Considerable Clinical Variability Research Articles

Morquio syndrome: Diagnosis in an adult

Morquio syndrome or mucopolysaccharidosis (MPS) type IV is a rare autosomal recessive disease in which keratan sulfate builds up in cells. There are two variants, A and B, corresponding to deficiencies of two different enzymes. Type A is usually severe, although considerable clinical variability occurs due to the existence of attenuated phenotypes, which may escape diagnosis until adulthood. We illustrate this little known possibility by reporting a case of MPS IV A diagnosed in a 38-year-old woman. We review the clinical and radiological features of this disease, with which pediatricians are more familiar than other physicians. Our case provides an opportunity to emphasize the need for management by a rheumatologist in addition to the standard surgical treatment.

Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson’s disease

Individuals with familial Parkinson's disease (PD) due to a monogenic defect can show considerable clinical and neuropathological variability. To identify factors underlying this variability, histopathological analysis was performed in two clinically different A53T alpha-synuclein heterozygotes from Family H, a multigenerational alpha-synuclein A53T kindred. To determine whether additional genetic factors could contribute to phenotypic variability, Family H and another multigenerational A53T kindred were analyzed for parkin polymorphisms. We identified a previously described variant in parkin exon 4 associated with increased PD risk (S167N). The two A53T heterozygotes had markedly different neuropathology and different parkin genotypes: A N167 homozygote had early onset rapidly progressive disease, early dementia, myoclonus and sleep disorder, while a S167 homozygote had late onset, slowly progressive disease and late dementia. Both had brainstem, cortical, and intraneuritic Lewy bodies (LB). The N167 individual had widespread cortical neurofibrillary degeneration, while the S167 individual had only medial temporal lobe neurofibrillary degeneration. The N167 individual had severe neuronal loss in CA2 associated with Lewy neurites (LN), while the S167 individual had severe neuronal loss in CA1 associated with TDP-43 immunoreactive neuronal inclusions. These findings implicate TDP-43 in the pathology of familial PD and suggest that parkin may act as a modifier of the A53T alpha-synuclein phenotype of familial PD. Furthermore, they suggest a mechanism by which a rare genetic variant that is associated with a minor increase of PD risk in the heterozygous state may, in the homozygous state, exacerbate a disease phenotype associated with a highly penetrant dominant allele.

The Neuropsychiatry and Neuropsychology Of Lipoid Proteinosis

The Neuropsychiatry and Neuropsychology Of Lipoid Proteinosis

SNP Array Karyotyping Improves Detection Rate of Clonal Chromosomal Abnormalities in Refractory Anemia with Ringed Sideroblasts.

Among WHO low-risk categories of MDS, refractory anemia with ringed sideroblasts (RARS) can be more accurately diagnosed by characteristic pathomorphology. Clonal hematopoiesis and chromosomal abnormalities exemplify a close pathogenetic relationship to other forms of MDS. RARS shows considerable clinical variability even for patients (pts) with identical cytogenetic defects. Due to the low resolution of metaphase cytogenetics (MC) and its dependence on cell growth in vitro, this test is often non-informative in MDS. High-density SNP arrays (SNP-A) allow for a precise identification of unbalanced genomic lesions and copy-neutral loss of heterozygozity. We hypothesize that cryptic chromosomal (chr) aberrations exist in most, if not all, pts with RARS. Their detection may help to improve prognostication, distinguish distinct phenotypes and point towards unifying pathogenic defects. Initially, we analyzed the results of MC in pts with MDS and MDS/MPD (N=455) and in a sub-cohort of RARS, RCMD-RS, RARSt and other MDS subtypes with >15% RS. When we compared pts with/without RS, chr defects were found at comparable frequencies (∼50%). The most commonly occurring defects associated with RS, compared to other forms of MDS, included those of chr 5 (9% vs. 16%, 7 (8% vs. 12%) and 20 (3% vs. 8%). DNA was available for 36 pts with RS and was subjected to 250K SNP-A karyotyping. Pathologic lesions were defined upon exclusion of normal copy number polymorphisms identified in 81 controls (O'Keefe at al ASH 2007), as well as the Database of Genomic Variants (http://projects.tcag.ca/variation). By MC, a defective karyotype was present in 16/36 pts (44%). Deletions involving chr 5, 7 and complex MC were found in 3, 5, and 2pts, respectively. However, when SNP-A was applied as a karyotyping tool (copy number and LOH analysis), all aberrations found by MC were confirmed, but also new lesions were detected so that an abnormal karyotype was established in 62% of pts. Several previously cryptic/recurrent lesions included losses of a portion of chr. 2 (N=2; 2p16.2, 2p16.3), and deletions (N=4; 7p11.1–14.1, 7p21.3, 7q11.23–21.11, 7q21.12-qter) as well as gains (N=1; 7q33) on chr 7. We have also detected segmental uniparental disomy (UPD) in chr 1 (N=2; 1p21.3–22.2, 1p). This type of lesion cannot be detected using MC and provides an additional mechanism leading to LOH. When both bone marrow and blood of 5 RARS patient were tested using SNP-A, blood analysis had 100% accuracy rate as compared to marrow; all defects seen in the marrow were also found in blood. We conclude that chromosomal defects are present in a majority of RARS patients and arrays with higher resolution will identify defects in most, if not all of the patients. Our study also demonstrates testing of peripheral blood by SNP-A can complement marrow MC, especially in cases in which marrow is not available. Detection of clonal marker aberrations in blood of RARS patients suggests that mostly clonal dysplastic progenitor cells contribute to blood production rather than residual “normal” progenitors.

Extreme variation in apoptosis capacity amongst lymphoid cells of Nijmegen breakage syndrome patients

The human genetic disorder, Nijmegen breakage syndrome (NBS), is characterised by radiosensitivity, immunodeficiency and an increased risk for cancer, particularly lymphoma. The NBS1 gene codes for a protein, nibrin, involved in the processing/repair of DNA double strand breaks and in cell cycle checkpoints. The majority of patients (>90%) are homozygous for a founder mutation. Despite this genetic homogeneity, the syndrome shows considerable clinical variability, for example, in age at development of a malignancy. We hypothesised that one reason for such variation might be individual differences in the clearance of heavily damaged precancerous cells by apoptosis. To test this hypothesis we have examined a set of 30 lymphoblastoid B-cell lines from NBS patients for their capacity to enter into apoptosis after a DNA-damaging treatment. There was a substantial 40-fold variation in apoptosis between cell lines from different patients. NBS patient cell lines could be grouped into a large, apoptosis-deficient group and a smaller group with essentially normal apoptotic response to DNA damage. In both groups, cell lines were proficient in TP53 phosphorylation and stabilisation after the same DNA-damaging treatment. Thus the observed variation in apoptosis capacity is not due to failure to activate TP53. Despite the large variation in apoptosis, no statistically significant correlation between apoptotic capacity of patient cell lines and clinical course of the disease was apparent.

Complex Inheritance Pattern Resembling Autosomal Recessive Inheritance Involving a Microdeletion in Thrombocytopenia–Absent Radius Syndrome

Thrombocytopenia-absent radius (TAR) syndrome is characterized by hypomegakaryocytic thrombocytopenia and bilateral radial aplasia in the presence of both thumbs. Other frequent associations are congenital heart disease and a high incidence of cow's milk intolerance. Evidence for autosomal recessive inheritance comes from families with several affected individuals born to unaffected parents, but several other observations argue for a more complex pattern of inheritance. In this study, we describe a common interstitial microdeletion of 200 kb on chromosome 1q21.1 in all 30 investigated patients with TAR syndrome, detected by microarray-based comparative genomic hybridization. Analysis of the parents revealed that this deletion occurred de novo in 25% of affected individuals. Intriguingly, inheritance of the deletion along the maternal line as well as the paternal line was observed. The absence of this deletion in a cohort of control individuals argues for a specific role played by the microdeletion in the pathogenesis of TAR syndrome. We hypothesize that TAR syndrome is associated with a deletion on chromosome 1q21.1 but that the phenotype develops only in the presence of an additional as-yet-unknown modifier (mTAR).

Anophthalmia‐esophageal atresia syndrome caused by an SOX2 gene deletion in monozygotic twin brothers with markedly discordant phenotypes

The clinical combination of anophthalmia/microphthalmia and esophageal atresia was first recognized in 1988 as a distinct variable multi-system malformation syndrome and since then at least 17 cases of the disease have been described, all of them sporadic in occurrence. We report a heterozygous SOX2 gene mutation underlying the syndrome of anophthalmia/microphthalmia-esophageal atresia and demonstrate that this entity can be associated to considerable clinical variability as shown by the discordant ocular phenotype observed in monozygotic twin brothers carrying an SOX2 deletion. This is the first report describing a strikingly discordant eye phenotype in monozygotic twins with the condition, with one of our patients being the first reported individual carrying an SOX2 lesion associated with unilateral eye defect. We discuss the probable sources for this remarkable phenotypic heterogeneity of the anophthalmia/microphthalmia syndrome in individuals with an identical genetic constitution.

行動療法と環境整備により著明な減量とその後の体重維持を成し得たPrader-Willi症候群の2例

Prader-Willi Syndrome (PWS) is a complex neurogenetic disorder with considerable clinical variability, and is considered to be mainly the result of a hypothalamic defect. PWS is characterized by hyperphagia, obesity, mental retardation and hypogonadism from a young age. Hyperphagia is one of the most serious problems, which is organic in origin, inducing morbid obesity and leading to respiratory failure. Most studies attempting to control obesity in children with PWS by dietary management reported limited success due to difficulty in controlling foraging and food stealing. Here we report 16- and 20-year-old female patients with PWS who showed marked weight loss and improvement of respiratory failure by behavior modification and improvement of the environment.

A Rare Tricuspid Anomaly

54-year-old Mexican American woman was admitted to the Erie County Medical Center, Buffalo, NY, with the general symptoms of tiredness, weight loss with loss of appetite, leg weakness, and low blood pressure (80/60 mm Hg). The patient denied any paroxysmal nocturnal dyspnea, orthopnea, or leg edema. She did have some facial swelling, a skin rash on both hands, and joint swelling, which was consistent with a previous diagnosis of polymyositis and dermatomyositis. The patient also had evidence of septic arthritis of the left elbow. Physical examination revealed extensive wheezing and a grade 2/3 systolic ejection murmur, heard predominantly over the tricuspid valve area. Laboratory workup revealed pancytopenia and an elevation in liver function tests. All the markers for autoimmune disease were negative. Biopsies and computerized tomographic scans performed to search for visceral malignancy were negative. Blood cultures grew methicillin-sensitive Staphylococcus aureus. Electrocardiography revealed normal sinus rhythm with evidence of right atrial enlarge

Spontaneous Pneumomediastinum: Descriptive Study of Our Experience With 36 Cases

Spontaneous pneumomediastinum is defined as a primary process characterized by the presence of air or gas in the mediastinum. We report all the cases of spontaneous pneumomediastinum diagnosed in our hospital between January 1996 and December 2004. We developed a protocol for data collection that included the following: medical history, triggers, signs, radiology, treatment, hospital stay, and complications. During this period we diagnosed 36 cases—25 men (69.4%) and 11 women (30.6%)—with a mean age of 36.8 years (range, 11-90 years) and a mean hospital stay of 8.56 days (range, 1-53 days). The most common clinical presentation was chest pain, either isolated (27%) or with associated dyspnea (19.4%). A triggering factor was identified for 14 patients (38.8%). There was no associated morbidity or mortality. In view of our findings, we concluded that spontaneous pneumomediastinum is an uncommon entity with considerable clinical variability and that correct diagnosis requires a high level of suspicion. Radiography provides the best evidence for diagnosis.

Clinical and molecular characterization of lipoid proteinosis in Namaqualand, South Africa.

Lipoid proteinosis (LiP) is a rare autosomal recessive disorder characterized by a hoarse voice, warty skin infiltration and scarring. Mutations within the extracellular matrix protein 1 (ECM1) gene cause LiP. Since the early 1970s it has been recognized that South Africa has one of the largest groups of LiP patients worldwide, suggesting a probable founder effect. As LiP patients present with considerable clinical variability, this group of patients offers a unique opportunity for genotype-phenotype correlation. To assess the clinical features and the molecular basis of LiP in patients from the Namaqualand area of the Northern Cape province of South Africa and to examine molecular evidence for a founder effect. The LiP patient cohort consisted of 29 Coloured patients from Namaqualand and a further seven Caucasoid patients from other areas of South Africa. The control group included 100 healthy geographically and ethnically matched individuals from Namaqualand. Samples were collected after informed consent and with ethics committee approval from the University of the Witwatersrand. LiP patients were examined clinically and a structured recording sheet was completed. A brief neurological evaluation was also performed. The LiP founder effect was investigated at the molecular level by ECM1 mutation detection and haplotype analysis. The most consistent clinical signs for a diagnosis of LiP in this group were a hoarse voice and thickened sublingual frenulum leading to restricted tongue movement. Homozygosity for a nonsense mutation in exon 7 of the ECM1 gene, Q276X, was identified in all patients (Coloured and Caucasoid). Despite this genetic homogeneity, considerable clinical variability in skin presentation and psychiatric involvement was observed. Haplotype analysis using markers from a 9.98-Mb region around the ECM1 locus confirmed the founder effect with a founder core haplotype, 19-Q276X-12 (ND1-ECM1-D1S2343), in all but four LiP-associated alleles (n = 58). A LiP carrier rate of 1 in 9 was observed among the 100 Namaqualand controls, predicting a LiP incidence of 1 in 324 in this community. Although several consistent clinical features in LiP patients homozygous for the Q276X mutation in the ECM1 gene were observed, there remains considerable clinical variability. This suggests the action of genetic and environmental modifiers of disease severity. Strong molecular evidence supports a single founder effect for the high prevalence of LiP in South Africans, both Coloured and Caucasoid.

Evaluation of alpha hemoglobin stabilizing protein (AHSP) as a genetic modifier in patients with β thalassemia

AbstractAlthough β thalassemia is considered to be a classic monogenic disease, it is clear that there is considerable clinical variability between patients who inherit identical β globin gene mutations, suggesting that there may be a variety of genetic determinants influencing different clinical phenotypes. It has been suggested that variations in the structure or amounts of a highly expressed red cell protein (alpha hemoglobin stabilizing protein [AHSP]), which can stabilize free α globin chains in vitro, could influence disease severity in patients with β thalassemia. To address this hypothesis, we studied 120 patients with Hb E-β thalassemia with mild, moderate, or severe clinical phenotypes. Using gene mapping, direct genomic sequencing, and extended haplotype analysis, we found no mutation or specific association between haplotypes of AHSP and disease severity in these patients, suggesting that AHSP is not a disease modifier in Hb E-β thalassemia. It remains to be seen if any association between AHSP and clinical severity is present in other population groups with a high frequency of β thalassemia. (Blood. 2004;103:3296-3299)

Predictive factors in early arthritis: long-term follow-up

Background Because recent-onset inflammatory arthritis exhibits considerable clinical and prognostic variability, it is important to attempt to predict which patients are likely to have a poor prognosis as early as possible. Most prognostic studies have looked at patients who fulfilled proposed criteria for a definite diagnosis of rheumatoid arthritis (RA) or other well-defined conditions; less information exists concerning predictive factors for other types of early arthritis. Objectives To examine prognosis in early arthritis, the authors assessed the long-term outcome in a cohort of patients who presented with inflammatory arthritis of short duration. Associations between outcome and patient clinical characteristics were analyzed to determine possible prognostic factors. Methods Since 1968, patients were selected to be followed up in 2 early-arthritis clinics if they had evidence of inflammatory joint disease and symptom duration was <1 year. Length of follow-up was variable, but was at least 1 year. At last follow-up, patients were classified as being in remission or as having persistent disease. Factors associated with a poor outcome were identified by using formal statistical methods. Results A total of 121 patients were included in this analysis. Mean disease duration to the first evaluation was 3 months, and median follow-up was 5 years (range, 1 to 30 months). Twenty-one patients (17%) had transient disease defined as total duration of <6 weeks. Sixty-three patients (52%) were in remission at final follow-up, with unclassified patients doing the best. Patients meeting criteria for RA or spondylarthropathies had more persistent disease. Polyarticular disease predicted more persistent disease ( P < .05). In multivariable analyses, patients with initial hand involvement were much less likely to achieve remission of their disease (odds ratio, 0.18; 95% confidence interval, 0.05 to 0.66). Only 4 patients had either class 4 function or joint replacement. Conclusions Our findings indicate that prognosis in early inflammatory arthritis is generally good, with more than half of all patients achieving remission in our cohort. Patients with unclassified arthritis fared better than those meeting criteria for RA or spondylarthropathy. Of the many clinical variables examined as possible prognostic factors, hand involvement was the strongest predictor of a poor outcome. Relevance The long follow-up of these patients with early arthritis provides clues for the clinician to the likely course and shows that many patients will do well.

Adverse drug reactions: role of pharmacogenomics

Adverse drug reactions (ADRs) are a significant cause of morbidity and mortality. The majority of ADRs can be considered common disorders with considerable clinical variability (clinical phenotype) in which many different genes are involved together with environmental variables. Pharmacogenomics is the study of how genes affect the individual response to drugs. There is some evidence that in the future the use of pharmacogenomics could help to reduce ADRs, as it aims to predict which patients are likely to respond to a particular drug and which patients are likely to have significant ADRs. In this article some examples of genetic polymorphisms affecting drug kinetics, drug toxicity and hypersensitivity related to ADRs are illustrated.

Disruption of the mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a complex neurogenetic disorder with considerable clinical variability that is thought in large part to be the result of a hypothalamic defect. PWS results from the absence of paternal expression of imprinted genes localized in the 15q11-q13 region; however, none of the characterized genes has so far been shown to be involved in the etiology of PWS. Here, we provide a detailed investigation of a mouse model deficient for NECDIN: Linked to the mutation, a neonatal lethality of variable penetrance is observed. Viable NECDIN: mutants show a reduction in both oxytocin-producing and luteinizing hormone-releasing hormone (LHRH)-producing neurons in hypothalamus. This represents the first evidence of a hypothalamic deficiency in a mouse model of PWS. NECDIN:-deficient mice also display increased skin scraping activity in the open field test and improved spatial learning and memory in the Morris water maze. The latter features are reminiscent of the skin picking and improved spatial memory that are characteristics of the PWS phenotype. These striking parallels in hypothalamic structure, emotional and cognitive-related behaviors strongly suggest that NECDIN is responsible for at least a subset of the multiple clinical manifestations of PWS.

Epidemiology of A3243G, the Mutation for Mitochondrial Encephalomyopathy, Lactic Acidosis, and Strokelike Episodes: Prevalence of the Mutation in an Adult Population

Mitochondrial diseases are characterized by considerable clinical variability and are most often caused by mutations in mtDNA. Because of the phenotypic variability, epidemiological studies of the frequency of these disorders have been difficult to perform. We studied the prevalence of the mtDNA mutation at nucleotide 3243 in an adult population of 245,201 individuals. This mutation is the most common molecular etiology of MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes), one of the clinical entities among the mitochondrial disorders. Patients with diabetes mellitus, sensorineural hearing impairment, epilepsy, occipital brain infarct, ophthalmoplegia, cerebral white-matter disease, basal-ganglia calcifications, hypertrophic cardiomyopathy, or ataxia were ascertained on the basis of defined clinical criteria and family-history data. A total of 615 patients were identified, and 480 samples were examined for the mutation. The mutation was found in 11 pedigrees, and its frequency was calculated to be >=16. 3/100,000 in the adult population (95% confidence interval 11.3-21. 4/100,000). The mutation had arisen in the population at least nine times, as determined by mtDNA haplotyping. Clinical evaluation of the probands revealed a syndrome that most frequently consisted of hearing impairment, cognitive decline, and short stature. The high prevalence of the common MELAS mutation in the adult population suggests that mitochondrial disorders constitute one of the largest diagnostic categories of neurogenetic diseases.

Molecular analysis and electromyoneurographic abnormalities in Croatian children with proximal spinal muscular atrophies.

Childhood onset proximal spinal muscular atrophy presents with considerable clinical variability. This study included 14 Croatian children aged 11 days to 8 years with spinal muscular atrophy types I-III verified clinically and electromyoneurographically. DNA of affected children was screened for deletions of exons 7 and 8 of the survival motor neuron gene and for deletion of exon 5 of the neuronal apoptosis inhibitor protein gene. Motor nerve conduction velocity and compound muscle action potential amplitude were decreased in children with spinal muscular atrophy type I and II. Deletions of exons 7 and 8 of the survival motor neuron gene and of exon 5 of the neuronal apoptosis inhibitor protein gene in children with spinal muscular atrophy type I-II suggested existence of more genetic abnormalities as compared to type III. A decrease in compound muscle action potential amplitude and motor nerve conduction velocity in children with spinal muscular atrophy correlated with the disease severity, probably as a result of axonal degeneration. Phenotypic severity in children onset spinal muscular atrophy is directly correlated with the extent of survival motor neuron and neuronal apoptosis inhibitor protein exon deletions.

A specific collagen type II gene (COL2A1) mutation presenting as spondyloperipheral dysplasia

We report on a patient with a skeletal dysplasia characterized by short stature, spondylo-epiphyseal involvement, and brachydactyly E-like changes. This condition has been described as spondyloperipheral dysplasia and the few published cases suggest autosomal dominant inheritance with considerable clinical variability. We found our sporadic case to be due to a collagen type II defect resulting from a specific COL2A1 mutation. This mutation is the first to be located at the C-terminal outside the helical domain of COL2A1. A frameshift as consequence of a 5 bp duplication in exon 51 leads to a stop codon. The resulting truncated C-propeptide region seems to affect helix formation and produces changes of chondrocyte morphology, collagen type II fibril structure and cartilage matrix composition. Our case with its distinct phenotype adds another chondrodysplasia to the clinical spectrum of type II collagenopathies. © 1996 Wiley-Liss, Inc.

Spondyloperipheral dysplasia

We present a patient with spondyloperipheral dysplasia, a rare skeletal dysplasia which is characterized by vertebral body abnormalities (platyspondyly, end-plate indentations) and brachydactyly. Our patient also manifested a characteristic "pugilistic" face, sensorineural deafness and mental retardation. This chondroosseous dysplasia appears to be inherited as an autosomal dominant disorder. It appears that there is considerable clinical variability in spondyloperipheral dysplasia.

Autosomal dominant cerebellar ataxia

We describe 263 patients with autosomal dominant cerebellar ataxia from the Holguín province, Cuba. There is evidence of a common ancestry and the population represents the largest homogeneous group of patients yet described. Primary features include gait ataxia, dysarthria, dysmetria, adiadochokinesia, cramps, tremor, hypotonia, abnormal reflexes, and slowed/limited eye movements. Age at onset ranged from 2 to 65 years. There was considerable clinical variability within the families. No patients had optic atrophy, spasticity, pigmentary retinal degeneration, or cogwheel rigidity, and only 1 had dementia.