Growth Hormone Deficiency in a Case of Crouzon Syndrome with Hydrocephalus

Crouzon syndrome is one of the most common craniofacial syndromes and is inherited as autosomal dominant with variable expression. We report an 11 and a half-year-old boy with Crouzon syndrome with severe growth retardation. He had hydrocephalus since infancy and recently suffered from frequent dizziness. His bone age was only 5 years according to the Greulich and Pyle atlas. Magnetic resonance imaging showed shallow orbits, obstructive hydrocephalus, and cerebellar tonsil herniation. Growth hormone provocative tests revealed a reduced peak growth hormone response in both insulin and clonidine tests. Severe iron deficiency anemia was noted at the same time. Molecular analysis identified a common mutation point of Cys278Phe for Crouzon syndrome in exon IIIa of the fibroblast growth factor receptor 2 (FGFR2) gene. Since growth retardation is not a common feature of Crouzon syndrome, we reviewed the literature for the incidence of hydrocephalus in Crouzon syndrome and the association with growth hormone deficiency

CD40 Gene Polymorphisms Associated with Susceptibility and Coronary Artery Lesions of Kawasaki Disease in the Taiwanese Population

Background. Kawasaki disease (KD) is characterized by systemic vasculitis of unknown etiology. Our previous studies showed expression of CD40 ligand on CD4+ T cells correlated to the coronary artery lesion (CAL) and disease progress in KD. Other studies from Japan suggested the role of CD40L in the pathogenesis of CAL, and this might help explain the excessive number of males affected with KD but cannot be reproduced by Taiwanese population. This study was conducted to investigate the CD40 polymorphism in KD and CAL formation. Methods. A total of 950 subjects (381 KD patients and 569 controls) were investigated to identify 2 tagging single-nucleotide polymorphisms (tSNPs) of CD40 (rs4810485 and rs1535045) by using the TaqMan allelic discrimination assay. Results. A significant association was noted with regards to CD40 tSNPs (rs1535045) between controls and KD patients (P = 0.0405, dominant model). In KD patients, polymorphisms of CD40 (rs4810485) showed significant association with CAL formation (P = 0.0436, recessive model). Haplotype analysis did not yield more significant results between polymorphisms of CD40 and susceptibility/disease activity of KD. Conclusions. This study showed for the first time that polymorphisms of CD40 are associated with susceptibility to KD and CAL formation, in the Taiwanese population

Effects of Growth Hormone Treatment on Height, Weight, and Obesity in Taiwanese Patients with Prader-Willi Syndrome

BackgroundInformation regarding the efficacy of growth hormone (GH) therapy in Asian Prader-Willi syndrome (PWS) patients is lacking. We report our experience with GH treatment in children with PWS in Taiwan.MethodsForty-six PWS patients (27 males, 19 females; age range, 1 year 4 months to 13 years 7 months) who received and/or who are currently receiving GH treatment (0.1 IU/kg/day subcutaneously) for a period from 1 year to 3 years were retro-spectively analyzed. We evaluated height, weight, body mass index (BMI) and Rohrer index, before and after GH treatment.ResultsAfter patients had received GH for 1, 2 and 3 years, a significant improvement in mean height standard deviation score (SDS) was noted from −1.24 to −0.31 (p <0.01), 0.00 (p <0.001) and −0.26 (p <0.001), respectively. Mean BMI SDS decreased significantly from 1.93 to 1.13 (p <0.05) after 1 year of treatment; however, no significant changes were observed afterward. Mean Rohrer index decreased significantly, from 224.2 to 186.6 (p <0.001), 178.9 (p <0.001) and 169.3 (p <0.001). No significant gender or genotype pattern differences were noted among the 4 parameters examined.ConclusionThis 3-year, retrospective study indicates that PWS patients benefit from GH therapy in height increase and improved body composition

Low penetrance of retinoblastoma for p.V654L mutation of the RB1 gene

<p>Abstract</p> <p>Background</p> <p>Retinoblastoma is caused by compound heterozygosity or homozygosity of retinoblastoma gene (<it>RB1</it>) mutations. In germline retinoblastoma, mutations in the <it>RB1 </it>gene predispose individuals to increased cancer risks during development. These mutations segregate as autosomal dominant traits with high penetrance (90%).</p> <p>Methods</p> <p>We screened 30 family members from one family using high resolution melting assay and DNA direct sequencing for mutations in the <it>RB1 </it>gene. We evaluate the phenotype and penetrance of germline mutations of the <it>RB1 </it>gene in a large Taiwanese family.</p> <p>Results</p> <p>The molecular analysis and clinical details of this family showed phenotypic variability associated with the p.V654L mutation in exon 19 of the <it>RB1 </it>gene in 11 family members. The phenotype varied from asymptomatic to presence of a unilateral tumor. Only four individuals (2 males and 2 females) developed unilateral retinoblastoma, which resulted in calculated low penetrance of 36% (4/11). The four individuals with retinoblastoma were diagnosed before the age of three years. None of their relatives exhibited variable severity or bilateral retinoblastoma.</p> <p>Conclusions</p> <p>The diseased-eye ratio for this family was 0.36, which is lower than current estimates. This suggests that the <it>RB1 </it>p.V654L mutation is a typical mutation associated with low penetrance.</p

Novel SOX9 Gene Mutation in Campomelic Dysplasia with Autosomal Sex Reversal

Campomelic dysplasia (CD; OMIM #114290) is an autosomal dominant, frequently lethal dysplasia syndrome whose primary features include angular bowing and shortening of the limbs, and sex reversal in the majority of affected XY individuals. Most CD cases have heterozygous de novo mutations in the coding region of the transcription factor gene SOX9 (SRY-related high-mobility group [HMG] box 9) in chromosome 17q. Here, we report a novel mutation of SOX9 in a female neonate with CD with autosomal sex reversal. Respiratory distress and cyanosis were noted at birth, and endotracheal intubation with mechanical ventilation was performed due to respiratory failure. The presenting phenotypes included dysmorphic face with macrocephaly prominent forehead, low nasal bridge, cleft palate and micrognathia. Skeletal deformities characteristic of CD were observed, including narrow thoracic cage, hypoplastic scapulae, scoliosis and short limbs with anterolateral femoral and tibial bowing. The karyotype was 46,XY despite female external genitalia. SOX9 gene analysis revealed frameshift mutation (at nucleotide position 1095G →AT) in the open reading frame, resulting in a frameshift with 211 new amino acids

Mutational Analysis of PTPN11 Gene in Taiwanese Children with Noonan Syndrome

Noonan syndrome (NS) is an autosomal dominant disorder presenting with characteristic facies, short stature, skeletal anomalies, and congenital heart defects. Mutations in protein-tyrosine phosphatase, nonreceptor-type 11 (PTPN11), encoding SHP-2, account for 33-50% of NS. This study screened for mutations in the PTPN11 gene in 34 Taiwanese patients with NS. Mutation analysis of the 15 coding exons and exon/intron boundaries was performed by polymerase chain reaction and direct sequencing of the PTPN11 gene. We identified 10 different missense mutations in 13 (38%) patients, including a novel missense mutation (855T > G, F285L). These mutations were clustered in exon 3 (n = 6) encoding the N-SH2 domain, exon 4 (n = 2) encoding the C-SH2 domain, and in exons 8 (n = 2) and 13 (n = 3) encoding the PTP domain. In conclusion, this study provides further support that PTPN11 mutations are responsible for Noonan syndrome in Taiwanese patients. [J Formos Med Assoc 2007;106(2):169-172

Comparison of Nucleotide Sequence of P2C Region in Diabetogenic and Non-Diabetogenic Coxsackie Virus B5 Isolates

Enteroviruses are environmental triggers in the pathogenesis of type 1 diabetes mellitus (DM). A sequence of six identical amino acids (PEVKEK) is shared by the 2C protein of Coxsackie virus B and the glutamic acid decarboxylase (GAD) molecules. Between 1995 and 2002, we investigated 22 Coxsackie virus B5 (CVB5) isolates from southern Taiwan. Four of these isolates were obtained from four new-onset type 1 DM patients with diabetic ketoacidosis. We compared a 300 nucleotide sequence in the 2C protein gene (p2C) in 24 CVB5 isolates (4 diabetogenic, 18 non-diabetogenic and 2 prototype). We found 0.3-10% nucleotide differences. In the four isolates from type 1 DM patients, there was only 2.4-3.4% nucleotide difference, and there was only 1.7-7.1% nucleotide difference between type 1 DM isolates and non-diabetogenic isolates. Comparison of the nucleotide sequence between prototype virus and 22 CVB5 isolates revealed 18.4-24.1% difference. Twenty-one CVB5 isolates from type 1 DM and non-type 1 DM patients contained the PEVKEK sequence, as shown by the p2C nucleotide sequence. Our data showed that the viral p2C sequence with homology with GAD is highly conserved in CVB5 isolates. There was no difference between diabetogenic and non-diabetogenic CVB5 isolates. All four type 1 DM patients had at least one of the genetic susceptibility alleles HLA-DR, DQA1, DQB1. Other genetic and autoimmune factors such as HLA genetic susceptibility and GAD may also play important roles in the pathogenesis in type 1 DM

Multiplex Ligation-dependent Probe Amplification Identification of Deletions and Duplications of the Duchenne Muscular Dystrophy Gene in Taiwanese Subjects

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X- linked recessive disorders caused by mutations in the DMD gene. We intended to determine the distribution of DMD gene deletions and duplications in local Taiwanese male patients and potential female carriers. Methods: A total of 102 unrelated subjects, including 89 unrelated DMD/BMD male patients and another 13 unrelated potential female carriers, were recruited for this study. Multiplex ligation-dependent probe amplification (MLPA) was employed to detect DMD gene deletions and duplications in the 102 subjects. Results: MLPA was informative in 60.7% (54/89) of these patients, identifying deletions in 36.0% (32/89) and duplications in 24.7% (22/89) of these patients. This assay revealed deletions in 30.8% (4/13) and duplications in 30.8% (4/13) of the 13 potential carriers. Deletions and duplications were detected in 35.3% (36/102) and 25.5% (26/102) of a total of 102 affected families, respectively in this series. The “hot spot” regions of the duplications were close to those of the deletions. Conclusion: MLPA was proven to be a powerful tool for the detection of DMD gene deletions and duplications in male patients and female carriers. There was a relatively lower frequency of deletion and a higher frequency of duplication of DMD gene in this population compared to previous reports

CYP17A1 intron mutation causing cryptic splicing in 17α-hydroxylase deficiency.

17α-Hydroxylase/17, 20-lyase deficiency (17OHD) is an autosomal recessive disease causing congenital adrenal hyperplasia and a rare cause of hypertension with hypokalemia. The CYP17A1 gene mutation leads to 17OHD and its clinical features. We described an 18 y/o female with clinical features of 17α-hydroxylase/17, 20-lyase deficiency and characterized the functional consequences of an intronic CYP17A1 mutation. The coding regions and flanking intronic bases of the CYP17A1 gene were amplified by PCR and sequenced. The patient is a compound heterozygote for the previously described p.R358X and IVS1 +2T>C mutations. A first intron splice donor site mutation was re-created in minigene and full-length expression vectors. Pre-mRNA splicing of the variant CYP17A1 intron was studied in transfected cells and in a transformed lymphoblastoid cell line. When the full-length CYP17A1 gene and minigene containing the intronic mutation was expressed in transfected cells, the majority (>90%) of mRNA transcripts were incorrectly spliced. Only the p.R358X transcript was detected in the EBV-transformed lymphoblastoid cell line. The IVS1 +2T>C mutation abolished most 17α-hydroxylase/17, 20-lyase enzyme activity by aberrant mRNA splicing to an intronic pseudo-exon, causing a frame shift and early termination