Thrombocytopenia-Absent Radius Syndrome: Descriptions of Three New Cases and a Novel Splicing Variant in RBM8A That Expands the Spectrum of Null Alleles.

Thrombocytopenia-absent radius (TAR) syndrome is a rare congenital disorder characterized by the bilateral absence of the radius and thrombocytopenia, and sometimes by other skeletal, gastrointestinal, cardiac, and renal abnormalities. The underlying genetic defect is usually the compound inheritance of a microdeletion in 1q21.1 (null allele) and a low-frequency, non-coding single nucleotide variant (SNV) in the RBM8A gene (hypomorphic allele). We report three new cases from two unrelated families. The two siblings presented the common genotype, namely the compound heterozygosity for a 1q21.1 microdeletion and the hypomorphic SNV c.-21G>A in RBM8A, whereas the third, unrelated patient presented a rare genotype comprised by two RBM8A variants: c.-21G>A (hypomorphic allele) and a novel pathogenic variant, c.343-2A>G (null allele). Of the eight documented RBM8A variants identified in TAR syndrome patients, four have hypomorphic expression and four behave as null alleles. The present report expands the RBM8A null allele spectrum and corroborates the particularities of RBM8A involvement in TAR syndrome pathogenesis.

Fryns type mesomelic dysplasia of the upper limbs caused by inverted duplications of the HOXD gene cluster.

The HoxD cluster is critical for vertebrate limb development. Enhancers located in both the telomeric and centromeric gene deserts flanking the cluster regulate the transcription of HoxD genes. In rare patients, duplications, balanced translocations or inversions misregulating HOXD genes are responsible for mesomelic dysplasia of the upper and lower limbs. By aCGH, whole-genome mate-pair sequencing, long-range PCR and fiber fluorescent in situ hybridization, we studied patients from two families displaying mesomelic dysplasia limited to the upper limbs. We identified microduplications including the HOXD cluster and showed that microduplications were in an inverted orientation and inserted between the HOXD cluster and the telomeric enhancers. Our results highlight the existence of an autosomal dominant condition consisting of isolated ulnar dysplasia caused by microduplications inserted between the HOXD cluster and the telomeric enhancers. The duplications likely disconnect the HOXD9 to HOXD11 genes from their regulatory sequences. This presumptive loss-of-function may have contributed to the phenotype. In both cases, however, these rearrangements brought HOXD13 closer to telomeric enhancers, suggesting that the alterations derive from the dominant-negative effect of this digit-specific protein when ectopically expressed during the early development of forearms, through the disruption of topologically associating domain structure at the HOXD locus.

Expanding the phenotype in Adams-Oliver syndrome correlating with the genotype.

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.

Langerhans cell histiocytosis and multiple reticulohistiocytomas in a patient with TAR syndrome: An association not previously described.

We describe a patient with thrombocytopenia-absent radius (TAR) syndrome, multisystemic Langerhans cell histiocytosis and multiple reticulohistiocytomas. A mutational study by massive sequencing identified the Val600Glu (V600E) BRAF mutation in the Langerhans cell histiocytosis lesions, but no molecular alterations were found in the reticulohistiocytoma lesions. The concomitant presence in the same patient of more than one type of histiocytosis from two different groups recognized in the most recent Histiocyte Society classification is an extremely rare event. Our case is the first reported case of multisystemic Langerhans cell histiocytosis and multiple reticulohistiocytomas in a patient with TAR syndrome.

Acute myeloid leukemia in a patient with thrombocytopenia with absent radii: A case report and review of the literature.

Thrombocytopenia with absent radii (TAR) syndrome is a rare congenital disorder characterized by low platelet counts of various severity, bilateral absent radii but thumbs are usually present. TAR syndrome is not generally associated with bone marrow failure or malignancy. Janus kinase-2, myeloproliferative leukemia protein, and calreticulin are not mutated in TAR patients. Only four cases of leukemia were reported in TAR patients in the literature: three acute myeloid leukemia (AML) and one acute lymphoblastic leukemia. Of the three cases of AML found in TAR patient, only one was reported in an adult. We report a case of myelodysplastic syndrome progressing to AML with calreticulin driver mutation in an adult male with TAR syndrome who was successfully treated with hematopoietic allogeneic stem cell transplantation.

Impact of genetic variants on haematopoiesis in patients with thrombocytopenia absent radii (TAR) syndrome.

Thrombocytopenia absent radii (TAR) syndrome is clearly defined by the combination of radial aplasia and reduced platelet counts. The genetics of TAR syndrome has recently been resolved and comprises a microdeletion on Chromosome 1 including the RBM8A gene and a single nucleotide polymorphism (SNP) either at the 5' untranslated region (5'UTR) or within the first intron of RBM8A. Although phenotypically readily diagnosed after birth, the genetic determination of particular SNPs in TAR syndrome harbours valuable information to evaluate disease severity and treatment decisions. Here, we present clinical data in a cohort of 38 patients and observed that platelet counts in individuals with 5'UTR SNP are significantly lower compared to patients bearing the SNP in intron 1. Moreover, elevated haemoglobin values could only be assessed in patients with 5'UTR SNP whereas white blood cell count is unaffected, indicating that frequently observed anaemia in TAR patients could also be SNP-dependent whereas leucocytosis does not correlate with genetic background. However, this report on a large cohort provides an overview of important haematological characteristics in TAR patients, facilitating evaluation of the various traits in this disease and indicating the importance of genetic validation for TAR syndrome.

Upper Limb Dimelia.

A patient with upper limb dimelia including a double scapula, humerus, radius, and ulna, 11 metacarpals and digits (5 on the superior side, 6 on the inferior side) was treated with a simple amputation of the inferior limb resulting in cosmetic improvement and maintenance of range of motion in the preserved limb. During the amputation, the 2 limbs were found to be anatomically separate except for the ulnar nerve, which, in the superior limb, bifurcated into the sensory branch of radial nerve in the inferior limb, and the brachial artery, which bifurcated into the radial artery. Each case of this rare anomaly requires its own individually carefully planned surgical procedure.

The Pathogenesis of Radial Ray Deficiency in Thrombocytopenia-Absent Radius (TAR) Syndrome.

The genetic basis of thrombocytopenia-absent radius (TAR) syndrome was recently identified to be related to the RBM8A gene. The encoded protein (known as the Y14 protein) is widely expressed in human cells (including osteoblasts) and plays several essential intracellular functions. Hence, the pathogenesis of radial ray deficiency in thrombocytopeniaabsent radius syndrome remains a mystery. The current paper reviews the pathogenesis of the clinical features of thrombocytopenia-absent radius syndrome and offers a hypothesis of pathogenesis through attenuation of the Fibroblast Growth Factor 8 signal in the mesoderm because of an increased degradation of the Fibroblast Growth Factor Receptor 1.

Chronic radial head dislocation caused by a rare solitary osteochondroma of the proximal radius in a child: a case report and review of the literature.

BACKGROUND: Osteochondroma is the most common benign bone tumor of the upper limbs that occurs during the developmental phase of children. Solitary epiphyseal enchondromas can be usually found in the humeral capitellum, and the proximal ulna of the elbow. CASE PRESENTATION: Herein, we report the case of a 12-year-old boy of Han ethnicity with a developmental radial head dislocation with a progressive radius deformities, caused by a solitary osteochondroma which originated from the proximal metaphysis of the radius. Obvious complaints and limitations were present. After tumor excision was performed, radial head reduction and deformity correction were achieved through a biplanar shortening osteotomy of the radius. CONCLUSIONS: After a follow-up of 18 months, the child remained asymptomatic and regained a full range of motion. Radiographic study revealed satisfactory reduction of the radial head with no recurrence of the osteochondroma.

Lábio duplo bilabial / Bilabial double lip

O lábio duplo é uma entidade rara, com poucos relatos, que geralmente afeta o lábio superior, sendo de fácil diagnóstico clínico. Pode ter origem congênita ou adquirida. O tratamento cirúrgico é indicado por queixa estética ou funcional, de simples execução. Este relato refere-se a um caso de lábio duplo bilabial em paciente do sexo masculino de 14 anos, em que foi realizada correção cirúrgica por motivação estética do paciente, com ótimo resultado dos pontos de vista estético e funcional.

There are few published reports on double lip, a rare entity that usually affects the upper lip, and that is easily diagnosed clinically. It may be congenital or acquired. Surgical treatment is indicated for aesthetic or functional complaints, and is simple to implement. This report describes a case of bilabial double lip in a 14-year-old male patient, in whom surgical correction was carried out for aesthetic reasons, with excellent aesthetic and functional results.

Braquiotoracoplastia em Z no tratamento do contorno corporal após perda ponderal maciça / Z brachiothoracoplasty for body contouring after massive weight loss

INTRODUÇÃO: A braquioplastia trata as deformidades dos membros superiores. A toracoplastia lateral visa o tratamento do torso superior. As braquioplastias, toracoplastias e também as braquiotoracoplastias em Z têm sido utilizadas no Hospital Estadual de Sapopemba no tratamento das deformidades dos membros superiores e terço superior do tórax. Objetivo: Propõe-se descrever as modificações na técnica cirúrgica resultando na braquiotoracoplastia em Z e analisar a casuística e os resultados obtidos, no tratamento das deformidades da região lateral do tórax. MÉTODO: Foram submetidos à braquiotoracoplastia e toracoplastia lateral 31 pacientes. A demarcação foi feita em posição ortostática, e os membros superiores abduzidos em 90o. Iniciou-se pela demarcação da braquioplastia, em duplo fuso, prolongando-se de maneira modificada a demarcação, seguindo pela linha axilar anterior em direção ao sulco inframamário em forma de Z. RESULTADOS: Todos os pacientes referiram melhora do contorno da região e não houve queixas quanto ao posicionamento da cicatriz. DISCUSSÃO: O procedimento da braquiotoracoplastia em Z atual consiste em estender a linha de incisão da face medial do braço, passando proximalmente à axila e continuando pela linha axilar média até o sulco mamário. Ocorreu a melhora do contorno da região dorsal e das dobras cutâneas da região torácica lateral. CONCLUSÃO: A braquiotoracoplastia em Z e a toracoplastia lateral têm a grande vantagem de eliminar a cicatriz circunferencial no torso superior, promovendo a melhoria do contorno dessa região por meio da ressecção cutânea tanto no sentido craniocaudal, como anteroposterior.

INTRODUCTION: Brachioplasty treats deformities of the upper limbs. Lateral thoracoplasty treats the upper torso. Brachioplasties, thoracoplasties, and brachiothoracoplasties have been performed with Z-plasty for deformities of the upper limbs and upper third of the chest, in the Sapopemba State Hospital. Objective: We describe modifications of surgical technique for the performance of Z brachiothoracoplasty, and evaluate the results of treatment of deformities of the lateral chest. METHOD: Thirty-one Patients underwent brachiothoracoplasty and lateral thoracoplasty. The demarcation was made with the patient upright, and the upper limbs abducted at 90º. Marking for brachioplasty was performed using a double-ellipse, to lengthen the modified demarcation along the anterior axillary line toward the inframammary crease in a Z shape. RESULTS: All patients reported an improvement in the contour of the region, and there were no complaints regarding the positioning of the scar. DISCUSSION: Z brachiothoracoplasty consists of extending the incision line on the medial aspect of the arm, passing proximally to the axilla, and continuing through the midaxillary line to the inframammary crease. There was an improvement in the contour of the dorsal region and the skin folds of the lateral thoracic region. CONCLUSION: Z brachiothoracoplasty and lateral thoracoplasty have the great advantage of eliminating a circumferential scar on the upper torso, thereby improving the contour of the region through skin resection in both the craniocaudal and anteroposterior directions.

Prenatal diagnosis and post-mortem examination in a fetus with thrombocytopenia-absent radius (TAR) syndrome due to compound heterozygosity for a 1q21.1 microdeletion and a RBM8A hypomorphic allele: a case report.

BACKGROUND: Thrombocytopenia-absent radius syndrome is a rare autosomal recessive disorder characterized by megakaryocytic thrombocytopenia and longitudinal limb deficiencies mostly affecting the radial ray. Most patients are compound heterozygotes for a 200 kb interstitial microdeletion in 1q21.1 and a hypomorphic allele in RBM8A, mapping in the deleted segment. At the moment, the complete molecular characterization of thrombocytopenia-absent radius syndrome is limited to a handful of patients mostly ascertained in the pediatric age CASE PRESENTATION: We report on a fetus with bilateral upper limb deficiency found at standard prenatal ultrasound examination. The fetus had bilateral radial agenesis and humeral hypo/aplasia with intact thumbs, micrognathia and urinary anomalies, indicating thrombocytopenia-absent radius syndrome. Molecular studies demonstrated compound heterozygosity for the 1q21.1 microdeletion and the RBM8A rs139428292 variant at the hemizygous state, inherited from the mother and father, respectively CONCLUSION: The molecular information allowed prenatal diagnosis in the following pregnancy resulting in the birth of a healthy carrier female. A review was carried out with the attempt to the trace the fetal ultrasound presentation of thrombocytopenia-absent radius syndrome and discussing opportunities for second-tier molecular studies within a multidisciplinary setting.

New insights into the genetic basis of TAR (thrombocytopenia-absent radii) syndrome.

Thrombocytopenia with absent radii (TAR) syndrome is a rare disorder combining specific skeletal abnormalities with a reduced platelet count. Rare proximal microdeletions of 1q21.1 are found in the majority of patients but are also found in unaffected parents. Recently it was shown that TAR syndrome is caused by the compound inheritance of a low-frequency noncoding SNP and a rare null allele in RBM8A, a gene encoding the exon-junction complex subunit member Y14 located in the deleted region. This finding provides new insight into the complex inheritance pattern and new clues to the molecular mechanisms underlying TAR syndrome. We discuss TAR syndrome in the context of abnormal phenotypes associated with proximal and distal 1q21.1 microdeletion and microduplications with incomplete penetrance and variable expressivity.

Sirenomelia: four further cases with discussion of associated upper limb defects.

Sirenomelia, also known as the 'mermaid malformation/syndrome', is a rare, serious congenital anomaly characterized by variable degrees of fusion of the lower limbs and associated severe malformations of the lower vertebral and genitourinary systems. In this report, we describe a series of African patients with sirenomelia. We present the clinical and radiological features of four black South African patients and illustrate some of the rarer associated abnormalities, which include asymmetrical upper limb defects, not confined to the radial ray. The clinical phenotypic overlap between caudal dysgenesis, VACTERL association and sirenomelia in our patients is highlighted, lending support to the theory that these entities may be different manifestations of a single pathogenic process.

Textiloma mimicking a pericardial hydatid cyst: a case report.

Textiloma is unusual and uncommon diagnosis which is rarely considered. We report the case of a 13 year-old patient with Holt-Oram syndrome. He was operated on in 2006 for ostium secundum atrial septal defect. The postoperative course was uneventful until 2010 when the child presented paroxysmal dyspnoea. Investigations revealed para-cardiac mass which was thought to be a hydatid cyst, but operative findings showed textiloma.

Whorled hairless nevus of the scalp, linear hyperpigmentation, and telangiectatic nevi of the lower limbs: a novel variant of the "phacomatosis complex".

The term "phacomatosis" refers to a growing number of sporadic genetic skin disorders characterized by the combination of two or more different nevi and possibly resulting from non-allelic twin spotting. While phacomatosis pigmentovascularis (PPV) and pigmentokeratotica represent the most common patterns, some patients do not fit with either condition and are temporarily classified as unique phenotypes. We report on an 8-year-old boy with striking right hemihypoplasia, resulting in limb asymmetry and fixed dislocation of right hip. Skin on the affected side showed three distinct nevi: (i) A whorled, hairless nevus of the scalp in close proximity with (ii) epidermal hyperpigmentation following lines of Blaschko on the neck and right upper limb, and (iii) multiple telangiectatic nevi of the right lower limb and hemiscrotum. Didymosis atricho-melanotica was proposed for the combination of adjacent patchy congenital alopecia and linear hyperpigmentation, while phacomatosis atricho-pigmento-vascularis appears to define the entire cutaneous phenotype, thus implying the involvement of three neighboring loci influencing the development of distinct constituents of the skin. Given the striking asymmetry of the observed phenotype, the effect of mosaicism (either genomic or functional) for a mutation in a single gene with pleiotropic action and influenced by the lateralization pattern of early development cannot be excluded.

Congenital cleft scapula with type V ulnar longitudinal deficiency: case report.

A rare case of malformation of the scapula, a cleft scapula, has been encountered. This case is associated with type V ulnar longitudinal deficiency of the ipsilateral upper limb. The scapular malformation has been treated with fusion of the 2 parts, with good aesthetic and functional outcome. In this report, the clinical, radiological, and surgical findings, as well as the surgical technique, are described. Four cases of similar malformation have been reported in the literature, and they were described as complete scapular duplication. According to the current findings and reinterpretation of the previous reports, this malformation is better called cleft scapula rather than scapular duplication.

Congenital longitudinal deficiency.

Radial and ulnar longitudinal deficiencies are the 2 most common types of congenital longitudinal deficiencies of the arm, with radial deficiency being 3 to 4 times more common. They are a spectrum of abnormalities, ranging from mild deficiency of the digits to complete loss of one-half the forearm, wrist, and fingers. Radial longitudinal deficiency is associated with a number of medical syndromes that require a comprehensive medical evaluation, while ulnar longitudinal deficiency (ULD) is associated with other musculoskeletal anomalies. Both conditions have a high incidence of ipsilateral thumb abnormalities. Wrist and forearm procedures, such as soft tissue distraction and centralization, are more often required in radial longitudinal deficiencies than in ULD. Elbow involvement can occur in both conditions but is more frequent and often more severe in ULD.

Embryology of the upper limb.

An increased understanding of embryogenesis has advanced our fundamental knowledge of limb anomalies. Animal models with similar limb patterning have been used to dissect and manipulate crucial signaling centers that affect limb development and orientation. Experimental embryologists can produce limb anomalies that are similar to the human phenotype encountered in clinical practice. The evaluating physician must possess a basic comprehension of embryogenesis and limb formation to comprehend congenital limb anomalies and to communicate relevant knowledge to the family. This Current Concepts article is intended to provide an update of limb development that is germane to the clinical scenario.