Adducted Thumbs Research Articles

Paraplejía espástica hereditaria ligada al cromosoma X por mutación en el gen L1CAM: presentación de tres casos del síndrome CRASH

Hereditary spastic paraplegia (HSP) is a set of neurodegenerative clinical features characterised by a progressive loss of strength in the lower limbs together with spasticity. It is the result of an axonal lesion in the corticospinal tracts. Type 1, known as SPG1, is the most common form of X-linked HSP. This is produced by a mutation in the gene for the L1 cell adhesion molecule (L1CAM). SPG1 presents with CRASH syndrome (corpus callosum hypoplasia, retardation, adducted thumbs, spasticity and hydrocephalus). We report the cases of three males, two brothers and a cousin (on the mother's side), with clinical features including intellectual disability, spastic paraparesis, long tract signs, facial dysmorphism and adducted thumbs. Neuroimaging revealed agenesis of the corpus callosum and ventriculomegaly in all three of them. Neurophysiological and metabolic studies were normal. The genetic study evidenced a specific mutation of the L1CAM gene (Xq28) in all three cases. We describe the clinical-radiological findings in three males with CRASH syndrome due to mutation c.516G>A in exon 5 of the L1CAM gene. These seem to be the first cases reported in Spain, according to the current literature. We recommend suspecting this syndrome when spastic paraparesis, intellectual disability and adducted thumbs are associated.

Mutation in the sixth immunoglobulin domain of L1CAM is associated with migrational brain anomalies.

Objective:To describe the phenotype of a patient with classical features of X-linked L1 syndrome associated with novel brain malformations.Methods:Diagnostic analysis included physical and dysmorphology examinations, MRI of the brain, and exome sequencing of the family trio.Results:We report a 2.5-year-old boy with developmental delay, dysmorphic facies, and adducted thumbs. MRI of the brain showed a truncated corpus callosum and periventricular heterotopias associated with polymicrogyria (PMG). Variant segregation analysis with exome sequencing discovered a novel maternally derived hemizygous variant in exon 14 of the L1CAM gene (c.1759 G>C; p.G587R).Conclusions:This novel L1CAM mutation was located in the protein's sixth immunoglobin domain and involved glycine-587, a key residue in the structure of L1CAM because of its interactions with lysine-606, which indicates that any mutation at this site would likely affect the secondary structure and function of the protein. The replacement of the small nonpolar glycine residue with a large basic arginine would have an even more dramatic result. The presentation of periventricular nodular heterotopias with overlying PMG is very uncommon, and its association with L1CAM may provide insight into other similar cases. Furthermore, this presentation indicates the important role that L1CAM plays in neuronal migration and brain development and extends the phenotype associated with L1CAM-associated disorders.

MG-113 A case ‘out of the blue’

Objective To delineate a retrospective diagnosis in a case of severe fixed encephalopathy. Case description Propositus was a male child, first born to 3rd degree consanguineous South Asian parents. Pregnancy, delivery and clinical examination at birth were normal. During the first months of life, he had generalised hypotonia with spontaneous dystonic leg extension spasm and frequent vomiting. All the developmental milestones were delayed, he never sat alone or never attained speech. From his available photographs head size appeared to be small, and esotropia and adducted thumbs were noted. Magnetic resonance imaging of his brain showed delayed myelination. He also had grade II/III gastro oesophageal reflux evidenced by GER Scintigraphy. Other investigations including routine biochemical and haematological parameters, neurometabolic screening and electrophysiological analysis were within normal limits. He was treated as spastic cerebral palsy from another centre without much improvement to the symptoms. Child expired at the age of 2 years followed by an attack of pneumonia; clinical exome test was performed later from his DNA. Results Long read sequencing revealed a homozygous, pathogenic novel variation p. Val112ProFSTer8 resulting from the deletion of exons 5–8 of CYB5R3 gene, associated with recessive hereditary methemoglobinemia (RHM) type II, which could explain the clinical profile. This large deletion was validated by polymerase chain reaction and carrier status of parents was established. Conclusion Type II RHM is a rare condition, with less than 100 cases reported worldwide. 1. Cyanosis is an invariable presenting feature and important clinical clue to methemoglobinemia. There was no history or documentation of cyanosis in our case. In the absence/failure to elicit the sign in children with severe encephalopathy, possibility of RHM might get overlooked. 2. Majority of the reported mutations in RHM type II are point mutations with two prior documentations of single exonic deletion. Ours is the first family with the largest deletion of multiple exons of CYB5R3 gene, thus expanding the genotype spectrum.

G.P.121 - A novel neuromuscular form of glycogen storage disease type IV characterized by spinal stiffness, arthrogrypotic features, and rare polyglucosan bodies in muscle biopsy

Glycogen storage disease type 4 (GSD-IV) is an autosomal recessive disorder characterized by the deposition of an amylopectin-like polysaccharide called polyglucosan in all tissues, associated with mutations in the gene encoding for the glycogen branching enzyme (GBE1). The clinical spectrum is wide ranging from isolated non-progressive hepathopathy, neuromuscular disorders with variable age of onset, to the adult polyglucosan body disease (APBD). Two infantile neuromuscular presentations consisting of fetal akinesia deformation sequence, or hypotonia, muscle wasting, and fatal neuronal involvement with cardiomyopathy have been described. Here we report on a 3-year-old boy, born from healthy consanguineous Turkish parents, presenting with neonatal hypotonia, poor sucking, and arthrogrypotic features (neck pterygium, adducted thumbs). He presented motor delay, important neck and periscapular muscle wasting, hip flexion contractures, hyperlordosis, and rigid spine. Brain MRI was normal and muscle MRI revealed thin neck muscular bulk, and alteration of trapezius, sternocleidomastoid, pectoral and erector spine muscles. A muscle biopsy performed at 3 years revealed the presence of only two muscle fibers harboring small PAS positive inclusions that remained undigested after alpha-amylase treatment. Electron microscopy confirmed the presence of storage material composed by filamentous structures. GBE1 gene sequencing revealed two pathogenic heterozygous variants (c.708G>C and c.2052+1G>A). With our report we describe a phenotype never of GSD type 4. The identification of polyglucosan bodies in muscle by light and electron microscopy was pivotal in orientating the molecular diagnosis toward GBE1 gene.

Is Kurjak Antenatal Neurodevelopmental Test Ready for Routine Clinical Application? Bucharest Consensus Statement

ABSTRACTBackgroundWhile two-dimensional ultrasound (2D US) is used only for the assessment of fetal startles and general movements, introduction of Kurjak antenatal neurodevelopmental test (KANET) by four-dimensional ultrasound (4D US) enabled assessment of not only movements but also some signs used in postnatal neurological assessment like cranial sutures, head circumference and finger movements of the hand for the detection of neurological thumb (adducted thumb in the clenched feast). Overall impression on general movement called by Prechtl ‘Gestalt perception’ is also a part of KANET assessment. These parameters cannot be assessed by 2D US, and according to our opinion they are making the difference enabling more accurate and functionally more reliable assessment of the young and immature CNS.After Osaka standardization of KANET has been published, many studies on fetal behavior from different centers using this method have been conducted and published. Although there is lack of long-term follow-up of children who were assessed by KANET as fetuses, some conclusions on the usage of KANET test in clinical practice can be made. There are still inconclusive results of prenatal neurological assessment using KANET test in fetuses with borderline scores, although it was revealed that negative predictive value of the test as well as inter-observer reliability were satisfactory and acceptable.ConclusionIt can be concluded that KANET test can be used in everyday clinical practice for the follow-up of fetuses at neurological risk with the strong recommendation for strict and reliable multidisciplinary postnatal follow-up till the corrected age of at least 3 years and longer whenever appropriate. This will enable to make better correlation of prenatal KANET scores with postnatal neurodevelopmental outcomes.How to cite this articleStanojevic M, Antsaklis P, Kadic AS, Predojevic M, Vladareanu R, Vladareanu S, Neto RM. Is Kurjak Antenatal Neurodevelopmental Test Ready for Routine Clinical Application? Bucharest Consensus Statement. Donald School J Ultrasound Obstet Gynecol 2015;9(3):260-265.

Prenatal Three-Dimensional Ultrasound Detection of Adducted Thumbs in X-Linked Hydrocephaly: Two Case Reports with Molecular Genetic Studies.

X-linked hydrocephaly is a rare sex-linked genetic recessive condition occurring in 1/30,000 deliveries. Adduction of thumbs and mental retardation are additional associated clinical findings. We describe two cases of X-linked hydrocephaly with associated adducted thumbs that were diagnosed prenatally with the combined use of three-dimensional (3D) ultrasound and fetal blood sampling for cytogenetic and molecular analyses. This report suggests that 3D ultrasound can facilitate the identification of adducted thumbs in fetuses affected by X-linked hydrocephaly and supports evaluation of the fetal hands as an integral part of the ultrasound anatomical assessment in male fetuses with hydrocephaly secondary to aqueductal stenosis.

Hand Surgery for Dystrophic Epidermolysis Bullosa

Epidermolysis bullosa (EB) is a group of inherited, mechanobullous disorders caused by mutations in various structural proteins in the skin. The manifestation of these disorders in the hand is of digital contractures and pseudosyndactyly or "cocoon hands," causing significant functional impairment.Our preferred surgical treatment of these patients involves separation of the digits from the palm by releasing the finger flexion contractures and separating them, primarily the adducted thumb. However, recurrence is common. Our hypothesis was that functional improvement is gained irrespective of recurrence of contractures. We retrospectively evaluated 4 patients, 2 male and 2 female, whose average age was 11 years, treated surgically by the separation of all their digits and by coverage with skin grafts. The follow-up period was between 1 and 3½ years. Partial recurrence of the deformity was observed in all patients. Recurrence was more pronounced in the nondominant hand, especially between the digits and of flexion contractures, but did not preclude the use of precision or oppositional pinch at final follow-up. The patient with the longest follow-up has been referred for revision surgery to gain further release of contractures.Significant rehabilitation goals were achieved in all 4 patients after surgery. After 6 months, both of the younger patients were measured for finger dexterity, which showed lower scores than the norm, although this was felt to be dependent on which daily manual activities they were more familiar with. These tests could not have been performed before surgery. All patients and families felt the effort was worthy. Separating the thumb and straightening the digits was found to be significant, yet the indication for separating all the digits is debatable. The need for revision surgery, to maintain the digit function, is clear. Level 4, case series.

L1CAM whole gene deletion in a child with L1 syndrome

L1 syndrome is a group of overlapping, X-linked disorders caused by mutations in L1CAM. Clinical phenotypes within L1 syndrome include X-linked hydrocephalus with stenosis of the aqueduct of sylvius (HSAS); mental retardation, adducted thumbs, shuffling gait, and aphasia (MASA) syndrome; spastic paraplegia type 1; and agenesis of the corpus callosum. Over 200 mutations in L1CAM have been reported; however, only a few large gene deletions have been observed. We report on a 4-month-old male with a de novo whole gene deletion of L1CAM presenting with congenital hydrocephalus, aqueductal stenosis, and adducted thumbs. Initial failure of L1CAM gene sequencing suggested the possibility of a whole gene deletion of L1CAM. Further investigation through chromosome microarray analysis showed a 62Kb deletion encompassing the first exon of the PDZD4 gene and the entire L1CAM gene. Investigations into genotype-phenotype correlations have suggested that mutations leading to truncated or absent L1 protein cause more severe forms of L1 syndrome. Based on the presentation of the proband and other reported patients with whole gene deletions, we provide further evidence that L1CAM whole gene deletions result in L1 syndrome with a severe phenotype, deletions of PDZD4 do not cause additional manifestations, and that X-linked nephrogenic diabetes insipidus reported in a subset of patients with large L1CAM deletions results from the loss of AVPR2.

A chromosome 1q44 deletion in a 4-month-old girl; The first report in Korea.

The deletion of the distal long arm of chromosome 1 is associated with a characteristic facial appearance and a pattern of associated malformations. Characteristic manifestations include a round face with prominent 'cupid's bow' and downturned corners of the mouth, thin vermilion borders of lips, a long upper lip with a smooth philtrum, a short and broad nose, epicanthal folds, apparently low-set ears, micrognathia, microcephaly, abnormal hands and feet, variable cardiac or genital anomalies, moderate to severe mental retardation, and growth retardation. Using fluorescent in situ hybridization (FISH) analysis to map precisely the deletion, we present a case of chromosome 1q44 deletion with craniofacial characteristics, multiple congenital anomalies, and growth and psychomotor retardation. In comparison with other reported cases of 1q43-44 deletion, the subject does not show hydrocephalus, seizure, syn- or polydactyly of hands, and a urogenital anomaly. However, an arachnoid cyst, pinpoint dimple on the midline of the forehead, a right-sided supernumerary nipple and auricular pit, polydactyly of the right foot, adducted thumb, and flexion restriction of the proximal interphalangeal joint with a simian line in both hands were observed additionally.

P.1.21 Congenital muscular dystrophy phenotype with excess of neuromuscular spindles in a 5-year old girl

We report on a 5-year-old girl who presents with an association between a congenital muscular dystrophy, and very peculiar abnormalities on muscle biopsy. The girl was the second child from healthy non related Algerian parents and has now a healthy younger brother. Family history was not informative. Weak fetal movements and polyhydramnios were noticed during the pregnancy. At birth, the child presented with moderate hypotonia, pectus excavatum, mild dysmorphia, club foot, adducted thumbs and generalized proximal arthrogryposis. The girl showed normal intelligence. She had acquired a sitting position, but no ambulation or standing position. She presented with severe shoulder, hip and knee contractures contrasting with distal hyperlaxity. In addition, there was severe cyphosis and a mild scoliosis. Weakness was axial, proximal and distal, facial musculature being mostly spared. A mild right strabismus was noted. The child also presents with mitral valve dysplasia with insufficiency that required surgical correction. There was no need for ventilatory support. Whole Body Muscular MRI demonstrated a diffuse hypotrophy of muscles without selective pattern of involvement. No abnormalities suggestive of collagen VI-related myopathy or other known myopathies were identified. Immunolabelling of collagen VI in cultured fibroblasts demonstrated the absence of secretion and intracytoplasmic retention, but no mutation was detected in the COL6A1-3 genes. Muscle biopsy especially showed a dense conjunctive tissue harboring numerous ovoid formations corresponding to the neuromuscular spindle. There were only few “extrafusal” muscle fibres. No necrotic regenerative fibers were observed. To our knowledge, this pathological aspect on the biopsy has only been described in patients with HRAS mutations (test ongoing), but in contrast with the previously reported cases, the child does not present organomegaly or hypertrophic cardiomegaly and is still living at five years of age.

Neuropathological review of 138 cases genetically tested for X-linked hydrocephalus: evidence for closely related clinical entities of unknown molecular bases

L1 syndrome results from mutations in the L1CAM gene located at Xq28. It encompasses a wide spectrum of diseases, X-linked hydrocephalus being the most severe phenotype detected in utero, and whose pathophysiology is incompletely understood. The aim of this study was to report detailed neuropathological data from patients with mutations, to delineate the neuropathological criteria required for L1CAM gene screening in foetuses by characterizing the sensitivity, specificity and positive predictive value of the cardinal signs, and to discuss the main differential diagnoses in non-mutated foetuses in order to delineate closely related conditions without L1CAM mutations. Neuropathological data from 138 cases referred to our genetic laboratory for screening of the L1CAM gene were retrospectively reviewed. Fifty-seven cases had deleterious L1CAM mutations. Of these, 100 % had hydrocephalus, 88 % adducted thumbs, 98 % pyramidal tract agenesis/hypoplasia, 90 % stenosis of the aqueduct of Sylvius and 68 % agenesis/hypoplasia of the corpus callosum. Two foetuses had L1CAM mutations of unknown significance. Seventy-nine cases had no L1CAM mutations; these were subdivided into four groups: (1) hydrocephalus sometimes associated with corpus callosum agenesis (44 %); (2) atresia/forking of the aqueduct of Sylvius/rhombencephalosynapsis spectrum (27 %); (3) syndromic hydrocephalus (9 %), and (4) phenocopies with no mutations in the L1CAM gene (20 %) and in whom family history strongly suggested an autosomal recessive mode of transmission. These data underline the existence of closely related clinical entities whose molecular bases are currently unknown. The identification of the causative genes would greatly improve our knowledge of the defective pathways involved in these cerebral malformations.

Adducted thumbs: A clinical clue to genetic diagnosis

Adducted thumbs are an uncommon congenital malformation. It can be an important clinical clue in genetic syndromes, e.g. the L1 syndrome.A retrospective survey was performed including patients with adducted thumbs referred to the Department of Clinical Genetics between 1985 and 2011 by perinatologists, (child) neurologists or paediatricians, in order to evaluate current knowledge on the genetic etiology of adducted thumbs. Twenty-five patients were included in this survey. Additional features were observed in 88% (22/25). In 25% (4/16) of the patients with adducted thumbs and congenital hydrocephalus L1CAM gene mutations were identified. One patient had a mosaic 5p13 duplication. Recommendations are made concerning the evaluation and genetic workup of patients with adducted thumbs.

Atypical amyoplasia congenita in an infant with Leigh syndrome: A mitochondrial cause of severe contractures?

Amyoplasia congenita is a distinct form of arthrogryposis with characteristic features including internally rotated and adducted shoulders, extended elbows, flexion, and ulnar deviation of the wrists, and adducted thumbs. Fetal hypokinesia, secondary to a variety of genetic conditions, neuromuscular disorders, and environmental agents, is associated with contractures. In order to increase our understanding of the phenotypic spectrum associated with SURF 1 deficiency, a common cause of mitochondrial respiratory chain complex IV deficiency and Leigh syndrome, we describe a now 6-year-old boy who presented in the neonatal period with amyoplasia congenita. His development was normal until age 10.5 months, at which time he developed severe hypotonia and choreoathetosis following an episode of viral gastroenteritis. Following the onset of neurological symptoms, he gradually developed severe kyphosis and lower limb contractures. Blood and cerebrospinal fluid lactate levels were elevated and head imaging showed characteristic features of Leigh syndrome. He was found to harbor two pathogenic heterozygous mutations in the SURF 1 gene. In this case, mitochondrial dysfunction and the resultant energy deficiency may have played a role in causing abnormal neuronal development during embryogenesis, causing arthrogryposis. A variety of mitochondrial respiratory chain complex deficiencies have been associated with contractures of varying severity. Therefore, mitochondrial disorders should be considered in the differential diagnosis of neonatal arthrogryposis, especially if other characteristic findings such as lactic acidemia or basal ganglia abnormalities are present.

Diagnostic difficulties in the floppy neonate

<h3>Background</h3> A term baby with no significant maternal, family or antenatal history was born in poor condition necessitating resuscitation which included intubation, cardiac compressions and subsequent admission to our NICU. On admission, he was noted to be markedly hypotonic, with absent gag and suck reflexes and displayed minimal spontaneous movements. Initially felt to be hypoxic ischaemic encephalopathy, he had a normal cranial ultrasound and normal EEG/CFM findings. <h3>Progress and management</h3> Invasive ventilation continued for 7 days, before extubation to BiPAP and later CPAP. He had frequent apnoeic and bradycardic episodes, including 2 respiratory arrests requiring resuscitation. A total of 76 days of respiratory support was needed. Full examination found a large, dolichocephalic head, adducted thumbs, cryptorchidism and a heart murmur (ECHO revealed a VSD, PDA and pericardial effusion). Neurological signs persisted, with hypotonia noted to be more significant in the upper versus lower limbs. Numerous sub-speciality reviews were undertaken, including genetics, neurology and metabolic. An abundance of investigations were performed which included MRI (structurally normal, immature brain), barium swallow, renal imaging, metabolic screen, karyotyping and EMG. No specific abnormalities were identified, and conditions such as Prader-willi, Soto9s, SMA and myotonic dystrophy were excluded. <h3>Outcome and issues</h3> He was eventually discharged from NICU at 100 days old, with NG feeds as he was felt to have an unsafe swallow, and with no formal diagnosis being made. Unfortunately, he was readmitted to hospital 3 weeks after discharge, with increased work of breathing and decreased oxygen saturations, with investigations revealing a rhinovirus and parainfluenza virus positive pneumonia. This episode required PICU admission for ventilation and ultimate tracheostomy placement. In view of continued hypotonia without diagnosis, a decision was made to perform a muscle biopsy. This revealed a diagnosis of myotubular myopathy. Our patient was eventually discharged home being non-invasive positive pressure ventilation dependant and with palliative care input. This case highlights the complexities of ascertaining a diagnosis in the hypotonic neonate, and the need for involvement of multiple members of the paediatric and sub-speciality teams.

Hydrocephalus with Hirschsprung disease: Severe end of X‐linked hydrocephalus spectrum

L1CAM molecule is a cell adhesion molecule in nervous and enteric systems and is responsible for X-linked hydrocephalus (XLH) spectrum, which is a rare condition with severe congenital hydrocephalus, dysgenesis of the corpus callosum, intellectual disability, spasticity, and adducted thumbs. Several cases of XLH accompanied by Hirschsprung disease (HSCR) have been reported in the literature, but whether HSCR results from a gain-of-function mutation in cases with XLH, i.e., a neomorphic mutation, or the severe end of the L1CAM mutation spectrum remains unclear. The present patient was a Japanese boy with severe congenital hydrocephalus with aqueductal stenosis as well as hypoplasia of the corpus callosum. HSCR had been confirmed by a biopsy. A mutation analysis of the L1CAM gene showed a C61T mutation in exon 1, resulting in a truncating nonsense mutation at amino acid position 21 and producing an extremely short protein that was unlikely to interact with other proteins. These findings suggest that XLH-HSCR represents the severe end of the XLH spectrum, rather than a neomorphic mutation. A thorough abdominal investigation to rule out HSCR should be considered in patients with XLH accompanied by severe constipation.

Association of X‐linked hydrocephalus and Hirschsprung disease: Report of a new patient with a mutation in the L1CAM gene

X-linked hydrocephalus (XLH) has an incidence of 1/30,000 male births and is characterized by intellectual disability, spastic paraplegia, adducted thumbs, and agenesis of corpus callosum, and/or corticospinal tract. The great proportion of cases is ascribed to loss of function mutations of L1CAM gene. Hirschsprung disease (HSCR) is characterized by the absence of ganglion cells in the submucosal and myenteric plexuses along a variable portion of the intestinal tract and has incidence of about 1/5,000. Although with several genes involved in its pathogenesis, the major HSCR gene is the RET proto-oncogene. To date only a few patients have been reported with both phenotypes and mutations in the L1CAM gene. In this report, we describe a new patient with concurrent XLH and HSCR. L1CAM mutational screening showed the presence of the G698R hemizygous mutation, which is a deleterious substitution affecting a key residue necessary for the correct folding of the protein. Moreover, the patient also carried the transcriptional enhancer RET mutation (c.73 + 9277T > C) in heterozygosis. We speculate that both the RET enhancer variant, and the L1CAM mutation may act in combination to produce the enteric phenotype, probably with the participation of other still unidentified molecular events. While it is obvious that additional studies are necessary to further delineate the association between XLH and HSCR in the presence of L1CAM mutations, the documentation of this new patient reinforces the role of this gene acting either in a direct or indirect way in the pathogenesis of Hirschsprung disease.

Exome sequencing of two patients in a family with atypical X‐linked leukodystrophy

We encountered a family with two boys similarly showing brain atrophy with reduced white matter, hypoplasia of the brain stem and corpus callosum, spastic paralysis, and severe growth and mental retardation without speaking a word. The phenotype of these patients was not compatible with any known type of syndromic leukodystrophy. Presuming an X-linked disorder, we performed next-generation sequencing (NGS) of the transcripts of the entire X chromosome. A single lane of exome NGS in each patient was sufficient. Six potential mutations were found in both affected boys. Two missense mutations, including c.92T>C (p.V31A) in L1CAM, were potentially pathogenic, but this remained inconclusive. The other four could be excluded. Because the patients did not show adducted thumbs or hydrocephalus, the L1CAM change in this family can be interpreted as different scenarios. Personal genome analysis using NGS is certainly powerful, but interpretation of the data can be a substantial challenge requiring a lot of tasks.

Musculocontractural Ehlers-Danlos Syndrome (former EDS type VIB) and adducted thumb clubfoot syndrome (ATCS) represent a single clinical entity caused by mutations in the dermatan-4-sulfotransferase 1 encoding CHST14 gene

We present clinical and molecular findings of three patients with an EDS VIB phenotype from two consanguineous families. The clinical findings of EDS kyphoscoliotic type (EDS type VIA and B) comprise kyphoscoliosis, muscular hypotonia, hyperextensible, thin and bruisable skin, atrophic scarring, joint hypermobility and variable ocular involvement. Distinct craniofacial abnormalities, joint contractures, wrinkled palms, and normal urinary pyridinoline ratios distinguish EDS VIB from EDS VIA. A genome-wide SNP scan and sequence analyses identified a homozygous frameshift mutation (NM_130468.2:c.145delG, NP_569735.1:p.Val49*) in CHST14, encoding dermatan-4-sulfotransferase 1 (D4ST-1), in two Turkish siblings. Subsequent sequence analysis of CHST14 identified a homozygous 20-bp duplication (NM_130468.2:c.981_1000dup, NP_569735.1:p.Glu334Glyfs*107) in an Indian patient. Loss-of-function mutations in CHST14 were recently reported in adducted thumb–clubfoot syndrome (ATCS). Patients with ATCS present similar craniofacial and musculoskeletal features as the EDS VIB patients reported here, but lack the severe skin manifestations. By identifying an identical mutation in patients with EDS VIB and ATCS, we show that both conditions form a phenotypic continuum. Our findings confirm that the EDS-variant associated with CHST14 mutations forms a clinical spectrum, which we propose to coin as “musculocontractural EDS” and which results from a defect in dermatan sulfate biosynthesis, perturbing collagen assembly.

Molecular characterization of a new patient with a non‐recurrent inv dup del 2q and review of the mechanisms for this rearrangement

We report on newborn baby with microcephaly, facial anomalies, congenital heart defects, hypotonia, wrist contractures, long fingers, adducted thumbs, and club feet. Cytogenetic studies revealed an inverted duplication with terminal deletion (inv dup del) of 2q in the patient and a paternal 2qter deletion polymorphism. Microsatellite markers demonstrated that the inv dup del was maternal in origin and intrachromosomal. Intra or interchromosomal rearrangements may cause this aberration either by a U-type exchange (end-to-end fusion), an unequal crossover between inverted repeats (non-allelic homologous recombination: NAHR), or through breakage-fusion-bridge (BFB) cycles leading to a sister chromatid fusion by non-homologous end joining (NHEJ). A high-resolution oligo array-CGH (244 K) defined the breakpoints and did not detect a single copy region with a size exceeding 12.93 Kb in the fusion site. The size of the duplicated segment was 38.75 Mb, extending from 2q33.1 to 2q37.3 and the size of the terminal deletion was 2.85 Mb in 2q37.3. Our results indicate that the inv dup del (2q) is likely a non-recurrent chromosomal rearrangement generated by a NHEJ mechanism. The major clinical characteristics associated with this 2q rearrangement overlap with those commonly found in patients with 2q duplication reported in the literature.

Técnica para elaborar férulas de mano en isopor y madera terciada

A technique has been developed in Paraguay for making hand splints from styrofoam, plywood and paper. Sheet styrofoam is cut to fit the palmar surface of the forearm and glued to plywood to provide strength. Pieces of paper are glued over the styrofoam and then painted with oil paint. Velcro is used to make straps. The splints made thus far include a resting hand splint for a flaccid hand, a finger-spreader splint for a spastic hand, a resting hand splint for a patient with shortening of the wrist flexors, a thumb support splint for a weak but functional thumb, a thumb positioning splint for a non-functional adducted thumb and a resting hand splint for a person with rheumatoid arthritis to prevent ulnar deviation The advantages and disadvantages of this technique are compared with those of other alternative splinting materials (PVC, metal, plaster of Paris bandage, leather, bamboo and polypropylene). The major advantages of this technique are low cost, high adaptability to the individual hand, use of techniques known by local artisans, low-cost tools and ease of repair or modification. The major disadvantages are non-availability of materials in some places, need to develop new relationships between therapists and local artisans and difficulty with thorough disinfecting. Future applications of the techniques for making dynamic hand splints and foot splints are discussed. This technique appears to have promise in low to middle income countries such as Paraguay.