Down syndrome (DS) is a major cause of mental retardation and congenital heart disease. Besides a characteristic set of facial and physical features, DS is associated with congenital anomalies of the gastrointestinal tract, an increased risk of leukemia, immune system defects, and an AMzelmer-like dementia. Moreover, DS is a model for the study of human aneuploldy. Although With the discovery that DS was caused by trisomy 21 (3, 4), and the subsequent proposal that chromosome 21 band q22 was "pathogenetic" for DS (5), the foundation was laid for elucidating the fundamental biochemical and morphogenetic pathways of abnormal development in this aneuploidy. There followed a series ofreports ofindividuals with "partial trisomy 21" (for review, see ref. 6) that appeared to indicate that regions might be defined that were likely to contain genes responsible for particular features of DS. These studies provide the basis for construction of a DS phenotypic map.By "phenotype" we mean a measurable parameter and include clinical, physical, cellular, and physiological components. By "phenotypic mapping" we mean the molecular definition of a physical region that is likely to contain the gene(s) whose overexpression is ultimately responsible in part for the phenotype. The current revolution in human molecular genetics and the development of a physical map of chromosome 21 now provide the possibility to understand the genetic basis for some of these defects and, therefore, to provide a necessary first step for their prevention, amelioration, and perhaps ultimately, their treatment.Phenotypic maps provide the basis for clinical prognosis for individuals with partial aneuploidy for chromosome 21, and when of high resolution, the basis for the identification of the genes responsible for the phenotypes. One approach to this combines the phenotypic information from individuals with "partial trisomy" such as those described above with a molecular definition of their duplicated chromosomal regions. Once the molecular markers for a region are defined, the genes within it may then be identified, characterized, and ultimately tested for their relationship to a given phenotype. This report describes the molecular and phenotypic definition of these individuals, provides a theoretical framework, and utilizes this to construct a molecular "map" of the phenotypes associated with DS.

Larsen syndrome is characterized by multiple congenital joint dislocations and flattened facies. Some cases have been familial, with both autosomal dominant and recessive patterns of inheritance. Reports of a form of Larsen syndrome, lethal in the neonatal period, are reviewed. We present a family in which recurrence of the syndrome was diagnosed prenatally, but a lethal outcome again resulted despite preparation for anticipated perinatal complications. Because of the wide clinical variation and the lack of a known metabolic defect, delineation between the various forms of Larsen syndrome is difficult. While the lethal variant appears to be a combination of the Larsen phenotype and pulmonary hypoplasia, other features noted in the lethal cases, such as abnormal palmar creases and laryngotracheomalacia, are also seen in patients with Larsen syndrome who survive.

No abstract

From animal and in vitro studies, it has been suggested that high environmental glucose, ketone, or insulin concentrations and low glucose or insulin concentrations may be etiologic factors for congenital malformations (CMs) in infants of diabetic mothers (IDMs). Transplacental passage of antibody-bound insulin has been demonstrated in humans. Controversy exists regarding the pathophysiology of CMs in human insulin-dependent diabetes mellitus (IDDM) pregnancies. We hypothesized that CMs in IDMs are associated with maternal vasculopathy, poor first-trimester glycemic control (i.e., hyper- and/or hypoglycemia), advanced White class, and high insulin requirements. We studied 165 first pregnancies of women with IDDM from 1978 to 1986. The goals of glucose control were a fasting blood glucose of less than 100 mg/dl and a 90-min postprandial blood glucose of less than 140 mg/dl. Insulin requirements, body weight, and pre- and postprandial blood glucose were recorded at weekly clinic visits. Maternal blood HbA1 was measured on entry and every 4 wk to confirm that adequate glycemic control was achieved. Women who enrolled in the project were interviewed during gestation by a geneticist/dysmorphologist who obtained genetic and environmental histories using a standard questionnaire. All live-born infants and stillbirths were examined. Each live-born infant was assessed systematically by two independent examiners, a neonatologist and a geneticist/dysmorphologist; examination with standardized checklists was performed in the newborn nursery as soon after birth as was practical. In first pregnancies in the study, there were 13 IDMs with major CMs (7.9%).(ABSTRACT TRUNCATED AT 250 WORDS)