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Lujan-Fryns Syndrome (LFS) is defined as a set of symptoms including mild-moderate mental retardation, marfanoid appearance, hypotonia at birth, hypernasal speech, characteristic craniofacial appearance and normal testis size. The frequency of the syndrome is not known thus the information obtained is solely based on case reports. Hereby, we present a patient with LFS diagnosis. The 29-year old male patient had mental retardation, aggression, and persecutory delusions, characteristic craniofacial and marfanoid features. During his speech pronominal reversal was observed ('the hurt him, he is so upset' when talking abour himself). After examination and genetic analysis, fragile X, Klinefelter, Marfan and Down syndromes and homocystinuria were eliminated as causes of mental retardation. A preliminary diagnoses of LFS done. No mutation was detected in exon 22 of the MED12 gene; but. Whole Exome Sequencing (WES) is ongoing. The patient was started on risperidone (4 mg/day) for psychotic symptoms and carbamazepine (200 mg/day) for impulse control and as an antiepileptic. After a follow up of 8 months, impulse control, psychotic symptoms and aggression improved significantly. Since the specific gene mutation of LFS was not determined in our case, we solely had to depend on clinical evaluation and genetic analysis. Although it is not easy to fully define or classify these syndromes, we believe every reported case will be a step in overcoming these difficulties.

International audience; SKI pathogenic variations are associated with Shprintzen-Goldberg Syndrome (SGS), a rare systemic connective tissue disorder characterized by craniofacial, skeletal and cardiovascular features. So far, the clinical description, including intellectual disability, has been relatively homogeneous, and the known pathogenic variations were located in two different hotspots of the SKI gene. In the course of diagnosing Marfan syndrome and related disorders, we identified nine sporadic probands (aged 2-47 years) carrying three different likely pathogenic or pathogenic variants in the SKI gene affecting the same amino acid (Thr180). Seven of these molecular events were confirmed de novo. All probands displayed a milder morphological phenotype with a marfanoid habitus that did not initially lead to a clinical diagnosis of SGS. Only three of them had learning disorders, and none had intellectual disability. Six out of nine presented thoracic aortic aneurysm, which led to preventive surgery in the oldest case. This report extends the phenotypic spectrum of variants identified in the SKI gene. We describe a new mutational hotspot associated with a marfanoid syndrome with no intellectual disability. Cardiovascular involvement was confirmed in a significant number of cases, highlighting the importance of accurately diagnosing SGS and ensuring appropriate medical treatment and follow-up.

International audience; We have previously reported on a consanguineous family where 2 siblings, a girl and a boy, presented with tall stature, long and triangular faces, prominent forehead, telecanthus, ptosis, everted lower eyelids, downslanting palpebral fissures, large ears, high arched palate, long arm span, arachnodactyly, advanced bone age, joint laxity, pectus excavatum, inguinal hernia, and myopia, suggestive of a new subtype of connective tissue disorder (Megarbane et al. AJMG, 2012; 158(A)5: 1185-1189). On clinical follow-up, both patients had multiple inguinal, crural, and abdominal herniae, intestinal occlusions, several huge diverticula throughout the gut and the bladder, and rectal prolapse. In addition, the girl had a mild hearing impairment, and the boy a left diaphragmatic hernia. Here we describe the molecular characterization of this disorder using Whole Exome Sequencing, revealing, in both siblings, a novel homozygous missense variant in the EFEMP1 gene, c.163T > C; p.(Cys55Arg) whose homozygous by descent, autosomal recessive transmission was confirmed through segregation analysis by Sanger sequencing. In addition, the girl exhibited a homozygous mutation in the MYO3A gene, c.1370_1371delGA; p.(Arg457Asnfs*25), associated with non-syndromic deafness. The siblings were also found to harbor a homozygous nonsense variant in the VCPKMT gene. We review the literature and discuss our updated clinical and molecular findings that suggest EFEMP1 to be the probable candidate gene implicated in this novel connective tissue disease.

Objective To discover whether patients with aortic root dilation and leptosomic features but without a diagnosis of Marfan syndrome (MFS) fare similarly to patients with MFS. Methods Of 124 patients with aortic root dilation identified from August 1, 1994, through October 31, 2012, 66 had MFS and 58 had leptosomic features but did not meet the Ghent criteria. Genetic testing was performed in 35% of patients (n=43). We compared z scores and aortic root diameters for patients who presented with aortic root dilation with and without an MFS diagnosis and with and without aortic root repair. Results No difference existed in initial aortic root diameters between groups ( P =.15); however, mean ± SD z scores for patients without MFS and with MFS were 3.1±2.3 vs 4.5±3.2 ( P =.005). Fourteen of 58 patients (24%) without MFS and 35 (53%) with MFS underwent aortic root operations ( P z scores remained similar at follow-up ( P =.20), as did 10-year survival: MFS, 100%; no MFS, 94.1% ( P =.98). No significant difference was found for mean ± SD root diameter (no MFS, 38.9±7.3 mm; MFS, 35±8.6 mm; P =.06) or z score (no MFS, 2.4±2.0; MFS, 2.1±2.0; P =.53) for patients who underwent surgery. Two patients in each group had aortic root dissections. Conclusion Similar rates of aortic dissection between the 2 groups warrant further study regarding patients with leptosomic features but no diagnosis of MFS. Aortic root dilation progressed similarly in patients who did not undergo surgery.

X-linked intellectual disability (XLID) is a genetically heterogeneous disorder involving more than 100 genes known to date. Here, we describe a Korean male infant with global developmental delay. He had neither facial dysmorphism nor skeletal abnormalities. Bayley scale of infant and toddler development third edition (Bayley-III) measured at age of 2 years revealed marked global developmental delays without Marfanoid habitus, structural brain abnormalities, or epilepsy. The patient's cognitive, motor, and language developmental ages were 8-9 months, 12 months, and 9 months, respectively. Targeted next-generation sequencing revealed a de novo mutation [NM_001008222.2(ZDHHC9): c.286C > T (p.(Arg96Trp))] in the affected patient. This mutation has been reported previously in a family XLID with Marfanoid features. Sanger sequencing analysis of the proband and his parents revealed that the missense mutation was present in the proband only (absent in his parents). This indicates that the mutation is de novo in origin. To the best of our knowledge, this is the first report describing sporadic XLID with de novo ZDHHC9 mutation identified by targeted next-generation sequencing.

We describe the clinical presentation and 17 years follow up of a boy, born to consanguineous parents and presenting with intellectual disability (ID), autism, "marfanoid" dysmorphic features, and moderate abnormalities of sulfite metabolism compatible with molybdenum cofactor deficiency, but normal sulfite oxidase activity in cultured skin fibroblasts. Genomic exome analysis revealed a homozygous MOCS3 missense mutation, leading to a p.Ala257Thr substitution in the highly conserved ubiquitin-like-domain of the protein. MOCS3 is the third protein, besides MOCS1 and MOCS2, involved in the biosynthesis of the molybdenum cofactor and has a dual ubiquitin-like function in tRNA thiolation. It is plausible that the phenotype results from deficiency of this dual function, not only from defective synthesis of molybdenum cofactor, which would explain similarities and differences from the MOCS1 and MOCS2-related disorders. This observation should encourage testing of additional ID patients with mild abnormalities of sulfite metabolism for MOCS3 mutations.

Tracheobronchomegaly (TBM) is a rare disease of unknown etiology, characterized by dilatation of the trachea and main bronchi. Despite its rarity, TBM has been reported to accompany several conditions, particularly Ehlers-Danlos syndrome. Herein, we report on a 15-year-old patient who was diagnosed with TBM on the basis of radiologic and endoscopic findings and with Ehlers-Danlos syndrome type IVB presenting with marfanoid features, severe kyphoscoliosis, increased skin elasticity, and ongoing hypotonia since the neonatal period.

Spontaneous intracranial hypotension (SIH) is an under-diagnosed cause of headache in children and adolescents. SIH results from cerebrospinal fluid (CSF) leak due to breach in the dura mater and the etiology for dural breach is often diverse. We report an adolescent boy who presented with chronic episodic headache that later progressed to daily headache. There was a typical history of worsening of headache on upright position and relief of headache on lying down. He was treated with migraine prophylaxis in another hospital but there was no response. Marfanoid features and brisk deep tendon reflexes were observed on clinical examination. Brain magnetic resonance imaging (MRI) revealed sagging of the brain stem, pachymeningeal enhancement, and tonsillar herniation. MRI of spine myelogram confirmed multiple levels of CSF leak. He was initially managed with supportive measures and fluoroscopic-guided fibrin glue injection. Although child remained symptom-free for the next 6 months, he again developed headache. MRI and computed tomography spine myelogram revealed a meningeal diverticulum in the lumbar spine. He was managed with an autologous epidural blood patch and he has been well since then. In this report, we highlight the clinical and radiological pointers to the presence of SIH in children with recurrent headache.

Biallelic variants in the AEBP1 gene cause a novel autosomal-recessive connective tissue disorder (CTD) reminiscent of Ehlers-Danlos Syndrome (EDS). The four previously reported individuals show considerable clinical variability. Unbiased high-throughput sequencing enables the rapid identification of additional cases for such rare entities. We identified the homozygous nonsense variant c.917dup, p.Tyr306* in AEBP1 using clinical exome sequencing in a female individual with previously unsolved CTD. Segregation testing confirmed homozygosity in the clinically affected brother and heterozygous carrier status in the healthy mother. Chromosomal microarray showed that the variant lies in a run of homozygosity, suggesting a common origin of this genomic segment. RT-PCR analysis in the mother revealed a monoallelic expression of the normal transcript supporting a nonsense-mediated mRNA decay and functional nullizygosity as disease mechanism. We describe two individuals from a fourth family with AEBP1-associated CTD. Our results further verify that autosomal-recessive inherited LOF variants in the AEBP1 gene cause clinical features of different EDS subtypes, but also of the marfanoid spectrum. As identification of further individuals is necessary to inform the clinical characterization, we stress the added value of exome sequencing for such rare diseases.

We review six previous reports between 2000 and 2014 of seven unrelated patients with mutations in the FBN1 gene affecting function. All mutations occurred in exon 64 of the FBN1 gene. A distinctive phenotype consisting of partial manifestations of Marfan syndrome, a progeroid facial appearance, and clinical features of lipodystrophy was present in all individuals. We suggest that this previously unknown genotype/phenotype relationship constitutes a new fibrillinopathy for which the name marfanoid–progeroid–lipodystrophy syndrome would be appropriate.

IF 3.512; International audience; Marfanoid habitus (MH) combined with intellectual disability (ID) is a genetically and clinically heterogeneous group of overlapping disorders. We performed exome sequencing in 33 trios and 31 single probands to identify novel genes specific to MH-ID. After the search for variants in known disease-causing genes and non-disease-causing genes with classical approaches, we searched for variants in non-disease-causing genes whose pLI was above 0.9 (ExAC Consortium data), in which truncating variants were found in at least 3 unrelated patients. Only DLG4 gene met these criteria. Data from the literature and various databases also indicated its implication in ID. DLG4 encodes post-synaptic density protein 95 (PSD-95), a protein expressed in various tissues, including the brain. In neurons, PSD-95 is located at the post-synaptic density, and is associated with glutamatergic receptor signaling (NMDA and AMPA). PSD-95 probably participates in dendritogenesis. Two patients were heterozygous for de novo frameshift variants and one patient carried a a consensus splice site variant. Gene expression studies supported their pathogenicity through haploinsufficiency and loss-of-function. Patients exhibited mild-to-moderate ID, similar marfanoid features, including a long face, high-arched palate, long and thin fingers, pectus excavatum, scoliosis and ophthalmological manifestations (nystagmus or strabismus). Our study emphasizes the role of DLG4 as a novel post-synaptic-associated gene involved in syndromic ID associated with MH.

Background: To clinically characterize a cohort of patients with ectopia lentis (EL), or Marfanoid features in whom a definite genetic diagnosis of Marfan syndrome (MFS) had been excluded (atypical MFS), and to evaluate the contribution of mutations in ADAMTSL4 (OMIM * 610113), and P3H2 (LEPREL1; OMIM * 610341) to disease in this population. Materials and Methods: Subjects underwent comprehensive ophthalmic examination, including keratometry. Mutational analysis of ADAMTSL4 and P3H2 was undertaken using PCR, high resolution melting analysis, and sequencing. The frequency of c.2237G>A; p.(Arg746His) was determined in an unaffected Polynesian cohort. Haplotype analysis used tagged single nucleotide polymorphic markers. Results: Mutational analysis of ADAMTSL4 identified two pathogenic variants in ADAMTSL4 in 11/31 (35%) probands, consistent with the autosomal recessive EL phenotype. A recurrent, rare missense variant in ADAMTSL4, c.2237G>A; p.(Arg746His), was present in 10 probands –(8 homozygotes), predominantly of Polynesian descent, and all shared the same haplotype. p.(Arg746His) affects the Thrombospondin1 (TSP1) domain of the protein and is predicted to be pathogenic. No pathogenic variants in P3H2 were identified. Conclusion: A recurrent pathogenic ADAMTSL4 variant is a major cause of early onset autosomal recessive EL in a Cook Island Māori population and associated with a common haplotype, suggesting a founder effect. Children presenting under the age of 5 years, particularly of Cook Island or New Zealand Māori descent, with isolated ectopia lentis, should in the first instance be tested for this single variant.

WOS: 000330013500010, PubMed: 24211323, Classical homocystinuria is the most commonly inherited disorder of sulfur metabolism, caused by the genetic alterations in human cystathionine beta-synthase (CBS) gene. In this study, we present comprehensive clinical findings and the genetic basis of homocystinuria in a cohort of Turkish patients. Excluding some CBS mutations, detailed genotype-phenotype correlation for different CBS mutations has not been established in literature. We aimed to make clinical subgroups according to main clinical symptoms and discussed these data together with mutational analysis results from our patients. Totally, 16 different mutations were identified; twelve of which had already been reported, and four are novel (p.N93Y, p.L251P, p.D281V and c.829-2A>T). The probands were classified into three major groups according to the clinical symptoms caused by these mutations. A psychomotor delay was the most common diagnostic symptom (n = 12, 46.2% neurological presentation), followed by thromboembolic events (n = 6, 23.1% vascular presentation) and lens ectopia, myopia or marfanoid features (n = 5, 19.2% connective tissue presentation). Pyridoxine responsiveness was 7.7%; however, with partial responsive probands, the ratio was 53.9%. In addition, five thrombophilic nucleotide changes including MTHFR c.677 C>T and c.1298 A>C, Factor V c.1691 G>A, Factor II c.20210 G>A, and SERPINE1 4G/5G were investigated to assess their contributions to the clinical spectrum. We suggest that the effect of these polymorphisms on clinical phenotype of CBS is not very clear since the distribution of thrombophilic polymorphisms does not differ among specific groups. This study provides molecular findings of 26 Turkish probands with homocystinuria and discusses the clinical presentations and putative effects of the CBS mutations. Crown Copyright (C) 2013 Published by Elsevier B.V. All rights reserved., State Planning Organization of Turkey [DPT2006K1206400603], This work was supported by a grant from the State Planning Organization of Turkey (Project number: DPT2006K1206400603).

Homocystinuria due to cystathionine β-synthase deficiency is an inborn error of metabolism first described almost 50 years ago, which involves the accumulation of plasma homocysteine and other metabolites. Without early detection and appropriate treatment, common and sometimes lethal consequences include ocular abnormalities, osteoporosis, developmental delays, marfanoid phenotype, vascular disease, and mental retardation. Almost 50 % of subjects develop a psychiatric disorder during their life, but only 2.8 % present a psychiatric symptom as the initial manifestation. Among this group, psychotic disorders are infrequent. We describe the case of a 17-year-old boy presenting with a first episode psychosis and an unknown homocystinuria due to cystathionine β-synthase deficiency, which led to a lethal outcome.

Background More than 100 X-linked intellectual disability (X-LID) genes have been identified to be involved in 10–15% of intellectual disability (ID). Method To identify novel possible candidates, we selected 18 families with a male proband affected by isolated or syndromic ID. Pedigree and/or clinical presentation suggested an X-LID disorder. After exclusion of known genetic diseases, we identified seven cases whose mother showed a skewed X-inactivation (>80%) that underwent whole exome sequencing (WES, 50X average depth). Results WES allowed to solve the genetic basis in four cases, two of which (Coffin-Lowry syndrome, RPS6K3 gene; ATRX syndrome, ATRX gene) had been missed by previous clinical/genetics tests. One further ATRX case showed a complex phenotype including pontocerebellar atrophy (PCA), possibly associated to an unidentified PCA gene mutation. In a case with suspected Lujan-Fryns syndrome, a c.649C>T (p.Pro217Ser) MECP2 missense change was identified, likely explaining the neurological impairment, but not the marfanoid features, which were possibly associated to the p.Thr1020Ala variant in fibrillin 1. Finally, a c.707T>G variant (p.Phe236Cys) in the DMD gene was identified in a patient retrospectively recognized to be affected by Becker muscular dystrophy (BMD, OMIM 300376). Conclusion Overall, our data show that WES may give hints to solve complex ID phenotypes with a likely X-linked transmission, and that a significant proportion of these orphan conditions might result from concomitant mutations affecting different clinically associated genes.

Primary congenital glaucoma (isolated trabeculodysgensis, PCG) generally presents between birth and 3 years of age. Recently, mutations in Latent Transforming Growth Factor (TGF)-beta Binding Protein 2 (LTBP2) have been reported in several families that were diagnosed with PCG, who actually had a more complex ocular phenotype with ectopia lentis and Marfanoid features. We screened this gene for mutations in the original Turkish GLC3C-linked PCG family and in a group of CYP1B1-negative British PCG cases and their matched normal control subjects.The 36-coding exons of the LTBP2 gene were sequenced in 94 familial or sporadic CYP1B1-negative PCG cases and 96 matched normal control subjects.No disease-causing mutations were identified in the original GLC3C-linked family. Screening of LTBP2 in 94 PCG and 96 control subjects identified three novel synonymous variations (L429L, P680P, S1031S) in 12 PCG and seven control subjects. A novel heterozygous missense mutation (R538W) was also identified in 1 of 90 PCG cases that is unlikely to be disease-causative.LTBP2 mutations were not found in the Turkish GLC3C-linked PCG family or in 94 British CYP1B1-negative PCG cases. Our data suggest that LTBP2 mutations are not a significant cause for isolated trabeculodysgenesis.

Sotos syndrome is a rare genetic disorder characterized by overgrowth associated with macrocephaly and delayed psychomotor development. Patients with Sotos syndrome show 5q35 deletions involving NSD1 or its point mutations. We identified the common 5q35 deletion in a patient with atypical Sotos syndrome manifesting extremely severe developmental delay, joint hypermobility, and skin hyperextensibility, which are recognized as Marfanoid hypermobility syndrome. Further analyses were performed to identify the genetic cause of these additional findings. aCGH analysis revealed an additional 862 kb deletion of Xq22.3 in this patient, which was inherited from his healthy mother. The deleted region included five genes, including the nik-related kinase gene (NRK), which would be a candidate gene for the patient's Marfanoid hypermobility, because it is a member of the glucokinase subfamily that are involved in activating the JNK pathway, and is expressed in developing skeletal musculature. Severe developmental delay seen in the patient may be derived from position effect of the deletion for neighboring interleukin 1 receptor accessory protein-like 2 gene (IL1RAPL2), which is a candidate gene for X-linked mental retardation. © 2011 Wiley-Liss, Inc.

The presence of a pectus excavatum (PE) requiring surgical repair is a major skeletal feature of Marfan syndrome. Marfanoid patients have phenotypic findings but do not meet all diagnostic criteria. We sought to examine the clinical and management differences between Marfan syndrome patients and those who are marfanoid compared with all other patients undergoing minimally invasive PE repair.A retrospective institutional review board-approved review was conducted of a prospectively gathered database of all patients who underwent minimally invasive repair of PE. Patients were grouped according to diagnosis of Marfan syndrome (MAR), Marfanoid appearance (OID), and all others (ALL). Patient demographics, preoperative imaging and testing, operative strategy, complications, and postoperative surveys were evaluated. Fisher's Exact test and chi(2) were applied for statistical analysis.From June 1987 to September 2008, 1192 patients underwent minimally invasive PE repair (MAR = 33, OID = 212, ALL = 947). There was a significantly higher proportion of females with either MAR or OID who underwent repair (21.5%vs 15.5%, P = .04). The MAR patients had significantly more severe PE determined by computed tomography index (MAR = 8.75, OID = 5.82, ALL = 4.94, P.0001) and required multiple pectus bars (or =2) to be placed during operation (MAR = 58%, OID = 36%, ALL = 29%, P = .001). There was a trend toward higher wound infection rates in MAR patients (MAR = 6%, OID = 1.4%, ALL = 1.3%, P = .07). The recurrence rate was similar among all groups (MAR = 0%, OID = 2%, ALL = 0.7%, P = .12). Successful outcome from surgeon perspective in either MAR or OID patients was similar to ALL (98%vs 98%, P = .88) and correlated well with patient satisfaction after repair (96%vs 95%, P = .43).Minimally invasive PE repair is safe in patients with Marfan syndrome or marfanoid features with equally good results. Patients with Marfan syndrome have clinically more severe PE requiring multiple bars for chest repair and may have slightly higher wound infection rates. Patients are satisfied with minimally invasive repair despite a phenotypically more severe chest wall defect.

Background It is unclear whether late outcome differs for Marfan syndrome and marfanoid patients. Thus, we compared characteristics of Marfan versus marfanoid patients and their survival and requirement for reoperation. Methods From 1978 to October 2003, 162 patients with a presumptive diagnosis of Marfan syndrome underwent operation. We recategorized them as confirmed Marfan (n = 122), marfanoid (n = 23), Ehlers-Danlos syndrome (n = 5), or other (n = 12). Patients categorized as marfanoid failed to meet the major criteria of Marfan syndrome. We compared characteristics of Marfan and marfanoid groups and assessed long-term survival and need for reoperation. Results Marfan and marfanoid patients had similar demographics (women, 33% versus 39%; age, 39 ± 13 versus 41 ± 12 years; height, 186 ± 12 cm versus 184 ± 9.6 cm), valve pathophysiology (aortic regurgitation, 66% versus 58%; mitral regurgitation, 58% versus 62%), and aortic pathology (dilated, 40% versus 39%; dissected, 17% versus 13%). Overall hospital survival was 99.3% (144/145), and 10-year survival was similar at 82% in the Marfan and 100% in marfanoid groups ( p = 0.13). Patients with aortic dissection ( p = 0.001) and mitral valve replacement ( p = 0.003) were at higher risk of death. Reoperation was more frequent after separate aortic valve–ascending aorta graft operations ( p = 0.04), and among taller patients ( p = 0.005). Of 24 Marfan patients with David root reimplantations, none has required reoperation. Conclusions Marfan and marfanoid patients have similar physical characteristics and postoperative survival, although reoperation was more frequent in Marfan patients. Surgery before occurrence of aortic dissection or mitral valve repair should reduce the risk of reoperation, but taller patients, irrespective of Marfan or gender, are more likely to require reoperation.

Chest pain is the second most common reason for referral to a pediatric cardiologist, because cardiovascular-related disorders are a major concern for children and their families when seeking medical attention. On the rare occasions when pediatric chest pain is a result of severe heart disease, it is usually associated with well-known cardiovascular risk factors such as fibrillinopathies. Type 1 fibrillinopathies are heritable disorders caused by mutations in the fibrillin genes that lead to a broad spectrum of connective tissue phenotypes ranging from Marfan syndrome, at the most severe end, to patients displaying mild marfanoid features, or milder Marfan (MM). We report the case of an adolescent patient with MM and suspected acute coronary syndrome, with chest pain and electrocardiographic changes suggestive of myocardial ischemia. Despite the low risk of coronary or aortic dissection/aneurysm in MM, these possibilities should be tested. Once they are ruled out, mitral valve prolapse should be considered as the main cause of chest pain with ischemic-like changes in the inferior electrocardiogram leads. We emphasize that clinical and echocardiographic follow-up over years is warranted in the pediatric population to ensure that the aortic root does not show progressive dilatation or a tendency to dissect. Finally, genotyping is clinically indicated for early and complete diagnosis in patients with MM as well as de novo Marfan syndrome to take advantage of educational and clinical programs for young carriers of the mutation.

Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS) are clinically related autosomal dominant systemic connective tissue disorders. Although mutations in several genes of the TGF-beta signalling and related pathways have been identified in the past (e.g. FBN1 , TGFBR1 , TGFBR2, SMAD3, TGFB2 ), there are still many individuals with “marfanoid” phenotypes in whom no causative mutations are identified. We performed whole exome sequencing in two of three affected individuals from a family with phenotypic features overlapping MFS and LDS. The two affected children and their affected father had tall stature, arachnodactyly, hyperextensible joints, hypertelorism, bifid uvula, but no cardiac involvement, aortic dilation or eye involvement. We detected a novel heterozygous mutation in TGFB3 , c.898C>G, predicting the missense substitution p.Arg300Gly. Sanger sequencing confirmed the mutation and its segregation with the phenotype. The first two TGFB3 mutations were reported previously in two unrelated individuals with marfanoid features: one individual with growth retardation carried a heterozygous loss-of-function mutation (c.1226G>A; p.Cys409Tyr; Rienhoff et al., 2013), whereas a child with overgrowth carried a mutation in the same codon as the mutation identified in the three affected individuals reported here (c.899G>A; p.Arg300Gln; Matyas et al., 2014). The mutations at codon Arg300 presumably lead to increased TGF-beta signalling, suggesting that the short or tall stature seen in patients with TGFB3 mutations may result from opposing effects of mutations on TGF-beta signalling. Thus, we add a novel human TGFB3 mutation, contribute to the clinical delineation of the emerging connective tissue disorder tentatively called Rienhoff syndrome and compare the data with a very recent report (Bertoli-Avella et al., 2015) on TGFB3 mutations associated with aortic aneurysms or dissections.

A 24-year-old man had experienced hip-girdle weakness since the age of 15 years and exercise-induced muscle cramps with ‘toe-walking’ since aged 12 years. He was thought to have Marfan's syndrome but had no known family history of muscle disease. His marfanoid features prompted a transthoracic echocardiogram at 18 years, showing a normal aortic root and cardiac size/function without mitral valve prolapse. On examination at the age of 24, he was tall (6 feet, 7 inches; 201 cm) with an asthenic habitus, disproportionate arm length to height (1.06), high-arched palate, arachnodactyly, marked pectus excavatum and pes planus, but no other features of Marfan's syndrome. Neuromuscular examination showed hypertrophy of calf muscles and shortening of the Achilles’ tendons as well as selective atrophy of the sternal heads of sternocleidomastoid muscles, proximal arms and quadriceps muscles. There was no scapular winging. The limb-girdle pattern of weakness was of moderate severity (Medical Research Council (MRC) grade 3) in the hip extensors and adductors, and knee flexors and mild weakness (MRC grade 4) in neck flexors, hip flexors and abductors, as well as knee extensors. The strength in other muscle groups and the remaining neurological examination, including tendon reflexes, was normal. He remained fully ambulant and functional at the age of 31 years, albeit with a moderately waddling gait. His 12-lead ECG at age 24 was abnormal, with a right-bundle branch pattern and a prominent R wave in chest lead V2. Echocardiography showed borderline dilatation and reduced function of both ventricles. The ECG and echocardiogram were unchanged when re-examined 7 years later. Laboratory tests showed a serum creatine kinase of 1640 IU/L (>10 times the upper limit of normal). Biopsy of the quadriceps femoris showed an increase in endomysial connective tissue, infiltration of adipose tissue and focal necrotic fibres. Immunohistochemistry showed normal spectrin and caveolin staining but decreased intensity (∼50%) in the …

A patient with Shprintzen-Goldberg syndrome was followed up for 24 years. The patient's parents were unrelated and unaffected. Walking and speech were delayed. Facial dysmorphism was obvious as well as pectus excavatum, scoliosis, bilateral dislocation of the radial heads, hammer toes and hallux valgus, pes planus, arachnodactyly, and camptodactyly. Skin was thin and fragile. CT scan showed ventricular enlargement. He had a mitral valve prolapse. He was operated on twice for bilateral inguinal and crural hernia and several times for his foot deformities. Puberty was delayed until 18 years. At 24 years of age he was still thin, dolichocephalic, and the facial dysmorphic features were still obvious. Pectus excavatum was still severe but the thoracolumbar scoliosis was mild. His foot deformities had improved and his joints were less hypermobile. Psychomotor development was quite normal. His main concern was the minimal subcutaneous fat and fragility of skin. Echocardiography was now normal.

An 18-year-old man, with a Marfanoid connective tissue disorder, presented with atrial flutter ( Panel C ). He was referred for electrophysiology study and ablation. Entrainment manoeuvres confirmed the presence of typical counterclockwise cavotricuspid isthmus (CTI)-dependent atrial flutter ( Panel D ). On intracardiac echocardiography (ICE; AcuNav, Biosense …

Congenital contractural arachnodactyly (CCA) is a heritable connective tissue disorder caused by defects in the gene encoding fibrillin-2 (FBN2). People with CCA typically have a marfanoid habitus, flexion contractures, severe kyphoscoliosis, abnormal pinnae, and muscular hypoplasia. Because of the relative infrequency of the syndrome and its generally mild to moderate severity, prenatal diagnosis had not previously been sought. Here we report prenatal diagnosis in a family with CCA. Because the course of the disease in the proband was rather severe, she had requested genetic counseling as early as age 17. She delayed childbearing until prenatal diagnosis for CCA became possible. This decision was supported by her mother and later her husband. Because she shared the same genotype with her husband, genetic linkage analysis of this family did not alter the a priori 50% risk of having an affected child. The possibility of unambiguously ascertaining the affected status of a fetus homozygous for the tested FBN2 marker was sufficient for the family to pursue prenatal diagnosis. This case strongly points to the importance of informed decisions now that genetic testing is becoming commonplace.

Background Since the advent of array-CGH, numerous new microdeletional syndromes have been delineated while others remain to be described. Although 3q29 subtelomeric deletion is a well-described syndrome, there is no report on 3q interstitial deletions. Methods We report for the first time seven patients with interstitial deletions at the 3q27.3q28 locus gathered through the Decipher database, and suggest this locus as a new microdeletional syndrome. Results The patients shared a recognisable facial dysmorphism and marfanoid habitus, associated with psychosis and mild to severe intellectual disability (ID). Most of the patients had no delay in gross psychomotor acquisition, but had severe impaired communicative and adaptive skills. Two small regions of overlap were defined. The first one, located on the 3q27.3 locus and common to all patients, was associated with psychotic troubles and mood disorders as well as recognisable facial dysmorphism. This region comprised several candidate genes including SST, considered a candidate for the neuropsychiatric findings because of its implication in interneuronal migration and differentiation processes. A familial case with a smaller deletion allowed us to define a second region of overlap at the 3q27.3q28 locus for marfanoid habitus and severe ID. Indeed, the common morphological findings in the first four patients included skeletal features from the marfanoid spectrum: scoliosis (4/4), long and thin habitus with leanness (average Body Mass Index of 15 (18.5

A 33-year-old man presented to the hospital with progressive dyspnea and palpitations. He had a history of scoliosis 14 years ago, requiring spinal fusion surgery. Physical examination revealed marfanoid habit and irregular heartbeats with a holosystolic murmur of …

Interstitial 2q deletions are very rare chromosome abnormalities. The 2q32q33 deletion was proposed as a distinct entity with characteristic phenotype. Most patients have feeding problems, growth restriction, moderate to severe developmental delay, speech delay or lack of speech, high, prominent forehead, thin sparse hair, teeth abnormalities and a high or cleft palate. We report on another rare case of interstitial 2q33 deletion found during routine karyotyping and further characterized by the use of a genomic SNP array. The patient presented here has a "Marfanoid" phenotype, hypothyroidism, and a marked tactile hypersensitivity. We concluded that hypothyroidism might be caused by the deletion of the CD28 and/or CTLA4 genes; also cardiological monitoring of patients with the deletion including BMPR2 may be considered in order to prevent the possible medical complications associated with pulmonary hypertension.

The pathophysiology of thoracic aortic aneurysms and dissections(TAAD) is complex and multifactorial. Classic cardiovascular risk fac-tors play an important role in a majority of patients but genetic fac-tors should always be considered, especially in younger subjectsand/or in the presence of a family history of TAAD. To date, severalgenes have been identified in both syndromic and non-syndromicforms of TAAD, including FBN1 (Marfan syndrome, MFS), TGFBR1/2(Loeys-Dietz syndrome, LDS), SMAD3 (Aneurysm-Osteoarthritissyndrome, AOS), ACTA2 (TAA6, TAAD with livedo reticularis and irisflocculi), MYH11 (TAAD with patent ductus arteriosus), and MYLK(TAAD7) [1–7]. Although clinical features show significant overlap,these entities differ in the extent of vascular involvement and clinicalcourse. As a consequence, molecular studies have become pivotal inthe evaluation, counselling and management of the patient withTAAD. Moreover, the identification of new genes has led to new in-sights into the pathogenesis of aneurysm formation.The crucial role of the transforming-growth-factor β (TGFβ)pathwayin TAAD became evident from both studies on mouse models and theanalysis of components of the TGF β pathway on human aortic tissue ofpatients with these disorders [3,8–11].WepreviouslysequencedTGFB2as a candidate gene for TAAD, but did not identify mutations in 40 pa-tients with isolated aortic root dilatation (Callewaert et al., unpublishedresults). The recent findings by Boileau and colleagues identifying thefirst TGFB2 mutations leading to familial TAAD in association with cere-brovascular disease and mild systemic features reminiscent of Marfansyndrome [16] have urged us toscreenthis geneinapatientgroupasso-ciatingTAADwithawiderphenotypicspectrumincludingcerebrovascu-lar disease, arterial tortuosity, ma rfanoid skeletal features and mitralvalve disease. In total, we assessed the prevalence of TGFB2 mutationsin 146 patients.Using direct sequencing after ampli fication of all exons and flankingintronic sequences of the TGFB2 gene on genomic DNA level (TGFB2NM_001135599.2), we identified 4 heterozygous TGFB2 mutations in 6patients: c.475C>T (p.Arg159X), c.979C>T (p.Arg327Trp), c.980G>A(p.Arg327Gln), and c.1125delT (p.Gly376GlufsX17). We found 2 prema-turetruncatingmutationsandalsoidenti fiedthe firstmissensemutationsin TGFB2. All mutations are expected to result in a loss-of-function. Anoverview of the clinical findings is provided in Table 1 and of the muta-tions in Fig. 1 and Supplemental Table 1.Aortic pathology was universally present at middle-age (z-scores >2.5),butaorticdissectionwasthepresentingfeatureinonlyonepatientat the age of 69 years (patient 1). Importantly, type A dissection oc-curredinanotherpatient5 yearsafterinitialevaluationandatanaorticroot diameter below the classical surgical threshold of 50 mm (patient6). Significant mitral valve prolapse occurred in 4 patients and was thereasonforinitialevaluationintwopatients(2and6)thatbothrequiredsurgical replacement. Patient 4 came to medical attention following aroutine echocardiography showing aortic root dilatation and mitralvalve prolapse without other manifestations. One patient (patient 3)was evaluated following transient ischemic attacks at the age of18 yearsoldwithunderlyingtortuosityofthevertebralarteries.Finally,patient 5 was evaluated for skeletal marfanoid features.Fouroutof6 patientshadskeletaland/orskinmanifestationsrem-iniscent of TGFβ-signalopathies which can be mild; 3 patients hadmyopia of which one had cataract. Importantly, family history wasnegative in 3 patients.Our data indicate a prevalence of TGFB2 mutations in the exam-ined TAAD cohort of around 4% (6/146), which is significantly lowerthan the previously reported prevalence of ACTA2 mutations (16%)[11]. The TGFβ superfamily includes 3 isoforms of TGFβ, TGFβ1, −2,and −3 (for a review [12]). The TGFβs are pleiotropic cytokines, con-trolling a broadrange of biologicalprocesses. The3 TGFβ isoforms ex-hibit both overlapping and divergent properties as illustrated by thephenotype of the respective knockout mouse models. Tgfb2 knockoutmice die perinatally and display a wide range of developmental de-fects, including cardiovascular, pulmonary, skeletal, ocular, inner ear

The nature and cause of President Abraham Lincoln's unusual physical features have long been debated, with the greatest attention directed at two monogenic disorders of the transforming growth factor β system: Marfan syndrome and multiple endocrine neoplasia type 2B. The present report examines newly discovered phenotypic information about Lincoln's biological mother, Nancy Hanks Lincoln, and concludes that (a) Lincoln's mother was skeletally marfanoid, (b) the President and his mother were highly concordant for the presence of numerous facial features found in various transforming growth factor β disorders, and (c) Lincoln's mother, like her son, had hypotonic skeletal muscles, resulting in myopathic facies and 'pseudodepression'. These conclusions establish that mother and son had the same monogenic autosomal dominant marfanoid disorder. A description of Nancy Hanks Lincoln as coarse-featured, and a little-known statement that a wasting disease contributed to her death at age 34, lends support to the multiple endocrine neoplasia type 2B hypothesis.

Background: The typical cardiac manifestations of Marfan syndrome are aortic regurgitation with progressive dilatation of the aortic root, which may cause dissection and rupture of the ascending aorta, mitral valve prolapse and mitral valve regurgitation. In this study, we aimed to show echocardiographic findings in 11 patients with Marfan syndrome. Methods: Diagnosis of Marfan syndrome was based on the Ghent criteria. All patients had a full echocardiographic evaluation. During the evaluation, we investigated the presence of mitral valve prolapse, mitral valve regurgitation, tricuspid valve prolapse, dilatation of the aortic root, and aortic regurgitation. Results: Eleven patients were diagnosed as Marfan syndrome(seven male, four female, age 4-14 years). All had mitral valve prolapse (nine with mitral valve regurgitation). Among these 11 patients, seven had accompanying tricuspid valve prolapse, six had dilatation of the aortic root and two had aortic regurgitation. Conclusion: Eleven patients in our clinic were diagnosed as Marfan syndrome since they had distinct characteristics of marfanoid phenotype. Echocardiographic evaluation of these patients showed marked heart valve involvement. In Marfan syndrome, it is known that the aortic valve is affected following mitral valve involvement. In our experience, aortic root dilatation is less common. However, particular attention should be given to following up aortic root status with noninvasive echocardiography to institute measures to prevent complications.

The most common mutations found in FBN1 are missense mutations (56%), mainly substituting or creating a cysteine in a cbEGF domain. Other mutations are frameshift, splice and nonsense mutations. There are only a few reports of patients with marfanoid features and a molecularly proven complete deletion of a FBN1 allele. We describe the clinical features of 10 patients with a complete FBN1 gene deletion. Seven patients fulfilled the Ghent criteria for Marfan syndrome (MFS). The other three patients were examined at a young age and did not (yet) present the full clinical picture of MFS yet. Ectopia lentis was present in at least two patients. Aortic root dilatation was present in 6 of the 10 patients. In three patients, the aortic root diameter was on the 95th percentile and in one patient, the diameter of the aortic root was normal, the cross-section, however, had a cloverleaf appearance. Two patients underwent aortic root surgery at a relatively young age (27 and 34 years). Mitral valve prolapse was present in 4 of the 10 patients, and billowing of the mitral valve in 1. All patients had facial and skeletal features of MFS. Two patients with a large deletion extending beyond the FBN1 gene had an extended phenotype. We conclude that complete loss of one FBN1 allele does not predict a mild phenotype, and these findings support the hypothesis that true haploinsufficiency can lead to the classical phenotype of Marfan syndrome. European Journal of Human Genetics (2011) 19, 247-252; doi:10.1038/ejhg.2010.174; published online 10 November 2010

A seventeen year-old boy developed left sided chorea in a few days, subsequently involving the four limbs. Although he presented a marfanoid phenotype, genetic analysis of the Fibrillin 1 was normal. The genes for familial chorea and Huntington's disease were also negative. Biological tests showed normal serum homocystein, but revealed very high levels of anti-beta2-GP1 IgG, anticardiolipin and lupus anticoagulant, which remained at similar values for a period of over three months. Electroencephalogram and cerebral magnetic resonance imaging (MRI) showed no abnormalities. Brain PET-scan disclosed bilateral striatal hypermetabolism. The patient was treated with methylprednisolone and low dose of acetylsalicylic acid. He improved markedly after six weeks of treatment, and choreic movements disappeared completely after two months. A control PET-scan performed at this time showed reversion of striated hypermetabolism to a normal pattern. The pathogenic aspects of this relatively rare case of chorea are discussed.

We report on a 20-year-old man who presented in infancy with severe generalized lipodystrophy with a progeroid appearance and some Marfanoid features. He subsequently was diagnosed with bilateral lens subluxations at the age of 16 years which prompted analysis of the FBN1 gene. This analysis showed him to have a novel heterozygous, de novo, c.8156_8175del, p.Lys2719ThrfsX12, frameshift mutation in exon 64 of his FBN1 gene. His phenotype is similar to a patient described by Graul-Neumann et al. [2010] who was found to have a de novo, heterozygous, c.8155_8156del deletion in exon 64 of FBN1. Both mutations result in a truncated protein with an extremely charged C-terminus, containing two positive and four negative charges in the last eight amino acids. This most likely has a profound impact on protein–protein interactions, which are very important in the extracellular matrix. The similarities in the phenotypes, and overlapping molecular defects, provides further evidence that the phenotype with features of Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy is a distinct clinical entity due to frameshift mutations in exon 64 of the FBN1 gene.

Introduction: Movement disorders associated with homocystinuria have been reported as rare cases. Their physiopathology has not yet been clarified. Methods: Three siblings in the same family have been described, all with homocystinuria but possessing phenotypic differences. Result: The first case presented oromandibular dyskinesia, spasmodic dysphonia, tremor, bradykinesia, and generalized dystonia along with the classic findings of homocystinuria. The second case had marfanoid features and ophthalmic complications of homocystinuria, and also evidence of mild rigidity of which the patient did not complain. The third case had only marfanoid features. The most severely affected family member was the first case who also had increased thyroid peroxidase antibodies, antithyroglobulin antibodies, and thyroiditis. Conclusion: The most severely affected sibling presented movement disorders and evidence of autoimmune thyroiditis. These findings have led us to think that research on the relations between movement disorders, basal ganglia, immunity, autoimmune thyroid diseases, and homocysteine should be continued.

A Caucasian family of mediterranean origin comprising a patient whose parents were first cousins, his wife and their three children, and his two sisters have been studied. The patient and his two daughters were afflicted with the same corneal opacities and hypoalphalipoproteinaemia. The disease was shown to be transmitted as a non-sex-linked recessive trait. The corneal opacities develop at the end of the second decade of life and consist of numerous minute greyish dots in the entire corneal stroma that give the cornea a misty appearance. Vision slowly deteriorated from 40 years of age. At about 50 years of age, except in one of the two daughters who showed Marfanoid syndrome, the three patients had good general health and no symptoms of atherosclerosis. Biochemical investigations showed hypoalphalipoproteinaemia (with a faint fast-moving HDL band on polyacrylamide gel gradient electrophoresis and small arcs of HDL2 and HDL3 of low mobility determined by agarose gel immunoelectrophoresis), low total cholesterol (3·5–4·9 mmol l-1), slightly decreased cholesteryl ester/total cholesterol ratio (0·52–0·63), extremely low HDL cholesterol (0·20–0·21 mmol l-1), mild hypertriglyceri-daemia (1·94–3·80 mmol l-1), and striking deficiency in apo A-I and apo A-II (0·45–0·72, 0·08–0·16 g l-1, respectively). The esterification of HDL cholesterol was low while that of LDL and VLDL was nearly normal. Other laboratory values were normal. The HDL subspecies and major apolipoprotein isoforms have been studied to differentiate FED from Tangier disease, LCAT deficiency, as Apo A-I, A-II, C-II, C-III deficiencies and variants. The data is discussed in comparison with the other familial syndromes of lipid deposition at the corneae associated with dyslipopro-teinaemias. Two of the three patients may be classified as having ‘Fish-eye disease’ as the three index patients described by Carlson in 1982 [1].

A 23 year-old man was admitted because of weakness and atrophy in both tights. He was 184 cm in height with arachnodactyly and had a mild dilatation of the ascending aorta which was detected by cardiac echogram and chest CT scan. A laboratory examination revealed normal serum values for mucopolysaccarides and amino acids, and 46XY chromosomes. These findings indicate a Marfan's syndrome phenotype. A neurological finding showed a proximal dominant muscle atrophy and increased deep tendon reflexes. The EMG revealed a polyphasic action potential, and a subsequent muscle biopsy demonstrated a small group atrophy and atrophy of Type II fibers. Neuroradiological studies of brain and spinal cord indicated no substantial abnormalities. Only 4 cases of Marfanoid habit accompanied by primary nervous system disturbances have been reported and these had variable complications or severe neurological deficits. The present case, which involved mild neurogenic muscle atrophy and brisk deep tendon reflexes without complications except myopia, was unique.

The Lujan-Fryns syndrome or X-linked mental retardation with marfanoid habitus syndrome is a syndromal X-linked form of mental retardation, affecting predominantly males. The prevalence is not known for the general population. The syndrome is associated with mild to moderate mental retardation, distinct facial dysmorphism (long narrow face, maxillary hypoplasia, small mandible and prominent forehead), tall marfanoid stature and long slender extremities, and behavioural problems. The genetic defect is not known. The diagnosis is based on the presence of the clinical manifestations. Genetic counselling is according to X-linked recessive inheritance. Prenatal testing is not possible. There is no specific treatment for this condition. Patients need special education and psychological follow-up, and attention should be given to diagnose early psychiatric disorders.

The recent identification of TGFBR2 mutations in Marfan syndrome II (MFSII) [Mizuguchi et al. (2004); Nat Genet 36:855-860] and of TGFBR1 and TGFBR2 mutations in Loeys-Dietz aortic aneurysm syndrome (LDS) [Loeys et al. (2005); Nat Genet 37:275-281] [OMIM 609192] has provided direct evidence of abnormal signaling in transforming growth factors beta (TGF-beta) in the pathogenesis of Marfan syndrome (MFS). In light of this, we describe the phenotypes and genotypes of five individuals. Patient 1 had MFS and abnormal cranial dura. Patient 2 had severe early onset MFS and an abnormal skull. Patients 3 and 4 had probable Furlong syndrome (FS). Patient 5 had marfanoid (MD) features, mental retardation (MR), and a deletion of chromosome 15q21.1q21.3. All patients had a condition within the MFS, MD-craniosynostosis (CS) or MD-MR spectrum. The names of these entities may become redundant, and instead, come to be considered within the spectrum of TGF-beta signaling pathway disorders. Two recurrent heterozygous FBN1 mutations were found in Patients 1 and 2, and an identical novel heterozygous de novo TGFBR1 mutation was found in Patients 3 and 4, in whom altered fibrillin-1 processing was demonstrated previously [Milewicz et al. (2000); Am J Hum Genet 67:279]. A heterozygous FBN1 deletion was found in Patient 5. These findings support the notion that perturbation of extracellular matrix homeostasis and/or remodeling caused by abnormal TGF-beta signaling is the core pathogenetic mechanism in MFS and related entities including the MD-CS syndromes.

A 22 year old man was found to have a 5.4 cm aortic root aneurysm upon screening echocardiogram. He had no Marfanoid features. His 19 year old brother had died suddenly of an acute ascending aortic dissection six weeks previously. A cardiology appointment was scheduled, but in the interim he developed transient chest, neck, and jaw burning. He was transferred pain-free from his local emergency room for further evaluation. A computed tomographic (CT) scan with …

Schizophrenia is considered to be a heterogenous disorder. Different etiopathological mechanisms can be attributed to a similar clinical picture as described in DSM-III-R criteria. We present a case of a young man diagnosed on different occasions as schizophrenic with mild mental retardation. Clinical examination revealed signs and symptoms most compatible with the diagnosis of Lujan-Fryns syndrome, an X-linked mental retardation syndrome with marfanoid features, frequently associated with psychotic or other psychiatric symptoms. In all patients with symptoms of schizophrenia and mental retardation Lujan-Fryns syndrome should be considered in the differential diagnosis. © 1996 Wiley-Liss, Inc.

We describe two unrelated patients with cytogenetically visible deletions of 21q22.2-q22.3 and mild phenotypes. Both patients presented minor dysmorphic features including thin marfanoid build, facial asymmetry, downward-slanting palpebral fissures, depressed nasal bridge, small nose with bulbous tip, and mild mental retardation (MR). FISH and molecular studies indicated common deleted areas but different breakpoints. In patient 1, the breakpoint was fine mapped to a 5.2 kb interval between exon 5 and exon 8 of the ETS2 gene. The subtelomeric FISH probe was absent on one homologue 21 indicating a terminal deletion spanning approximately 7.9 Mb in size. In patient 2, the proximal breakpoint was determined to be 300-700 kb distal to ETS2, and the distal breakpoint 2.5-0.3 Mb from the 21q telomere, indicating an interstitial deletion sized approximately 4.7-7.3 Mb. The 21q- syndrome is rare and typically associated with a severe phenotype, but different outcomes depending on the size and location of the deleted area have been reported. Our data show that monosomy 21q of the area distal to the ETS2 gene, representing the terminal 7.9 Mb of 21q, may result in mild phenotypes comprising facial anomalies, thin marfanoid build, and mild MR, with or without signs of holoprosencephaly.

We present a consanguineous Pakistani family in which four patients (two males and two females) had a new Troyer-like phenotype. All four patients showed some marfanoid features (span more than height, arachnodactyly, high arched palate), and generalized hyper-reflexia. The two affected males and the younger female also had microcephaly and mental retardation. Features only present in the affected males included short stature, dysarthria, amyotrophy of the distal muscles, fasciculations and tremor. The distal muscle wasting in the two affected brothers reflected the presence of axonal neuropathy demonstrated both electrophysiologically and by nerve biopsy. Although neither of the sisters had any degree of distal muscle wasting, both had reduced M-wave amplitude of the tibial and peroneal nerves, bilaterally. The described phenotype does not fit any of the recognized forms of hereditary spastic paraparesis with distal muscle wasting. The specific axonal neuropathy differentiates it from familial motor neuron disease with mental retardation. The reported phenotype represents a possible new Troyer-like syndrome similar to that described by Neuhauser (1976), but differs from it by the lack of major dysmorphic features.

Recent reports have described a distinct and recurrent pattern of systemic malformation that associates craniosynostosis and neurodevelopmental abnormalities with many clinical features of the Marfan syndrome (MFS), an autosomal dominant disorder of the extracellular microfibril caused by defects in the gene encoding fibrillin-1, FBN1 (ref. 8). Additional common findings include other craniofacial anomalies, hypotonia, obstructive apnea, foot deformity, and congenital weakness of the abdominal wall. So far, only 11 cases have been reported precluding the assignment of definitive diagnostic criteria. While it remains unclear whether these cases represent a discrete clinical entity with a single aetiology, they have been pragmatically grouped under the rubric Marfanoid-craniosynostosis or Shprintzen-Goldberg syndrome (SGS). Because of the significant clinical overlap between MFS and SGS, we proposed that they may be caused by allelic mutations. We now report two SGS patients who harbour mutations in FBN1. While it remains unclear whether these mutations are sufficient for the clinical expression of the entire SGS phenotype, these data suggest a role for fibrillin-1 in early craniofacial and central nervous system development. Our recent observation that FBN1 transcript is expressed as early as the 8-cell stage of human embryogenesis is consistent with this hypothesis.

Here we report a new case in which the clinical manifestation were compatible with the phenotype described by Lujan et al. [Am J Med Genet 1984; 17: 311-22] as 'X-linked mental retardation with marfanoid habitus'. Based upon the presence of mild psychomotor retardation, epilepsy and skeletal malformations, a sister can be considered an affected carrier, whereas an older brother showed skeletal abnormalities and juvenile glaucoma. The mother had bilateral palpebral ptosis with minimal mitochondrial abnormalities at muscle biopsy.

Sixty-two patients admitted for elective reconstructive surgery of the temporomandibular joint (TMJ) and eight seen as outpatients with a chief complaint of TMJ dysfunction during the same time interval were evaluated for possible etiologic factors contributing to the disease. All hospitalized patients had severe, end-stage degenerative changes within the TMJ, whereas outpatients had less severe disease and did not require surgery. TMJ dysfunction in some patients was said to be a result of established causes including bruxism, malocclusion, and trauma. No patient in this series had evidence of a systemic inflammatory polyarthritis. Of the 70 patients, 38 (54%) met criteria, based on those of Carter and Wilkinson, as modified by Beighton et al., sufficient to warrant a diagnosis of the hypermobile joint syndrome. Five patients had classic Ehlers-Danlos syndrome and therefore were not patients with "benign hypermobility," and an additional two cases were described as "marfanoid" and as possible Ehlers-Danlos syndrome, respectively. Radiographs showed TMJ hyperextensibility in four hypermobile patients. Long-term surgical outcome was identical in the hypermobile and nonhypermobile groups. The incidence of hypermobility in this series is strikingly higher than the expected incidence in an otherwise population. Magnetic resonance images of the TMJs on separate groups of asymptomatic normal and hypermobile women identified excessive anterior movement in the hypermobile group, together with abnormal anterior disk position in some. We hypothesize that hypermobility within the TMJ may cause accelerated disk destruction and degenerative disease.

Medullary thyroid carcinoma (MTC) occurs as a component of three well-described autosomal dominant familial cancer syndromes. Multiple endocrine neoplasia type 2A (MEN 2A) is characterized by MTC, pheochromocytomas, and parathyroid hyperplasia. Patients with the rarer multiple endocrine neoplasia type 2B (MEN 2B) syndrome develop MTC and pheochromocytomas, as well as mucosal neuromas, ganglioneuromatosis of the gastrointestinal tract, and a characteristic “marfanoid” habitus. Finally, MTC is transmitted in an autosomal dominant pattern in some families without associated pheochromocytomas or parathyroid hyperplasia (familial medullary thyroid carcinoma, MTC1 2 . Sixty-one members of two well-characterized kindreds segregating MTC1 members of six families segregating MEN2B were genotyped using a panel of RFLP probes from the pericentromeric region of chromosome 10 near a locus for MEN 2A. Statistically significant linkage was observed between the chromosome 10 centromere-specific marker D10Z1 and MTC1 (maximum pairwise lod score 5.88 with 0% recombination) and D10Z1 and MEN2B (maximum pairwise lod score 3.58 with 0% recombination). A maximum multipoint lod score of 4.08 was obtained for MEN2B at the position of D10Z1. In addition, 92 members of a previously unreported large MEN 2A kindred were genotyped, and linkage to the pericentromeric region of chromosome 10 is reported (maximum pairwise lod score of 11.33 with 0% recombination between MEN2A and RBP3). These results demonstrate that both a locus for familial MTC and a locus for MEN 2B map to the pericentromeric region of chromosome 10, in the same region as a locus for MEN 2A. The finding that each of these three clinically distinct familial cancer syndromes maps to the same chromosomal region suggests that all are allelic mutations at the same locus or represent a cluster of genes involved in the regulation of neuroendocrine tissue development.

Contains fulltext : 52286.pdf (Publisher’s version ) (Closed access) Cobalamin is an essential cofactor for two mammalian enzymes: methionine synthase and methylmalonyl-CoA mutase. Patients with the cobalamin C (CblC) defect have combined methylmalonic aciduria and homocystinuria. Recently, the gene responsible for the CblC type, MMACHC, was identified, which enables molecular diagnostics. In this study, we describe two siblings, a 16-year-old girl and her 11-year-old brother, of a consanguineous family who presented with a very distinct clinical manifestation. The girl presented at the age of 13 years with macrocytic anaemia, cognitive regression and Marfanoid features such as increased arm-span, arachnodactyly, joint hyperlaxity and scoliosis. Her brother presented at the age of 10 months with developmental delay and behavioural abnormalities. Biochemical analysis showed severely increased homocysteine and methylmalonic acid levels in plasma of both siblings. In addition, plasma cysteine levels were decreased in the girl but not in her brother. The diagnosis of CblC defect was confirmed by genomic sequencing of the coding exons of the MMACHC gene. Two heterozygous mutations were identified in both siblings; the common c.271dupA p.Arg91LysfsX14 and a novel mutation, c.1A > G p.Met1?. Therapy consisting of folic acid, vitamin B6, l-carnitine and intramuscular vitamin B12 resulted in a clear improvement of biochemical parameters and, importantly, resulted in amelioration of the Marfanoid features in the girl. These data might suggest that low cysteine levels account for the Marfanoid features observed in the girl and indicate that the CblC type of combined methylmalonic aciduria and homocystinuria should be considered in the differential diagnosis of patients with Marfanoid features.

A 40-year-old man was admitted to hospital with an acute onset of paraplegia of 5 days' duration, preceded by vague back pain in the interscapular region for 2 months. The pain was intermittent and was relieved by rest and analgesics. He had no significant past medical history. Physical examination revealed a gibbus at the level of the thoracic (T4–T6) vertebrae and signs of extramedullary cord compression at T7 level. Cardiovascular, respiratory, abdominal and ophthalmological examination was unremarkable and there were no Marfanoid features. Full blood count, biochemical and lipid profile, and electrocardiogram were within the normal range. Sputum examination was negative for acid-fast bacilli. Chest X-ray (Figure 1) showed mediastinal widening and X-ray of dorsolumbar spine showed scoliosis at T5–T8 with convexity to the right. Magnetic resonance imaging revealed gross dilatation of the arch of aorta and two large saccular aneurysms with size of 11.3 cm × 10.8 cm and 9.4 cm × 10.2 cm, causing destruction of T6–T9 vertebrae and spinal cord compression (Figure 2). A positive serum VDRL (venereal disease research laboratory test) and TPHA (Treponema pallidum haemaglutination assay) confirmed that the patient had syphilis. Enzyme-linked immunosorbent assay (ELISA) for human immunodeficiency virus (HIV) was negative. CSF analysis was normal and the CSF VDRL and TPHA were non-reactive. A diagnosis of cardiovascular syphilis was made and oral prednisolone was started followed by 2.4 million units of benzathine penicillin G. While awaiting surgery the patient's condition deteriorated rapidly as a result of a rupture of the aneurysm and he died despite aggressive resuscitation efforts. Autopsy confirmed syphilitic aortic aneurysm with destruction of vertebrae and direct spinal cord compression.

A case is reported of dissecting aneurysm of the donor ascending aorta and root 4 years after orthotopic cardiac transplantation. The pathology raises the possibility of Marfan's syndrome in the donor.