CLCN5 chloride-channel mutations in six new North American families with X-linked nephrolithiasis.

BACKGROUND: X-linked nephrolithiasis, or Dent's disease, encompasses several clinical syndromes of low molecular weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and renal failure, and is associated with mutations in the CLCN5 gene encoding a kidney-specific voltage-gated chloride channel. Some patients from Europe have rickets, and all symptomatic patients confirmed by mutation analysis have been male. METHODS: We analyzed the CLCN5 DNA sequence in six new families with this disease. RESULTS: In three probands, a single-base substitution yielded a nonsense triplet at codons 28, 34, and 343, respectively, and in two families, one of which was Hispanic, we found single-base deletions at codons 40 and 44, leading to premature termination of translation. In the sixth family, a single-base change from C to T predicted substitution of leucine for serine at codon 244, previously reported in two European families with prominent rickets, though this patient of Ashkenazi origin did not have rickets. Each of these mutations was confirmed by restriction endonuclease analysis, or repeat sequencing and CFLP. The R34X mutation occurred in a Canadian infant with severe rickets. The family with the R28X nonsense mutation included one woman with recurrent kidney stones and another woman with glomerular sclerosis. In another family, a woman heterozygous for the W343X mutation also had nephrolithiasis. CONCLUSIONS: These studies expand the range of mutations identified in this disease, and broaden the phenotypic range to include clinically affected women and the first North American case with severe rickets.

Prenatal diagnosis of familial ring 21 chromosome.

Ring chromosome 21 is a rare chromosome anomaly often associated with mental retardation and dysmorphic features. Less commonly, the ring chromosome can be familial and associated with a normal phenotype. Phenotypically normal female carriers, however, are at increased risk of having children with Down syndrome, mosaic monosomy 21, and variable duplication or deletion of chromosome 21. Because of the relative mitotic and meiotic instability of ring chromosomes, abnormal cytogenetic findings encountered during prenatal diagnosis may not reflect the true genetic status of the fetus. This is a report of a phenotypically normal female carrier of a familial ring 21 chromosome. Prenatal diagnosis on her twin pregnancy revealed a mosaic 46,XX,r(21)(p13;q22) (77 per cent)/45,XX,-21 in one fetus and a normal male karyotype in the second. The pregnancy was carried to term. Both infants are completely normal, with a non-mosaic ring 21 karyotype from the lymphocytes of one twin. The diagnostic uncertainty and problematic genetic counselling related to fetal cytogenetic abnormalities are the subjects of this report.

Blepharophimosis, ptosis and mental retardation: further delineation of Ohdo syndrome.

The Ohdo syndrome is characterized by blepharophimosis, ptosis, abnormal ears, and mental retardation. This report describes a child with the Ohdo syndrome who, in addition, has microcephaly and growth retardation. Her phenotype probably represents variable expression or genetic heterogeneity of the Ohdo syndrome.

Identification of a small supernumerary ring chromosome 8 by fluorescent in situ hybridization in a child with developmental delay and minor anomalies.

We report a 15-month-old female with developmental delay, hypotonia, and minor anomalies whose karyotype is 47,XX,+r. Due to its small size, the origin of the ring chromosome was indeterminate by standard G-banded karyotyping. Fluorescent in situ hybridization was performed, which indicated that the ring chromosome was derived from the pericentric region of chromosome 8.

Prospective management of a child with neonatal citrullinemia.

A patient with neonatal citrullinemia caused by severe deficiency of argininosuccinate synthetase was treated prospectively according to the currently accepted protocol. We gradually reduced the doses and then discontinued treatment with sodium benzoate and phenylacetate; blood glutamine levels were maintained in the normal range, but ammonia was mildly elevated. Growth and development progressed normally through 31 months of age. Some patients with citrullinemia can be successfully managed without daily sodium benzoate and phenylacetate therapy.

Interstitial deletion of chromosome 2 region in a malformed infant.

We describe an infant with a lumbar meningomyelocele and other congenital anomalies and a de novo deletion of 2q36 with a non-mosaic karyotype 46,XX,del(2)(q36).

Rett syndrome and mitochondrial enzyme deficiencies.

The etiology of Rett syndrome is unknown. Structural mitochondrial abnormalities have been described in muscle in patients with Rett syndrome. We report three children with Rett syndrome and normal muscle mitochondrial structure on light and electron microscopy. However, all had abnormalities in mitochondrial respiratory chain enzymes.

Down syndrome complicated by hemoglobin S/beta+ thalassemia. Atypical expression of coexistent disease.

The chance occurrence of Down syndrome and sickle cell disease is an extremely rare event. The patient presented in this article is the only reported case, based on medical literature review, of Down syndrome coexisting with sickle cell disease due to hemoglobin S/beta+ thalassemia. He had multiple recurrent aplastic crises and severe psychomotor and growth retardation. The physiologic basis for the atypical manifestations of both of his disorders is the subject of this report.

Pseudoleukemia in Down's syndrome. Analysis of immunophenotype and gene rearrangement.

This report demonstrates a case of transient abnormal myelopoiesis (TAM) evolving in a patient with Down's syndrome. A diagnosis was established after the patient's blast cell count decreased considerably three weeks after the initial leukemic phase. The blast population in the authors' case expressed Leu-9 (CD7), 6D1, and TdT+. Cytochemistries showed some of the blast population to be peroxidase positive and Sudan black positive. Platelet peroxidase by electron microscopic examination showed some positive blasts. Therefore, surface markers and cytochemical studies in this case suggested an abnormal proliferation involving a pluripotential stem cell capable of expressing myeloid and lymphoid characteristics. Cytogenetics was performed at birth and showed 47,XY,+21/48,XY,+21,+mar, confirming the diagnosis of Down's syndrome. The origin of the chromosomal fragment was uncertain. It was of interest that during the remission phase of his pseudoleukemia there was a concomitant decrease in the extra chromosomal fragment. Immunoglobulin and T-cell antigen receptor gene rearrangement studies showed only germline patterns, indicating that the lymphoid cells in the blast population were not clonally expanded. Therefore, immunoglobulin and T-cell antigen receptor rearrangement analysis and immunophenotyping are extremely valuable techniques in distinguishing between TAM and acute lymphoblastic leukemia in patients with Down's syndrome.

Mesodermal induction defect as a possible cause of ear malformations.

Deafness due to inner ear anomalies is rarely associated with malformations of the auricles. We describe two brothers with profound congenital sensorineural deafness, abnormal vestibular function, normal ossicles, and delayed motor development. Since the external and inner ear originate from distinctly separate structures, the embryogenesis of this malformation association is less clear than in the more common association of external and middle anomalies, where the latter two structures are derived from the first and second branchial arches. The combination of auricular and inner ear anomalies, with sparing of the middle ear structures, can be explained on the assumption that mesodermal induction is responsible for normal differentiation of both the otocyst and of the branchial arch ectoderm. A recessive mutant gene may lead to a deficiency of a mesodermal inducer substance of a target tissue receptor site. A similar mechanism may be involved in other multiple malformation syndromes, whereby a mutant gene acting during a specific period of organogenesis causes disruption of the normal induction-competence relationship.

Malformation syndrome of duplication 12q24.1 leads to qter.

While duplication and deletion of the short arm of chromosome 12 cause well-recognized syndromes, duplication of the long arm chromosome 12 is rarely observe. We are reporting a duplication of chromosome 12 distal to band q24.1 in a five-month-old child. His chromosome constitution is 46,XY,-4+der(4),t(4:12)(p16;q24.1)mat. The balanced translocation is also carried by his maternal grandmother and two of the mother's brothers. The malformation syndrome consisted of unusual facial appearance and anomalies of the musculoskeletal, cardiovascular, genitourinary, and central nervous systems. Four previously reported patients had similar break points on chromosome 12 with similar malformations; therefore, phenotype-karyotype correlation suggests a definitive malformation syndrome associated with duplication of chromosome region 12q24.1 leads to qter.