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Background: Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) is a rare neurological disorder characterized by abnormal brain size, vascular malformations, and body overgrowth. MCAP is caused by somatic mosaicism of PIK3CA, a crucial gene in regulation of cell growth and survival, and is one of the disorders in the PIK3CA-related overgrowth spectrum., Methods: We present a unique clinical report of a male infant diagnosed with MCAP from prenatal stages to age 12 months. Prenatal imaging unveiled ventricular asymmetry, later confirmed postnatally as megalencephaly. Genetic analysis identified a PIK3CA mutation. The patient underwent early interventions, including ventriculoperitoneal shunt placement and posterior fossa decompression., Results: Despite early interventions, the patient developed progressive macrocrania, hydrocephalus, and significant neurodevelopmental delay. Multidisciplinary management and continuous neuroimaging were crucial in addressing complications associated with the disorder., Conclusions: This case underscores the critical need for multidisciplinary care and continual neuroimaging surveillance to effectively navigate the progressive complications associated with PIK3CA-related overgrowth spectrum. The diagnostic hurdles and management challenges intrinsic to the disorder's natural course are elucidated. Although current treatments manage symptoms, emerging therapies hold promise for improving patient outcomes., Competing Interests: Declaration of competing interest Drs. Andrade, Hierro, Castro, Pereira, Nunes, and Grenha have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: The megalencephaly capillary malformation polymicrogyria (MCAP syndrome) results from mosaic gain-of-function PIK3CA variants. The main clinical features are macrocephaly, somatic overgrowth, neurodevelopmental delay and brain anomalies. Alpelisib (Vijoice) is a recently FDA-approved PI3Kα-specific inhibitor for patients with PIK3CA-related overgrowth spectrum (PROS). During its development, in patients with the MCAP subgroup of PROS, there was no specific, standardised evaluation of the effect on neuro-cognitive functioning. Moreover, it remains unknown if the molecule crosses the blood-brain barrier. Our objective is to evaluate the efficacy of a 24 month treatment with alpelisib on adaptive behaviour in patients with MCAP syndrome., Methods and Analysis: SESAM is an industry-sponsored two-period multicentre French academic phase II trial, with a 6-month double-blind, placebo-controlled period followed by an open-label period. The primary endpoint is a ≥4-point improvement in the Vineland II Adaptive Behaviour Scale (VABS), 24 months after treatment initiation. Secondary objectives are safety, VABS improvement at 6 months, impact on the quality of life, epilepsy and hypotonia. 20 patients aged 2 to 40 years with an MCAP diagnosis and neurodevelopmental disorders of various degrees, will be followed monthly in local centres, centrally assessed (clinical, biological, neuropsychological and functional evaluation) at baseline and every 6 months. Patients will be evaluated by volumetric MRI at baseline and at 24 months. An optional lumbar puncture will be performed to investigate blood-brain barrier crossing. Inclusions were completed by April 2024, with the end of follow-up in November 2026.Given the efficacy of alpelisib in patients with PROS, if the drug crosses the blood-brain barrier, we can expect a clinical benefit for patients with neurocognitive disorders., Ethics and Dissemination: Ethical approval was given by CPP Sud-Ouest et Outre-Mer I (reference: 2022-500197-34-01). Findings from this study will be disseminated via publication, reports and conference presentations., Trial Registration Number: NCT05577754., Competing Interests: Competing interests: A patent application ('BYL719 (alpelisib) for the use in the treatment of PIK3CA-related overgrowth spectrum' #WO2017140828A1) has been filed by INSERM (Institut National de la Santé et de la Recherche Médicale), Centre National De La Recherche Scientifique (CNRS), Université Paris Cité and Assistance Publique-Hôpitaux De Paris (AP-HP) for the use of BYL719 (alpelisib) in the treatment of PIK3CA-related overgrowth spectrum (PROS/CLOVES syndrome). Dr Canaud is the inventor. This patent is licensed to Novartis Pharmaceutical. ML has received consulting fees from Novartis Pharmaceutical. GC receives or has received consulting fees from Novartis Pharmaceutical, Fresenius Medical Care, Vaderis, Alkermes, IPSEN and BridgeBio., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

PIK3CA-related overgrowth spectrum (PROS) disorders are caused by somatic mosaic variants that result in constitutive activation of the phosphatidylinositol-3-kinase/AKT/mTOR pathway. Promising responses to molecularly targeted therapy have been reported, although identification of an appropriate agent can be hampered by the mosaic nature and corresponding low variant allele frequency of the causal variant. Moreover, our understanding of the molecular consequences of these variants-for example how they affect gene expression profiles-remains limited. Here we describe in vitro expansion of a human capillary malformation followed by molecular characterization using exome sequencing, single cell gene expression, and targeted long-read single cell RNA-sequencing in a patient with clinical features consistent with Megalencephaly-Capillary Malformation Syndrome (MCAP, a PROS condition). These approaches identified a targetable PIK3CA variant with expression restricted to PAX3+ fibroblast and undifferentiated keratinocyte populations. This study highlights the innovative combination of next-generation single cell sequencing methods to better understand unique transcriptomic profiles and cell types associated with MCAP, revealing molecular intricacies of this genetic syndrome., (© 2024. The Author(s).)

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Cutis marmorata telangiectatica congenita is a rare congenital vascular malformation characterised by cutaneous vascular abnormalities, typically diagnosed at birth or in the early postnatal period. Although typically benign, this disease is associated with other systemic abnormalities, including rare ocular alterations, such as congenital glaucoma, cataracts and retinopathy.This manuscript describes a female infant, who presented with generalised livedo reticularis, a band of alopecia and cutaneous atrophy in the temporal region above the coronal suture. The patient was diagnosed with cutis marmorata telangiectatica congenita by a paediatrician, and an ophthalmological evaluation was requested. A funduscopy examination in both eyes showed temporal and superior retina with avascular areas with new vessels, venous dilations and shunts, and no retinal detachments. Given these findings, we performed retinal photocoagulation laser treatment with excellent results.This case report highlights the importance of early ophthalmological evaluation of children with this disease to prevent secondary complications, such as vitreous haemorrhage and tractional retinal detachment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The modulation of cell behavior during culture is one of the most important aspects of bone tissue engineering because of the necessity for a complex mechanical and biochemical environment. This study aimed to improve the physicochemical properties of chitosan/multi-phase calcium phosphate (MCaP) scaffolds using an optimized mixture design experiment and evaluate the effect of biofunctionalization of the obtained scaffolds with the bone morphogenetic protein BMP-2 on stem cell behavior. The present study evaluated the compressive strength, elastic modulus, porosity, pore diameter, and degradation in simulated body fluids and integrated these responses using desirability. The properties of the scaffolds with the best desirability (18.4% of MCaP) were: compressive strength of 23 kPa, elastic modulus of 430 kPa, pore diameter of 163 μm, porosity of 92%, and degradation of 20% after 21 days. Proliferation and differentiation experiments were conducted using dental pulp stem cells after grafting BMP-2 onto scaffolds via the carbodiimide route. These experiments showed that MCaP promoted cell proliferation and increased alkaline phosphatase activity, whereas BMP-2 enhanced cell differentiation. This study demonstrates that optimizing the composition of a mixture of chitosan and MCaP improves the physicochemical and biological properties of scaffolds, indicating that this solution is viable for application in bone tissue engineering., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Edwin Patino Gonzalez reports financial support was provided by AM LTDA. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Activating variants in the PIK3CA gene cause a heterogeneous spectrum of disorders that involve congenital or early-onset segmental/focal overgrowth, now referred to as PIK3CA-related overgrowth spectrum (PROS). Historically, the clinical diagnoses of patients with PROS included a range of distinct syndromes, including CLOVES syndrome, dysplastic megalencephaly, hemimegalencephaly, focal cortical dysplasia, Klippel-Trenaunay syndrome, CLAPO syndrome, fibroadipose hyperplasia or overgrowth, hemihyperplasia multiple lipomatosis, and megalencephaly capillary malformation-polymicrogyria (MCAP) syndrome. MCAP is a sporadic overgrowth disorder that exhibits core features of progressive megalencephaly, vascular malformations, distal limb malformations, cortical brain malformations, and connective tissue dysplasia. In 2012, our research group contributed to the identification of predominantly mosaic, gain-of-function variants in PIK3CA as an underlying genetic cause of the syndrome. Mosaic variants are technically more difficult to detect and require implementation of more sensitive sequencing technologies and less stringent variant calling algorithms. In this study, we demonstrated the utility of deep sequencing using the Illumina TruSight Oncology 500 (TSO500) sequencing panel in identifying variants with low allele fractions in a series of patients with PROS and suspected mosaicism: pathogenic, mosaic PIK3CA variants were identified in all 13 individuals, including 6 positive controls. This study highlights the importance of screening for low-level mosaic variants in PROS patients. The use of targeted panels with deep sequencing in clinical genetic testing laboratories would improve diagnostic yield and accuracy within this patient population., (© 2023 Wiley Periodicals LLC.)

Introduction: Cutis marmorata telangiectatica congenita (CMTC) is a rare capillary malformation characterized by persistent reticular and violaceous erythema. We present two cases of CMTC., Clinical Observation: The first case involved a 13-month-old male with a reticular violaceous macule on the left gluteal region and a brownish papule with Darier's sign on the inner malleolus of the left foot, which was biopsied, revealing > 15 mast cells per field, leading to a diagnosis of CMTC and solitary cutaneous mastocytoma. The second case involved a newborn with a characteristic CMTC lesion without other malformations at birth, who subsequently developed two cutaneous tumors consistent with infantile hemangiomas during follow-up., Discussion: CMTC is a benign condition. However, approximately 50% of cases exhibit associated anomalies. When CMTC is suspected, musculoskeletal, ophthalmological, and cutaneous malformations should be ruled out. To the best of our knowledge, this is the first report of CMTC associated with mastocytoma and one of the few cases associated with infantile hemangioma.

Background: Hypoketotic hypoglycaemia with suppressed plasma fatty acids and detectable insulin suggests congenital hyperinsulinism (CHI). Severe hypoketotic hypoglycaemia mimicking hyperinsulinism but without detectable insulin has recently been described in syndromic individuals with mosaic genetic activation of post-receptor insulin signalling. We set out to expand understanding of this entity focusing on metabolic phenotypes., Methods: Metabolic profiling, candidate gene and exome sequencing were performed in six infants with hypoketotic, hypoinsulinaemic hypoglycaemia, with or without syndromic features. Additional signalling studies were carried out in dermal fibroblasts from two individuals., Results: Two infants had no syndromic features. One was mistakenly diagnosed with CHI. One had mild features of megalencephaly-capillary malformation-polymicrogyria (MCAP) syndrome, one had non-specific macrosomia, and two had complex syndromes. All required intensive treatment to maintain euglycaemia, with CHI-directed therapies being ineffective. Pathogenic PIK3CA variants were found in two individuals - de novo germline c.323G>A (p.Arg108His) in one non-syndromic infant and postzygotic mosaic c.2740G>A (p.Gly914Arg) in the infant with MCAP. No causal variants were proven in the other individuals despite extensive investigation, although rare variants in mTORC components were identified in one. No increased PI3K signalling in fibroblasts of two individuals was seen., Conclusions: We expand the spectrum of PI3K-related hypoinsulinaemic hypoketotic hypoglycaemia. We demonstrate that pathogenic germline variants activating post-insulin-receptor signalling may cause non-syndromic hypoinsulinaemic hypoketotic hypoglycaemia closely resembling CHI. This distinct biochemical footprint should be sought and differentiated from CHI in infantile hypoglycaemia. To facilitate adoption of this differential diagnosis, we propose the term "pseudohyperinsulinism"., (© 2023. The Author(s).)

Background: Subjects with Megalencephaly-Capillary Malformation-Polymicrogyria syndrome (MCAP) can present with a Chiari Malformation Type 1 and resulting alterations in cerebrospinal fluid (CSF) dynamics, which may require surgical treatment. The aim of this paper is to describe the features of children with MCAP who underwent surgical decompression for CM1, and to explore the PIK3CA variant allele frequency (VAF) identified in cerebellar parenchyma and other adjacent structures., Methods: This study reviewed two cases of children with CM1 and MCAP who underwent surgical decompression treatment. These two cases were part of a national cohort of 12 MCAP patients who had CM1, due to their surgical eligibility. Tissue samples were obtained from the cerebellar tonsils and adjacent anatomical structures during the surgical procedures. Samples were then subsequently analyzed for PIK3CA postzygotic variants., Results: In both cases, alterations in CSF dynamics, specifically hydrocephalus and syringomyelia, were observed and required surgical treatment. PIK3CA targeted sequencing determined the VAF of the postzygotic variant in both cerebellar and adjacent bone/connective tissues., Discussion: The recognition of a CM1 comorbidity in MCAP patients is of paramount importance when considering personalized treatment options, especially because these patients are at higher risk of developing complications during surgical decompression surgery. The variable PIK3CA VAF identified in the different analyzed tissues might help explain the heterogeneous nature and severity of anomalies observed in the volume of the posterior fossa structures in MCAP patients and associated CSF and venous disorders., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Masson SAS.)

Biallelic variants in DI3SL2 cause Perlman Syndrome, associated increased risk for Wilms tumor. Cutis Marmorata Telangiectatica Congenita (CMTC) is a rare congenital disorder characterized by cutaneous vascular anomalies. We report a 2-year-old boy with both Wilms tumor and CMTC. Genetic testing, prompted by his complex presentation, revealed 1 somatic mutation and 1 familial germline mutation in the DIS3L2 gene, suggesting a 2-hit causation of Wilms tumor. Separately, a single GNA11 somatic mutation was identified to explain the CMTC. We suggest that genetic testing for germline mutations associated with Wilms tumor susceptibility be considered even in cases without known family history., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Hemimegalencephaly (HME) is a rare neurological diagnosis defined as hamartomatous overgrowth of one cerebral hemisphere. The hypothesised pathogenesis is due to an increased number or size of neural cells; however, the exact mechanism can vary widely, depending on the underlying aetiology. We report a case outlining the prenatal diagnostic process and obstetric considerations for delivering an infant with HME secondary to megalencephaly-capillary malformation syndrome. After diagnosis, our patient was induced and delivered at 37 weeks of gestation via operative vaginal delivery. To our knowledge, this is the first report describing the course from prenatal diagnosis through delivery of a fetus with HME., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

PIK3CA-related overgrowth spectrum (PROS) disorders are caused by somatic, gain-of-function mutations in PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) that result in hyperactivation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway. PROS encompasses a broad spectrum of overlapping phenotypes that vary considerably in their severity and tissue distribution, leading to different and complex experiences for affected children and their families. The parent of a child with the PROS disorder megalencephaly-capillary malformation (MCAP) coauthored this article. MCAP is characterized by significant neurological involvement, and she describes personal experiences with this condition, including delays associated with obtaining a correct diagnosis, finding an experienced care team, challenges with schooling, medical complications, and the ongoing emotional and financial impacts on their lives. A physician perspective, which reinforces the challenges faced by the young child and his family, is provided by a clinician and researcher specializing in PROS disorders with central nervous system involvement. The physician reviews the mechanism of disease, some of the challenges in accurately diagnosing PROS conditions, disease-related complications, current treatment options and their limitations, and emerging therapeutic options including ongoing clinical trials. Our objective is to share these experiences and insights to benefit patients with PROS disorders, their families, and health care professionals involved with caring for patients with PROS., (© 2022. The Author(s).)

Somatic and germline PI3K-AKT-mTOR pathway pathogenic variants are involved in several segmental overgrowth phenotypes such as the PIK3CA-related overgrowth spectrum (PROS), Proteus syndrome, and PTEN hamartoma tumor syndrome. In this study, we describe five patients with PROS. We identified by high-throughput sequencing four different somatic PIK3CA pathogenic variants in five individuals. The Glu726Lys variant, which was previously reported in megalencephaly-capillary malformation-polymicrogyria (MCAP) syndrome, was identified in two patients with unclassified PROS. The Cys420Arg substitution, which was previously reported in CLOVES, was found in a patient with fibroadipose hyperplasia. Additionally, relatively rare pathogenic variants, His1047Tyr and Tyr1021Cys, were detected in two patients with MCAP. Therefore, we suggest performing deep sequencing of PIK3CA in all patients with suspected PROS, instead of targeted polymerase chain reaction for hotspot pathogenic variants., (© 2022 Wiley Periodicals LLC.)

Cutis marmorata telangiectatica congenita (CMTC) is characterized by coarse-meshed capillary malformations arranged in asymmetrically distributed patches. The disorder may be associated with hyper- or hypoplastic limbs, syndactyly, cleft palate, and glaucoma. Because the disease usually occurs sporadically, the concept of a lethal mutation surviving by mosaicism was proposed about 30 years ago. Here we describe three children with CMTC due to a postzygotic GNA11 mutation c547C > T (p.Arg183Cys), documented in saliva (patient 1) or lesional cutaneous tissue (patients 2 and 3). All three individuals had widespread and asymmetric CMTC which was present from birth and became fainter during the first years of life. Variably associated anomalies included glaucoma, choroidal capillary malformation, and body asymmetry. In previous case reports, postzygotic GNA11 mutations were documented in two cases of phacomatosis cesiomarmorata, being characterized by CMTC coexisting with segmental dermal melanocytosis. Moreover, postzygotic GNA11 mutations were noted in two CMTC patients described under the incorrect diagnosis of "nevus vascularis mixtus". Hence, the present cases convincingly support the concept that CMTC can be caused by mosaic GNA11 mutations and thus belongs to the GNA11-Related Capillary Nevus (GNARCAN) spectrum. In two other bona fide cases of CMTC, however, we were unable to find a mutation in GNA11, which may be explained either by our inability to detect a very low percentage of mutant cells or by genetic heterogeneity of the phenotype., (Copyright © 2022. Published by Elsevier Masson SAS.)

The megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth disorder caused by mosaic gain-of-function variants in PIK3CA It is characterized by megalencephaly or hemimegalencephaly, vascular malformations, somatic overgrowth, among other features. Epilepsy is commonly associated with MCAP, and a subset of individuals have cortical malformations requiring resective epilepsy surgery. Like other mosaic disorders, establishing a molecular diagnosis is largely achieved by screening lesional tissues (such as brain or skin), with a low diagnostic yield from peripheral tissues (such as blood). Therefore, in individuals with MCAP in whom lesional tissues are scarce or unavailable or those ineligible for epilepsy surgery, establishing a molecular diagnosis can be challenging. Here we report on the utility of cerebrospinal fluid (CSF)-derived cfDNA for the molecular diagnosis of an individual with MCAP syndrome harboring a mosaic PIK3CA variant (c.3139C > T, p.His1047Tyr). The proband presented with asymmetric megalencephaly without significant dysgyria. He did not have refractory epilepsy and was therefore not a candidate for epilepsy surgery. However, he developed diffuse large B-cell lymphoma (DLBCL) in late childhood, with four CSF samples obtained via lumbar puncture for cancer staging during which one sample was collected for cfDNA extraction and sequencing. PIK3CA variant allele fractions in CSF cell-free DNA (cfDNA), skin fibroblasts, and peripheral blood were 3.08%, 37.31%, and 2.04%, respectively. This report illustrates the utility of CSF-derived cfDNA in MCAP syndrome. Minimally invasive-based molecular diagnostic approaches utilizing cfDNA not only facilitate accurate genetic diagnosis but also have important therapeutic implications for individuals with refractory epilepsy as repurposed PI3K-AKT-MTOR pathway-inhibitors become more widely available., (© 2022 Chen et al.; Published by Cold Spring Harbor Laboratory Press.)

Case Presentation: A 55-year-old woman with a medical history of hereditary hemorrhagic telangiectasia (HHT) complicated by recurrent nosebleeds, severe blood loss anemia, hepatic arterial-venous malformation (AVM), pulmonary hypertension, and severe tricuspid regurgitation presented to the HHT specialty clinic with acute hypoxic respiratory failure (new 3-L O 2 requirement), weight gain, and volume overload. She was directly admitted to the pulmonary hypertension unit of our hospital. She had two recent admissions for similar symptoms thought to be due to worsening pulmonary arterial hypertension. In prior admissions, she had undergone right heart catheterization demonstrating mild pulmonary hypertension (pulmonary arterial pressure, 29 mm Hg, cardiac output by Fick 5.76, and cardiac index 3.22, mildly elevated pulmonary vascular resistance to 5.5 woods units). She would undergo diuresis with symptomatic improvement; however, after discharge she would rapidly develop recurrent heart failure symptoms. She reported compliance with guideline-directed medications, diuretics, and dietary restrictions and was still suffering severe symptoms. Notably she had previously elevated liver enzymes concerning for cirrhosis and had begun a workup to evaluate for causes of cirrhosis; she had a history of mild alcohol use, negative hepatitis viral serology, and no known history of liver disease., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cell division cycle 42 (CDC42) is a small Rho GTPase, which serves as a fundamental intracellular signal node regulating actin cytoskeletal dynamics and several other integral cellular processes. CDC42-associated disorders encompass a broad clinical spectrum including Takenouchi-Kosaki syndrome, autoinflammatory syndromes and neurodevelopmental phenotypes mimicking RASopathies. Dysregulation of CDC42 signaling by genetic defects in either DOCK6 or ARHGAP31 is also considered to play a role in the pathogenesis of Adams-Oliver syndrome (AOS). Here, we report a mother and her child carrying the previously reported pathogenic CDC42 variant c.511G>A (p.Glu171Lys). Both affected individuals presented with short stature, distinctive craniofacial features, pectus deformity as well as heart and eye anomalies, similar to the recently described Noonan syndrome-like phenotype associated with this variant. Remarkably, one of the patients additionally exhibited aplasia cutis congenita of the scalp. Multi-gene panel sequencing of the known AOS-causative genes and whole exome sequencing revealed no second pathogenic variant in any disease-associated gene explaining the aplasia cutis phenotype in our patient. This observation further expands the phenotypic spectrum of CDC42-associated disorders and underscores the role of CDC42 dysregulation in the pathogenesis of aplasia cutis congenita., (© 2020 Wiley Periodicals LLC.)

Competing Interests: Competing interests: None declared.

Purpose: To report a rare case of peripheral retinal neovascularization in a patient diagnosed with cutis marmorata telangiectatica congenita (CMTC)., Methods: Observational case report., Results: A 16-year-old girl was referred to clinic for retinal evaluation. The patient had a clinical diagnosis of CMTC later confirmed by skin biopsy. Examination revealed temporal peripheral retinal sheathing, as well as lattice degeneration in both eyes. Wide-field fluorescein angiogram showed substantive peripheral retinal nonperfusion with evidence of vascular leakage from areas of presumed retinal neovascularization. The patient subsequently had pan retinal photocoagulation laser treatment to each eye without complication., Discussion: Cutis marmorata telangiectatica congenita is a rare vascular condition known to affect multiple organ systems including the eyes. Although ocular manifestations of CMTC are rare, instances of congenital glaucoma, suprachoroidal hemorrhage, and bilateral total retinal detachments resulting in secondary neovascular glaucoma have been reported. Our patient demonstrates the first reported findings of peripheral nonperfusion and retinal neovascularization related to CMTC in a 16-year-old girl. We propose early retinal examination, wide-field fluorescein angiogram, and early pan retinal photocoagulation laser treatment in patients with peripheral nonperfusion and retinal neovascularization from CMTC., (Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

A full-term, 2-day-old female neonate with a congenital non-tender reticular patch that did not disappear with local warming was referred to our department for consultation. The family history as well as the antenatal course and delivery were unremarkable. On examination, we evidenced a fixed, marbled, bluish to deep purple lesion with a fishnet appearance extending over the right side of her body, face, and scalp. There was presence of atrophy of the involved skin, along with ulceration above the right lateral malleolus. Upon blanching, the lesions could not be emptied completely. Routine laboratory studies, chest X-rays, and abdominal and cranial ultrasound scan results were nonsignificant. Head and limb circumferences were within normal ranges. The patient was checked by the ophthalmology and neurology department to screen for associated anomalies, which were not detected. Based on the medical history and clinical presentation, the diagnosis of cutis marmorata telangiectatica congenita was established. The infant's parents were reassured about the benign nature of the cutaneous disorder as well as the need for periodic follow-up on an outpatient basis. Cutis marmorata telangiectatica congenita (CMTC), first described by the Dutch pediatrician Van Lohuizen in 1922, is an exceedingly rare congenital sporadic condition with fewer than 300 cases described in the medical literature to date. Affected infants have discolored vascular patches of skin with a blue-violet marbled appearance. The disorder may present with a segmental or generalized persistent reticular mottling but more frequently has localized distribution over the lower limbs (1,2). Skin lesions are reminiscent of cutis marmorata, a common benign response observed in infants, which resolves with warming of the skin surface. In contrast, CMTC lesions do not disappear with rewarming and occasionally present with ulceration and atrophy of the involved skin (aplasia cutis) (1,3). Cutis marmorata telangiectatica congenita is described as occuring in association with a plethora of extracutaneous malformations, including undergrowth or overgrowth of the involved extremity, ocular and neurological abnormalities, growth and developmental delays, as well as additional vascular anomalies. The pathogenesis is not fully elucidated, but a lethal gene hypothesis has been suggested by some authors, while others indicate that the disorder may be inherited as an autosomal dominant trait with low penetrance (1,2,4). Skin biopsy is nonspecific and differential diagnosis is rarely difficult due to the distinctive appearance of cutaneous lesions, and the diagnosis can thus be established on clinical grounds alone. CMTC can be associated with other congenital syndromes including phacomatosis pigmentovascularis and Adams-Oliver syndrome (2,4). Cutaneous lesions carry a good prognosis and show a tendency for fading or spontaneous resolution over the first years of life in most cases, but the extremity discrepancy tends to persist. A thorough screening for associated anomalies as well as annual controls of skin changes and psychomotor development of the patients should be performed (2-3).

Cutis marmorata telangiectatica congenita (CMTC) is a rare congenital cutaneous vascular anomaly with a reticular marbled erythematous pattern, which can result in isolated benign skin lesions or less commonly be associated with systemic anomalies. Occasionally, the characteristic pattern of CMTC lesions is masked on initial presentation, creating a diagnostic conundrum that can result in unnecessary workups to rule out vasculopathy. We present the case of a female newborn with a red-blue ulcerated skin lesion on the right leg and foot, which initially appeared as retiform purpura but evolved to exhibit the mottled pattern of CMTC by 5 days of age. Clinicians must be made aware of this potential diagnostic trap in early CMTC to avoid invasive skin biopsies and unnecessary laboratory testing in neonates., (© 2020 Wiley Periodicals LLC.)

Cutis marmorata telangiectatica congenita (CMTC) is a rare vascular disorder characterized by blue-purple reticulated patches and plaques that can be localized or generalized. Associated skin atrophy and soft tissue hypoplasia is common while ulceration is relatively uncommon. As CMTC is exceedingly rare and spontaneous remission in childhood can occur in mild cases, evidence for treatment of severe, refractory disease is limited. We present the case of a four-year-old female with CMTC and associated painful, recalcitrant ulcers successfully treated with a combination of pulsed dye laser and intense pulsed light therapy.

Cutis marmorata telangiectatica congenita (CMTC) is a rare, congenital, vascular disorder that may sometimes be associated with ulcerations of the involved skin. We present a case of CMTC, asymptomatic since birth, that began developing painful ulcerations during adolescence. Although laser therapy may benefit the superficial aspect of this vascular anomaly, the presence of deeper involvement in lesions with ulcerations may not respond favorably to laser therapy and the best approach needs to be further evaluated.

Cutis marmorata telangiectasia congenita is a rare cutaneous vascular disorder that may be associated with different systemic manifestations like body asymmetry, cutaneous, ophthalmologic, vascular, and neurological manifestations. We describe ophthalmologic alterations found in three patients with cutis marmorata telangiectatica congenita highlighting the rare retinal manifestations.

Purpose: Cutis marmorata telangiectatica congenita (CMTC) is a rare congenital disorder typified by localized or generalized cutaneous vascular anomalies, which dissipate over time. We review the diagnostic approach to CMTC and present a comprehensive examination of its ocular manifestations. Additionally, we offer recommendations for the ophthalmologic workup for patients with CMTC. Finally, we examine the possible causes of CMTC and summarize the current efforts to establish an etiologic mechanism for this disease. Methods: Thirty-three published cases of CMTC with ocular anomalies are examined in detail. Results: CMTC is diagnosed based on a specific set of congenital cutaneous symptoms, principally congenital reticular erythema that is unresponsive to local warming and absence of venectasia within the skin lesions. Ocular findings are not currently employed in this diagnostic process, likely due to an incomplete understanding into their presentation, frequency, and natural history. We show that the majority of ophthalmic manifestations are congenital, with glaucoma and posterior segment anomalies, consisting of retinal perfusion defects and vascular abnormalities, as the most frequently reported findings. Typical ophthalmic medical and surgical interventions appear to be effective for management of these CMTC-related pathology. Unfortunately, the etiology and pathophysiology of CMTC remains unknown, which obfuscates efforts to identify, examine, and initiate treatment in patients. Conclusions: While the ophthalmic community has traditionally viewed glaucoma as the classic ocular anomaly of CMTC, this dataset advocates for the prompt investigation of posterior segment abnormalities as well. However, our understanding of CMTC's ocular anomalies is complicated by a lack of reporting and/or incomplete (or nonexistent) ophthalmic examinations, and we strongly encourage comprehensive ophthalmic examinations for all CMTC patients at the time of diagnosis, followed by appropriate screening and surveillance throughout life. We believe these recommendations will spur additional data and disease insights that may be useful for future refinements to CMTC diagnostic algorithms.

Background: Cutis marmorata telangiectatica congenita (CMTC) is a rare capillary malformation characterised by persistent reticulated marbled erythema. It tends to be associated with cutaneous atrophy, ulcerations and body asymmetry. CMTC is usually reported to be a benign condition; however, associated anomalies are not rare. Here, we have compiled information on published CMTC patients with the aim to evaluate the proposed diagnostic criteria by Kienast et al. and address the clinical manifestations, associated anomalies, differential diagnoses, management and prognosis. Our review is based on a search of the PubMed database which retrieved studies between 1922 and April 2019. The search yielded 148 original articles with a total of 485 patients., Results: Of the identified patients, 24.5% had generalised CMTC, 66.8% had localised and 8.7% had a non-specified distribution of CMTC. Associated anomalies were observed in 42.5% of patients, predominantly body asymmetry and neurological defects like seizure and developmental delay. Fewer patients (10.1%) had ophthalmological defects, usually glaucoma. The major criterium "absence of venectasia" was not met in 20.4% of patients., Conclusion: We suggest that children with CMTC should be referred to an ophthalmologist for regular follow-up, and children with CMTC affecting the legs should be monitored for leg length discrepancy throughout the growth period. Furthermore, we suggest reconsideration of the major criterium "absence of venectasia" from the proposed diagnostic criteria, and instead include body asymmetry.

Purpose: To describe the range of ocular manifestations in cutis marmorata telangectatica congenita (CMTC)., Design: Multicenter, retrospective, nonconsecutive case series., Participants: Patients with a diagnosis of CMTC referred for ophthalmologic evaluation between January 1, 2015, and December 31, 2018., Methods: Evaluation of ocular findings at presentation, systemic manifestations suggestive of a diagnosis of CMTC, genetic testing, and visual outcomes after treatment., Main Outcome Measures: Visual acuity, findings on ophthalmoscopy, and results of fluorescein angiography., Results: Nine patients with CMTC diagnosed clinically based on stereotypical cutaneous vascular malformations were included. The median age at presentation was 8 weeks (range, 2 weeks-4 years). Six patients were female and 3 were male. Avascular retina was identified on dilated fundus examination, fluorescein angiography, or both in 11 eyes of 6 patients. Retinal neovascularization was present bilaterally in 2 patients at presentation. One patient demonstrated retinal venous tortuosity, and another patient showed mild straightening of nasal retinal vessels in both eyes. Two patients (2 eyes) demonstrated retinal detachment (RD). Both were managed surgically. One infant demonstrated RD, whereas the other child showed extensive neovascularization and later progressed to combined tractional-rhegmatogenous detachment. A unique constellation of lacy peripheral capillary anomalies with prominent terminal vascular bulbs was noted in 3 patients. Granular pigment abnormalities were noted in the macula in 5 patients. Two patients demonstrated glaucoma, 1 requiring surgical intervention. Two patients demonstrated features of Adams-Oliver syndrome, with genetic testing identifying a Notch1 mutation in 1 patient., Conclusions: Retinal vascular abnormalities in CMTC may occur more frequently than recognized previously. Given the variability of ocular involvement and the potential for rapidly progressive retinal vascular abnormalities and development of RD, complete ophthalmologic evaluation including measurement of intraocular pressure, gonioscopy, dilated fundus examination, and fluorescein angiography is recommended in infants with suspected CMTC shortly after birth. The distinct pattern of lacy capillary anomalies with prominent terminal bulbs seen in CMTC has not been described in other syndromes of vascular dysgenesis. Therefore, ophthalmic examination may be a valuable method to distinguish CMTC from other disorders demonstrating similar dermatologic and systemic manifestations., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Adams-Oliver syndrome (AOS) is a congenital condition characterized by congenital aplasia cutis and transverse limb defects. Herein we report a case of an infant with severe intra-uterine growth restriction presenting AOS associated with cutis marmorata telangiectatica but with no other organ complications. The outcome was complicated by hemorrhagic and septic shock, which resulted in the death of the infant in a setting of multiorgan failure., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

We report a case of a fetus diagnosed at 28 weeks' gestation with a spontaneous prenatal hemothorax. Fetal intervention consisted of 2 thoracenteses with analysis of the pleural effusion. The pregnancy was further complicated by recurrence of the hemothorax, with subsequent mediastinal shift, hydrops, and nonreassuring antenatal testing requiring delivery at 31 weeks' gestation. Postnatal workup established the diagnoses of cutis marmorata telangiectatica congenita (CMTC) and pulmonary lymphangiectasia. The child is currently 4 years old and without any active medical issues or sequelae from the CMTC, pulmonary lymphangiectasia, or prenatal interventions., (© 2018 S. Karger AG, Basel.)

Competing Interests: Competing interests: None declared.

Purposes: To correlate the clinical picture and fundus fluorescein angiography findings in case of presumed cutis marmorata telangiectatica congenita., Methods: A 41-year-old woman with presumed cutis marmorata telangiectatica congenita who is a known case of hypothyroidism for the last 6 years and has bilateral peripheral retinal vascular abnormalities, peripheral retinal nonperfusion on fluorescein angiography and bilateral optic disk drusen., Result: A patient presented with blurring of vision in both eyes for last 6 months. On examination, livedo reticularis skin lesions in both upper and lower extremities were noted. Best-corrected visual acuity in the right eye was 6/18 and left eye was 6/36. Slit-lamp examination revealed posterior subcapsular cataract in the right eye. Fundus examination showed bilateral optic disk drusen, tortuous blood vessels, and peripheral fan-shaped sclerosed neovascularization. Fundus fluorescein angiography showed peripheral retinal nonperfusion. She underwent peripheral laser photocoagulation of the left eye and cataract surgery in the right eye. After 2 years of follow-up, her best-corrected visual acuity was 6/9 in both eyes. Her fundus examination and fundus fluorescein angiography findings were stable in both eyes., Conclusion: Presumed cutis marmorata telangiectatica congenita is a rare cutaneous vascular disorder that can manifest with nonprogressive retinal vascular abnormality and optic disk drusen.

Background: Mitotic fission is increased in pulmonary arterial hypertension (PAH), a hyperproliferative, apoptosis-resistant disease. The fission mediator dynamin-related protein 1 (Drp1) must complex with adaptor proteins to cause fission. Drp1-induced fission has been therapeutically targeted in experimental PAH. Here, we examine the role of 2 recently discovered, poorly understood Drp1 adapter proteins, mitochondrial dynamics protein of 49 and 51 kDa (MiD49 and MiD51), in normal vascular cells and explore their dysregulation in PAH., Methods: Immunoblots of pulmonary artery smooth muscle cells (control, n=6; PAH, n=8) and immunohistochemistry of lung sections (control, n=6; PAH, n=6) were used to assess the expression of MiD49 and MiD51. The effects of manipulating MiDs on cell proliferation, cell cycle, and apoptosis were assessed in human and rodent PAH pulmonary artery smooth muscle cells with flow cytometry. Mitochondrial fission was studied by confocal imaging. A microRNA (miR) involved in the regulation of MiD expression was identified using microarray techniques and in silico analyses. The expression of circulatory miR was assessed with quantitative reverse transcription-polymerase chain reaction in healthy volunteers (HVs) versus patients with PAH from Sheffield, UK (plasma: HV, n=29, PAH, n=27; whole blood: HV, n=11, PAH, n=14) and then confirmed in a cohort from Beijing, China (plasma: HV, n=19, PAH, n=36; whole blood: HV, n=20, PAH, n=39). This work was replicated in monocrotaline and Sugen 5416-hypoxia, preclinical PAH models. Small interfering RNAs targeting MiDs or an miR mimic were nebulized to rats with monocrotaline-induced PAH (n=4-10)., Results: MiD expression is increased in PAH pulmonary artery smooth muscle cells, which accelerates Drp1-mediated mitotic fission, increases cell proliferation, and decreases apoptosis. Silencing MiDs (but not other Drp1 binding partners, fission 1 or mitochondrial fission factor) promotes mitochondrial fusion and causes G1-phase cell cycle arrest through extracellular signal-regulated kinases 1/2- and cyclin-dependent kinase 4-dependent mechanisms. Augmenting MiDs in normal cells causes fission and recapitulates the PAH phenotype. MiD upregulation results from decreased miR-34a-3p expression. Circulatory miR-34a-3p expression is decreased in both patients with PAH and preclinical models of PAH. Silencing MiDs or augmenting miR-34a-3p regresses experimental PAH., Conclusions: In health, MiDs regulate Drp1-mediated fission, whereas in disease, epigenetic upregulation of MiDs increases mitotic fission, which drives pathological proliferation and apoptosis resistance. The miR-34a-3p-MiD pathway offers new therapeutic targets for PAH., (© 2018 American Heart Association, Inc.)

Cutis marmorata telangiectatica congenita is a rare disorder characterized by cutis marmorata, telangiectasia with or without recurrent ulcerations. It is a benign vascular anomaly with dilatation of capillaries and veins in the dermis. There is no satisfactory treatment for the ulcerative variety of cutis marmorata telangiectatica congenita. In this case, intense pulse light therapy was used with almost near total cure. Intense pulse light with its vascular filter of wavelength 550-1200 nm was used every fortnight till complete resolution of lesions.

A patient with extensive multisystem overgrowth caused by a somatic gain of function PIK3CA-mutation is described. This case is an example of the clinical diversity of the PIK3CA-Related Overgrowth Spectrum (PROS) as the patient had overlapping features of Congenital Lipomatous Overgrowth Vascular malformations Epidermal nevi and Skeletal abnormalities (CLOVES) syndrome and Megalencephaly-Capillary malformation Polymicrogyria (MCAP) syndrome and underlines the utility of this umbrella term., (© 2018 Wiley Periodicals, Inc.)