Parental pre-pregnancy BMI is a dominant early-life risk factor influencing BMI of offspring in adulthood.

OBJECTIVE: We examined parental and early-life variables in order to identify risk factors for adulthood overweight and obesity in offspring. We report here on the longitudinal prevalence of overweight and obesity in Australian children born between 1989 and 1991 and followed from birth to age 22. METHODS: Data were analysed on 1355 participants from the Western Australian Pregnancy Cohort (Raine) Study, with anthropometry collected during pregnancy, at birth, one year and at three yearly intervals thereafter. Multivariate analyses and cross-sectional logistic regression quantified the timing and contribution of early-life risk factors for overweight and obesity in young-adulthood. RESULTS: At five years of age 12.6% of children were overweight and 5.2% were obese. By early adulthood, the prevalence of obesity had increased to 12.8%, whilst overweight remained relatively stable at 14.2% (range from early childhood to adulthood 11-16%). Parental pre-pregnancy body mass index (BMI) was the strongest determinant of adult offspring BMI. Although rapid first year weight gain was associated with increased offspring BMI, the impact of first year weight-gain diminished over childhood, whilst the impact of parental BMI increased over time. CONCLUSIONS: Parental pre-pregnancy BMI and rapid early-life weight gain predispose offspring to obesity in adulthood.

DICER1 hotspot mutations in non-epithelial gonadal tumours.

BACKGROUND: Non-epithelial gonadal tumours largely comprise sex cord-stromal tumours (SCSTs) and germ cell tumours (GCTs). Specific somatic mutations in DICER1, a microRNA maturation pathway gene, have been identified in these tumours. We conducted a study that aimed to confirm, refine and extend the previous observations. METHODS: We used Sanger sequencing to sequence the RNase IIIa and IIIb domains of DICER1 in 154 gonadal tumours from 135 females and 19 males, as well as 43 extra-gonadal GCTs from 26 females and 17 males. RESULTS: We identified heterozygous non-synonymous mutations in the RNase IIIb domain of DICER1 in 14/197 non-epithelial tumours (7.1%). Mutations were found in 9/28 SCSTs (32%), 5/118 gonadal GCTs (4.2%), 0/43 extra-gonadal GCTs and 0/8 miscellaneous tumours. The 14 mutations affected only five residues: E1705, D1709, E1788, D1810 and E1813. In all five patients where matched and constitutional DNA was available, the mutations were only somatic. There were no mutations found in the RNase IIIa domain. CONCLUSION: More than half (8/15) of Sertoli-Leydig cell tumours (SLCTs) harbour DICER1 mutations in the RNase IIIb domain, while mutations are rarely found in GCTs. Genetic alterations in SLCTs may aid in classification and provide new approaches to therapy.

Biallelic DICER1 mutations occur in Wilms tumours.

DICER1 is an endoribonuclease central to the generation of microRNAs (miRNAs) and short interfering RNAs (siRNAs). Germline mutations in DICER1 have been associated with a pleiotropic tumour predisposition syndrome and Wilms tumour (WT) is a rare manifestation of this syndrome. Three WTs, each in a child with a deleterious germline DICER1 mutation, were screened for somatic DICER1 mutations and were found to bear specific mutations in either the RNase IIIa (n = 1) or the RNase IIIb domain (n = 2). In the two latter cases, we demonstrate that the germline and somatic DICER1 mutations were in trans, suggesting that the two-hit hypothesis of tumour formation applies for these examples of WT. Among 191 apparently sporadic WTs, we identified five different missense or deletion somatic DICER1 mutations (2.6%) in four individual WTs; one tumour had two very likely deleterious somatic mutations in trans in the RNase IIIb domain (c.5438A>G and c.5452G>A). In vitro studies of two somatic single-base substitutions (c.5429A>G and c.5438A>G) demonstrated exon 25 skipping from the transcript, a phenomenon not previously reported in DICER1. Further we show that DICER1 transcripts lacking exon 25 can be translated in vitro. This study has demonstrated that a subset of WTs exhibits two 'hits' in DICER1, suggesting that these mutations could be key events in the pathogenesis of these tumours.

21-hydroxylase genotyping in Australasian patients with congenital adrenal hyperplasia.

Mutations in CYP21 (21-hydroxylase) lead to congenital adrenal hyperplasia (CAH). We genotyped 26 probands with CAH by PCR-sequencing the entire CYP21 gene. 25/26 had homozygous or compound heterozygous mutations. The frequencies of mutations were similar to other populations with deletion/hybrid, I2 G splice and I172N the most common. Five patients with a I172N allele predicting simple-virilising CAH had a salt-wasting phenotype. Two other probands also had a more severe phenotype than predicted by genotype. Two families had both non-classic and salt-wasting phenotypes arising from combinations of three deleterious alleles. Two novel CYP21 alleles were detected: D106N and a large deletion encompassing CYP21 and adjacent pseudogene. Two rare CYP21 alleles were also found. Three of these four novel/rare alleles were only detected as a result of sequencing the entire CYP21 gene. Entire CYP21 sequencing will increase the number of mutations detected in CAH, and in combination with functional studies should contribute a greater understanding of phenotype-genotype correlations.

Androgen receptor genotyping in a large Australasian cohort with androgen insensitivity syndrome; identification of four novel mutations.

We genotyped the androgen receptor (AR) gene in 31 Australasian patients with androgen insensitivity syndrome (AIS). The entire coding region of AR was examined including analysis of polymorphic CAG and GGN repeats in all patients. AR defects were found in 66.7% (6/9) of patients with complete AIS (CAIS) and 13.6% (3/22) of patients with partial AIS (PAIS). A novel deletion (N858delG) leading to a premature stop codon was found in CAIS patient P1. CAIS patient P2 has a novel deletion (N2676delGAGT) resulting in a stop at codon 787. These mutations would result in inactivation of AR protein. A novel insertion of a cysteine residue in the first zinc finger of the AR DNA-binding domain (N2045_2047dupCTG) was found in CAIS patient P3. PAIS patient P4 has a novel amino acid substitution (Arg760Ser) in the AR ligand binding domain, which may impair ligand binding. Five patients were found to have previously reported AR mutations and no mutations were identified in the remaining patients.

Acute scrotum in Henoch-Schönlein purpura.

Henoch-Schönlein purpura (HSP) is a systemic vasculitis with manifestations usually involving the skin, gastrointestinal tract, kidney and joints. Epididymitis is rarely seen as a complication of HSP. It is easily misdiagnosed as testicular torsion, causing the patient to undergo unnecessary surgery, because the patient may have complained of severe scrotal pain and swelling. We report a 5-year-old boy who was suffering from HSP associated with acute scrotal pain and swelling of the left testicle. No gastrointestinal signs were noted but severe joint pain, swelling and palpable skin lesions in the lower limbs and the buttocks were found. Prednisolone was prescribed and the boy recovered without surgical intervention.

Congenital varicella syndrome in the absence of cutaneous lesions.

A case of congenital varicella syndrome characterized by intrauterine growth retardation, ocular and neurologic abnormalities, but no cutaneous lesions is reported. This case highlights the risk of embryopathy from varicella infection during pregnancy in non-immune women.

Survival rate for liver cancer in Taiwan.

BACKGROUND: There is no nationwide population-based study of the survival rate for liver cancer in Taiwan. Consequently, the true rate of liver cancer survival is unknown. Our aim was to determine the survival rate for liver cancer patients in Taiwan. METHOD: The Taiwan Cancer Registry was searched for liver cancer cases in 1987 and 2,558 cases were found. Of these, 485 lacked an identification number, 29 lacked documentation of age, 33 were metastatic, nine lived in Kinmen and Lienkiang Hsien of Fukien Province leaving 2,002 to be studied. With the help of identification numbers, we linked our cases with the Death Registry of the Department of Health, Executive Yuan, ROC, for the 1987 to 1992 period and calculated the five-year survival rate using actuarial life tables. For analyzing factors affecting the five-year survival rate, multivariate analysis with the Cox proportional hazards model was used. RESULTS: Of the 2,002 patients, 752 were diagnosed histopathologically and 1,250 patients were diagnosed clinically. A total of 15% of patients survived for five years or longer after diagnosis. Of those diagnosed histopathologically, 17% survived for five or more years, and of those diagnosed clinically, 13% survived for five or more years. The sex, age, residential area and ethnic origin did not affect the five-year survival rate significantly. Only diagnosis type affected the five-year survival rate significantly (p < 0.05). The 660 pathologically diagnosed liver cancer patients had a better survival rate than the 1,250 patients diagnosed clinically. CONCLUSIONS: The overall five-year survival rate for liver cancer in Taiwan was 15%. The prognosis for liver cancer patients in Taiwan is still unfavorable. The aim is to persuade affected patients to accept treatment.

Descending mesocolon defect herniation: case report.

Internal hernia, herniation of the internal organs through defects in the intraabdominal cavity, is rare. Due to the rarity of this pathology and lack of the specific symptoms and signs, early diagnosis and treatment are always stressful to the clinician and misdiagnoses may occur in the emergency room. The prognosis of a patient with uncomplicated internal hernia is excellent. We report a 21-year-old Chinese man with internal herniation through a defect of mesocolon, presented as an impalpable abdominal mass which was shown only on imaging studies. In addition to the typical whirlpool pattern, a huge solid mass between the pancreatic tail and stomach was found under computed tomography (CT) scan. The major symptoms were intermittent epigastralgia and abdominal fullness that had bothered him for years. Physical examination results showed only mild epigastric tenderness. Computed tomography scans and exploratory laparotomy of the abdomen played vital roles during diagnosis. The herniated organ was a portion of jejunum with partial small intestinal obstruction.

Recognition of functional pulmonary atresia by color Doppler echocardiography.

Vigorous crying aids right ventricular ejection into the pulmonary artery. This phenomenon can differentiate functional pulmonary atresia from anatomic pulmonary atresia.

Left multicystic dysplastic kidney with contralateral ureteropelvic obstruction: report of one case.

Multicystic dysplastic kidney (MCDK) is a common cause of abdominal mass in neonates. It is frequently associated with malformation of the contralateral kidney, such as ureteropelvic obstruction, etc. Because MCDK is usually functionless, it is important to evaluate the condition of the contralateral kidney. The presence of severe obstruction in the contralateral ureteropelvic junction is life-threatening and prompt treatment should be made to preserve the remaining renal function. We report on a neonate with left MCDK and contralateral ureteropelvic obstruction, presenting as anuria after birth, and also we review the literature.

Pyomyositis in childhood: a case report.

Pyomyositis is a primary infection of skeletal muscle. We report the case of a previously healthy six-year-old who suffered from pyomyositis in the right lower back. He presented with lower back pain and low-grade fever for one week. After a series of laboratory and imaging studies, the diagnosis of right multifidus muscle pyomyositis with abscess formation was made. The patient recovered rapidly after incision and drainage therapy, accompanied by antibiotic treatment. Methicillin-resistant Staphylococcus aureus was cultured from the abscess discharge. It was strongly suspected that herbal medicines and common cold medication the patient had been prescribed before admission to our hospital produced a masking effect that delayed the diagnosis.

Evolution of the primate androgen receptor: a structural basis for disease.

Androgen effects mediated by the androgen receptor (AR) are essential for male reproductive development and virilization. Comparison of AR DNA coding sequence from five primate species, Homo sapiens (human), Pan troglodytes (chimpanzee), Papio hamadryas (baboon), Macaca fascicularis (macaque), and Eulemur fulvus collaris (collared brown lemur), supports their phylogeny with complete conservation of the DNA and steroid binding domain protein sequence. A linear increase in trinucleotide repeat expansion of homologous CAG and GGC sequences occurs in the NH2-terminal transcriptional activation region and is proportional to the time of species divergence. A serine phosphate/glutamine repeat interaction is observed where increasing CAG repeat length is associated with an increased rate of serine 94 phosphorylation. Disparity in the calculated and apparent molecular weight with CAG repeat expansion of an AR NH2-terminal fragment suggests self-aggregation with increasing glutamine repeat length into the pathological range. These results suggest that a CAG/glutamine repeat expanded during divergence of the higher primate species, which may have a direct effect on AR structure and support a common pathway in CAG trigenic diseases in the pathophysiology of neurodegeneration observed in X-linked spinal bulbar and muscular atrophy.

Neonatal intracardiac rhabdomyomatosis: a case report.

Intracardiac tumors are rare in neonates. Most of these lesions are rhabdomyomas and they occur almost exclusively during infancy. Rhabdomyomas are commonly associated with tuberous sclerosis and often involve the brain, kidneys and pancreas; they are frequently multiple and originate most commonly from the ventricular septum. Surgical intervention is indicated for rhabdomyoma with either mechanical cardiac obstruction or dysrhythmias resulting in symptoms or sudden death. A newborn with diffuse rhabdomyomatosis over the right atrium, right ventricle and left ventricle of the heart complicated with congestive heart failure and intractable supraventricular tachycardia is reported herein. No tuberous sclerosis or other organ involvement was noted. The tumor was resected.

Group A streptococcal septicemia with retropharyngeal abscess: a case report.

Group A streptococcal (GAS) septicemia is rare in occurrence but has a significant morbidity and mortality, whereas retropharyngeal abscess (RPA) is infrequent and it is most commonly found in children under the age of 6 years, with half of the cases occurring in children between 6 and 12 months old. This report concerns a case of GAS septicemia complicated with RPA. The patient, a five-year-old boy, was referred from a local medical department under the impression of meningitis. However, blood and throat cultures were both found to be positive for group A streptococci. Widening of the retropharyngeal space was noted in lateral neck roentgenography. RPA was confirmed by computed tomography (CT) of the neck. Ampicillin was prescribed for a period of four weeks. The patient was then discharged and oral form ampicillin was continued for four more weeks. No surgical incision and drainage was performed. Complete disappearance of the abscesses were noted via CT of the neck at an Outpatient Department follow-up.

Cockayne syndrome with tetralogy of Fallot: a case report.

Cockayne syndrome (CS) is a rare autosomal recessive disorder characterized by growth retardation, senile-like appearance, loss of subcutaneous adipose tissue, photosensitive dermatitis, microcephaly, deafness, pigmentary degeneration of retina, disproportionately long limbs, skeletal malformations with knee contractures and neurologic abnormalities. This is a description of a three-year-old boy with typical features of Cockayne syndrome complicated with tetralogy of Fallot, pneumonia and hepato-splenomegaly. He had been suffering from frequent attacks of pneumonia and had been hospitalized for several times since birth. Tetralogy of Fallot was diagnosed under echocardiography study and he died suddenly in hospital during a mydriatic procedure in the Ophthalmologic Clinic.

Reduced expression and normal nucleotide sequence of androgen receptor gene coding and promoter regions in a family with partial androgen insensitivity syndrome.

BACKGROUND AND OBJECTIVES: Androgen insensitivity syndrome (AIS) is an X-linked disorder of XY males characterized by varying degrees of impaired masculinization. In many AIS cases, mutations have been identified in the coding sequence of the human androgen receptor (AR) gene which impair receptor function. Cases have also been reported in which reduced AR mRNA expression may contribute to AIS in association with AR gene mutations. The purpose of this study was to define the molecular basis of AIS in members of a family with clinical and laboratory features of partial androgen insensitivity (PAIS). DESIGN: Genital skin fibroblast (GSF) cultures were established from foreskin tissue for androgen receptor binding analysis. Genomic DNA was obtained from blood leucocytes for AR gene nucleotide sequence analysis. AR mRNA levels were determined in total RNA extracted from GSF cultures. PATIENTS: Three related subjects with perineo-scrotal hypospadias, bifid scrotum and microphallus were studied. The family pedigree of these subjects suggested an X-linked pattern of inheritance. Hormone assay results were consistent with AIS. MEASUREMENTS: AR binding capacity and affinity were determined in three subjects and compared with unaffected male controls. The coding sequence and 1.4 kb of promoter region of the AR gene were amplified in overlapping fragments by polymerase chain reaction from genomic DNA and sequenced. GSF AR mRNA was measured by a competitive PCR technique. RESULTS: In the PAIS subjects, AR affinity in cultured GSF was normal (Kd = 0.24, 0.30, 0.48 vs 0.27 +/- 0.07 (SD) nmol/l) but binding capacity was reduced (Bmax = 0.31, 0.36, 0.27 vs 1.26 +/- 0.37 (SD) fmol/microgram DNA). Sequence analysis of the CAG repeat polymorphism within exon 1 of the AR gene showed that both mothers were heterozygous at this locus, and that the three subjects had inherited the same allele. GSF AR mRNA levels were reduced in all three patients compared with controls (0.25, 0.74 and 0.74 vs 3.8 +/- 0.9 (SEM), range 1.8-7.3 amol/microgram total RNA). The nucleotide sequences of the entire AR coding region and of a 1.4 kb segment containing the promoter region were normal. CONCLUSION: Members of this family with clinical and biochemical evidence of X-linked partial androgen insensitivity syndrome demonstrated normal androgen receptor binding affinity and androgen receptor gene nucleotide sequence but reduced androgen receptor binding capacity and reduced androgen receptor mRNA. These results suggest that partial androgen insensitivity syndrome in this family may be caused by reduced expression of a normal androgen receptor gene.

Reduced androgen receptor gene expression with first exon CAG repeat expansion.

The molecular basis for partial androgen insensitivity associated with adult onset spinal/bulbar muscular atrophy was investigated by transient transfection of human androgen receptor (AR) expression vectors containing increasing CAG repeat lengths in the first exon. An inverse relationship was observed between CAG repeat length and AR mRNA and protein levels. Trinucleotide repeat lengths of 43 and 65 associated with spinal/bulbar muscular atrophy decreased AR mRNA and protein levels but did not alter equilibrium binding affinity for [3H]R1881 or inherent transcriptional activity of AR, expressed as androgen-dependent fold induction of a mouse mammary tumor virus promoter-luciferase reporter vector. The findings indicate that glutamine expansion up to 66 residues in the NH2-terminal domain of AR does not alter AR functional activity. Rather, CAG repeat expansion in the region of the first exon reduces AR mRNA and protein expression. The study reveals a previously unrecognized effect of CAG repeat length on AR mRNA expression and a novel molecular mechanism for androgen resistance.