Identification of Compound Heterozygous Variants in LRP4 Demonstrates That a Pathogenic Variant outside the Third ß-Propeller Domain Can Cause Sclerosteosis.

Sclerosteosis is a high bone mass disorder, caused by pathogenic variants in the genes encoding sclerostin or LRP4. Both proteins form a complex that strongly inhibits canonical WNT signaling activity, a pathway of major importance in bone formation. So far, all reported disease-causing variants are located in the third ß-propeller domain of LRP4, which is essential for the interaction with sclerostin. Here, we report the identification of two compound heterozygous variants, a known p.Arg1170Gln and a novel p.Arg632His variant, in a patient with a sclerosteosis phenotype. Interestingly, the novel variant is located in the first ß-propeller domain, which is known to be indispensable for the interaction with agrin. However, using luciferase reporter assays, we demonstrated that both the p.Arg1170Gln and the p.Arg632His variant in LRP4 reduced the inhibitory capacity of sclerostin on canonical WNT signaling activity. In conclusion, this study is the first to demonstrate that a pathogenic variant in the first ß-propeller domain of LRP4 can contribute to the development of sclerosteosis, which broadens the mutational spectrum of the disorder.

Looking for new anabolic treatment from rare diseases of bone formation.

Bone remodelling is a complex mechanism regulated by osteoclasts and osteoblasts and perturbation of this process leads to the onset of diseases, which may be characterised by altered bone erosion or formation. In this review, we will describe some bone formation-related disorders as sclerosteosis, van Buchem disease, hypophosphatasia and Camurati-Engelmann disease. In the past decades, the research focused on these rare disorders offered the opportunity to understand important pathways regulating bone formation. Thus, the identification of the molecular defects behind the etiopathology of these diseases will open the way for new therapeutic approaches applicable also to the management of more common bone diseases including osteoporosis.

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.

Symbrachydactyly: Finger nubbins are not always amniotic band disruption sequence.

Although congenital hand anomalies associated with finger nubbins may be produced by amniotic band disruption sequence (ABDS), symbrachydactyly should be considered in the differential diagnosis. ABDS usually affects more than one limb but symbrachydactyly largely is limited to one upper extremity, and has five distinct clinical presentations: short-fingered, atypical cleft, monodactylous, peromelic, and a forearm proximal transverse deficiency. This article discusses the diagnosis of symbrachydactyly compared with ABDS and outlines plans for managing patients with symbrachydactyly.

A Recurrent Mosaic Mutation in SMO, Encoding the Hedgehog Signal Transducer Smoothened, Is the Major Cause of Curry-Jones Syndrome.

Curry-Jones syndrome (CJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. Cerebellar medulloblastoma has been described in a single affected individual; in another, biopsy of skin lesions showed features of trichoblastoma. The combination of asymmetric clinical features, patchy skin manifestations, and neoplastic association previously led to the suggestion that this could be a mosaic condition, possibly involving hedgehog (Hh) signaling. Here, we show that CJS is caused by recurrent somatic mosaicism for a nonsynonymous variant in SMO (c.1234C>T [p.Leu412Phe]), encoding smoothened (SMO), a G-protein-coupled receptor that transduces Hh signaling. We identified eight mutation-positive individuals (two of whom had not been reported previously) with highly similar phenotypes and demonstrated varying amounts of the mutant allele in different tissues. We present detailed findings from brain MRI in three mutation-positive individuals. Somatic SMO mutations that result in constitutive activation have been described in several tumors, including medulloblastoma, ameloblastoma, and basal cell carcinoma. Strikingly, the most common of these mutations is the identical nonsynonymous variant encoding p.Leu412Phe. Furthermore, this substitution has been shown to activate SMO in the absence of Hh signaling, providing an explanation for tumor development in CJS. This raises therapeutic possibilities for using recently generated Hh-pathway inhibitors. In summary, our work uncovers the major genetic cause of CJS and illustrates strategies for gene discovery in the context of low-level tissue-specific somatic mosaicism.

From disease to treatment: from rare skeletal disorders to treatments for osteoporosis.

During the past 15 years there has been an expansion of our knowledge of the cellular and molecular mechanisms regulating bone remodeling that identified new signaling pathways fundamental for bone renewal as well as previously unknown interactions between bone cells. Central for these developments have been studies of rare bone disorders. These findings, in turn, have led to new treatment paradigms for osteoporosis some of which are at late stages of clinical development. In this article, we review three rare skeletal disorders with case descriptions, pycnodysostosis and the craniotubular hyperostoses sclerosteosis and van Buchem disease that led to the development of cathepsin K and sclerostin inhibitors, respectively, for the treatment of osteoporosis.

Transverse soft tissue distraction preceding separation of complex syndactylies.

UNLABELLED: Various surgical techniques are described for separation of syndactylies leading to good results. However, the use of standard techniques is limited in complex syndactylies with extensive bony fusion and tight soft tissues. The aim of this study was to assess the outcomes of a two-stage procedure involving progressive soft tissue distraction prior to syndactyly release. Between 1996 and 2012 we treated 168 complex syndactylies with this technique. The main indications were syndactylies in Apert syndrome. The digits were distracted through an external fixator at 0.5 mm/day. Distraction of 15-25 mm was achieved. Soft tissue distraction provided additional skin, a wider nail matrix and more bone in the form of callus. Thus subsequent modelling of the fingertips was improved, especially if they were closely fused. This technique facilitates treatment of complex cases and improves aesthetic outcome. LEVEL OF EVIDENCE: Therapeutic IV.

Fraser syndrome with laryngeal webs: Report of two cases and a review of the literature.

Fraser syndrome is a rare genetic disorder characterized by cryptophthalmos, syndactyly and laryngeal atresia. Although laryngeal webs occur uncommonly, they are the main cause of death in the first week of life in these patients. In this paper, we report two cases of Fraser syndrome with laryngeal webs. One of them was a twelve-year-old girl, primarily diagnosed with a supraglottic laryngeal web. In the course of treatment, a second web was also identified at the level of vocal cords, which is to our knowledge the first case of Fraser syndrome with two laryngeal webs in different levels.

Amniotic band syndrom at Bobo Dioulasso university teaching hospital (Burkina-Faso): about two cases.

Amniotic band syndrome is a rare congenital disorder. The authors report the first cases documented at Souro Sanou University Hospital in Bobo-Dioulasso (CHUSS) in 2 male new borns. The malformations found at birth, were worn only on limbs and were in the form of skin furrow necking with a major lymphedema downstream. In both cases, the constriction furrow at member pelvic was associated with a club foot and a pseudosyndactyly in one case. Surgical treatment consisted of a section of the constrictor ring and a Z-plasty. The functional outcome was satisfactory with the acquisition of a plantar support for both children. Through these two observations, epidemiological, diagnostic, and particularities of the management of this condition are discussed in the Burkina-Faso.

Postburn contractures of the hand.

Several functionally limiting sequelae can follow deep thermal injury to the hand. Despite appropriate initial management, contractures are common. Whereas acute burn care is often managed by multidisciplinary, specialized burn units, postburn contractures may be referred to hand surgeons, who should be familiar with the patterns of burn contracture and nonsurgical and operative options to improve function and expected outcomes. The most common and functionally limiting sequelae are contractures of the webspace, hand, and digits. Webspace contractures and postburn syndactyly are managed with scar excision and local soft tissue rearrangement or skin grafting. The burn claw hand presents as extension contracture of the metacarpophalangeal joints and flexion contractures of the proximal interphalangeal joints. The mainstays of management of these contractures include complete surgical excision of scar tissue and resurfacing of the resultant soft tissue defect, most commonly with full-thickness skin grafts. If scar contracture release results in major exposure of the tendons or joints, distant tissue transfer may be required. Early motion and rehabilitative modalities are essential to prevent initial contracture formation and recontracture after surgical release.

Síndrome de CLOVES / CLOVES syndrome

El síndrome de CLOVES fue recientemente descrito en el 2007 por Sapp et al. y se caracteriza por la presencia de un sobre crecimiento lipomatoso de predominio troncal, malformaciones vasculares, nevo epidérmico y malformaciones esqueléticas, como escoliosis y variables alteraciones espinales. Estos fenómenos determinan su nombre, CLOVES, Congenital, Lipomatous, Overgrowth, Vascular malformations, Epidermal nevi,Skeletal/Scoliosis/Spinal abnormalities. Se produce por una alteración de origen genético, esporádico, pero no necesariamente heredable, secundario a una mutación somática en el periodo embrionario. Se describe un caso clínico de paciente portador de esta patología.

CLOVES syndrome was recently described in 2007 by Sapp et al. and is characterized by the presence of lipomatous growth mainly on trunk, vascular malformations, epidermal nevi, and skeletal malformations such as scoliosis and variables spinal abnormalities. These phenomena determine its name, CLOVES, congenital lipomatous overgrowth, Vascular malformations, Epidermal nevi, Skeletal / Scoliosis / Spinal abnormalities. It is produced by a genetic alteration, sporadic, but not necessarily heritable, CLOVES secondary to a somatic mutation in embryonic period. We described a clinical case of a patient with this condition.

Microdeleción 2q23.1 y hallazgos sindrómicos / Microdeletion 2q23.1 and syndromic findings

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Treatment of congenital syndactyly of the fingers.

BACKGROUND: Syndactyly or webbed fingers is one of the most common congenital malformations of the upper extremities, but it comprises few new cases annually. The purpose of treatment is to enhance hand function. METHOD: The article is based on current text books and literature searches in PubMed as well as the authors' clinical experience within this field. RESULTS: The purpose of surgical treatment is to separate the fingers and reconstruct a webspace. It is difficult to indicate exact treatment results because of large variations in the extent of the deformity. For syndactyly involving only soft tissue (simple syndactyly), a good functional result is achieved with a less than 10% risk of complications. Syndactyly where also the bones have fused (complex syndactyly) or where there is additional bone formation between two digital rays (complicated syndactyly), gives a poorer functional outcome and a higher risk of complications. Gradual stretching of the tissue using a distraction device enables separation of fingers one was previously reluctant to separate. INTERPRETATION: It should be possible to expect safe separation with a good and independent function of the fingers with surgical treatment. The parents should be informed that the surgical treatment is a reconstructive procedure that may require secondary corrections.

Displasias ectodérmicas: revisión clínica y molecular / Ectodermal Dysplasias: A Clinical and Molecular Review

Las displasias ectodérmicas son un amplio grupo de trastornos hereditarios que se caracterizan por la alteración de estructuras derivadas del ectodermo. Aunque algunos de estos síndromes poseen características específicas, determinados rasgos clínicos son comunes en muchos de ellos. De modo general, se diferencian 2 grupos de trastornos: uno caracterizado por la aplasia o hipoplasia de los derivados ectodérmicos, que fracasan en su desarrollo y diferenciación por la ausencia de señales recíprocas específicas entre ectodermo y mesénquima, y otro en el que la característica más llamativa es la queratodermia palmoplantar, que se presenta en asociación con otras manifestaciones cuando se afectan otros epitelios altamente especializados. En las últimas décadas se ha logrado identificar el gen responsable en al menos 30 entidades, permitiéndonos entender los mecanismos patogénicos y su correlación con la clínica (AU)

The ectodermal dysplasias are a large group of hereditary disorders characterized by alterations of structures of ectodermal origin. Although some syndromes can have specific features, many of them share common clinical characteristics. Two main groups of ectodermal dysplasias can be distinguished. One group is characterized by aplasia or hypoplasia of ectodermal tissues, which fail to develop and differentiate because of a lack of reciprocal signaling between ectoderm and mesoderm, the other has palmoplantar keratoderma as its most striking feature, with additional manifestations when other highly specialized epithelia are also involved. In recent decades, the genes responsible for at least 30 different types of ectodermal dysplasia have been identified, throwing light on the pathogenic mechanisms involved and their correlation with clinical findings (AU)

Congenital cytomegalovirus infection and finger anomaly.

Congenital cytomegalovirus (CMV) infection is the most common cause of intrauterine infection. It affects the central nervous system and causes microcephaly, hydrocephalus, mental retardation, hearing disorder, chorioretinitis and rarely finger anomalies. We present the case of a 4-month-old girl with an agenesis of the middle finger and syndactyly of the fourth and fifth fingers as a result of congenital CMV; this is the first such case in the literature. Here, congenital CMV infection is examined along with finger anomalies.

Colgajo en alas: una alternativa para la reconstrucción de las neosindactilias cicatriciales postquemaduras pediátricas / Use of wing flaps to correct web space sequels of hand burns in children

Background: With finger growth, sequels of burns in children located in the palm of the hand and web spaces tend to form syndactylyes, which can limit the opening of fingers. These sequels need a reconstructive surgical approach. Aim: To describe the use of flap wings for syndactylyes occurring after burns in children and analyze its surgical results. Materials and methods: Retrospective review of 50 medical records of children undergoing surgery using the flap wings technique in the hand, collecting demographic, clinical and surgical variables. Results: In the 50 children analyzed, 69 surgical procedures using the flap wing technique were performed, corresponding to 1.38 procedures per patient. The burn occurred at 2.2 +/- 3.0 years of age. The surgical procedures were carried out 6.7 +/- 4.5 years after the burn episode, at 8.9 ± 4.9 years of age. Wing flaps were located predominantly in second and third web spaces. Average operating time was 72.2 +/- 34 minutes. Only three (6 percent) children had minor complications. Conclusions: The proposed surgical technique is a useful surgical approach for the burned web space of the hand, with a low proportion of complications.

Introducción: Con el crecimiento de los dedos, las secuelas postquemaduras infantiles localizadas a nivel de la palma y comisuras tenderán a formar neosindactilias cicatriciales, lo que puede limitar la apertura de los dedos, necesitando un abordaje quirúrgico reconstructivo. Objetivo: Describir la técnica "colgajo en alas" en las neosindactilias cicatriciales post quemaduras en niños y, analizar los resultados de las cirugías en que se ha utilizado este procedimiento. Materiales y Métodos: Estudio descriptivo retrospectivo, de revisión aleatoria de 50 fichas de niños sometidos a cirugía con colgajo en alas en mano, de un total de 980 cirugías de mano realizadas en COANIQUEM por cualquier técnica, entre los años 2000-2009, recolectando variables demográficas, clínicas y quirúrgicas. Resultados: Se realizan 69/50 = 1,38 cirugías por paciente usando la técnica de colgajo en alas. La quemadura se produjo en promedio a los 2,2 +/- 3,0 años; la cirugía se realizó a los 6,7 +/- 4,5 años de evolución y a los 8,9 +/- 4,9 años de edad. El tiempo de cirugía en promedio duró 72,2 +/- 34,7 minutos; los colgajos en alas se localizaron con mayor frecuencia en segunda y tercera comisura. Sólo el 6 por ciento de los niños presentó complicaciones menores (3/50). Conclusiones: La técnica quirúrgica propuesta, constituye una herramienta útil en el abordaje de las neosindactilias cicatriciales postquemaduras, de gran versatilidad de uso hacia palmar, dorsal o comisuras contiguas y baja proporción de complicaciones.

[Palmar and plantar keloid in a black African male]. / Chéloïdes palmaire et plantaire chez un Noir africain.

The keloid scar is a fibrous skin tumor, intradermal, and exuberant. It is commonly found on the glabrous skin. The keloid of the palms and soles are rare. Small series are reported in English literature. The authors report a case of large keloids located on both palms and soles, within a context of keloid disease, in a man of 37 years. On the left hand, the keloid scar caused a partial syndactyly IV-V. Large keloid tumors occupied the inner edge and, weight-bearing areas of both feet. These tumors rendered wearing of shoes impossible and interfered with walking. The treatment consisted of total excision of palmar and plantar keloid tumors. The residual defects were covered by a total skin graft taken from the suprapubic region. The results were satisfactory aesthetically, functionally and psychosocially.