Genotype-phenotype correlation of renal lesions in the tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominant disease caused by loss-of-function mutations in either of two tumor suppressor genes, TSC1 and TSC2. These mutations lead to the growth of benign tumors and hamartomas in many organs, including those of the central nervous system, the skin, and the kidneys. To investigate the genotype-phenotype correlation, we performed sequence analysis of the TSC1/2 genes using next-generation sequencing. We classified 30 patients with TSC whose pathogenic variants were identified into two groups: those with mutations producing premature termination codons (PTCs) and those with missense mutations. Then, we compared the phenotypes between the two groups. Patients with a PTC were significantly more likely to manifest the major symptoms of the diagnostic criteria than those without a PTC (P = 0.035). The frequencies of subependymal nodules (P = 0.026), cortical tubers (P = 0.026), and renal cysts (P = 0.026) were significantly higher in PTC-containing variants than in cases without a PTC. When the analyses were limited to renal angiomyolipoma (AML) cases with TSC2 mutations, there was no difference in tumor size between cases with and without a PTC. However, the cases with a PTC showed a trend toward disease onset at a younger age and multiple tumors, and bilateral disease was observed in their AML lesions. TSC patients with PTC-producing mutations might potentially manifest more severe TSC phenotypes than those with missense mutations. A larger-scale study with appropriate samples deserves further investigation.

Novel mutation in the KITLG gene in familial progressive hyperpigmentation with or without hypopigmentation.

We herein report a novel mutation in familial progressive hyper- and hypopigmentation (FPHH). The KITLG gene encoding the KIT ligand protein is a disease-causing gene for FPHH. Various disease-causing gain-of-function mutations, which reside within or adjacent to the conserved VTNN motif of this gene, have been described to date. We have now identified a novel KITLG mutation, c.337G>A (p.Glu113Lys), in FPHH which is located within another ligand-receptor interaction site.

A female patient with retinoblastoma and severe intellectual disability carrying an X;13 balanced translocation without rearrangement in the RB1 gene: a case report.

BACKGROUND: Female carriers of a balanced X; autosome translocation generally undergo selective inactivation of the normal X chromosome. This is because inactivation of critical genes within the autosomal region of the derivative translocation chromosome would compromise cellular function. We here report a female patient with bilateral retinoblastoma and a severe intellectual disability who carries a reciprocal X-autosomal translocation. CASE PRESENTATION: Cytogenetic and molecular analyses, a HUMARA (Human androgen receptor) assay, and methylation specific PCR (MSP) and bisulfite sequencing were performed using peripheral blood samples from the patient. The patient's karyotype was 46,X,t(X;13)(q28;q14.1) by G-banding analysis. Further cytogenetic analysis located the entire RB1 gene and its regulatory region on der(X) with no translocation disruption. The X-inactivation pattern in the peripheral blood was highly skewed but not completely selected. MSP and deep sequencing of bisulfite-treated DNA revealed that an extensive 13q region, including the RB1 promoter, was unusually methylated in a subset of cells. CONCLUSIONS: The der(X) region harboring the RB1 gene was inactivated in a subset of somatic cells, including the retinal cells, in the patient subject which acted as the first hit in the development of her retinoblastoma. In addition, the patient's intellectual disability may be attributable to the inactivation of the der(X), leading to a 13q deletion syndrome-like phenotype, or to an active X-linked gene on der (13) leading to Xq28 functional disomy.

Prenatal diagnosis of premature chromatid separation/mosaic variegated aneuploidy (PCS/MVA) syndrome.

Premature chromatid separation/mosaic variegated aneuploidy (PCS/MVA) syndrome is a rare genetic disorder. In this case report, we describe the prenatal diagnosis of PCS/MVA syndrome in a 24-year-old, gravida 1, para 1, woman who was referred to us in her second trimester due to fetal growth restriction and extreme microcephaly (-5.0 standard deviations). Amniocentesis and chromosomal analysis confirmed PCS in 80% of cultured fetal cells. PCS findings were positive in 9% of paternal cells and 11% of maternal cells, indicative that both were PCS carriers. Genetic analysis confirmed that the fetus carried a combined heterozygote of maternal G > A point mutation of the promoter area of the BUB1B gene and a paternal Alu sequence insertion between intron 8 and exon 9 of the BUB1B gene. As PCS/MVA syndrome is associated with the development of various malignancies in early life, prenatal diagnosis is important for effective planning of post-natal care.

Reduced hydration status characterized by disproportionate elevation of blood urea nitrogen to serum creatinine among the patients with cerebral infarction.

The significance of fluid metabolism among the patients with cerebral infarction has barely mentioned in the literature despite the several reports suggesting the potential risk of reduced hydration status for the development of cerebral infarction. The aim of the this study is to explore the validity of the presumable relationship between hydration status and cerebral infarction. Ninety-seven patients with cerebral infarction from April 1, 2008 to March 31, 2009 were retrospectively investigated, and their hydration status were evaluated by using several clinical parameters such as a blood urea nitrogen to serum creatinine (BUN/Cr) ratio of >25 and plasma osmolality. Subjects with active infection, congestive heart failure, hepatic failure, gastrointestinal bleeding, or a malignancy were excluded since these conditions should modulate the absolute value of BUN/Cr ratio without a change in hydration status. Twenty-eight patients (29%) were considered as having reduced hydration status. The BUN/Cr ratio decreased significantly after the initiation of medical support (median 21.3; IR: 18.1-24.6), including oral or parenteral fluid supplementation, in comparison to the values at the time of patient admission (median 30.0; IR: 26.8-40.7; p<0.0001). Similar decreases were also observed in the hematocrit, hemoglobin, and plasma osmolality. The group considered to have reduced hydration status had a significantly higher prevalence of cardioembolic stroke than the other subjects. The hydration status may be a contributing factor to subtypes of cerebral infarction. Whether our findings are also the case with overall patients with cerebral infarction should be evaluated in greater detail.

[Case of lupus nephritis and enteritis associated with bilateral hydronephrosis].

A case of nephrotic syndrome associated with bilateral hydronephrosis in a 26-year-old female is reported. She was referred to our hospital because of persistent diarrhea, abdominal pain, and urinary disorders. On admission, ascites, intestinal edema, and bilateral hydronephrosis, were demonstrated by radiographic analysis. The findings of both physical and laboratory examinations showed evidence of systemic lupus erythematosus (SLE). In addition, diffuse proliferative lupus nephritis was consistently confirmed by a renal biopsy. Immediately after the initiation of steroid treatment, her abdominal symptoms disappeared followed by an improvement in the symptoms of intestinal edema, hydronephrosis, and the renal function. The relationship between ureterohydronephrosis and lupus cystitis, and the fact that lupus enteritis is often associated with lupus cystitis have been demonstrated by previous studies. Finally, the clinical manifestations observed in our case led us to consider the association of lupus enteritis and cystitis. We should bear in mind the possible association of several disorders, including nephrotic syndrome, enteritis, and hydronephrosis due to cystitis, in cases presenting with SLE.

[Case of Henoch-Schönlein purpura nephritis complicated with essential mixed cryoglobulinemia].

We report a case of purpura nephritis complicated with essential mixed cryoglobulinemia. The patient was referred to our hospital because of a petechial rash on the lower extremities, microscopic hematuria, and progressive deterioration of renal function. The presumptive diagnosis of Henoch-Schönlein purpura (HSP) was made, and the patient was treated with prednisolone at the dose of 40 mg/day. However, there was a persistent purpuric skin rash. On the other hand, immunoelectrophoresis of the serum revealed the presence of IgA-lambda and polyclonal IgG in the cryoprecipitate. Granular staining for polyclonal rather than monoclonal IgA and C3 segmentally along the capillary walls demonstrated by immunofluorescence analysis of renal biopsy led to the diagnosis of purpura nephritis as the major mechanism of renal damage. After three sessions of cryofiltration, the patient's serum cryoglobulins decreased and the active rash finally settled, along with improvement of renal function. These observations suggest that the presence of cryoglobulinemia modulated the clinical course of HSP in our case. Therefore, the possibility of the latent presence of cryoglobulinemia in cases with HSP having an active rash refractory to steroid treatment should not be overlooked.