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American Journal of Medical Genetics.... Dec 2018The TWIST family is a group of highly conserved basic helix-loop-helix transcription factors. In humans, TWIST1 haploinsufficiency causes Saethre-Chotzen syndrome, which...
The TWIST family is a group of highly conserved basic helix-loop-helix transcription factors. In humans, TWIST1 haploinsufficiency causes Saethre-Chotzen syndrome, which is characterized by craniosynostosis. Heterozygous localized TWIST1 and TWIST2 basic domain substitutions exert antimorphic effects to cause Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia syndrome, respectively. Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia syndrome share the facial features of ablepharon, hypertelorism, underdevelopment of the eyelids, and cheek pads adjacent to the corners of the mouth. Existence of phenotypic overlap between Saethre-Chotzen syndrome and Sweeney-Cox syndrome remains unknown. Herein, we document a male infant with the distinctive facial features of ablepharon, hypertelorism, cheek pads adjacent to the corners of the mouth, and bilateral coronal suture craniosynostosis who had a de novo heterozygous mutation in the basic domain of TWIST1, that is, c.351C>G p.Glu117Asp. The pathogenicity of this variant was supported by in silico and in vivo evidence. Our review showed that Sweeney-Cox syndrome appears to share many characteristics with Barber-Say syndrome and ablepharon-macrostomia syndrome except for craniosynostosis, which is a cardinal feature of Saethre-Chotzen syndrome. An amino acid substitution from Glu117 to Asp, both of which are the sole members of negatively charged amino acids, resulted in a prototypic Sweeney-Cox syndrome phenotype. This suggests that any amino acid substitutions at Glu117 would likely lead to the Sweeney-Cox syndrome phenotype or lethality. The present observation suggests that a localized TWIST1 basic domain substitution, that is, p.Glu117Asp, in TWIST1 may exert a mild antimorphic effect similar to that of haploinsufficiency, leading to craniosynostosis and ablepharon.
Topics: Alleles; Amino Acid Substitution; Craniosynostoses; Eye Abnormalities; Facies; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Infant, Newborn; Male; Nuclear Proteins; Protein Domains; Syndrome; Tomography, Spiral Computed; Twist-Related Protein 1
PubMed: 30450715
DOI: 10.1002/ajmg.a.40525 -
Methods (San Diego, Calif.) Nov 2018The use of CRISPR/Cas9 to knockout genes in zebrafish has been well established. However, to better model many human diseases that are caused by point mutations, a...
The use of CRISPR/Cas9 to knockout genes in zebrafish has been well established. However, to better model many human diseases that are caused by point mutations, a robust methodology for generating desirable DNA base changes is still needed. Recently, Cas9-linked cytidine deaminases (base editors) evolved as a strategy to introduce single base mutations in model organisms. They have been used to convert cytidine to thymine at specific genomic loci. Here we describe a protocol for using the base editing system in zebrafish and its application to reproduce a single base mutation observed in human Ablepharon-Macrostomia Syndrome.
Topics: Abnormalities, Multiple; Animals; Base Sequence; CRISPR-Cas Systems; Cytidine; Cytidine Deaminase; Disease Models, Animal; Embryo, Nonmammalian; Eye Abnormalities; Female; Gene Editing; Humans; Macrostomia; Male; Mutagenesis, Site-Directed; Point Mutation; RNA, Guide, CRISPR-Cas Systems; Thymine; Twist-Related Protein 2; Zebrafish; Zebrafish Proteins
PubMed: 30076894
DOI: 10.1016/j.ymeth.2018.07.010 -
Cornea Jul 2018To report a case of ablepharon-macrostomia syndrome and surgical treatment options. (Review)
Review
PURPOSE
To report a case of ablepharon-macrostomia syndrome and surgical treatment options.
METHODS
Case report and literature review.
RESULTS
A prematurely born male baby presented with severe ablepharon, hypertelorism, macrostomia, low-set dysplastic ears, broad nasal bridge, coarse and redundant body skin, absent scalp and body hair, lax abdominal wall, absent nipples, camptodactyly, and ambiguous genitalia. Despite intensive ocular lubrication, severe exposure keratopathy developed within the first days after birth. The eyes were closed using masquerade flaps for 6 weeks. In a secondary procedure at the adjusted age of 3 weeks, the flaps were partially divided, and visual input and development were successfully achieved, while maintaining corneal protection.
CONCLUSIONS
We present a rare case of a prematurely born infant with a severe phenotype of ablepharon-macrostomia syndrome, surgically treated with masquerade flaps to preserve corneal health and allow bilateral visual input.
Topics: Abnormalities, Multiple; Cornea; Eye Abnormalities; Eyelids; Humans; Infant, Newborn; Macrostomia; Male; Ophthalmologic Surgical Procedures; Surgical Flaps; Treatment Outcome
PubMed: 29538102
DOI: 10.1097/ICO.0000000000001563 -
Molecular Syndromology Jun 2017Barber-Say syndrome (BSS) and ablepharon-macrostomia syndrome (AMS) are infrequently reported congenital malformation disorders caused by mutations in the gene. Both...
Barber-Say syndrome (BSS) and ablepharon-macrostomia syndrome (AMS) are infrequently reported congenital malformation disorders caused by mutations in the gene. Both are characterized by abnormalities in ectoderm-derived structures and cause a very unusual morphology of mainly the face in individuals with otherwise normal cognition and normal physical functioning. We studied the impact that the presence of BSS and AMS has on psychosocial functioning of affected individuals and their families, using their point of view to start with. We tabulated frequently asked questions from affected individuals and families, and a parent of an affected child and an affected adult woman offered personal testimonies. We focused on perception of illness, body satisfaction, and the consequences for an otherwise normal individual who has a disorder that interferes with body image. The importance of paying particular attention to the management of both the physical appearance and the consequences of these entities on the quality of life is stressed by the affected individuals themselves.
PubMed: 28690482
DOI: 10.1159/000472408 -
Clinical Case Reports Jul 2017Barber-Say syndrome is a rare disorder characterized by hypertrichosis, redundant skin, and facial dysmorphism. gene mutation previously described in this syndrome was...
Barber-Say syndrome is a rare disorder characterized by hypertrichosis, redundant skin, and facial dysmorphism. gene mutation previously described in this syndrome was identified in our patient. Genetic testing is recommended in patients presenting with these phenotypic abnormalities, along with their parents, to establish de novo or inherited mutations.
PubMed: 28680619
DOI: 10.1002/ccr3.1014 -
Journal of Medical Genetics Sep 2017Focal facial dermal dysplasias (FFDDs) are rare genetic/developmental disorders characterised by bilateral 'scar-like' facial lesions. Four subtypes are classified by... (Review)
Review
Focal facial dermal dysplasias (FFDDs) are rare genetic/developmental disorders characterised by bilateral 'scar-like' facial lesions. Four subtypes are classified by the bitemporal (FFDD1-3) or preauricular (FFDD4) lesion location. FFDD1-3 are differentiated by additional facial abnormalities and inheritance patterns. Although the genetic defects causing FFDD1 and FFDD2 remain unknown, recent studies identified defects causing FFDD3 and FFDD4. Here, the clinical phenotypes, genetic defects and inheritance of the four FFDD subtypes are described. In addition, the overlapping facial abnormalities in FFDD3 and two other genetic disorders, Ablepharon macrostomia syndrome and Barber-Say syndrome, are noted. Familiarity with the FFDDs by clinicians will further delineate the phenotypes and genetic/developmental defects of these dermal facial disorders.
Topics: Ectodermal Dysplasia; Face; Female; Focal Dermal Hypoplasia; Focal Facial Dermal Dysplasias; Genetic Heterogeneity; Humans; Male; Phenotype; Skin Diseases
PubMed: 28663233
DOI: 10.1136/jmedgenet-2017-104561 -
Human Molecular Genetics Jun 2017Twist transcription factors, members of the basic helix-loop-helix family, play crucial roles in mesoderm development in all animals. Humans have two paralogous genes,...
Twist transcription factors, members of the basic helix-loop-helix family, play crucial roles in mesoderm development in all animals. Humans have two paralogous genes, TWIST1 and TWIST2, and mutations in each gene have been identified in specific craniofacial disorders. Here, we describe a new clinical entity, Sweeney-Cox syndrome, associated with distinct de novo amino acid substitutions (p.Glu117Val and p.Glu117Gly) at a highly conserved glutamic acid residue located in the basic DNA binding domain of TWIST1, in two subjects with frontonasal dysplasia and additional malformations. Although about one hundred different TWIST1 mutations have been reported in patients with the dominant haploinsufficiency Saethre-Chotzen syndrome (typically associated with craniosynostosis), substitutions uniquely affecting the Glu117 codon were not observed previously. Recently, subjects with Barber-Say and Ablepharon-Macrostomia syndromes were found to harbor heterozygous missense substitutions in the paralogous glutamic acid residue in TWIST2 (p.Glu75Ala, p.Glu75Gln and p.Glu75Lys). To study systematically the effects of these substitutions in individual cells of the developing mesoderm, we engineered all five disease-associated alleles into the equivalent Glu29 residue encoded by hlh-8, the single Twist homolog present in Caenorhabditis elegans. This allelic series revealed that different substitutions exhibit graded severity, in terms of both gene expression and cellular phenotype, which we incorporate into a model explaining the various human disease phenotypes. The genetic analysis favors a predominantly dominant-negative mechanism for the action of amino acid substitutions at this highly conserved glutamic acid residue and illustrates the value of systematic mutagenesis of C. elegans for focused investigation of human disease processes.
Topics: Abnormalities, Multiple; Acrocephalosyndactylia; Amino Acid Sequence; Amino Acid Substitution; Animals; Base Sequence; Caenorhabditis elegans; Child; Child, Preschool; Disease Models, Animal; Eye Abnormalities; Haploinsufficiency; Helix-Loop-Helix Motifs; Humans; Macrostomia; Male; Mutation; Nuclear Proteins; Phenotype; Protein Domains; Repressor Proteins; Transcription Factors; Twist-Related Protein 1
PubMed: 28369379
DOI: 10.1093/hmg/ddx107 -
Reviews in Endocrine & Metabolic... Sep 2016Male fertility can be affected by a variety of organs diseases, including the skin. Several genodermatoses affect the skin and several other organs including the male... (Review)
Review
Male fertility can be affected by a variety of organs diseases, including the skin. Several genodermatoses affect the skin and several other organs including the male reproductive system, commonly in the form of cryptorchidism and hypogonadism. The most relevant syndromes are associated with dyschromias, such as deSanctis-Cacchione, poikiloderma congenital, LEOPARD, and H syndrome; others with ichthyosis, such as Rud, and trichothiodystrophy; or a group of unrelated genodermatoses, such as ablepharon macrostomia, Coffin-Siris, Gorlin-Goltz, and Werner. Acquired skin diseases may also affect male fertility usually in the form of orchitis or epididymal obstruction or androgen antagonists. These include infections (leprosy and HIV), autoimmune (erythema nodosum leprosum), granulomatous (sarcoidosis, Langerhans cell histiocytosis), nutritional deficiency (zinc), and malignancy. Several therapeutics of skin diseases are notorious for their effects on male fertility, most notably are the cytotoxic drugs (methotrexate), irradiation, and antiandrogens (spironolactone, finasteride). Although the prevalence of these skin diseases is low, the associated male infertility represents a challenge due to the difficulty of its management. Clinical management of the skin diseases should include consideration of their effects not only on the diseases but also on the male reproductive system.
Topics: Humans; Infertility, Male; Male; Skin Diseases
PubMed: 27342409
DOI: 10.1007/s11154-016-9368-x -
American Journal of Medical Genetics.... Aug 2016Barber-Say syndrome (BSS) and Ablepharon-Macrostomia syndrome (AMS) are congenital malformation syndromes caused by heterozygous mutations in TWIST2. Here we provide a... (Meta-Analysis)
Meta-Analysis Review
Barber-Say syndrome (BSS) and Ablepharon-Macrostomia syndrome (AMS) are congenital malformation syndromes caused by heterozygous mutations in TWIST2. Here we provide a critical review of all patients published with these syndromes. We excluded several earlier reports due to misdiagnosis or insufficient data for reliable confirmation of the diagnosis. There remain 16 reliably diagnosed individuals with BSS and 16 with AMS. Major facial characteristics present in both entities, albeit often in differing frequencies, are excessive facial creases, hypertelorism, underdevelopment of the anterior part of the eyelids (anterior lamella), ectropion, broad nasal ridge and tip, thick and flaring alae nasi, protruding maxilla, wide mouth, thin upper vermillion, and attached ear lobes. In BSS a remarkable extension of the columella on the philtrum can be seen, and in both the medial parts of the cheeks bulge towards the corners of the mouth (cheek pads). Scalp hair is sparse in AMS only, but sparse eyebrows and eyelashes occur in both entities, and general hypertrichosis occurs in BSS. We compare these characteristics with those in Setleis syndrome which can also be caused by TWIST2 mutations. The resemblance between the three syndromes is considerable, and likely differences seem larger than they actually are due to insufficiently complete evaluation for all characteristics of the three entities in the past. It is likely that with time it can be concluded that BSS. AMS and Setleis syndrome form a continuum. © 2016 Wiley Periodicals, Inc.
Topics: Abnormalities, Multiple; Eye Abnormalities; Eyelid Diseases; Facies; Genetic Association Studies; Genotype; Hirsutism; Humans; Hypertelorism; Hypertrichosis; Macrostomia; Mutation; Phenotype; Skin Abnormalities; Twist-Related Protein 2
PubMed: 27196381
DOI: 10.1002/ajmg.a.37757 -
Case Reports in Ophthalmology 2015We describe a rare case of an infant who was born with multiple congenital anomalies, including the absence of eyelids. This patient had many dysmorphic features...
We describe a rare case of an infant who was born with multiple congenital anomalies, including the absence of eyelids. This patient had many dysmorphic features consistent with a severe phenotype of ablepharon-macrostomia syndrome (AMS) including a fish-like appearance of the mouth, rudimentary ears, absence of body hair, thin skin, absent nipples, abdominal distension, and genital abnormalities. Upon presentation, there was severe exposure keratopathy causing large bilateral sterile ulcers culminating in corneal melting of both eyes. An amniotic membrane graft was used to attempt to maintain the corneal surface integrity. However, because of the late presentation, the corneas could not be salvaged. Extensive surgical reconstruction of both eyelids and bilateral penetrating keratoplasty was ultimately performed successfully to protect the ocular surfaces while trying to maximize the visual potential. Early amniotic membrane grafting may be done at the bedside and may help preserve the ocular in patients with severe eyelid deformities until more definitive treatment is performed.
PubMed: 26600791
DOI: 10.1159/000441615