Bi-allelic variants in CHST14, encoding dermatan 4-O-sulfotransferase-1 (D4ST1), cause musculocontractural Ehlers-Danlos syndrome (MC-EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures, and developmental anomalies. Recently, the identification of bi-allelic variants in DSE, encoding dermatan sulfate epimerase-1 (DS-epi1), in a child with MC-EDS features, suggested locus heterogeneity for this condition. DS-epi1 and D4ST1 are crucial for biosynthesis of dermatan sulfate (DS) moieties in the hybrid chondroitin sulfate (CS)/DS glycosaminoglycans (GAGs). Here, we report four novel families with severe MC-EDS caused by unique homozygous CHST14 variants and the second family with a homozygous DSE missense variant, presenting a somewhat milder MC-EDS phenotype. The glycanation of the dermal DS proteoglycan decorin is impaired in fibroblasts from D4ST1- as well as DS-epi1-deficient patients. However, in D4ST1-deficiency, the decorin GAG is completely replaced by CS, whereas in DS-epi1-deficiency, still some DS moieties are present. The multisystemic abnormalities observed in our patients support a tight spatiotemporal control of the balance between CS and DS, which is crucial for multiple processes including cell differentiation, organ development, cell migration, coagulation, and connective tissue integrity.

Fraser syndrome (FS) is an autosomal recessive malformation disorder characterized by cryptophthalmos, syndactyly, and abnormalities of the respiratory and urogenital tract. FS is considered to be the human equivalent of the murine blebbing mutants: in the mouse mutations at five loci cause a phenotype that is comparable to FS in humans, and thus far mutations in two syntenic human genes, FRAS1 and FREM2, have been identified to cause FS. Here we present the molecular analysis of 48 FS patients from 18 consanguineous and 15 nonconsanguineous families. Linkage analysis in consanguineous families indicated possible linkage to FRAS1 and FREM2 in 60% of the cases. Mutation analysis identified 11 new mutations in FRAS1 and one FREM2 mutation. Manifestations of these patients and previously reported cases with an FRAS1 mutation were compared to cases without detectable FRAS1 mutations to study genotype-phenotype correlations. Although our data suggest that patients with an FRAS1 mutation have more frequently skull ossification defects and low insertion of the umbilical cord, these differences are not statistically significant. Mutations were identified in only 43% of the cases suggesting that other genes syntenic to murine genes causing blebbing may be responsible for FS as well.

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Klinefelter syndrome is the most common chromosome abnormality in humans. The estimated prevalence is one in 500 to one in 1000 males but due to the widely variable and often aspecific features, only one in four cases are recognized. The most specific clinical features which can be observed at adult age are small testes, gynecomastia, female distribution of fat and body hair, slightly increased body length due to an increased leg length and azoospermia. Cognition is characterized by verbal deficits and psychosocial features include autistiform behavior. Structural brain abnormalities have been observed by MRI, such as decreased brain volumes and a decrease of asymmetry in areas corresponding to language performance. In the vast majority of cases a non-mosaic 47,XXY karyotype is observed. Parental imprinting of the extra X chromosome, variable inactivation of some X-chromosomal genes and CAG repeat length polymorphism of the androgen receptor may all be related to the variability of the phenotype. Surgical procedures of obtaining sperm in combination with repeated intracytoplasmic sperm injection/in vitro fertilization treatment may allow up to one in four men with Klinefelter syndrome to father children.

PurposeAt the start of the implementation of TESE-ICSI for Klinefelter men in the Netherlands, we aimed to evaluate their wish to father children and their attitudes towards this artificial reproduction technique.MethodsQuestionnaires were distributed to members of the Dutch Klinefelter Association (n = 365) and to Klinefelter cases known at our Department (n = 58). Questions addressed several aspects: socio-demographic characteristics, ascertainment of diagnosis, children and child wish, and TESE-ICSI. Data were characterized using descriptive statistics.ResultsA total of 260 questionnaires (corresponding to 194 cases, 46%) were returned. A possible wish to father children was reported by 90% of Klinefelter men. 70% of Klinefelter men and 74% of their partners would (probably) opt for TESE-ICSI.ConclusionThe majority of Dutch Klinefelter men and their partners desire to have children and have a positive attitude towards TESE-ICSI. Concerns include the risk of congenital malformations/developmental delay of the child and the limited success rate of TESE-ICSI.Electronic supplementary materialThe online version of this article (doi:10.1007/s10815-011-9603-z) contains supplementary material, which is available to authorized users.