Association of 45, X/46, XY mosaicism with disorders of sex development: the clinical analysis of 5 cases / 中华儿科杂志

<p><b>OBJECTIVE</b>To analyze clinical characteristics of children with 45, X/46, XY mosaicism and explore effective managements for them.</p><p><b>METHOD</b>Five children with 45, X/46, XY mosaicism were all in puberty period, of whom, three were female and two male. The standing height, weight and sexual development were measured. The levels of sex hormones, other endocrine parameters were also determined, and imaging examinations were performed.</p><p><b>RESULT</b>All the patients had disorders of sex development, of whom, 4 had short stature, and the HtSDs was -2.8 ± 1.1. The results of laboratory indexes suggested that 4 had hypergonadotropic hypogonadism, with the average level of LH (13.5 ± 5.8) IU/L and FSH (56.8 ± 37.4) IU/L. Imaging examinations revealed that 2 cases had cryptorchidism, 1 had immature uterus, 1 had testicular dysgenesis and 1 had normal testis. Three patients received rhGH treatment and 1 took gender assignment into account.</p><p><b>CONCLUSION</b>Patients with mosaic 45, X/46, XY karyotypes had a wide range of phenotypic manifestations, and disorders of sex development and short stature were the main clinical features. However, the disorders of sex development varied among these patients. And the management for them depends upon many factors and needs to be individualized based on the cooperation with different clinical departments.</p>

Long-term follow-up of isolated-growth hormone deficiency typeIA: the clinical analysis of 2-sister cases / 中华儿科杂志

<p><b>OBJECTIVE</b>To elucidate the curative and adverse effect of recombinant human growth hormone (rhGH) in 2 patients with isolated-growth hormone deficiency type IA (IGHDIA), to track sexual development and pregnancy, and reassess the quality of life in the adulthood.</p><p><b>METHOD</b>The authors summarized the data of 2-sister cases with IGHDIA; followed up for assessment of height, weight, blood pressure and sexual development; detected fasting blood lipids, glucose, insulin, insulin growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3); made an investigation of education and occupation, and so on.</p><p><b>RESULT</b>After 6.2 and 7.3 years treatment with rhGH, the two sisters had considerably improved height from -7.8 SDS, -8.8 SDS to -2.6 SDS and -1.3 SDS respectively. No evident side effect was observed. They had normal sexual development and pregnancy. The levels of IGF-1 and IGFBP-3 were still low, in the elder sister they were 46.6 µg/L, 2460 µg/L, and in the younger 52.4 µg/L, 2430 µg/L. No hyperlipidemia, diabetes or obesity occurred.</p><p><b>CONCLUSION</b>Long term therapy with rhGH may improve final adult height of individuals with IGHDIA. They can have normal sexual development and pregnancy. Metabolic syndrome did not occur during the follow-up period.</p>

Genetic mutation analysis of a kindred with a patient suffering from 17 alpha-hydroxylase/17, 20-lyase deficiency / 中华儿科杂志

<p><b>OBJECTIVE</b>To detect CYP17A1 gene mutation in a patient with 17 alpha-hydroxylase/17, 20-lyase deficiency and her family members.</p><p><b>METHOD</b>Genomic DNA was extracted from the blood of the patient, her parents and twin sister. The 8 exons of CYP17A1 gene were amplified with polymerase chain reaction (PCR) and screened for mutations by sequencing.</p><p><b>RESULT</b>The analysis revealed that the patient was a compound heterozygote carrying two different inherited point mutations on CYP17A1 gene. They were nt186delC on exon 1 and nt1085G > A on exon 6. This type of mutation could induce 17OHD because of complete loss of 17 alpha-hydroxylase activities. And her parents and the twin sister were carriers on CYP17A1 gene. In addition, the mutation nt186delC was a novel point mutation and it was not discovered in normal children.</p><p><b>CONCLUSION</b>A new compound heterozygote carrying two different inherited point mutations on CYP17A1 gene was found, and her parents and twin sister were carriers. This is probably the first report in the world of a twin sisters of whom one is a patient with 17OHD and the other is a carrier of CYP17A1 gene mutation.</p>

Identification of a novel missense mutation of the DAX-1 gene in a Chinese pedigree with X-linked adrenal hypoplasia congenita / 中华儿科杂志

<p><b>OBJECTIVE</b>Inactivating mutations of DAX-1 give rise to the X-linked form of adrenal hypoplasia congenita (AHC). Affected individuals are at risk of early postnatal Addisonian crisis, but the variable phenotypic expression of DAX-1 insufficiency renders this diagnosis challenging. This study aimed to understand the clinical features and identify DAX-1 gene mutation of the affected individuals and their relatives in a Chinese adrenal hypoplasia congenita kindred.</p><p><b>METHODS</b>The proband was diagnosed as adrenal insufficiency shortly after birth and his elder cousin was also diagnosed as having this disease at the age of about 8 years. Clinical data were obtained from 2 affected individuals when they were hospitalized into the department of pediatrics, Ruijin Hospital in 2006; 20 peripheral blood samples were obtained from the affected individuals and their relatives; exons in DAX-1 gene were amplified, and PCR product was purified and sequenced directly for analyzing mutation.</p><p><b>RESULTS</b>A novel hemizygous mutation (T785C) was found in DAX-1 gene in both patients. Some clinical features such as the age of onset were different although these 2 patients carried the same mutation. There were 5 carriers of this mutation in the patients' maternal pedigree.</p><p><b>CONCLUSION</b>The results suggested that adrenal hypoplasia congenita in this kindred was caused by a novel mutation (T785C) in DAX-1 gene, and the same mutation can give rise to the variable phenotype.</p>

Prader-Willi syndrome and genomic imprinting / 中华儿科杂志

<p><b>OBJECTIVE</b>Prader-Willi syndrome (PWS) is an example of a human genetic disorder that involves imprinting genes on the proximal long arm of chromosome 15 and SNRPN gene as a candidate gene for this syndrome. The purpose of this study was to show the molecular genetic defects and genomic imprinting basis in Chinese PWS patients and to evaluate the clinical applications of a differential diagnostic test for PWS.</p><p><b>METHODS</b>Fluorescence in situ hybridization (FISH) and methylation-specific PCR (MSPCR) techniques were applied for 4 clinically suspected PWS patients. Using three probes, including SNRPN probe for identification of the critical locus in PWS region, D15Z1 and PML control probes for identification of the 15p arm and 15q arm, the authors detected the deletions 15q in PWS. MSPCR was based on sodium bisulfite treatment of DNA and PCR primers specific for the maternal and paternal allele.</p><p><b>RESULTS</b>When hybridized with mixed probes, it was found in 2 patients that the central specific signal was absent, but both the flanking control signals were retained, indicating SNRPN gene deletion of chromosome 15q11-13. Bisulfite-modified DNA from all PWS children amplified with methylated allele-specific primer pair showed only maternal 131bp PCR product, indicating the maternal uniparental disomy (UPD15).</p><p><b>CONCLUSION</b>Genomic imprinting plays an important role in the molecular pathogenesis of PWS that caused by paternal microdeletions of 15q11-q13 or maternal UPD of chromosome 15. The basic defect seemed to be an absence of function of PWS genes that are normally expressed only from the paternal chromosome 15. MSPCR is a rapid and simple PCR-based assay compared with other cyto-molecular tests and its results were consistent with the clinical diagnosis of PWS, so it seems to be a reliable diagnostic method for PWS patients who show abnormal methylation at SNRPN. The genetic differential tests for PWS are important in determining familial recurrence risk.</p>