Primary Hyperoxaluria Type 1 with Homozygosity for a Double-mutated AGXT Allele in a 2-year-old Child.

Primary hyperoxaluria (PH) Type 1 is a rare, genetic disorder caused by deficiency of the liver enzyme alanine-glyoxylate aminotransferase, which is encoded by AGXT gene. We report a 2-year-old South Indian Tamil child with nephrocalcinosis due to PH Type 1, in whom a homozygous genotype for two missense mutations in the AGXT gene was found: first, a C to G transversion (c. 32C>G) in exon 1 resulting in the amino acid substitution p.Pro11Arg; second, a T to A transversion (c. 167T>A) in exon 2 resulting in p.Ile56Asn. A therapy based on potassium citrate and pyridoxine was started. This is the first report of molecular testing-proven childhood onset-PH Type 1 from South India and is notable for the co-occurrence of two missense mutations in one AGXT allele, which might lead to different and more severe phenotype than each mutation alone. To the best of our knowledge, AGXT allele carrying two already known mutations has not been previously reported.

Copy number variants analysis in a cohort of isolated and syndromic developmental delay/intellectual disability reveals novel genomic disorders, position effects and candidate disease genes.

BACKGROUND: Array-comparative genomic hybridization (array-CGH) is a widely used technique to detect copy number variants (CNVs) associated with developmental delay/intellectual disability (DD/ID). AIMS: Identification of genomic disorders in DD/ID. MATERIALS AND METHODS: We performed a comprehensive array-CGH investigation of 1,015 consecutive cases with DD/ID and combined literature mining, genetic evidence, evolutionary constraint scores, and functional information in order to assess the pathogenicity of the CNVs. RESULTS: We identified non-benign CNVs in 29% of patients. Amongst the pathogenic variants (11%), detected with a yield consistent with the literature, we found rare genomic disorders and CNVs spanning known disease genes. We further identified and discussed 51 cases with likely pathogenic CNVs spanning novel candidate genes, including genes encoding synaptic components and/or proteins involved in corticogenesis. Additionally, we identified two deletions spanning potential Topological Associated Domain (TAD) boundaries probably affecting the regulatory landscape. DISCUSSION AND CONCLUSION: We show how phenotypic and genetic analyses of array-CGH data allow unraveling complex cases, identifying rare disease genes, and revealing unexpected position effects.

Unbiased next generation sequencing analysis confirms the existence of autosomal dominant Alport syndrome in a relevant fraction of cases.

The mode of inheritance of Alport syndrome (ATS) has long been controversial. In 1927, the disease was hypothesized as a dominant condition in which males were more severely affected than females. In 1990, it was considered an X-linked (XL) semidominant condition, due to COL4A5 mutations. Later on, a rare autosomal recessive (AR) form due to COL4A3/COL4A4 mutations was identified. An autosomal dominant (AD) form was testified more recently by the description of some large pedigrees but the real existence of this form is still questioned by many and its exact prevalence is unknown. The introduction of next generation sequencing (NGS) allowed us to perform an unbiased simultaneous COL4A3-COL4A4-COL4A5 analysis in 87 Italian families (273 individuals) with clinical suspicion of ATS. In 48 of them (55%), a mutation in one of the three genes was identified: the inheritance was XL semidominant in 65%, recessive in 4% and most interestingly AD in 31% (15 families). The AD form must therefore be seriously taken into account in all pedigrees with affected individuals in each generation. Furthermore, a high frequency of mutations (>50%) was shown in patients with only 1 or 2 clinical criteria, suggesting NGS as first-level analysis in cases with a clinical suspicion of ATS.

Constitutional FLCN mutations in patients with suspected Birt-Hogg-Dubé syndrome ascertained for non-cutaneous manifestations.

Birt-Hogg-Dubé syndrome (BHDS) is characterized by a clinical triad including cutaneous hamartomas originating from hair follicles, lung cysts/pneumothorax, and kidney tumors. Inactivating mutations of the tumor suppressor gene FLCN are identified in most families with BHDS. Usually, patients are referred for genetic examination by dermatologists because of the presence of typical multiple skin tumors with or without additional symptoms. However, because of phenotypic variability and incomplete penetrance, the clinical presentation of BHDS is not yet fully defined. Criteria for genetic testing and diagnosis that take into account variable manifestations have recently been proposed by the European BHD Consortium. We sequenced the FLCN gene coding region in a series of 19 patients selected for kidney and/or lung manifestations. Overall, FLCN mutations were found in 9 of 19 (47%) families and were detected only in probands who had either >2 components of the clinical triad or a single component (renal or pulmonary) along with a family history of another main BHDS manifestation. Typical cutaneous lesions were present only in 8 of 21 FLCN mutation carriers aged >20 years identified in the mutation-positive families. In addition, we provide clinical and molecular evidence that parotid oncocytoma, so far reported in six BHDS cases, is associated with this condition, based on the observation of a patient with bilateral parotid involvement and marked reduction of the wild-type FLCN allele signal in tumor DNA. Overall, the results obtained in this study contribute to the definition of the phenotypic characteristics that should be considered for BHDS diagnosis and FLCN mutation testing.

Primary hyperoxaluria: report of an Italian family with clear sex conditioned penetrance.

We report the clinical and genetic study of a primary hyperoxaluria type I (PH1) family with two sisters homozygous for p.Gly170Arg who are still asymptomatic at age 29 and 35, and two brothers, also homozygous for the same mutation, who are affected since age 27 and 30. The clear sex difference observed in this family and in others reported in the literature fits well with the prevalence of males over females in the Italian registry. In the KO model of PH1, only male mice develop renal stones, suggesting that the sex difference may affect both oxalate production and stone formation. A likely mechanism is the sex-related expression of glycolate oxidase shown in experimental animals. The stable isotope method recently developed by Huidekoper and van Woerden for in vivo assessment of the endogenous oxalate production could help to clarify the issue in humans.

[Unexpected tumour of the distal esophagus]. / Unerwarteter, intraoperativer Befund im Bereiche des distalen Osophagus.

We report a patient with unexpected intraoperative diagnosis of a big leiomyoma of the distal esophagus found during laparoscopic repair of a typ III hiatal hernia complicated by Cameron ulcer and chronic anaemia. Laparoscopic transhiatal enucleation of the tumour was performed with closure of the myotomy, Nissen fundoplication, and crural repair. Briefly, the literature of leiomyoma of the esophagus is reviewed with special regard to different therapeutic strategies.

Stage IB malignant thymoma in a Lynch syndrome patient with multiple cancers: response to incidental administration of oxaliplatin and 5-fluorouracil.

Chemotherapy is active against malignant thymomas, improving the resectability rate and the outcome of the advanced stages. The CAP and ADOC schemes are considered the standard schedules today, but these regimens can have important side effects in patients treated with combined approaches, such as toxic deaths due to congestive heart failure or hepatic insufficiency. We report the case of a 55 year-old woman with a history of multiple neoplasms including a mixed malignant thymoma WHO type B2 and three synchronous adenocarcinomas of the colon. The patient refused to undergo surgical resection of her mediastinal mass. However, 8 cycles of chronomodulated oxaliplatin, 5-fluorouracil and leucovorin as adjuvant treatment for her colon cancers resulted in a > 30% decrease in the longest diameter of the mediastinal mass. This occasional observation may be important for clinicians and especially for those faced with relapsed, cisplatin-refractory disease or when planning new studies aiming to reduce overall toxicity of multimodal schedules.

CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms.

BACKGROUND: Rett syndrome is a severe neurodevelopmental disorder, almost exclusively affecting females and characterised by a wide spectrum of clinical manifestations. Both the classic form and preserved speech variant of Rett syndrome are due to mutations in the MECP2 gene. Several other variants of Rett syndrome have been described. In 1985, Hanefeld described a variant with the early appearance of convulsions. In this variant, the normal perinatal period is soon followed by the appearance of seizures, usually infantile spasms. We have observed two patients with signs of Rett syndrome showing acquired microcephaly and stereotypic midline hand movements. The disease started with generalised convulsions and myoclonic fits at 1.5 months in the first patient and with spasms at 10 days in the other, suggesting a diagnosis of the Hanefeld variant. In these patients, MECP2 point mutations and gross rearrangements were excluded by denaturing high performance liquid chromatography and real time quantitative PCR. The ARX and CDKL5 genes have been associated with West syndrome (infantile spasms, hypsarrhythmia, and mental retardation). METHODS: Based on the clinical overlap between the Hanefeld variant and West syndrome, we analysed ARX and CDKL5 in the two girls. RESULTS: We found frameshift deletions in CDKL5 in both patients; one in exon 5 (c.163_166delGAAA) and the other in exon 18 (c.2635_2636delCT). CDKL5 was then analysed in 19 classic Rett and 15 preserved speech variant patients, all MECP2 negative, but no mutations were found. CONCLUSION: Our results show that CDKL5 is responsible for a rare variant of Rett syndrome characterised by early development of convulsions, usually of the spasm type.

A new surgical concept for rectal replacement after low anterior resection: the transverse coloplasty pouch.

OBJECTIVE: To analyze the feasibility, safety, complication and death rates, and early functional results of the transverse coloplasty pouch procedure after low anterior rectal resection and total mesorectal excision. SUMMARY BACKGROUND DATA: The authors previously developed a novel neorectal reservoir, the transverse coloplasty pouch, in an animal model; they report the first clinical data of a prospective phase 1 study. METHODS: Forty-one patients underwent low anterior rectal resection with total mesorectal excision for rectal cancer (n = 37) or benign pathology (n = 4). The continuity was restored with a transverse coloplasty pouch anastomosis, and the colon was defunctionalized for 3 months. Patients were followed up at 2-month intervals for functional outcome. RESULTS: Intraoperative complications occurred in three patients (7%), none related to the transverse coloplasty pouch. There were no hospital deaths and the total complication rate was 27% (11/41); an anastomotic leakage rate of 7% was recorded. The stool frequency was 3.4 per 24 hours at 2 months follow-up and gradually decreased to 2.1 per 24 hours at 8 months. Stool dysfunctions such as stool urgency, fragmentation, and incontinence grade 1 and 2 were regularly observed until 6 months; the incidence significantly decreased thereafter. None of the patients had difficulties in pouch evacuation. CONCLUSIONS: The transverse coloplasty pouch is a small-volume reservoir that can safely be used for reconstruction after sphincter-preserving rectal resection. The early functional outcome is favorable and can be compared to other colonic reservoirs. The concept of reducing early dysfunction seen after straight coloanal anastomosis and avoiding long-term problems of pouch evacuation is supported by this study. Future trials will compare the transverse coloplasty pouch with other techniques of restorative resections of the rectum.

Altered insulin sensitivity, hyperinsulinemia, and dyslipidemia in individuals with a hypertensive parent.

PURPOSE: Essential hypertension is, in some patients, complicated by impairment of insulin-mediated glucose disposal and hyperinsulinemia. Whether this metabolic disturbance is a consequence of the hypertensive process or whether it may precede, and thus possibly promote, the development of hypertension has been unknown. SUBJECTS AND METHODS: Searching for hereditary or familial defects in hypertension-prone humans, we prospectively investigated insulin sensitivity, plasma insulin and glucose, and serum lipoproteins in normotensive offspring of essential hypertensive as compared with age- and body habitus-matched offspring of normotensive families. RESULTS: Compared with 78 control subjects, 70 offspring of essential hypertensive parents had similar age (mean +/- SEM: 24 +/- 1 versus 24 +/- 1 years, respectively) and body mass index (22.3 +/- 0.2 versus 22.4 +/- 0.2 kg/m2), a blood pressure of 127/77 +/- 1/1 versus 123/76 +/- 1/1 mm Hg (p less than 0.05 for systolic), and significantly elevated (p less than 0.01 to 0.001) fasting plasma insulin levels (9.9 +/- 0.3 versus 8.6 +/- 0.3 microU/mL), serum total triglycerides (1.03 +/- 0.06 versus 0.83 +/- 0.03 mmol/L), total cholesterol (4.37 +/- 0.08 versus 3.93 +/- 0.07 mmol/L), low-density lipoprotein cholesterol (2.45 +/- 0.08 versus 2.14 +/- 0.07 mmol/L), and total/high-density lipoprotein cholesterol ratio (4.3 +/- 0.1 versus 3.7 +/- 0.1). Insulin sensitivity was lower (9.4 +/- 0.7 versus 13.2 +/- 1.1 x 10(-4) x minute-1/microU/mL, p less than 0.001), while post-glucose-load plasma insulin levels were higher (p less than 0.05) in the 41 offspring of essential hypertensive parents than in the 38 offspring of normotensive parents so investigated. CONCLUSION: These findings demonstrate that young normotensive humans in apparently excellent health but with one essential hypertensive parent tend to have an impairment of insulin-mediated glucose disposal, hyperinsulinemia, and dyslipidemia. It follows that a familial trait for essential hypertension seems to coexist commonly with defects in carbohydrate and lipoprotein metabolism that can be detected before or at least at a very early stage of the development of high blood pressure as judged by resting blood pressure measurements.

Unaltered insulin sensitivity during calcium channel blockade with amlodipine.

The sensitivity of peripheral tissues to insulin is of pathophysiological, therapeutic and possibly also of prognostic relevance. Calcium channel blockers are widely used in the treatment of cardiovascular disorders that are commonly associated with decreased insulin sensitivity (SI). To evaluate the effects of calcium channel blokkade on SI, glucose homoeostasis and lipid profiles, studies were made of SI (determined by the Minimal Model Method of Bergman), basal glucose and insulin levels, serum total triglyceride (Tg) and lipoprotein cholesterol (C) fractions and certain other variables in 38 healthy young men (24 y) during placebo and after 3 weeks of calcium channel blockade with amlodipine 5 mg once daily. Measurements were made after 3 days on a standard diet (2200 kcal.day-1, 45% carbohydrates, 40% fat and 15% proteins) and after an overnight fast. Compared to placebo, amlodipine decreased supine systolic blood pressure (P less than 0.01). Heart rate, body weight and 24 h urinary sodium excretion were unaltered, and so were fasting plasma glucose (placebo vs amlodipine: 4.86 vs 4.83 mmol.l-1, respectively) and insulin levels (7.7 vs 7.9 microU.ml-1), SI (10.5 vs 9.6.10(-4) x min-1 pro microU.ml-1), serum total Tg, C and lipoprotein C fractions. The findings demonstrate unchanged insulin sensitivity and secretion, as well as lipoprotein regulation, during maintenance administration of 5 mg amlodipine daily to healthy young men.