Growth hormone (GH), insulin-like growth factors (IGFs), and IGF-binding protein-3 (IGFBP-3) in a child with Proteus syndrome.

Proteus syndrome is a congenital hamartomatous disorder characterized by partial overgrowth involving all germ layers. A somatic mutation model has been proposed since familial cases are extremely rare. We report on a 3-year-old girl with typical manifestations of Proteus syndrome, including local, asymmetric hypertrophy of various parts of the body. Total body length was reduced. Serum levels of IGF-I and especially IGF-II and their major growth hormone dependent binding protein (IGFBP-3) were significantly reduced, although growth hormone secretion after a pharmacological stimulus was normal. In vitro studies of fibroblasts derived from hypertrophied tissue showed normal IGF-I production and somewhat reduced IGF-II and IGFBP-3 production as compared to normal human skin fibroblasts. Affinity cross-linking experiments showed that fibroblasts of the affect tissue in Proteus syndrome produced an unusual pattern of IGF bindings proteins containing large amounts of an IGFBP with high affinity to IGF-II. The data suggest that IGF production is generally disturbed in Proteus syndrome with imbalanced levels of specific IGFBP in affected tissue.

[Subacute necrotizing encephalomyelopathy (Leigh's disease) (author's transl)]. / Die subakute nekrotisierende Enzephalomyelopathie (Leigh). Ein Uberblick

The characteristic neuropathological features of subacute necrotizing encephalomyelopathy (Leigh), their histology and distribution are described. Clinical findings are unspecific. Impairment of feeding. vomitus, respiratory abnormality, retardation of psychomotor development, familial incidence and onset in early childhood are prominent symptoms. Atactic and athetoid movements, optic atrophy, oculomotor abnormalities are observed in most cases. An enzyme inhibitor excreted in the urine seems to be related to an inborn error of thiamine dependent metabolism in brain tissue. Treatment with thiamine derivatives may have a beneficial effect on the clinical course.

Hemoglobin chain synthesis in two children with trisomy 13. Evidence for temporary imbalance during switch from gamma to beta chain synthesis.

Hemoglobin chain synthesis was studied in 2 infants with trisomy 13, one in the newborn period, the other at 5 months of age. The relative rate of beta globin synthesis was much below normal in the newborn, resulting in an overall imbalance of nonalpha/alpha globin synthesis. In the 5-month-old child, globin synthesis was balanced, although gamma globin synthesis accounted for a larger than normal percentage of nonalpha globin synthesis. Thus, the presence of a third 13 chromosome causes sever disturbances in the gamma to beta switch mechanism primarily affecting the onset of beta globin synthesis. The appearance of two previously unobserved bands in isoelectric focusing gels of the newborn's Hb is suggestive of the presence of embryonic hemoglobins.

Genetic counselling in cases of anal and rectal atresia.

The familial occurrence of anal and rectal atresia is investigated in literature including a material of 169 patients of children's hospitals in Munich. Positive family history was found for only one of 169 patients. The mode of inheritance in those families with more than one affected member is generally considered to be autosomal recessive, although several families with X-chromosomal recessive inheritance have been described. In approximately 50% of the cases, anal atresia is associated with other malformations. Twin studies indicate that genetic factors play only a minor role in the etiology. The genetic risk in cases of isolated anorectal atresia is estimated to be well below 1%.

Course of pregnancy and family history in children with malformations of the urinary tract.

Catamnestic investigations were performed in 291 children with malformations of the urinary tract. In renal and vesical malformations both sexes were equally affected, whereas girls were more affected (1.5 :1) than boys with malformations of the renal pelvis and the ureter. Malformations of the urethra included only boys. Parental age was not different from the average parental age at time of delivery in any group. Genetic influences could be assumed in 8.8%. The incidence of malformations of both the urinary and other organ systems in relatives was 8-times higher than in the average population (P less than 0.005). Malformations of the urinary system and unspecified renal diseases were observed in relatives of 22.5% of our children. Nothing conspicuous could be found in the menstrual cycle, abortion rate, haemorrhage during pregnancy and smoking behaviour during pregnancy in the women of the study; 35.1% of them took drugs and 8.2 underwent X-ray investigations during pregnancy.

Catamnestic investigations in children with malformations of the gastrointestinal tract and the abdominal wall.

Catamnestic investigations were performed in 288 children with malformations of the gastrointestinal tract and the abdominal wall, among them 41 with oesophageal atresia, 41 with stenosis/atresia of the small and large bowel, 78 with anorectal malformations, 75 with Hirschsprung's disease, 28 with omphalocele and 25 with gastroschisis. In atresias/stenoses of the gastrointestinal tract both sexes were equally affected whereas boys were significantly more often affected in both Hirschsprung's disease (p 0.0005) and omphalocele/gastroschisis (p 0.05). The babies were more frequently preterm (p 0.025) than it was the case in controls. Parental age was not higher than the average parental age at time of delivery. Incidence of malformations was significantly higher in the relatives of our patients than in the average population and reached 20% (p 0.0005) in relatives of children with omphalocele/gastroschisis. Teratogenic effects of alcohol, diseases, X-rays and drugs during pregnancy could be suspected in several instances, whereas adverse effects of smoking, previous abortions and cycle disorders before pregnancy could not be established.

[Interruption of pregnancy based on prenatal diagnosis]. / Uber den Schwangerschaftsabbruch aufgrund pränataler Diagnostik.

Prenatal examination is indicated when there is a risk of hereditary disease causing alterations in the amnion cells, the amnion fluid, in the blood or the morphology of the fetus. Routine screening is performed in four groups: suspected chromosomalaberration, x-chromosomal heredopathy, metabolic defect or neural tube defect. Dermatologists have special interest in the second and third groups (Fabry disease, Xeroderma pigmentosum and recently Ichthyosis vulgaris). An interruption was proposed in 2,9% of all examinations performed up to now. On the other hand, most of pregnant women whose child was prenatally diagnosed to be healthy, had planned their pregnancy only with respect to the possibility of prenatal examination.

[Anhidrotic ectodermal dysplasia--Identification of heterocygote (carrier) females (author's transl)]. / Ektodermale Dysplasie vom anhidrotischen Typ--Identifizierung heterocygoter Merkmalsträgerinnen.

We report on a newborn male infant suffering from anhidrotic ectodermal dysplasia. This x-linked recesive disorder has a high letality during the first year of life. Survivors are psychologically grossly impaired. This necessitates identification of carrier females. Characteristics of heterocygotes (e.g. palmar ridge flattening, paucety of pores, dermoglyphic pattern) are described. In pregnancy amniocentesis and chromosome analysis for sex determination are to be recommended.

[Prenatal diagnosis in pregnancies at advanced maternal age (author's transl)]. / Pränatale Diagnostik bei erhöhtem Gebäralter.

Among 113 prenatal diagnoses in pregnancies at advanced maternal age (mothers older than 37 years) 7 aberrant fetal karyotypes were found (6.2%). Detailed reports of one case of trisomy 21, 18 and 13 each, as well as of XXY-, XYY- and XXX gonosomal constitution respectively are presented in the following. The frequency and severity of chromosome aberrations occurring in fetuses from elder women are discussed with respect to data from the literature. It seems that this group bears a higher risk for chromosomally abnormal offspring than has been suggested before.

[Transsexualism and the H-Y antigen]. / Transsexualität und H-Y Antigen.

First reports about incongruous H-Y antigen status in male-to-female and female-to-male transsexuals have been published by us in 1979. Meanwhile H-Y antigen expression was analyzed with the cytotoxicity assay of Goldberg et al. in 61 transsexuals. In 55 cases H-Y antigen status was found discordant with the anatomical, chromosomal and hormonal sex and corresponded to the gender identity of transsexuals. The relative frequency was 0,91. In 33 male-to-female transsexuals 29 were H-Y negative, one was intermediate, three were H-Y positive. In 28 female-to-male transsexuals 25 were H-Y positive, one was intermediate, two were H-Y negative. The new findings of an incongruous H-Y antigen status in genuine transsexuals may lead to new considerations about the pathogenesis of the disease and about the function of H-Y antigen.

Paternal age and Down's syndrome: data from prenatal diagnoses (DFG).

From prenatal diagnosis data obtained on mothers aged 35 years and above in the Federal Republic of Germany (DFG data), older fathers are demonstrated to have an increased risk of having trisomy 21 offspring. For paternal ages of 41 years upward, the age effect is quite strong. The risk for a fetus to have any de novo chromosomal aberration increases more with advancing paternal age for older mothers than for younger ones. Thus the ages of both parents have to be taken into account as an indication for prenatal diagnosis. Risk figures for trisomy 21 and for any de novo chromosomal aberration are given, together with preliminary recommendations for prenatal diagnosis for different combinations of parental ages.

[The chromosome bands. Significance for clinical and cytogenetic research (author's transl)]. / Die Chromosomenbanden. Bedeutung für Klinik und zytogenetische Forschung

The methods of performing chromosomal investigations have been fundamentally changed in the last few years through the discovery of differential staining methods. While only a rough classification of the chromosomes into single groups could be carried out earlier, it is now possible to identify every individual pair of chromosomes on the basis of a typical pattern of bands. By means of these banding techniques smaller chromosomal variations can be recognized which were overlooked earlier and which have led to the delineation of new chromosomal malformation syndromes. In the present work, the modern methods of chromosome analysis are reviewed. Examples from clinical diagnosis show the necessity of using these techniques.

[Prenatal diagnosis of Sandhoff's disease (GM2-gangliosidosis, type 2)]. / Pränatale Diagnose der GM2-Gangliosidose Typ 2 ("Sandhoff-Jatzkewitz-Krankheit")

The diagnosis of GM2-gangliosidosis type 2 (Sandhoff's disease) was made prenatally (23rd week of pregnancy) by amniocentsis. A sibling with "Tay-Sachs disease" had died shortly before. Severe deficiency of total beta-hexosaminidase was found in amniotic fluid and amnion-cell culture. After interruption of the pregnancy the enzyme defect was also found in the fetal brain tissue and the concentration of ganglioside GM2 was three times normal, confirming the diagnosis.

New chromosomal dysmorphic syndromes. 3. Partial trisomy 3q.

Chromosome analysis in a newborn, the daughter of diabetic parents, who showed multiple dysmorphic signs and malformations revealed direct duplication of a long arm segment of chromosome 3(3q2100 leads to 3q2700). Both parents have normal karyotypes. Compilation of the phenotype stigmata with those of 7 other patients and 1 fetus with partial trisomy 3q confirmed that clinical recognition of this syndrome is possible. It is characterized by hypertrichosis, typical craniofacial dysmorphia, frequent organ malformations and skeletal anomalies, as well as a peculiar dermatoglyphic pattern. It is a severe genetic disturbance, leading to death in the first months of life in many cases and only symptomatic care is advised.

New chromosomal dysmorphic syndromes. 2. Trisomy 10p.

This is the report of a family in which a balanced translocation in the mother t(5;10)(p15;p13) led to an unbalanced chromosomal constitution in two children. It was identified by G-banding analysis as trisomy of the distal portion of the short arm of chromosome 10 (p13 leads to pter). Comparison with 15 previous reports of trisomy 10p confirms the existence of a characteristic dysmorphic syndrome.

[Transexuality and X-Y antigen (author's transl)]. / Transsexualität und H-Y Antigen.

Eleven transexuals with transexuality from man to woman and a karotype 46 X-Y and 11 transexuals with transexuality from woman to man and the karotype 46 X-X were investigated for H-Y antigen. Eight of the 46 X-Y transexuals were H-Y antigen negative, one intermediately slightly positive and two H-Y antigen positive. Of the 46 X-X transexuals 9 were H-Y antigen positive, one was intermediately slightly positive and one was H-Y antigen negative. Two groups of transexuals can be distinguished. Genuine transexuals and secondary transexuals with a transvestite past who have suffered a sexual identity crisis due to the environment. The H-Y antigen is an expression of a complex of the genes which is responsible for virilization and is likely located in the Y chromosone. The gene responsible for the H-Y antigen expression is not identical with the inductor for testicular development. An explanation for the disordance of the H-Y antigen findings in transexuals is translocation or gene exchange from a Y-chromosome to an X-chromosome during meisis of the spermatogonia. In this way a morphological substrate for transexuality has been detected. H-Y antigen negative 46 X-Y males and H-Y antigen positive 46 X-X females can now be diagnosed as genuine morphological transexuals.

New chromosomal dysmorphic syndromes. 4. Trisomy 12p.

This is the report of two independent families in which a balanced maternal translocation led to trisomy 12 p in one of each their offspring. Evaluation of 21 further case reports indicates that this is a phenotypically well defined syndrome which leads to severe developmental retardation. It can be recognized by a characteristic combination of craniofacial anomalies which are summarized in a phantom picture. The gene sequences which produce the typical features in the trisomic state must be localized distally to band 12p12, which is the breakpoint in the partial trisomies. The specific craniofacial anomalies are not visibly modified by the length of the trisomic segment or additional small monosomies or trisomies of recipient chromosomes. However, the frequency and severity of organ malformations and the resulting probability of survival seem to decrease with increasing degrees of chromosomal imbalance. A cytogenetic classification of the 21 inherited translocations and a segregation analysis from the pedigree data was performed. For the different types of translocations the calculated risk figures are given.