João M. Pina-Neto

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.

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.

The phenotypic spectrum of congenital Zika syndrome

In October 2015, Zika virus (ZIKV) outbreak the Brazilian Ministry of Health (MoH). In response, the Brazilian Society of Medical Genetics established a task force (SBGM‐ZETF) to study the phenotype of infants born with microcephaly due to ZIKV congenital infection and delineate the phenotypic spectrum of this newly recognized teratogen. This study was based on the clinical evaluation and neuroimaging of 83 infants born during the period from July, 2015 to March, 2016 and registered by the SBGM‐ZETF. All 83 infants had significant findings on neuroimaging consistent with ZIKV congenital infection and 12 had confirmed ZIKV IgM in CSF. A recognizable phenotype of microcephaly, anomalies of the shape of skull and redundancy of the scalp consistent with the Fetal Brain Disruption Sequence (FBDS) was present in 70% of infants, but was most often subtle. In addition, features consistent with fetal immobility, ranging from dimples (30.1%), distal hand/finger contractures (20.5%), and feet malpositions (15.7%), to generalized arthrogryposis (9.6%), were present in these infants. Some cases had milder microcephaly or even a normal head circumference (HC), and other less distinctive findings. The detailed observation of the dysmorphic and neurologic features in these infants provides insight into the mechanisms and timings of the brain disruption and the sequence of developmental anomalies that may occur after prenatal infection by the ZIKV.

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.

Two new Brazilian patients with Gómez–López‐Hernández syndrome: Reviewing the expanded phenotype with molecular insights

Gómez–López‐Hernández (GLH) syndrome or cerebello‐trigeminal dysplasia is a neurocutaneous syndrome whose etiology is unknown at the present time. We report two additional Brazilian patients, including the oldest one known to date (age 29). Here, we review the expanded phenotype in four patients with new clinical, psychiatric, radiological, and molecular investigations. One patient may have hypomania within the bipolar spectrum disorder with onset in childhood and adolescence. Primary growth hormone (GH) deficiency was ruled out in all patients, although one of them might have developed secondary GH deficiency due to partial hypopituitarism following severe hydrocephalus. Brain magnetic resonance angiography disclosed no azygous anterior cerebral artery (ACA) but only normal variants. Molecular analysis of the lysosomal acid phosphatase gene (ACP2) was performed, but no pathogenic mutations were identified. We present an overview of the phenotypic features of all patients described to date. There are currently 12 unrelated patients reported in the literature, 5 of whom are Brazilian. We discuss new molecular insights and speculate about the pathogenesis of GLH syndrome.

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.

Sotos syndrome (cerebral gigantism): analysis of 8 cases

Sotos syndrome or cerebral gigantism is characterized by macrocephaly, overgrowth, mental retardation and central nervous system abnormalities. Congenital heart defects may be present. We report 8 patients with this syndrome and relate their clinical features, neuroimaging and echocardiographic findings.

Autosomal dominant atretic cephalocele with phenotype variability: Report of a Brazilian family with six affected in four generations†

Atretic cephalocele is a clinicopathological entity, which is different from the common form of cephalocele. Its etiopathogenesis has not been completely explained and there are only two previous reports of familial recurrence. We report a Brazilian family with autosomal dominant inheritance with variable expressivity.

Splenopancreatic Field Abnormality Is Not Unique to Trisomy 13

Splenopancreatic fusion is an uncommon finding, usually only seen as part of the splenopancreatic field abnormality associated with trisomy 13. It may present itself either as ectopic splenic tissue in the cauda pancreatis, as ectopic pancreatic tissue in the spleen or accessory spleen, or as fusion of the cauda pancreatis and splenic hilum. In this study, we report four unrelated congenital anomaly cases presenting trisomy 21, osteocraniostenosis syndrome, isolated congenital heart defect, and oligohydramnios sequence due to prune belly syndrome, in which fusion was observed. This demonstrates that, although it may be more common in trisomy 13, this phenomenon should not be interpreted as pathognomonic to that syndrome.

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.