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Adams-Oliver syndrome (AOS) is a rare inherited disorder characterized by aplasia cutis congenita, cutis marmorata telangiectatica congenita, and terminal limb defects. Ocular associations have been rarely reported. We report a 6-month-old boy with AOS associated with refractory glaucoma, megalocornea, and anterior polar cataract. To our knowledge, this is the first case of glaucoma to be reported in association with AOS., (Copyright © 2024 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Pathogenic variants in NOTCH1 are associated with non-syndromic congenital heart disease (CHD) and Adams-Oliver syndrome (AOS). The clinical presentation of individuals with damaging NOTCH1 variants is characterized by variable expressivity and incomplete penetrance; however, data on systematic phenotypic characterization are limited. We report the genotype and phenotype of a cohort of 33 individuals (20 females, 13 males; median age 23.4 years, range 2.5-68.3 years) from 11 families with causative NOTCH1 variants (9 inherited, 2 de novo; 9 novel), ascertained from a proband with CHD. We describe the cardiac and extracardiac anomalies identified in these 33 individuals, only four of whom met criteria for AOS. The most common CHD identified was tetralogy of Fallot, though various left- and right-sided lesions and septal defects were also present. Extracardiac anomalies identified include cutis aplasia (5/33), cutaneous vascular anomalies (7/33), vascular anomalies of the central nervous system (2/10), Poland anomaly (1/33), pulmonary hypertension (2/33), and structural brain anomalies (3/14). Identification of these findings in a cardiac proband cohort supports NOTCH1-associated CHD and NOTCH1-associated AOS lying on a phenotypic continuum. Our findings also support (1) Broad indications for NOTCH1 molecular testing (any familial CHD, simplex tetralogy of Fallot or hypoplastic left heart); (2) Cascade testing in all at-risk relatives; and (3) A thorough physical exam, in addition to cardiac, brain (structural and vascular), abdominal, and ophthalmologic imaging, in all gene-positive individuals. This information is important for guiding the medical management of these individuals, particularly given the high prevalence of NOTCH1 variants in the CHD population., (© 2024. The Author(s).)

Patients with Aarskog-Scott syndrome (AAS) have short stature, facial anomalies, skeletal deformities, and genitourinary malformations. FYVE, RhoGEF, and PH domain-containing 1 (FGD1) is the only known causative gene of AAS. However, the diagnosis of AAS remains difficult, and specific treatments are still absent. Patients suspected with AAS were recruited, and clinical information was collected. Genetic testing and functional analysis were carried out for the diagnosis. By literature review, we summarized the clinical and genetic characteristics of FGD1-related AAS and analyzed the genotype-phenotype correlation. Five patients were recruited, and four novel FGD1 variants were identified. The diagnosis of AAS was confirmed by genetic analysis and functional study. Three patients treated with growth hormone showed improved heights during the follow-up period. By literature review, clinical features of AAS patients with FGD1 variants were summarized. Regarding FGD1 variations, substitutions were the most common form, and among them, missense variants were the most frequent. Moreover, we found patients with drastic variants showed higher incidences of foot and genitourinary malformations. Missense variants in DH domain were related to a lower incidence of cryptorchidism.   Conclusion: We reported four novel pathogenic FGD1 variations in AAS patients and confirmed the efficacy and safety of growth hormone treatment in FGD1-related AAS patients with growth hormone deficiency. Additionally, our literature review suggested the crucial role of DH domain in FGD1 function. What is Known: • Aarskog-Scott syndrome is a rare genetic disease, and the only known cause is the variant in FGD1 gene. The typical clinical manifestations of AAS include facial, skeletal, and urogenital deformities and short stature. What is New: • We reported four novel FGD1 variants and reported the treatment of growth hormone in FGD1-related AAS patients. Our genotype-phenotype correlation analysis suggested the crucial role of DH domain in FGD1 function., (© 2024. The Author(s).)

Cutis verticis gyrata (CVG), characterized by cerebriform overgrowth of the scalp, is rarely observed in congenital melanocytic nevi (CMN). We describe a 13-year-old male with autism and a large CMN of the scalp with numerous satellite nevi whose scalp nevus exhibited evolution with poliosis and CVG. Given the potential association of CVG (independent of CMN) with seizures, neuropsychiatric, and ophthalmologic disorders, and nevus-associated CVG (cerebriform intradermal nevus) with melanoma, multidisciplinary evaluation of CMN patients with CVG is important to guide management and treatment., (© 2022 Wiley Periodicals LLC.)

Notch signaling is a conserved pathway that converts extracellular receptor-ligand interactions into changes in gene expression via a single transcription factor (CBF1/RBPJ in mammals; Su(H) in Drosophila). In humans, RBPJ variants have been linked to Adams-Oliver syndrome (AOS), a rare autosomal dominant disorder characterized by scalp, cranium, and limb defects. Here, we found that a previously described Drosophila Su(H) allele encodes a missense mutation that alters an analogous residue found in an AOS-associated RBPJ variant. Importantly, genetic studies support a model that heterozygous Drosophila with the AOS-like Su(H) allele behave in an opposing manner to heterozygous flies with a Su(H) null allele, due to a dominant activity of sequestering either the Notch co-activator or the antagonistic Hairless co-repressor. Consistent with this model, AOS-like Su(H) and Rbpj variants have decreased DNA binding activity compared to wild type proteins, but these variants do not significantly alter protein binding to the Notch co-activator or the fly and mammalian co-repressors, respectively. Taken together, these data suggest a cofactor sequestration mechanism underlies AOS phenotypes associated with RBPJ variants, whereby the AOS-associated RBPJ allele encodes a protein with compromised DNA binding activity that retains cofactor binding, resulting in Notch target gene dysregulation., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: R.A.K is on the scientific advisory board of Cellestia Biotech AG and has received research funding from Cellestia for projects unrelated to this manuscript. The remaining authors have declared that no competing interests exist.

Heterozygous loss-of-function mutation in Delta-like ligand-4 ( Dll4 ) is an important cause of Adams-Oliver syndrome (AOS). Cardiac defects, in particular outflow tract (OFT) alignment defects, are observed in about one-fourth of patients with this syndrome. The mechanism underlying this genotype-phenotype correlation has not yet been established. Dll4-mediated Notch signaling is known to play a crucial role in second heart field (SHF) progenitor cell proliferation. We hypothesized that the depletion of the SHF progenitor pool of cells due to partial loss of Dll4 is responsible for the OFT alignment defects seen in AOS. To demonstrate this, we studied Dll4 expression by murine SHF progenitor cells around E9.5, a crucial time-point in SHF biology. We used SHF-specific (Islet1-Cre) conditional knockout of Dll4 to bypass the early embryonic lethality seen in global Dll4 heterozygotes. Dll4-mediated Notch signaling is critically required for SHF proliferation such that Dll4 knockout results in a 33% reduction in proliferation and a fourfold increase in apoptosis in SHF cells, leading to a 56% decline in the size of the SHF progenitor pool. A reduction in SHF cells available for incorporation into the developing heart leads to underdevelopment of the SHF-derived right ventricle and OFT. Similar to the clinical syndrome, 32% of SHF-specific Dll4 heterozygotes demonstrate foreshortened and misaligned OFT, resulting in a double outlet right ventricle. Our murine model provides a molecular mechanism to explain the cardiac defects observed in AOS and establishes a novel clinical role for Dll4-mediated Notch signaling in SHF progenitor biology.

Background: Adams-Oliver syndrome is characterized by the combination of congenital scalp defects and terminal transverse limb defects. In some instances, cardiovascular malformations and orofacial malformations have been observed. Little is written with regards to the anesthetic management and airway concerns of patients with Adams-Oliver syndrome., Case Presentation: A five-year-old female with Adams-Oliver syndrome presented for repeat lower extremity surgery. Airway exam was significant for dysmorphic features, such as hypertelorism, deviated jaw, and retrognathia. Video laryngoscope was utilized for intubation due to the patients retrognathic jaw, cranial deformities, and facial dysmorphism. A vein finder with ultrasound guidance was needed to place the peripheral intravenous line due to her history of difficult intravenous access. The patient was successfully intubated with slight cricoid pressure applied to direct the endotracheal tube smoothly. Surgery and recovery were both unremarkable., Conclusions: Due to varying presentations of Adams-Oliver syndrome, anesthetic and airway management considerations should be carefully assessed prior to surgery. Anesthesiologists must take into consideration possible orofacial abnormalities that may make intubation difficult. Amniotic band syndrome and other limb defects could potentially impact intravenous access as well.

Rationale: Familial exudative vitreoretinopathy (FEVR) is an inherited disorder, which is mostly reported to be associated with the mutation of genes involved in the Wnt signaling pathway related to β-catenin. To the best of our knowledge, the involvement of Adams-Oliver syndrome (AOS) genes in FEVR patients have not been reported before., Patient Concerns: Two patients with FEVR presented with microcephaly. One of them showed slight scarring of the scalp vertex which is a typical manifestation of AOS. The whole exon sequencing confirmed the diagnosis of AOS with 2 AOS-gene mutations at DOCK6 and ARHGAP31. Further clinical examination revealed that their parents with the same mutations showed FEVR-like vascular anomalies., Diagnosis: Both patients were diagnosed with AOS through whole exon sequencing, and they presented with some FEVR-like retinopathy including retinal detachment., Interventions: Both patients received vitrectomy for tractional retinal detachment with proliferative vitreoretinopathy. During the follow-up, 1 patient received additional laser photocoagulation for tractional retinal detachment., Outcomes: The 2 patients remained stable in the latest follow up after the treatment., Lessons: Microcephaly could be associated with some form of retinopathy. We proposed that mutation of DOCK6 and ARHGAP31 genes could be the possible cause of FEVR associated with microcephaly. Our study suggested that these genes may be candidate genes of FEVR., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Adams-Oliver syndrome (AOS) is a rare, inherited multi-systemic malformation syndrome characterized by a combination of aplasia cutis congenita and transverse terminal limb defects along with variable involvement of the central nervous system, eyes, and cardiovascular system. AOS can be inherited as both autosomal-dominant and recessive traits. Pathogenic variants in the DOCK6, ARHGAP31, EOGT, RBPJ, DLL4 , and NOTCH1 genes have been associated with AOS., Purpose: To report a novel homozygous variant in the DOCK6 gene associated with Adams-Oliver syndrome type 2., Materials and Methods: Case report., Results: We report a case of a 4-month-old male who presented with microcephaly, global developmental delay, truncal hypotonia, and limb reduction defects. Ophthalmic examination revealed bilateral nystagmus and retinal detachment with mild cataractous changes in addition to retrolental plaque in the left eye. Next generation sequencing analysis identified a novel homozygous frameshift likely pathogenic variant (c.1269_1285dup (p.Arg429Glnfs*32)) in the DOCK6 gene. The constellation of the clinical findings and the genetic mutation were consistent with a diagnosis of AOS type 2., Conclusion: The discovery of this new likely pathogenic variant enriches the genotypic spectrum of DOCK6 gene and contributes to genetic diagnosis and counseling of families with AOS. Neurologic and ocular findings appear to be consistent with AOS type 2 for which multidisciplinary clinical evaluation is crucial.

Adams-Oliver syndrome (AOS) is a rare hereditary disorder characterized by aplasia cutis congenita (ACC) and terminal transverse limb defects. The etiology of AOS has remained largely unknown, although mutations in the notch receptor 1 ( NOTCH1 ) gene are most common genetic alteration associated with this disease. In this study, we aimed to identify the case of a 6-year-old boy, who presented with large ACC of the scalp and aortic valve stenosis, suggesting the possibility of AOS. Whole-exome sequencing identified a novel, de novo , in-frame deletion in the NOTCH1 gene ( NOTCH1 c.1292_1294del, p.Asn431del) in the patient. The p.Asn431del variant was evaluated by several in silico analyses, which predicted that the mutant was likely to be pathogenic. In addition, molecular modeling with the PyMOL Molecular Graphics System suggested that the NOTCH1-N431del destabilizes calcium ion chelation, leading to decreased receptor-ligand binding efficiency. Quantitative reverse transcription PCR showed further significant downregulation of the Notch target genes, hes-related family bHLH transcription factor with YRPW motif 1 ( HEY1 ) and hes family bHLH transcription factor 1 ( HES1 ), suggesting that this mutation causes disease through dysregulation of the Notch signaling pathway. Our study provides evidence that the NOTCH1-N431del mutation is responsible for this case of AOS. To our knowledge, this is the first report of a patient with AOS caused by NOTCH1 mutation in Asia, and this information will be useful for providing the family with genetic counseling that can help to guide their future plans.

Rationale: Adams-Oliver syndrome (AOS) is a genetic disorder characterized by the association of aplasia cutis congenita (ACC), terminal transverse limb defect (TTLD), congenital cardiac malformation (CCM), and minor features, such as cutaneous, neurological, and hepatic abnormalities (HAs). The aim of the study is to emphasize phenotype-genotype correlations in AOS., Methods: We studied 29 AOS patients. We recorded retrospectively detailed phenotype data, including clinical examination, biological analyses, and imaging. The molecular analysis was performed through whole exome sequencing (WES)., Results: Twenty-nine patients (100%) presented with ACC, the principal inclusion criteria in the study. Seventeen of twenty-one (81%) had cutis marmorata telangiectasia congenita, 16/26 (62%) had TTLD, 14/23 (61%) had CCM, 7/20 (35%) had HAs, and 9/27 (33%) had neurological findings. WES was performed in 25 patients. Fourteen of twenty-five (56%) had alterations in the genes already described in AOS. CCM and HAs are particularly associated with the NOTCH1 genotype. TTLD is present in patients with DOCK6 and EOGT alterations. Neurological findings of variable degree were associated sometimes with DOCK6 and NOTCH1 rarely with EOGT., Conclusion: AOS is characterized by a clinical and molecular variability. It appears that degrees of genotype-phenotype correlations exist for patients with identified pathogenic mutations, underlining the need to undertake a systematic but adjusted multidisciplinary assessment., (© 2019 Wiley Periodicals, Inc.)

Adams-Oliver syndrome (AOS) is a rare congenital disease characterized by aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD). It shows significant genetic heterogeneity and can be transmitted by autosomal dominant or recessive inheritance. Recessive inheritance is associated with mutations of DOCK6 or EOGT; however, only few cases have been published so far. We present two families with EOGT-associated AOS. Due to pseudodominance in one family, the recognition of the recessive inheritance pattern was difficult. We identified two novel AOS-causing mutations (c.404G>A/p.Cys135Tyr and c.311+1G>T). The phenotype in the presented families was dominated by large ACC, whereas TTLD were mostly subtle or even absent and no major malformations occured. Our observations along with the previously published cases indicate that the two types of recessive AOS (EOGT- vs. DOCK6-associated) differ significanty regarding the frequency of neurologic or ocular deficits., (© 2019 Wiley Periodicals, Inc.)

Introduction: Adams-Oliver syndrome (AOS) is a rare developmental disorder characterized by the combination of aplasia cutis congenita of the scalp vertex and terminal transverse limb defects. DOCK6 (Dedicator of cytokinesis 6) is one of the six identified AOS genes., Methods: We performed targeted next-generation sequencing (NGS) of a child with an AOS phenotype. Sanger DNA sequencing further validated her lineal consanguinity. To explore the pathological features of the mutation, a minigene assay was used to investigate the effects of the mutation on splicing., Results: Two compound heterozygous DOCK6 mutations (c.4106+2T>C and c.3063 C>G (p.Y1021*)) were identified in this family, and both mutations have not been reported previously. Sanger DNA sequencing indicated that the mutations were inherited maternally and paternally, respectively. The results of the minigene assay showed that the c.4106+2T>C mutation resulted in aberrant splicing and caused a four-nucleotide insertion in the transcript and a premature stop codon., Conclusions: Our findings expanded the number of reported cases of this rare disease and the mutation spectrum of DOCK6 mutations, which can serve as the basis for prenatal diagnosis and genetic counseling., (Copyright © 2019 Elsevier B.V. All rights reserved.)

DOCK6 is a RAC1/CDC42 guanine nucleotide exchange factor, however, little is known about its function and sub-cellular localization. DOCK6 regulates the balance between RAC1 and RHOA activity during cell adhesion and is important for CDC42-dependent mitotic chromosome alignment. Surprisingly, a cell intrinsic adaptation mechanism compensates for errors in these DOCK6 functions that arise as a consequence of prolonged DOCK6 depletion or complete removal in DOCK6 knockout cells. Down-regulation of the ubiquitin-like modifier ISG15 accounts for this adaptation. Strikingly, although most other DOCK family proteins are deployed on the plasma membrane, here we show that DOCK6 localizes to the endoplasmic reticulum (ER) in dependence of its DHR-1 domain. ER localization of DOCK6 opens up new insights into its functions.

Objective: To detect pathogenic mutation of DOCK6 gene in a patient with convulsive seizure and refractory epilepsy., Methods: CytoScan HD-Array and next generation sequencing were used to detect the potential mutation in the patient., Results: The proband has carried compound heterozygous mutations of c.188C>T (p.Arg63Gln) and c.5374C>T (p.Glu1792Lys) of the DOCK6 gene, which were respectively inherited from his mother and father. Neither mutation was reported previously. Bioinformatic analysis indicated that the two amino acids are highly conserved. Based on the ACMG guidelines, the c.188C>T mutation was predicted to be likely pathogenic, while the c.5374C>T mutation was of uncertain significance., Conclusion: The compound heterozygous mutations of c.188C>T (p.Arg63Gln) and c.5374C>T (p.Glu1792Lys) of the DOCK6 gene probably underlie the disease in this patient.

Competing Interests: Competing interests: None declared.

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.)

The NOTCH signalling pathway is an essential pathway, involved in many cellular processes, including cell fate decision, cell proliferation, and cell death and important in the development of most organs. Mutations in genes encoding components of the NOTCH signalling pathway lead to a spectrum of congenital disorders. Over the past decades, mutations in human NOTCH signalling genes have been identified in several diseases with cardiovascular involvement. NOTCH1 mutations have been described in bicuspid aortic valve disease, left-sided congenital heart disease, and Adams-Oliver syndrome. NOTCH2 mutations lead to the development of Alagille syndrome, while mutations in NOTCH3 cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. To date, mutations in NOTCH4 have not been associated with cardiovascular disease. This review focuses on the mutations described in NOTCH1, NOTCH2, and NOTCH3 and their associated cardiovascular phenotypes., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Scalp lesions are common pediatric findings that present for neurosurgical evaluation and management. The majority will be benign. Meningothelial hamartomas represent a rare subset of congenital cutaneous lesions with the potential for intracranial extension and microscopic infiltration of the surrounding tissues. The authors report in this paper a case of meningothelial hamartoma of the scalp that demonstrated serial growth and invasion of the scalp. The degree of microscopic involvement and growth necessitated close follow-up and repeat excision.

The use of dermatoscopy to assist in the diagnosis of a variety of proliferative, pigmentary, inflammatory, infectious, congenital, and genetic cutaneous and skin appendage disorders is constantly increasing, as it is effective, affordable, noninvasive, and quick to perform., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Adams-Oliver syndrome (AOS) is a rare developmental disorder, characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance. Data on the frequency and distribution of mutations in large cohorts are currently limited. The purpose of this study was therefore to comprehensively examine the genetic architecture of AOS in an extensive cohort. Molecular diagnostic screening of 194 AOS/ACC/TTLD probands/families was conducted using next-generation and/or capillary sequencing analyses. In total, we identified 63 (likely) pathogenic mutations, comprising 56 distinct and 22 novel mutations, providing a molecular diagnosis in 30% of patients. Taken together with previous reports, these findings bring the total number of reported disease variants to 63, with a diagnostic yield of 36% in familial cases. NOTCH1 is the major contributor, underlying 10% of AOS/ACC/TTLD cases, with DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort. We confirm the relevance of genetic screening across the AOS/ACC/TTLD spectrum, highlighting preliminary but important genotype-phenotype correlations. This cohort offers potential for further gene identification to address missing heritability., (© 2018 The Authors. Human Mutation published by Wiley Periodicals, Inc.)

The Notch signaling pathway is highly conserved and essential for animal development. It is required for cell differentiation, survival, and proliferation. Regulation of Notch signaling is a crucial process for human health. Ligands initiate a signal cascade by binding to Notch receptors expressed on a neighboring cell. Notch receptors interact with ligands through their epidermal growth factor-like repeats (EGF repeats). Most EGF repeats are modified by O -glycosylation with residues such as O -linked N -acetylglucosamine ( O -GlcNAc), O -fucose, and O -glucose. These O -glycan modifications are important for Notch function. Defects in O -glycosylation affect Notch-ligand interaction, trafficking of Notch receptors, and Notch stability on the cell surface. Although the roles of each modification are not fully understood, O -fucose is essential for binding of Notch receptors to their ligands. We reported an EGF domain-specific O -GlcNAc transferase (EOGT) localized in the endoplasmic reticulum. Mutations in genes encoding EOGT or NOTCH1 cause Adams-Oliver syndrome. Dysregulation of Notch signaling because of defects or mutations in Notch receptors or Notch signal-regulating proteins, such as glycosyltransferases, induce a variety of congenital disorders. In this review, we discuss O -glycosylation of Notch receptors and congenital human diseases caused by defects in O -glycans on Notch receptors.

Intracranial calcifications in young infants, while suggesting intrauterine infections, can also be due to numerous other conditions, including rare genetic disorders. We describe 2 children in whom the presence and pattern of intracranial calcifications led to the diagnosis of uncommon genetic disorders, Adams-Oliver syndrome and Aicardi-Goutieres syndrome. Differentiating genetic conditions from intrauterine infections or other causes of intracranial calcifications enables practitioners to provide accurate counseling regarding prognosis and recurrence risk., (Copyright © 2017. Published by Elsevier Inc.)

Adams-Oliver syndrome (AOS) is characterized by a combination of congenital scalp defects (aplasia cutis congenita) and terminal transverse limb malformations of variable severity. When neurological findings are present, patients are reported as AOS variants. We describe a child with compound heterozygosity of the DOCK6 gene, aplasia cutis, terminal transverse limb defects, cardiovascular impairment, intellectual disability, and brain malformations with intracranial calcifications. He suffers from a severe refractory epileptic encephalopathy characterized by polymorphic seizures with prolonged periods of electroencephalogram (EEG), continuous epileptiform activity related to clinical inactivity, and closure of eyes with an "ON-OFF" behavior., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Georg Thieme Verlag KG Stuttgart · New York.)

Congenital melanocytic nevi (CMN) are nevi that are present at birth or arise within the first few weeks of life. They are often found on the trunk, head and neck and extremities. We report herein an unusual presentation of a CMN as a cerebriform tumour presenting as secondary cutis verticis gyrata on the scalp of an 18-year-old Filipino male., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Adams-Oliver syndrome (AOS) is a multiple congenital anomaly syndrome characterized by aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLDs). We present a case of type 2 autosomal recessive AOS associated with heterozygous mutations in the dedicator of cytokinesis 6 (DOCK6) gene, with characteristic findings of ACC, TTLD, intracerebral periventricular calcifications, and polymicrogyria., (© 2017 Wiley Periodicals, Inc.)

Adams-Oliver syndrome (AOS, OMIM; 100300) is a rare genetic disease characterized by aplasia cutis congenita, terminal transverse limb defects and cutis marmorata with vascular anomalies such as congenital heart defects. The etiology of this syndrome has remained largely unknown but defective Notch signaling during vascular formation has been suggested. Here we describe a sporadic Japanese newborn case with clinically diagnosed AOS. Trio whole-exome sequencing identified a de novo, novel, heterozygous missense mutation in the Delta-like 4 ligand gene (DLL4 c.572G>A, p.Arg191His) in the patient. DLL4 functions as a requisite ligand for NOTCH1 receptor, which is essential for vascular formation. Amino acid substitution of Arg191 to His was predicted by molecular models to interfere with direct binding between DLL4 and NOTCH1. DLL4 has recently been identified as a causative gene of an autosomal dominant type of AOS with milder symptoms. The case described here showed gradual recovery from skull defects after birth and no psychomotor developmental delay has been observed. This is the second report of an AOS case with DLL4 mutation, and the phenotypic characteristics between the two cases are compared and discussed.

Adams-Oliver syndrome is a rare disorder with varying degrees of scalp and cranial bone defects as well as limb anomalies, which can range from mild to more pronounced manifestations. In mild cases, closure of these defects can be achieved with a conservative approach. However, surgical closure is recommended in cases where the defect is extensive and includes cranial involvement. Several complicated cases of Adams-Oliver syndrome have been reported, in which flap failures were encountered and other alternatives had to be used to close critical scalp defects. Here, the case of a 4-year-old child with Adams-Oliver syndrome and a complex cranial defect with exposed titanium mesh is described. The patient was successfully treated with epidermal growth factor (EGF) infused foam dressings and subsequent split-thickness skin grafting. The EGF has been highlighted for its essential role in dermal wound repair through the stimulation of the proliferation and migration of keratinocytes, and showed accelerated wound healing when used in partial or full-thickness skin wounds.

Notch signaling regulates a vast array of crucial developmental processes. It is therefore not surprising that mutations in genes encoding Notch receptors or ligands lead to a variety of congenital disorders in humans. For example, loss of function of Notch results in Adams-Oliver syndrome, Alagille syndrome, spondylocostal dysostosis and congenital heart disorders, while Notch gain of function results in Hajdu-Cheney syndrome, serpentine fibula polycystic kidney syndrome, infantile myofibromatosis and lateral meningocele syndrome. Furthermore, structure-abrogating mutations in NOTCH3 result in CADASIL. Here, we discuss these human congenital disorders in the context of known roles for Notch signaling during development. Drawing on recent analyses by the exome aggregation consortium (EXAC) and on recent studies of Notch signaling in model organisms, we further highlight additional Notch receptors or ligands that are likely to be involved in human genetic diseases., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

Here, we describe a recently discovered O -GlcNAc transferase termed EOGT for EGF domain-specific O -GlcNAc transferase. EOGT transfers GlcNAc ( N -acetylglucosamine) to Ser or Thr in secreted and membrane proteins that contain one or more epidermal growth factor-like repeats with a specific consensus sequence. Thus, EOGT is distinct from OGT, the O -GlcNAc transferase, that transfers GlcNAc to Ser/Thr in proteins of the cytoplasm or nucleus. EOGT and OGT are in separate cellular compartments and have mostly distinct substrates, although both can act on cytoplasmic (OGT) and lumenal (EOGT) domains of transmembrane proteins. The present review will describe known substrates of EOGT and biological roles for EOGT in Drosophila and humans. Mutations in EOGT that give rise to Adams-Oliver Syndrome in humans will also be discussed., (© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.)

The Adams-Oliver syndrome (AOS) is defined as aplasia cutis congenita (ACC) with transverse terminal limb defects (TTLD). Frequencies of associated anomalies are not well characterized. Six causative genes have been identified: ARHGAP31, DOCK6, EOGT, RBPJ, NOTCH1, and DLL4. We review 385 previously described individuals (139 non-familial and 246 familial probands and family members) and add clinical data on 13 previously unreported individuals with AOS. In addition to ACC and TTLD, the most commonly associated anomalies included a wide variety of central nervous system (CNS) anomalies and congenital heart defects each seen in 23%. CNS anomalies included structural anomalies, microcephaly, vascular defects, and vascular sequelae. CNS migration defects were common. Cutis marmorata telangiectasia congenita (CMTC) was found in 19% of the study population and other vascular anomalies were seen in 14%. Hemorrhage was listed as the cause of death for five of 25 deaths reported. A relatively large number of non-familial probands were reported to have hepatoportal sclerosis with portal hypertension and esophageal varices. Non-familial probands were more likely to have additional anomalies than were familial probands. The data reported herein provide a basis for refining the diagnostic features of AOS and suggest management recommendations for probands newly diagnosed with AOS. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Competing Interests: Conflicts of Interest: None declared.

Genome-editing technologies allow systematic inactivation of human genes. Whether knockout phenotypes always reflect gene functions as determined by acute RNAi is an important question. Here we show how the acute knockdown of the Adams-Oliver syndrome (AOS) gene DOCK6, coding for a RAC1/CDC42 guanine nucleotide exchange factor, results in strikingly different phenotypes to those generated by genomic DOCK6 disruption. Cell-intrinsic adaptation compensates for loss of DOCK6 function. Prolonged DOCK6 loss impacts upon the MRTF-A/SRF transcription factor, reducing levels of the ubiquitin-like modifier ISG15. Reduced ISGylation of the IQGAP1 protein increases levels of active CDC42 and RAC1 to compensate for DOCK6 disruption. Similar downregulation of ISG15 in cells from DOCK6 AOS patients indicates that such adaptation can compensate for genetic defects during development. Thus, phenotypes of gene inactivation are critically dependent on the timescale, as acute knockdown reflects a transient state of adjustment to a new equilibrium that is attained following compensation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Adams-Oliver syndrome is a rare congenital condition that should be considered in persons with terminal transverse limb deficiencies and scalp defects (aplasia cutis congenita). Broad phenotypic variability exists in this condition. In its more severe forms, Adams-Oliver syndrome can involve the cardiovascular system, central nervous system, gastrointestinal tract, and genitourinary system and should require prompt evaluation by appropriate subspecialists. Extremity involvement is typically bilateral and asymmetrical, with lower extremities involved more than upper extremities. Brachydactyly is the most common limb defect, and severity ranges from hypoplastic nails to complete absence of the distal limb. The syndrome has been described as resulting from autosomal dominant and recessive modes of inheritance, but most cases are sporadic. No gene has been identified. Although the exact pathogenic mechanism is unknown, a common hypothesis is that a vascular disturbance occurs in watershed areas, such as cranial vertex and limbs, during fetal development., (Copyright © 2016 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)