Marfanoid Syndrome Research Articles

A spectrum of clinically-identified cysteine mutations in fibulin-3 (EFEMP1) highlight its disulfide bonding complexity and potential to induce stress response activation.

Fibulin-3 (FBLN3), also known as EFEMP1, is a secreted extracellular matrix (ECM) glycoprotein that contains forty cysteine residues. These cysteines, which are distributed across one atypical and five canonical calcium-binding epidermal growth factor (EGF) domains, are important for regulating FBLN3 structure, secretion, and presumably function. As evidence of this importance, a rare homozygous p.C55R mutation in FBLN3 negates its function, alters disulfide bonding, and causes marfanoid syndrome. Additional studies suggest that heterozygous premature stop codon mutations in FBLN3 may also cause similar, albeit less severe, connective tissue disorders. Interestingly, a series of twenty-four cysteine mutations in FBLN3 have been identified in the human population and published in the Clinical Variation (ClinVar) and gnomAD databases. We tested how seven of these cysteine mutants (five loss-of-cysteine variants: C42Y, C190R, C218R, C252F, and C365S, two gain-of-cysteine variants: R358C, Y369C) and two newly developed mutations (G57C and Y397C) altered FBLN3 secretion, disulfide bonding, MMP2 zymography, and stress response activation Surprisingly, we found a wide variety of biochemical behaviors: i) loss-of-cysteine variants correlated with an increased likelihood of disulfide dimer formation, ii) N-terminal mutations were less likely to disrupt secretion, and were less prone to aggregation, iii) in contrast to wild-type FBLN3, multiple, but not all variants failed to induce MMP2 levels in cell culture, and iv) C-terminal mutations (either loss or gain of cysteines) were more prone to significant secretion defects, intracellular accumulation/misfolding, and stress response activation. These results provide molecular and biochemical insight into FBLN3 folding, secretion, and function for many cysteine mutations found in the human population, some of which may increase the likelihood of subclinical connective tissue or other FBLN3-associated haploinsufficiency diseases.

Decoding marfanoid syndrome: Breakthroughs in genetic understanding

Marfanoid Syndrome (MFS), a rare and complex genetic disorder, has long eluded a complete understanding of its intricate web of manifestations and underlying genetic factors. This review navigates the recent landscape of genetic research, offering an in-depth exploration of breakthroughs that have reshaped our comprehension of MFS. Focusing on pivotal genetic markers such as FBN1, TGFBR1, and TGFBR2, it unveils the specific mutations integral to the syndrome's clinical tapestry. Advancements in genomic technologies, notably next-generation sequencing and CRISPR-Cas9 gene editing, have propelled the field forward, accelerating the identification and analysis of genetic mutations with unprecedented precision. The review sheds light on how these technological strides have not only uncovered new genetic markers but also illuminated the intricate interplay of genes influencing the pathogenesis of MFS. Precision medicine takes center stage in the therapeutic frontiers, as understanding specific genetic mutations enables tailored interventions. This review provides a holistic perspective, encompassing genetic landscapes, technological revolutions, and emerging therapeutic paradigms, aiming to contribute to the ongoing discourse, foster a proactive approach to patient care, and inspire further research in the dynamic realm of MFS.

Malignant Hyperthermia in Dental and Facial Plastic surgeries

Preoperative evaluation of the patients scheduled for ambulatory surgery is of great importance in regards of both surgery and anesthesia considerations. Malignant Hyperthermia (MH) is a pharmacogenetic clinical syndrome which mostly arises from volatile anesthesia with halothane and the depolarizing muscle relaxant succinylcholine. Clinical manifestations of MH are acidosis and rhabdomyolysis which occur following uncontrolled increases in skeletal muscle metabolism and rapidly increasing body temperature (by as much as 1°C/5 min) (1). Primary cases of MH were reported to be of a 70% mortality rate; however, thanks to the emergence of diagnostic tools such as end-expired carbon dioxide and the administration of dantrolene, this rate has decreased to less than 5%. MH might occur even in those with no previous or familial history. Even a safe history of the previous surgery under the administration of MH triggering agents cannot guarantee a next safe surgery. A noteworthy point in the preoperative evaluation is the probable association of MH with certain musculoskeletal disorders including Duchenne, Becker, and myotonic muscular dystrophies, strabismus, osteogenesis imperfecta, ptosis, myelomeningocele, kyphoscoliosis, King-Denborough syndrome, periodic paralysis, hernias, marfanoid syndrome, and central core disease (1). These diseases are frequently encountered by dental and facial plastic surgeons and having the knowledge of the probable association between MH and these conditions could aware the dental and facial plastic surgeons and the anesthesiologists to be more vigilant. Although MH workup leads to the definite diagnosis, no convincing intraoperative diagnostic tool has been introduced so far. Masseter spasm is a condition which might follow administration of depolarizing neuromuscular blocking agents due to the slow tonic fibers of masseter and lateral pterygoid muscles (2-4). The severer forms of masseter spasm would result in masseter tetany or “jaws of steel” preventing any mouth opening. In cases with exclusively jaws of steel or those with Masseter spasm in combination with the rigidity of other body muscles, the occurrence of MH is almost definite and the surgical procedure should be terminated. Nevertheless, if either the jaw is only slightly resistant to opening or the rigidity of other muscles does not accompany the Masseter spasm, anesthesia might continue with non-triggering agents under proper monitoring including end-tidal CO2, pigmenturia evaluation, and arterial or venous blood sampling for creatine kinase, acid-base status, and electrolyte levels, mainly potassium. Considering the fact that anesthesiologists do not have access to the head and neck of the patients throughout dental and facial plastic surgeries, the vigilance and awareness of the surgeons in detecting masseter spasms in patients would immensely help with the early diagnosis of MH and save the lives of susceptible patients.

Atrial flutter ablation in a patient with Marfanoid syndrome and anomalous cavotricuspid isthmus

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 …

Further evidence for a marfanoid syndrome with neonatal progeroid features and severe generalized lipodystrophy due to frameshift mutations near the 3′ end of the FBN1 gene

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.

Hypothermia-related Electrocardiographic Abnormalities: Osborn Waves

A 42-YR-OLD man with marfanoid syndrome was scheduled for repair of thoracoabdominal aneurysm. Sevoflurane/oxygen was used as the primary anesthetic. At the completion of the operation (9 h and 42 min), the temperature had decreased to 33.9°C (blood), and sinus bradycardia (heart rate 56 beats/min) was noted (Lead II) and seemed to periodically decrease to 42 beats/min. (The preoperative electrocardiogram demonstrated normal sinus rhythm, heart rate of 84 beats/min, and left ventricular hypertrophy.) During this episode of bradycardia, blood pressure and cardiac output remained unchanged from previously recorded measurements. Arterial blood gas analysis did not reveal any acid–base or electrolyte abnormality that might explain the presence of bradycardia. After intravenous administration of 0.4 mg atropine, there was only a minimal increase in heart rate (60 beats/min). On admission to the cardiothoracic intensive care unit (33.0°C blood temperature), bradycardia was still present; Osborn waves (J-waves) and a prolonged QT interval were noted on the electrocardiogram (fig. 1A). The Osborn waves disappeared 8 h postoperatively (36.8°C blood temperature; fig. 1B). The electrocardiographic abnormalities associated with hypothermia are Osborn waves, prolonged PR and QT interval, sinus bradycardia, atrial and ventricular dysrhythmias, and shivering artifacts (muscular tremor). Hypothermia induces a difference between epicardial and endocardial potassium channel currents. The Osborn waves represent the electrocardiographic reflection of this transmural voltage gradient. The amplitude and the duration of the Osborn waves are inversely related to body temperature. The Osborn waves can persist 12–24 h after resumption of normothermia. The differential diagnosis of Osborn waves includes hypercalcemia, central nervous system lesions, coronary vasospasm, left ventricular hypertrophy, Brugada syndrome, and drug abuse, and it can appear as a normal variant (early repolarization). As shown in this case, the electrocardiogram provides early and important end-point core organ information regarding the electrophysiologic effect of a potentially lifethreatening degree of hypothermia.

Pulmonary dysfunction patterns in patients with Marfan and Marfanoid syndrome associated with scoliosis and the influencing factors

To investigate the impairment pattern and the influencing factors of pulmonary function in patients with Marfan and Marfanoid syndrome associated scoliosis (MS). In this retrospective study, totally 25 MS patients (aged 11 - 20 years, 11 boys and 14 girls) who received posterior instrumentation and fusion (Group A) and 38 adolescent idiopathic scoliosis (AIS) patients (Group B) (aged 10 - 19 years, 11 boys and 27 girls) were included from February 1998 to September 2007. The curve pattern was matched in both groups. The preoperative pulmonary function test (PFTs) were compared in two groups. And the parameters influencing the preoperative pulmonary function were analyzed in group A. In Group A, the Cobb angle of thoracic curve was negatively correlated with the percentage of predicted pulmonary volumes (VC%, FVC% and FEV1%) (r = -0.514, -0.503, -0.464, P < 0.05). And the reduction of lung function parameters (VC%, FVC%, FEV1% and MMEF%) was more severe in Group A than in Group B with compared magnitude of thoracic curve (P < 0.05). In Group A, the extent of impairment of pulmonary function in patients with the number of vertebrae involved ≥ 8 were more severe than those involved < 8 vertebrae (P < 0.05). However, there was no significant difference of deterioration of lung function between the higher apex (T₄₋₈) subgroup and lower apex (T₉₋₁₂) subgroup. And no correlation was found between thoracic kyphosis and the degrees of impairment of respiration function. Patients with MS have mixed ventilation dysfunction, which is more severe than AIS patients with matched age and Cobb angle. The pulmonary dysfunction in MS patients can be influenced by the severity of thoracic curve and the number of involved vertebrae.

Mental retardation with marfanoid syndrome: presentation of a family with different phenotypical expression

Here we report a new case in which the clinical manifestations 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.

A ‘Fish-eye disease’ familial condition with massive corneal opacities and hypoalphalipoproteinaemia: clinical, biochemical and genetic features

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 hypertriglyceridaemia (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.(ABSTRACT TRUNCATED AT 250 WORDS)