Marvin E. Miller

Compression-related defects from early amnion rupture: Evidence for mechanical teratogenesis

The features of 27 cases of limb/body wall deficiency (formerly termed cyllosomus and pleurosomus) were evaluated and the anomalies were interpreted as being band-related defects and/or compression-related defects. The latter included limb deficiency, body wall deficiency, neural tube defects, scoliosis, postural deformations, growth deficiency, and short umbilical cord. It is hypothesized that the single event of early amnion rupture can explain both the band-related defects and the compression-related defects. Experimental animal studies are in accord with this hypothesis; amnion puncture of rat fetuses during early gestation produces a comparable array of defects. The term amnion rupture sequence is suggested to describe the overall pattern of malformation that results from amnion rupture whether these defects are band related, compression related, or a combination of the two. There is considerable variation in the phenotype of amnion rupture sequence, with limb/body wall deficiency representing the more severe end of the spectrum. It is important to recognize and correctly diagnose amnion rupture sequence because it is usually a sporadic event.

Postaxial acrofacial dysostosis syndrome

Three patients with a postaxial acrofacial syndrome are presented; the features of these and three other previously described examples are set forth. The facies can be strikingly similar to that of the Treacher Collins syndrome. The limb deficiencies are postaxial, with absence or incomplete development of the fifth digital rays in both the upper and lower limbs. Accessory nipples have been found in most of the patients. The nature of the limb deficiencies and the accessory nipples help to distinguish this condition from Nager AFD. All of the children have normal intelligence and development; most show normal growth. All of the six cases have occurred sporadically.

Limb Reduction Anomalies and Early in Utero Limb Compression

Seven instances of limb reduction defects are reported with a presumed common underlying etiologic theme of early in utero limb compression, deduced as being due to a bicornuate uterus in four instances, a large fibroid in one instance, and early amnion rupture with transient amniotic fluid loss in two instances. Similar types of limb reduction defects have been experimentally produced as a consequence of early withdrawal of amniotic fluid with resultant compression of the developing limbs, leading to vascular disruption. A similar mechanism is hypothesized to have caused these seven instances of limb reduction defects.

POSSIBLE MATERNAL EFFECT ON SEVERITY OF NEUROFIBROMATOSIS

62 patients with neurofibromatosis (from 54 families) whose signs or symptoms began in childhood were assessed as to the severity of disease and whether the individual was a new mutation or born to an affected father or mother. The morbidity of disease was much more severe in cases born to affected mothers than in those born to affected fathers or those who were new mutations. This finding suggests that there may be a maternal effect in neurofibromatosis similar to that which has been observed in myotonic dystrophy. This effect may be humorally mediated.

Theophylline metabolism: Variation and genetics

Variation of theophylline metabolism in 54 healthy, nonmedicated adults (13 monozygotic [MZ] twin pairs, 11 dizygotic [DZ] twin pairs, and 6 single individuals) was assessed by kinetic study. Elimination rate constant, clearance (CI), t½, and apparent volume of distribution, as well as urine excretion of unchanged theophylline and of the three major metabolites (1‐methyluric acid, 3‐methyl‐xanthine, and 1,3‐dimethyluric acid) were studied. Smokers and men had increased theophylline elimination rates compared to nonsmokers and women. Identical (MZ) twins resembled each other more closely than nonidentical (DZ) twins in the various kinetic parameters, but mean intrapair differences between MZ and DZ twins for all but one of the serum and urinary parameters examined (including t½) were not statistically significant. Correspondingly, estimates of heritability and of intrapair correlation coefficients showed a smaller contribution of genetic factors to variation in theophylline metabolism than had been reported for other drugs investigated by twin studies. Nevertheless, in the family of the individual with the longest theophylline t½, the operation of a rare major gene retarding theophylline metabolism could not be excluded. A father and two out of four children had very slow Cls. This finding would be consistent with, but does not prove, monogenic inheritance.

Tension: The basis of umbilical cord growth

THE DETERMINANTS of human umbilical cord growth were examined through evaluations of infants with strikingly short umbilical cords? Two groups of babies were found: infants with evidence of intrauterine compression caused by amnion rupture, oligohydramnios, or structural uterine anomalies, and infants with decreased limb movement because of amelia, acardia, arthrogryposis, or Spinal muscular atrophy. The finding of short cords in these patients suggests that linear umbilical cord growth is determined by availability of intrauterine space and intact fetal limb function and that umbilical cord tension from fetal movement is the impetus for umbilical cord growth. Experimental animal studies 2 support this idea. The umbilical cords of rat fetuses exposed to experimentally produced oligohydramnios or paralysis by curare are signifi

Uterine malformation and fetal deformation

Beyond the enhanced miscarriage and prematurity associated with the structurally abnormal uterus, we have found 14 examples of fetal deformation secondary to uterine malformation with its consequent uterine constraint. In several instances the constellation of deformations had been misinterpreted as a multiple malformation disorder. One patient died of pulmonary hypoplasia, but all the survivors showed restoration toward normal form postnatally. Recognition of the basic problem allows for surgical reconstruction of the uterus, which is generally accompanied by an improved outlook for subsequent pregnancies.

Acetylator Phenotype in Human Bladder Cancer

The acetylator phenotype of 26 bladder cancer patients and 26 controls was determined by the sulfamethazine method to evaluate whether patients with the slow acetylator phenotype have a greater susceptibility for bladder cancer. This hypothesis has been suggested by experimental animal and human epidemiological observations. Of the 26 bladder cancer patients 12 (46 per cent) had the slow acetylator phenotype compared to 18 of 26 controls (69 per cent). Within the bladder cancer group there was no striking excess of the slow acetylator phenotype when subgrouped by occupational and smoking history. Our results show no significant association between the slow acetylator phenotype and human bladder cancer.

Clonazepam acetylation in fast and slow acetylators

Six slow acetylators (SAs) and six rapid acetylators (RAs), as determined by sulfamethazine (SMZ) phenotyping, were each given a 2‐mg oral dose of clonazepam. Ninety‐six‐hour urine collections from these subjects were analyzed for clonazepam, 7‐amino clonazepam (7‐AM, clonazepam nitroreduced metabolite), and 7‐acetamido clonzepam (7‐ACT, N‐acetylated 7‐AM). The SA group excreted more 7‐AM and less 7‐ACT than the RA group; mean (±SD) recovered as 7‐AM was 22.7 ± 5.0% for the SA group and 13.6 ± 4.1% for the RA group and mean (±SD) recovered as 7‐ACT was 1.5 ± 0.4% for the SA group and 3.9 ± 1.8% for the RA group. Both differences were substantial (p < 0.02 by unpaired t test) and indicate that the rate of acetylation of 7‐AM to 7‐ACT in the biotransformation of clonazepam is determined by the acetylator phenotype.

Short Umbilical Cord: Its Origin and Relevance

A short umbilical cord was found in newborns for whom there was evidence of early intrauterine constraint and in those with gross structural or functional limb defects that limited intrauterine movement. These findings were interpreted as showing that umbilical cord growth occurs in response to tensile forces relating to intrauterine space availability and fetal movement during early development. Thus, the finding of a short umbilical cord may indicate diminished fetal movement from either early intrauterine constraint or fetal limb dysfunction.