Association between ARID2 and RAS-MAPK pathway in intellectual disability and short stature.

BACKGROUND: ARID2 belongs to the Switch/sucrose non-fermenting complex, in which the genetic defects have been found in patients with dysmorphism, short stature and intellectual disability (ID). As the phenotypes of patients with ARID2 mutations partially overlap with those of RASopathy, this study evaluated the biochemical association between ARID2 and RAS-MAPK pathway. METHODS: The phenotypes of 22 patients with either an ARID2 heterozygous mutation or haploinsufficiency were reviewed. Comprehensive molecular analyses were performed using somatic and induced pluripotent stem cells (iPSCs) of a patient with ARID2 haploinsufficiency as well as using the mouse model of Arid2 haploinsufficiency by CRISPR/Cas9 gene editing. RESULTS: The phenotypic characteristics of ARID2 deficiency include RASopathy, Coffin-Lowy syndrome or Coffin-Siris syndrome or undefined syndromic ID. Transient ARID2 knockout HeLa cells using an shRNA increased ERK1 and ERK2 phosphorylation. Impaired neuronal differentiation with enhanced RAS-MAPK activity was observed in patient-iPSCs. In addition, Arid2 haploinsufficient mice exhibited reduced body size and learning/memory deficit. ARID2 haploinsufficiency was associated with reduced IFITM1 expression, which interacts with caveolin-1 (CAV-1) and inhibits ERK activation. DISCUSSION: ARID2 haploinsufficiency is associated with enhanced RAS-MAPK activity, leading to reduced IFITM1 and CAV-1 expression, thereby increasing ERK activity. This altered interaction might lead to abnormal neuronal development and a short stature.

Brachymetacarpia and Brachymetatarsia in Patients with Multiple Hereditary Exostosis.

BACKGROUND: Multiple hereditary exostosis is a common autosomal dominant inherited musculoskeletal disorder that manifests with multiple osteochondromas. The clinical manifestations and pathological characteristics of osteochondromas found in the long bone and genetic alterations related to multiple hereditary exostosis have been widely reported. In this study, we investigated the characteristics of brachymetacarpia and brachymetatarsia associated with multiple hereditary exostosis. METHODS: Of the 133 patients with a diagnosis of multiple hereditary exostosis who were recruited from 2005 to 2018, 101 patients who underwent plain radiography after 10 years of age were included. There were 55 male (54.5%) and 46 female (45.5%) patients. Brachymetacarpia or brachymetatarsia was diagnosed when disruption of the Lièvre parabola connecting the metacarpal or metatarsal heads was observed on plain radiographs. Three orthopedic surgeons individually reviewed hand and foot plain radiographs. RESULTS: Of the 101 patients, 41 patients (40.6%) had more than 1 brachymetacarpia (88 cases) or brachymetatarsia (81 cases). Among 41 cases, 22 (53.7%) were male and 19 (46.3%) were female. The mean age at the time of radiographic evaluation of the hands and feet was 14.6 years (range, 10-63 years). Shortening was most commonly found in the 3rd and 4th metacarpal or metatarsal bones. CONCLUSIONS: We found a relatively high incidence of brachymetacarpia and brachymetatarsia in our patients. Physicians should suspect the presence of brachymetacarpia and brachymetatarsia when treating patients with multiple hereditary exostosis.

Multiple digit camptodactyly caused by anomalous ulnar sided flexor digitorum superficialis insertions.

We report an anomalous insertion of the flexor digitorum superficialis (FDS) tendon causing multiple digit camptodactyly. The abnormal tendon was present in the ring and middle fingers, passing from the FDS tendon (proximal to the proximal interphalangeal-PIP-joint) to the extensor expansion (distal to the PIP joint). It was present on the ulnar aspect only, with no corresponding structure on the radial side. Division of the anomalous insertion corrected the fixed flexion deformity at the PIP joint. This anomaly has not been reported in clinical or cadaveric studies and could have been overlooked if a volar approach had been used.

First Korean Case of Coffin-Siris Syndrome with a Novel Frameshift ARID1B Mutation.

Coffin-Siris Syndrome (CSS) is a rare neurodevelopmental disorder characterized by intellectual disability, coarse facial features, hypoplastic digits/nails, and hypertrichosis. The genes causative of CSS mainly encode the SWI/SNF complex, which contributes to chromatin remodeling and regulates the access of transcriptional factors to specific gene sites. While ARID1B mutations account for a third of all CSS cases, the condition's phenotypic features vary widely. We document the case of a girl with CSS who presented with a variant facial appearance, global developmental delay with speech impairment, agenesis of the corpus callosum, funnel chest, and bilateral renal stones without hypertrichosis or hypoplasia of the fifth fingernail. Genetic analysis revealed that the patient had a novel heterozygous frameshift mutation c.2201dupG (p.Ser736Ilefs*27) on the ARID1B gene.

First case of compound heterozygous BHLHA9 variants in mesoaxial synostotic syndactyly with phalangeal reduction.

Mesoaxial synostotic syndactyly with phalangeal reduction (MSSD) is an extremely rare autosomal recessive limb abnormality characterized by the fusion of third and fourth fingers. To date, only homozygous missense and frameshift mutations have been reported in BHLHA9 associated to MSSD. In this study, we report a patient who presented with clinical and radiological features of MSSD. A customized skeletal dysplasia NGS panel revealed the presence of two novel compounds heterozygous variants in BHLHA9: NM_001164405.1: c.[226A>T][269G>C]; p.[(Lys76*)][(Arg90Pro)]. Thus, this is the first case of MSSD in a nonconsanguineous family.

Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases.

Proteins anchored to the cell surface via glycosylphosphatidylinositol (GPI) play various key roles in the human body, particularly in development and neurogenesis. As such, many developmental disorders are caused by mutations in genes involved in the GPI biosynthesis and remodeling pathway. We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI. Ten different PIGB variants were found in these individuals. Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins. Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy. Eight children passed away before four years old. Two of them had a clinical diagnosis of DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), a condition that includes sensorineural deafness, shortened terminal phalanges with small finger and toenails, intellectual disability, and seizures; this condition overlaps with the severe phenotypes associated with inherited GPI deficiency. Most individuals tested showed elevated alkaline phosphatase, which is a characteristic of the inherited GPI deficiency but not DOORS syndrome. It is notable that two severely affected individuals showed 2-oxoglutaric aciduria, which can be seen in DOORS syndrome, suggesting that severe cases of inherited GPI deficiency and DOORS syndrome might share some molecular pathway disruptions.

Gain-of-Function Mutations in KCNN3 Encoding the Small-Conductance Ca2+-Activated K+ Channel SK3 Cause Zimmermann-Laband Syndrome.

Zimmermann-Laband syndrome (ZLS) is characterized by coarse facial features with gingival enlargement, intellectual disability (ID), hypertrichosis, and hypoplasia or aplasia of nails and terminal phalanges. De novo missense mutations in KCNH1 and KCNK4, encoding K+ channels, have been identified in subjects with ZLS and ZLS-like phenotype, respectively. We report de novo missense variants in KCNN3 in three individuals with typical clinical features of ZLS. KCNN3 (SK3/KCa2.3) constitutes one of three members of the small-conductance Ca2+-activated K+ (SK) channels that are part of a multiprotein complex consisting of the pore-forming channel subunits, the constitutively bound Ca2+ sensor calmodulin, protein kinase CK2, and protein phosphatase 2A. CK2 modulates Ca2+ sensitivity of the channels by phosphorylating SK-bound calmodulin. Patch-clamp whole-cell recordings of KCNN3 channel-expressing CHO cells demonstrated that disease-associated mutations result in gain of function of the mutant channels, characterized by increased Ca2+ sensitivity leading to faster and more complete activation of KCNN3 mutant channels. Pretreatment of cells with the CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole revealed basal inhibition of wild-type and mutant KCNN3 channels by CK2. Analogous experiments with the KCNN3 p.Val450Leu mutant previously identified in a family with portal hypertension indicated basal constitutive channel activity and thus a different gain-of-function mechanism compared to the ZLS-associated mutant channels. With the report on de novo KCNK4 mutations in subjects with facial dysmorphism, hypertrichosis, epilepsy, ID, and gingival overgrowth, we propose to combine the phenotypes caused by mutations in KCNH1, KCNK4, and KCNN3 in a group of neurological potassium channelopathies caused by an increase in K+ conductance.

Analysis of Causes for Congenital Ulnar Deviated Thumbs at the Distal Phalanx Level in 157 Thumbs.

PURPOSE: To investigate anatomic abnormalities causing a congenital ulnarly deviated thumb at the distal phalanx. METHODS: A total of 122 children with 157 congenital ulnarly deviated thumbs at the distal phalanges were reviewed, including those with isolated deformity or polydactyly. We analyzed the incidence and characteristics of the underlying anatomic abnormalities as well as the differential diagnoses. RESULTS: Three main causes of an ulnarly deviated thumb were observed. Abnormal hypertrophic epiphyses were found in 96 thumbs. An extra phalanx lying between the normal proximal and distal phalanges was found in 59 thumbs. A previously undescribed cause was found in 2 thumbs with Wassell IV polydactyly, in which an obliquely angled articular surface of the proximal phalanx manifested with ulnar deviation at the interphalangeal joint. Radiographic analysis showed that in cases with abnormal epiphyses, the epiphysis was in good apposition and good alignment with its relevant distal phalanx; the distance from the abnormal epiphysis to the phalanx was usually less than 1 mm. In contrast, in cases of extra phalanges, the distance from the epiphysis to the phalanx averaged more than 2 mm and there was poor apposition between the distal phalanx and the extra bone. CONCLUSIONS: Abnormal hypertrophic epiphysis and triphalangeal thumb are the 2 main causes of a congenital ulnarly deviated thumb. A distance of more than 2 mm between the abnormal bone and the distal phalanx suggests a triphalangeal thumb. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

RADIATE - Radial Dysplasia Assessment, Treatment and Aetiology: protocol for the development of a core outcome set using a Delphi survey.

BACKGROUND: Radial dysplasia (RD) is a disfiguring, potentially disabling congenital upper limb anomaly. Multiple surgical techniques are in current use, with little agreement on the optimal treatment approach. At present, no core outcome set exists specifically for RD, and the literature is dominated by retrospective case series. A recent systematic review by this group demonstrated significant heterogeneity on which outcomes are measured and how they are measured. METHODS/DESIGN: The RADIATE study will conduct a three-round online Delphi process, involving adult RD patients, the parents of children with RD, hand surgeons and hand therapists. The initial list of outcomes was drawn from our recent systematic review and will be supplemented by suggestions from the stakeholder groups. Following the Delphi process, outcomes that meet the consensus in definition will be ratified at a final consensus meeting. We will then follow the COSMIN guidelines to select outcome measurement instruments. Where appropriate, these will overlap with the outcome measures specified in the forthcoming standard set for congenital upper limb anomalies published by the International Consortium for Health Outcomes Measurement. DISCUSSION: The Radial Dysplasia Assessment, Treatment and Aetiology (RADIATE) study aims to address the uncertainty in the treatment of RD, and to begin to answer the question 'What is the most appropriate treatment of the forearm and hand for children with RD?' by establishing a core outcome set. TRIAL REGISTRATION: COMET initiative study, 902 . Registered in May 2016.

Three additional patients with EED-associated overgrowth: potential mutation hotspots identified?

Variants have been identified in the embryonic ectoderm development (EED) gene in seven patients with syndromic overgrowth similar to that observed in Weaver syndrome. Here, we present three additional patients with missense variants in the EED gene. All the missense variants reported to date (including the three presented here) have localized to one of seven WD40 domains of the EED protein, which are necessary for interaction with enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2). In addition, among the seven patients reported in the literature and the three new patients presented here, all of the reported pathogenic variants except one occurred at one of four amino acid residues in the EED protein. The recurrence of pathogenic variation at these loci suggests that these residues are functionally important (mutation hotspots). In silico modeling and calculations of the free energy changes resulting from these variants suggested that they not only destabilize the EED protein structure but also adversely affect interactions between EED, EZH2, and/or H3K27me3. These cases help demonstrate the mechanism(s) by which apparently deleterious variants in the EED gene might cause overgrowth and lend further support that amino acid residues in the WD40 domain region may be mutation hotspots.

Myhre syndrome: Clinical features and restrictive cardiopulmonary complications.

Myhre syndrome, a connective tissue disorder characterized by deafness, restricted joint movement, compact body habitus, and distinctive craniofacial and skeletal features, is caused by heterozygous mutations in SMAD4. Cardiac manifestations reported to date have included patent ductus arteriosus, septal defects, aortic coarctation and pericarditis. We present five previously unreported patients with Myhre syndrome. Despite varied clinical phenotypes all had significant cardiac and/or pulmonary pathology and abnormal wound healing. Included herein is the first report of cardiac transplantation in patients with Myhre syndrome. A progressive and markedly abnormal fibroproliferative response to surgical intervention is a newly delineated complication that occurred in all patients and contributes to our understanding of the natural history of this disorder. We recommend routine cardiopulmonary surveillance for patients with Myhre syndrome. Surgical intervention should be approached with extreme caution and with as little invasion as possible as the propensity to develop fibrosis/scar tissue is dramatic and can cause significant morbidity and mortality.

[THE ADVERSE EFFECTS OF SMOKING ON THE HANDS].

Cigarette smoking is known to cause a multitude of harmful effects throughout the body. There are only a few accounts in the literature of these effects as related to the hands. This is a review of the literature, demonstrating the collected knowledge of decreased hand vascularity due to tobacco use and assessing the evidence connecting smoking and supposed resultant maladies, including Raynaud's phenomenon, hand-arm vibration syndrome, Buerger's disease, Dupuytren's contracture, carpal tunnel syndrome, effects on skin and fingernails, decreased skin and bone healing, complications of digit replantation and complex regional pain syndrome. Also presented is the possible increased risk of congenital hand malformations as related to maternal smoking.

The pathogenesis of Kirner's deformity: A clinical, radiological and histological study.

UNLABELLED: The distal phalanx in Kirner's disease is abnormal and recognizable both clinically and radiologically. Despite previous investigation, the cause of these abnormalities is not clear. The current study seeks to evaluate the abnormal physis in Kirner's deformity using radiological investigation, intraoperative observation and histopathological assessment in three clinical cases. Similarities with clinodactyly are described. Three patients with Kirner's deformity underwent plain-film radiography and magnetic resonance imaging. Intraoperative observations were recorded, and histologic assessment of anatomically abnormal tissue was performed in all three cases. All three modalities of investigation (plain-film X-rays, magnetic resonance imaging and histological findings) were consistent and supported the intraoperative observation of cartilage abnormally situated anterior to the diaphysis and deep to the flexor tendon. There is thus evidence for the presence of an incomplete volar bracket or L-shaped physis in Kirner's deformity, analogous with the C-shaped bracket found in clinodactyly. LEVEL OF EVIDENCE: Aetiological Study; Level 4.

The ARID1B phenotype: what we have learned so far.

Evidence is now accumulating from a number of sequencing studies that ARID1B not only appears to be one of the most frequently mutated intellectual disability (ID) genes, but that the range of phenotypes caused by ARID1B mutations seems to be extremely wide. Thus, it is one of the most interesting ID genes identified so far in the exome sequencing era. In this article, we review the literature surrounding ARID1B and attempt to delineate the ARID1B phenotype. The vast majority of published ARID1B patients have been ascertained through studies of Coffin-Siris syndrome (CSS), which leads to bias when documenting the frequencies of phenotypic features. Additional observations of those individuals ascertained through exome sequencing studies helps in delineation of the broader clinical phenotype. We are currently establishing an ARID1B consortium, aimed at collecting ARID1B patients identified through genome-wide sequencing strategies. We hope that this endeavor will eventually lead to a more comprehensive view of the ARID1B phenotype.

Coffin-Siris syndrome and related disorders involving components of the BAF (mSWI/SNF) complex: historical review and recent advances using next generation sequencing.

This issue of Seminars in Medical Genetics, American Journal of Medical Genetics Part C investigates the human diseases caused by mutations in the BAF complex (also known as the mammalian SWI/SNF complex) genes, particularly focusing on Coffin-Siris syndrome (CSS). CSS is a rare congenital malformation syndrome characterized by developmental delay or intellectual disability (ID), coarse facial appearance, feeding difficulties, frequent infections, and hypoplasia/aplasia of the fifth fingernails and fifth distal phalanges. In 2012, 42 years after the first description of CSS in 1970, five causative genes (SMARCB1, SMARCE1, SMARCA4, ARID1A, ARID1B), all encoding components of the BAF complex, were identified as being responsible for CSS through whole exome sequencing and pathway-based genetic screening. The identification of two additional causative genes (PHF6, SOX11) followed. Mutations in another BAF complex gene (SMARCA2) and (TBC1D24) were found to cause clinically similar conditions with ID, Nicolaides-Baraitser syndrome and DOORS syndrome, respectively. Also, ADNP was found to be mutated in an autism/ID syndrome. Furthermore, there is growing evidences for germline or somatic mutations in the BAF complex genes to be causal for cancer/cancer predisposition syndromes. These discoveries have highlighted the role of the BAF complex in the human development and cancer formation. The biology of BAF is very complicated and much remains unknown. Ongoing research is required to reveal the whole picture of the BAF complex in human development, and will lead to the development of new targeted therapies for related disorders in the future.

Females with de novo aberrations in PHF6: clinical overlap of Borjeson-Forssman-Lehmann with Coffin-Siris syndrome.

Recently, de novo aberrations in PHF6 were identified in females with intellectual disability and with a distinct phenotype including a characteristic facial gestalt with bitemporal narrowing, prominent supraorbital ridges, synophrys, a short nose and dental anomalies, tapering fingers with brachytelephalangy, clinodactyly and hypoplastic nails, short toes with hypoplastic nails, and linear skin hyperpigmentation. In adolescent or older patients, this phenotype overlaps but is not identical with Borjeson-Forssman-Lehmann syndrome in males, caused by X-linked recessive mutations in PHF6. In younger girls there seems to be a striking phenotypic overlap with Coffin-Siris syndrome, which is characterized by intellectual disability, sparse hair and hypoplastic nails. This review will summarize and characterize the female phenotype caused by de novo aberrations in PHF6 and will discuss the overlapping and distinguishing features with Coffin-Siris syndrome.

Genotype-phenotype correlation of Coffin-Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A.

Coffin-Siris syndrome (CSS) is a rare congenital malformation syndrome, recently found to be caused by mutations in several genes encoding components of the BAF complex. To date, 109 patients have been reported with their mutations: SMARCB1 (12%), SMARCA4 (11%), SMARCE1 (2%), ARID1A (7%), ARID1B (65%), and PHF6 (2%). We review genotype-phenotype correlation of all previously reported patients with mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A through reassessment of their clinical and molecular findings. Cardinal features of CSS included variable degrees of intellectual disability (ID) predominantly affecting speech, sucking/feeding difficulty, and craniofacial (thick eyebrows, long eyelashes), digital (hypoplastic 5th fingers or toes, hypoplastic 5th fingernails or toenails), and other characteristics (hypertrichosis). In addition, patients with SMARCB1 mutations had severe neurodevelopmental deficits including severe ID, seizures, CNS structural abnormalities, and no expressive words as well as scoliosis. Especially, those with a recurrent mutation "p.Lys364del" represented strikingly similar phenotypes including characteristic facial coarseness. Patients with SMARCA4 mutations had less coarse craniofacial appearances and behavioral abnormalities. Patients with SMARCE1 mutations had a wide spectrum of manifestations from severe to moderate ID. Patients with ARID1A also had a wide spectrum of manifestations from severe ID and serous internal complications that could result in early death to mild ID. Mutations in SMARCB1, SMARCA4, and SMARCE1 are expected to exert dominant-negative or gain-of-function effects, whereas those in ARID1A are expected to exert loss-of-function effects.

Clinical features, diagnostic criteria, and management of Coffin-Siris syndrome.

Coffin-Siris syndrome (OMIM#135900) is a multiple congenital anomaly syndrome classically characterized by hypo- or aplasia of the fifth digit nails or phalanges, as well as coarse facial features, sparse scalp hair, and moderate to severe cognitive and/or developmental delay. The recent identification of molecular etiologies has served to effectively characterize a large set of patients who have been described with Coffin-Siris between the time of its initial description and the present. However, despite recent advances, a number of patients who traditionally fit the diagnosis have yet to have identified causes. This could be due to patients who lie outside the defined phenotype, or alternatively, to additional as yet unidentified genes which may play roles. Here we outline the range of clinical features described in the broader diagnostic category, review the continuing phenotypic challenges and note those subsets of patients for whom molecular causes have yet to be clarified. Finally, we discuss recommendations for clinical management of these individuals.