Smith-Fineman-Myers syndrome in two brothers

We report on 2 brothers with a distinctive facial appearance, severe mental retardation, short stature, cryptorchidism, asplenia in one, dramatic failure to thrive, early hypotonia, and later hypertonia all suggestive of the Smith-Fineman-Myers syndrome. All 5 of the reported cases have been males, suggesting X-linked inheritance.     

Sotos syndrome in two brothers

Two brothers presented from birth with features characteristic of Sotos syndrome (cerebral gigantism): overgrowth, craniofacial abnormalities, and mental retardation with hyperactive and aggressive behavior. X-ray examination of the hands revealed imbalanced and advanced skeletal age in one, whereas anterior fontanel bones were present in both brothers. Various hormone concentrations in plasma were all within normal limits, as were the results of a search for abnormal metabolites in plasma and urine. The occurrence of this usually sporadic syndrome in two sons of possibly remotely consanguineous, healthy parents, suggests that in some cases Sotos syndrome may be inherited as an autosomal recessive trait. Thus our observation may support the suggestion of heterogeneity of Sotos syndrome. Until specific tests for the identification of various types are available, genetic counseling for this syndrome is difficult.     

Microcephaly-cardiomyopathy syndrome: confirmation of the phenotype

We report a 9 year old girl with microcephaly and self-limiting dilated cardiomyopathy. Additional features include mental retardation, delayed developmental milestones, and minor dysmorphic features. This is the second reported case of this phenotype, which is believed to be a new autosomal recessive syndrome.     

Costello or facio-cutaneous-skeletal syndrome?

X-linked mental retardation (XLMR) can be subdivided into syndromic and nonsyndromic or nonspecific. Patients with nonsyndroml XLMR show no characteristic manifestations, biochemical defects, or distinct fragile sites. Nevertheless, nonspecific XLMR seems to be heterogeneous. To determine the number and location of the genes responsible for XLMR, linkage studies in large pedigrees have to be performed. Here we report the data of linkage analysis in a large Brazilian family with 7 patients affected by a severe form of XLMR, with no other associated malformations. All the obligate carriers are normal. A close linkage without recombination (lod scores 1.95 and 3.25) was found between the disease locus and polymorphic DNA loci DXS255 (Xp11.22), DXS14 (Xp11.21). These results suggest tht the gene responsible for the disease in this family maps in the Xp11-cent of the X chromosome. Positive lod score in this region have also been reported for other XLMR genealogie, but with a much milder phenotype. The possibility of intragenic or locus heterogeneity is discussed. © 1993 Wiley-Liss, Inc.     

amamutdb.no: A Relational Database for MAN2B1 Allelic Variants that Compiles Genotypes,Clinical Phenotypes,and Biochemical and Structural Data of Mutant MAN2B1 in α‐Mannosidosis

α‐Mannosidosis is an autosomal recessive lysosomal storage disorder caused by mutations in the MAN2B1 gene, encoding lysosomal α‐mannosidase. The disorder is characterized by a range of clinical phenotypes of which the major manifestations are mental impairment, hearing impairment, skeletal changes, and immunodeficiency. Here, we report an α‐mannosidosis mutation database, amamutdb.no, which has been constructed as a publicly accessible online resource for recording and analyzing MAN2B1 variants ( http://amamutdb.no ). Our aim has been to offer structured and relational information on MAN2B1 mutations and genotypes along with associated clinical phenotypes. Classifying missense mutations, as pathogenic or benign, is a challenge. Therefore, they have been given special attention as we have compiled all available data that relate to their biochemical, functional, and structural properties. The α‐mannosidosis mutation database is comprehensive and relational in the sense that information can be retrieved and compiled across datasets; hence, it will facilitate diagnostics and increase our understanding of the clinical and molecular aspects of α‐mannosidosis. We believe that the amamutdb.no structure and architecture will be applicable for the development of databases for any monogenic disorder.     

Hereditary spastic diplegia with mental retardation in two young siblings

Two young siblings with hereditary spastic diplegia and mental retardation (Böök's syndrome) have had detailed clinical investigations since infancy. The inheritance pattern of this syndrome in the present family fits well with an autosomal recessive trait - with affected sibs of opposite sex, born to consanguineous healthy parents.     

Identification of 83 novel alpha-mannosidosis-associated sequence variants: functional analysis of MAN2B1 missense mutations

The lysosomal storage disorder alpha-mannosidosis is caused by deficiency of the enzyme lysosomal alpha-mannosidase (MAN2B1). In this study, 96 disease-associated sequence variants were identified in 130 unrelated alpha-mannosidosis patients from 30 countries. Eighty-three novel variants were detected, extending the mutation spectrum from 42 to 125. In total, 256 of the 260 mutant alleles (98.5%) were identified. Most of the variants were unique to each family, however, c.2248C>T (p.Arg750Trp) was detected in 50 patients from 16 countries, and accounted for 27.3% of the disease alleles. Haplotype analysis revealed that the c.2248T variant was present on four MAN2B1 haplotype backgrounds, where one major haplotype accounted for 95% of the alleles. The distribution of the c.2248T-associated haplotypes differed remarkably from those of the control populations, suggesting that c.2248C>T has occurred on a few ancestral haplotypes where the major haplotype subsequently has spread by founder effects. The disease-associated missense mutations were introduced into the human MAN2B1 cDNA, expressed in cell culture and assayed for MAN2B1 activity. The majority of the variants were inactive, however, ten showed MAN2B1 activity above background, and more detailed studies are necessary to further evaluate the pathogenicity of these variants.     

Glycerol kinase deficiency in two brothers with and without clinical manifestations

We report two brothers with glycerol kinase deficiency (GKD). The older brother had serious clinical symptoms, mental and growth retardation, abnormal skeleton, spontaneous fractures and premature loss of abnormal teeth. He and his mother had low serum phosphate levels. He had elevated serum and urine glycerol levels and GKD was found in cultured fibroblasts. Prenatal diagnosis was performed in the second pregnancy. Glycerol kinase activity was considered normal in a chorionic villus sample of the foetus. After birth, it was found that the boy had elevated serum and urine glycerol levels. Enzymatic analysis in cultured fibroblasts revealed that this boy also had GKD, in spite of having no expression of the disease. Chromosomal analyses in the parents and both boys were normal. Major rearrangements or deletions were not detected in molecular studies of DNA from the two brothers. The hybridisation pattern was normal and no allelic loss was observed.     

Variable phenotype associated with duplication of different regions of 2p

Previous reports suggest that duplication of the distal part of 2p causes a distinct syndrome. Of the 20 published cases, all resulted from a parental translocation. We report here clinical and cytogenetic data on three patients with dup(2p) and few, if any, of the physical findings of the syndrome. Our data suggest that dup(2p) is associated with an extremely variable phenotype which may be quite mild in some cases. It is also possible that many of the nonspecific developmental anomalies thought to be part of the syndrome may be caused by the accompanying deletion.     

Mental retardation,macrocephaly, short stature and craniofacial dysmorphism in three sisters: A new entity among the mental retardation-macrocephaly syndromes?

In this report we describe a true macrocephaly-mental retardation syndrome in three sisters. In addition, they present a distinct craniofacial dysmorphism with coarse facial features. Further family investigation revealed a similar macrocephaly in the mother and her father, suggesting autosomal dominant transmission of this familial macrocephaly. Present knowledge of the nosology of the mental retardation-macrocephaly association is reviewed and discussed.     

非特异性精神发育迟滞的遗传异质性

目的　探讨非特异性精神发育迟滞 (non- specific mental retardation,NSMR)的遗传方式。方法　采用分离分析法、Finney法和 Falconer法 ,对山东省遗传病群体调查中筛选出的 15 7个 NSMR家系进行了研究。结果　 U×U多发家庭接受常染色体隐性遗传 ;U× U总体属于常染色体隐性遗传 ,同时还有多基因的主基因效应 ,散发病例为 46 % ;U× A符合常染色体显性遗传 ,不完全外显。结论　 NSMR的遗传方式具有遗传异质性     

Bombay phenotype in two North Indian brothers: a case report

Bombay phenotype is unique in the aspect that the red cells are not agglutinated by antisera A, B and H. However the serum of such individuals contains anti A, B and strongly reactive anti H which agglutinates red cells of 'O' group individuals through a wide thermal range. The blood specimen of a 35 year old male donor who donated blood for the first time was subjected to detailed cell and serum grouping. There was a discrepancy between the results. The possibility of Bombay phenotype was considered and the sample was tested with anti H lectin. Further confirmation of blood group and secretor status was done from a reference laboratory. Family studies showed the same blood group in the elder sibling of the propositus. The present case highlights the significance of correlating cell and serum grouping results. Moreover, this blood group is very rare in North India. Family studies revealed the propositus to possess the B gene which was suppressed in the donor but expressed in the offsprings. The use of anti H in discrepant blood grouping results is recommended.     

Monozygotic twin brothers with the fragile X syndrome: different CGG repeats and different mental capacities

Little is known about the mechanism of CGG instability and the time frame of instability early in embryonic development in the fragile X syndrome. Discordant monozygotic twin brothers with the fragile X syndrome could give us insight into the time frame of the instability. We describe monochorionic diamniotic twin brothers with the fragile X syndrome who had different CGG repeats and different mental capacities, whereas the normal mother had a premutation. The more retarded brother had a full mutation in all his cells and no FMR-1 protein expression in lymphocytes, whereas the less retarded brother had 50%/50% mosaicism for a premutation and full mutation and FMR-1 protein expression in 26% of his lymphocytes. The differences in repeat size could have arisen either before or after the time of splitting. The time of splitting in this type of twin is around day 6-7. Given the high percentage of mosaicism, we hypothesise that the instability started before the time of splitting at day 6-7.     

Molecular analysis of the L1CAM gene in patients with X-linked hydrocephalus demonstrates eight novel mutations and suggests non-allelic heterogeneity of the trait

Eight novel mutations were identified in the gene encoding L1CAM, a neural cell adhesion protein, in patients/families with X-linked hydrocephalus (XHC) providing additional evidence for extreme allelic heterogeneity of the trait. The two nonsense mutations (Gln440Ter and Gln1042Ter) result most likely in functional null-alleles and complete absence of L1CAM at the cell surface. The four missense mutations (Leu482Pro, Ser542Pro, Met741Thr, and Val752Met) as well as delSer526 may considerably alter the structure of L1CAM. Interestingly, a missense mutation in an XHC family predicting the Val768Ile change in the second fibronectin type III domain of L1CAM was found not only in the two affected cousins and their obligate carrier mothers but also in two unaffected male relatives of the patients. Several possible explanations of this finding are discussed; the most likely being that Val768Ile is a rare non-pathogenic variant. If this were indeed the case, our data suggest that the XHC in this family is not due to a mutation of the L1CAM gene, i.e., that, in addition to the extreme allelic heterogeneity of XHC, a non-allelic form of genetic heterogeneity may also exist in this trait. Am. J. Med. Genet. 71:336–340, 1997. © 1997 Wiley-Liss, Inc.     

Mild Brachmann–de Lange syndrome: Changes of phenotype with age

We present a girl with mild manifestations of the Brachmann-de Lange syndrome (BDLS) with gradual change of the phenotype. Her findings support the hypothosis of variability of the phenotypic spectrum of the disorder.