Case report. Familial balanced translocation leading to an offspring with phenotypic manifestations of 9p syndrome.

We report two similarly affected cousins (children of monozygotic twin sisters) with phenotypic features consistent with 9p deletion syndrome, including dysmorphic craniofacial features (trigonocephaly, midface hypoplasia, upward-slanting palpebral fissures and long philtrum), intellectual disability and disorders of sex development. Initial cytogenetic examination showed normal karyotypes in the probands and their respective parents, though multiplex ligation probe amplification revealed a 1q terminal duplication and a 9p terminal deletion in both affected children. Further analysis by fluorescence in situ hybridization, identified a familial balanced cryptic translocation t(1;9)(q44;p23) in the mothers, showing the importance of the association of molecular cytogenetic techniques in clinical genetics, given the implications for the care of patients and for genetic counseling.

Somatic cytogenetic and azoospermia factor gene microdeletion studies in infertile men.

The objective of the present study was to determine the frequency of somatic chromosomal anomalies and Y chromosomal microdeletions (azoospermia factor genes, AZF) in infertile males who seek assisted reproduction. These studies are very important because the assisted reproduction techniques (mainly intracytoplasmic sperm injection) bypass the natural selection process and some classical chromosomal abnormalities, microdeletions of AZF genes or some deleterious genic mutations could pass through generations. These genetic abnormalities can cause in the offspring of these patients male infertility, ambiguous external genitalia, mental retardation, and other birth defects. We studied 165 infertile men whose infertility was attributable to testicular problems (60 were azoospermic, 100 were oligospermic and 5 were asthenospermic). We studied 100 metaphases per patient with GTG banding obtained from temporary lymphocyte culture for chromosomal abnormality detection and performed a genomic DNA analysis using 28 Y chromosome-specific sequence-tagged sites for Y AZF microdeletion detection. Karyotyping revealed somatic anomalies in 16 subjects (16/165 = 9.6%). Of these 16, 12 were in the azoospermic group (12/60 = 20%) and 4 were in the oligospermic group (4/100 = 4%). The most common chromosomal anomaly was Klinefelter syndrome (10/165 = 6%). Microdeletions of AZF genes were detected in 12 subjects (12/160 = 7.5%). The frequencies detected are similar to those described previously. These results show the importance of genetic evaluation of infertile males prior to assisted reproduction. Such evaluation can lead to genetic counseling and, consequently, to primary and secondary prevention of mental retardation and birth defects.

Phylloid pattern of pigmentary disturbance in a case of complex mosaicism.

Among the various types of pigmentary disturbances associated with mosaicism, the phylloid pattern (Greek phyllon = leaf, eidos = form) is characterized by multiple leaf-like patches reminiscent of an art nouveau painting. The number of cases displaying this unusual pattern is so far limited. We describe a phylloid pattern of hypomelanosis in a 3-year-old girl with multiple congenital anomalies including microcephaly, midfacial hypoplasia, cleft lip, coloboma, posteriorly rotated ears, pectus carinatum, and pronounced mental and physical retardation. In addition, this child had oval or oblong patches of hyperpigmentation involving the trunk in a horizontal arrangement dissimilar from the phylloid hypomelanotic pattern. In peripheral blood lymphocytes a karyotype 46,XX,-13,+t(13q;13q) was consistently found, whereas cultured skin fibroblasts showed a complex form of mosaicism comprising three different abnormal cell lines (46,XX,-13,+t(13q;13q)/45,XX,-13/45,XX,-13,+frag). This case provides further evidence that the phylloid pattern represents a separate category of pigmentary disturbance to be distinguished from other types of cutaneous mosaicism such as the lines of Blaschko or the checkerboard arrangement.

Spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL): a Brazilian case.

This is a report on a Brazilian patient with spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL; MIM 271640), a rare autosomal recessive skeletal dysplasia characterized by dwarfism, articular hypermobility, progressive intractable spinal malalignment, a typical facies and a propensity to joint dislocation and subluxation. The condition has been described only in 20 children of Afrikaans-speaking parents in South Africa. This is the first report of a non-Afrikaans patient with this genetic entity.

Cerebello-trigeminal-dermal dysplasia (Gómez-López-Hernández syndrome): description of three new cases and review.

Cerebello-trigemino-dermal "dysplasia" is a rare neurocutaneous syndrome of craniosynostosis, ataxia, trigeminal anesthesia, scalp alopecia, cerebellar anomaly, midface hypoplasia, corneal opacities, apparently low-set ears, mental retardation, and short stature. It seems to be a sporadic condition but little is known about its cause and pathogenesis in the few cases reported so far. We present three new unrelated patients and magnetic resonance images of the central nervous system, and review the four cases reported previously. We think that this is not such a rare condition, and that it is underdiagnosed.

Ablepharon-macrostomia syndrome: first report of familial occurrence.

Ablepharon-macrostomia syndrome (AMS) is a rare condition comprising severe deficiency of the anterior lamella of both eyelids, abnormal ears, macrostomia, anomalous genitalia, redundant skin, and absence of lanugo. There is no agreement about cause; some authors suggest autosomal recessive inheritance. We describe familial occurrence of AMS in a girl, sister of a previously reported patient. The father has facial anomalies that suggest autosomal dominant inheritance. Am. J. Med. Genet. 94:281-283, 2000.

Partial 3p trisomy and different rearrangements involving chromosome 3 in the proposita's family.

A case of partial 3p trisomy is reported here. A review of published cases (8 males, 2 females, 7 families) shows a characteristic pattern of anomalies, constituting one more syndrome of multiple congenital anomaly and mental retardation (MCA/MR) characterized by microcephaly, brachycephaly, frontal bossing, temporal identation, square hypertelorism or telecanthus, epicanthus, short nose with a large tip, prominent cheeks, long and protruding philtrum, large and downturned mouth, protruding mid-upper lip, micro- or retrognathia, short neck, congenital heart defects, gastrointestinal malformation, penile hypoplasia, neuromotor or mental retardation, and predominance of whorls on digits. The proposita had a 46,XX,der(11),t(3;11)(p21;q25) karyotype. The mother was carrier of a de novo 3;11 balanced translocation. Chromosome mosaicism was detected in a female sibling of the proposita: 46% of her cells were 46,XX and 54% had 46,22,t(3;20(p21;13) karyotype - ie, a de novo 3;20 balanced translocation. We discuss the origin of this mosaicism and the possible meaning of the breaks involving the same region of chromosome 3 (region 3p 21) in the members of the proposita's family.

Cherubism, gingival fibromatosis, epilepsy, and mental deficiency (Ramon syndrome) with juvenile rheumatoid arthritis.

This is a report on four persons in one family with a condition similar to that described by Ramon et al [Oral Surg 24:436-48, 1967] in two sibs born to a consanguineous couple. Our patients also had mental deficiency, epilepsy, cherubism due to fibrous dysplasia of the maxillae, gingival fibromatosis, hypertrichosis, and stunted growth. This appears to be an autosomal recessive trait in both families. Our patients are the second set reported with this syndrome; they also have juvenile rheumatoid arthritis, which was not described in the family reported by Ramon et al [Oral Surg 24:436-48, 1967]. We conclude that the Ramon syndrome should also include juvenile rheumatoid arthritis.

Three new cases of spondylocarpotarsal synostosis syndrome: clinical and radiographic studies.

Spondylocarpotarsal synostosis syndrome (SSS) or congenital synspondylism is a recently delineated clinical entity. At least 15 patients have been reported. We present 3 new patients, 2 of whom were sibs born to first-cousin parents. All of our patients had multiple synostoses involving cervical, thoracic and/or lumbar vertebral bodies and carpal/tarsal bones, scoliosis/lordosis, and short stature. Sensorineural deafness was found in 2 of the 3 patients. Analysis of clinical manifestations suggests clinical variability and genetic heterogeneity in SSS. Of a total of 18 SSS patients, 10 were five pairs of sibs from five families, with first-cousin consanguinity of parents in 3, indicating that at least one type of SS is an autosomal-recessive disorder.

Retinal changes and tumorigenesis in Ramon syndrome: follow-up of a Brazilian family.

We report on the clinical evolution of the Brazilian family with Ramon syndrome described by de Pina-Neto et al. [1986, Am J Med Genet 25:441-443]. Three members (patients IV-2, IV-18, and IV-19) have developed pigmentary changes in the retina and paleness of the optic disk. Patient IV-18 also has developed giant hypertrophy of the labia minora that, when examined histopathologically, was found to be due to neoplastic fibroblast and epithelial proliferation caused by a fibromatous process similar to that reported in the gingivae of the patients with this syndrome. Audiologic function of patient IV-2 was normal, and no skin lesions were detected. The articular signs and symptoms show that the affected relatives developed rheumatoid arthritis, which is currently inactive in patient IV-18, whereas patient IV-2 did not develop these alterations.

Tetrasomy 9p caused by idic (9) (pter----q13----pter).

Cytogenetic investigation on a malformed male infant showed an extra chromosome similar to chromosome 9 in all metaphases studied. GTG, CBG, and G-11 staining suggested that the extra chromosome was an abnormal 9, permitting the identification of the chromosome constitution as 47,XY,+idic (9) (pter----q13----pter).

Effect of paternal age on human sperm chromosomes.

OBJECTIVE: To investigate whether increased age alters the frequency and type of chromosomal anomalies in human spermatozoa. DESIGN: Semen specimens were collected from donors via masturbation; cytogenetic studies were performed on sperm chromosomes after heterologous (human-hamster) in vitro fertilization. SETTING: Cytogenetics Laboratory, Genetics Department, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil. PATIENT(S): Seven men ages 59-74 (older group) and five men ages 23-39 (control group). MAIN OUTCOME MEASURE(S): Frequency and types of chromosomal anomalies in older and control group donors. RESULT(S): The frequency of numerical and structural aberrations (acentric fragments and complex radial figures) was significantly greater in chromosomes of older donors when compared with those of the control group. CONCLUSION(S): The higher frequency of sperm chromosome aberrations in older men was mainly a result of increased nondisjunction, acentric fragments, and complex radial figures.

DNA extraction and quantification from touch and scrape preparations obtained from autopsy liver cells.

The objective of the present study was to develop a simplified low cost method for the collection and fixation of pediatric autopsy cells and to determine the quantitative and qualitative adequacy of extracted DNA. Touch and scrape preparations of pediatric liver cells were obtained from 15 cadavers at autopsy and fixed in 95% ethanol or 3:1 methanol:acetic acid. Material prepared by each fixation procedure was submitted to DNA extraction with the Wizard genomic DNA purification kit for DNA quantification and five of the preparations were amplified by multiplex PCR (azoospermia factor genes). The amount of DNA extracted varied from 20 to 8,640 microg, with significant differences between fixation methods. Scrape preparation fixed in 95% ethanol provided larger amount of extracted DNA. However, the mean for all groups was higher than the quantity needed for PCR (50 ng) or Southern blot (500 ng). There were no qualitative differences among the different material and fixatives. The same results were also obtained for glass slides stored at room temperature for 6, 12, 18 and 24 months. We conclude that touch and scrape preparations fixed in 95% ethanol are a good source of DNA and present fewer limitations than cell culture, tissue paraffin embedding or freezing that require sterile material, culture medium, laboratory equipment and trained technicians. In addition, they are more practical and less labor intensive and can be obtained and stored for a long time at low cost.

Clinical, cytogenetical and molecular analyses of Angelman syndrome.

A total of 95 patients suspected with the clinical diagnosis of AS were evaluated and 37 cases (39%) were confirmed by cytogenetic or molecular studies as affected by Angelman syndrome. The clinical analysis was performed according to a specific clinical protocol for the diagnosis of AS. Cytogenetical analysis was used to detect chromosome rearrangements by determining the karyotype in lymphocytes by GTG banding and revealed an abnormal karyotype in two cases (5.4%), both of them presenting a new pericentromeric inversion in chromosome 15. Molecular analyses included determination of DNA methylation within the 15q11-13 region by Southern blotting and microsattelite analysis within the 15q11-13 region by PCR and the UBE3A gene was also studied by mutational screening. In 16 cases (43.2%) a de novo deletion was detected in the maternal chromosome 15:3 cases (8.1%) presented imprinting defect at the 15q11-13 region; one case is due to a paternal uniparental dissomy (2.7%) and another two cases showed a inherited mutation at the UBE3A gene (5.4%). Thirteen cases (35.1%) showed no deletion, no UPD, no imprinting defect, no UBE3A mutation and the diagnosis of AS could be ruled out in 58 patients. The objective of the present work was to describe the clinical and laboratory protocols employed at our laboratory in order to establish the AS study. We conclude that the protocols employed here were efficient for the diagnosis of AS, a frequently underdiagnosed pathology.

De novo unbalanced t(11q;21q) leading to a partial monosomy 21pter-q22.2 and 11q24-qter in a patient initially diagnosed as monosomy 21.

We describe a patient in whom full monosomy 21 was initially assumed from routine GTG banded karyotyping. Re-examination with chromosome painting demonstrated an unbalanced translocation between the long arms of chromosomes 11 and 21. Fluorescence in situ hybridization (FISH) and microsatellite marker analysis revealed partial monosomy of chromosome 21 (pter-q22.2) and 11 (q24-qter). The patient was prematurely born in the 31st week of gestation and expired 3 days after delivery. She showed multiple minor anomalies, a complex cardio-vascular malformation, intestinal malrotation and cerebellar hypoplasia.

De novo complex chromosome rearrangement: a study of two patients.

Complex chromosome rearrangements (CCR) involving multiple breaks in two or more chromosomes are rare. We describe a girl with development delay and overgrowth who presents a nine-break apparently balanced de novo rearrangement involving chromosomes 1, 2, 3, 4 and 12, and a boy with developmental delay and seizures with a complex three-chromosome apparently balanced de novo rearrangement involving chromosomes 2, 7 and 13. The relationship between clinical abnormalities and apparently balanced rearrangements is discussed.

Syndrome of psychomotor retardation, bulbous nose, and epilepsy (Hernandez syndrome): a Brazilian case.

A new case of Hernandez syndrome is described in a 16-year-old Brazilian girl. The syndrome consists mainly of psychomotor retardation, epilepsy, a bulbous nose and obesity.

Raine dysplasia: a Brazilian case with a mild radiological involvement.

We report a preterm male infant, the first child of a young consanguineous couple, whose physical examination revealed craniofacial disproportion with microcephaly, wide fontanelles, exophthalmos, low nasal root and hypoplastic nose, long philtrum, small mouth, high arched and narrow palate, micrognathia, dysplastic, low-set and rounded ears, short neck and, arthrogryposis. Postmortem findings included hypoplastic lungs. Radiological examinations showed mild and localized increased of bone density in the cranial vault and skull base and facial bones and undermodelled in the long bones. The above findings are characteristics of Raine dysplasia but the case reported here presents a mild bone involvement with only a localized bone sclerosis and absence of prenatal fractures. We discuss the possibility that this case represents an allelic mutation of the Raine gene. The consanguinity of the parents reinforces the hypothesis of autosomal recessive inheritance for this entity.

Noonan syndrome associated with unilateral iris coloboma and congenital chylothorax in an infant.

Chylothorax and colobomas are uncommon features reported in Noonan syndrome. We describe an infant with Noonan phenotype, congenital chylothorax and a unilateral iris coloboma. The presence of these both abnormalities in the same patient has not previously been reported.

Fragile X syndrome. Clinical and cytogenetic studies.

Three families with the fragile X syndrome were studied with the aim to establish the most frequent clinical signs in the affected individuals and heterozygous women. The clinical evaluation, IQ level measurements and cytogenetic studies were performed in 40 subjects, 20 males and 20 females. The fragile X diagnosis was confirmed in all the male individuals with mental retardation. In the postpubertal subjects the most frequent clinical signs were inner canthal distance < 3.5 cm, macro-orchidism, long and narrow face and high arched palate while in the prepubertal subjects the behavioral characteristics as hyperactivity and poor eye contact were the most frequent and were observed in all patients. Twenty six percent of the heterozygous women presented with mental retardation and showed clinical signs rather than behavioral ones. All male individuals with mental retardation were observed as having fragile X [fra(X)] in lymphocytes culture. Sixty three percent of women showed fra(X). There was a positive correlation between the frequency of fra(X) and the clinical characteristics. We emphasize the importance of the clinical evaluation in the study of familial mental retardation and in the screening of isolated cases with suspect of having the fragile X syndrome.