L. Tiepolo

Localization of factors controlling spermatogenesis in the nonfluorescent portion of the human y chromosome long arm

SummaryA deletion of the Y chromosome at the distal portion of band q11 was found in 6 men with normal male habitus but with azoospermia. Five of them were found during a survey of 1170 subfertile males while the sixth was karyotyped because of slight bone abnormalities. These findings, together with a review of the literature, suggest that on the distal portion of the nonfluorescent segment of the long arm of the Y, factors are located controlling spermatogenesis.

Assignment by deletion mapping of the steroid sulfatase X-linked ichthyosis locus to Xp223.

SummaryA male child and his mother who are nullisomic and monosomic, respectively, for the distal portion of Xp because of an unbalanced X-Y translocation were tested for steroid sulfatase activity after clinical examination had yielded evidence for ichthyosis in the boy. Deficiency of steroid sulfatase was found in the male patient, while in his mother enzyme levels were in the heterozygous range. These results, based on cytogenetic evidence obtained with an elongation technique, indicate that the STS locus is at Xp223.

The “Cat Eye syndrome”: Dicentric small marker chromosome probably derived from a No. 22 (Tetrasomy 22pter→q11) associated with a characteristic phenotype

Eleven patients with the so-called Cat Eye syndrome are reported including a more detailed description of the original cases reported by Schmid and Fraccaro. All cases had, in addition to a normal karyotype, a small extra G-like chromosome which appeared to be an isochromosome for the juxtacentromeric region (pter to q11) of an acrocentric chromosome. None were mosaics. Clinical findings and further cytogenetic studies in a few cases suggest that these markers probably derive from a No. 22 chromosome. Characteristic features of the Cat Eye syndrome in these 11 patients and those reviewed from the literature are: ocular coloboma which may involve the iris, choroid and/or optic nerve, preauricular skin tags and/or pits which are probably the most consistent feature, congenital heart defect, anal atresia with a fistula, renal malformations such as unilateral absence, unilateral or bilateral hypoplasia, and cystic dysplasia, and antimongoloid position of eyes. Intelligence is usually low-normal, although moderate retardation is also seen. There is great variability in the clinical findings ranging from near normal to lethal malformations. Less frequent, but also characteristic findings are: microphthalmia, microtia with atresia of the external auditory canal, intrahepatic or extrahepatic biliary atresia and malrotation of the gut. Direct transmission of the marker from one generation to the other was observed in both sexes. In those families, there was considerable variability in the clinical findings between affected family members. These cases show that there is a bias of ascertainment for patients who have the more striking malformations, especially those with ocular coloboma and anal atresia, a combination which appears to be present in only a minority of cases. Many mildly affected patients probably remain undetected. It is proposed that the term Cat Eye syndrome should be applied only to cases with trisomy or tetrasomy of not more than 22pter to q11 and without additional duplication or deletion of another autosomal segment.SummaryEleven patients with the so-called Cat Eye syndrome are reported including a more detailed description of the original cases reported by Schnid and Fraccaro. All cases had, in addition to a normal karyotype, a small extra G-like chromosome which appeared to be an isochromosome for the juxtacentromeric region (pter→q11) of an acrocentric chromosome. None were mosaics. Clinical findings and further cytogenetic studies in a few cases suggest that these markers probably derive from a No. 22 chromosome.Characteristic features of the Cat Eye syndrome in these 11 patients and those reviewed from the literature are: ocular coloboma which may involve the iris, choroid and/or optic nerve, preauricular skin tags and/or pits which are probably the most consistent feature, congenital heart defect, anal atresia with a fistula, renal malformations such as unilateral absence, unilateral or bilateral hypoplasia, and cystic dysplasia, and antimongoloid position of eyes. Intelligence is usually low-normal, although moderate retardation is also seen. There is great variability in the clinical findings ranging from near normal to lethal malformations. Less frequent, but also characteristic findings are: microphthalmia, microtia with atresia of the external auditory canal, intrahepatic or extrahepatic biliary atresia and malrotation of the gut.Direct transmission of the marker from one generation to the other was observed in both sexes. In those families, there was considerable variability in the clinical findings between affected family members. Theses cases show that there is a bias of ascertainment for patients who have the more striking malformation, especially those with ocular coloboma and anal atresia, a combination which appears to be present in only a minority of cases. Many mildly affected patients probably remain undetected.It is proposed that the term Cat Eye syndrome should be applied only to cases with trisomy or tetrasomy of not more than 22pter→q11 and without additional duplication or deletion of another autosomal segment.

Monosomy of distal 4q does not cause facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary neuromuscular disorder transmitted in an autosomal dominant fashion. FSHD has been located by linkage analysis in the most distal part of chromosome 4q. The disease is associated with deletions within a 3.2 kb tandem repeat sequence, D4Z4. We have studied a family in which an abnormal chromosome 4 segregates through three generations in phenotypically normal subjects. This chromosome is the derivative of a (4;D or G) (q35;p12) translocation. Molecular analysis of the region 4q35 showed the absence of the segment ranging from the telomere to locus D4F104S1. Probe p13E-11 (D4F104S1), which detects polymorphic EcoRI fragments containing D4Z4, in Southern blot analysis showed only one allele in the carriers of the abnormal chromosome 4. Probe p13E-11 EcoRI fragments are contained in the subtelomeric region of 4q and their rearrangements associated with FSHD suggested that the gene responsible for the muscular dystrophy could be subject to a position effect variegation (PEV) because of its proximity to subtelomeric heterochromatin. The absence of the 4q telomeric region in our phenotypically normal cases indicates that haploinsufficiency of the region containing D4Z4 does not cause FSHD.

Agenesis of corpus callosum, ocular, and skeletal anomalies (X-linked dominant aicardi's syndrome) in a girl with balanced X/3 translocation

SummaryAicardis syndrome, which is characterized by agenesis of the corpus callosum, specific chorioretinal abnormalities, and defects of vertebrae and ribs, is considered a probable X-linked dominant trait with male lethality. All features of this syndrome were seen in a girl with a de novo balanced X/3 translocation (46,X,t(X;3)(p22;q12)). It is hypothesized that the clinical picture is the consequence of chromosome breakage within the Aicardi locus. Then, unusual X-inactivation patterns in blood and fibroblasts of this patient can be explained by somatic selection against cells with the Aicardi phenotype.

Multibranched chromosomes 1, 9, and 16 in a patient with combined IgA and IgE deficiency

SummaryInstability of the centromeric region of chromosome 1 and multibranched configurations formed by different numbers and combinations of arms of chromosomes 1, 9, and 16 were found in cultured lymphocytes of 12-year-old male with combined IgA and IgE deficiency. No chromosome abnormalities were found in fibroblast cultures from the patient or in blood cultures from his parents.A possible effect on the frequency of the abnormalities of the almost continuous antibiotic treatment received by the patient was found both in vivo and in vitro, but no abnormalities were found in blood cultures from control subjects who received similar treatment. Interphase association of chromosomes 1, 9, and 16 and a high frequency of interchanges among the centromeric regions of these chromosomes due to the presence of a fragile site is assumed to be the cause of the abnormalities.

Familial XX true hermaphroditism and the H-Y antigen

SummaryTwo 46,XX sibs, one of female, one of male gender, and both with ambiguous external genitalia and ovotestis, were H-Y positive. The mother was H-Y negative. It is assumed that the underlying mutation was transmitted by the father, resulting in an autosomal dominant mode of inheritance. The common origin and the nature of the mutation leading to XX sex reversal are discussed.

Cytogenetical and clinical investigations in four subjects with anomalies of sexual development

The Y chromosome of mammals is male determining and either the X , the autosomes or both are female determining. At present there is no evidence indicating whether one or several major or minor genes are involved in sex determination (Stern, 1963). Nor is it demonstrated, though conceivable, that the Y chromosome is necessary for the development and function of testicular tissue. Determination of a male or female phenotype is obviously also dependent on other internal and/or external factors acting during development (review in Witschi & Opitz, 1963). In man the existence of two rare types of X Y females who exhibit the clinical syndromes known as pure gonadal dysgenesis and testicular feminization indicates that the possession of a Y chromosome is not always sufficient to ensure a male phenotype. In pure gonadal dysgenesis, a condition as yet poorly understood, there are fibrous gonads at the site of the ovaries and in spite of the presence (at least in some cases) of the Ychromosome (Harnden & Stewart, 1959) the internal and external genitalia develop into female ones. The experiments of Jost (1954) on the effect of castration a t different stages of development in the rabbit indicate that the action of the gonads is responsible for the differentiation of the internal genitals. I n the absence of the foetal testis the Wolffian ducts degenerate and the Mullerian ducts develop into Fallopian tubes and uterus. The external genital anlage transforms into masculine type only in the presence of substance(s) normally produced by the testes (see also Turner & Asakawa, 1964). These findings indicate that the basic phenotype is the female one and removal of the gonads a t the appropriate time of development will produce a female phenotype irrespective of the chromosomal sex. This hypothesis can explain the phenotypical females with sex chromosomes of the X Y type, as in the case of pure gonadal dysgenesis. The syndrome of testicular feminization is characterized by the presence of testes in femalelooking individuals. It accumula.tes in families and in the affected sibships there is a deficiency of normal males. Puck, Robinson & Tjio (1960) postulate the involvement of a single mutant gene, probably a sex-limited autosomal dominant. On the basis of Jost’s hypothesis, the two allelic states of the presumptive gene, the normal and the mutant, should be active during male sex development, favouring and preventing respectively the effect of the morphogenetic substance(s) produced by the testis.

An analysis of Xq deletions

We characterized by fluorescence in situ hybridization and Southern blotting 14 partial Xq monosomies, 11 due to terminal deletions and 3 secondary to X/autosome translocations. Three cases were mosaics with a XO cell line. In view of the possible role played by telomeres in chromosome segregation, we hypothesize a relationship between the loss of telomeric sequences in terminal deletions and the presence of 45,X cells. A correlation between phenotype and extent of deletion revealed that there is no correspondence between the size of the deletion and impairment of gonadal function. Turner stigmata are absent in patients without an XO cell line, when the breakpoint is distal to Xg24. A low birthweight is present whenever the breakpoint is at q22 or more proximal.

Timing of Sex Chromosome Replication in Somatic and Germ-Line Cells of the Mouse and the Rat

Timing differences of the G2 periods were found among bone marrow cells labelled with 3H-thymidine in vivo , cultured kidney cells labelled in vitro<