1055, was identified in an individual diagnosed with idiopathic lymphedema. The variant was introduced into the equivalent position of rat SUR2A, and inside-out patches were used to characterize the KATP channels formed by Kir6.2 and WT or mutant SUR2A subunits coexpressed in Cosm6 cells. The indel1055 variant causes gain-of-function of the channel, with an increase of the IC50 for ATP inhibition compared to WT. Retrospective consideration of this individual reveals clear features of Cantu Syndrome. An additional heterozygous ABCC9 variant, p.(Ile419Thr), was identified in a second individual diagnosed with lymphedema. In this case, there were no additional features consistent with CS, and the properties of p.(Ile416Thr) (the corresponding mutation in rat SUR2A)--containing channels were not different from WT. This proof-of-principle study shows that idiopathic lymphedema may actually be a first presentation of otherwise unrecognized Cantu Syndrome, but molecular phenotyping of identified variants is necessary to confirm relevance.

A Unique High-Output Cardiac Hypertrophy Phenotype Arising From Low Systemic Vascular Resistance in Cantu Syndrome.

Background Cardiomegaly caused by left ventricular hypertrophy is a risk factor for development of congestive heart failure, classically associated with decreased systolic and/or diastolic ventricular function. Less attention has been given to the phenotype of left ventricular hypertrophy with enhanced ventricular function and increased cardiac output, which is potentially associated with high-output heart failure. Lack of recognition may pose diagnostic ambiguity and management complexities. Methods and Results We sought to systematically characterize high-output cardiac hypertrophy in subjects with Cantu syndrome (CS), caused by gain-of-function variants in ABCC9, which encodes cardiovascular KATP (ATP-sensitive potassium) channel subunits. We studied the cardiovascular phenotype longitudinally in 31 subjects with CS with confirmed ABCC9 variants (median [interquartile range] age 8 years [3-32 years], body mass index 19.9 [16.5-22.9], 16 male subjects). Subjects with CS presented with significant left ventricular hypertrophy (left ventricular mass index 86.7 [57.7-103.0] g/m2 in CS, n=30; 26.6 [24.1-32.8] g/m2 in controls, n=17; P<0.0001) and low blood pressure (systolic 94.5 [90-103] mm Hg in CS, n=17; 109 [98-115] mm Hg in controls, n=17; P=0.0301; diastolic 60 [56-66] mm Hg in CS, n=17; 69 [65-72] mm Hg in control, n=17; P=0.0063). Most (21/31) subjects with CS exhibited eccentric hypertrophy with normal left ventricular wall thickness. Congestive heart failure symptoms were evident in 4 of the 5 subjects with CS aged >40 years on long-term follow-up. Conclusions The data define the natural history of high-output cardiac hypertrophy resulting from decreased systemic vascular resistance in subjects with CS, a defining population for long-term consequences of high-output hypertrophy caused by low systemic vascular resistance, and the potential for progression to high-output heart failure.

Kir6.1 and SUR2B in Cantú syndrome.

Kir6.1 and SUR2 are subunits of ATP-sensitive potassium (KATP) channels expressed in a wide range of tissues. Extensive study has implicated roles of these channel subunits in diverse physiological functions. Together they generate the predominant KATP conductance in vascular smooth muscle and are the target of vasodilatory drugs. Roles for Kir6.1/SUR2 dysfunction in disease have been suggested based on studies of animal models and human genetic discoveries. In recent years, it has become clear that gain-of-function (GoF) mutations in both genes result in Cantú syndrome (CS)-a complex, multisystem disorder. There is currently no targeted therapy for CS, but studies of mouse models of the disease reveal that pharmacological reversibility of cardiovascular and gastrointestinal pathologies can be achieved by administration of the KATP channel inhibitor, glibenclamide. Here we review the function, structure, and physiological and pathological roles of Kir6.1/SUR2B channels, with a focus on CS. Recent studies have led to much improved understanding of the underlying pathologies and the potential for treatment, but important questions remain: Can the study of genetically defined CS reveal new insights into Kir6.1/SUR2 function? Do these reveal new pathophysiological mechanisms that may be important in more common diseases? And is our pharmacological armory adequately stocked?

[Identification of a novel frameshift variant in the KMT2A gene of a child with Wiedemann-Steiner syndrome].

OBJECTIVE: To analyze pathogenic variant s of KMT2A gene in a child with Wiedemann-Steiner syndrome (WDSTS) and provide reliable evidences for clinical diagnosis of WDSTS. METHODS: Whole-DNAs were extracted from an 9 years-old boy and his parents. Trio-whole exome sequencing (trio-WES) was performed to identify candidate pathogenic variants that can explain the boy's condition and sanger sequencing was conducted to prove it. The impact of detected variants were predicted and validated by bioinformatics tools. RESULTS: A de novo frameshift variant c.10488dupG (p.Leu3498Thrfs*41) in exon 27 of KMT2A gene was detected and this de novo variant (PS2) had not been reported in the world previously. This frameshift variant was absent in major allele frequency databases (PM2) and had been predicted to be pathogenic based on MutationTaster. Through HomoloGene and CD-search system, the 3498 locus (Leu) in KMT2A protein, which was an important histone modifying enzyme that regulated gene expression in early embryonic development and encoded by the KMT2A gene, was predicted as a high conserved locus (PP3), and that replacement of Lue3498 may result in frame-shifts with premature termination in 3539 locus by introducing stop codon, causing deletion of multiple functional domains which all played important roles on histone modifications and recognition (PVS1+PM1). According to the American College of Medical Genetics and Genomics variant classification guideline, the variant c.10488dupG (p.Leu3498Thrfs*41) in KMT2A was classified as pathogenic variant (PVS1+PS2+PM1+PM2+PP3). CONCLUSION: The patient's condition may be attributed to the de novo frameshift variant c.10488dupG (p.Leu3498Thrfs*41) in KMT2A gene. This study reported a pathogenic KMT2A variant that had not been reported previously in WDSTS, it expanded the genotypic spectrums of KMT2A variants.

Missense variants causing Wiedemann-Steiner syndrome preferentially occur in the KMT2A-CXXC domain and are accurately classified using AlphaFold2.

Wiedemann-Steiner syndrome (WDSTS) is a neurodevelopmental disorder caused by de novo variants in KMT2A, which encodes a multi-domain histone methyltransferase. To gain insight into the currently unknown pathogenesis of WDSTS, we examined the spatial distribution of likely WDSTS-causing variants across the 15 different domains of KMT2A. Compared to variants in healthy controls, WDSTS variants exhibit a 61.9-fold overrepresentation within the CXXC domain-which mediates binding to unmethylated CpGs-suggesting a major role for this domain in mediating the phenotype. In contrast, we find no significant overrepresentation within the catalytic SET domain. Corroborating these results, we find that hippocampal neurons from Kmt2a-deficient mice demonstrate disrupted histone methylation (H3K4me1 and H3K4me3) preferentially at CpG-rich regions, but this has no systematic impact on gene expression. Motivated by these results, we combine accurate prediction of the CXXC domain structure by AlphaFold2 with prior biological knowledge to develop a classification scheme for missense variants in the CXXC domain. Our classifier achieved 92.6% positive and 92.9% negative predictive value on a hold-out test set. This classification performance enabled us to subsequently perform an in silico saturation mutagenesis and classify a total of 445 variants according to their functional effects. Our results yield a novel insight into the mechanistic basis of WDSTS and provide an example of how AlphaFold2 can contribute to the in silico characterization of variant effects with very high accuracy, suggesting a paradigm potentially applicable to many other Mendelian disorders.

An update on Becker's nevus: Pathogenesis and treatment.

Becker's nevus (BN) manifests as a hyperpigmented, sometimes hypertrichotic plaque/patch over the chest and shoulder, and it is in the category of benign cutaneous hamartomas. BN has elongation and fusion of the rete ridge, keratotic plugging, sebaceous hyperplasia, smooth muscle hyperplasia, and hyperpigmentation of the basal/suprabasal layer histologically. This article highlights all issues involved in pathogenesis and treatment options of BN. According to current research, postzygotic ACTB mutations induce BN and Becker's nevus syndrome (BNS). Although several therapy strategies were utilized to treat the pigmentary and hypertrichotic aspects of BN, no definitive standard treatment was identified to far, and further research is needed to better educate BN care.

Cantù syndrome: Report of a patient with a novel variant in KCNJ8 and revision of literature.

Cantù syndrome (CS) is a rare multisystemic disorder, characterized by congenital hypertrichosis, macrocephaly, facial dysmorphisms, cardiomegaly, vascular, and skeletal anomalies. From the cognitive point of view, most of the patients show a mild speech delay and a few of them present intellectual disability and learning difficulties. To date, most CS-reported cases are caused by heterozygous ABCC9 gene mutations. Only three patients with CS and heterozygous KCNJ8 gene variants have been reported. The authors here present the fourth case of CS with a variant in KCNJ8 in a 6-month-old baby. Diagnosis was reached through Trio-Whole Exome analysis that revealed a de novo missense variant in KCNJ8.