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PubMed2002

No evidence for submicroscopic 22qter deletions in patients with features suggestive for Angelman syndrome.

Patients with monosomy 22q13.3 --> qter have, in addition to (usually severe) developmental delay, hypotonia, severe expressive language delay leading to absence of speech, pervasive developmental abnormalities, and subtle facial anomalies. Thus far, it has been one of the more common submicroscopic telomere deletions seen in patients with mental retardation. Due to the phenotypic overlap between monosomy 22q13.3 and Angelman syndrome (AS), 44 patients with AS features but without one of the characteristic molecular 15q abnormalities were tested for 22qter deletions. In the study group, 31/44 (70%) were heterozygous for locus D22S163 with probe cMS607 (distance 0.125 Mb from telomere). The remaining 13/44 (30%) patients were heterozygous for one or more of four microsatellite markers centromeric from D22S163 in the 22qter region (distances 1.5-4.3 Mb from telomere). Based on the present study, there is no evidence that patients with an "Angelman-like" phenotype are more likely to have a 22qter deletion than other individuals with mental retardation.

Adolescent↗
PubMed2002

Clinical presentation of genetically defined patients with hypokalemic salt-losing tubulopathies.

PURPOSE: Hypokalemic salt-losing tubulopathies (Bartter-like syndromes) comprise a set of clinically and genetically distinct inherited renal disorders. Mutations in four renal membrane proteins involved in electrolyte reabsorption have been identified in these disorders: the furosemide-sensitive sodium-potassium-chloride cotransporter NKCC2, the potassium channel ROMK, the chloride channel ClC-Kb, and the thiazide-sensitive sodium-chloride cotransporter NCCT. The aim of this study was to characterize the clinical features associated with each mutation in a large cohort of genetically defined patients. PATIENTS AND METHODS: The phenotypic characteristics of 65 patients with molecular defects in NKCC2, ROMK, ClC-Kb, or NCCT were collected retrospectively. RESULTS: ROMK and NKCC2 patients presented with polyhydramnios, nephrocalcinosis, and hypo- or isosthenuria. Hypokalemia was less severe in the ROMK patients compared with the NKCC2 patients. In contrast, NCCT patients had hypocalciuria, hypomagnesemia, and marked hypokalemia. While this dissociation of renal calcium and magnesium handling was also observed in some ClC-Kb patients, a few ClC-Kb patients presented with hypercalciuria and hypo- or isosthenuria. CONCLUSIONS: ROMK, NKCC2, and NCCT mutations usually have uniform clinical presentations, whereas mutations in ClC-Kb occasionally lead to phenotypic overlaps with the NCCT or, less commonly, with the ROMK/NKCC2 cohort. Based on these results, we propose an algorithm for the molecular diagnosis of hypokalemic salt-losing tubulopathies.

Algorithms↗
PubMed2003

Temtamy-like syndrome associated with translocation of 2p24 and 9q32.

We describe the phenotype of a 5 year old girl with features resembling Temtamy syndrome, including agenesis of the corpus callosum, ventriculomegaly, frontal bossing, peaked eyebrows, ptosis, malformed and low set ears, a depressed nasal bridge, a long philtrum, and iris and chorioretinal colobomas. Features unique to this child include profound mental retardation, bilateral sensorineural hearing loss, agenesis of the corpus callosum, patent ductus arteriosus, ventricular septal defect, unilateral renal agenesis, neurogenic bladder and hydronephrosis. High resolution chromosome analysis demonstrated a de novo, balanced translocation [46,XX,t(2;9)(p24;q32)]; and her case has some overlapping phenotypic features with cases of monosomy for 2p. This is the first documented case of Temtamy syndrome with a specific chromosomal anomaly, and will assist with the elucidation of the syndrome's underlying genetic defect.

Abnormalities, Multiple↗
PubMed1988

G syndrome: an unusual family.

The G syndrome is a multiple congenital anomaly (MCA) syndrome of hypertelorism, hypospadias, stridor, and swallowing difficulties. Cleft lip and palate, cardiac defects, cranial asymmetry, and bowel obstruction are occasional manifestations. Family data suggest autosomal dominant inheritance. Males appear to have more serious manifestations, whereas most females with the G syndrome have a benign course and are ascertained through affected male relatives. In the family reported here, the proposita was first seen at age 7 weeks because of swallowing difficulties, stridor, and unusual facial appearance, reminiscent of the G syndrome. Evaluation of the family showed striking facial changes in her father and all four of his sibs. These five individuals had megalencephaly, hypertelorism, and a broad prominent nasal root and bridge, reminiscent of the facial appearance in the BBB syndrome. There was no evidence for dysphagia, respiratory abnormality, or hoarse voice in any other relative. These individuals with the G syndrome display two unusual manifestations. There are no males with hypospadias; the proposita has the most severe laryngotracheoesophageal symptoms. Although hypospadias is not an invariable manifestation of the G syndrome and although six females with severe dysphagia or respiratory abnormalities have been reported previously, the manifestations in this family underline the variability of this condition and provide further support that the G syndrome can be expressed with equal severity in both males and females. Although phenotypic overlap between the BBB and G syndromes has long been recognized, many still consider them to be distinct nosologic entities. The occurrence of both BBB and G syndrome in different members of the same family has been observed previously.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Multiple↗
PubMed2003

Cree encephalitis is allelic with Aicardi-Goutiéres syndrome: implications for the pathogenesis of disorders of interferon alpha metabolism.

Aicardi-Goutiéres syndrome (AGS) is an early onset, progressive encephalopathy characterised by calcification of the basal ganglia, white matter abnormalities, and a chronic cerebrospinal fluid (CSF) lymphocytosis. Cree encephalitis shows phenotypic overlap with AGS although the conditions have been considered distinct because of immunological abnormalities observed in Cree encephalitis. We report that levels of interferon alpha (IFN-alpha), a marker of AGS, are raised in Cree encephalitis. Moreover, linkage analysis indicates that the disorders are allelic and refines the AGS1 locus to a 3.47 cM critical interval. Our data show that a CSF lymphocytosis is not necessary for the diagnosis of AGS and strongly suggest that AGS and pseudo-TORCH syndrome are the same disorder. Recognition of immunological dysfunction as part of the AGS phenotype provides further evidence of a primary pathogenic role for abnormal IFN-alpha production in AGS.

Abnormalities, Multiple↗
PubMed1991

On lumping and splitting: a fetus with clinical findings of the oral-facial-digital syndrome type VI, the hydrolethalus syndrome, and the Pallister-Hall syndrome.

The three midline malformation complexes, the oral-facial-digital syndrome type VI (OFDS VI) or Váradi syndrome, the hydrolethalus syndrome (HS), and the Pallister-Hall syndrome (PHS) have been described as distinct genetic entities. Here, we report a fetus with a combination of clinical findings of all 3 syndromes similar to the twin fetuses described in the accompanying paper (Hingorani et al., 1991). The phenotypic overlap in these fetuses with the OFDS VI, HS, and PHS raises the question as to whether or not they indeed represent separate genetic entities as previously assumed.

Abnormalities, Multiple↗
PubMed2002

Mutation of the signal peptide region of the bicistronic gene DSPP affects translocation to the endoplasmic reticulum and results in defective dentine biomineralization.

Dentine dysplasia type II is an autosomal dominant disorder in which mineralization of the dentine of the primary teeth is abnormal. On the basis of the phenotypic overlap between, and shared chromosomal location with, dentinogenesis imperfecta type II, a second disorder of dentine mineralization, it has been proposed that the two conditions are allelic. As recent studies have shown that dentinogenesis imperfecta type II results from mutation of the bicistronic dentine sialophosphoprotein gene (DSPP ), we have tested this hypothesis by sequencing DSPP in a family with a history of dentine dysplasia type II. Our results have shown that a missense change, which causes the substitution of a tyrosine for an aspartic acid in the hydrophobic signal peptide domain of the protein, underlies the phenotype in this family. Biochemical analysis has further demonstrated that this mutation causes a failure of translocation of the encoded proteins into the endoplasmic reticulum, and is therefore likely to lead to a loss of function of both dentine sialoprotein and dentine phosphoprotein.

Dentin↗
PubMed1986

Phenotype-karyotype correlation in patients trisomic for various segments of chromosome 13.

Analysis of clinical and cytogenetic findings taken from 62 published cases of partial trisomies of chromosome 13 showed that 15 had partial trisomy for the proximal long arm and 47 had trisomy for the distal long arm. Persistence of fetal haemoglobin (Hb F), increased projections of polymorphonuclear leucocytes (PMN), depressed nasal bridge, cleft lip/palate, and clinodactyly were more frequent in patients with proximal trisomy 13. In the distal trisomy group, the common features included haemangioma, bushy eyebrows, long curled eyelashes, prominent nasal bridge, long philtrum, thin upper lip, highly arched palate, and hexadactyly. In addition, several other features were common to both the groups, often showing inconsistency even when the same segment was in trisomy. The influence of the second aneusomy as the most likely cause for such inconsistent and overlapping phenotypes is discussed in view of the fact that 42 of 62 cases were derived from a balanced translocation carrier parent.

Aneuploidy↗
PubMedDate not supplied

Phenotypic analysis of human peripheral blood lymphocytes by automatic sampling flow cytometry after stimulation with mitogens or allogeneic cells.

Human peripheral blood lymphocyte (PBL) phenotypes have been analyzed before and after stimulation with phytohemagglutinin (PHA), concanavalin A (ConA) and pokeweed mitogen (PWM) for 3 days and in mixed lymphocyte culture (MLC) for 7 days. PBL labeled with each of 10 fluorescent monoclonal antibodies were automatically sampled for flow cytometry from 96-well microtiter plates using a microsample delivery system. The reference phenotypic ranges were determined in fresh cells and control cultures. PHA was mostly mitogenic for T PBL bearing the CD3, CD5, CD7, CD8 and CD25 differentiation clusters, and a low density of CD1 and CD4 had a small effect on human natural killer cells (HNK) and also did not stimulate B (CD19) and HLA-DR+ PBL. There was an incomplete phenotypic overlapping between PHA- and ConA-stimulated cultures, ConA being more mitogenic for CD4 and less mitogenic for CD8 PBL. The mitogenic effect of PWM was evident on CD3, CD5, CD7, CD4, CD25 and CD8, but not on HNK, HLA-DR and CD19 B PBL, which presumably had already differentiated into antibody-secreting cells. After MLC stimulation all T, B and HNK PBL subsets tested were increased, but the cells bearing CD1, CD4, CD5, CD7, CD25, HNK, CD19 and HLA-DR had the greatest proliferation with respect to the unmixed control PBL. The present approach to the phenotyping of PBL subsets could offer more complete and accurate data for monitoring and follow-up of patients in transplantation and immunopathology hospital wards.

Antibodies, Monoclonal↗
PubMed1987

Oro-facial-digital syndrome II. Transitional type between the Mohr and the Majewski syndromes: report of two new cases.

Two patients with the oro-facial-digital syndrome II or Mohr syndrome presented laryngeal anomalies and hallucal and postaxial polysyndactyly of the feet. Those rare malformations are typically observed in patients with the Majewski syndrome, a lethal, short rib-polydactyly skeletal dysplasia with orofacial findings almost identical to those of the Mohr syndrome. Phenotypic overlap between the Mohr and the Majewski syndromes has already been reported in the literature, and it has been suggested that the two syndromes may be mild and severe expressions of the same autosomal recessive disorder. Our two cases give further support to this hypothesis.

Abnormalities, Multiple↗
PubMedDate not supplied

[Marshall syndrome--case report].

A girl, 15, with Marshall syndrome, was hospitalized for retinal tear and detachment of the left eye. The results of ophthalmological examination and applied eye surgery have been described. The authors confirm the essential phenotypical overlap of Marshall and Stickler syndromes. This suggest that they are caused by variable expression of a differently mutated gene, probably the type II procollagen gene (COL2A1), known to play a part in the etiology of Stickler syndrome. This justifies the usage, by some authors, of the common name of Marshall-Stickler syndrome.

Adolescent↗
PubMed2000

Mutations in the chloride channel gene, CLCNKB, leading to a mixed Bartter-Gitelman phenotype.

Gitelman syndrome is an inherited renal disorder characterized by impaired NaCl reabsorption in the distal convoluted tubule and secondary hypokalemic alkalosis. In clinical practice, it is distinguished from other hypokalemic tubulopathies by the presence of both hypomagnesemia and normocalcemic hypocalciuria. To date, only mutations in a single gene encoding the thiazide-sensitive NaCl cotransporter have been found as the molecular basis of GS. We describe three unrelated patients presenting with the typical laboratory findings of GS. Mutational analysis in these patients revealed no abnormality in the SLC12A3 gene. Instead, all patients were found to carry previously described mutations in the CLCNKB gene, which encodes the kidney-specific chloride channel ClC-Kb, raising the possibility of genetic heterogeneity. Review of the medical histories revealed manifestation of the disease within the first year of life in all cases. Clinical presentation included episodes of dehydration, weakness, and failure to thrive, much more suggestive of classic Bartter syndrome than of GS. The coexistence of hypomagnesemia and hypocalciuria was not present from the beginning. In the follow-up, however, a drop of both parameters below normal range was a consistent finding reflecting a transition from cBS to GS phenotype. The phenotypic overlap may indicate a physiologic cooperation of the apical thiazide-sensitive NaCl cotransporter and the basolateral chloride channel for salt reabsorption in the distal convoluted tubule.

Alkalosis↗
PubMed1998

Clinical phenotype of desmosterolosis.

We describe a child with lethal multiple malformations and generalised accumulation of desmosterol. The infant had macrocephaly, a hypoplastic nasal bridge, thick alveolar ridges, gingival nodules, cleft palate, total anomalous pulmonary venous drainage, ambiguous genitalia, short limbs, and generalised osteosclerosis. Gas chromatography-mass spectrometry demonstrated an abnormal accumulation of desmosterol in kidney, liver. and brain. Higher than normal levels of the same sterol were detected in plasma samples obtained from both parents. The biochemical phenotype in this infant is highly suggestive of a novel inborn error of cholesterol biosynthesis caused by an autosomal recessive deficiency of 3betahydroxysterol-delta24-reductase. A phenotypic overlap of this case with Raine syndrome was noted; however, desmosterol accumulation was not found on postmortem tissue samples from a previously reported case of this disorder.

Abnormalities, Multiple↗
PubMed2003

Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice.

Fanconi anemia (FA) is a genetic disorder characterized by hypersensitivity to DNA damage, bone marrow failure, congenital defects, and cancer. To further investigate the in vivo function of the FA pathway, mice with a targeted deletion in the distally acting FA gene Fancd2 were created. Similar to human FA patients and other FA mouse models, Fancd2 mutant mice exhibited cellular sensitivity to DNA interstrand cross-links and germ cell loss. In addition, chromosome mispairing was seen in male meiosis. However, Fancd2 mutant mice also displayed phenotypes not observed in other mice with disruptions of proximal FA genes. These include microphthalmia, perinatal lethality, and epithelial cancers, similar to mice with Brca2/Fancd1 hypomorphic mutations. These additional phenotypes were not caused by defects in the ATM-mediated S-phase checkpoint, which was intact in primary Fancd2 mutant fibroblasts. The phenotypic overlap between Fancd2-null and Brca2/Fancd1 hypomorphic mice is consistent with a common function for both proteins in the same pathway, regulating genomic stability.

Animals↗
PubMed1996

The gene encoding collagen alpha1(V)(COL5A1) is linked to mixed Ehlers-Danlos syndrome type I/II.

The Ehlers-Danlos syndrome (EDS) is a heterogeneous group of inherited connective tissue disorders in which cutaneous fragility and ligamentous laxity often combine with vascular, gastrointestinal, and skeletal deformities. There is considerable phenotypic overlap between the more common forms of EDS (types I and II), in which specific molecular defects have not yet been identified. Recently, genetic linkage has been demonstrated between the COL5A1 gene, which encodes the alphal chain of type V collagen, and EDS type II in a large British kindred. Using a polymorphic intragenic simple sequence repeat at the COL5A1 locus, we now demonstrate tight linkage to EDS type I/II in a three-generation family, giving a LOD score (log10 of the odds for linkage) of 4.07 at zero recombination. The variation in expression in this family suggests that EDS types I and II are allelic, and the linkage data support the hypothesis that mutation in COL5A1 can cause both phenotypes.

Aged↗
PubMed2006

Angiogenic murine endothelial progenitor cells are derived from a myeloid bone marrow fraction and can be identified by endothelial NO synthase expression.

OBJECTIVE: Endothelial progenitor cells (EPCs) contribute to postnatal neovascularization and are therefore of great interest for autologous cell therapies to treat ischemic vascular disease. However, the origin and functional properties of these EPCs are still in debate. METHODS AND RESULTS: Here, ex vivo expanded murine EPCs were characterized in terms of phenotype, lineage potential, differentiation from bone marrow (BM) precursors, and their functional properties using endothelial NO synthase (eNOS)-green fluorescent protein transgenic mice. Despite high phenotypic overlap with macrophages and dendritic cells, EPCs displayed unique eNOS expression, endothelial lineage potential in colony assays, and angiogenic characteristics, but also immunologic properties such as interleukin-12p70 production and low levels of T-cell stimulation. The majority of EPCs developed from an immature, CD31(+)Ly6C+ myeloid progenitor fraction in the BM. Addition of myeloid growth factors such as macrophage-colony-stimulating factor (M-CSF) and granulocyte/macrophage (GM)-CSF stimulated the expansion of spleen-derived EPCs but not BM-derived EPCs. CONCLUSIONS: The close relationship between EPCs and other myeloid lineages may add to the complexity of using them in cell therapy. Our mouse model could be a highly useful tool to characterize EPCs functionally and phenotypically, to explore the origin and optimize the isolation of EPC fractions for therapeutic neovascularization.

Animals↗
PubMed2004

Mevalonate kinase deficiency: Evidence for a phenotypic continuum.

Both mevalonic aciduria, characterized by psychomotor retardation, cerebellar ataxia, recurrent fever attacks, and death in early childhood, and hyper-immunoglobulin D (hyper-IgD) syndrome, with recurrent fever attacks without neurologic symptoms, are caused by a functional deficiency of mevalonate kinase. In a systematic review of known mevalonate kinase-deficient patients, the authors identified five adults with phenotypic overlap between these two syndromes, which argues for a continuous spectrum of disease. Mevalonate kinase deficiency should be considered in adult patients with fitting neurologic symptoms, with or without periodic fever attacks.

Adolescent↗
PubMed2006

HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy.

Costello syndrome (CS) is a complex developmental disorder involving characteristic craniofacial features, failure to thrive, developmental delay, cardiac and skeletal anomalies, and a predisposition to develop neoplasia. Based on similarities with other cancer syndromes, we previously hypothesized that CS is likely due to activation of signal transduction through the Ras/MAPK pathway [Tartaglia et al., 2003]. In this study, the HRAS coding region was sequenced for mutations in a large, well-characterized cohort of 36 CS patients. Heterogeneous missense point mutations predicting an amino acid substitution were identified in 33/36 (92%) patients. The majority (91%) had a 34G --> A transition in codon 12. Less frequent mutations included 35G --> C (codon 12) and 37G --> T (codon 13). Parental samples did not have an HRAS mutation supporting the hypothesis of de novo heterogeneous mutations. There is phenotypic variability among patients with a 34G --> A transition. The most consistent features included characteristic facies and skin, failure to thrive, developmental delay, musculoskeletal abnormalities, visual impairment, cardiac abnormalities, and generalized hyperpigmentation. The two patients with 35G --> C had cardiac arrhythmias whereas one patient with a 37G --> T transversion had an enlarged aortic root. Of the patients with a clinical diagnosis of CS, neoplasia was the most consistent phenotypic feature for predicating an HRAS mutation. To gain an understanding of the relationship between constitutional HRAS mutations and malignancy, HRAS was sequenced in an advanced biphasic rhabdomyosarcoma/fibrosarcoma from an individual with a 34G --> A mutation. Loss of the wild-type HRAS allele was observed, suggesting tumorigenesis in CS patients is accompanied by additional somatic changes affecting HRAS. Finally, due to phenotypic overlap between CS and cardio-facio-cutaneous (CFC) syndromes, the HRAS coding region was sequenced in a well-characterized CFC cohort. No mutations were found which support a distinct genetic etiology between CS and CFC syndromes.

Abnormalities, Multiple↗