Developmental delay and multiple congenital anomalies in a child with a unique combination of partial monosomy 18 and partial trisomy 16.

A male child with multiple congenital anomalies and developmental delay is described. Cytogenetic evaluation showed that the patient was partially monosomic for the short arm of chromosome 18 and partially trisomic for the short arm of chromosome 16: a combination of chromosomal syndromes not previously described.

Pharmacogenetic screening for susceptibility to fetal malformations in women.

OBJECTIVE: To present a review of the literature and research on the pharmacogenetics of congenital defects, with a focus on the need for predictive maternal genotype assays. DATA SOURCE: MEDLINE searches (January 1985-January 1999), past reference reviews, and unpublished research. STUDY SELECTION: Review of relevant human, animal, and basic science studies. DATA EXTRACTION: Data on research on polymorphisms, genotyping, cytochrome P450 enzyme systems, epoxide hydrolase, folate metabolism, metabolism of anticonvulsant medications, molecular genetics of neural tube defects, variations in drug metabolism, and environmental exposures were evaluated. DATA SYNTHESIS: Data synthesis includes not only a review of the literature but suggests ways such data might be used to facilitate the development of maternal genotype assays, with the goal of preventing birth defects. CONCLUSIONS: Individuals vary in how they metabolize drugs and handle toxic environmental exposures. In an ideal pregnancy, there is no or limited exposure to medications and environmental agents. However, in women with chronic medical conditions such as heart disease and seizures, this is often not possible. Unfortunately, no techniques have been available to identify those at risk in this population. Gene polymorphisms for a specific enzyme may result in an absence or reduction in the level of enzyme activity or in no change at all, with little effect on the structure/function of the gene product(s); they are not associated with clinical phenotypes in either the mother or the fetus. Other polymorphisms may be only markers. Thus, developing genotyping assays for women that are predictive of phenotype expression in the fetus is the key to screening for polymorphisms. As more mutations are identified and clinical, pharmacologic, biologic, and pharmacokinetic relationships are established, using these polymorphisms to develop a genotyping assay for women may become a clinical reality, possibly leading to preventive prepregnancy or prenatal treatment that may play an increasingly effective role in maternal care.

Premature sexual development in individuals with neurodevelopmental disabilities.

Studies on precocious puberty have primarily focused on children with typical patterns of growth and cognitive development. This study reviewed diagnostic data from the records of 15,719 patients with neurodevelopmental disabilities for diagnoses associated with premature sexual development/precocious puberty. Thirty-two individuals with premature sexual development were identified, with the earliest changes seen in one girl at 1 year 7 months of age. In this group, the mean age at onset was 7 years 2 months in boys and 5 years 11 months in girls. Central precocious puberty, which was the most common cause of onset of early pubertal changes, was present in 15 of the 32 children. The results of this study suggest that children with a neurodevelopmental disability are at increased risk of premature pubertal changes when compared to children without a neurodevelopmental disability. This study indicates the need for health-care providers to be vigilant in screening for early pubertal changes in children with neurodevelopmental disabilities.

Drug and environmental factors associated with adverse pregnancy outcomes. Part III: Folic acid: pharmacology, therapeutic recommendations, and economics.

OBJECTIVE: To review folic acid's mechanism of action, adverse effects, therapeutic recommendations, compliance, and cost. DATA SOURCES: A MEDLINE search was conducted through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included folate, folic acid, neural tube defect, homocysteine, and methylenetetrahydrofolate reductase. STUDY SELECTION: Animal and human studies examining the effects of folate were reviewed. DATA EXTRACTION: Data collected included mechanism of action, safety issues, dosing recommendations, compliance with recommendations, and economics. DATA SYNTHESIS: Folic acid decreases neural tube defect risk through an effect on methionine-homocysteine metabolism. In addition, increased folate intake may reduce cardiovascular morbidity and mortality. Since toxicity is minimal, everyone can potentially benefit from increased folate consumption. To help achieve this, the Food and Drug Administration has mandated that cereal grain be fortified with 140 micrograms of folic acid per 100 g of grain, which will add approximately 0.1 mg of folate to the average diet. Studies recommend supplementing with 0.2 mg to promote optimal homocysteine concentrations and for preventing neural tube defects. CONCLUSIONS: Despite fortification, most women will still receive less folate than the 0.4 mg/d recommended by the Public Health Service. All population groups would benefit from increased folate intake. Current studies indicate 200 micrograms/d may be the minimum effective amount of fortification needed for normalizing homocysteine concentrations and preventing a significant number of neural tube defects; thus, a higher level of food fortification may be warranted.

Drug and environmental factors associated with adverse pregnancy outcomes. Part II: Improvement with folic acid.

OBJECTIVE: To provide a comprehensive review of periconceptional folic acid supplementation and factors affecting folate supplementation trials. DATA SOURCES: A MEDLINE search was conducted through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included folate, folic acid, neural tube defect, spina bifida, and anencephaly. STUDY SELECTION: Relevant animal and human studies examining the effects of folate were reviewed. DATA EXTRACTION: Data collected included: type of study, folate dosing, dietary folate intake, serum and red blood cell folate concentrations, type of defect(s) studied, vitamin usage, parental risk factors, factors affecting trial results. DATA SYNTHESIS: Nine key factors have been identified that affect outcomes of folic acid supplementation trials. Daily doses of 0.8 mg decreased the occurrence and doses of 4 mg decreased the recurrence of neural tube defects in randomized clinical trials. Since lower folic acid doses were effective in nonrandomized trials, research is needed to determine the lowest effective dosage. Other benefits involving pregnancy outcome are suggested. CONCLUSIONS: Women of childbearing age should take a daily folic acid supplement to reduce the risk of pregnancies resulting in infants with a neural tube defect and other potential adverse pregnancy outcomes. Further health benefits from folic acid supplementation are reviewed in Part III of this series.

Drug and environmental factors associated with adverse pregnancy outcomes. Part I: Antiepileptic drugs, contraceptives, smoking, and folate.

OBJECTIVE: Part I of this review examines the relationship between antiepileptic drugs (AEDs) and pregnancy outcomes. Drug-induced folate deficiency and the role of AED metabolism are emphasized. Part II will discuss periconceptional folate supplementation for prevention of birth defects. Part III will discuss the mechanism of folate's protective effect, therapeutic recommendations, compliance, and cost. DATA SOURCES: A MEDLINE search was conducted for journal articles published through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included phenytoin, carbamazepine, phenobarbital, primidone, valproic acid, oral contraceptives, clomiphene, drug-induced abnormalities, spina bifida, anencephaly, neural tube defect, folate, folic acid, and folic acid deficiency. STUDY SELECTION: Relevant animal and human studies examining the effects of AEDs, smoking, and oral contraceptives on folate status and pregnancy outcome are reviewed. DATA EXTRACTION: Studies and case reports were interpreted. Data extracted included dosing, serum and red blood cell folate concentrations, teratogenicity of anticonvulsant medications, metabolism of AEDs and folate, and genetic susceptibility to AED-induced teratogenicity. DATA SYNTHESIS: Low serum and red blood cell folate concentrations are associated with adverse pregnancy outcomes. Decreases in serum folate are seen with AEDs, oral contraceptives, and smoking. Since similar birth defects are observed with multiple AEDs, metabolism of aromatic AEDs to epoxide metabolites and genetic factors may play a role in teratogenesis. CONCLUSIONS: Adequate prepregnancy planning is essential for women who have epilepsy. Women receiving folate-lowering drugs may be at increased risk of adverse pregnancy outcomes. Therefore, epileptic women contemplating pregnancy should be treated with the minimum number of folate-lowering drugs possible and receive folic acid supplementation.

Phenytoin-folic acid interaction.

OBJECTIVE: To review information regarding the dual and interdependent drug-nutrient interaction between phenytoin and folic acid and other literature involving phenytoin and folic acid. DATA SOURCES: Information was retrieved from a MEDLINE search of English-language literature conducted from 1983 (time of the last review) to March 1995. Search terms included folic acid, phenytoin, and folic acid deficiency. Additional references were obtained from Current Contents and from the bibliographies of the retrieved references. STUDY SELECTION: All human studies examining the effects of phenytoin on serum folate concentrations and folic acid supplementation on serum phenytoin concentrations were selected. These included studies of patients with epilepsy and healthy volunteers as well as case reports. Case reports were included because of the extensive length of time needed to study this drug interaction. DATA EXTRACTION: Data extracted included gender, dosing, serum folate concentrations if available, pharmacokinetics, and adverse events. DATA SYNTHESIS: Serum folate decreases when phenytoin therapy is initiated alone with no folate supplementation. Folic acid supplementation in folate-deficient patients with epilepsy changes the pharmacokinetics of phenytoin, usually leading to lower serum phenytoin concentrations and possible seizure breakthrough. Folate is hypothesized to be a cofactor in phenytoin metabolism and may be responsible for the "pseudo-steady-state," which is a concentration where phenytoin appears to be at steady-state, but in reality, is not. Phenytoin and folic acid therapy initiated concomitantly prevents decreased folate and phenytoin obtains steady-state concentrations sooner. CONCLUSIONS: Folic acid supplementation should be initiated each time phenytoin therapy commences because of the hypothesized cofactor mechanism, decreased adverse effects associated with folate deficiency, and better seizure control with no perturbation of phenytoin pharmacokinetics.

Management of the adopted child in the craniofacial clinic.

Because of the decrease in the number of children available for adoption, there has been an increase in frequency of parents who are willing to adopt children of different ethnic and racial groups, children from other countries, older children, and children with special needs. More of these children, particularly those with special needs such as cleft lip and palate, are being seen in cleft palate or craniofacial clinics. It is important that medical care providers understand some of the potential special considerations surrounding their care. Legal status, history, medical history, genetic history, development, emotional and behavioral concerns, and the need for counseling are management issues that need to be considered in the overall multidisciplinary management of these children.

Early identification and treatment necessary to prevent malnutrition in children and adolescents with severe disabilities.

Children with severe developmental disabilities frequently have nutrition and growth problems that range from moderate to severe. Because of notable continuing medical concerns and lowered growth expectations, parents and physicians may fail to recognize gradual deterioration in nutritional status before severe medical complications occur. The two cases reported in this article illustrate the need for early identification and treatment to prevent the development of notable morbidity secondary to malnutrition. Children and adolescents who have growth parameters consistently below age norms require assessment and monitoring by a registered dietitian to detect feeding problems and intake changes and to provide early intervention to help prevent negative consequences (eg, dehydration, protein-energy malnutrition, decubitus ulcers, increased rate and duration of infections, and altered bowel motility). An initial assessment should consist of measurement of length or height, weight, triceps, and subcapsular skinfolds; dietary and feeding history and a review of medical history; and biochemical testing as indicated by the medical and dietary histories. Monitoring frequency, which is determined by age, severity of condition, and response to treatment, may vary from weekly to bimonthly.

Concentrations of adipsin in blood and rates of adipsin secretion by adipose tissue in humans with normal, elevated and diminished adipose tissue mass.

Adipsin, which is identical to complement factor D, is synthesized by fat cells, circulates in the bloodstream and is profoundly deficient in mice with genetic and hypothalamic obesity. With the recent cloning of human adipsin, a quantitative human immunoassay has been developed. In the present study, we measured adipsin blood concentrations in humans with increased and decreased adipose stores as well as adipsin secretion by adipose tissue obtained from lean and obese individuals. The results demonstrate that adipsin is released by human adipose tissue fragments as has previously been shown in mice, and that, in contrast to obese mice, blood adipsin concentrations were not reduced in the obese humans tested in this study. We also observed that blood adipsin concentrations can vary as a function of feeding or adiposity, in that they tend to be mildly elevated in obese individuals or mildly reduced in individuals with total lipo-atrophy, cachexia related to AIDS and anorexia nervosa. Thus, the circulating concentration of adipsin tends to correlate positively with degree of adiposity. Clearly, no deficiency in blood adipsin concentrations or adipsin secretion by adipose tissue was observed in the obese individuals studied.

Differences in phenytoin biotransformation and susceptibility to congenital malformations: a review.

The clinical variability of teratogenic response to fetal drug exposure has been well documented. Metabolic differences in biotransformation have been shown to extend to multiple drugs and may involve many steps in drug metabolism with alterations of key intermediates. Although metabolic differences have been reported to be associated with complications of medication use, it has only recently been appreciated that such differences also may be associated in the unborn with the potential for the disruption of normal embryologic development and the production of congenital malformations. It has long been suspected that the teratogenicity of phenytoin may be mediated not only by the parent compound, but also by toxic intermediary metabolites that are produced during the biotransformation of the parent compound. Recent work elucidating differences in isoenzyme forms of cytochrome P-450 enzyme systems, glutathione, and microsomal epoxide hydrolase has provided increased interest in the multiple individual pharmacogenetic differences that may be significant factors affecting increased susceptibility to birth defects in individuals and families with fetal exposure to phenytoin.

Autistic disorder associated with an iso-dicentric Y chromosome.

The relationship between a fragile site on the X chromosome and autism has been well documented. The authors report a three-year-old child with partial duplication of the short arm of chromosome Y, who had an autistic disorder. He was microcephalic, but otherwise had a normal phenotype. There was a history of preterm birth and maternal diabetes. This is the sixth case of sex chromosome Y aneuploidy associated with autism, but the first with an isodicentric Y. In well-substantiated cases of autism, clinicians should now consider abnormalities of the Y as well as the X chromosome.

Clinical management issues in males with sex chromosomal mosaicism and discordant phenotype/sex chromosomal patterns.

The recent availability of Y DNA probes has made it possible to identify two forms of 46,XX male syndrome: Y DNA positive and Y DNA negative. The Y DNA positive male results from a X;Y translocation with a low recurrence risk; the Y DNA negative males are due to a mutation with a high recurrence risk. 46,XX males and mosaic forms are phenotypically indistinguishable. A review of the case histories for 11 individuals indicates that affected males have highly variable genital and nongenital phenotypes. Physical findings may be clearly apparent or nonexistent. With the exception of external genitalia, the basis for this variability is unknown. It may be related to differences in Y chromatin expression as the result of variable inactivation of the X chromosomes, or to the existence of minor deletions or point mutations secondary to an exchange of genetic material. Common and uncommon clinical problems in these individuals require evaluation and follow-up care that is provided through a cooperative, interdisciplinary approach.

Clinical management considerations in long-term survivors with trisomy 18.

As many as 90% or more of children with trisomy 18 die within the first year of life. A review of six patients with trisomy 18 documented by karyotype surviving past 1 year of age and of the trisomy 18 files of the Support Organization for Trisomy 18 and 13 indicated that a small number of children with trisomy 18 survive beyond their first year of life; a few live into their teens and twenties. In addition to medical problems that are unique to this chromosomal syndrome, these patients present complex medical problems common to all persons with chromosomal anomalies. The primary and tertiary care consultants who are able to provide knowledge and sensitive supportive care to children with trisomy 18 and to their parents are performing a service of significant benefit, no matter how brief the life span of the child may be.

Fetal drug exposure and its possible implications for learning in the preschool and school-age population.

For the past 5 years there has been an exponential increase in the use of cocaine, phenylcyclidine hydrochloride (PCP), and other central nervous system (CNS) active drugs. A significant amount of this accelerated usage is in sexually active females, resulting in some urban hospitals reporting positive drug screens in over 16% of the infants born on their busy obstetrical service. There is a growing body of data showing that fetal exposure to cocaine, phenylcyclidine hydrochloride (PCP), and other CNS-active drugs results in infants and children with abnormal brain wave patterns, short-term neurologic signs, depression of interactive behavior, and poor organizational responses to environmental stimuli. Whether such neurologic findings will translate into a significant number of children with learning and behavioral problems needs to be the focus of long-term longitudinal studies of children with fetal drug exposure to cocaine, PCP, and other CNS-active drugs.