Reproductive risks for carriers of complex chromosome rearrangements: analysis of 25 families.

We have determined the empirical reproductive risks for heterozygous carriers of complex chromosome rearrangements (CCRs). CCRs are structural rearrangements involving at least three chromosomes and three or more chromosomal breakpoints. Pregnancy outcome, the frequency and type of chromosomal imbalance in the offspring, and the localization and distribution of chromosome breakpoints were analyzed in 25 CCR families ascertained by the birth of a malformed child or repeated spontaneous abortions. This study included two newly ascertained familial CCRs and a total of 67 informative pregnancies. Analysis of the data, after correction for ascertainment bias, showed that the incidence of spontaneous abortions in CCR families was 48.3%. Approximately one in ten pregnancies and 18.4% of all live births to CCR carriers resulted in phenotypically abnormal offspring. One-half of all CCR carrier liveborn offspring were also CCR carriers. There was a 53.7% incidence of an abnormal pregnancy outcome to CCR carriers. We failed to detect any evidence for a non-random involvement of specific chromosomes in CCRs. However, we did observe a non-random distribution of specific breakpoints at sites 1q25, 4q13, 6q27, 7p14, 9q12, 11p11, 11p15, 12q21, 13q31, and 18q21.

Ocular histopathologic and biochemical studies of the cerebrohepatorenal syndrome (Zellweger's syndrome) and its relationship to neonatal adrenoleukodystrophy.

The eyes of three infants with cerebrohepatorenal disease (Zellweger's syndrome) who died demonstrated ganglion cell loss, gliosis of the nerve fiber layer and optic nerve, optic atrophy, and changes resembling those of retinitis pigmentosa in the retina and pigment epithelium. Ultrastructural examination showed bileaflet inclusions identical to those seen in neonatal adrenoleukodystrophy in the pigment epithelium and in pigmented macrophages, but these were absent in the cornea. Biochemical analysis of tissues demonstrated an excessive amount of very-long-chain fatty acids in the ocular tissues, an abnormality also found in adrenoleukodystrophy. These histopathologic and biochemical results demonstrated that the cerebrohepatorenal syndrome and neonatal adrenoleukodystrophy are similar in regard to ocular abnormalities and the presence of saturated very-long-chain fatty acids.

Clinical manifestations of familial 13;18 translocation.

Female first cousins, aged 21 and 2 1/2 years, with many of the characteristic features of trisomy 18, were found to have identical unbalanced translocations, 46,XX,--13, + der(13)t(13;18) (p13;q12)mat. Clinical features of another cousin, two uncles, and an aunt suggested that they, too, had a partial trisomy 18 phenotype. The long survival and normal menstrual and secondary sexual development in one case are remarkable. A heritable balanced translocation, 46,XX or XY, t(13;18) (p13;q12), was detected in the mothers of the cases, a sib, an aunt, and two uncles. Translocation carriers had abnormalities in gonadal structure or function, with aspermia in males and polycystic ovaries with infertility in several females, suggesting that some gene controlling reproductive development occurs on the long arm of chromosome 18, with normal function interrupted at the breakpoint. Balanced translocation carriers may also be at greater risk for both benign and malignant neoplasms, which included acute leukaemia in an uncle and adenocarcinoma of the stomach at an early age in the grandmother. Although aetiological laboratory studies identified no premalignant state, the clinical findings suggest a defect that may predispose to cytogenetic abnormalities and malignancy.

Quinacrine fluorescence and Giemsa banding in trisomy 22.

Using quinacrine fluorescence and Giemsa banding techniques we have identified an extra chromosome 22 in three non-mongoloid children with similar phenotypes and 47 chromosomes. In one of the children, the long arm of the extra 22 was shorter than usual. This 22q-chrcmcscme was observed in 4 normal family members with 46 chromosomes. In a fourth child, with similar physical findings, the extra G chromosome was shown to be neither a normal 21 nor 22. It must have arisen from a rearrangement in a parental gamete since it was not present in either parent's karyotype.No constellation of clinical findings, in association with an extra G chromosome, is sufficient evidence for the diagnosis of trisomy 22. The positive identification of the extra chromosome must be made using fluorescence and banding.

Focal dermal hypoplasia symdrome in a male.

Focal dermal hypoplasia (Goltz syndrome) is characterized by a pathognomonic abnormality of the skin in association with other congenital defects. There are only seven males among the 52 reported cases. We report the eighth case in a male and evaluate the possible genetic origin of the syndrome. A critical review of the literature provides no evidence for the previously accepted single gene mode of inheritance.

The association of the DiGeorge anomalad with partial monosomy of chromosome 22.

We have seen three unrelated patients with the DiGeorge anomalad who also had the same deletion of chromosome 22 (pter leads to qll). In each, the remaining long arm material (qll leads to qter) was translocated to a different autosome. Our patients and a review of the literature, including a recent report of a family having four infants with the DiGeorge anomalad and the same deletion of chromosome 22 (de la Chapelle et al: Hum Genet 57:253, 1981), make a strong argument for at least some cases of the DiGeorge anomalad arising from a deletion of the pericentromeric region of chromosome 22.

An Xp22 microdeletion associated with ocular albinism and ichthyosis: approximation of breakpoints and estimation of deletion size by using cloned DNA probes and flow cytometry.

Ocular albinism of the Nettleship-Falls type (OA1) and X-linked ichthyosis (XI) due to steroid sulfatase (STS) deficiency are cosegregating in three cytogenetically normal half-brothers. The mother has patchy fundal hypopigmentation consistent with random X inactivation in an OA1 carrier. Additional phenotypic abnormalities that have been observed in other STS "deletion syndromes" are not present in this family. STS is entirely deleted on Southern blot in the affected males, but the loci MIC2X, DXS31, DXS143, DXS85, DXS43, DXS9, and DXS41 are not deleted. At least part of DXS278 is retained. Flow cytometric analysis of cultured lymphoblasts from one of the XI/OA1 males and his mother detected a deletion of about 3.5 million bp or about 2% of the X chromosome. Southern blot and RFLP analysis in the XI/OA1 family support the order tel-[STS-OA1-DXS278]-DXS9-DXS41-cen. An unrelated patient with the karyotype 46,X,t(X;Y) (p22;q11) retains the DXS143 locus on the derivative X chromosome but loses DXS278, suggesting that DXS278 is the more distal locus and is close to an XI/OA1 deletion boundary. If a contiguous gene deletion is responsible for the observed XI/OA1 phenotype, it localizes OA1 to the Xp22.3 region.

Globoid cells, glial nodules, and peculiar fibrillary changes in the cerebro-hepato-renal syndrome of Zellweger.

In addition to a distinct malformation (pachymicrogyria, heterotaxic lamination of the cerebellar cortex, olivary dysplasia), unusual degenerative changes were found in the nervous system of 2 unrelated babies with the Zellweger syndrome. Cerebral clefts were present in 1 case. In both infants there was neuron loss and accumulation of glial nodules and globoid cells in the gray matter as well as degeneration of the white matter. There was fatty change in astrocytes and diffuse gliosis. Neurons in the column of Clarke and the lateral cuneate nucleus showed peculiar fibrillary changes. Cytoplasmic inclusion bodies were seen in the spinal ganglia. Swelling of cortical astrocytes was remarkable in the older infant. The combination of a rare malformation with the cell changes described here gives the syndrome a unique neuropathological profile.

OA1 mutations and deletions in X-linked ocular albinism.

X-linked ocular albinism (OA1), Nettleship-Falls type, is characterized by decreased ocular pigmentation, foveal hypoplasia, nystagmus, photodysphoria, and reduced visual acuity. Affected males usually demonstrate melanin macroglobules on skin biopsy. We now report results of deletion and mutation screening of the full-length OA1 gene in 29 unrelated North American and Australian X-linked ocular albinism (OA) probands, including five with additional, nonocular phenotypic abnormalities (Schnur et al. 1994). We detected 13 intragenic gene deletions, including 3 of exon 1, 2 of exon 2, 2 of exon 4, and 6 others, which span exons 2-8. Eight new missense mutations were identified, which cluster within exons 1, 2, 3, and 6 in conserved and/or putative transmembrane domains of the protein. There was also a splice acceptor-site mutation, a nonsense mutation, a single base deletion, and a previously reported 17-bp exon 1 deletion. All patients with nonocular phenotypic abnormalities had detectable mutations. In summary, 26 (approximately 90%) of 29 probands had detectable alterations of OA1, thus confirming that OA1 is the major locus for X-linked OA.