Unique Syndrome Research Articles

Acute Myeloid Leukemia with Translocation (8;16)(p11;p13): A Distinct Syndrome– Case Report and Literature Review

Acute myeloid leukemia with the translocation (8;16)(p11;p13) is a rare type of acute leukemia with a number of unique features including erythrophagocytosis, extramedullary disease, and poor prognosis with high relapse rate. These cases of AML are often categorized as M4, M5a, or M5b AML under the FAB system of AML classification. However, the clinical and pathological features of AML with t(8;16) (p11;p13) do not fit into any of these French- American-British (FAB) classification system subtypes, nor is it recognized as a recurrent genetic abnormality within the WHO classification system. Here, we report the case of a 50-year-old female with a history of low-grade carcinoid tumor on surveillance who developed de novo AML with histiocytic differentiation and t(8;16)(p11;p13). Immunohistochemistry and morphology of the patient’s bone marrow biopsy was not consistent with any specific AML subtype, which resulted in diagnostic and therapeutic delays. AML with t(8;16)(p11;p13) has been described a number of times in the literature as a unique leukemic syndrome based on clinical, cytochemical, and DNA microarray features. As such, AML with t(8;16)(p11;p13) should be added to the WHO classification system list of AML with recurrent genetic abnormalities.

Anti–N-Methyl-D-Aspartate Receptor Encephalitis and Rasmussen-like Syndrome: An Association?

BackgroundN-methyl-D-aspartate (NMDA) receptor encephalitis is an immune-mediated condition that has a broad spectrum of manifestations, including seizures, coma, psychosis, and focal neurological deficits. Although usually a diffuse process, unihemispheric involvement mimicking early stages of Rasmussen encephalitis can occur. Rasmussen's encephalitis is a unique syndrome characterized by progressive hemiplegia, drug-resistant focal epilepsy, cognitive decline, and hemispheric brain atrophy contralateral to the hemiplegia. Patient DescriptionWe describe a two-year-old girl with progressive right weakness and epilepsia partialis continua, concerning for early Rasmussen's encephalitis, who tested positive for anti-NMDA receptor antibodies. She experienced complete clinical recovery after immunotherapy. Anti-NMDA receptor antibodies were absent at three weeks and again at one year after the first treatment of intravenous immunoglobulin. ConclusionsThere are few reports of Rasmussen-like encephalitis in individuals with anti-NMDA receptor antibody positivity. Thus the clinical significance of this association is yet to be determined. In addition, several other antibodies have been documented in individuals with Rasmussen encephalitis. The lack of a consistently reported antibody in Rasmussen encephalitis patients and the temporary nature of the anti-NMDA receptor antibody in our patient raise the following question: Is the presence of anti-NMDA receptor antibodies the cause of the symptoms or secondary to the pathogenic process?

Evaluation of the Japanese Metabolic Syndrome Risk Score (JAMRISC): a newly developed questionnaire used as a screening tool for diagnosing metabolic syndrome and insulin resistance in Japan.

ObjectivesTo prevent the onset of lifestyle-related diseases associated with metabolic syndrome (MetS) in Japan, research into the development of a useful screening method is strongly desired. We developed a new screening questionnaire (JAMRISC) utilizing a logistic regression model and evaluated its ability to predict the development of MetS, type 2 diabetes and other lifestyle-related diseases in Japanese populace.MethodsJAMRISC questionnaire was sent to 1,850 individuals in Rumoi, a small city in Hokkaido. We received a total of 1,054 valid responses. To maximize the target individuals accurately diagnosed with MetS, logistic regression analysis was used to generate a unique metabolic syndrome score calculation formula as taking into consideration the clinical relevance of each question item as individual coefficients.ResultsThe results of our comparative research utilizing both JAMRISC and Finnish Diabetes Risk Score (FINDRISC) questionnaires revealed the usefulness of JAMRISC for its ability to detect risks for MetS, pre-MetS, diabetes, and pre-diabetes. Study of disease risk detection via JAMRISC questionnaire targeting the 4283 residents of Rumoi indicated a high detection rate for pre-MetS (98.8 %), MetS (94.2 %), pre-diabetes (85.1 %) and type 2 diabetes (94.9 %). In addition, JAMRISC was useful not only as a MetS risk score test, but also as a screening tool for diagnosing insulin resistance.ConclusionsJAMRISC questionnaire is a useful instrument for the detection of early risk of not only MetS and type 2 diabetes but also insulin resistance.

Timing of rapid diversification and convergent origins of active pollination within Agavoideae (Asparagaceae).

Yucca species are ideal candidates for the study of coevolution due to the obligate mutualism they form with yucca moth pollinators (genera Tegeticula and Parategeticula). Yuccas are not the only species to exhibit a mutualism with yucca moths; the genus Hesperoyucca is pollinated by the California yucca moth (Tegeticula maculata). Relationships among yuccas, Hesperoyucca, and other members of subfamily Agavoideae are necessary to understand the evolution of this unique pollination syndrome. Here, we investigate evolutionary relationships of yuccas and closely related genera looking at the timing and origin of yucca moth pollination. In this study, we sequenced the chloroplast genomes of 20 species in the subfamily Agavoideae (Asparagaceae) and three confamilial outgroup taxa to resolve intergeneric phylogenetic relationships of Agavoideae. We estimated divergence times using protein-coding genes from 67 chloroplast genomes sampled across monocots to determine the timing of the yucca moth pollination origin. We confidently resolved intergeneric relationships in Agavoideae, demonstrating the origin of the yucca-yucca moth mutualism on two distinct lineages that diverged 27 million years ago. Comparisons of Yucca and Hesperoyucca divergence time to those of yucca moths (Tegeticula and Parategeticula, Prodoxidae) indicate overlapping ages for the origin of pollinating behavior in the moths and pollination by yucca moths in the two plant lineages. Whereas pollinating yucca moths have been shown to have a single origin within the Prodoxidae, there were independent acquisitions of active pollination on lineages leading to Yucca and Hesperoyucca within the Agavoideae.

Novel insights into the polycythemia-paraganglioma-somatostatinoma syndrome.

Worldwide, the syndromes of paraganglioma (PGL), somatostatinoma (SOM) and early childhood polycythemia are described in only a few patients with somatic mutations in the hypoxia-inducible factor 2 alpha (HIF2A). This study provides detailed information about the clinical aspects and course of 7 patients with this syndrome and brings into perspective these experiences with the pertinent literature. Six females and one male presented at a median age of 28 years (range 11-46). Two were found to have HIF2A somatic mosaicism. No relatives were affected. All patients were diagnosed with polycythemia before age 8 and before PGL/SOM developed. PGLs were found at a median age of 17 years (range 8-38) and SOMs at 29 years (range 22-38). PGLs were multiple, recurrent and metastatic in 100, 100 and 29% of all cases, and SOMs in 40, 40 and 60%, respectively. All PGLs were primarily norepinephrine-producing. All patients had abnormal ophthalmologic findings and those with SOMs had gallbladder disease. Computed tomography (CT) and magnetic resonance imaging revealed cystic lesions at multiple sites and hemangiomas in 4 patients (57%), previously thought to be pathognomonic for von Hippel-Lindau disease. The most accurate radiopharmaceutical to detect PGL appeared to be [18F]-fluorodihydroxyphenylalanine ([18F]-FDOPA). Therefore, [18F]-FDOPA PET/CT, not [68Ga]-(DOTA)-[Tyr3]-octreotate ([68Ga]-DOTATATE) PET/CT is recommended for tumor localization and aftercare in this syndrome. The long-term prognosis of the syndrome is unknown. However, to date no deaths occurred after 6 years follow-up. Physicians should be aware of this unique syndrome and its diagnostic and therapeutic challenges.

The clinical relevance of complex regional pain syndrome type I: The Emperor's New Clothes.

The management of patients with chronic pain is a nearly daily challenge to rheumatologists, neurologists, orthopedic surgeons, pain specialists and indeed a issue in nearly every clinical practice. Among the myriad of causes of pain are often included a unique syndrome, generally referred to as complex regional pain syndrome type I (CRPS). Unfortunately CRPS I has become a catch all phase and there are serious questions on whether it exists at all; this has led to an extraordinary number of poorly defined diagnostic criteria. It has also led to an etiologic quagmire that includes features as diverse as autoimmunity to simple trauma. These, in turn, have led to overdiagnosis and often overzealous use of pain medications, including narcotics. In a previous paper, we raised the issue of whether CRPS type I reflected a valid diagnosis. Indeed, the diagnostic criteria for CRPS I, and therefore the diagnosis itself, is unreliable for a number of reasons: 1) the underlying pathophysiology of the signs and symptoms of CPRS I are not biologically plausible; 2) there are no consistent laboratory or imaging testing available; 3) the signs and symptoms fluctuate over time without a medical explanation; 4) the definitions of most studies are derived from statistical analysis with little consideration to required sample size, i.e. power calculations; 5) interobserver reliability in the assessment of the signs and symptoms are often only fair to moderate, and agreement on the diagnosis of "CRPS I" is poor. Even physicians who still believe in the concept of "CRPS I" admit that it is vastly overdiagnosed and has become a diagnosis of last resort, often without a complete differential diagnosis and an alternative explanation. Finally, one of the most convincing arguments that there is no clinical entity as "CRPS I" comes from the enormous heterogeneity in sign and symptom profiles and the heterogeneity of pathophysiological mechanisms postulated. This observation is underscored by the diversity of responses among "CRPS I" patients to essentially all treatment modalities. It has even led to the concept that the signs and symptoms of CRPS can spread throughout the body, as if it is an infectious disease, without any medical plausible explanation. If true progress is to be made in helping patients with pain, it will require entirely new and different concepts and abandoning CRPS I as a legitimate diagnosis.

Spontaneous Lung Lesions in Aging Laboratory Rabbits ( Oryctolagus cuniculus).

Spontaneous age-related lesions of laboratory rabbits are not well documented in the contemporary scientific literature. A retrospective study of diagnostic necropsies of 36 rabbits >2 years of age found a number of common lung lesions. Fibromuscular intimal hyperplasia affected medium and to a lesser extent large pulmonary arteries and was present to a variable extent in all 36 rabbits >2 years of age. The lesions were characterized by fragmentation and/or reduplication of the internal elastic lamina (IEL), proliferation of smoothelin+/alpha-smooth muscle actin (α-SMA)+/vimentin- smooth muscle cells and fewer smoothelin-/α-SMA+/vimentin+ myofibroblasts, and intimal deposition of collagen without thrombosis, embolism, or evidence of pulmonary hypertension. Pulmonary emphysema, present in 30/36 rabbits, was characterized by the loss of alveolar septa; most affected rabbits did not have clinical signs of respiratory disease. In 8/13 rabbits of the inbred EIII/JC audiogenic strain, we identified a unique syndrome of granulomatous pneumonia containing hyaline brown to gray, globular to ring-like acellular material that was Alcian blue and periodic acid-Schiff positive. The material was immunoreactive for surfactant protein-A and had the ultrastructural appearance of multilamellar vesicles, suggesting a genetic defect in surfactant metabolism. Additionally, we found small benign primary lung tumors (fibropapillomas, 5 rabbits) not previously described. Other findings included heterotopic bone (5 rabbits), subacute to chronic suppurative bronchopneumonia, pyogranulomatous pneumonia with plant material, and pulmonary artifacts from barbiturate euthanasia solution.

Physiopathology of Atypical Evolutions of Idiopathic Focal Epilepsies in Childhood

This article aims to discuss if the underlying etiology is an important determinant of atypical evolution of idiopathic focal epilepsy (IFE) in childhood and if there might be biomarkers that would predict atypical evolution. It appears that the determinants of atypical evolution remain largely unknown but that both genetic and epigenetic factors are likely to be involved. The analysis of scalp electroencephalography remains the best biomarker of atypical evolution. However, functional neuroimaging methods of investigation are helpful to better understand how epileptic activity affects brain functioning at rest and during goal-directed tasks and to delineate the extent of brain networks that are impaired by epileptic activity. Moreover, neuroimaging bring new arguments favoring the idea that typical and atypical IFE should not be viewed as distinct entities but as a unique syndrome with various degrees of severity that should be treated using tailored strategies and robust biomarkers of efficacy.

A Case Report of Kartagener Syndrome

Kartagener syndrome/Primary ciliary dyskinesia (PCD) is a rare ciliopathic autosomal recessive genetic disorder that causes defects in the action of cilia lining the respiratory tract (both lower and upper, sinuses, eustachian tube, middle ear) and fallopian tube as well as in the flagella of sperm cells. In 1933, Kartagener described a unique syndrome characterized by the triad of situs inversus, chronic sinusitis, and bronchiactesis, which was named Kartagener syndrome. Our case presented with recurrent respiratory tract infections with situs inversus, nasal polyps and early pulmonary changes of bronchiactesis.

Diagnostic delay in narcolepsy type 1: combining the patients' and the doctors' perspectives.

Narcolepsy type 1 is a neurological disorder characterized by a unique syndrome, including the pathognomonic symptom of cataplexy. The diagnosis can be confirmed by objective measures, such as typical findings in the multiple sleep latency test, reduced or undetectable levels of orexin (hypocretin) in the cerebrospinal fluid, and linkage to a specific HLA haplotype. Nevertheless, the mean time that elapses from symptom onset to the correct diagnosis ranges between 10 and 20years, and the causes and correlates of this delay are poorly understood. Diagnostic delay was assessed on 52 well-defined patients with narcolepsy type 1, evaluating clinical, electrophysiological and neurochemical parameters and the results of a 41-item questionnaire developed to obtain the patients' perspective on various aspects of the diagnostic process. The mean time gap between disease onset and first medical consultation was 3.2±5.1years; the mean diagnostic delay was 8.9±11.0years. Prior to correct diagnosis, patients received a wide variety of misdiagnoses. The self-ratings of the patients revealed that the undiagnosed symptoms caused high levels of anxiety and unjustified criticism by family, friends and employers. Multiple regression analysis identified higher cerebrospinal fluid orexin levels (β=0.311, P=0.01), and a longer interval between the onset of excessive daytime sleepiness and cataplexy (β=0.368, P=0.002) as independent associates of longer diagnostic delay. The diagnostic delay decreased over the last decades (β=-0.672, P<0.001). In conclusion, delayed diagnosis of narcolepsy type 1 is very common, associated with many adverse consequences, and requires educational efforts to improve awareness on narcolepsy among healthcare providers and the general population.

Ammonia level at admission predicts in-hospital mortality for patients with alcoholic hepatitis.

Objective. Alcoholic hepatitis (AH), a unique clinical syndrome among patients with chronic and active alcohol use, is associated with high short-term mortality. An elevated ammonia level is associated with mortality in patients with acute liver failure; however, its impact in AH has not been well-studied. Methods. A retrospective study was performed on patients admitted to a tertiary-care hospital with the discharge diagnosis of AH. Patients meeting criteria for AH were included in the final data analysis. Multivariate logistic regression models were built to examine the impact of serum ammonia in predicting in-hospital mortality (IHM) and 30-day mortality (TDM). Subgroup analysis was also performed, which was limited to patients who had hepatic encephalopathy. Results. Of the 105 AH patients included, 26 (25%) died during the initial hospitalization. Among the 79 patients who survived initial hospitalization, 30 (39%) died within 30 days. Information about ammonia levels at admission was available for 82 patients. Of these, 25 patients had IHM and significantly higher ammonia level (97 vs. 69 μmol/L, P < 0.01). Among the 57 who survived hospitalization, ammonia levels were not significantly different (71 vs. 67 μmol/L, P = 0.69) in patients with and without TDM. The addition of ammonia to the multivariate regression models including age, sex, cirrhosis, treatment and model for end-stage liver disease (MELD) score improved the C statistics for IHM from 0.708 to 0.801 and for TDM from 0.756 to 0.766, respectively. These results were identical, even when limited to patients with hepatic encephalopathy. Conclusion. AH patients with elevated ammonia levels at admission have higher IHM; however, they do not seem to play a significant role in 30-day mortality for patients who survived hospitalization.

HP-04-002 Ischemic Priapism: an extreme and unique compartment syndrome

HP-04-002 Ischemic Priapism: an extreme and unique compartment syndrome

Fat Embolism Syndrome: Fact or Myth?

Fat embolism syndrome (FES) is thought to occur most commonly in patients who suffer severe trauma and orthopedic injuries and may be associated with potentially life-threatening pulmonary complications. However, despite its original description hundreds of years ago, it remains a difficult diagnosis to establish and the process by which a fat embolism leads to the clinical syndrome of FES is poorly understood. Some wonder, therefore, if it is a unique syndrome or just part of the spectrum of systemic inflammatory response syndrome (SIRS) common to other critically ill patients. In this review, we will summarize the clinical and experimental evidence that supports FES as a unique clinical condition.

Metabolic Syndrome Components After Pediatric Liver Transplantation: Prevalence and the Impact of Obesity and Immunosuppression.

Metabolic syndrome is associated with long-term morbidity and mortality after adult liver transplantation (LT). Whether pediatric LT recipients have a higher prevalence of metabolic syndrome remains controversial. In a cross-sectional study, we evaluated pediatric LT recipients aged 8-30 years using National Health and Nutrition Examination Survey (NHANES) protocols. LT recipients were matched by gender, race/ethnicity, and age with controls from NHANES. Pediatric LT recipients (n = 83), after adjusting for overweight/obesity and glucocorticoid use, had increased prevalence of prehypertension and hypertension, impaired glucose tolerance (IGT; 2-h glucose after oral glucose tolerance test ≥140 mg/dL), and low high-density lipoprotein compared to matched NHANES controls (n = 235) despite a lower prevalence of overweight/obesity. Among LT recipients, the adjusted odds of IGT doubled for every 7.5 years taking calcineurin inhibitors (odds ratio = 2.10, 95% confidence interval 1.06-4.17 per 7.5 years taking calcineurin inhibitors, p = 0.03). Among all subjects with IGT, LT recipients had a lower prevalence of overweight/obesity and less insulin resistance (homeostatic model assessment of insulin resistance) than did controls with IGT. Among normal weight subjects, LT recipients were significantly more likely than controls to have prehypertension/hypertension, IGT, low high-density lipoprotein, and metabolic syndrome. Pediatric LT recipients have unique metabolic syndrome profiles and risk factors and will require tailored screening and management protocols.

Stone Throwing in the Glass House.

A small girl with a unique genetic syndrome lies in bed since birth. Her brain does not work. She is in a persistent vegetative state. Recurrent seizures punctuate her intractable epilepsy. She shows no meaningful interaction. Her breathing is insufficient. Upper airway obstruction, repeated aspiration events, chronic lung disease, and scoliosis make her struggle to breathe. Her parents never wanted her to suffer. Two years ago, they agreed to a Physician Orders for Life-Sustaining Treatment (POLST). Their daughter would not undergo resuscitation. Death did not come, however. With meticulous medical care, her body grew. Her breathing worsened. Offered either palliation or a tracheostomy tube, her parents chose “trach.” With easier breathing, the girl expended fewer calories. She continued gastrostomy tube feeds and gained 10 pounds in 3 months. Now she is rehospitalized with respiratory distress. Her weight rises another 2 pounds. We put off calorie reduction for the outpatient setting. For the first time, we discharge the family home with a mechanical ventilator. Our collective health-care efforts have set up a protracted course whose likely end will come in overwhelming sepsis or ARDS, rather than allowing natural death with palliative care. How many ethical issues were raised by this case? I count more than 40 (Table ​(Table11).

The diagnostic challenge of Divry van Bogaert and Sneddon Syndrome: Report of three cases and literature review

Divry van Bogaert Syndrome (DBS) is a familial juvenile-onset disorder characterized by livedo racemosa, white matter disease, dementia, epilepsy and angiographic finding of “cerebral angiomatosis”. A similar syndrome including livedo racemosa and cerebrovascular disease, often associated with anticardiolipin antibodies, has been described as Sneddon Syndrome (SS) highlighting the question whether these two conditions have to be considered different entities or indeed different features of a unique syndrome. Herein, we report the clinical, neuroradiological, histopathological findings and follow up of three cases diagnosed as Divry-van Bogaert Syndrome, including an updated review of literature of both DBS and SS cases. Our findings support the assumption that DBS and SS are different disease entities. DBS is characterized by the typical angiographic feature of angiomatosis, a hereditary trait and a juvenile onset of cognitive impairment and leukoaraiosis, whereas SS has less severe manifestations of cerebrovascular disease associated with livedo racemosa but without the characteristic cerebral angiography. The report of our cases and the literature review underline the necessity of a detailed work-up and the collection of larger series to better clarify the DBS and SS phenotype and course.

The Kidney-Vascular-Bone Axis in the Chronic Kidney Disease-Mineral Bone Disorder.

The last 25 years have been characterized by dramatic improvements in short-term patient and allograft survival after kidney transplantation. Long-term patient and allograft survival remains limited by cardiovascular disease and chronic allograft injury, among other factors. Cardiovascular disease remains a significant contributor to mortality in native chronic kidney disease as well as cardiovascular mortality in chronic kidney disease more than doubles that of the general population. The chronic kidney disease (CKD)-mineral bone disorder (MBD) is a syndrome recently coined to embody the biochemical, skeletal, and cardiovascular pathophysiology that results from disrupting the complex systems biology between the kidney, skeleton, and cardiovascular system in native and transplant kidney disease. The CKD-MBD is a unique kidney disease-specific syndrome containing novel cardiovascular risk factors, with an impact reaching far beyond traditional notions of renal osteodystrophy and hyperparathyroidism. This overview reviews current knowledge of the pathophysiology of the CKD-MBD, including emerging concepts surrounding the importance of circulating pathogenic factors released from the injured kidney that directly cause cardiovascular disease in native and transplant chronic kidney disease, with potential application to mechanisms of chronic allograft injury and vasculopathy.

Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations.

Protein-losing enteropathy (PLE) is a clinical disorder of protein loss from the gastrointestinal system that results in hypoproteinemia and malnutrition. This condition is associated with a wide range of gastrointestinal disorders. Recently, a unique syndrome of congenital PLE associated with biallelic mutations in the DGAT1 gene has been reported in a single family. We hypothesize that mutations in this gene are responsible for undiagnosed cases of PLE in infancy. Here we investigated three children in two families presenting with severe diarrhea, hypoalbuminemia and PLE, using clinical studies, homozygosity mapping, and exome sequencing. In one family, homozygosity mapping using SNP arrays revealed the DGAT1 gene as the best candidate gene for the proband. Sequencing of all the exons including flanking regions and promoter regions of the gene identified a novel homozygous missense variant, p.(Leu295Pro), in the highly conserved membrane-bound O-acyl transferase (MBOAT) domain of the DGAT1 protein. Expression studies verified reduced amounts of DGAT1 in patient fibroblasts. In a second family, exome sequencing identified a previously reported splice site mutation in intron 8. These cases of DGAT1 deficiency extend the molecular and phenotypic spectrum of PLE, suggesting a re-evaluation of the use of DGAT1 inhibitors for metabolic disorders including obesity and diabetes.

Therapeutic Strategies for the Treatment of Alcoholic Hepatitis.

Acute alcoholic hepatitis is a unique clinical syndrome among patients with chronic and active heavy alcohol use. Presenting with acute or chronic liver failure, a severe episode has a potential for 30 to 40% mortality at 1 month from presentation, if not recognized and left untreated. Alcoholic hepatitis patients need supportive therapy for abstinence and nutritional supplementation for those patients with markedly reduced caloric intake. Results of the recently published STOPAH (Steroids or Pentoxifylline for Alcoholic Hepatitis) Study showed only a benefit of corticosteroids on short-term mortality without any benefit of pentoxifylline. Neither of these two drugs impacts medium- and long-term mortality, which is mainly driven by abstinence from alcohol. With the emerging data on the benefits of liver transplantation, liver transplantation could be an important salvage option for a very highly select group of AH patients. More data are needed on the use of liver transplantation in AH as the basis for deriving protocols for selecting cases and for posttransplant management. Currently, many clinical trials are examining the efficacy and safety of new or repurposed compounds in severe AH. These drugs are targeted at various pathways in the pathogenesis of AH: the gut-liver axis, the inflammatory cascade, and liver injury. With increasing interest of researchers and clinicians, supported by funding from the National Institute on Alcohol Abuse and Alcoholism, the future seems promising for the development of effective and safe pharmacological interventions for severe AH.

A distinct X-linked syndrome involving joint contractures, keloids, large optic cup-to-disc ratio, and renal stones results from a filamin A (FLNA) mutation.

We further evaluated a previously reported family with an apparently undescribed X-linked syndrome involving joint contractures, keloids, an increased optic cup-to-disc ratio, and renal stones to elucidate the genetic cause. To do this, we obtained medical histories and performed physical examination on 14 individuals in the family, five of whom are affected males and three are obligate carrier females. Linkage analysis was performed on all but one individual and chromosome X-exome sequencing was done on two affected males. The analysis localized the putative gene to Xq27-qter and chromosome X-exome sequencing revealed a mutation in exon 28 (c.4726G>A) of the filamin A (FLNA) gene, predicting that a conserved glycine had been replaced by arginine at amino acid 1576 (p.G1576R). Segregation analysis demonstrated that all known carrier females tested were heterozygous (G/A), all affected males were hemizygous for the mutation (A allele) and all normal males were hemizygous for the normal G allele. The data and the bioinformatic analysis indicate that the G1576R mutation in the FLNA gene is very likely pathogenic in this family. The syndrome affecting the family shares phenotypic overlap with other syndromes caused by FLNA mutations, but appears to be a distinct phenotype, likely representing a unique genetic syndrome.