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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.)

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.)

The megalencephaly capillary malformation syndrome (MCAP, OMIM 602501) is known to be associated with mosaic mutations in PIK3CA occurring during embryogenesis. Standard sequencing technologies are relatively poor at indentifying sequence changes that only affect a small percentage of cells, and the mutations are frequently not identified in lymphocyte DNA, with biopsies of the affected tissues often being required to detect mosaic mutations. Such invasive procedures are not always acceptable to parents. We describe the case of a patient in whom we were able to confirm a causative PIK3CA mutation, first found thorugh next-generation sequencing, in several tissue types including a secondary tooth. As part of this work, we were also able to begin validating dental tissue for potential use in genetic testing, as we achieved excellent DNA yields with minimal effort, even from deciduous teeth shed some years earlier.

Cutis Marmorata Telangiectatica Congenita (CMTC) is a congenital localized or generalized vascular anomaly, usually sporadic in occurrence. It can be associated with other cutaneous or systemic manifestations. About 300 cases have been reported. The molecular etiology remains largely unknown. The main purpose of this study is to delineate the molecular basis for a syndromic CMTC phenotype in a consanguineous Saudi family. Clinical phenotyping including detailed neurological imaging, followed by autozygosity mapping and trio whole exome sequencing (WES) are also studied. We have identified a homozygous truncating mutation in ARL6IP6 as the likely cause of a syndromic form of CMTC associated with major dysmorphism, developmental delay, transient ischemic attacks and cerebral vascular malformations. This gene was previously implicated by genome wide association study (GWAS) as a susceptibility locus to ischemic stroke in young adults. We identify ARL6IP6 as a novel candidate gene for a syndromic form of CMTC. This suggests that ischemic stroke or transient ischemic attacks (TIA) may represent, at least in some cases, the mild end of a phenotypic spectrum that has at its severe end autosomal recessive CMTC. This finding contributes to a growing appreciation of the continuum of Mendelian and common complex diseases.

Megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth syndrome that is diagnosed by clinical criteria. Recently, somatic and germline variants in genes that are involved in the PI3K-AKT pathway (AKT3, PIK3R2 and PIK3CA) have been described to be associated with MCAP and/or other related megalencephaly syndromes. We performed trio-exome sequencing in a 6-year-old boy and his healthy parents. Clinical features were macrocephaly, cutis marmorata, angiomata, asymmetric overgrowth, developmental delay, discrete midline facial nevus flammeus, toe syndactyly and postaxial polydactyly--thus, clearly an MCAP phenotype. Exome sequencing revealed a pathogenic de novo germline variant in the PTPN11 gene (c.1529A>G; p.(Gln510Arg)), which has so far been associated with Noonan, as well as LEOPARD syndrome. Whole-exome sequencing (>100 × coverage) did not reveal any alteration in the known megalencephaly genes. However, ultra-deep sequencing results from saliva (>1000 × coverage) revealed a 22% mosaic variant in PIK3CA (c.2740G>A; p.(Gly914Arg)). To our knowledge, this report is the first description of a PTPN11 germline variant in an MCAP patient. Data from experimental studies show a complex interaction of SHP2 (gene product of PTPN11) and the PI3K-AKT pathway. We hypothesize that certain PTPN11 germline variants might drive toward additional second-hit alterations.

Purpose: In patients receiving radiotherapy for breast cancer where the heart is within the radiation field, cutaneous telangiectasiae could be a marker of potential radiation-induced heart disease. We hypothesized that single nucleotide polymorphisms (SNPs) in genes known to cause heritable telangiectasia-associated disorders could predispose to such late, normal tissue vascular damage., Methods and Materials: The relationship between cutaneous telangiectasia as a late normal tissue radiation injury phenotype in 633 breast cancer patients treated with radiotherapy was examined. Patients were clinically assessed for the presence of cutaneous telangiectasia and genotyped at nine SNPs in three candidate genes. Candidate SNPs were within the endoglin (ENG) and activin A receptor, type II-like 1 (ACVRL1) genes, mutations in which cause hereditary hemorrhagic telangiectasia and the ataxia-telangiectasia mutated (ATM) gene associated with ataxia-telangiectasia., Results: A total of 121 (19.1%) patients exhibited a degree of cutaneous telangiectasiae on clinical examination. Regression was used to examine the associations between the presence of telangiectasiae in patients who underwent breast-conserving surgery, controlling for the effects of boost and known brassiere size (n=388), and individual geno- or haplotypes. Inheritance of ACVRL1 SNPs marginally contributed to the risk of cutaneous telangiectasiae. Haplotypic analysis revealed a stronger association between inheritance of a ATM haplotype and the presence of cutaneous telangiectasiae, fibrosis and overall toxicity. No significant association was observed between telangiectasiae and the coinheritance of the candidate ENG SNPs., Conclusions: Genetic variation in the ATM gene influences reaction to radiotherapy through both vascular damage and increased fibrosis. The predisposing variation in the ATM gene will need to be better defined to optimize it as a predictive marker for assessing radiotherapy late effects., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In a 15-year-old Taiwanese girl, multiple purple punctate lesions arranged in a systematized, segmental pattern had developed since childhood, beginning from the right thigh and gradually progressing upwards to the right buttock, the left side of the abdomen, circumventing to the left side of the back, and extending to the right arm as well as to the posterolateral aspect of the left leg. Histopathological examination showed dilated capillaries in the uppermost part of the dermal papillae characteristic of angioma serpiginosum. The systematized, segmental and asymmetric arrangement of lesions as noted in the present case suggest that angioma serpiginosum reflects genetic mosaicism.

MRI and neurological findings in macrocephaly-cutis marmorata telangiectatica congenita syndrome: report of ten cases and review of the literature: We describe the clinical history and magnetic resonance imaging (MRI) findings in 10 children with the Macrocephaly-Cutis Marmorata Telangiectatica Congenita syndrome (M-CMTC--MIM 602501). This syndrome has recently been delineated within the general group of patients with Cutis Marmorata Telangiectatica (CMTC) as a distinct and easily recognisable entity. In contrast to most children with CMTC, patients with M-CMTC syndrome have a high risk of neurological abnormalities, such as hydrocephalus, megalencephaly, developmental delay and mental retardation. An MRI scan showed structural cerebral abnormalities in all of our patients, including megalencephaly, asymmetry of the cerebral hemispheres and abnormally increased signal of white matter. Seven patients also had Chiari type I malformation. Reviewing all reported cases, we propose appropriate surveillance for known complications.

Objective: To describe the convergence of five rare phenotypic features in a woman with premature ovarian failure referred for reproductive endocrinology evaluation., Design: Case report and literature review., Setting: Major urban infertility referral center., Patient(s): A 24-year-old nulligravida with cutis marmorata telangiectatica congenita (CMTC), premature ovarian failure, unilateral ovarian agenesis, septate uterus, and de novo balanced autosomal translocation., Intervention(s): High-resolution chromosomal evaluation, radiographic study of reproductive organs, and assessment of endogenous estrogen production., Main Outcome Measure: Patient counseling regarding future reproductive options (i.e., donor oocyte in vitro fertilization/embryo transfer), and satisfactory management of hypoestrogenism using oral contraceptives., Result(s): We identified a balanced reciprocal translocation 46,XX t(8;9)(q22.1;p24.1), and confirmed unilateral ovarian agenesis with midline intrauterine septum., Conclusion(s): Although genetic factors considered contributory to premature ovarian failure usually involve the X chromosome, in our patient a previously undescribed autosomal translocation was identified in association with CMTC, a rare vascular disorder. The fundamental role of follicular oxygenation in oocyte competence and subsequent ovarian function is discussed. From the clinical and laboratory findings evident in this unusual case, a developmental hypothesis connecting the vascular abnormalities of CMTC and premature ovarian failure is offered.

We describe a 20-year-old man with naevus anaemicus on the chest where, after dermabrasion of the epidermis, enlarged teleangiectatic dark-red vessels were seen within the previously pale area. They were clearly different from those seen on dermabrasion at this site in normal skin and in patients with vitiligo where the area is lighter red with only small punctual bleedings from arterial capillaries. The naevus anaemicus and a port-wine stain (naevus flammeus) in the same location is a phenomenon of vascular twin spotting, which was revealed when the epidermis was removed. The area was transplanted with thin epidermal grafts and healed within 2 weeks. One year later the naevus looked the same as before grafting. Much thicker grafts than those used by us will be needed, but they are not cosmetically acceptable.

Cutis marmorata telangiectatica congenita (CMTC) is a rare congenital vascular anomaly that virtually always occurs sporadically and in a patchy, quadrant, unilateral or otherwise segmental manifestation. This would suggest mosaicism of a postzygotic mutation. Some authors, however, described CMTC occurring in several members of a family. This paradox may be explained by the concept of paradominant inheritance. Heterozygous individuals carrying a 'paradominant' mutation are, as a rule, phenotypically normal. The mutation can therefore be transmitted unperceived through many generations. The trait only becomes manifest when a postzygotic mutation occurring during early embryogenesis gives rise to loss of heterozygosity and forms a mosaic population of cells being either homozygous or hemizygous for the mutation. This concept may explain the occasional familial occurrence of CMTC., (Copyright 2001 S. Karger AG, Basel)

Multiple familial cutaneous telangiectases occurring over 3 generations are reported. The morphology of the lesions, the absence of haemorrhagic episodes and the pattern of inheritance are consistent with the diagnosis of hereditary benign telangiectasia described by Ryan and Wells. The differential diagnosis and a possible association with other mesodermal anomalies are discussed.

Two sibs are reported with Ramon syndrome with the previously undescribed associations of insulin dependent diabetes mellitus and vascular skin lesions.