Renal manifestations of Dent disease and Lowe syndrome

To date, two responsible genes for the development of Dent disease have been identified: CLCN5 and OCRL1. In this study, genotype-phenotype correlations were studied in patients with Dent disease and those with Lowe syndrome. Among the 12 boys with a phenotype typical of Dent disease, nine had a mutation in CLCN5 (Dent disease 1), two had a mutation in OCRL1 (Dent disease 2), and one had no mutations in either gene. All seven boys with a clinical diagnosis of Lowe syndrome had a mutation in OCRL1. Patients with Lowe syndrome showed more frequent hypophosphatemia/rickets and more prominent tubular proteinuria than patients with Dent disease 1, and patients with Dent disease 2 had higher degree of tubular proteinuria and hypercalciuria than patients with Dent disease 1. Additionally, one patient with Dent disease 2 showed a mild degree of developmental delay, elevated serum muscle enzyme levels, and cryptorchidism. In this study, the genetic heterogeneity in Dent disease and the phenotypic heterogeneity in Lowe syndrome were confirmed. In patients with Dent disease, the presence of the above-mentioned extrarenal manifestations indicates that it is more likely that the patient is affected by Dent disease 2 than by Dent disease 1.     

Association between single nucleotide polymorphism in collagen IX and intervertebral disc disease in the Indian population

Background:

Symptomatic intervertebral disc degeneration is being recently reported in younger population, questions the basis of its degenerative etiology. Latest evidences show that genetics play a significant role. Collagen IX, an important constituent of disc, is found to be altered in genetically predisposed individuals. Mutations have been reported in COL9A2 and COL9A3 genes, which encode Collagen IX, in Finnish and various other populations. The purpose of the present study is to test the significance of these genes in the Indian population.

Materials and Methods:

One hundred proven cases of intervertebral disc disease (IDD) of various regions of spine were selected for the study, along with matched controls. They were tested for the above mentioned alleles by allelic discrimination method with real-time polymerase chain reaction (PCR) study after isolation of DNA from blood sample. Each blood sample was classified into one of the three types – homozygous, heterozygous, and wild (normal) type allele – separately for COL9A2 and COL9A3 genes.

Results:

Homozygosity for COL9A2 allelic variation was associated with 100% occurrence of the disease. Heterozygous allele of COL9A2 was significantly higher in the study group (42%) as compared to the control group (17%). In contrast, allelic variation in COL9A3 gene was found to have no significant correlation with disc disease. There was no single patient with homozygous allelic variation for COL9A3, suggesting predominance of COL9A2 variation in the Indian population.

Conclusion:

This candidate gene strategy approach adds considerably to our knowledge of genetic makeup of Indian populations in relation with disc disease. This study highlights importance of COL9A2 gene variation especially of homozygous variety in contrast to COL9A3 variation in causing disc disease in Indian population.     

Mild Recessive Mutations in Six Fraser Syndrome–Related Genes Cause Isolated Congenital Anomalies of the Kidney and Urinary Tract

Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately 40% of children with ESRD in the United States. Hitherto, mutations in 23 genes have been described as causing autosomal dominant isolated CAKUT in humans. However, >90% of cases of isolated CAKUT still remain without a molecular diagnosis. Here, we hypothesized that genes mutated in recessive mouse models with the specific CAKUT phenotype of unilateral renal agenesis may also be mutated in humans with isolated CAKUT. We applied next-generation sequencing technology for targeted exon sequencing of 12 recessive murine candidate genes in 574 individuals with isolated CAKUT from 590 families. In 15 of 590 families, we identified recessive mutations in the genes FRAS1, FREM2, GRIP1, FREM1, ITGA8, and GREM1, all of which function in the interaction of the ureteric bud and the metanephric mesenchyme. We show that isolated CAKUT may be caused partially by mutations in recessive genes. Our results also indicate that biallelic missense mutations in the Fraser/MOTA/BNAR spectrum genes cause isolated CAKUT, whereas truncating mutations are found in the multiorgan form of Fraser syndrome. The newly identified recessive biallelic mutations in these six genes represent the molecular cause of isolated CAKUT in 2.5% of the 590 affected families in this study.     

Variations in aganglionic segment length of the enteric neural plexus in Mowat-Wilson syndrome

Background/Purpose

Patients with zinc finger homeo box 1B (ZFHX1B) mutations or deletions develop multiple congenital anomalies including Hirschsprung disease, known as Mowat-Wilson syndrome (MWS). In this study, we investigated variations in the enteric neural plexus abnormalities in MWS using morphometry-based histopathologic analysis.

Methods

Seven patients with MWS (3 with mutations in exon 8 of ZFHX1B and 4 with deletions) who had undergone modified Duhamel's operations for Hirschsprung disease were examined. Surgically resected rectosigmoid specimens were analyzed morphometrically.

Results

The length of the aganglionic segment was longer than 3 cm in all the patients with deletions. In 3 patients with mutations, the aganglionic region was not detected in the surgically resected specimens; however, the parameters of the ganglions and plexus were significantly smaller than those of controls (cloaca and aproctia), indicative of a transitional zone. Variation in the severity of pathological changes among the 3 patients with mutations was also noted.

Conclusions

The variations in myenteric plexus pathologies in MWS appear to be caused by both variations in ZFHX1B abnormalities and epigenetic factors.     

Familial associations in medullary thyroid carcinoma with Hirschsprung disease: the role of the RET-C620 “Janus” genetic variation

Introduction

Hirschsprung disease (HSCR) is associated with the later development of multiple endocrine neoplasia (MEN2), because RET gene variations are associated with both conditions. Specifically, HSCR-MEN2 cosegregation mostly relates to the cysteine-rich area at the RET-620 (the “Janus gene”).

Aim

The aim of this study was to explore the clinical and genetic associations of HSCR-MEN2 in a cohort of HSCR patients.

Methods

RET gene variation was evaluated by heteroduplex single-strand conformational polymorphism analysis and validated with automated sequencing techniques in HSCR patients (including 18 kindreds). Those with RET C620 variations were subjected to familial evaluation for coexisting HSCR-MEN2.

Results

A cohort of 118 patients with HSCR (n = 89) or medullary thyroid carcinoma (n = 29) were studied, including 3 families where a RET-620 point mutation was identified. No C618, C609, or C611 variations were detected. In 1 remarkable 6-generational family (family 3), HSCR in early generations seemed to be later replaced by MEN2A. In the other 2 families with total colonic aganglionosis, a relative with a medullary thyroid carcinoma was identified.

Conclusion

Gene mutation in the RET-620 position carries significant risk and may be part of a targeted investigation of high-risk areas in HSCR. We propose an alternative hypothesis of endoplasmic reticulum control to explain the changing phenotypic expression.     

Cryptosporidium parvum diarrhea in an infant with short bowel syndrome

Cryptosporidium parvum is an underdiagnosed cause of diarrhea in children. The case of a 1-year-old girl with short bowel syndrome presenting with severe dehydrating diarrhea with a protozoon named C parvum is reported. Although the resection of the small bowel in this patient seemed to cause this severe infection with C parvum, more cases are needed to include the resection of the small bowel as a risk factor for Cryptosporidium infection and/or for a more severe form of diarrhea. Awareness of this infection among clinicians will help to diagnose this infection since special acid fast staining is made on special request.     

Clinical features and HLXB9 gene mutation of a sporadic Chinese Currarino's syndrome case

Background/Purpose

The Currarino's syndrome (CS), which is characterized by sacral bony anomalies, anorectal malformation, and a presacral mass, is associated with mutations of HLXB9 gene. The aim of this study was to clearly define the clinical manifestations and molecular anomalies of CS in China.

Methods

We studied the medical history and clinical manifestations of a child with presacral mass. Genomic DNA was extracted from lymphocytes, and mutation analysis of the HLXB9 gene was conducted by using polymerase chain reaction and direct sequencing in the child and her parents.

Results

A previously unreported heterozygous missense mutation of HLXB9 gene was detected in the child.

Conclusions

The HLXB9 gene mutation could take place in sporadic cases of CS without a typical hemisacrum.     

Cutaneous lipoma in children: 5 cases with Bannayan-Riley-Ruvalcaba syndrome

Cutaneous lipoma is rare in children, but it can be part of a syndrome such as the Bannayan-Riley-Ruvalcaba syndrome (BRRS). The BRRS is a dominant autosomal disorder characterized by cutaneous lipomas, macrocephaly, intestinal polyps, and developmental delay associated with PTEN gene mutations. This syndrome is thought to represent a pediatric form of the Cowden syndrome, characterized among other features by an increased risk of cancer. We report 5 cases of BRRS, all diagnosed in children with lipoma and macrocephaly. Children presenting with lipomas need a complete physical examination to look for other signs of BRRS, because they may need further follow-up for tumor screening in adulthood.     

Phenotyping Clostridium septicum infection: a surgeon's infectious disease

BACKGROUND: Clostridium septicum infection is associated with malignancy. Whether disease phenotype is affected by malignant status is not known. Surgical treatment is used frequently but its impact on survival has not been examined in a cohort >30 patients. METHODS: A PubMed search of English language journal articles yielded 320 cases. Full information (infection location, cancer type, operative intervention, and survival) was available for 224 cases + 7 at our institution not previously reported. RESULTS: Seventy-two percent of patients had malignancy or malady of the gastrointestinal (GI) or hematologic (HEME) organ systems. HEME survival was inferior to GI survival (35% versus 55%, P = 0.03). Overall, patients who underwent operation had improved survival (57% versus 26%; P < 0.0001) and this association was maintained within GI and HEME cohorts (P = 0.002 and 0.005, respectively). More GI than HEME patients underwent operation (81% versus 51%, P < 0.001). GI patients were more likely than HEME patients to experience infection of skin and soft tissues (SSTI, P = 0.006). Diabetics were more likely to experience SSTI than nondiabetics (77% versus 45%, P < 0.001). CONCLUSIONS: C. septicum infectious phenotype varies with host milieu. The SSTI phenotype is more common in GI and diabetic patients. This recognition may aid in directing the search for occult malignancy, which must be performed given the >70% incidence of concomitant cancer. This infection is more fatal in HEME versus GI patients, perhaps due in part to less HEME group operative intervention. Primary surgical therapy should be considered in GI or HEME patients as operative intervention benefits both groups.     

Novel xylan-controlled delivery of therapeutic proteins to inflamed colon by the human anaerobic commensal bacterium

Introduction

Growth factors such as keratinocyte growth factor-2 (KGF-2) and transforming growth factor-beta (TGF-β) are important immunoregulatory and epithelial growth factors. They are also potential therapeutic proteins for inflammatory bowel disease. However, owing to protein instability in the upper gastrointestinal tract, it is difficult to achieve therapeutic levels of these proteins in the injured colon when given orally. Furthermore, the short half-life necessitates repeated dosage with large amounts of the growth factor, which may have dangerous side effects, hence the importance of temporal and spatial control of growth factor delivery.

Methods

The human commensal gut bacterium, Bacteroides ovatus, was genetically engineered to produce human KGF-2 or TGF-β ₁ (BO-KGF or BO-TGF) in a regulated manner in response to the dietary polysaccharide, xylan. The successful application of BO-KGF or BO-TGF in the prevention of dextran sodium sulphate induced murine colitis is presented here.

Results

This novel drug delivery system had a significant prophylactic effect, limiting the development of intestinal inflammation both clinically and histopathologically. The ability to regulate heterologous protein production by B ovatus using xylan is both unique and an important safety feature of this drug delivery system.

Conclusions

The use of genetically engineered B ovatus for the controlled and localised delivery of epithelial growth promoting and immunomodulatory proteins has potential clinical applications for the treatment of various diseases targeting the colon.     

Two cases of Klebsiella pneumoniae liver abscess necessitating liver resection for effective treatment

We report two British cases of liver abscess, due to Klebsiella pneumoniae and associated with synchronous infection elsewhere, which required liver resection for definitive treatment. They illustrate the geographic spread of aggressive K pneumoniae liver infection and demonstrate the importance of early aggressive treatment.     

Chronic suppurative cryptococcal extensor tenosynovitis in a patient with Castleman's disease: a case report

Cryptococcus neoformans is an ubiquitously occurring encapsulated fungus that is commonly found in the environment. It is also an opportunistic pathogen that has potential to cause systemic fungal infection, predominantly in the immunocompromised host with cell-mediated immunological defects. Cryptococcal tenosynovitis is an extremely rare condition, with only a few cases previously documented in the literature. We report a case of chronic suppurative cryptococcal extensor tenosynovitis in a patient with Castleman's disease who was successfully managed with surgical debridement and antifungal therapy.     

Two coding single nucleotide polymorphisms in the SALL1 gene in Townes-Brocks syndrome: a case report and review of the literature

Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited malformation syndrome characterized by imperforate anus and limb and ear malformations with sensorineural hearing loss. Mutations in SALL1, a gene mapping to chromosome 16q21.1, are responsible for TBS. Here, we described a 16-month-old male patient with typical TBS clinical features including imperforate anus and preaxial polydactyly. Two coding polymorphism sites were identified in this case. One is silent (rs1965024, 2574 C > T), whereas the other yields a new codon encoding a different amino acid (rs4614723, 3823 G > A). The hot spot mutations in exon 2 were not suggested. Therefore, lack of SALL1 gene mutations and the presence of variable phenotypes in the sporadic cases might suggest DNA alternations in the noncoding regions of SALL1 gene and/or in other genes modulating SALL1 gene expression or functions.     

Mutation analysis of the motor neuron and pancreas homeobox 1 (MNX1, former HLXB9) gene in Swedish patients with Currarino syndrome

Background

Currarino syndrome (CS) is a triad consisting of partial sacral agenesis, presacral mass, and anorectal malformations, typically anal stenosis but the phenotype varies. The main cause of this monogenic disorder is mutations in the motor neuron and pancreas homeobox 1 gene. We describe the clinical and genetic findings in 4 unrelated Swedish cases with CS and their relatives.

Methods

We performed mutation analysis of the motor neuron and pancreas homeobox 1 gene in 4 cases with CS by DNA sequence analysis as well as multiplex ligation-dependent probe amplification. In addition, array comparative genome hybridization was performed in 2 cases. Including relatives, totally, 14 individuals were analyzed.

Results

We found 2 previously described mutations, 1 de novo nonsense mutation (p.Gln212X) and 1 maternally inherited frameshift mutation (p.Pro18ProfsX38). In the family with the frameshift mutation, we also detected the same maternally inherited mutation in 3 of the proband's 4 brothers, who displayed varying symptoms. All mutation carriers had presacral tumors, although 2 were asymptomatic.

Conclusion

Our findings emphasize the need for genetic counseling and mutation analysis in patients with CS to detect tumors early. It shows the importance of evaluation of the sacrum and the presacral region in patients with anal stenosis with or without funnel anus. Family members of index cases should be considered for evaluation even if they are asymptomatic.