Decreased bone mineral density in Costello syndrome

IntroductionCostello syndrome (CS) is a multisystemic disorder characterized by postnatal reduced growth, facial dysmorphism, cardiac defects, cognitive impairment, skin and musculo-skeletal anomalies, and predisposition to certain cancers. CS is caused by activating germline mutations in the HRAS proto-oncogene. Similar to what is observed in other RASopathies, CS causative HRAS mutations promote enhanced signal flow through the RAF–MEK–ERK and PI3K–AKT signaling cascades. While decreased bone mineralization has been documented in other RASopathies, such as neurofibromatosis type 1 and Noonan syndrome, systematic studies investigating bone mineral density (BMD) are lacking in CS.Materials and methodsDual-energy X-ray absorptiometry (DXA) was utilized to assess BMD and body composition (fat and fat-free mass) in a cohort of subjects with molecularly confirmed diagnosis of CS (n = 9) and age-matched control individuals (n = 29). Using general linear regression, subtotal body (total body less head), lumbar, femoral neck and femur BMD parameters were compared considering age, sex, body mass index (BMI) and Tanner stage. Blood and urine biomarkers of bone metabolism were also assessed.ResultsAll individuals with CS showed significantly lower mean values of subtotal, lumbar and femoral neck BMD compared to the control group (p ≤ 0.01). Similarly, mean total body mass and fat-free mass parameters were lower among the CS patients than in controls (p < 0.01). Low 25-OH vitamin D concentration was documented in all individuals with CS, with values below the reference range in two patients. No significant correlation between vitamin D levels and BMD parameters was observed.DiscussionCS belongs to a family of developmental disorders, the RASopathies, that share skeletal defects as a common feature. The present data provide evidence that, similar to what is recently seen in NF1 and NS, bone homeostasis is impaired in CS. The significant decrease in BMD and low levels of vitamin D documented in the present cohort, along with the risk for pathologic fractures reported in adult individuals with CS, testifies the requirement for a preventive treatment to alleviate evolutive complications resulting from dysregulated bone metabolism.     

Ultrastructural pathology of aortic dissections in patients with Marfan syndrome: Comparison with dissections in patients without Marfan syndrome.

Despite the discovery in 1990 that mutations in the fibrillin-1 gene cause the Marfan syndrome, the pathogenesis of the life-threatening dissections associated with this disease is far from elucidated. Both the massive number of known fibrillin-1 mutations that result in a heterogeneous patient population and the strongly heterogeneous histology of patients' aortae presumably contribute to this lack of knowledge. We performed a detailed ultrastructural immunoelectron microscopic and histochemical analysis of the dissected media of ascending aortae of 10 patients with Marfan syndrome and compared them with those of 6 patients without Marfan syndrome and 77 individuals without known aortic disease. Relatively similar abnormalities were found in both patient groups, although they were more numerous and more diffusely spread in the patients with Marfan syndrome than in the patients without Marfan syndrome. The most conspicuous ultrastructural defects were the formation of abrupt transverse tears in thick and compact elastic lamellae and the local breaking up of smooth muscle cell-elastic lamella connections (that largely consist of microfibrils and elastic extensions, protruding from the elastic lamellae). This breaking up was characterized by a strongly reduced number of microfibrils and a severe shortening of the elastic extensions. Finally, the elastic extensions detached from the lamellae to ultimately degenerate and disappear. These changes were found mainly in the oldest group of patients with Marfan syndrome, indicating that they represented a loss of previously normally developed structures. We also compared our findings with those from a recently developed murine Marfan model (Pereira L, Lee SY, Gayraud B, Andrilopoulos K, Shapiro SD, Bunton T, Biery NJ, Dietz HC, Sakai LY, Ramirez F. Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proc Natl Acad Sci. U. S. A. 1999: 96: 3819-3823). Next to similarities, several striking differences existed, demonstrating that this model is not fully representative of the human Marfan syndrome.     

Hypercoagulability in a patient with Marfan syndrome.

A 39 year old man with Marfan syndrome presented with multiple pulmonary emboli and renal, hepatic, and splenic infarcts of unknown aetiology. The combination of thromboemboli and physical features initially suggested homocystinuria; however, laboratory examination showed no evidence for this disorder. Laboratory evaluation identified no coagulation abnormalities. This patient represents the unusual occurrence of hypercoagulability in a patient with Marfan syndrome.     

Dural ectasia in children with Marfan syndrome: a prospective, multicenter, patient-control study

The clinical diagnosis of Marfan syndrome in childhood is difficult, because symptoms may not have developed to their full expression until adulthood. The Ghent nosology for the diagnosis of Marfan syndrome classifies dural ectasia as a major diagnostic criterion. More than two thirds of adult patients with Marfan syndrome show dural ectasia, while the frequency in childhood is unknown. This prospective multicenter observational patient-control study was performed to identify pathologic changes of the lumbosacral spine in young patients with Marfan syndrome. Design: Prospective clinical trial, multicentric, cross-sectional. Setting: MRI of the lumbosacral spine. Patients: Twenty patients with proven Marfan syndrome, 20 patients suspicious for Marfan syndrome and 38 healthy controls. Outcome measures: Vertebral body diameter (VBD) from L1 to S1, dural sac diameter (DSD) from L1 to S1, dural sac ratio (DSR), qualitative assessment of the lumbosacral spine. Results: DSD and VBD in different age groups were higher in patients with proven or suspected Marfan syndrome than in healthy controls (DSD: L1, 6-8 years, P < 0.05). VBD related to body height showed a similar growth related increase in patients with proven or suspected Marfan syndrome and controls. DSD related to body height was elevated in patients with proven or suspected Marfan syndrome at different levels of the lumbar spine. DSD at levels L1, L5, and S1, and DSR at levels L5 and S1 of patients with proven Marfan syndrome were significantly higher (P < 0.05) than in controls. Conclusion: Even during childhood pathologic changes inside the lumbosacral spine of patients with Marfan syndrome can be observed. Dural ectasia, which occurs at different levels of the lumbar spine, can be detected at levels L5 and S1 in up to 40% of patients with Marfan syndrome.     

Primary trabeculodysgenesis in association with neonatal Marfan syndrome

We present the clinical and ophthalmological findings in two infants with neonatal Marfan syndrome (nMFS) and primary trabeculodysgenesis (PT). Fibrillin 1 (FBN1) mutations were confirmed in both cases. Numerous eye anomalies have been recognized in infants with nMFS, but PT has not been reported previously. Our report expands the phenotype of nMFS, and highlights the importance of early and careful ophthalmological assessment of these infants.     

Anthropometry fails in classifying bone mineral status in postmenopausal women

This study tested two hypotheses: (1) that simple anthropometric parameters can be used to identify patients at risk of decreased bone mineral content and (2) that an inverse relationship exists between waist:hip ratio (WHR) and bone mineral density (BMD). Bone mineral content (BMC) and BMD were evaluated by dual-energy X-ray absorptiometry in 1873 free-living women. Of these, 1819 (97%) were post-menopausal. One thousand and thirteen women (54%) had normal BMD, 705 (38%) osteopenia and 155 (8%) osteoporosis. Body weight (Wt), body mass index and arm muscle and fat areas were significantly lower in osteoporotics than osteopenics (p < 0.0001) and in these latter than controls (p < 0.0001). However, values of WHR were similar in all groups (p = ns). Body weight was the anthropometric parameter better correlated with BMC (rho = 0.650, p < 0.0001) and only Wt and age were identified as significant predictors of bone mineral status (normal-BMD/osteopenic/osteoporotic) at polytomous logistic regression (p = 0.0001 for each). However, Wt could not be employed as an indicator of bone mineral status at the individual level because of high variations in BMC for the same level of Wt. Under- (< 5th percentile) and normal-Wt (5th-95th percentile) women had the same frequency of osteopenia (39%) while it was lower in over-Wt (> 95th) women (13%). The frequency of osteoporosis was higher in under- than normal-Wt women (37 vs 7%) and none of the over-Wt women had osteoporosis. This study shows that: (1) simple anthropometric measurements cannot be used to select subjects at risk of decreased BMC and, (2) BMD does not vary with WHR.     

Neuromuscular features in Marfan syndrome

Marfan syndrome is a clinically and allelic heterogeneous, heritable connective tissue disorder with infrequently reported neuromuscular features. This study is the first to delineate these symptoms in a non-selected population. Neuromuscular involvement was evaluated in 10 Marfan patients through a standardized questionnaire, physical examination, nerve conduction study (NCS), needle electromyography (EMG), muscle ultrasound, laboratory investigation, and muscle biopsy. Existing neuroimages were screened for dural ectasia and spinal meningeal cysts. Twenty healthy controls with similar age distribution completed the questionnaire.
The results showed that various neuromuscular symptoms occur more frequently in the patients. Four older patients reported muscle weakness, five patients had a mild-to-moderate reduction in vibration sense, and all older patients mentioned mild functional impairments. NCS showed axonal polyneuropathy in four and EMG myopathic and neurogenic changes in all patients. Increased echo intensity and atrophy on muscle ultrasound was found in more than half of the patients. Muscle biopsies obtained in two patients showed myopathic changes in the older, female patient.
In conclusion, the majority of Marfan patients exhibited neuromuscular symptoms characterized as myopathy or polyneuropathy or both, and signs of lumbosacral radiculopathy, with symptoms being most pronounced in the older patients. Although meriting corroboration, these findings indicate a need to further the awareness of neuromuscular involvement in this population.     

Methods for measuring the mineral status of bone tissue

Scientific Research Institute for Medical Instrument Engineering, Moscow. Translated from Meditsinskaya Tekhnika, No. 3, pp. 3–6, May–June, 1993.     

Abdominal visceral findings in patients with Marfan syndrome.

PURPOSE: Marfan syndrome is an autosomal dominant disorder historically defined by well-characterized features in the cardiovascular, ocular, and skeletal systems. To date, there have been no reports concerning abdominal visceral findings in this disorder. The purpose of this study was to determine the prevalence of abdominal visceral findings in patients with Marfan syndrome. METHODS: Computed tomography or magnetic resonance studies of 69 patients with Marfan syndrome and an age- and sex-matched cohort of control subjects were reviewed. The presence of abdominal visceral findings was noted. Chi-square and Student t tests were used to determine significance of differences between the patient and control groups. This retrospective study was approved by the local institutional review board and determined to be exempt from Health Insurance Portability and Accountability Act reporting requirements. RESULTS: Renal cysts were present in 41 Marfan patients (59.4%) versus 21 control subjects (30.4%), P=0.001. The average number of renal cysts was greater in Marfan patients than controls (2.4 vs. 0.9, P=0.005). Hepatic cysts were present in 24 Marfan patients (34.8%) versus 12 control patients (17.3%), P=0.02. The average number of hepatic cysts was also greater in Marfan patients than controls (0.9 vs. 0.3, P=0.027). Cholelithiasis was present in 12 Marfan patients (18.1%) versus one control patient (1.5%), P<0.001. CONCLUSIONS: Marfan syndrome patients have liver and renal cysts more often, in increased number, and at an earlier age than controls, in addition to an increased prevalence of cholelithiasis. Further study will be needed to relate these findings to recent developments concerning the underlying molecular genetics of this disorder.     

Neuropsychological aspects of Marfan syndrome

We evaluated the neuropsychological status of 13 adult patients with Marfan syndrome. All subjects were administered the same neuropsychological test battery that included nine measures covering a broad range of cognitive abilities such as attention and concentration, learning and memory, and verbal and non-verbal abilities. Compared to a control group of 13 normal healthy subjects matched for sex, age and verbal intelligence, Marfan patients only performed significantly worse on tests measuring sustained visual attention and visuoconstruction. Although these tests use visual material and depend on visual perception and processing, the visual acuity problems associated with the syndrome could not explain these differences, nor could the use of beta-blocking medication or the presence of joint hypermobility. The findings suggest that problems with sustained visual attention and visuoconstruction may be present in Marfan syndrome over and above visual acuity problems and other phenomena associated with the disease. Further research on the neuropsychological aspects of Marfan syndrome is needed, using larger patient groups and more adequate control groups such as non-affected siblings and matched controls with similar visual impairment.     

Decreased bone mineral density in Prader-Willi syndrome: comparison with obese subjects.

Bone density, anthropometric data, and markers of bone turnover were collected on 21 subjects diagnosed with Prader-Willi syndrome (PWS) and compared with 9 subjects with obesity of unknown cause. In addition, urinary N-telopeptide levels were obtained in all subjects. N-telopeptides are the peptide fragments of type I collagen, the major bone matrix material. During periods of active bone degradation or high bone turnover, high levels of N-telopeptides are excreted in the urine. However, no significant difference was detected in the urinary N-telopeptide levels when corrected for creatinine excretion (raw or transformed data) between our subjects with obesity or PWS and the observed effect size of the between-group difference was small. Although N-telopeptide levels were higher but not significantly different in the subjects with PWS compared with obese controls, the subjects with PWS had significantly decreased total bone and spine mineral density and total bone mineral content (all P < 0.001). No differences in N-telopeptide levels or bone mineral density were observed between subjects with PWS and chromosome 15q deletion or maternal disomy. Thus, decreased bone mineral density in subjects with PWS may relate to the lack of depositing bone mineral during growth when bones are becoming more dense (e.g., during adolescence), possibly because of decreased production of sex or growth hormones and/or long-standing hypotonia. It may not be caused by loss, or active degradation, of bone matrix measurable by the methods described in this study further supporting the possible need for hormone therapy during adolescence.     

Systematic review of chronic pain in persons with Marfan syndrome

The purpose of this study was to explore the literature on chronic pain in adults with Marfan syndrome (MFS), critically appraising and synthesizing relevant literature. A systematic review was conducted by searching the published literature databases using available medical, physical, psychological, social databases and other sources. All studies that addressed pain in MFS, published in peer‐reviewed journals were assessed. Of 351 search results, 18 articles satisfied the eligibility criteria. All studies were cross‐sectional and quantitative; no randomized controlled trials or intervention studies were found. Most studies had small sample sizes, low response rates and mainly dealt with other aspects of the diagnosis than pain. Only one article dealt mainly with pain. The research on chronic pain in MFS is limited in size and quality. Despite these limitations, studies describe that the prevalence of pain in patients with MFS is high, varying from 47 to 92% and affecting several anatomic sites. In addition, chronic pain limits daily function and few studies describe treatment options for pain in patients with MFS. Research is needed to obtain more evidence‐based knowledge for developing more appropriate rehabilitation programs for people with MFS.     

Growth and maturation in Marfan syndrome

Understanding the growth pattern in Marfan syndrome is important for prediction of expected growth, prevention of excessive growth by hormone therapy, timing of surgical epiphysiodesis for cessation of growth, and instituting brace treatment for scoliosis. In this study, we analyze growth patterns and generate growth charts for persons with Marfan syndrome. From the charts of 180 clinically diagnosed Marfan patients, longitudinal height and weight measurements were obtained. From this data, growth charts and growth velocity charts were generated for males and females. Skeletal maturation was studied by determining the Risser signs from the x-rays of 71 males and 56 females. From 22 female patients, age of menarche was available and retrieved either by reviewing the charts or contacting the patients. Mean length at birth was 53 +/- 4.4 cm for males and 52.5 +/- 3.5 cm for females. Mean final height was 191.3 +/- 9 cm for males and 175.4 +/- 8.2 cm for females. Mean birth weight was 3.51 +/- 0.74 kg for males and 3.48 +/- 0.68 kg for females. The puberty-associated peak in growth velocity was 2.4 years earlier than the gender-matched general population for males with Marfan syndrome and 2.2 years earlier for females. Age of menarche was 11.7 +/- 2 years of age, which is also early compared to the general population. This study suggests that the growth spurt and pubertal skeletal maturation occur early in Marfan syndrome. The growth curves generated should help more accurately predict adult stature, as well as monitor progression toward it.     

Marfan syndrome in the third Millennium

The Marfan syndrome (MFS) is a prominent member of heritable disorders of connective tissue with manifestations involving primarily the skeletal, ocular and cardiovascular systems but also and less systematically investigated the lung, skin and integument, and dura. Over the last two decades, a considerable amount of clinical, molecular and protein data had accumulated. In combination with the study of natural and transgenic animal models, this new information provides greater insight into the pathogenic mechanisms underlying not only the pleiotropic manifestations of MFS but also the important degree of clinical variability (age of onset and severity) observed between patients. The following aspects will be described in this review: the structure and function of fibrillin-1; the fibrillin proteins; mutations in the FBN1 gene and pathogenic mechanisms; animal models. Finally, the currently available laboratory diagnostic tests and their limits will be discussed.     

Linkage analysis in Marfan syndrome.

We have analysed 40 marker loci on 13 chromosomes for linkage with Marfan syndrome. None of the loci was linked to the Marfan syndrome locus at theta = 0.00. This study provides a basis for an exclusion map and for further collaboration in mapping of the locus.     

Avoiding the under-diagnosis of low bone mineral density in Egyptian children with chronic medical conditions affecting bone health

Introduction

The International Society for Clinical Densitometry recommended that the lumbar spine and total body less head (TBLH) are the most accurate and reproducible skeletal sites for performing areal bone mineral density (BMD) measurements. Our objective is to evaluate the role of measurement of femoral neck BMD in avoiding the under-diagnosis of low BMD being a risk for fractures in subjects with chronic medical conditions that might affect bone health.

Material and methods

Subjects with chronic medical conditions that might affect bone health were studied (n = 468) and 36 healthy children were recruited as control subjects. Physical examinations, height, weight measurements and BMI were calculated. Dual-energy radiographic absorptiometry of the lumbar spine and femoral neck were measured.

Results

Bone mineral density z scores in both sites were significantly reduced in chronic patients, compared with control subjects. Prevalence of very low BMD z scores (–2 or more) using lumbar DXA, femoral DXA, and either of the sites were 1.38%, 3.37%, and 3.96%, respectively, while low BMD Z scores (–1 to less than –2) were 9.52%, 18.05% and 21.14% respectively.

Conclusions

We identified a significant decrease in both lumbar and femoral BMDs in studied children. Sometimes femoral BMD is decreased while lumbar BMD is still within the normal range. For this reason we recommend that, when technically feasible and there is no facility to measure TBLH, all those patients should have lumbar spine and femoral neck bone mineral density measurements to avoid under-diagnosis of low BMD being a risk for fractures.