Neonatal mucolipidosis type II alpha/beta due to compound heterozygosity for a known and novel GNPTAB mutation, and a concomitant heterozygous change in SERPINF1 inherited from the mother.

We report on a newborn with IUGR, rhizomelic dwarfism, and suspected chondrodysplasia punctata. At birth, OI was suspected; however, a skeletal survey suggested ML II alpha/beta. Sequencing revealed compound heterozygosity for a reported pathogenic and novel but expected pathogenic GNPTAB variant. Molecular testing for autosomal recessive OI identified a SERPINF1 variant.

Aortic Disease Presentation and Outcome Associated With ACTA2 Mutations.

BACKGROUND: ACTA2 mutations are the major cause of familial thoracic aortic aneurysms and dissections. We sought to characterize these aortic diseases in a large case series of individuals with ACTA2 mutations. METHODS AND RESULTS: Aortic disease, management, and outcome associated with the first aortic event (aortic dissection or aneurysm repair) were abstracted from the medical records of 277 individuals with 41 various ACTA2 mutations. Aortic events occurred in 48% of these individuals, with the vast majority presenting with thoracic aortic dissections (88%) associated with 25% mortality. Type A dissections were more common than type B dissections (54% versus 21%), but the median age of onset of type B dissections was significantly younger than type A dissections (27 years versus 36 years). Only 12% of aortic events were repair of ascending aortic aneurysms, which variably involved the aortic root, ascending aorta, and aortic arch. Overall, cumulative risk of an aortic event at age 85 years was 0.76 (95% confidence interval, 0.64-0.86). After adjustment for intrafamilial correlation, sex and race, mutations disrupting p.R179 and p.R258 were associated with significantly increased risk for aortic events, whereas p.R185Q and p.R118Q mutations showed significantly lower risk of aortic events compared with other mutations. CONCLUSIONS: ACTA2 mutations are associated with high risk of presentation with an acute aortic dissection. The lifetime risk for an aortic event is only 76%, suggesting that additional environmental or genetic factors play a role in expression of aortic disease in individuals with ACTA2 mutations.

Novel SMAD3 Mutation in a Patient with Hypoplastic Left Heart Syndrome with Significant Aortic Aneurysm.

Aneurysms-osteoarthritis syndrome (AOS) caused by haploinsufficiency of SMAD3 is a recently described cause of syndromic familial thoracic aortic aneurysm and dissection (TAAD). We identified a novel SMAD3 mutation in a patient with hypoplastic left heart syndrome (HLHS) who developed progressive aortic aneurysm requiring surgical replacement of the neoaortic root, ascending aorta, and proximal aortic arch. Family screening for the mutation revealed that his father, who has vascular and skeletal features of AOS, and his brother, who is asymptomatic, also have the pathogenic mutation. This is the first case report of a SMAD3 mutation in a patient with hypoplastic left heart syndrome. This case highlights the importance of genetic testing for known causes of aneurysm in patients with congenital heart disease who develop aneurysmal disease as it may significantly impact the management of those patients and their family members.

Similarity of geleophysic dysplasia and Weill-Marchesani syndrome.

The acromelic dysplasias comprise short stature, hands and feet, and stiff joints. Three disorders are ascribed to this group, namely Weill-Marchesani syndrome, geleophysic dysplasia, and acromicric dysplasia, although similar in phenotype, can be distinguished clinically. Weill-Marchesani syndrome, on the basis of microspherophakia and ectopia lentis; geleophysic dysplasia by progressive cardiac valvular thickening, tracheal stenosis, and/or bronchopulmonary insufficiency, often leading to early death. Microspherophakia has not been reported previously in geleophysic dysplasia. Mutations in FBN1, ADAMTS10, or ADAMTS17 cause Weill-Marchesani syndrome by disrupting the microfibrillar environment, while geleophysic dysplasia is associated with enhanced TGF-ß signaling mediated through mutations in FBN1 or ADAMTSL2. We studied a 35-year-old woman with geleophysic dysplasia, with short stature, small hands and feet, limitation of joint mobility, mild skin thickening, cardiac valvular disease, restrictive pulmonary disease, and microspherophakia. Sequencing of ADAMTSL2 demonstrated two changes: IVS8-2A>G consistent with a disease-causing mutation, and IVS14-7G>A with potential to generate a new splice acceptor site and result in aberrant mRNA processing. The unaffected mother carries only the IVS8-2A>G transition providing evidence that the two changes are in trans-configuration in our patient.

Active holography in InGaAs/InP quantum-well microcavities.

High-efficiency dynamic holography at 1.55 µm is demonstrated in a broad-area InGaAs/InP multiple-quantum-well vertical microcavity. The design places single quantum wells at the cavity antinodes, reducing mode-pulling and enabling a higher Q-factor. The device is pumped by interference fringes through an amorphous mirror that is transparent to a high-energy hologram writing pulse at a wavelength of 1.06 µm. Optically pumped free carrier gratings are probed by a tunable 1.5 µm laser in a four-wave mixing configuration. Diffraction efficiency into both m=±1 diffraction orders of 35% (70% total) has been obtained with a phase grating contribution approaching the maximum π phase shift by combining absorption bleaching with asymmetric Fabry-Perot reflectivity. The diffracted signal exhibits rise/fall times of 5 ns, demonstrating the high speed capabilities of this device.

Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue.

We present two patients with Atelosteogenesis Type I (AO type I) caused by two novel Filamin B (FLNB) mutations affecting the same FLNB residue: c.542G > A, predicting p.Gly181Asp and c.542G > C, predicting p.Gly181Arg. Both children had typical manifestations of AO type I, with severe rhizomelic shortening of the extremities, limited elbow and knee extension with mild webbing, pectus excavatum, broad thumbs with brachydactyly that was most marked for digits 3-5, dislocated hips and bilateral talipes equinovarus. Facial features included proptosis, hypertelorism, downslanting palpebral fissures, cleft palate, and retromicrognathia. The clinical course of one child was influenced by airway instability and bronchopulmonary dysplasia that complicated intubation and prevented separation from ventilator support. Respiratory insufficiency with tracheal hypoplasia, laryngeal stenosis, and pulmonary hypoplasia have all been described in patients with AO type I and we conclude that compromised pulmonary function is a major contributor to morbidity and mortality in this condition.

Ectopia lentis as the presenting and primary feature in Marfan syndrome.

Marfan syndrome (MFS) is a multisystem connective tissue disorder with primary involvement of the ocular, cardiovascular, and skeletal systems. We report on eight patients, all presenting initially with bilateral ectopia lentis (EL) during early childhood. These individuals did not have systemic manifestations of MFS, and did not fulfill the revised Ghent diagnostic criteria. However, all patients had demonstratable, disease-causing missense mutations in the FBN1 gene. Based on molecular results, cardiovascular imaging was recommended and led to the identification of mild aortic root changes in seven of the eight patients. The remaining patient had mitral valve prolapse with a normal appearing thoracic aorta. The findings presented in this paper validate the necessity of FBN1 gene testing in all individuals presenting with isolated EL. As we observed, these individuals are at increased risk of cardiovascular complications. Furthermore, we also noted that the majority of our patient cohort's mutations occurred in the 5' portion of the FBN1 gene, and were found to affect highly conserved cysteine residues, which may indicate a possible genotype-phenotype correlation. We conclude that in patients with isolated features of EL, FBN1 mutation analysis is necessary to aid in providing prompt diagnosis, and to identify patients at risk for potentially life-threatening complications. Additionally, knowledge of the type and location of an FBN1 mutation may be useful in providing further clinical correlation regarding phenotypic progression and appropriate medical management.

A loss of function mutation in the COL9A2 gene causes autosomal recessive Stickler syndrome.

Stickler syndrome is characterized by ocular, auditory, skeletal, and orofacial abnormalities. We describe a family with autosomal recessive Stickler syndrome. The main clinical findings consisted of high myopia, vitreoretinal degeneration, retinal detachment, hearing loss, and short stature. Affected family members were found to have a homozygous loss-of-function mutation in COL9A2, c.843_c.846 + 4del8. A family with autosomal recessive Stickler syndrome was previously described and found to have a homozygous loss-of-function mutation in COL9A1. COL9A1, COL9A2, and COL9A3 code for collagen IX. All three collagen IX α chains, α1, α2, and α3, are needed for formation of functional collagen IX molecule. In dogs, two causative loci have been identified in autosomal recessive oculoskeletal dysplasia. This dysplasia resembles Stickler syndrome. Recently, homozygous loss-of-function mutations in COL9A2 and COL9A3 were found to co-segregate with the loci. Together the data from the present study and the previous studies suggest that loss-of-function mutations in any of the collagen IX genes can cause autosomal recessive Stickler syndrome.

Genotype-phenotype correlation in DTDST dysplasias: Atelosteogenesis type II and diastrophic dysplasia variant in one family.

Mutations in diastrophic dysplasia sulfate transporter (DTDST) cause a spectrum of autosomal recessive chondrodysplasias. In decreasing order of severity, they include processes designated as achondrogenesis type IB (ACG-1B), atelosteogenesis type II (AO2), diastrophic dysplasia (DTD), diastrophic dysplasia variant (DTDv), and recessively inherited multiple epiphyseal dysplasia (rMED). This is the first report of an extended family with unequivocally distinct phenotypes on the DTDST spectrum. Two siblings have DTDv and their first cousin had AO2. They all share the common Finnish mutation (IVS1 + 2C>T). The two patients with DTDv have the previously reported R279W extracellular domain missense mutation. The second mutation in the patient with AO2 is c.172delA, a deletion of one nucleotide causing a previously unreported frameshift mutation. This is the first published case of an individual with a frameshift mutation combined with the Finnish mutation. These three patients provide an opportunity, in concert with a review of previous literature, to further examine the genotype-phenotype correlation of DTDST. Analysis suggests that, while the DTDST family of disorders contains at least seven different conditions, mutations in the DTDST gene, in fact, appear to cause a phenotypic continuum. Furthermore, DTDST genotype alone is an imperfect predictor of clinical severity along this continuum.

De novo ACTA2 mutation causes a novel syndrome of multisystemic smooth muscle dysfunction.

Smooth muscle cells (SMCs) contract to perform many physiological functions, including regulation of blood flow and pressure in arteries, contraction of the pupils, peristalsis of the gut, and voiding of the bladder. SMC lineage in these organs is characterized by cellular expression of the SMC isoform of α-actin, encoded by the ACTA2 gene. We report here on a unique and de novo mutation in ACTA2, R179H, that causes a syndrome characterized by dysfunction of SMCs throughout the body, leading to aortic and cerebrovascular disease, fixed dilated pupils, hypotonic bladder, malrotation, and hypoperistalsis of the gut and pulmonary hypertension.

Absence of TGFBR2 mutations in patients with spontaneous spinal CSF leaks and intracranial hypotension.

A heritable connective-tissue-disorder often is suspected in patients with spontaneous spinal CSF leaks and intracranial hypotension, but the nature of the disorder remains unknown in most patients. The aim of this study was to assess the gene encoding TGF-beta receptor-2 (TGFBR2) as a candidate gene for spinal CSF leaks. We searched the TGFBR2 gene for mutations in eight patients with spontaneous spinal CSF leaks who also had other features associated with TGFBR2 mutations, i.e., skeletal features of Marfan syndrome, arterial tortuosity, and(or) thoracic aortic aneurysm. The mean age of these 7 women and 1 man was 38 years (range 14-60 years). We detected no TGFBR2 mutations and conclude that TGFBR2 mutations are not a major factor in spontaneous spinal CSF leaks.

COL2A1-related skeletal dysplasias with predominant metaphyseal involvement.

Skeletal dysplasias induced by mutations in the collagen 2 gene (the so-called "type 2 collagenopathies") form a wide spectrum in severity and are distinguished by subtle clinical and radiographic differential signs. The unifying features are predominant involvement of the vertebral bodies and the epiphyses of the long bones ("spondylo-epiphyseal" pattern). A mild degree of metaphyseal dysplasia can be seen in the so-called Strudwick variant of spondyloepimetaphyseal dysplasia and is generally mild or absent in other forms. We report here on four individuals with COL2A1 mutations associated with marked metaphyseal involvement with only mild epiphyseal and spondylar changes. One patient who carried a Gly283Arg substitution had a pattern of metaphyseal dysplasia that corresponded precisely to what was termed "Murdoch type metaphyseal dysplasia" in 1960s and was renamed Strudwick type SEMD in 1980s; the second patient carried a Gly181Arg substitution and had severe metaphyseal dysplasia with fractures at the metaphyses reminiscent of the "corner fractures" or Sutcliffe type spondylometaphyseal dysplasia. The third patient also had major metaphyseal involvement but more epiphyseal changes than the others in this study and had a Gly922Arg mutation in COL2A1. The final patient had a small in-frame deletion and unusually ballooned and distorted metaphyses. While it remains true that most individuals with COL2A1 mutations have chondrodysplasia with a spondylo-epiphyseal pattern, metaphyseal involvement is not incompatible with a COL2A1 dysplasia and mutation analysis can be indicated. The observation of these individuals with metaphyseal dysplasia indicates that the phenotypic spectrum associated with mutations in type 2 collagen, the main cartilage protein, is even wider than hitherto assumed.

Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans.

Osteogenesis imperfecta (OI) is a generalized disorder of connective tissue characterized by fragile bones and easy susceptibility to fracture. Most cases of OI are caused by mutations in type I collagen. We have identified and assembled structural mutations in type I collagen genes (COL1A1 and COL1A2, encoding the proalpha1(I) and proalpha2(I) chains, respectively) that result in OI. Quantitative defects causing type I OI were not included. Of these 832 independent mutations, 682 result in substitution for glycine residues in the triple helical domain of the encoded protein and 150 alter splice sites. Distinct genotype-phenotype relationships emerge for each chain. One-third of the mutations that result in glycine substitutions in alpha1(I) are lethal, especially when the substituting residues are charged or have a branched side chain. Substitutions in the first 200 residues are nonlethal and have variable outcome thereafter, unrelated to folding or helix stability domains. Two exclusively lethal regions (helix positions 691-823 and 910-964) align with major ligand binding regions (MLBRs), suggesting crucial interactions of collagen monomers or fibrils with integrins, matrix metalloproteinases (MMPs), fibronectin, and cartilage oligomeric matrix protein (COMP). Mutations in COL1A2 are predominantly nonlethal (80%). Lethal substitutions are located in eight regularly spaced clusters along the chain, supporting a regional model. The lethal regions align with proteoglycan binding sites along the fibril, suggesting a role in fibril-matrix interactions. Recurrences at the same site in alpha2(I) are generally concordant for outcome, unlike alpha1(I). Splice site mutations comprise 20% of helical mutations identified in OI patients, and may lead to exon skipping, intron inclusion, or the activation of cryptic splice sites. Splice site mutations in COL1A1 are rarely lethal; they often lead to frameshifts and the mild type I phenotype. In alpha2(I), lethal exon skipping events are located in the carboxyl half of the chain. Our data on genotype-phenotype relationships indicate that the two collagen chains play very different roles in matrix integrity and that phenotype depends on intracellular and extracellular events.

Novel fibrillin 1 mutation in a case of neonatal Marfan syndrome: the increasing importance of early recognition.

Neonatal Marfan syndrome (MFS) is a severe form of classic MFS caused by mutations in a specific region of the fibrillin 1 gene (FBN1). We report a case of an infant with neonatal MFS who presented with flexion contractures in utero and severe skeletal and cardiovascular manifestations at birth. A novel de novo missense mutation in exon 26 of FBN1 was demonstrated. Because of potential new therapies, it is increasingly important to recognize neonatal MFS in utero as well as shortly after birth to initiate the appropriate diagnostic work-up and management.

A dominantly inherited spondylometaphyseal dysplasia with "corner fractures" and congenital scoliosis.

Spondylometaphyseal dysplasia (SMD) is a term applied to a varied group of skeletal dysplasias that principally involve the spine and the metaphyses of long bones. SMD Sutcliffe or "Corner Fracture" type is characterized by short stature, developmental coxa vara, fragmented appearance of the metaphyses ("corner fractures"), abnormally shaped vertebrae, odontoid hypoplasia, and dominant inheritance. We report a family with a dominantly inherited SMD with "corner fractures" and severe, congenital scoliosis but neither coxa vara nor odontoid abnormalities. This could either represent phenotypic variability in SMD-"Corner Fracture" type, or be a new, dominantly inherited SMD. The presence of severe, congenital scoliosis and short stature is present in all members of this family, and not typically seen in SMD-"Corner Fracture" type, supporting our hypothesis that this might represent a new, dominantly inherited SMD.

Lack of correlation between the type of COL1A1 or COL1A2 mutation and hearing loss in osteogenesis imperfecta patients.

Osteogenesis imperfecta (OI) is caused by mutations in COL1A1 and COL1A2 that code for the alpha1 and alpha2 chains of type I collagen. Phenotypes correlate with the mutation types in that COL1A1 null mutations lead to OI type I, and structural mutations in alpha1(I) or alpha2(I) lead to more severe OI types (II-IV). However, correlative analysis between mutation types and OI associated hearing loss has not been previously performed. A total of 54 Finnish OI patients with previously diagnosed hearing loss or age 35 or more years were analyzed here for mutations in COL1A1 or COL1A2. Altogether 49 mutations were identified, of which 41 were novel. The 49 mutations represented the molecular genetic background of 41.1% of the Finnish OI population. A total of 38 mutations were in COL1A1 and 11 were in COL1A2. Of these, 16 were glycine substitutions and 16 were splicing mutations in alpha1(I) or alpha2(I). In addition, 17 null allele mutations were detected in COL1A1. A total of 32 patients (65.3%) with a mutation had hearing loss. That is slightly more than in our previous population study on Finnish adults with OI (57.9%). The association between the mutation types and OI type was statistically evident. Patients with COL1A1 mutations more frequently had blue scleras than those with COL1A2 mutations. In addition, patients with COL1A2 mutations tended to be shorter than those with COL1A1 mutations. However, no correlation was found between the mutated gene or mutation type and hearing pattern. These results suggest that the basis of hearing loss in OI is complex, and it is a result of multifactorial, still unknown genetic effects.

Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database.

Fibrillin is the major component of extracellular microfibrils. Mutations in the fibrillin gene on chromosome 15 (FBN1) were first described in the heritable connective disorder, Marfan syndrome (MFS). FBN1 has also been shown to harbor mutations related to a spectrum of conditions phenotypically related to MFS, called "type-1 fibrillinopathies." In 1995, in an effort to standardize the information regarding these mutations and to facilitate their mutational analysis and identification of structure/function and phenotype/genotype relationships, we created a human FBN1 mutation database, UMD-FBN1. This database gives access to a software package that provides specific routines and optimized multicriteria research and sorting tools. For each mutation, information is provided at the gene, protein, and clinical levels. This tool is now a worldwide reference and is frequently used by teams working in the field; more than 220,000 interrogations have been made to it since January 1998. The database has recently been modified to follow the guidelines on mutation databases of the HUGO Mutation Database Initiative (MDI) and the Human Genome Variation Society (HGVS), including their approved mutation nomenclature. The current update shows 559 entries, of which 421 are novel. UMD-FBN1 is accessible at www.umd.be/. We have also recently developed a FBN1 polymorphism database in order to facilitate diagnostics.