Antoine Hamel

Mesomelia-Synostoses Syndrome Results from Deletion of SULF1 and SLCO5A1 Genes at 8q13

Mesomelia-synostoses syndrome (MSS) or mesomelic dysplasia with acral synostoses Verloes-David-Pfeiffer type is a rare autosomal-dominant disorder characterized by mesomelic limb shortening, acral synostoses, and multiple congenital malformations. So far, five patients in four unrelated families have been reported worldwide with MMS. By using whole-genome oligonucleotide array CGH, we have identified an interstitial deletion at 8q13 in all patients. The deletions vary from 582 Kb to 738 Kb in size, but invariably encompass only two genes: SULF1, encoding the heparan sulfate 6-O-endosulfatase 1, and SLCO5A1, encoding the solute carrier organic anion transporter family member 5A1. SULF1 acts as a regulator of numerous growth factors in skeletal embryonic development whereas the function of SLCO5A1 is yet unknown. Breakpoint sequence analyses performed in two families showed nonrecurrent deletions. Real-time quantitative RT-PCR analysis showed the highest levels of SULF1 transcripts in human osteoblasts and cartilage whereas SLCO5A1 was highly expressed in human fetal and adult brain and heart. Our results strongly suggest that haploinsufficiency of SULF1 contributes to this mesomelic chondrodysplasia, highlighting the critical role of endosulfatase in human skeletal development. Codeletion of SULF1 and SLCO5A1--which does not result from a low-copy repeats (LCRs)-mediated recombination event in at least two families--was found in all patients, so we suggest that haploinsufficiency of SULF1 combined with haploinsufficiency of SLCO5A1 (or the altered expression of a neighboring gene through position effect) could be necessary in the pathogenesis of MSS.

Mutations in FAM111B Cause Hereditary Fibrosing Poikiloderma with Tendon Contracture, Myopathy, and Pulmonary Fibrosis

Congenital poikiloderma is characterized by a combination of mottled pigmentation, telangiectasia, and epidermal atrophy in the first few months of life. We have previously described a South African European-descent family affected by a rare autosomal-dominant form of hereditary fibrosing poikiloderma accompanied by tendon contracture, myopathy, and pulmonary fibrosis. Here, we report the identification of causative mutations in FAM111B by whole-exome sequencing. In total, three FAM111B missense mutations were identified in five kindreds of different ethnic backgrounds. The mutation segregated with the disease in one large pedigree, and mutations were de novo in two other pedigrees. All three mutations were absent from public databases and were not observed on Sanger sequencing of 388 ethnically matched control subjects. The three single-nucleotide mutations code for amino acid changes that are clustered within a putative trypsin-like cysteine/serine peptidase domain of FAM111B. These findings provide evidence of the involvement of FAM111B in congenital poikiloderma and multisystem fibrosis.

Autosomal Dominant Spondylocarpotarsal Synostosis Syndrome : Phenotypic Homogeneity and Genetic Heterogeneity

Spondylocarpotarsal synostosis syndrome (SCT) (OMIM 272460), originally thought to be a failure of normal spine segmentation, is characterized by progressive fusion of vertebras and associates unsegmented bars, scoliosis, short stature, carpal and tarsal synostosis. Cleft palate, sensorineural or mixed hearing loss, joint limitation, clinodactyly, and dental enamel hypoplasia are variable manifestations. Twenty‐five patients have been reported. Thirteen affected individuals were siblings from six families and four of these families were consanguineous. In four of those families, Krakow et al. [Krakow et al. (2004) Nat Genet 36:405–410] found homozygosity or compound heterozygosity for mutations in the gene encoding FLNB. This confirmed autosomal recessive inheritance of the disorder. We report on two new patients (a mother and her son) representing the first case of autosomal dominant inheritance. These patients met the clinical and radiological criteria for SCT and did not present any features which could exclude this diagnosis. Molecular analysis failed to identify mutations in NOG and FLNB. SCT is therefore, genetically heterogeneous. Both dominant and autosomal recessive forms of inheritance should be considered during genetic counseling.

Protein-altering MYH3 variants are associated with a spectrum of phenotypes extending to spondylocarpotarsal synostosis syndrome

Spondylocarpotarsal synostosis syndrome (SCT) is a rare Mendelian disorder (OMIM #272460) characterized by prenatal vertebral fusion, scoliosis, short stature and carpal and tarsal synostosis. SCT is typically known as an autosomal recessive disease caused by variants in the FLNB gene. The genetic basis of the rarer cases of vertical transmissions remains unknown. In two independent families with symptoms related to autosomal dominant SCT, we identified – by exome sequencing – two protein-altering variants in the embryonic myosin heavy chain 3 (MYH3) gene. As MYH3 variants are also associated with distal arthrogryposis (DA1, DA2A, DA2B) and autosomal dominant multiple pterygium syndromes (MPS), the present study expands the phenotypic spectrum of MYH3 variants to autosomal dominant SCT. Vertebral, carpal and tarsal fusions observed in both families further confirm that MYH3 plays a key role in skeletal development.

Expanding the clinical spectrum of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis due to FAM111B mutations

BackgroundHereditary Fibrosing Poikiloderma (HFP) with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP [MIM 615704]) is a very recently described entity of syndromic inherited poikiloderma. Previously by using whole exome sequencing in five families, we identified the causative gene, FAM111B (NM_198947.3), the function of which is still unknown. Our objective in this study was to better define the specific features of POIKTMP through a larger series of patients.MethodsClinical and molecular data of two families and eight independent sporadic cases, including six new cases, were collected.ResultsKey features consist of: (i) early-onset poikiloderma, hypotrichosis and hypohidrosis; (ii) multiple contractures, in particular triceps surae muscle contractures; (iii) diffuse progressive muscular weakness; (iv) pulmonary fibrosis in adulthood and (v) other features including exocrine pancreatic insufficiency, liver impairment and growth retardation. Muscle magnetic resonance imaging was informative and showed muscle atrophy and fatty infiltration. Histological examination of skeletal muscle revealed extensive fibroadipose tissue infiltration. Microscopy of the skin showed a scleroderma-like aspect with fibrosis and alterations of the elastic network. FAM111B gene analysis identified five different missense variants (two recurrent mutations were found respectively in three and four independent families). All the mutations were predicted to localize in the trypsin-like cysteine/serine peptidase domain of the protein. We suggest gain-of-function or dominant-negative mutations resulting in FAM111B enzymatic activity changes.ConclusionsHFP with tendon contractures, myopathy and pulmonary fibrosis, is a multisystemic disorder due to autosomal dominant FAM111B mutations. Future functional studies will help in understanding the specific pathological process of this fibrosing disorder.

Mesomelic dysplasia with acral synostoses Verloes–David–Pfeiffer type: Follow‐up study documents progressive clinical course

Verloes–David–Pfeiffer mesomelia‐synostoses syndrome is an autosomal‐dominant form of mesomelic dysplasia comprising typical acral synostoses combined with ptosis, hypertelorism, palatal abnormality, CHD, and ureteral anomalies. Since the original reports in 1995, two other patients have been described with this syndrome, one of them the patient reported in 1998 by Day‐Salvatore. In this article, we report on the follow‐up of some of the original cases and review the literature. We confirm that the Verloes–David–Pfeiffer syndrome (VDPS) is a progressive skeletal disorder that despite repeated corrective surgical intervention leads to severe limb deformities. No mutations were detected in the FLNB gene. To date, the cause and the pathogenesis of VDPS remain unknown. The latter is characterized in this study as a syndromic type of skeletal dysplasia because besides congenital malformations and multiple acromelic synostoses arising prenatally, VDPS manifests in postnatal life as a severe osteochondrodysplasia.

Electrochemical skin conductance for quantitative assessment of sweat function: Normative values in children

Highlights • Sudomotor function can be assessed through the measurement of electrochemical skin conductance using the Sudoscan system.• This test is easily done in children and normative data are provided.• It can be helpful in case of small fibre neuropathy in children.

G.P.156

Hereditary Fibrosing Poikiloderma (HFP) with tendon contracture and pulmonary fibrosis has been described in a South-African family with autosomal dominant inheritance by Khumalo et al. in 2006. Recently, we confirmed the existence of this new syndrome by reporting four additional cases and identified the causative gene called FAM111B (NM_198947.3) by whole exome sequencing. Here we report the clinical and molecular data of seven independent patients: four males and three females (ages 3–38). Key features consist of: (i) congenital poikiloderma, hypotrichosis, hypohidrosis; (ii) muscle contractures in particular triceps surae and/or biceps brachii muscle contractures; (iii) progressive muscular weakness with a proximal and distal pattern and (iv) progressive pulmonary fibrosis. Muscle MRI showed extensive fatty infiltration confirmed by muscle biopsy. Histological examination of skeletal muscle revealed a partial loss of muscle tissue associated with extensive fibrofatty tissue infiltration regardless of age. There was no indication of denervation, necrosis, or inflammation. Microscopy of the skin showed a sclerodermiform aspect with fibrosis and alterations of the elastic network. FAM111B gene analysis identified five different missense variants (two mutations were shared respectively by three and two patients). All the mutations were predicted to localize in the trypsin-like cysteine/serine peptidase domain of the protein. We suggest gain of function or dominant negative mutations resulting in FAM111B enzymatic activity changes. Functional studies are ongoing to better understand the pathophysiology of this entity. In conclusion, HFP with tendon contracture, myopathy and pulmonary fibrosis, a phenotypically recognisable syndrome, is caused by autosomal dominant mutations in FAM111B gene. These findings provide genetic evidence for a new pathogenetic pathway for muscle impairment.