Terminal Transverse Limb Defects Research Articles

A novel pathogenic variation of DOCK6 gene: the genotype-phenotype correlation in Adams-Oliver syndrome.

Adams-Oliver syndrome (AOS) (#614,219) is a multiple malformation disorder characterized by the presence of aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). We describe a confirmed case of AOS with a novel pathogenic variation in Dedicator Of Cytokinesis 6 (DOCK6) gene, with neurological abnormalities, characterized by the presence of a multiple malformation entity with extensive cardiological and neurological abnormalities. In AOS, genotype-phenotype correlations have been described. DOCK6 mutations appear to be related with congenital cardiac and central nervous system malformations associated with intellectual disability, as illustrated in the present case.

Homozygosity for a novel DOCK6 variant in an individual without aplasia cutis congenita of the scalp and terminal transverse limb defects.

Homozygosity for a novel DOCK6 variant in an individual without aplasia cutis congenita of the scalp and terminal transverse limb defects.

Adams-Oliver syndrome and associated complications: Report of a family in Colombia and review of the literature

The Adams-Oliver syndrome is a rare congenital disorder characterized by aplasia cutis congenita of the scalp, terminal transverse limb defects, and congenital telangiectatic cutis marmorata. It can occur through different inheritance patterns: autosomal dominant, autosomal recessive, or de novo dominant mutations. Although the Adams-Oliver syndrome is a rare disease, it is essential to know its clinical characteristics and inheritance patterns, to establish a correct diagnosis and its possible complications during follow-up. In the present study, we describe the case of an adolescent with Adams-Oliver syndrome with an autosomal dominant inheritance pattern, pulmonary hypertension and plastic bronchitis, and several compromised family members.

Intrafamilial phenotypic variability in autosomal recessive DOCK6-related Adams-Oliver syndrome

Adams-Oliver syndrome (AOS) is diagnosed in presence of aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). The autosomal recessive (AR) DOCK6-related form of AOS is most often associated with a severe phenotype including also central nervous system and ocular abnormalities. We report a sister and brother with different expression of the phenotype. Both were compound heterozygous pathogenic variants in the DOCK6 gene, including a heterozygous c.5939+2T > C intronic variant that was maternally inherited, and a heterozygous deletion of exons 10 to 21 that was paternally inherited. The sister had microcephaly, periventricular calcifications, minor retinal vasculopathy, and mild impaired neurodevelopment, but only very subtle limb abnormalities and no ACC. Her brother showed a classical DOCK6-related AOS phenotype, including a severe bilateral peripheral ischemic retinopathy. From a review of 22 molecularly confirmed cases with DOCK6-related AOS with ophthalmic examination, we found that 16 of them had retinal vascular pathology (72.7%), confirming as the major ocular anomaly. Documented intrafamilial variability in our family and the evidence revised from previous reports, confirm that AR DOCK6-related AOS expressivity can produce a “milder” phenotype without ACC or TTLD, which could be underdiagnosed in simplex cases because it is difficult to recognize out of a familial context. Therefore, in order to know its real magnitude is required the future inclusion of DOCK6 gene in NGS panels directed to the study of simplex cases of patients with microcephaly, periventricular calcifications, retinal vasculopathy, and/or cardiovascular defects.

Synergistic effects of rare variants of ARHGAP31 and FBLN1 in vitro in terminal transverse limb defects.

Background: Aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLDs) are the most common features of Adams-Oliver syndrome (AOS). ARHGAP31 is one of the causative genes for autosomal dominant forms of AOS, meanwhile its variants may only cause isolated TTLD. Here, we report a proband presented with apparent TTLD but not ACC. Methods: Whole exome sequencing (WES) and Sanger sequencing were applied to identify causative genes. Expression vectors were constructed for transfections in mammalian cell cultures followed by biochemical and functional analysis including immunoblotting, immunofluorescence staining, and cell counting kit-8 assay. Results: WES and Sanger sequencing suggested that the proband inherited rare ARHGAP31 variant [c.2623G > A (p.Glu875Lys)] and a rare FBLN1 variant [c.1649G > A (p.Arg550His)] from one of her asymptomatic parents, respectively. Given FBLN1 variation has also been linked to syndactyly, we suspected that the two genes together contributed to the TTLD phenotype and explored their possible roles in vitro. Mutant FBLN1 showed reduced expression resulted from impaired protein stability, whereas ARHGAP31 protein expression was unaltered by mutation. Functional assays showed that only in the co-transfected group of two mutants cell viability was decreased, cell proliferation was impaired, and apoptosis was activated. Cdc42 activity was declined by both ARHGAP31 mutation and FBLN1 mutation alone, and the two together. Furthermore, the MAPK/ERK pathway was only activated by two mutants co-transfected group compared with two wild-type transfections. Conclusion: We report a case carrying two rare variants of limb defects associated genes, ARHGAP31 and FBLN1, and provide in vitro evidence that synergistic disruption of cellular functions attributed by the two mutants may potentiate the penetrance of clinical manifestations, expanding our knowledge of clinical complexity of causal gene interactions in TTLD and other genetic disorders.

Hypothesis: Symbrachydactyly.

The term symbrachydactyly has been used for the phenotype of two or three short fingers or toes, hypoplasia of the middle and distal phalanges and variable syndactyly of the affected digits. Some clinicians have extended this diagnosis to include other phenotypes, specifically cleft hand, terminal transverse limb defects, hypoplasia of the thumb and fifth finger with nubbins for fingers 2, 3, and 4 and the hand deformity of the Poland anomaly. A malformations surveillance program can identify enough affected infants to characterize a phenotype. In the Active Malformations Surveillance Program in Boston (1972-2012) among 289,365 births, all infants and fetuses with structural abnormalities were identified from reading the examination findings by the pediatricians and pathologists and the results of diagnostic tests. Liveborn and stillborn infants were included, as well as fetuses from elective terminations because of anomalies identified in prenatal testing. We present the findings in 14 infants, all liveborn, who had symbrachydactyly of one or both hands (n=12) or feet (n=2). We suggest restricting the term symbrachydactyly to this single phenotype to improve counseling and to focus future research on identifying the cause(s).

Severe Adams-Oliver Syndrome after Maternal COVID-19 Infection Could Be Another Effect of the SARS-CoV-2 Inflammatory Storm? Case Report

Background. Adams-Oliver syndrome is a congenital disease whose main findings are aplasia cutis congenita of the scalp and terminal transverse limb defects. The pathogenesis is unknown, but it is postulated that ischemic events in susceptible tissues cause the lesions in the embryonic period. Case report. We present a newborn with a severe phenotype of Adams-Oliver syndrome. The infant’s mother had a SARS-CoV-2 infection in the first trimester of pregnancy. Prenatal ultrasound indicates a probable worsening of the disease after the first trimester. Conclusion. This study shows a previously unpublished severe AOS phenotype in a term newborn. There are some signs that the disease could have progressed beyond the first trimester, either spontaneously or by the inflammatory mechanisms of SARS-CoV-2.

Adams-oliver syndrome with congenital absence of lower lip

Adams-Oliver syndrome is a rare disease characterized by aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Both familial and non-familial cases have been described with predominantly autosomal dominant inheritance and autosomal recessive inheritance in a few. Various systemic involvements lik e central nervous system, cardiovascular system etc. have also been described. We describe here a case of ACC with TTLD characterized by syndactyly of hands and feet without any systemic involvement in a 13 months old female child, without any family history. She also had congenital absence of lower lip, not being described earlier.

A case of Adams-Oliver syndrome associated with c.3190_3191del and c.4491 + 1G > T mutations in the DOCK6 gene

BackgroundAdams–Oliver syndrome (AOS [MIM 100300]) is a rare, multiple malformation syndrome commonly characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Brain abnormalities and heart defects are also present in most patients. Both autosomal-dominant and autosomal-recessive inheritance of the disease have been observed. To date, six causative genes have been identified: ARHGAP31, DOCK6, EOGT, RBPJ, NOTCH1, and DLL4. Autosomal-recessive mutations are mostly associated with DOCK6 (MIM: 614219) and EOGT (MIM: 615297), while mutations in ARHGAP31 (MIM: 100300), RBPJ (MIM: 614814), NOTCH1 (MIM: 616028), and DLL4 (MIM: 616589) have been linked to autosomal-dominant inheritance.CaseWe report a case of AOS caused by DOCK6 mutations (c.3190_3191del and c.4491 + 1G > T), showing no signs of scalp ACC or TTLD, but with bilateral ventricular dilation and ophthalmic abnormalities. Results of whole-exome high-throughput sequencing were analyzed using a combination of pathogenicity prediction algorithms, query of variant databases, and review of the literature. Candidate gene variation sites were identified for pedigree verification.ConclusionsThe correlation between the genotype and phenotype of AOS has great variability, and the specific pathogenesis of AOS remains to be further studied.

Terminal transverse limb defects with "nubbins".

A terminal transverse limb defect with absence of the forearm and hand or just the hand is an uncommon limb deformity in an otherwise healthy newborn. Most of the affected infants also have tiny digit-like nubbins on the stump of the affected limb, a finding that could represent an attempt at regeneration following vascular obstruction in early limb development. One hundred ninety-four newborn infants with a limb deficiency were identified among 289,365 births in an active malformations surveillance program at Brigham and Women's Hospital in Boston, MA from 1972 to 2012. Twenty-eight infants with terminal transverse limb defects were identified. Twenty-four had tiny digit-like nubbins (0.5cm in length) on the stump at one of three levels: the proximal portion of the forearm, the wrist or the forefoot. The examination of the placentas of eight affected infants showed no evidence of amnion rupture. Three of these 28 infants had associate chromosome abnormalities: trisomy 21, chromosome 11q deletion and the deletion of 22q11.2. Terminal transverse limb defects reflect failure of early limb development. Awareness of this phenotype at birth, or when identified by ultrasound screening, can provide more accurate counseling than occurs with the more common misdiagnosis of "amniotic band syndrome."

Case report and review of literature of a rare congenital disorder: Adams-Oliver syndrome

BackgroundAdams-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 presentationA 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.ConclusionsDue 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.

Novel compound heterozygous mutations of the DOCK6 gene in a familial case of Adams-Oliver syndrome 2

IntroductionAdams-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. MethodsWe 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. ResultsTwo 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. ConclusionsOur 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.

Novel genetic inheritance with a rare presentation of Adams–Oliver syndrome

Adams–Oliver syndrome (AOS) is a rare heterogeneous inherited disorder, characterized by the combination of the congenital scalp and terminal transverse limb defects. Various expressions of AOS have been reported. Most cases of the syndrome appear to follow autosomal dominant inheritance, but autosomal recessive inheritance has also been reported. However, genetic inheritance involving both autosomal recessive and dominant genes within the same patient was not previously reported. We report a newborn case of AOS with novel genetic profile and a rare clinical presentation.

Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.

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.

Síndrome de Adams-Oliver

A Síndrome de Adams-Oliver é uma desordem rara caracterizada por aplasia cútis congênita e defeitos nos membros distais transversais. Geralmente esporádica, mas também autossômica recessiva ou dominante, apresenta um amplo espectro de apresentações fenotípicas, que podem incluir variadas malformações múltiplas sistêmicas. A doença pode ser fatal, quando inclui principalmente anomalias cardíacas, cerebrais ou renais graves. Acredita-se que a etiopatogenia se dá em função de distúrbios na vasculogênese, e mutações em seis genes foram identificados. Ampla revisão da literatura foi realizada, discutindo critérios diagnósticos e terapêuticos. Por fim, foi relatado o caso de um menino brasileiro de 11 anos de idade, com fenótipo característico e doença leve, sem achados de anomalias sistêmicas, mas retardo mental, epilepsia e traços autistas, com ressonância encefálica normal.

Malformations attributed to the process of vascular disruption.

Several malformations have been attributed to the process of vascular disruption. The central hypothesis for this etiology is that blood flow to a structure has been altered after that structure had formed normally. The decreased blood flow leads to hypoxia, endothelial cell damage, hemorrhage, tissue loss, and repair. After recovery, some structures are normal and others show either tissue loss or structural abnormalities, such as syndactyly and constriction rings. The phenotypic features of the 7,020 infants with one or more malformations, who were born to women who had always planned to deliver at Brigham and Women's Hospital (BWH) between, 1972 and 2012, that is, maternal nontransfers, were reviewed. The phenotypes associated with vascular disruption, such as the amniotic band syndrome and terminal transverse limb defects (TTLD), were identified. One hundred and five fetuses and infants had malformations attributed to the process of vascular disruption. Some specific causes of the amniotic band limb deformity were identified. TTLD with associated small digit-like nubbins occurred at three levels: proximal forearm, wrist, and metacarpal-phalangeal joint. Other causes included severe hemoglobinopathies and exposures to misoprostol and to prenatal procedures. Malformations attributed to the process of vascular disruption were a distinctive entity, among the recognized etiologies. The timing of the causative event in the first trimester was established for infants with exposures to either the prostaglandin misoprostol or the prenatal diagnosis procedure chorionic villus sampling. One challenge is to identify the developmental steps in vascular disruption when no causative exposure can be identified.

Yenidoğanda Adams Oliver Sendromu

Adams Oliver syndrome (AOS) is characterized by a combination of congenital scalp defects (aplasia cutis congenita) and terminal transverse limb defects. Various expressions of AOS have been reported. It can also be associated with extensive lethal anomalies of central nervous, cardiopulmonary, gastrointestinal, and genitourinary systems. Here we report a newborn diagnosed AOS with severe scalp defect, terminal limb defects and cutis marmorata telangiectatica congenita without systemic involvement. During hospitalization menengitis developed as a major complication and treated with appropriate antibiotheraphy. Scalp defect was treated with local wound care. In conclusion it is important to be aware of different presentations of AOS. All newborn infants with aplasia cutis congenita should be evaluated carefully with physical examination and laboratory workup to rule out associated diseases.

DOCK6Mutations Are Responsible for a Distinct Autosomal-Recessive Variant of Adams-Oliver Syndrome Associated with Brain and Eye Anomalies

Adams-Oliver syndrome (AOS) is characterized by the association of aplasia cutis congenita with terminal transverse limb defects, often accompanied by additional cardiovascular or neurological features. Both autosomal-dominant and autosomal-recessive disease transmission have been observed, with recent gene discoveries indicating extensive genetic heterogeneity. Mutations of the DOCK6 gene were first described in autosomal-recessive cases of AOS and only five DOCK6-related families have been reported to date. Recently, a second type of autosomal-recessive AOS has been attributed to EOGT mutations in three consanguineous families. Here, we describe the identification of 13 DOCK6 mutations, the majority of which are novel, across 10 unrelated individuals from a large cohort comprising 47 sporadic cases and 31 AOS pedigrees suggestive of autosomal-recessive inheritance. DOCK6 mutations were strongly associated with structural brain abnormalities, ocular anomalies, and intellectual disability, thus suggesting that DOCK6-linked disease represents a variant of AOS with a particularly poor prognosis.

Mutations in NOTCH1 Cause Adams-Oliver Syndrome

Notch signaling determines and reinforces cell fate in bilaterally symmetric multicellular eukaryotes. Despite the involvement of Notch in many key developmental systems, human mutations in Notch signaling components have mainly been described in disorders with vascular and bone effects. Here, we report five heterozygous NOTCH1 variants in unrelated individuals with Adams-Oliver syndrome (AOS), a rare disease with major features of aplasia cutis of the scalp and terminal transverse limb defects. Using whole-genome sequencing in a cohort of 11families lacking mutations in the four genes with known roles in AOS pathology (ARHGAP31, RBPJ, DOCK6, and EOGT), we found a heterozygous de novo 85 kb deletion spanning the NOTCH1 5' region and three coding variants (c.1285T>C [p.Cys429Arg], c.4487G>A [p.Cys1496Tyr], and c.5965G>A [p.Asp1989Asn]), two of which are de novo, in four unrelated probands. In a fifth family, we identified a heterozygous canonical splice-site variant (c.743-1 G>T) in an affected father and daughter. These variants were not present in 5,077 in-house control genomes or in public databases. In keeping with the prominent developmental role described for Notch1 in mouse vasculature, we observed cardiac and multiple vascular defects in four of the five families. We propose that the limb and scalp defects might also be due to a vasculopathy in NOTCH1-related AOS. Our results suggest that mutations in NOTCH1 are the most common cause of AOS and add to a growing list of human diseases that have a vascular and/or bony component and are caused by alterations in the Notch signaling pathway.

The etiology of möbius syndrome: a social problem?

In this edition, we would like to highlight the article Mobius Syndrome (MS): Misoprostol Use and Speech and Language Characteristics. This study aims to verify speech and language performance of children with MS whose mothers reported use of misoprostol (Cytotec, Pfizer, Connecticut, United States) compared with children with MS from mothers who did not report use. The sample of this study consisted of 18 girls and boys with a previous diagnosis of MS, aged from 4 months to 10 years. The stomatognathic system beyond receptive and expressive language and speech was evaluated in children with MS, and their mothers were questioned whether they used misoprostol during the pregnancy or not. From the total, 61.1% admitted taking the drug Cytotec at some time during pregnancy, usually in the first few weeks. The researchers concluded that there was a large contingent of women who took misoprostol without knowing its teratogenic action. Moreover, the lack of facial expressions and speech disorders were common characteristics of the individuals with MS, whether the mothers took misoprostol during the pregnancy or not. MS is described as a very rare disease with just 500 cases reported worldwide by the year 2008.1 It is a congenital condition characterized by facial unilateral or bilateral paralysis, complete or incomplete, in association with bilateral palsy of abducens nerve. The child may concomitantly present lingual weakness, and ∼30% of cases present talipes equinovarus (deformity of the feet). It is postulated that this syndrome arises from abnormal development of the seventh cranial nerve, facial muscles, or motor nucleus of the facial nerve; other causes include intrauterine hypoxia.2 3 However, other cranial nerves, unilateral or bilateral, may also be involved, causing ptosis, divergent strabismus, deafness, disturbances of sensibility in regions innervated by the trigeminal nerve, dysphagia, dysphonia, and tongue atrophy, which can be verified in different combinations.4 Misoprostol is a synthetic drug similar to prostaglandin E1, administered orally for prevention and treatment of gastric ulcer. It is a drug widely used in obstetrics for its uterotonic action and may cause abortion, embryonic death of the fetus, and changes in labor. Although not approved for clinical use by the U.S. Food and Drug Administration, misoprostol is widely used for abortion purposes in Latin America, mainly in Brazil.5 6 7 The popularization of misoprostol as an abortifacient in our environment led to many studies linking the drug as the cause of the increased number of cases of MS in recent years.8 9 In a systematic review, aiming to estimate the risk of congenital anomalies and other adverse events in children exposed to misoprostol during fetal life, the authors concluded that prenatal exposure to misoprostol is associated with an increased risk of MS and terminal transverse limb defects. The data source consisted of case–control studies that analyzed the effect of prenatal exposure to misoprostol on pregnancy outcome, which were located in electronic databases and published up to June 2005.9 Therefore, the research presented here has great scientific importance to clarify the etiopathogenic aspects of the syndrome as more patients are being studied. Furthermore, the possibility to investigate a larger number of cases expands the opportunity to better characterize clinical conditions, methods of assessment, prognosis, and prevention program development, as well as health promotion of individuals diagnosed with MS. Geraldo Pereira Jotz Editor-Chefe International Archives of Otorhinolaryngology