Mason Barr

Angiotensin-converting enzyme inhibitor fetopathy.

Angiotensin-converting enzyme (ACE) inhibitors are widely used for controlling hypertension. Their use in women who are pregnant is not without risk to the fetus. We describe three infants exposed in utero to ACE inhibitors who had adverse outcomes. These cases, combined with other reports in the literature, suggest strongly that these drugs are fetotoxic. ACE inhibitor fetopathy is characterized by fetal hypotension, anuria-oligohydramnios, growth restriction, pulmonary hypoplasia, renal tubular dysplasia, and hypocalvaria. Although the true frequency of adverse fetal effects has yet to be determined, because of the debilitating and lethal nature of the fetal damage when it occurs, it is our recommendation that ACE inhibitors not be used in pregnancy, particularly in the second and third trimesters.

Mutation of a gene encoding a putative chaperonin causes McKusick-Kaufman syndrome.

McKusick-Kaufman syndrome (MKKS, MIM 236700) is a human developmental anomaly syndrome comprising hydrometrocolpos (HMC), postaxial polydactyly (PAP) and congenital heart disease (CHD). MKKS has been mapped in the Old Order Amish population to 20p12, between D20S162 and D20S894 (ref. 3). Here we describe the identification of a gene mutated in MKKS. We analysed the approximately 450-kb candidate region by sample sequencing, which revealed the presence of several known genes and EST clusters. We evaluated candidate transcripts by northern-blot analysis of adult and fetal tissues. We selected one transcript with widespread expression, MKKS, for analysis in a patient from the Amish pedigree and a sporadic, non-Amish case. The Old Order Amish patient was found to be homozygous for an allele that had two missense substitutions and the non-Amish patient was a compound heterozygote for a frameshift mutation predicting premature protein truncation and a distinct missense mutation. The MKKS predicted protein shows amino acid similarity to the chaperonin family of proteins, suggesting a role for protein processing in limb, cardiac and reproductive system development. We believe that this is the first description of a human disorder caused by mutations affecting a putative chaperonin molecule.

Holoprosencephaly in infants of diabetic mothers

We report seven infants of diabetic mothers, affected with holoprosencephaly malformation sequence. An additional 15 cases assembled from personal communications and the literature indicate that holoprosencephaly, like neural tube, cardiac, and caudal defects, is specifically increased in children of diabetic mothers. Incidence figures from newborn surveys demonstrate a risk for holoprosencephaly in infants of diabetic mothers comparable to the 1% risk for caudal regression malformation sequence. The embryologic timing of cranial, cardiac, and caudal defects emphasizes the need for pregnancy planning and diabetes control.

Holoprosencephaly survival and performance

Parents of children with holoprosencephaly often have been told that their children will die within days or weeks. When this does not happen, they are distrustful of the information they have received and want to know what they can really expect and how they can cope with the many problems these children have. We have recorded our experiences and gleanings from the literature with regard to survival and performance of these children. Survival data were obtained from 62 cases of alobar holoprosencephaly known to us or to our colleagues. Performance data were obtained on 35 survivors, by direct examination and/or detailed parent questionnaires and interviews.

Fronto-otopalatodigital osteodysplasia : Clinical evidence for a single entity encompassing melnick-needles syndrome, otopalatodigital syndrome types 1 and 2, and frontometaphyseal dysplasia

Otopalatodigital syndrome type 2 is an X-linked disorder with minimal expression in carrier females and comprises typical facial anomalies and a generalized bone dysplasia with osteodysplastic changes, brachydactyly, and impaired survival. Recently several other severe malformations were reported in the condition. Melnick-Needles syndrome is an X-linked dominant disorder. Affected males are usually sporadic cases. The exceptional males born to symptomatic women present with a lethal disorder comprising generalized osteodysplasia, deficiency of the first ray, and facial anomalies strikingly similar to those of otopalatodigital syndrome type 2. We report here on three boys with classical, severe, and lethal otopalatodigital type 2 syndrome, and three boys with severe (lethal) Melnick-Needles syndrome, born to affected mothers. We suggest that otopalatodigital type 1 and 2, Melnick-Needles syndrome and frontometaphyseal dysplasia, sharing many clinical manifestations and a similar mode of inheritance, are variants of the same condition: fronto-otopalatodigital osteodysplasia. The relationships to similar syndromes (i.e., Saint-Martin-Gardner-Morrisson syndrome, serpentine fibula syndrome, atelosteogenesis type 3, boomerang dysplasia, and Yunis-Varon syndrome) are discussed.

Organ Weight Standards for Human Fetuses

Five hundred fifty-eight fresh human embryos and fetuses were obtained from the universities of Washington and Michigan following spontaneous loss, elective termination, or neonatal death within 2 days of delivery. The body weights ranged from 1.5 to 1500 g. Each of these autopsied specimens was morphologically normal. Specimens from diabetic or hypertensive mothers were not included. Correlations between fetal body weight and weights of adrenal, brain, kidney, liver, lung, spleen, and thymus were established. For analysis, regression curves were calculated as quadratic equations of best fit by the weighted least squares. The relation of the weights of brain, heart, and liver to body weight appeared linear. The ratios of thymus, spleen, and kidney to body weight were nonlinear and gradually increased. The ratios of lung and adrenal weights to body weight were also nonlinear and gradually decreased. Ninety-five percent prediction intervals were generated for each of the eight organs using a computerized statistical package. The results compare closely with smaller studies in the literature.

Twin gestation: Influence of placentation on fetal growth

To study fetal growth in twin gestation, morphometric autopsy data of 52 midgestation twin pairs who were stillborn or who died less than or equal to 24 hours after birth were analyzed. Twins were divided into three groups: (1) monozygotic: diamniotic, monochorionic placenta (n = 18); (2) dizygotic: diamniotic, dichorionic placenta, unlike sex (n = 12); (3) like-sex: placenta diamniotic, dichorionic in 63.6%, unknown in 36.4% (n = 22). The monozygotic group had a significantly higher rate of growth discordance, which was defined as a greater than 20% difference in body weight (monozygotic 72.2%, dizygotic 16.7%, like-sex 0%), and polyhydramnios (monozygotic 50%, dizygotic 0%, like-sex 9.1%). Organ weight z scores for body weight and brain weight standards were calculated for the smaller and larger of each twin pair. In the monozygotic group highly significant z scores were obtained for brain weight in the smaller twin (z = 2.71, p = 0.003, body weight standards) and heart weight in the larger twin (body weight standards, z = 3.87, p less than 0.001; brain weight standards, z = 3.64, p less than 0.001). We conclude that monozygotic twins with diamniotic, monochorionic placentation have a high degree of brain-sparing growth restriction in the smaller twin and cardiac hyperplasia in the larger twin, most likely caused by hemodynamic inequalities.

Renal tubular dysgenesis in twins

Abstract. In a fetal autopsy series, we have explored the occurrence of renal tubular dysgenesis in twins. Renal tubular dysgenesis was found exclusively among those monozygotic twins with evidence of twin transfusion syndrome, particularly in those donor twins with oligohydramnios and growth restriction. We infer that hypotension in the donor twin of the twin transfusion syndrome pair is responsible for the failure of proximal convoluted tubule differentiation, and the disturbance of renal function is manifested as oligohydramnios prenatally, and either oliguria or tubular dysfunction postnatally.

Combining humerus and femur length for improved ultrasonographic identification of pregnancies at increased risk for trisomy 21

OBJECTIVE Our purpose was to evaluate the value of the combination of femur and humerus length measurements in ultrasonographic screening for trisomy 21. STUDY DESIGN Direct necropsy measurements were analyzed on 703 midgestational fetuses (641 normal, 62 with trisomy 21). The (leg+arm length)/foot length ratio was found to be significantly shortened for fetuses with trisomy 21. On the basis of necropsy data 576 midgestational pregnancies were evaluated ultrasonographically for (femur+humerus length)/foot length ratio to identify fetuses at increased risk for trisomy 21. RESULTS An ultrasonographic (femur+humerus length)/foot length ratio < or = 1.75 gave a 15.3 odds ratio risk for trisomy 21 in our high-risk population and correctly identified 53% of fetuses with trisomy 21, with a false-positive rate of 7%. In addition, the use of this ratio eliminates the need for gestational age-corrected nomograms and complicated calculations in ultrasonographic screening. CONCLUSION The (femur+humerus length)/foot length ratio may be an additional effective ultrasonographic marker for identification of fetuses at increased risk for trisomy 21.

Fetal leg and femur/foot length ratio: a marker for trisomy 21.

OBJECTIVE Our purpose was to determine whether the femur/foot length ratio is useful in the prenatal detection of trisomy 21. STUDY DESIGN Direct necropsy measurements were analyzed on 436 midgestational fetuses (391 normal, 45 with trisomy 21). Necropsy leg/foot length ratio versus gestational age was found to be significantly different between normal fetuses and those with trisomy 21. On the basis of the necropsy data, 345 midgestational pregnancies were evaluated ultrasonographically for femur/foot length ratio versus gestation age to identify fetuses at risk for trisomy 21. RESULTS A leg/foot length ratio versus gestation age < or = 2.3 correctly identified 84% of fetuses with trisomy 21 between 110 to 155 days gestation age at necropsy. An ultrasonographic femur/foot length ratio versus gestational age < or = 0.9 had an 18.3 odds ratio risk for trisomy 21 in our high-risk population and correctly identified 71% of fetuses with trisomy 21 (positive predictive value 0.24, negative predictive value 0.98). CONCLUSION The femur/foot length ratio is an additional ultrasonographic marker for identification of fetuses at increased risk for trisomy 21.