Genetic Mosaicism Research Articles

6694 A Case of an Extraneous Organ: A Uterus Found in a Genotypic and Phenotypic Male

Abstract Disclosure: R.A. Zielinski: None. S. Shteyman: None. A.G. Samat: None. Background: Persistent Mullerian Duct Syndrome (PMDS) is a rare entity that occurs when a phenotypic male is found to have female reproductive organs. In our case we describe an XY male who was found to have an abdominal mass consistent with a uterus on pathology. Clinical Case: Our patient is a 58-year-old male with hypertension, obesity, and obstructive sleep apnea who presented to the ED with 3 weeks of left upper quadrant pain. Abdominal CT showed two homogeneous enhancing oval lesions in the pelvis superior to the urinary bladder; 8.3 x 4.6 cm on the right and 3.6 x 3 cm on the left. Exploratory laparotomy was performed, and intraoperatively the mass was firm with a left satellite lesion and two fibrous bands that appeared similar in structure to round ligaments. Microscopically the tissue contained mullerian-type epithelium and smooth muscle with cystic degeneration. It was CK7 positive, estrogen receptor variable positive, and CK20 negative. Genetic testing confirmed the patient’s karyotype to be XY without genetic mosaicism. Our patient had two children spontaneously, regular spontaneous erections, and occasional hot flashes. Physical exam revealed an obese male (BMI 51) with bilateral gynecomastia and normal testicular size. He had no history of intra-abdominal or undescended testes requiring surgery. Labs showed increased total estrogen (283.7 pg/mL, n 60-190 pg/mL) and estradiol (39 pg/mL, n <= 29 pg/mL), decreased total testosterone (86 ng/dL, n 250-1,100 ng/dL), and normal free testosterone when corrected for SHBG (140 ng/dL, n 110-574 ng/dL). Testicular ultrasound was unrevealing. 3 years postoperatively his estradiol level normalized (34 pg/mL) and his total testosterone improved from 86 ng/dL to 223 ng/dL after losing 40 pounds on semaglutide. Discussion and Conclusion: Although the exact incidence of PMDS is unknown, it is a rare phenomenon. Only 200 cases between 1964 and 2000 and 34 cases between 2013 and 2017 have been reported. Mullerian ducts are embryologic structures present in both XY and XX fetuses until week 8 of life, when XY fetuses produce anti-mullerian hormone (AMH). In PMDS, the XY fetus either fails to produce AMH, or there is a defect in the AMH receptors, leading to the persistence of mullerian ducts. These ducts can then differentiate into a uterus, fallopian tubes, and/or the upper vagina. Our patient is a genotypical and phenotypical male with a uterus-like organ. The mild elevation in his estrogen level is likely secondary to his obesity. The estrogen could have increased the size of the uterus, causing the patient’s initial symptoms of abdominal pain which prompted his presentation to the hospital.

Putative MutS2 Homologs in Algae: More Goods in Shopping Bag?

MutS2 proteins are presumably involved in either control of recombination or translation quality control in bacteria. MutS2 homologs have been found in plants and some algae; however, their actual diversity in eukaryotes remains unknown. We found putative MutS2 homologs in various species of photosynthetic eukaryotes and performed a detailed analysis of the revealed amino acid sequences. Three groups of homologs were distinguished depending on their domain composition: MutS2 homologs with full set of specific domains, MutS2-like sequences without endonuclease Smr domain, and MutS2-like homologs lacking Smr and clamp in domain IV, the extreme form of which are proteins with only a complete ATPase domain. We clarified the information about amino acid composition and set of specific motifs in the conserved domains in MutS2 and MutS2-like sequences. The models of the predicted tertiary structure were obtained for each group of homologs. The phylogenetic analysis demonstrated that all eukaryotic sequences split into two large groups. The first group included homologs belonging to species of Archaeplastida and a subset of haptophyte homologs, while the second-sequences of organisms from CASH groups (cryptophytes, alveolates, stramenopiles, haptophytes) and chlorarachniophytes. The cyanobacterial MutS2 clustered together with the first group, and proteins belonging to Deltaproteobacteria (orders Myxococcales and Bradymonadales) showed phylogenetic affinity to the CASH-including group with strong support. The observed tree pattern did not support a clear differentiation of eukaryotes into lineages with red and green algae-derived plastids. The results are discussed in the context of current conceptions of serial endosymbioses and genetic mosaicism in algae with complex plastids.

495P Genetic mosaicism, an underestimated event in genetically unsolved neuromuscular patients: study of two families

495P Genetic mosaicism, an underestimated event in genetically unsolved neuromuscular patients: study of two families

Genomic mosaicism reveals developmental organization of trunk neural crest-derived ganglia.

The neural crest generates numerous cell types, but conflicting results leave developmental origins unresolved. Here using somatic mosaic variants as cellular barcodes, we infer embryonic clonal dynamics of trunk neural crest, focusing on the sensory and sympathetic ganglia. From three independent adult neurotypical human donors, we identified 1,278 mosaic variants using deep whole-genome sequencing, then profiled allelic fractions in 187 anatomically dissected ganglia. We found a massive rostrocaudal spread of progenitor clones specific to sensory or sympathetic ganglia, which unlike in the brain, showed robust bilateral distributions. Computational modeling suggested neural crest progenitor fate specification preceded delamination from neural tube. Single-cell multiomic analysis suggested both neurons and glia contributed to the rostrocaudal clonal organization. CRISPR barcoding in mice and live imaging in quail embryos confirmed these clonal dynamics across multiple somite levels. Our findings reveal an evolutionarily conserved clonal spread of cells populating peripheral neural ganglia.

The Clinical Spectrum of Mosaic Genetic Disease.

Genetic mosaicism is defined as the presence of two or more cell lineages with different genotypes arising from a single zygote. Mosaicism has been implicated in hundreds of genetic diseases with diverse genetic etiologies affecting every organ system. Mosaic genetic disease (MDG) is a spectrum that, on the extreme ends, enables survival from genetic severe disorders that would be lethal in a non-mosaic form. On the milder end of the spectrum, mosaicism can result in little if any phenotypic effects but increases the risk of transmitting a pathogenic genotype. In the middle of the spectrum, mosaicism has been implicated in reducing the phenotypic severity of genetic disease. In this review will describe the spectrum of mosaic genetic disease whilst discussing the status of the detection and prevalence of mosaic genetic disease.

Human embryos harbor complex mosaicism with broad presence of aneuploid cells during early development

Pre-implantation genetic testing for aneuploidy (PGT-A) is used in approximately half of in vitro fertilization cycles. Given the limited understanding of the genetics of human embryos, the current use of PGT-A is based on biologically uncertain assumptions and unvalidated guidelines, leading to the possibility of disposing of embryos with pregnancy potential. We isolated and sequenced all single cells (1133) from in vitro cultured 20 human blastocysts. We found that all blastocysts exhibited mosaicism with mitotic-induced aneuploid cells and showed an ~25% aneuploidy rate per embryo. Moreover, 70% (14/20) of blastocysts contained ‘chromosome-complementary’ cells, suggesting genetic mosaicism is underestimated in routine PGT-A. Additionally, the analysis of 20,945 single cells from day 8–14 embryos (in vitro cultured) and embryonic/fetal organs showed that 97% of the analyzed embryos/organs were mosaic. Over 96% of their aneuploid cells harbored ≤ 2 chromosome errors. Our findings have revealed a high prevalence of mosaicism in human embryos.

A retrospective analysis of sheep generated by somatic cell nuclear transfer

Somatic cell nuclear transfer (SCNT) is one of the primary methods for production of genetically engineered sheep, which allows for gene editing or transgene introduction in somatic cells. The use of SCNT eliminates the risk of genetic mosaicism in embryos and animals that is commonly observed after zygote micromanipulations. This retrospective analysis of SCNT in sheep performed at Utah State University, spanning from 2016 to 2021, examined parameters that may impact pregnancy and full-term development, including donor oocytes (donor age), donor cell lines, SCNT parameters (time of oocyte activation following SCNT, number of transferred embryos, in vitro maturation and culture conditions), and recipients (surgical number and ovulatory status), as well as factors that may correlate with large offspring syndrome or abnormal offspring syndrome (LOS/AOS) in the fetuses and lambs. Our findings indicated that compared to prepubertal oocytes, the SCNT embryos produced from adult sheep oocytes had comparable in vitro maturation rates, pregnancy and full-term development rates, as well as SCNT efficiency. In addition, earlier activation time of SCNT embryos (e.g. 24–26 h post maturation) was correlated to the early pregnancy loss rate, full-term rate, and SCNT efficiency. Compared to our standard serum-containing medium, commercial serum-free culture medium showed a positive correlation with the full-term development of sheep SCNT embryos. Transferring 15–30 embryos per recipient resulted in consistently good pregnancy rates. Surgical numbers and ovulatory status (having at least one follicle between 6 and 12 mm in size or a corpus hemorrhagicum (CH)) of recipients did not affect pregnancy and full-term development rates. In summary, this retrospective analysis identified parameters for improving pregnancy and full-term development of SCNT embryos in sheep.

Effects of centrifugation treatment before electroporation on gene editing in pig embryos.

Genetic mosaicism, characterized by multiple genotypes within an individual, is considered an obstacle to CRISPR/Cas9 genome editing in animal models. Despite the various strategies for minimizing mosaic mutations, no definitive methods exist to eliminate them. This study aimed to enhance gene editing efficiency in porcine zygotes using CRISPR/Cas9, which targets specific genes through centrifugation and zona pellucida removal before electroporation. Centrifugation at 2000 × g did not adversely affect blastocyst formation rates in zygotes electroporated with gRNA targeting the GGTA1 gene; instead, it led to increased total and monoallelic mutation rates compared with control zygotes without centrifugation. However, the groups had no significant differences in biallelic mutation rates. In zygotes electroporated with gRNA targeting the CMAH gene, centrifugation treatments exceeding 1000 × g significantly increased both biallelic mutation rates and mutation efficiency. The combination of centrifugation and zona pellucida removal did not have a detrimental effect on blastocyst formation rates. It led to a higher rate of double biallelic mutations in embryos targeting both GGTA1 and CMAH compared to embryos without centrifugation treatment. In summary, our results demonstrate that pre-electroporation treatments, including centrifugation and zona pellucida removal, positively influenced the reduction of mosaic mutations, with the effectiveness of centrifugation depending on the specific gRNA used.

Tackling mosaicism in gene edited livestock

The farming of livestock has a critical role to play in global nutritional security and poverty alleviation. To meet these goals through more efficient, environmentally sustainable and animal welfare focused means, gene editing technologies could be integrated into current breeding programs. A common issue with gene editing in livestock zygotes is the high incidence of genetic mosaicism. Genetic mosaicism, characterised by a single individual carrying distinct genotypes in different cell lineages, can lead to inconsistent presentation of a desired trait phenotypically, or the absence of the intended genotype in the animal’s germline. This review explores the present status of genetic mosaicism associated with CRISPR-Cas9 gene editing in cattle, sheep, and pigs, and identifies four areas for refinement; (1) the type of CRISPR-Cas9 genome editor used; (2) the CRISPR-Cas9 formats and timing of gene editing during embryonic development; (3) the method used to deliver the genome editor and (4) the genetic screening strategies applied. We also discuss alternatives to direct zygote gene editing, including surrogate sire technology and blastomere separation, which circumvent the production of mosaic offspring. By exploring these avenues for reducing mosaicism, gene editing protocols in livestock could become more efficient and effective, which will ultimately pave the way for traits to be introduced that improve animal welfare standards and help address gaps in the security of global nutrition access.

Localized translation and sarcomere maintenance requires ribosomal protein SA in mice.

Cardiomyocyte sarcomeres contain localized ribosomes, but the factors responsible for their localization and the significance of localized translation are unknown. Using proximity labeling, we identified Ribosomal Protein SA (RPSA) as a Z-line protein. In cultured cardiomyocytes, the loss of RPSA led to impaired local protein translation and reduced sarcomere integrity. By employing CAS9 expressing mice along with adeno-associated viruses expressing CRE recombinase and single-guide RNAs targeting Rpsa, we knocked out Rpsa in vivo and observed mis-localization of ribosomes and diminished local translation. These genetic mosaic mice with Rpsa knockout in a subset of cardiomyocytes developed dilated cardiomyopathy, featuring atrophy of RPSA-deficient cardiomyocytes, compensatory hypertrophy of unaffected cardiomyocytes, left ventricular dilation, and impaired contractile function. We demonstrate that RPSA C-terminal domain is sufficient for localization to the Z-lines and that if the microtubule network is disrupted RPSA loses its sarcomeric localization. These findings highlight RPSA as a ribosomal factor essential for ribosome localization to the Z-line, facilitating local translation and sarcomere maintenance.

From genetic mosaicism to tumorigenesis through indirect genetic effects.

Genetic mosaicism has long been linked to aging, and several hypotheses have been proposed to explain the potential connections between mosaicism and susceptibility to cancer. It has been proposed that mosaicism may disrupt tissue homeostasis by affecting intercellular communications and releasing microenvironmental constraints within tissues. The underlying mechanisms driving these tissue-level influences remain unidentified, however. Here, we present an evolutionary perspective on the interplay between mosaicism and cancer, suggesting that the tissue-level impacts of genetic mosaicism can be attributed to Indirect Genetic Effects (IGEs). IGEs can increase the level of cellular stochasticity and phenotypic instability among adjacent cells, thereby elevating the risk of cancer development within the tissue. Moreover, as cells experience phenotypic changes in response to challenging microenvironmental conditions, these changes can initiate a cascade of nongenetic alterations, referred to as Indirect non-Genetic Effects (InGEs), which in turn catalyze IGEs among surrounding cells. We argue that incorporating both InGEs and IGEs into our understanding of the process of oncogenic transformation could trigger a major paradigm shift in cancer research with far-reaching implications for practical applications.

An indirect perspective to link genetic mosaicism and tumorigenesis.

An indirect perspective to link genetic mosaicism and tumorigenesis.

Genetic Variability and Genetic Differentiation of Populations in the Grooved Carpet Shell Clam (Ruditapes decussatus) Based on Intron Polymorphisms

Genetic Variability and Genetic Differentiation of Populations in the Grooved Carpet Shell Clam (Ruditapes decussatus) Based on Intron Polymorphisms

Toward a Unified Theory of Why Young People Develop Cancer.

Epidemiologic and genetic studies have now defined specific patterns of incidence and distinct molecular features of cancers in young versus aging people. Here, I review a general framework for the causes of cancer in children and young adults by relating somatic genetic mosaicism and developmental tissue mutagenesis. This framework suggests how aging-associated cancers such as carcinomas, glioblastomas, and myelodysplastic leukemias are causally distinct from cancers that predominantly affect children and young adults, including lymphoblastic and myeloid leukemias, sarcomas, neuroblastomas, medulloblastomas, and other developmental cancers. I discuss the oncogenic activities of known developmental mutators RAG1/2, AID, and PGBD5, and describe strategies needed to define missing developmental causes of young-onset cancers. Thus, a precise understanding of the mechanisms of tissue-specific somatic mosaicism, developmental mutators, and their control by human genetic variation and environmental exposures is needed for improved strategies for cancer screening, prevention, and treatment.

Human embryonic genetic mosaicism and its effects on development and disease.

Nearly every mammalian cell division is accompanied by a mutational event that becomes fixed in a daughter cell. When carried forward to additional cell progeny, a clone of variant cells can emerge. As a result, mammals are complex mosaics of clones that are genetically distinct from one another. Recent high-throughput sequencing studies have revealed that mosaicism is common, clone sizes often increase with age and specific variants can affect tissue function and disease development. Variants that are acquired during early embryogenesis are shared by multiple cell types and can affect numerous tissues. Within tissues, variant clones compete, which can result in their expansion or elimination. Embryonic mosaicism has clinical implications for genetic disease severity and transmission but is likely an under-recognized phenomenon. To better understand its implications for mosaic individuals, it is essential to leverage research tools that can elucidate the mechanisms by which expanded embryonic variants influence development and disease.

Genetic mosaic of the Mediterranean fig: comprehensive genomic insights from a gene bank collection.

High-depth whole-genome resequencing of 53 diverse fig tree genotypes yielded a rich dataset of genetic variants. We successfully identified 5,501,460 single-nucleotide polymorphisms (SNPs) and 1,228,537 insertions and deletions (InDels), providing a high-density and excellent-quality genetic map of the fig tree. We also performed a detailed population structure analysis, dividing the 53 genotypes into three geographical groups and assessing their genetic diversity and divergence. Analysis of structural variants (SVs) and copy number variations (CNVs) revealed their potential functional impact, particularly in plant-pathogen interaction and secondary metabolism. Metabolomic fingerprinting of fig genotypes uncovered extensive variation in primary metabolites and polyphenolic compounds, highlighting the influence of genotype on fruit quality traits such as nutritional content and bioactive compound composition. The genome-wide association study (GWAS) identified critical SNPs associated with fruit quality and morphological features. The discovery of significant candidate genes, such as AGL62, GDSL, and COBRA-like protein 4 genes, offers promising targets for marker-assisted selection and genome editing approaches to improve fig fruit morphological and quality traits. This extensive genomic analysis of fig trees enhances our understanding of the genetic basis of important agronomic traits and provides a rich resource for future research in this economically and nutritionally significant fruit.

Phased genomics reveals hidden somatic mutations and provides insight into fruit development in sweet orange.

Although revisiting the discoveries and implications of genetic variations using phased genomics is critical, such efforts are still lacking. Somatic mutations represent a crucial source of genetic diversity for breeding and are especially remarkable in heterozygous perennial and asexual crops. In this study, we focused on a diploid sweet orange (Citrus sinensis) and constructed a haplotype-resolved genome using high fidelity (HiFi) reads, which revealed 10.6% new sequences. Based on the phased genome, we elucidate significant genetic admixtures and haplotype differences. We developed a somatic detection strategy that reveals hidden somatic mutations overlooked in a single reference genome. We generated a phased somatic variation map by combining high-depth whole-genome sequencing (WGS) data from 87 sweet orange somatic varieties. Notably, we found twice as many somatic mutations relative to a single reference genome. Using these hidden somatic mutations, we separated sweet oranges into seven major clades and provide insight into unprecedented genetic mosaicism and strong positive selection. Furthermore, these phased genomics data indicate that genomic heterozygous variations contribute to allele-specific expression during fruit development. By integrating allelic expression differences and somatic mutations, we identified a somatic mutation that induces increases in fruit size. Applications of phased genomics will lead to powerful approaches for discovering genetic variations and uncovering their effects in highly heterozygous plants. Our data provide insight into the hidden somatic mutation landscape in the sweet orange genome, which will facilitate citrus breeding.

Early-Onset Ovarian Cancer <30 Years: What Do We Know about Its Genetic Predisposition?

Ovarian cancer (OC) is one of the leading causes of cancer-related deaths in women. Most patients are diagnosed with advanced epithelial OC in their late 60s, and early-onset adult OC diagnosed ≤30 years is rare, accounting for less than 5% of all OC cases. The most significant risk factor for OC development are germline pathogenic/likely pathogenic variants (GPVs) in OC predisposition genes (including BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, Lynch syndrome genes, or BRIP1), which contribute to the development of over 20% of all OC cases. GPVs in BRCA1/BRCA2 are the most prevalent. The presence of a GPV directs tailored cancer risk-reducing strategies for OC patients and their relatives. Identification of OC patients with GPVs can also have therapeutic consequences. Despite the general assumption that early cancer onset indicates higher involvement of hereditary cancer predisposition, the presence of GPVs in early-onset OC is rare (<10% of patients), and their heritability is uncertain. This review summarizes the current knowledge on the genetic predisposition to early-onset OC, with a special focus on epithelial OC, and suggests other alternative genetic factors (digenic, oligogenic, polygenic heritability, genetic mosaicism, imprinting, etc.) that may influence the development of early-onset OC in adult women lacking GPVs in known OC predisposition genes.

Maladaptive Somatic Rescue in FLT3 Mutations of Suspected Germline Nature

Somatic genetic rescue (SGR) is a very rare process in which the occurrence of a somatic genetic event offsets the consequences of a germline (GL) mutation resulting in genetic mosaicism and, in some cases, in a milder disease phenotype 1. Acquired somatic mutations may be adaptive by countering the negative effects of the primary mutation ( e.g., improving hematopoiesis) or maladaptive by overcorrecting the initial impairment causing a different, possibly opposite, disease phenotype ( e.g., leading to the development of a myeloid malignancy) 2. Exemplary cases of the latter scenario are mainly represented by severe congenital neutropenia (SCN) cases developing AML as consequence of somatic CSF3R mutations 3 and, sporadically, by adaptive SGR in the context of germline GATA2 and secondary acquisition of somatic GATA2 mutation, counterbalancing the germline effect 4. Although SGR has been functionally demonstrated in these two above mentioned cases, given the molecular heterogeneity of myeloid neoplasia (MN) and the rarity of such genetic events, one can suspect that, in various clinical contexts, any mutation in any gene could be the SG rescuer. During our clinical experience, we encountered a case of a 57yo. woman with newly diagnosed aplastic anemia (AA) who was found to harbor a rare germline FLT3R311W mutation (VAF 50%; predicted to be a loss-of-function/hypomorphic alteration; Fig1) who subsequently evolved to MDS with monosomy 7. Coexisting somatic hits included non RUNT-homology domain, RUNX1P398L mutation (VAF 19%). Ultimately, the patient progressed to AML with emergence of a FLT3D825V (VAF 14%) and a NRASG13D (24%) lesions. In this case carrying GL FLT3 variant, biallelic somatic FLT3 mutation may represent maladaptive SGR. Therefore, we reviewed NGS sequencing results of 5,308 patients with MN and found three other suspected cases harboring GL variants in FLT3 gene, which inspired further investigations. In total we identified 3 additional cases (total of 4/5308 screened patients and among 248 somatic FLT3 mutations. Interestingly, the other case GL FLT3A680T occurred in a patient with AA (35yo.) who subsequently progressed to MDS and AML and acquired somatic NPM1L258fs, PTPN11 A72V, WT1 A365fs and most importantly, a somatic CSF3RL619S . The latter may represent an illustrative case of SGR, in analogy to AML developing in the context of SCN. In addition, 2 other cases with MDS or MDS/MPN were identified both presenting with cytopenia. A 53yo. woman diagnosed with MDS/MPN and GL FLT3L262F (gnomAD: 0.00000399) with a compound heterozygous somatic JAK2V617F mutation, again possibly serving as maladaptive clonal SGR event. Finally, we have identified a GL FLT3A291P mutation (VAF 60%, gnomAD frequency: 1.59×10-5) in a 58yo. man who eventually developed AML. In sum, similar to other phosphotyrosine receptor kinases (PTRKs) such as CSF3R, somatic FLT3 mutations may in rare biallelic cases correspond to SGR events of hypomorphic GL mutation or alternatively but not exclusively somatic mutations in other PTRK could evolve to reveal the GL FLT3 deficiency. Indeed, in another abstract by our group (Abstract#187151) we show that somatic FLT3 mutations can accompany GL variants in CSF3R, CSF2RB, and CSF1R. References 1 Revy P, Kannengiesser C, Fischer A. Somatic genetic rescue in Mendelian haematopoietic diseases. Nat Rev Genet. 2019 Oct;20(10):582-598. 2 Kennedy AL, Shimamura A. Genetic predisposition to MDS: clinical features and clonal evolution. Blood. 2019 Mar 7;133(10):1071-1085. 3 Germeshausen M, Kratz CP, Ballmaier M, Welte K. RAS and CSF3R mutations in severe congenital neutropenia. Blood. 2009 Oct 15;114(16):3504-5. 4 Catto LFB, Borges G, Pinto AL, Clé DV, Chahud F, Santana BA, Donaires FS, Calado RT. Somatic genetic rescue in hematopoietic cells in GATA2 deficiency.

Photogallery. Genodermatoses. Part I

Genodermatoses are skin diseases caused by the inheritance of a pathological gene responsible for the formation of a particular skin structure.
 Hereditary diseases can be monogenic, polygenic and chromosomal. Genodermatoses follow Mendelian inheritance (autosomal dominant, autosomal recessive or sex-linked). Some genodermatoses appear as a result of genetic mosaicism (parts of two different chromosomes exchange their fragments).
 Autosomal dominant disorder manifest in every generation in women and men with the same frequency. Recessive genodermatoses are usually more severe and rarer. In this case, both parents are carriers of the pathological gene, but are clinically (phenotypically) healthy. The risk of developing of autosomal recessive pathology increases highly in closely related marriages.
 We present a gallery of the hereditary dermatoses.
 Neurofibromatosis is a neurocutaneous syndrome characterized by the formation of benign tumors in the skin, soft tissues, nervous system and internal organs.
 Congenital epidermolysis bullosa is a group of genodermatoses with the development of intraepidermal blisters that arise spontaneously or as a result of minor trauma.
 Tuberous sclerosis (Bourneville–Pringle disease) is a hereditary disease characterized by hyperplasia of ectodermal and mesodermal derivatives, leading to disruption of embryonic differentiation. It damages the skin, central nervous system and other organs.
 Pseudoxanthoma elasticum is characterized by calcification of elastic fibers of the skin with damage to the vision organ, cardiovascular system and reproductive function.