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.

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.

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.

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.

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.

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.

Myhre-LAPs syndrome and intubation related airway stenosis: keys to diagnosis and critical therapeutic interventions.

OBJECTIVES: Myhre-LAPS syndrome is a recently recognized disease caused by a mutation in the SMAD4 gene. This results in a range of pathology including laryngotracheal stenosis, arthropathy, prognathism and short stature, or LAPS syndrome. We aim to delineate the role of intubation in development of airway stenosis in these patients as well as provide insight into diagnosis and management of this syndrome. Herein we present four patients with Myhre-LAPS syndrome complicated by airway stenosis and perform a systematic review of all cases of Myhre-LAPS syndrome with reported airway pathology. STUDY DESIGN: Retrospective review METHODS: All patients diagnosed with Myhre-LAPS syndrome and airway stenosis at a single institution from 1981 to 2014 were reviewed. RESULTS: Four patients (4F, median age 42) were identified that met inclusion criteria. Initial presenting signs included progressive shortness of breath, dyspnea on exertion and respiratory distress. All four (100%) patients had multi-level airway stenosis most commonly in the subglottic and glottic regions and all patients had undergone at least one endotracheal intubation prior to presentation. One patient with a history of nasal tracheal intubation presented with nasal obstruction and was found to have choanal as well as subglottic stenosis. Two of the four (50%) patients are tracheostomy tube dependent, 1/4 (25%) died of a fatal cardiac arrhythmia and 1/4 (25%) has had 6 endoscopic treatments for subglottic stenosis in 4 years with rapid symptom recurrence. CONCLUSIONS: Myhre-LAPS syndrome is characterized by progressive systemic fibrosis and patients are diagnosed by characteristic findings of prognathism, short stature, abnormal facies, and thick skin among other abnormalities. Airway management is complicated by recurrent, refractory subglottic stenosis often preceded by elective intubation as well as maxillary hypoplasia, trismus, and limited neck extension. Endotracheal intubation and surgical intervention should be approached with caution in these patients and multidisciplinary care teams are necessary to address all manifestations of this syndrome.

Stronger relation between impairment and manual capacity in the non-dominant hand than the dominant hand in congenital hand differences; implications for surgical and therapeutic interventions.

OBJECTIVES: To evaluate manual activity capacity (i.e. activity capacity to perform hand activities) and its relation with body functions of the hand and forearm in children with congenital hand differences (CHD) METHODS: We assessed 10-14 year-old children with CHD (N = 106) using a functional handgrips test. Measurements of body functions included joint mobility and muscle strength. Patient characteristics were hand dominance and severity. RESULTS: We found a stronger relation between body functions and manual activity capacity in non-dominant hands than dominant hands. Dominant hands scored significantly higher on manual activity capacity than nondominant hands that were similarly impaired at body functions level. Severity of the CHD and body functions had only small effects on manual activity capacity. CONCLUSION: The relation between body functions and manual activity capacity is stronger in non-dominant hands than dominant hands, indicating that improvement in body functions lead to larger changes in manual activity capacity in the non-dominant hand. This may suggest that in bilaterally-affected children surgery should be done at the non-dominant hand first since this hand would benefit most from surgery-induced body functions improvement.

CLOVES syndrome.

A cohort of patients with overgrowth syndromes has been identified with congenital lipomatous overgrowth, dysregulated fat deposits, and mixed vascular malformations. The acronym CLOVES was given on a heuristic basis to stand for congenital lipomatous overgrowth (CLO), vascular malformation (V), epidermal nevi (E), and scoliosis and spinal deformities (S). These patients have upper limb anomalies with variable phenotypes. Although hand anomalies alone cannot make the diagnosis, the foot, truncal, cutaneous and spinal anomalies are particularly diagnostic. CLOVES syndrome has emerged as a distinct clinical entity diagnosed by clinical and radiographic examinations. The overgrowth pattern is now easily distinguished from other overgrowth syndromes.

[Vohwinkel syndrome. Hearing loss and keratoderma on the hands and feet]. / Vohwinkel-Syndrom. Schwerhörigkeit und Keratosen an Hand und Fuß

The combination of sensorineural hearing loss and keratoderma on the hands and feet is rare. We report the case of a child that failed newborn hearing screening and also showed keratoderma on both hands and feet. The child's father exhibited the same constellation of symptoms, which is typical for mutilating keratoderma with deafness (Vohwinkel syndrome). This hereditary autosomal dominant disease is caused by mutation of the GJB2 gene that encodes the protein connexin 26. In our case it was highly likely that the GJB2 gene in the father carried a spontaneous mutation that was inherited by the daughter.

Tel Hashomer camptodactyly syndrome: a case report.

Tel Hashomer camptodactyly syndrome (THCS) is a rare autosomal recessive camptodactyly with muscular involvement. The manifestations of THCS other than camptodactyly are clubbed feet, thenar and hypothenar hypoplasia, abnormal palmar creases and dermatoglyphic ridges, spina bifida and mitral valve prolapse. The syndrome was first described by Goodman et al in 1972 and thereafter two further cases with similar phenotype were seen. Herein, we present another case report and review of the literature of other syndromes associated with camptodactyly and mitral valve prolapse. Further cases with this syndrome need to be reported for mapping of the candidate loci. This will help in planning management and genetic counselling.

[Camptodactyly: early nonoperative treatment]. / Il trattamento conservativo precoce nella camptodattilia.

PURPOSE: To analyse the classifications and the conservative protocols used by hand surgery operative's units and published in the last 15 years. To draw a comparison between those classifications and protocols and the ones used in our unit. MATERIAL AND METHODS: The published conservative treatments have been analysed and then our protocol has been described through the analysis of three cases currently treated in our division. RESULTS: It has been highlighted that camptodactyly classifications are not homogeneous. Moreover, in conservative treatment, different typology and posology of splints have been adopted. Our unit uses the Foucher's classification to define the type of splint that it is necessary. CONCLUSIONS: Despite the authors choose different types of splint, they agree that in the most cases of camptodactily the initial approach is conservative. In our unit static and dynamic splints are made directly on the patient's hand and they are monitored with goniometrical measurements, obtaining great results.

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.

Cleft hand in Kabuki make-up syndrome: case report.

Kabuki make-up syndrome (KMS) is a multiple malformation/mental retardation syndrome that was first described in Japan but is now reported in many other ethnic groups. Kabuki make-up syndrome is characterized by multiple congenital abnormalities: craniofacial, skeletal, and dermatoglyphic abnormalities; mental retardation; and short stature. Common hand anomalies associated with KMS include persistent fingertip pad, brachydactyly, clinodactyly, and lax joints. We report a patient with KMS who presented with cleft hand, a feature that has not yet been described in KMS, and describe the potential genetic cause.

Developmental biology and classification of congenital anomalies of the hand and upper extremity.

Recent investigations into the mechanism of limb development have clarified the roles of several molecules, their pathways, and interactions. Characterization of the molecular pathways that orchestrate limb development has provided insight into the etiology of many limb malformations. In this review, we describe how the insights from developmental biology are related to clinically relevant anomalies and the current classification schemes used to define, categorize, and communicate patterns of upper limb malformations. We advocate an updated classification scheme for upper limb anomalies that incorporates our current molecular perspective of limb development and the pathogenetic basis for malformations using dysmorphology terminology. We anticipate that this scheme will improve the utility of a classification as a basis for diagnosis, treatment, and research.

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.