Severe clinical course of Hirschsprung disease in a Mowat-Wilson syndrome patient

We present a clinical case of a female infant with multiple anomalies and distinctive facial features, with an exceptionally severe clinical course of Hirschsprung disease. The girl was also diagnosed with Mowat-Wilson syndrome, confirmed by molecular analysis as a heterozygous deletion of theZEB2 gene. Moreover, molecular karyotyping revealed a deletion involving further genes (KYNU, ARHGAP15, andGTDC1).     

Molecular analysis of congenital scoliosis: a candidate gene approach

The etiology of congenital scoliosis is largely unknown. The severe vertebral disorder, spondylocostal dysostosis type 1, is associated with a homozygous delta-like 3 (DLL3) mutation. Scoliosis has been observed in a heterozygous DLL3 carrier, raising the possibility of its involvement in congenital scoliosis. We present the first molecular study of congenital scoliosis by analysis of the candidate gene DLL3 and demonstrate one novel missense variant. However, no novel or previously described mutations are present in our cohort, indicating that DLL3 mutations may not be a major cause of congenital scoliosis. Additionally, we have evaluated patients with congenital scoliosis not diagnosed with a known syndrome and identified a significant number of associated renal and cardiac anomalies and familial incidence of idiopathic scoliosis in this group.     

Overnight Dexamethasone Suppression Test: A Reliable Screen for Cushing's Syndrome in the Obese

Objective: Reevaluation of the validity of the 1-mg overnight dexamethasone suppression test (ODST) as a screening test for Cushing's syndrome in obese patients. Research Methods and Procedures: Eighty-six obese patients (body mass index, 30 to 53 kg/m²) that were referred to a general endocrine outpatient clinic for evaluation of simple obesity, diabetes mellitus, hypertension, polycystic ovary disease, or pituitary tumor. One milligram dexamethasone was administered orally at 11:00 pm , and serum cortisol levels were measured the following morning between 8:00 am and 9:00 am . Suppression of serum cortisol to <80 nM (3 μg/dL) was chosen as the cut-off point for normal suppression. Patients with serum cortisol levels ≥80 nM were evaluated for Cushing's syndrome. Results: Suppression of morning cortisol levels to <80 nM occurred in 79 of the 86 obese patients. Seven patients had serum cortisol levels higher than 80 nM; five were eventually diagnosed with Cushing's syndrome and two were considered false positive results in view of normal 24-hour free urinary cortisol and normal suppression on a low dose dexamethasone suppression test (0.5 mg of dexamethasone every 6 hours for 2 days). We found a false positive rate of 2.3% for the ODST using a cut-off serum cortisol of 80 nM. Discussion: The ODST is a valid screening test for Cushing's syndrome in the obese population. The false positive rate was 2.3%, even when using a strict cut-off serum cortisol of 80 nM. Abnormal cortisol suppression in obese patients should be investigated and not be considered false positive results.     

Novel SCN5A variants identified in a group of Iranian Brugada syndrome patients

Brugada syndrome (BrS) is a rare hereditary arrhythmia syndrome that increases an individual’s risk for sudden cardiac death (SCD) due to ventricular fibrillation. This disorder is regarded as a notable cause of death in individuals aged less than 40 years, responsible for up to 40% of sudden deaths in cases without structural heart disease, and is reported to be an endemic in Asian countries. Mutations in SCN5A are found in approximately 30% of patients with Brugada syndrome. This study aimed to investigate mutations in the SCN5A gene in a group of Iranian Brugada syndrome patients. Nine probands (n = 9, male, mean age = 39) diagnosed with Brugada syndrome were enrolled in this study. Exon 2 to 29 were amplified by PCR and subjected to direct sequencing. Eight in silico prediction tools were used to anticipate the effects of non-synonymous variants. Seven known polymorphisms and 2 previously reported disease-causing mutations, including H558R and G1406R, were found in the studied cases. Twenty novel variants were identified: 15 missense, 2 frameshift, 2 synonymous, and one nonsense variants. In silico tools predicted 11 non-synonymous variants to have damaging effects, whereas frameshift and nonsense variants were considered inherently pathogenic. The novel variants identified in this study, alongside previously reported mutations, are highly likely to be the cause of the Brugada syndrome phenotype observed in the patient group. Further analysis is required to understand the physiological effects caused by these variants.

     

Paternal age and Down's syndrome genotypes diagnosed prenatally: No association in New York State data

Summary An investigation of a paternal age effect independent of maternal age was undertaken for 98 cases of Down's syndrome genotypes diagnosed prenatally compared to 10,329 fetuses with normal genotype diagnosed prenatally in data reported to the New York State Chromosome Registry. The mean of the difference (delta) in paternal age of cases compared to those with normal genotypes after controlling for maternal age, was slightly negative,-0.27 with a 95% confidence interval of-1.59 to +1.06. A regression analysis was also done in which the data were first fit to an equation of the type lny=(bx+c) and then to the equation ln y=(bx+dz+c) where y = rate of Down's syndrome, x = maternal age, z = paternal age, and b, d, and c are parameters. This also revealed no evidence for a paternal age effect. The value of d (the paternal age coefficient) was in fact slightly negative,-0.0058, with an asymptotic 95% confidence interval of-0.0379 to +0.0263. Lastly, multiple applications of the Mantel-Haenszel test considering various boundaries in paternal age also revealed no statistically significant evidence for a paternal age effect independent of maternal age. These results are at variance with claims of others elsewhere of a very strong paternal age effect detected in studies at prenatal diagnoses. Five different hypotheses are suggested which may account for discrepancies among studies to date in findings on paternal age effects for Down's syndrome: (i) there are temporal, geographic, or ethnic variations in paternal age effects, (ii) there is no paternal age effect and statistical fluctuation accounts for all trends to date; (iii) methologic artifacts have obscured a paternal age effect in some studies which did not find a positive outcome; (iv) methodologic artifacts are responsible for the positive results in some studies to date; (v) there is a rather weak paternal age effect independent of maternal age in most if not all populations, but because of statistical fluctuation the results are significant only in some data sets. The results of all data sets to date which we have been able to analyze by one year intervals are consistent with a mean delta of +0.04 to +0.48 and in the value of d (the paternal age coefficient) of +0.006 to +0.017, and it appears the fifth hypothesis cannot be excluded. Projections based on this assumption are presented.     

Estrogen and progesterone receptors in gynecomastia

The etiology of gynecomastia is unknown. There seems to be no increased incidence of malignancies in patients with idiopathic gynecomastia; however, patients with Klinefelter syndrome exhibit an increased incidence of malignancy. The authors reviewed the results of 34 patients with gynecomastia diagnosed in adolescence who, following initial evaluation, had a mastectomy. The estrogen and progesterone receptors were analyzed in these patients. Three of the patients were diagnosed with Klinefelter syndrome. These three patients exhibited elevated amounts of estrogen and progesterone receptors. None of the patients who were not diagnosed with this syndrome demonstrated significant elevation of their estrogen or progesterone receptors. The presence of elevated estrogen and progesterone receptors in patients with Klinefelter syndrome provides a potential mechanism by which these patients may develop breast neoplasms. The absence of elevated estrogen and progesterone receptors in patients with idiopathic gynecomastia may serve to clarify why these patients' disease rarely degenerates into malignancy.     

A Novel Gata3 Nonsense Mutation In A Newly Diagnosed Adult Patient Of Hypoparathyroidism,Deafness, And Renal Dysplasia (Hdr) Syndrome

ObjectiveHypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is an autosomal dominant disorder caused by a GATA3 gene mutation. Here we report a novel mutation of GATA3 in a patient diagnosed with HDR syndrome at the age of 58 with extensive intracranial calcification.MethodsA 58-year-old Japanese man showed severe hypocalcemia and marked calcification in the basal ganglia, cerebellum, deep white matter, and gray-white junction on computed tomography (CT). The serum intact parathyroid hormone level was relatively low against low serum calcium concentration. The patient had been diagnosed with bilateral sensorineural deafness in childhood and had a family history of hearing disorders. Imaging studies revealed no renal anomalies. The patient was diagnosed with HDR syndrome, and genetic testing was performed.ResultsGenetic analysis of GATA3 showed a novel nonsense mutation at codon 198 (S198X) in exon 3. The S198X mutation leads to a loss of two zinc finger deoxyribonucleic acid (DNA) binding domains and is considered to be responsible for HDR syndrome.ConclusionWe identified a novel nonsense mutation of GATA3 in an adult patient with HDR syndrome who showed extensive intracranial calcification. (Endocr Pract. 2013;19:e17-e20)     

Results of first year (1989) of a national register of Down's syndrome in England and Wales.

OBJECTIVE--To examine the feasibility of a national register of Down''s syndrome and its effectiveness in evaluating prenatal screening for the syndrome. DESIGN--Information for the register was obtained from all eligible cytogenetic laboratories on relevant cytogenetic diagnoses, including date and place of birth or termination, maternal age, indication for karyotyping, and type of diagnostic test used. SETTING--Cytogenetic laboratories in England and Wales. SUBJECTS--All fetuses with trisomy 21 diagnosed prenatally and live births with Down''s syndrome diagnosed at birth. MAIN OUTCOME MEASURES--Number of prenatal and postnatal diagnoses of Down''s syndrome. National and maternal age specific prevalence of Down''s syndrome. RESULTS--For 1989 there were 1060 registrations--323 prenatal diagnoses and 737 postnatal diagnoses--after exclusion of postnatally diagnosed miscarriages and stillbirths. The estimated national rate of affected births for mothers resident in England and Wales was 1.4/1000 live births, assuming no terminations of affected pregnancies and after correction for natural losses which would have occurred in the absence of termination. The corrected maternal age specific rates were close to those found in previous population based studies. The proportion of affected pregnancies diagnosed prenatally in mothers aged 35 to 39 was 44%, and for those aged 40 or more it was 71%. Abnormal findings on ultrasonography played an unexpectedly important part in initiating cytogenetic investigation (13% of the prenatal diagnoses). CONCLUSIONS--The findings establish the feasibility of a national Down''s syndrome register and its use in evaluating prenatal screening services. Together with information held by the Office of Population Censuses and Surveys on congenital malformations, data from the register will permit studies of environmental variables affecting the prevalence of the syndrome.     

Genetic analysis of the CHD7 gene in Korean patients with CHARGE syndrome

CHARGE syndrome is an autosomal dominant congenital disorder known to be caused by the haploinsufficiency of the CHD7 gene. Heterozygous mutations in the CHD7 gene have been identified in approximately 60–70% of patients clinically diagnosed with CHARGE syndrome. Although there have been many reports on the mutational spectrum of the CHD7 gene in patients with CHARGE syndrome worldwide, little is known about this syndrome in the Korean population. In this study, three Korean patients with CHARGE syndrome including one patient with Patau syndrome were evaluated for genetic analysis of the CHD7 gene using direct sequencing of all 38 exons and the flanking intronic regions. One nonsense and two novel missense mutations were identified in the CHD7 gene. Clinical symptoms caused by the missense mutations were much milder compared to the nonsense mutation, confirming the previously determined genotype–phenotype correlation in CHARGE syndrome. Our study demonstrates the importance of mutational screening of CHD7 in patients who have been diagnosed with other syndromes but display clinical features of CHARGE syndrome.     

Nutrition and husbandry conditions of Palearctic tortoises (Testudo spp.) in captivity

Mediterranean and Russian tortoises (Testudo spp.) are popular companion animals (pets), despite ongoing controversy concerning privately keeping reptiles. The arguments used during these controversial discussions have often been based on outdated facts. Therefore, a survey was developed to evaluate the current population structure, husbandry conditions, diet regime, and health status of Testudo species in captivity. More than 75% of the 1075 respondents housed their tortoises in an outdoor enclosure containing a greenhouse or cold frame, which is considered the most species-appropriate way of husbandry. Of the respondents, 67.7% fed their tortoises with the optimum diet of more than 80% grasses and weeds during the summer vegetation period. Only 8.2% of respondents owned a tortoise with a diagnosed disease. According to the results, the likelihood of tortoises developing pyramidal growth syndrome, which can be used as an indicator of the quality of tortoise husbandry, was high in tortoises kept in a terrarium and/or fed a diet of less than 80% grasses and weeds in summer. This likelihood varied among species, with a higher incidence in Hermann’s tortoises (Testudo hermanni).     

Of PCOS Symptoms,Hirsutism Has the Most Significant Impact on the Quality of Life of Iranian Women

Introduction

Polycystic ovary syndrome is a common endocrine disorder affecting women both physically and psychologically and can lead to a poor quality of life compared to their normal counterparts. The aim of the present study was to assess the impact of various clinical features of polycystic ovary syndrome on the health-related quality of life of Iranian women diagnosed with this syndrome.

Materials and Methods

A total of 796 women diagnosed with polycystic ovary syndrome, aged 15–49 years, completed the questionnaires, interviews, and medical assessments required for this study. A reliable and validated Persian version of the health-related quality of life questionnaire for polycystic ovary syndrome patients was used. Linear regression models were used to assess the association between the symptoms of polycystic ovary syndrome and health-related quality of life.

Results

The mean age of participants was 28.02 years. 35.4% of the subjects were classified as overweight or obese. Hirsutism, was reported to have the strongest impact on the patients’ health-related quality of life, followed in descending order by body mass index, irregular menses and infertility. The relative level of hirsutism was directly proportional to decrease in health-related quality of life score (p<0.001).

Conclusions

The results of the study found that hirsutism had the strongest impact on the health-related quality of life measures in Iranian women diagnosed with polycystic ovary syndrome. Health care officials need to evaluate in depth the effect of each clinical feature of polycystic ovary syndrome separately and design management strategies, keeping in mind the psychological and physical manifestations.     

Mirizzi Syndrome: an unexpected problem of cholelithiasis. Our experience with 27 cases

Purpose

Mirizzi syndrome is a rare complication of long standing cholelithiasis. The purpose of this study is to retrospectively estimate the diagnostic and treatment methods applied in patients with Mirizzi syndrome.

Materials and methods

Our experience with 27 cases with Mirizzi syndrome is presented. They were diagnosed either by imaging techniques, or during surgical operation. All of the patients were managed surgically.

Results

8 patients were diagnosed preoperatively and the rest intraoperatively. Morbidity rate after surgery was 18,5%, and mortality rate was zero. The patients presented free of symptoms three months after surgery during the follow-up.

Conclusion

Mirizzi syndrome is rarely diagnosed preoperatively and US proved inadequate for this purpose. Surgery is the only therapy and usually provides additionally definitive diagnosis.

     

Novel variants in the BLOC1S3 gene in patients presenting a mild form of Hermansky–Pudlak syndrome

Hermansky–Pudlak syndrome (HPS) associates oculocutaneous albinism and systemic affections including platelet dense granules anomalies leading to bleeding diathesis and, depending on the form, pulmonary fibrosis, immunodeficiency, and/or granulomatous colitis. So far, 11 forms of autosomal recessive HPS caused by pathogenic variants in 11 different genes have been reported. We describe three HPS‐8 consanguineous families with different homozygous pathogenic variants in BLOC1S3 (NM_212550.3), one of which is novel. These comprise two deletions leading to a reading frameshift (c.385_403del, c.338_341del) and one in frame deletion (c.444_467del). All patients have moderate oculocutaneous albinism and bleeding diathesis, but other HPS symptoms are not described. One patient diagnosed with HPS‐8 suffered from lymphocyte‐predominant Hodgkin lymphoma. The mild severity of HPS‐8 is consistent with other HPS forms caused by variants in BLOC‐1 complex coding genes (HPS‐7, DTNBP1; HPS‐9, BLOC1S6, HPS‐11, BLOC1S5).     

Magnesium profile in autism

The aim of the present study was to determine and compare plasma and erythrocyte concentrations of magnesium in 12 autistic children (10 boys, 2 girls), 17 children with other autistic spectrum disorders (14 boys, 3 girls), 5 girls with classic Rett syndrome, and 14 normal children (7 boys, 7 girls) of the same age. No differences in intracellular Mg were found between controls and pathological subjects; however, autistic children and children with other autistic spectrum disorders had significantly lower plasma concentrations of Mg than normal subjects (p=0.013 and p=0.02, respectively). Although our study population was small, we conclude that children with autistic spectrum disorders require special dietary management. If these cases are diagnosed at an early stage, they can be helped through diet.     

A homozygous <Emphasis Type="Italic">RAB3GAP2</Emphasis> mutation causes Warburg Micro syndrome

Warburg Micro syndrome and Martsolf syndrome are clinically overlapping autosomal recessive conditions characterized by congenital cataracts, microphthalmia, postnatal microcephaly, and developmental delay. The neurodevelopmental and ophthalmological phenotype is more severe in Warburg Micro syndrome in which cerebral malformations and severe motor and mental retardation are common. While biallelic loss-of-function mutations in RAB3GAP1 are present in the majority of patients with Warburg Micro syndrome; a hypomorphic homozygous splicing mutation of RAB3GAP2 has been reported in a single family with Martsolf syndrome. Here, we report a novel homozygous RAB3GAP2 small in-frame deletion, c.499_507delTTCTACACT (p.Phe167_Thr169del) that causes Warburg Micro syndrome in a girl from a consanguineous Turkish family presenting with congenital cataracts, microphthalmia, absent visually evoked potentials, microcephaly, polymicrogyria, hypoplasia of the corpus callosum, and severe developmental delay. No RAB3GAP2 mutations were detected in ten additional unrelated patients with RAB3GAP1-negative Warburg Micro syndrome, consistent with further genetic heterogeneity. In conclusion, we provide evidence that RAB3GAP2 mutations are not specific to Martsolf syndrome. Rather, our findings suggest that loss-of-function mutations of RAB3GAP1 as well as functionally severe RAB3GAP2 mutations cause Warburg Micro syndrome while hypomorphic RAB3GAP2 mutations can result in the milder Martsolf phenotype. Thus, a phenotypic severity gradient may exist in the RAB3GAP-associated disease continuum (the “Warburg–Martsolf syndrome”) which is presumably determined by the mutant gene and the nature of the mutation.     

多囊卵巢综合征患者肠道菌群和生化免疫分子特征

【目的】比较多囊卵巢综合征(polycysticovariansyndrome,PCOS)患者与健康对照间肠道菌群谱结构特征差异,并探讨多囊卵巢综合征患者差异菌群与生化免疫指标之间的联系。【方法】选取初诊多囊卵巢综合征患者23例和健康女性对照23例,每例患者于初诊时留取粪便标本和血液标本,粪便标本提取DNA进行宏基因组测序,血清用于检测性激素和炎症因子。通过生物信息分析比较多囊卵巢综合征患者与健康对照间肠道菌群谱结构特征差异,以及与相关指标的联系。【结果】发现多囊卵巢综合征患者与健康对照的肠道菌群在门、属、种水平均有明显差异。两组间差异菌种为4个,普通拟杆菌(Bacteroides vulgatus)和弗格森埃希菌(Escherichia fergusonii)在PCOS组中的相对丰度高于对照组,并且这两种菌与PCOS的发病机制密切相关。凸腹真杆菌(Eubacteriumventriosum)和Subdoligranulum unclassified菌的相对丰度低于健康对照组。其中普通拟杆菌、凸腹真杆菌和Subdoligranulum unclassified菌3个菌种彼此间存在相关性...     

Sizeable acquired subglottic cyst in a baby with Williams–Beuren syndrome: Association or coincidence?

We describe a case of an acquired subglottic cyst presented with persistent stridor and voice hoarsening in a baby diagnosed with Williams–Beuren syndrome that was born premature and required intubation during neonatal period. We also comment on whether this is a coincidence or there can be an association between impaired elastogenesis, a feature of patients with the syndrome and the formation of a subglottic cyst.