Integrating whole-genome sequencing and transcriptomic findings in the diagnosis and management of Coffin-Siris syndrome.

INTRODUCTION: Although the whole-exome sequencing (WES) approach has been widely used in clinic, many rare diseases with syndromic and nonsyndromic neurological manifestations remain undiagnosed. Coffin-Siris syndrome (CSS) is a rare autosomal dominant genetic disease characterized by neurodevelopmental delay. A suspected diagnosis can be made based on the typical CSS clinical features; however, molecular genetic testing is necessary for a confirmed diagnosis. OBJECTIVES: Three CSS-like patients with negative results in the WES and chromosomal microarray analysis (CMA) were recruited in this study. METHODS: We used whole-genome sequencing (WGS) technology to sequence the peripheral blood of the three families. To further explore the possible pathogenesis of CSS, we performed RNA-sequencing (RNA-seq). RESULTS: WGS identified the three CSS patients were carrying de novo copy number variants of the ARID1B gene, which have not been reported before. RNA-seq identified 184 differentially expressed genes (DEGs), with 116 up-regulated and 68 down-regulated. Functional annotation of DEGs showed that two biological processes (immune response, chemokine activity) and two signaling pathways (cytokine-cytokine receptor interaction, chemokine activity) were highlighted. We speculated that ARID1B deficiency might trigger abnormal immune responses, which may be involved in the pathophysiologic mechanisms of CSS. CONCLUSION: Our research provided further support for WGS application in CSS diagnosis and made an investigational approach for the underlying mechanisms of CSS.

Crisponi/cold-induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts.

Crisponi/cold-induced sweating syndrome (CS/CISS) is an autosomal recessive disease characterized by hyperthermia, camptodactyly, feeding and respiratory difficulties often leading to sudden death in the neonatal period. The affected individuals who survived the first critical years of life, develop cold-induced sweating and scoliosis in early childhood. The disease is caused by variants in the CRLF1 or in the CLCF1 gene. Both proteins form a heterodimeric complex that acts on cells expressing the ciliary neurotrophic factor receptor (CNTFR). CS/CISS belongs to the family of "CNTFR-related disorders" showing a similar clinical phenotype. Recently, variants in other genes, including KLHL7, NALCN, MAGEL2 and SCN2A, previously linked to other diseases, have been associated with a CS/CISS-like phenotype. Therefore, retinitis pigmentosa and Bohring-Optiz syndrome-like (KLHL7), Congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome (NALCN), Chitayat-Hall/Schaaf-Yang syndrome (MAGEL2), and early infantile epileptic encephalopathy-11 syndrome (SCN2A) all share an overlapping phenotype with CS/CISS, especially in the neonatal period. This review aims to summarize the existing literature on CS/CISS, focusing on the current state of differential diagnosis, pathogenesis and treatment concepts in order to achieve an accurate and rapid diagnosis. This will improve patient management and enable specific treatments for the affected individuals.

Congenital Deformities of the Hands.

Evaluation of the pediatric musculoskeletal system may be difficult because of differences between children and adults. As children mature, their physical structure approaches that of an adult. However, in the meantime, varying stages of ossification and developmental timelines may confuse the average clinician. Congenital abnormalities of the upper extremity are extremely numerous, but here we present 10 that often are seen in clinical practice. The article discusses the diagnosis, evaluation, treatment, and outcomes of each condition.

Monogenic Forms of Hypertension.

Essential hypertension is a highly prevalent disease in the general population. Secondary hypertension is characterized by a specific and potentially reversible cause of increased blood pressure levels. Some secondary endocrine forms of hypertension are common (caused by uncontrolled cortisol, aldosterone, or catecholamines production). This article describes rare monogenic forms of hypertension, characterized by electrolyte disorders and suppressed renin-aldosterone axis. They represent simple models for the physiology of renal control of sodium levels and plasma volume, thus reaching a high scientific interest. Furthermore, they could explain some features closer to the essential phenotype of hypertension, suggesting a mechanistically driven personalized treatment.

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.

Camptodactyly resulting from anatomical variation of lumbrical muscles: imaging findings.

We report three cases of camptodactyly in adolescent patients, presenting with a passive flexion deformity of the fifth finger. Ultrasound findings include aberrant lumbrical insertion and decreased lumbrical size, confirmed with magnetic resonance imaging, and aberrant dynamics. Surgery confirmed these findings in one patient. To the best of our knowledge, these imaging findings have not been reported previously.

DOOR syndrome: A case report and its embryological basis.

DOOR syndrome is an extremely rare genetic disorder. "DOOR″ is an acronym to describe the combination of: deafness, onychodystrophy, osteodystrophy and mental retardation. We present a patient, with all of the above-mentioned main symptoms, that was rehabilitated with convencional hearing aids. The presented case suggested that every case of deafness and abnormal nails and phalanges in the hands and feet should have a clinical diagnosis of possible DOOR syndrome. Based on embryological process, congenital abnormal nails or phalanges highlights the importance for detailed hearing screening.

First data from a parent-reported registry of 81 individuals with Coffin-Siris syndrome: Natural history and management recommendations.

Coffin-Siris syndrome (CSS; MIM 135900) is a multisystem congenital anomaly syndrome caused by mutations in the genes in the Brg-1 associated factors (BAF) complex. Classically, individuals with CSS have been described with hypo- or aplasia of the fifth digit nails or phalanges (hence the term "fifth digit syndrome"). Other physical features seen include growth restriction, coarse facial features, hypertrichosis or hirsutism, sparse scalp hair, dental anomalies, and other organ-system abnormalities. Varying degrees of developmental and intellectual delay are universal. To date, approximately 200 individuals have been described in the literature. With the advent of large-scale genetic testing such as whole-exome sequencing is becoming more available, more individuals are being found to have mutations in this pathway, and the phenotypic spectrum appears to be broadening. We report here a large cohort of 81 individuals with the diagnosis of CSS from the first parent-reported CSS/BAF complex registry in an effort to describe this variation among individuals, the natural history of the syndrome, and draw some gene-phenotype correlations. We propose that changes in the BAF complex may represent a spectrum of disorders, including both ARID1B-related nonsyndromic intellectual disability (ARID1B-ID) and CSS with classic physical features. In addition, we offer surveillance and management recommendations based on the medical issues encountered in this cohort to help guide physicians and patients' families.

Femoral bifurcation and bilateral tibial hemimelia: case report.

Femoral bifurcation and tibial hemimelia are rare anomalies described as a variant of Gollop-Wolfgang complex. This article presents a case of Gollop-Wolfgang complex without hand ectrodactyly. A 5-year old patient presented with bilateral tibial hemimelia and left femoral bifurcation. The patient's left limb lacked knee extensor mechanism, disarticulation was done. The right leg which had Jones type 2 tibia hemimelia was treated with tibiofibular synostosis. Currently patient is ambulant with prosthesis on the left limb and ankle foot orthosis on the right. In the absence of proximal tibial anlage, especially in patients with femoral bifurcation, the knee should be disarticulated. Tibiofibular synostosis is a good choice in the presence of a proximal tibial anlage with good quadriceps function.

A Case of Acrorenal Syndrome.

Urinary tract anomalies are common and comprise about 20% to 30% of total congenital anomalies. This spectrum consists of many different anomalies of the urinary tract that may be syndromic or nonsyndromic with different etiologies. In this case report, a patient with single kidney and urinary tract signs is introduced that was diagnosed accidentally. The finding of different anomalies in different organ systems should lead us to examination of the intactness of the urinary tract. In these disorders, if there is no need for immediate intervention, long-term follow-up can be helpful to postpone chronic kidney disease progression.

Treating Congenital Proximal Interphalangeal Joint Contracture.

The management of congenital proximal interphalangeal joint deformity, also known as camptodactyly, is challenging. There are numerous theories on the cause of this abnormal finger posture, leading to variations in classification, definition, and treatment approaches. This article assesses the previous literature and provides clarity and guidance for the practical treatment of camptodactyly.

The case for early use of rapid whole-genome sequencing in management of critically ill infants: late diagnosis of Coffin-Siris syndrome in an infant with left congenital diaphragmatic hernia, congenital heart disease, and recurrent infections.

Congenital diaphragmatic hernia (CDH) results from incomplete formation of the diaphragm leading to herniation of abdominal organs into the thoracic cavity. CDH is associated with pulmonary hypoplasia, congenital heart disease, and pulmonary hypertension. Genetically, it is associated with aneuploidies, chromosomal copy-number variants, and single gene mutations. CDH is the most expensive noncardiac congenital defect. Management frequently requires implementation of extracorporeal membrane oxygenation (ECMO), which increases management expenditures 2.4-3.5-fold. The cost of management of CDH has been estimated to exceed $250 million per year. Despite in-hospital survival of 80%-90%, current management is imperfect, as a great proportion of surviving children have long-term functional deficits. We report the case of a premature infant prenatally diagnosed with CDH and congenital heart disease, who had a protracted and complicated course in the intensive care unit with multiple surgical interventions, including postcardiac surgery ECMO, gastrostomy tube placement with Nissen fundoplication, tracheostomy for respiratory failure, recurrent infections, and developmental delay. Rapid whole-genome sequencing (rWGS) identified a de novo, likely pathogenic, c.3096_ 3100delCAAAG (p.Lys1033Argfs*32) variant in ARID1B, providing a diagnosis of Coffin-Siris syndrome. Her parents elected palliative care and she died later that day.

Otorhinolaryngologic manifestations of Hartsfield syndrome: Case series and review of literature.

Diagnosis of Hartsfield syndrome includes recognition of three distinct clinical anomalies: holoprosencephaly, ectrodactyly, and bilateral cleft-lip and palate syndrome. A family including three male siblings all affected by Hartsfield syndrome presented to our institution for care. An autosomal dominant variant in Fibroblast Growth Factor Receptor 1 (FGFR1) was identified. This report focuses on otorhinolaryngologic manifestationsof Hartsfield syndrome, previously undescribed, including midline defects of holoprosencephaly, bilateral cleft-lip and palate, retrognathia, gastroesophageal reflux disease, external ear anomalies, eustachian tube dysfunction, and midface abnormalities, in addition to multidisciplinary, long-term management strategies. Multidisciplinary management is imperative in the care of these children with modification of approach based on their medical complexity.

FATCO Syndrome (Fibular Aplasia, Tibial Campomelia, Oligosyndactyly with Talar Aplasia). A Case Study.

FATCO syndrome consists of fibular hemimelia, tibial campomelia and oligosyndactyly. FATCO syndrome can also be associated with other congenital anomalies; therefore, every case needs thorough evaluation so as to make the management of the patient easier. A few cases of this syndrome have been described in literature but only two cases have been reported in India so far. We present a 3-year-old male child born of a non-con-sanguinous marriage with FATCO syndrome and ipilateral talar aplasia without any other congenital anomalies.

The fate of hips that are conservatively treated in multiple epiphyseal dysplasia.

We reviewed the radiologic and clinical outcomes of hip joints affected by multiple epiphyseal dysplasia in 40 patients. The average patient age was 9.6 years. All patients were followed up for an average of 7.2 years. No patient underwent surgical treatment. The variances of the center-edge angle and femoral head coverage had the greatest tendency to increase with conservative treatment and follow-up (P=0.011 and 0.015, respectively). The acetabular angle and the acetabular depth index at the first visit and the latest follow-up were statistically significantly different (P=0.046 and 0.027, respectively). According to the Stulberg classification, the severity of hip deformity became less severe with age, but this was not statistically significant (P=0.090). Larger improvements in Harris hip scores were identified after conservative treatment (P=0.003). Favorable midterm outcomes were obtained for the treatment of hip deformity in multiple epiphyseal dysplasia patients by conservative treatment.

Kirner's deformity of the fifth finger: a case report.

BACKGROUND: Kirner's deformity is a rare bony deformity that is characterized by radial and volar curvature of the distal phalanx of the fifth finger. Affected patients usually present after the age of 5 years, with girls more affected than boys and bilateral involvement more common than unilateral. CASE PRESENTATION: We report a case of an eight-year-old girl who presented with progressive deformity of the right little finger. Radiographic evaluation revealed volar and radial curvature of the distal phalanx of the right fifth digit. Magnetic resonance imaging (MRI) further revealed the deformity along with widening of the physeal plate, lack of soft tissue enhancement and normal insertion of the flexor digitorum profundus tendon. The patient was followed conservatively for two years and is now being considered for corrective osteotomy. CONCLUSION: Kirner's deformity is a rare abnormality of unknown etiology. Diagnosis is made with clinical examination and imaging evaluation. Clinicians should be aware of this uncommon deformity and differentiate it from other mimickers such as infection, physeal fracture, camptodactyly, and clinodactyly.

[Malformations of hand and forearm : Conspicuous postpartum]. / Fehlbildungen an Hand und Unterarm : Postpartal auffallend.

Many congenital malformations of the hand and forearm, e. g. polydactyly, thumb duplication, syndactyly and radial aplasia, are already evident at birth and newborns are promptly referred to specialized departments. In contrast, orthopedic surgeons are often confronted with malformations of the hand and forearm, which gradually become clinically conspicuous during growth. This review article focuses on these specific malformations, which regularly upset the patients in practice and in most cases the parents even more so. In addition to the diagnostics and differential diagnostics, the conservative and surgical treatment options are presented.

Gain-of-function mutations in SMAD4 cause a distinctive repertoire of cardiovascular phenotypes in patients with Myhre syndrome.

Myhre syndrome is a rare, distinctive syndrome due to specific gain-of-function mutations in SMAD4. The characteristic phenotype includes short stature, dysmorphic facial features, hearing loss, laryngotracheal anomalies, arthropathy, radiographic defects, intellectual disability, and a more recently appreciated spectrum of cardiovascular defects with a striking fibroproliferative response to surgical intervention. We report four newly described patients with typical features of Myhre syndrome who had (i) a mildly narrow descending aorta and restrictive cardiomyopathy; (ii) recurrent pericardial and pleural effusions; (iii) a large persistent ductus arteriosus with juxtaductal aortic coarctation; and (iv) restrictive pericardial disease requiring pericardiectomy. Additional information is provided about a fifth previously reported patient with fatal pericardial disease. A literature review of the cardiovascular features of Myhre syndrome was performed on 54 total patients, all with a SMAD4 mutation. Seventy percent had a cardiovascular abnormality including congenital heart defects (63%), pericardial disease (17%), restrictive cardiomyopathy (9%), and systemic hypertension (15%). Pericarditis and restrictive cardiomyopathy are associated with high mortality (three patients each among 10 deaths); one patient with restrictive cardiomyopathy also had epicarditis. Cardiomyopathy and pericardial abnormalities distinguish Myhre syndrome from other disorders caused by mutations in the TGF-ß signaling cascade (Marfan, Loeys-Dietz, or Shprintzen-Goldberg syndromes). We hypothesize that the expanded spectrum of cardiovascular abnormalities relates to the ability of the SMAD4 protein to integrate diverse signaling pathways, including canonical TGF-ß, BMP, and Activin signaling. The co-occurrence of congenital and acquired phenotypes demonstrates that the gene product of SMAD4 is required for both developmental and postnatal cardiovascular homeostasis. © 2016 Wiley Periodicals, Inc.