Clinical lesson learned from genetic analysis in patients prior to surgical repair of hypospadias

In Indonesia,undervirilisation in 46,XY males is the most common form of difference of sex development(DSD).This can include hypospadias(misplacement of the urethra),micropenis,bifid scrotum,and undescended testis[1].Undervirilisation or 46,XY DSD can be associated with a number of congenital syndromes,including Smith-Lemli-Opitz Syndrome(OMIM 602858),caused by an inborn error of cholesterol synthesis,and characterised by growth delay,intellectual disability,microcephaly,distinctive facial features,cleft palate,limb anomalies,and hypospadias[2]or Opitz syndrome(also known as Opitz G/BBB syndrome).Opitz syndrome can be caused by variants in the X-linked midline 1(MID1)gene(Type I)or in an autosomal dominant manner by monoallelic variants in sperm antigen with calponin homology and coiled-coil domains 1-like(SPECC1L)on chromosome 22q11.2(Type II)[3].Opitz syndrome is characterised by hypospadias,hypertelorism,cleft lip/palate,and heart defects[4].The prevalence of X-linked Opitz syndrome is estimated to be from 1 in 50000 to 1 in 100000 males[5].Recognition of a syndrome informs appropriate clinical management and patient care.Therefore,although these syndromes are rare,hypospadias may be diagnosed before the emergence of other comorbidities meaning that it is crucial for clinicians to perform a thorough clinical evaluation with syndromic causes in mind.

Australian children living with rare diseases:health service use and barriers to accessing care

Background Children with rare diseases experience challenges at home and school and frequently require multi-disciplinary healthcare.We aimed to determine health service utilization by Australian children with rare diseases and barriers to access-ing healthcare.Methods Parents completed an online survey on health professional and emergency department(ED)presentations,hospi-talization,and barriers to accessing services.Potential barriers to service access included residential location(city,regional,remote)and child health-related functioning,determined using a validated,parent-completed measure-of-function tool.Results Parents of 462 children with over 240 rare diseases completed the survey.Compared with the general population,these children were more likely to be hospitalized[odds ratio(OR)=17.25,95%confidence interval(CI)=15.50-19.20]and present to the ED(OR=4.15,95%CI=3.68-4.68)or a family physician(OR=4.14,95%CI=3.72-4.60).Child functional impairment was nil/mild(31%),moderate(48%)or severe(22%).Compared to children with nil/mild impair-ment,those with severe impairment were more likely to be hospitalized(OR=13.39,95%CI=7.65-23.44)and present to the ED(OR=11.16,95%CI=6.46-19.27).Most children(75%)lived in major cities,but children from regional(OR=2.78,95%CI=1.72-4.55)and remote areas(OR=9.09,95%CI=3.03-25.00)experienced significantly more barriers to healthcare access than children from major cities.Barriers included distance to travel,out-of-pocket costs,and lack of specialist medical and other health services.Conclusions Children with rare diseases,especially those with severe functional impairment have an enormous impact on health services,and better integrated multidisciplinary services with patient-centered care are needed.Access must be improved for children living in rural and remote settings.

An everlasting role of genetics and genomics in public health: a meeting report of ACGA-HKSMG International Conference on Genetic and Genomic Medicine 2008

The Association of Chinese Geneticists in America （ACGA） and the Hong Kong Society of Medical Genetics （HKSMG） held their first joint Conference on Genetic and Genomic Medicine in Hong Kong from June 9-11 in 2008 at the Cheung Kung Hai Conference Center, William MW Mong Block, Li Ka Shing Faculty of Medicine, the University of Hong Kong. Other co-organizers included the University of Hong Kong and Chinese Society of Medical Genetics. A satellite conference ＂ACGA-WZMC International Symposium of Genetics and Translational Medicine＂, co-organized with Wenzhou Medical College and Chinese Society of Medical Genetics, was held from June 12-14, 2008 at Wenzhou, Zhejiang Province of China.

Expanding the genetic landscape of Rett syndrome to include lysine acetyltransferase 6A(KAT6A)

Pathogenic variants in methyl-Cp G protein 2(MECP2;OMIM300005)result in an X-linked,severe,and progressive epigenetic disorder,Rett syndrome(RTT,OMIM:312750),that predominantly affects females(Rett,1966).Using Neul’s revised diagnostic criteria,affected individuals can be clinically classified as classic or atypical RTT(Neul et al.,2010).

A different spectrum of DMD gene mutations in local Chinese patients with Duchenne/Becker muscular dystrophy

Background Duchenne muscular dystrophy （DMD） and Becker muscular dystrophy （BMD） are X-linked recessive, allelic disorders. This study was conducted to look into the spectrum of DMD gene mutations in Hong Kong Chinese patients with Duchenne or Becker muscular dystrophy （DMD/BMD）, and to study genotype-phenotype correlation.

THREE NOVEL FOXL2 GENE MUTATIONS IN CHINESE PATIENTS WITH BLEPHAROPHIMOSIS-PTOSIS-EPICANTHUS INVERSUS SYNDROME

Blepharophimosis-ptosis-epicanthus inversus Psyndrome （BPES, OMIM # 110100） is a rare autosomal dominant disorder affecting the eyelid and ovarian development. When co-occurred together, it is type Ⅰ and when only the eyelid abnormalities are present, it is type Ⅱ. Both types had been mapped to the same locus 3q23 on the basis of cytogenetic rearrangements 1-3 and linkage analyses. 4-6 Subsequently,

Molecular basis of von Hippel-Lindau syndrome in Chinese patients

Background Von Hippel-Lindau （VHL） syndrome is an autosomal dominant familial cancer syndrome predisposing the affected individuals to multiple tumours in various organs.The genetic basis of VHL in Southern Chinese is largely unknown.In this study,we characterized the mutation spectrum of VHL in nine unrelated Southern Chinese families.Methods Nine probands with clinical features of VHL,two symptomatic and eight asymptomatic family members were included in this study.Prenatal diagnosis was performed twice for one proband.Two probands had only isolated bilateral phaeochromocytoma.The VHL gene was screened for mutations by polymerase chain reaction,direct sequencing and multiplex ligation-dependent probe amplification （MLPA）.Results The nine probands and the two symptomatic family members carried heterozygous germline mutations.Eight different VHL mutations were identified in the nine probands.One splicing mutation,NM_000551.2：c.463＋1G〉T,was novel.The other seven VHL mutations,c.233A〉G [p.Asn78Ser],c.239G〉T [p.Ser80lle],c.319C〉G [p.Arg107Gly],c.481C〉T [p.Arg161X],c.482G〉A [p.Arg161GIn],c.499C〉T [p.Arg167Trp] and an exon 2 deletion,had been previously reported.Three asymptomatic family members were positive for the mutation and the other five tested negative.In prenatal diagnosis,the fetuses were positive for the mutation.Conclusions Genetic analysis could accurately confirm VHL syndrome in patients with isolated tumours such as sporadic phaeochromocytoma or epididymal papillary cystadenoma.Mutation detection in asymptomatic family members allows regular tumour surveillance and early intervention to improve their prognosis.DNA-based diagnosis can have an important impact on clinical management for VHL families.

Delayed diagnosis of 22q11.2 deletion syndrome in an adult Chinese lady

We report a 32 year-old Chinese lady with history of tetralogy of Fallot, presented to us with chest pain due to hypocalcemia secondary to hypoparathyroidism. With her dysmerphic facial features and intellectual disability 22q11.2 deletion was suspected and confirmed by genetic study. Clinicians should consider the diagnosis of DiGeorge syndrome in adult patient with past medical history of congenital heart disease, facial dysmorphism, intellectual disability and primary hypoparathyroidism.

Spectrum of NSD1 gene mutations in southern Chinese patients with Sotos syndrome

Background Sotos syndrome is an overgrowth syndrome with characteristic facial gestalt and mental retardation of variable severity. Haploinsufficiency of the NSD 1 gene has been implicated as the major cause of Sotos syndrome, with a predominance of microdeletions reported in Japanese patients. This study was conducted to investigate into the spectrum of NSD1 gene mutations in southern Chinese patients with Sotos syndrome. Methods Thirty-six Chinese patients with Sotos syndrome and two patients with Weaver syndrome were subject to molecular testing. Results NSD1 gene mutations were detected in 26 （72%） Sotos patients. Microdeletion was found in only 3 patients, while the other 23 had point mutations （6 frameshift, 8 nonsense, 2 spice site, and 7 missense）. Of these, 19 mutations were never reported. NSD1 gene mutations were not found in the two patients with Weaver syndrome. Conclusions Most cases of Sotos syndrome are caused by NSD1 gene defects, but the spectrum of mutations is different from that of Japanese patients. Genotype-phenotype correlation showed that patients with microdeletions might be more prone to congenital heart disease but less likely to have somatic overgrowth. The two patients with Weaver syndrome were not found to have NSD1 gene mutations, but the number was too small for any conclusion to be drawn.

PHOX2B mutations in three Chinese patients with congenital central hypoventilation syndrome

Congenital central hypoventilation syndrome （CCHS, OMIM #209880） is a rare autosomal dominant disorder of the autonomic nervous system （ANS） characterized by an abnormal autonomic ventilatory response to progressive hypercarbia and sustained hypoxemia. Patients typically present in the newborn period with hypoventilation or apnea asleep, awake, or both, without any associated cardiac, pulmonary, neuromuscular or brainstem lesions. Rarely, some patients may present at a later age and are diagnosed to have late onset central hypoventilation syndrome （LOCHS）.1 Other features of ANS dysfunction such as feeding difficulty due to oesophageal dysmotility, severe constipation in the absence of Hirschsprung disease, poor regulation of basal body temperature, episodes of profuse sweating, pupillary and ocular abnormalities, decreased beat-to-beat variability of heart rate, attenuated response of heart rate to exercise, abnormal fluctuation of blood pressure, decreased perception to pain, and decreased perception to anxiety may be variably present but not essential for diagnosis Furthermore, this central hypoventilation can occur as an isolated feature or in association with a number of neurocristopathies, notably Hirschsprung disease （Haddad syndrome, OMIM #209880） and tumours of the sympathetic nervous system particularly neuroblastoma, ganglioneuro- blastoma, and ganglioneuroma, which were found in 20% and 5%--10% of CCHS patients, respectively.2 Studies of genes pertinent to the early embryologic development of the neural crest cells, specifically the endothelin and the RET-GDNF signaling pathways, have recently led to the identification of PHOX2B as the major disease causing gene for CCHS.2-6 PHOX2B was mapped to chromosome 4p12 and consists of 3 exons. It encodes a highly conserved paired-like homeobox transcription factor of 314 amino acids linked to the RET-GDNF signaling