Dyggve–Melchior–Clausen syndrome: clinical, genetic, and radiological study of 15 Egyptian patients from nine unrelated families

Introduction  

Dyggve–Melchior–Clausen (DMC) syndrome is a rare autosomal recessive type of skeletal dysplasia. It is characterized by the association of progressive spondyloepimetaphyseal dysplasia (SEMD), microcephaly, mental retardation (MR), and coarse facies. The radiographic appearance of generalized platyspondyly with double-humped end plates and the lace-like appearance of iliac crests are pathognomonic and distinctive of DMC syndrome. The disorder results from mutations in the DYM gene mapped in the 18q12-12.1 chromosomal region.     

46,XX male: clinical,hormonal/genetic findings

The clinical genetics and hormonal status of the 46,XX male is well determined. This is a rare condition that affects one out 20,000 male births. This study evaluates 5 infertile patients with no abnormalities in sex definition in whom we noted variants in their phenotype, like small penis, hypospadias, cryptorchidism, flat scrotum, and in some of them small testis. Only one patient had gynecomastia; all patients were azoospermics. Otherwise, serum FSH levels were elevated in only 3 patients and LH in 2. Serum levels of testosterone were low in 3 cases. Karyotype was 46,XX without evidence of mosaicism. PCR of genomic DNA studied revealed only the presence of SRY gene. DNA material in the Y chromosome was similar in all patients, but this did not correlate with the phenotype findings and hormonal levels in all of them. Testing new chromosomal markers should be of great value in the definition of clinical difference.     

Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity

Wolcott-Rallison syndrome (WRS) is a rare autosomal-recessive disorder characterized by the association of permanent neonatal or early-infancy insulin-dependent diabetes, multiple epiphyseal dysplasia and growth retardation, and other variable multisystemic clinical manifestations. Based on genetic studies of two inbred families, we previously identified the gene responsible for this disorder as EIF2AK3, the pancreatic eukaryotic initiation factor 2alpha (eIF2alpha) kinase. Here, we have studied 12 families with WRS, totalling 18 cases. With the exception of one case, all patients carried EIF2AK3 mutations resulting in truncated or missense versions of the protein. Exclusion of EIF2AK3 mutations in the one patient case was confirmed by both linkage and sequence data. The activities of missense versions of EIF2AK3 were characterized in vivo and in vitro and found to have a complete lack of activity in four mutant proteins and residual kinase activity in one. Remarkably, the onset of diabetes was relatively late (30 months) in the patient expressing the partially defective EIF2AK3 mutant and in the patient with no EIF2AK3 involvement (18 months) compared with other patients (<6 months). The patient with no EIF2AK3 involvement did not have any of the other variable clinical manifestations associated with WRS, which supports the idea that the genetic heterogeneity between this variant form of WRS and EIF2AK3 WRS correlates with some clinical heterogeneity.     

Combined Alport syndrome,Klinefelter syndrome and Fanconi syndrome in a Chinese boy

Alport syndrome (AS) is a progressive renal disease characterized by hematuria and progressive renal failure. X-linked dominant (XLAS) is the major inheritance form, accounting for almost 80% of the cases, caused by mutations in COL4A5 genes. Klinefelter syndrome (KS) is the most common genetic cause of human male gonadal dysgenesis. AS and KS are both rare disease, there are only three cases of combined AS and KS in the literatures. Fanconi syndrome (FS) caused by AS is also very rare. We report here the first case combined AS, KS and FS in a Chinese boy. We suggest that the severe renal phenotype and FS might be due to the two homozygous COL4A5 variants in our boy, and cases of AS combined KS will be good research objects for X chromosome inactivation.     

Lynch syndrome: clinical,pathological, and genetic insights

Introduction  

Lynch syndrome as the most common hereditary colorectal cancer syndrome and the most common cause of hereditary endometrial cancer is characterized by an autosomal dominant inheritance with a penetrance of 85–90%. The molecular genetic underlying mechanism is a mutation in one of the mismatch repair genes.     

Inner ear abnormalities in four patients with dRTA and SNHL: clinical and genetic heterogeneity

A significant number of patients affected by autosomal recessive primary distal renal tubular acidosis (dRTA) manifest sensorineural hearing loss (SNHL). Mutations in ATP6V1B1 are associated with early onset SNHL, whereas ATP6V0A4 mutations have been described in dRTA and late-onset SNHL. Enlarged vestibular aqueduct (EVA) was described in patients with recessive dRTA and SNHL, and recently, this abnormality has been associated with mutations in the ATP6V1B1 gene. In our study, we evaluated the presence of inner-ear abnormalities in four patients affected by dRTA and SNHL, characterized by molecular analysis. Two patients affected by severe dRTA with early onset SNHL showed the same mutation in the ATP6V1B1 gene and bilateral EVA with a different degree of severity. The other two presented similar clinical manifestations of dRTA and different mutations in the ATP6V0A4 gene: one patient, showing EVA, developed an early SNHL, whereas in the other one, the SNHL appeared in the second decade of life and the vestibular aqueduct was normal. Our study confirms the association of EVA and mutations in the ATP6V1B1 gene and demonstrates that mutations in the ATP6V0A4 gene can also be associated with EVA probably only when the SNHL has an early onset. The pathophysiology of SNHL and EVA are still to be defined.     

Further genetic evidence suggesting a role for the RhoGTPase-RhoGEF pathway in osteoporosis

Osteoporosis is a highly heritable trait that appears to be influenced by multiple genes. Genome-wide linkage studies have highlighted the chromosomal region 3p14-p21 as a quantitative trait locus for BMD. We have previously published evidence suggesting that the ARHGEF3 gene from this region is associated with BMD in women. The product of this gene activates the RHOA GTPase, the gene for which is also located within this region. The aim of this study was to evaluate the influence of genetic polymorphism in RHOA on bone density in women. Sequence variation within the RHOA gene region was determined using 9 single nucleotide polymorphisms (SNPs) in a discovery cohort of 769 female sibs. Of the 9 SNPs, one was found to be monomorphic with the others representing 3 distinct linkage disequilibrium (LD) blocks. Using FBAT software, significant associations were found between two of these LD blocks and BMD Z-score of the spine and hip (P = 0.001–0.036). The LD block tagged by the SNP rs17595772 showed maximal association, with the more common G allele at rs17595772 associated with decreased BMD Z-score. Genotyping for rs17595772 in a replication cohort of 780 postmenopausal women confirmed an association with BMD Z-score (P = 0.002–0.036). Again, the G allele was found to be associated with a reduced hip and spine BMD Z-score. These results support the implication of the RhoGTPase-RhoGEF pathway in osteoporosis, and suggest that one or more genes in this pathway may be responsible for the linkage observed between 3p14-p21 and BMD.     

The VIPoma: Further confirmation of VIP as the hormonal agent in the WDHA syndrome

The WDHA syndrome characterized by watery diarrhea, hypokalemia, and achlorhydria is being diagnosed with increasing frequency. The diagnosis has been made to date only due to severe clinical symptomatology. In a review of the literature gastrin, secretin, glucagon, enteroglucagon, gastric inhibitory peptide (GIF), vasoactive intestinal peptide (VIP), and prostaglandins have been variously suggested as a possible etiologic agent for this syndrome. A case of the WDHA syndrome is reported in which hormonal assays of the serum preoperatively and two years postoperatively and tumor for many of the proposed agents is performed. A discussion of possible cross-reactivity among these similarly structured polypeptides in the radioimmunoassays systems is used to explain the multitude of possible hormonal agents presented in the literature. Standardization of the VIP assays will result in increasing diagnosis of this disease state prior to its fulminant clinical presentation.     

Clinical and diagnostic features of patients with suspected Klinefelter syndrome

Klinefelter syndrome, with an incidence of 1:600 male newborns, is the most frequent form of male hypogonadism. However, despite its relatively high frequency, the syndrome is often overlooked. To prevent such oversights, the clinical features should be better characterized, and simple screening tests should be used more frequently. In a cohort of 309 patients suspected of having Klinefelter syndrome, we evaluated the clinical symptoms as well as the diagnostic value of the Barr body test for screening procedures. On the basis of chromosome analysis, 85 patients (group I) were diagnosed as having Klinefelter syndrome, and 224 patients had a 46,XY karyotype (group II). Barr body analysis revealed a specificity of 95% and a sensitivity of 82% for the diagnosis of Klinefelter syndrome. General features (eg, reason for admission, age, age of the parents, body weight, and frequency of maldescended testes) were not different between the groups, except that group I had a higher proportion of patients with a lower educational background. Compared to group II, patients with Klinefelter syndrome were taller (P <.001); had smaller testis volumes (P <.0001), higher follicle-stimulating hormone (FSH) and luteinizing hormone (LH) values; and carried a tendency for less androgenic phenotype and secondary hair distribution. Testosterone, estradiol, sex hormone-binding globulin (SHBG), and prostate-specific antigen (PSA) serum levels as well as prostate volume were not significantly different between the groups. In patients who provided an ejaculate, azoospermia was found in 54% of the patients in group II and in 93% of the patients with Klinefelter syndrome. Although not exclusively characteristic for Klinefelter syndrome, the combination of low testicular volume and azoospermia, together with elevated gonadotropins, is highly indicative for a Klinefelter syndrome and should stimulate further clinical investigations. Barr body analysis provides a quick and reliable screening test, which, however, must be confirmed by karyotyping.     

Congenital bilateral anorchia: clinical, hormonal and imaging study in 12 cases

Summary. Twelve anorchid pre-pubertal and post-pubertal patients, aged between 8.5 and 41 years, were studied. The FSH and LH basal levels as well as their responses to Gn-RH (100 μg i.v.) were increased and prolonged in the post-pubertal patients. The testosterone levels were in the prepubertal range and failed to increase after HCG administration (1500 I.U. t.i.d. for 3 days).
Ultrasonography of the pelvis was performed in all the patients. Computed tomography and magnetic resonance of the abdomen were also performed in 6 and 5 patients respectively. These techniques failed to show any testicular tissue. Lastly, in 4 patients, surgical exploration confirmed the absence of testicular structure.     

Agreement between diagnoses reached by clinical examination and available reference standards: a prospective study of 216 patients with lumbopelvic pain

Background  

The tissue origin of low back pain (LBP) or referred lower extremity symptoms (LES) may be identified in about 70% of cases using advanced imaging, discography and facet or sacroiliac joint blocks. These techniques are invasive and availability varies. A clinical examination is non-invasive and widely available but its validity is questioned. Diagnostic studies usually examine single tests in relation to single reference standards, yet in clinical practice, clinicians use multiple tests and select from a range of possible diagnoses. There is a need for studies that evaluate the diagnostic performance of clinical diagnoses against available reference standards.     

Further evidence supporting the existence of the celiac artery compression syndrome

A 23-year-old man presented with prolonged postprandial epigastric pain and an epigastric bruit with systolic and diastolic components, the intensity of which decreased with inspiration as demonstrated by abdominal phonography. Arteriography demonstrated significant narrowing of the origin of the celiac artery. At operation, the origin of the celiac artery was found to be constricted by fibers of the median arcuate ligament of the diaphragm, and this ligament was divided. Intraoperative flow measurements demonstrated an increase in blood flow through the main branches of the celiac axis, after division of the ligament. Four years following successful surgery, the patient has continued to be in good health without symptoms, and the bruit has remained absent. Further abdominal arteriography has demonstrated the normality of the celiac artery. We believe this to be a well-proven case of the "celiac artery compression syndrome."     

Psoriatic arthritis among Egyptian patients with psoriasis attending the dermatology clinic: prevalence,comorbidities, and clinical predictors

ObjectivesEarly diagnosis and treatment of psoriatic arthritis (PsA) help to prevent progressive joint involvement and disabilities. There is a problem in the early diagnosis of PsA worldwide, which may be attributed to the dermatologists missing PsA symptoms and signs and a lack of effective screening tools.Aim of the studyThe current study was designed to assess the prevalence, comorbidities, and clinical predictors associated with the development of PsA in psoriasis patients.Material and methodsA cross-sectional observational study was performed. Screening questionnaires – the Psoriasis Epidemiology Screening Tool (PEST) and Early Arthritis for Psoriatic Patients (EARP) – were applied to 200 psoriasis patients; among them n = 22 (11% of all tested patients) were in developmental age. Those with positive questionnaires were classified as having PsA or not according to the classification for psoriatic arthritis criteria. Body surface area, psoriasis area and severity index, and psoriasis disability index tools were used for assessing psoriasis patients. A full rheumatological and dermatological evaluation were carried out for PsA patients.ResultsThe prevalence of PsA was found to be 30%, with a mean age of 45.48 ±10.79 years. Further, psoriasis preceded the onset of PsA in 46 patients (76.6%), arthritis began before psoriasis in 6 individuals (10%), and both psoriasis and arthritis coincided in 8 (13.3%) patients. Obesity (OR 7.0, 95% CI: 2.61–18.85), nail psoriasis (OR 5.02, 95% CI: 2.02–12.476), and intergluteal cleft site (OR 12.659, 95% CI: 4.302–37.255) were associated with increased risk of PsA. However, classic plaque psoriasis (OR 0.149, 95% CI: 0.051–0.433) and flexure site (OR 0.238, 95% CI: 0.076–0.746) were linked with a decreased risk of PsA development.ConclusionsScreening for PsA in patients with psoriasis revealed a significant number of undiagnosed cases of PsA that should be treated early. Obesity, nail psoriasis, and psoriasis at the intergluteal sites can help predict the PsA development.     

Polymerase chain reaction-based assays facilitate the breeding and study of mouse models of Klinefelter syndrome

Klinefelter syndrome(KS)is one of the most frequent genetic abnormalities and the leading genetic cause of nonobstructive azoospermia.The breeding and study of ...     

Lynch syndrome in a predominantly Afrocentric population: a clinicopathological and genetic study

Background

We investigated the prevalence of Lynch syndrome as a hereditary cause of colon cancer in the young Jamaican colorectal cancer (CRC) population.

Methods

We identified patients aged 40 years or younger in whom primary CRC was diagnosed at the University Hospital of the West Indies from January 2004 to December 2008. We reviewed the medical records and hematoxylin and eosin (H&E)–stained histopathology slides. Tumour blocks were tested for microsatellite instability (MSI). Patients with MSI–high phenotype (MSI-H) tumours had genetic counselling, after which genomic DNA was extracted from peripheral blood to test for MLH1 and MSH2 germline mutations. Patients also had pedigree mapping.

Results

There were 25 patients with CRC aged 40 years or younger with no history of hereditary colon cancer syndrome. The patients’ mean age was 33 (range 21–40) years. Histopathologic review confirmed CRC in all patients; 8 of 25 (32%) showed morphologic features suggestive of MSI. We detected MSI-H in 5 of 23 (22%) tumour blocks tested. Review with H&E staining correctly identified 80% of cases positive for MSI-H. The false-positive rate and positive predictive value on H&E review was 50%. The negative predictive value of histomorphologic H&E review was 94%. Three patients were available for and had mutational analysis of DNA mismatch repair genes; 2 were positive for mutations in keeping with Lynch syndrome and 1 had MLH1 alterations of uncertain significance. All 3 met the Amsterdam criteria for hereditary nonpolyposis CRC.

Conclusion

Thirteen percent of the population had mutations in keeping with Lynch syndrome. This prevalence is similar to that reported for white populations.     

Tuberculosis in Egyptian kidney transplant recipients: study of clinical course and outcome

BACKGROUND: Tuberculosis (TB) is an important infection encountered post-transplantation especially in developing countries, with high incidences of morbidity and mortality. In this report, we study the risk factors and impact of TB on the outcome of kidney transplantation. METHODS: Of 1200 live-donor Egyptian kidney transplantations, 45 (3.8%) patients developed post-transplant TB. Of these, five had had TB pre-transplantation and 40 were male. The mean age was 32.6 +/- 10.5 years. Primary immunosuppression treatment for 39 (86.7%) patients was cyclosporine (CsA). RESULTS: The mean time interval between transplantation and TB diagnosis was 49.8 +/- 41.5 (range 2-180) months. In 86.7% of patients, TB was diagnosed one year post-transplantation. Urinary TB was the most common form (53%), while pleuropulmonary TB accounted for 38%. All post-transplant TB patients received a triple anti-tuberculous therapy (rifampicin, ethambutol and INH) with a favorable response in all but two patients who needed another 24-month course. Hepatotoxicity was seen in 11 patients, eight were mild with normalization after temporary withdrawal of rifampicin, and three cases were severe, but mortality was not attributable to hepatocellular failure. Twelve patients died, 11 of them due to unrelated causes. Chronic rejection occurred in more than half of the patients (55.6%), of whom 24 (96%) were CsA-treated, which can be attributed to rifampicin/CsA interaction. More than 35% of TB patients lost their graft as a result. Pre-transplant tuberculosis patients had a comparable post-transplant course. CONCLUSIONS: TB is a common infection in renal transplant recipients with a peak incidence occurring one year post-transplant. Chronic rejection is a serious complication that had a negative impact on the graft survival, especially in CsA-treated recipients. INH prophylaxis is safe in pre-transplant TB. The post-transplantation outcome in the pre-transplant tuberculosis patients is no different from non-TB patients.     

A genome-wide scan in families with maturity-onset diabetes of the young: evidence for further genetic heterogeneity

Maturity-onset diabetes of the young (MODY) is a heterogeneous single gene disorder characterized by non-insulin-dependent diabetes, an early onset and autosomal dominant inheritance. Mutations in six genes have been shown to cause MODY. Approximately 15-20% of families fitting MODY criteria do not have mutations in any of the known genes. These families provide a rich resource for the identification of new MODY genes. This will potentially enable further dissection of clinical heterogeneity and bring new insights into mechanisms of beta-cell dysfunction. To facilitate the identification of novel MODY loci, we combined the results from three genome-wide scans on a total of 23 families fitting MODY criteria. We used both a strict parametric model of inheritance with heterogeneity and a model-free analysis. We did not identify any single novel locus but provided putative evidence for linkage to chromosomes 6 (nonparametric linkage [NPL]score 2.12 at 71 cM) and 10 (NPL score 1.88 at 169-175 cM), and to chromosomes 3 (heterogeneity LOD [HLOD] score 1.27 at 124 cM) and 5 (HLOD score 1.22 at 175 cM) in 14 more strictly defined families. Our results provide evidence for further heterogeneity in MODY.     

A family with the branchio-oto-renal syndrome: clinical and genetic correlations.

BACKGROUND: The branchio-oto-renal (BOR) syndrome is an autosomal dominant disease characterized by hearing loss of early onset, preauricular pits, branchial clefts, and early progressive chronic renal failure in up to 40% of family affected members. So far, it has not received due attention in the adult European nephrology literature and because of the combination of deafness with chronic renal failure it may be confused with the Alport syndrome. The BOR syndrome is caused by mutations in the EYA1 gene that maps on chromosome 8q13.3. METHODS: A three-generation, 20-member large BOR Greek-Cypriot family has been studied and followed up clinically over a 27-year period. The findings in four individuals who developed early onset renal failure are described in detail. Genetic DNA linkage studies have also been carried out. RESULTS: Of the 15 family members at risk, 14 were tested with DNA linkage analysis. Ten members were genetically affected and four were normal. All 10 affected members developed early-onset deafness. Some had different ear lobe abnormalities. Nine affected members had preauricular pits. In some of the patients these pits were deep and prominent while in others they were minor and superficial. Eight affected members had early-onset branchial clefts that needed early corrective surgery without the correct familial diagnosis ever being made. End-stage renal disease (ESRD) developed in four members at ages 36, 14, 17, and 17 with minimal proteinuria, if any. This was due to unilateral renal agenesis with contralateral hypodysplasia or bilateral, severe renal hypodysplasia. CONCLUSION: The BOR syndrome is an infrequent but well-described entity that combines early-onset renal failure and deafness together with branchial clefts and preauricular pits. Renal agenesis and dysplasia are the causes of ESRD in these individuals. Other renal abnormalities include bifid kidneys with double ureters, vesico-ureteric reflux and pelvi-ureteric stenoses. The BOR syndrome should be included in the differential diagnosis of deafness and chronic renal failure in childhood and adolescence.