Subject(s)
Chromosomes, Human, Pair 10 , Mosaicism/diagnosis , Prenatal Diagnosis , Adult , DNA Probes , Diagnosis, Differential , Fathers , Female , Genetic Counseling , Humans , Male , Maternal Age , Pregnancy , Pregnancy, High-RiskABSTRACT
We report on a patient born to consanguineous parents and presenting with pseudopapilledema, mixed hearing loss, and minor facial and limb anomalies. To our knowledge, there is just one similar description of this syndrome in three members of a Brazilian kindred whose parents were also consanguineous, suggesting autosomal recessive inheritance. We compare the findings of our patient with these previous reported cases and discuss the differential diagnoses of this new syndrome, which we suggest be named the acro-oto-ocular syndrome.
Subject(s)
Face/abnormalities , Hearing Loss/genetics , Toes/abnormalities , Adolescent , Adult , Consanguinity , Eye/pathology , Female , Genes, Recessive , Growth Disorders/genetics , Humans , Keratosis/genetics , Male , Nails/pathology , Papilledema/genetics , SyndromeABSTRACT
A family of male limited gonadotrophin independent precocious puberty was examined for activating mutation of the LH receptor. A transition of A to G in nucleotide 1733 of the human LH receptor gene was identified in all affected males and in an unaffected carrier female. The mutation was shown by identifying a new restriction site created by the mutation. This mutation appears to be a common feature of the disorder, as it has been reported previously in unrelated families. Therefore, the presence of this new restriction site can serve as a diagnostic tool in males at risk before the onset of symptoms, as well as identifying carrier females.
Subject(s)
Point Mutation , Puberty, Precocious/genetics , Receptors, LH/genetics , Adenylyl Cyclases/metabolism , Base Sequence , Child, Preschool , DNA Mutational Analysis , Enzyme Activation , Female , Heterozygote , Humans , Male , Molecular Sequence Data , Pedigree , Polymerase Chain Reaction , Receptors, LH/metabolismABSTRACT
Longitudinal assessments of three brothers with alpha-mannosidosis were performed biochemically by determining levels of leukocyte enzyme activity, and neurodevelopmentally by testing of general intelligence, language, visual spatial skills, and overall adaptive abilities. During the follow-up examination, enzyme activity was assessed in fibroblasts to evaluate the uniformity of biochemical deficits. The biochemical findings demonstrated profound deficits of leukocyte alpha-mannosidase that remained remarkably stable over time and were very similar to levels of the same enzyme activity in fibroblasts. The cognitive findings showed that the patients manifested mild cognitive deficits. Cognitive deficits were generally uniform with no signs of progressive deterioration, except receptive language abilities. Suggestions are made for careful follow-up of auditory abilities in patients with mannosidosis.
Subject(s)
Cognition , alpha-Mannosidosis/metabolism , Adaptation, Psychological , Child , Child, Preschool , Follow-Up Studies , Humans , Language , Male , Neuropsychological Tests , Space Perception/physiology , Time Factors , Visual Perception/physiology , alpha-Mannosidosis/psychologyABSTRACT
Three brothers with mannosidosis were assessed both biochemically by levels of enzyme activities and developmentally by serial testing of language and cognitive development. The findings indicated that while the leukocyte enzyme activity of alpha-mannosidase was exceptionally low, only mild intellectual deficits were present that did not progress during a two-year follow-up. These results do not substantiate the expected relationship between the severities of enzyme deficiency and developmental delays. Language and cognitive deficits appeared uniform with no areas of strengths or weaknesses. Deficits in development did not progress during a two-year follow-up.
Subject(s)
Cognition Disorders/diagnosis , Language Development Disorders/diagnosis , alpha-Mannosidosis/psychology , Child, Preschool , Cognition Disorders/genetics , Humans , Infant , Language Development Disorders/genetics , Language Tests , Leukocytes/enzymology , Male , Psychological Tests , alpha-Mannosidosis/blood , alpha-Mannosidosis/enzymology , alpha-Mannosidosis/geneticsABSTRACT
High densities of 6-thioguanine-sensitive Chinese hamster V79 cells reduce the recovery of co-cultured 6-thioguanine-resistant cells through a form of intercellular communication (metabolic cooperation). Diphenylhydantoin and phenobarbital, suspected human and animal teratogens and tumor promoters, were able to inhibit intercellular communication at noncytotoxic doses. A potentiation was observed when a mixture of the two chemicals was used.
Subject(s)
Cell Communication/drug effects , Phenobarbital/toxicity , Phenytoin/toxicity , Animals , Cell Line , Cell Survival/drug effects , Cricetinae , Cricetulus , Drug Interactions , Drug Resistance , Lung , Thioguanine/toxicityABSTRACT
The child with testicular enlargement in the absence of gonadotrophin stimulation presents a difficult diagnostic dilemma. Leydig cell tumors, Leydig cell hyperplasia, and tumors of adrenal rest tissue are the primary etiologic considerations. Because of considerable overlap in clinical presentation, careful biochemical and histologic evaluations are necessary to make the diagnosis. These should include serum levels of testosterone, dehydroepiandosterone, androstenedione, 17-hydroxyprogesterone, and 11-desoxycortisol, as well as urinary levels of 17-ketosteroids. If diagnostic changes in the biochemical profile are not present, then testicular biopsy is indicated. Encapsulation, presence or absence of the crystalloids of Reinke, degree of seminiferous tubule maturation, and the site of any abnormal tissue are important observations in the examination of the tissue specimen. Once the diagnosis has been established, then appropriate and specific medical or surgical therapy can be instituted. With appropriate treatment, the long-term prognosis in each condition is good.
Subject(s)
Adrenal Rest Tumor/pathology , Leydig Cell Tumor/pathology , Leydig Cells/pathology , Puberty, Precocious/etiology , Testicular Neoplasms/pathology , Testis/pathology , Adolescent , Adrenal Hyperplasia, Congenital/pathology , Child , Child, Preschool , Dehydroepiandrosterone/blood , Humans , Hyperplasia , Male , Testosterone/bloodABSTRACT
This paper reports simultaneous occurrence of cryptorchidism and testicular tumor in three brothers within a single family. Two of the brothers had seminoma and the third brother had embryonal carcinoma. Tumor markers such as alpha fetoprotein, assay for beta subunit of human chorionic gonadotrophic hormone, and carcinoembryonic antigen were all negative. The simultaneous occurrence of familial cryptorchidism and testicular tumor has not been reported, although familial occurrence of both entities has been described separately. Because of the known risk of testicular malignancy in cryptorchidism, aggressive screening and examination are recommended in the form of either serial palpation or serial testicular biopsies. Hormonal replacement with testosterone cypionate is recommended for pubertal patients undergoing bilateral orchiectomy as a result of tumor removal. The overall prognosis of patients with cryptorchidism and abdominal testicular tumor seems to be good provided an early diagnosis is made.
Subject(s)
Cryptorchidism/genetics , Testicular Neoplasms/genetics , Adolescent , Adult , Cryptorchidism/complications , Dysgerminoma/genetics , Humans , Male , Teratoma/genetics , Testicular Neoplasms/etiologySubject(s)
Congenital Hypothyroidism , Infant, Newborn , Thyroid Gland/physiology , Alpha-Globulins/deficiency , Cross Reactions , Diagnosis, Differential , False Negative Reactions , Female , Fetal Blood/analysis , Humans , Hypopituitarism/diagnosis , Hypothyroidism/epidemiology , Male , Mass Screening , Thyroid Function Tests , Thyrotropin/blood , Thyrotropin-Releasing Hormone/deficiency , Thyroxine/blood , Thyroxine-Binding Proteins/deficiencyABSTRACT
The anticonvulsant diphenylhydantion (DPH) causes embryonic folate antagonism in the animal model of the fetal hydantoin syndrome. Thus, comparisons were made between the metabolic effects of the teratogens DPH and 9-methyl pteroylglutamic acid (9-methyl PGA), a folate antagonist. The DPH inhibited ornithine decarboxylase (ODC), the rate-limiting enzyme in putrescine biosynthesis, and caused reduced levels of this precursor diamine as well as the resultant polyamines, spermidine and spermine. In contrast, embryos from rats treated with 9-methyl PGA had ODC activity similar to controls and increased levels of putrescine, spermidine, and spermine. Because ODC is an enzyme of major importance for embryogenesis, any alterations in ODC activity may indicate abnormal development.
Subject(s)
Abnormalities, Drug-Induced/enzymology , Carboxy-Lyases/antagonists & inhibitors , Disease Models, Animal , Ornithine Decarboxylase Inhibitors , Phenytoin/toxicity , Animals , DNA/analysis , Embryo, Mammalian/analysis , Female , Male , Methotrexate/analogs & derivatives , Methotrexate/toxicity , Mice , Polyamines/analysis , Pregnancy , RNA/analysisABSTRACT
The regulatory function of the central nervous system encompasses diverse endocrine, metabolic, and behavioral processes. Many of these originate, are integrated, or are coordinated through hypothalamic pathways or nuclei. Thus, tumors affecting areas projecting to the hypothalamus, tumors of the hypothalamus, and tumors invading or compressing the hypothalamus can produce abnormalities of hypothalamic function.
Subject(s)
Hypothalamic Neoplasms/physiopathology , Hypothalamus/physiopathology , Autonomic Nervous System/physiopathology , Behavior , Body Weight , Diabetes Insipidus/etiology , Endocrine Glands/physiopathology , Endocrine System Diseases/etiology , Female , Gonads/physiopathology , Growth Hormone/metabolism , Humans , Male , Vision Disorders/etiology , Water-Electrolyte Imbalance/etiologyABSTRACT
The anucleate mature erythrocyte also lacks ribosomes and mitochondria and thus cannot synthesize enzymes or derive energy from the Krebs citric acid cycle. Nevertheless, the red blood cell is metabolically active and contains numerous residual enzymes and their products which are essential for its survival and normal functioning. Enzyme deficiencies in the Embden-Myerhoff glycolytic pathway can result in nonspherocytic hemolytic anemia (NSHA), and some are also associated with neuromuscular or neurologic disorders. Glucose-6-phosphate dehydrogenase deficiency in the hexose monophosphate shunt also results in hemolytic anemia, especially following exposure to various drugs. Defects in glutathione synthesis and pyrimidine 5'-nucleotidase deficiency also cause NSHA, as does increased adenosine deaminase activity. Gluthathione synthetase deficiency which is not limited to the red cell also presents as oxoprolinuria with neurologic signs. All red cell enzyme defects appear as single gene errors, in most cases recessive in inheritance, either autosomal of X-linked.
Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/blood , Erythrocytes/enzymology , 5'-Nucleotidase , Adenosine Deaminase/blood , Anemia, Hemolytic, Congenital Nonspherocytic/genetics , Bisphosphoglycerate Mutase/deficiency , Fructose-Bisphosphate Aldolase/deficiency , Glucosephosphate Dehydrogenase Deficiency/blood , Glutathione/biosynthesis , Glyceraldehyde-3-Phosphate Dehydrogenases/deficiency , Hexokinase/deficiency , Humans , Nucleotidases/deficiency , Phosphofructokinase-1/deficiency , Phosphoglycerate Kinase/deficiency , Phosphopyruvate Hydratase/deficiency , Phosphoric Monoester Hydrolases/deficiency , Pyrimidine Nucleotides/deficiency , Pyruvate Kinase/deficiency , Triose-Phosphate Isomerase/deficiencyABSTRACT
Initial year growth responses to single weekly injections of 2.5 units human growth hormone (hGH) in 29 patients with hypopituitarism (130 units/yr/patient) were compared to responses in a series using smaller doses in conjunction with androgen (48 to 112 units/yr); the US collaborative study experience with the standard dose (2 units 3 times/wk = 312 units/yr), and with two size-adjusted doses (0.06 units/kg 3 times/wk = 212 +/- 94 SD units/yr, 0.03 units/kg 3 times/wk = 116 +/- 33 units/yr); and to the British experience with much larger doses (1,040 units/yr). During the first year of hGH treatment our patients grew an average 13% faster than the androgen-supplemented and collaborative study-0.03 units/kg/dose groups. They had a similar pace to the collaborative study-312 units/yr and 0.06 units/kg/dose patients, but grew 15% more slowly than did the British patients. Growth response correlated positively with age and negatively with hGH dose per kilogram of body weight. Of 17 patients with isolated growth hormone deficiency ten developed hypothyroidism with hGH therapy, leading to a policy of routine adjunctive thyroxine replacement.
Subject(s)
Growth Hormone/administration & dosage , Hypopituitarism/drug therapy , Adolescent , Child , Child, Preschool , Drug Administration Schedule , Drug Therapy, Combination , Female , Growth Hormone/therapeutic use , Humans , Injections , Male , Thyroxine/therapeutic useABSTRACT
The clinical features of the multiple mucosal neuromas (MMN) syndrome permit the recognition of these patients and their potential development of the associated medullary thyroid carcinoma (MTC). The distinctive physical appearance caused by the mucosal neuromas, the Marfanoid habitus and, occasionally, the positive family history aid in establishing the diagnosis. Neurogangliomas are frequently present in the gastrointestinal tract of these patients who may have megacolon, constipation and diarrhea. The third instance of the MMN syndrome is reported in the newborn as intestinal obstruction. It is suggested that the syndrome be considered in the differential diagnosis of Hirschsprung's disease and bowel obstruction in the neonate. Serum calcitonin measurements following stimulation by calcium or pentagastrin infusion reliably detect incipient MTC and may be used to select those MMN patients requiring thyroid surgery. Recognition of patients with the MMN syndrome and subsequent calcitonin screening and early surgical intervention will significantly reduce the chance of their developing terminal MTC. All MMN patients with mucosal neuromas or intestinal neurogangliomas should have such evaluations at least yearly. Relatives who are at risk for inheriting this dominant disease should be similarly evaluated, regardless of their normal appearance.
Subject(s)
Adrenal Gland Neoplasms/genetics , Carcinoma/genetics , Intestinal Neoplasms/genetics , Neuroma/genetics , Pheochromocytoma/genetics , Thyroid Neoplasms/genetics , Colonic Neoplasms/genetics , Female , Follow-Up Studies , Humans , Infant, Newborn , Intestinal Mucosa , Male , Mucous Membrane , SyndromeABSTRACT
The occurrence of vaginal clear cell adenocarcinoma in young women following exposure in utero to diethylstilbestrol (DES) is now well documented. In addition to this carcinogenic potential. DES has been shown to be teratogenic. In females, the DES-related malformations include vaginal adenosis, transverse ridges of the vagina or cervix and uterine abnormalities. Although no neoplasms have been observed in DES-exposed males, malformations of the epididymis, testes and phallus are relatively common and may result in infertility. The carcinogenic mechanism of DES may be either a direct induction of malignant potential in vaginal cells or a teratogenic effect causing ectopic Müllerian epithelium which could be exposed later to mutagenic agents in the vagina. The absence of malignancy in DES-exposed males may favor the latter hypothesis since male Müllerian remnants are internal structures and thus would not be exposed to surface carcinogens.
Subject(s)
Adenocarcinoma/etiology , Carcinoma, Squamous Cell/etiology , Diethylstilbestrol , Vaginal Neoplasms/etiology , Female , Fetus/drug effects , Humans , Male , Pregnancy , Semen/physiology , Sperm Motility/drug effects , TeratogensABSTRACT
Previous studies have reported indirect evidence for the mediation of folate antagonism in the induction of malformations by diphenylhydantion. We have demonstrated that a teratogenic regimen of folate-deficiency and antagonism using 9-methyl PGA in the rat produces significantly decreased rates of oxygen consumption in the maldeveloping embryos. The present study reports similar reductions in oxygen uptake by mouse embryos from mothers treated with teratogenic doses of diphenylhydantoin, and documents a significant depression of the actual folate levels in such embryos. The differences are less significant with lower doses of diphenylhydantoin, and do not occur with a nonteratogenic dose.
Subject(s)
Abnormalities, Drug-Induced/etiology , Folic Acid Antagonists/toxicity , Folic Acid Deficiency/chemically induced , Phenytoin/toxicity , Animals , Female , Fetal Resorption/chemically induced , Fetus/metabolism , Male , Mice , Oxygen Consumption/drug effects , PregnancyABSTRACT
Alterations in multiple molecular forms of enzymes have been described during normal embryogenesis. Changes in electrophoretic patterns, which differ from the normal isozyme ontogeny, occur in embryos and their yolk-sacs during incipient maldevelopment secondary to teratogen exposure. One such isozyme change, in response to a teratogenic regimen using 9-methyl pteroylglutamic acid (PGA), is persistence of lactate dehydrogenase-5 (LDH-5) beyond its time of normal involution in the rat yolk-sac. Since LDH-5 is an allosteric regulatory enzyme which favors anaerobic metabolism, the cellular respiration of 9-methyl PGA-treated embryos was investigated and found to be depressed. However, no changes were found in the oxidative metabolism of visceral yolk-sacs from similarly treated pregnancies. A possible explanation for the unchanged oxygen consumption is the observed simultaneous quantitative alterations in other LDH-yolk-sac isozymes following 9-methyl PGA treatment. Other potential causes include known changes in isozymes other than LDH, limitation of enzyme function by its substrate or co-factor or the presence of a functionally inert LDH-5 isozyme. Changes in LDH and other isozyme patterns and their associated metabolic alterations may eventually prove useful in predicting chemical teratogenicity.
Subject(s)
Embryo, Mammalian , Enzymes/physiology , Animals , Female , Folic Acid/adverse effects , Folic Acid/analysis , Isoenzymes , L-Lactate Dehydrogenase/adverse effects , Oxidation-Reduction/drug effects , Oxygen Consumption/drug effects , Pregnancy , Rats , Vitelline Membrane/cytology , Vitelline Membrane/drug effectsSubject(s)
Folic Acid/analogs & derivatives , Oxygen Consumption/drug effects , Teratogens/pharmacology , Animals , Embryo, Mammalian/drug effects , Embryo, Mammalian/metabolism , Female , Folic Acid/pharmacology , Folic Acid Deficiency/metabolism , Folic Acid Deficiency/physiopathology , Gestational Age , Maternal-Fetal Exchange , Pregnancy , RatsABSTRACT
During a three-year period of prospective epidemiologic surveillance for adverse drug reactions in a pediatric population, 72 (2.0%) of 3,556 medical admissions were the result of adverse drug reactions. Antineoplastic drugs were most frequently cited as causing a reaction leading to admission. Approximately 40% of the reactions were severe, and four reactions contributed to death.