Restoration of effective hemopoiesis preceding suppression of leukemic clone in myeloblastic leukemia.

A 63 year old Caucasian woman presented with myeloblastic leukemia and a hyperdiploid C group chromosome change in 10 per cent of marrow metaphases. Treatment iwth cytotoxic agents resulted in an increased percentage (52 per cent) of these hyperdiploid marrow cells. Furthermore, the marrow continued to show leukemic fearures morphologically and in culture. Despite the indications of persistence or progression of the hyperdiploid, putatively leukemic line at cessation of chemotherapy and for a period of time thereafter, remission was achieved and blood and marrow cell numbers one year after cessation of all treatment are normal. The hyperdiploid line is no longer detectable. This case raises questions concerning the mechanism whereby remission is attained in some cases of acute leukemia and is discussed in terms of the restoration of normal hemopoiesis eliminating the leukemic process.

Risks associated with an elevated amniotic fluid alpha-fetoprotein level.

Two and two-tenths percent of 85,000 consecutive amniotic fluid (AF) samples had alpha-fetoprotein (AFP) levels greater than or equal to 2.0 MoM. Half measured 2.0-2.4 MoM, and 93% had a normal outcome. Sixty-seven percent of those with higher levels had abnormalities. A positive acetylcholinesterase (AChE) increased the risk from 67% for levels between 2.0 and 2.4 MoM to 99% at greater than or equal to 5.0 MoMs. After a normal ultrasound and chromosome studies, the risk for a fetal abnormality was 1% for AF AFP measuring 2.0-2.4 MoM and 3% for higher levels.

Routine amniotic fluid alphafetoprotein assay: experience with 40,000 pregnancies.

Of 40,000 initial amniotic fluid samples, 0.7% had an alphafetoprotein (AFP) level greater than or equal to +3 standard deviations above the mean. The risk of an open neural tube defect (NTD) or other serious fetal abnormality was 61% when AFP levels measured greater than or equal to +3 and 87% for levels greater than or equal to 5 standard deviations. If the acetylcholinesterase (AChE) was positive, this risk was 84% and 95% for AFP levels of greater than or equal to +3 and greater than or equal to +5 SD, respectively, and 29% and 62% for the same levels if the AChE was negative. If the second amniocentesis AFP was also greater than or equal to +3, the risk of an abnormality was 96%. In this series, there were 93 open neural tube defects, and all were identified. The true false-positive rate was 1 per 13,000 of the cases screened. The recurrence risk for an NTD was 1.8%, and the incidence of NTDs in women having amniocentesis only for maternal age was 1.5 per 1,000.

Prenatal diagnosis of neural tube defects: experiences with acetylcholinesterase gel electrophoresis.

We assessed the qualitative test for AChE in addition to AFP for the diagnosis of NTD in 420 AF samples selected from 16,000 second trimester amniocenteses. Three-hundred and thirty were from normal and ninety from abnormal pregnancies. There were three false positives by this test, two from stored samples containing fetal blood and one from a clear specimen; all had normal outcomes and two had had abnormal AFPs. Forty-seven of forty-seven NTDs were positive by AChE and included 26 cases of anencephaly, 16OSBs, and 5 encephaloceles. In addition, about half of the cases of omphalocele, fetal demise, cystic hygroma, and hydrops gave positive results. One case of congenital nephrosis was negative. We conclude that AChE gel electrophoresis is a useful adjunctive test when AFP levels measure +3 SD above the mean. Although no false negative occurred in this series identified by elevated AFP or increased risk for NTDs, the number in unselected pregnancies is not known.

Review article: mucolipidosis IV.

We review all reported cases of Mucolipidosis IV, add a new one, and present evidence for a generalized phospholipid storage. All phospholipids were increased in the liver, skin fibroblasts and urine. Lysobisphosphatydic acid which was markedly elevated in these samples was the only lipid stored in muscle. A slowly progressive neurological disease with mental retardation and corneal opacities, but lacking mucopolysaccharide excretion, skeletal changes and organomegaly should raise the suspicion of this disease. At this time, the diagnosis is made by EM studies of skin or conjunctiva which should be done if results of tests on serum or bone marrow for lysosomal diseases are normal. We found some of the typical inclusions in skin fibroblasts from an obligate carrier, which suggests that distinction between the homozygote and heterozygote may be difficult. Despite this, two succeeding pregnancies with normal outcomes were successfully monitored.

Preliminary phenotypic map of chromosome 4p16 based on 4p deletions.

We have collected and analyzed clinical information from 11 patients with chromosome 4p deletions or rearrangements characterized by various molecular techniques. Comparing the extent of these patients' deletions with their respective clinical presentations led to the proposal of a preliminary phenotypic map of chromosome 4p. This map consists of regions which, when deleted, are associated with specific clinical manifestations. Nonspecific changes such as mental and growth retardation are not localized, and probably result from the deletion of more than one gene or region. The region associated with most of the facial traits considered typical in Wolf-Hirschhorn syndrome (WHS) patients coincides with the currently proposed WHS critical region (WHSCR), but some anomalies commonly seen in WHS appear to map outside of the WHSCR. The observation of clinodactyly in 2 patients with nonoverlapping deletions allows assignment of these defects to at least 2 separate regions in 4p16. These initial observations and attempts at genotype/phenotype correlation lay the groundwork for identifying the genetic basis of these malformations, a common objective of gene mapping efforts and chromosome deletion studies.

Chromosome findings in 2,500 second trimester amniocenteses.

We have analyzed the chromosome abnormalities found in 2,500 amniocenteses for prenatal diagnosis; 1,887 (75%) were performed because the maternal age was 34 years or more. Chromosome abnormalities were detected in 1.80% of those referred for advanced maternal age, 1.2% between ages 34 and 39 years and 4.6% 40 years and over. Of these, four occurred in women who would have been 34 years at delivery (2.9%). Trisomy 21 accounted for 50% of the chromosome abnormalities; sex chromosome abnormalities, for 25%; the remaining 25% was divided equally between trisomy 18 and partial trisomies and mosaics. Unexpected translocations were found in 0.4%, of which two-thirds were balanced and identified in one parent. The accuracy was 99.6%.

Radiographic and morphologic findings in a previously undescribed type of mesomelic dysplasia resembling atelosteogenesis type II.

The mesomelic chondrodysplasias are a heterogeneous group of dwarfing disorders characterized by shortness of the middle segments of limbs. We report on a 25-week fetus with disproportionate shortness of limbs with an apparently distinct form of mesomelic dysplasia. Radiographic findings at necropsy included ulnar deviation of hands, talipes equinovarus, distal tapering of the humeri, and hypoplastic fibulae, radii, and ulnae. Chondro-osseous morphology showed mild shortness of the physeal columns, overgrowth of perichondral bone, peripheral ingrowth of mesenchymal cells into the physis, and numerous areas of fibrillar degeneration with rings of collagen surrounding the chondrocytes. Ultrastructural findings included a degenerated territorial matrix, pericellular halos of collagen, and dilated loops of rough endoplasmic reticulum in chondrocytes. The radiographic appearance of the long bones is distinct from that of previously described mesomelic dysplasias. The chondro-osseous morphologic findings and the distal tapering of the humerus are somewhat reminiscent of atelosteogenesis type II, but the pattern of matrix degeneration and the presence of inclusion bodies in the chondrocytes distinguish it from disorders of sulfate transport.

Amniocentesis follow-up: infant developmental evaluation.

The Gesell Developmental Evaluation was administered to 150 children between 8 and 37 months of age whose mothers had second-trimester amniocentesis. The results of the evaluation were analyzed with respect to 1) maternal age at the time of the amniocentesis; 2) volume of fluid aspirated; 3) presence of bloody amniotic fluid; 4) repeat amniotic taps; and 5) medical problems during the first year of life. There was no statistical relationship found between an abnormal developmental score and any of the above 5 items. The results from the same developmental test administered to the control group of 64 young children were not significantly different from the index group.

Prenatal genetic diagnosis in 350 amniocenteses.

Three hundred and fifty second trimester amniocenteses performed for prenatal diagnosis of genetic disorders are reported. One hundred and ninety-three of these were performed because maternal age was greater than 35 years, and 6 fetuses with unbalanced chromosomal abnormalities (3%) were identified. Thirteen procedures were performed because a previous child had had a neural tube defect; 1 anencephalic fetus was identified. Ninety-six percent of the initial taps were cultured successfully; we failed to obtain amniotic fluid in 3% of patients. The risk of a spontaneous abortion occurring at some time after the amniocentesis was 0.85%, and no cases of fetal injury were identified.

Pregnancy outcomes after increasing maternal serum alpha-fetoprotein levels.

Five hundred sixty women among 35,787 screened had an initial maternal serum alpha-fetoprotein (MSAFP) of 2.5 or more multiples of the median. They were divided into three groups: group 1, 2.5-2.9; group 2, 3.0-3.9; and group 3, over 4.0 multiples of the median. These groupings determined the relationship to adverse pregnancy outcome, defined as fetal death, fetus with significant anomalies, and prematurity/growth retardation. The overall risk of adverse outcome after an initial elevation was 38%, after excluding pregnancies with incorrect dates or multiple gestations with levels below 4.5 multiples of the median: 27, 39, and 45% in groups 1, 2, and 3, respectively. This risk rose to 86% for levels over 6.0 multiples of the median. There was a significant positive correlation between abnormalities and death detected with ultrasound and amniocentesis and those indicated by increasing MSAFP levels: 10, 20, and 31% in groups 1, 2, and 3, respectively. After normal ultrasound and amniocentesis studies, there was a trend toward increasing risks for fetal death after 20 weeks between groups 2 and 3 (5 and 11%), but not for growth retardation/prematurity (12, 17, and 13%). After an elevated MSAFP, the overall risk of a late pregnancy complication after normal ultrasound and amniocentesis was 22%: 19, 23, and 25% in groups 1, 2, and 3, respectively. This figure increased to 67% for levels above 6.0 multiples of the median.

Combining maternal age and serum alpha-fetoprotein to predict the risk of Down syndrome.

Twenty-eight cases of Down syndrome with maternal serum alpha-fetoprotein (AFP) measured at second trimester were added to 137 previously reported cases. Seventy-eight percent of affected pregnancies had levels at or below the median AFP value, compared with 50% of unaffected pregnancies. Maternal age at delivery and serum AFP levels by multiples of the median were used to construct a table to determine the risk of Down syndrome. This was compared with the risk for a 35-year-old woman (one in 365). Similar risks were estimated for a 21-year-old with AFP below 0.4 multiples of the median, a 23-year-old below 0.5, a 26-year-old below 0.6, and a 29-year-old below 0.7 multiples of the median. This study provides guidelines for counseling pregnant women who have low serum AFP levels.

Elevated maternal serum alpha-fetoprotein and amniotic fluid alpha-fetoprotein after multifetal pregnancy reduction.

Forty patients underwent fetal reduction at approximately 12 weeks' gestation for multiple pregnancy. Twenty-two had maternal serum alpha-fetoprotein (MSAFP) determinations and all but one was elevated, with a mean value of 9.41 multiples of the median (MOM). A total of 53 amniotic fluid specimens were evaluated for AFP; 25% were elevated above 2.0 MOM and one sample was positive for acetylcholinesterase. None of these elevations were associated with a neural tube defect, although two neural tube defects were detected by other means. Routine MSAFP is not recommended for patients with multifetal pregnancy reduction.

Follow-up of 2000 second-trimester amniocenteses.

The authors analyzed the outcome of 2000 consecutive second-trimester amniocenteses. Seventy-three percent were performed for maternal age of 34 years or more. The risk of spontaneous abortion before 28 weeks' gestation was 1.3% and for stillbirth or neonatal death, 1.4%. Total fetal loss was 2.7%, compared with 2.2% in a control population. Congenital malformations were found in 1.6% of the study group and in 1.9% of controls; no increase in skeletal problems was observed. Prematurity, defined as a birth weight of less than 2500 g, was noted in 3.6%, compared with 3.7% and 3.9% in 2 control populations. Respiratory difficulties persisting for more than 24 hours were observed in 0.8% of patients, compared with 0.7% of controls. Analyses of the outcome of amniocenteses performed at a single large center do not show an increase in perinatal complications or malformations.

Ocular manifestations of the lacrimo-auriculo-dento-digital syndrome.

We studied a mother and daughter with an extremely rare constellation of signs and symptoms. One or both had absent lacrimal puncta, nasolacrimal duct obstruction, chronic dacryocystitis, dry eyes, and epiphora. Systemic findings included salivary gland hyposecretion, dental hypoplasia and dysplasia, cup-shaped ears with hearing loss, and digital anomalies. These findings are consistent with those of the lacrimo-auriculo-dento-digital syndrome, a genetic disorder. Our study supports the autosomal dominant inheritance of this syndrome, delineates the ophthalmic manifestations, and provides evidence that renal anomalies are part of the disorder.

Neural tube defects: maternal serum screening and prenatal diagnosis.

Neural tube defects represent some of the most common and serious of the congenital malformations. Although elevation of alpha-fetoprotein in amniotic fluid is not diagnostic, it does indicate an abnormality of the fetus in a very high proportion of cases. A normal level, however, does not exclude the possibility of a closed neural tube defect. It is therefore recommended that all amniocenteses performed between 15 and 20 weeks of gestation include measurement of alpha-fetoprotein. Maternal serum alpha-fetoprotein assay is a screening test and pilot studies will be necessary to determine its value as a routine prenatal blood test.

Constriction of the umbilical cord as a cause of fetal demise following midtrimester amniocentesis.

Two cases of constriction of the umbilical cord resulting in fetal demise following midtrimester amniocentesis are presented. In both cases, real-time ultrasonography prior to amniocentesis revealed a viable fetus. Fetal demise was identified immediately following the procedure in the first case and one month later in the other. A localized constriction at the fetal end of the umbilical cord in both, with torsion of the constricted segment in the second case, was observed. Wharton's jelly was noted to be deficient in this segment of the cord in the first case. The mechanism of fetal demise is discussed. It is suggested that this abnormality should be considered when fetal demise follows midtrimester amniocentesis.

Osteopathia striata syndrome. Clinical, genetic and radiologic considerations.

Osteopathia striata, an autosomal dominant disorder, has been diagnosed in a 19-year-old mildly retarded woman. In addition, she has macrocephaly, a leonine facies, disfigurement of the lower jaw, a cleft palate and mixed hearing loss. Roentgenograms of the skull and long bones show thickening of the calvarium, particularly at the base, mandibular hyperplasia, and striations in the long bones and pelvis. Except for the cleft palate, which has not been previously reported, and the retardation, which appears to be quite uncommon in this condition, these findings are characteristic of osteopathia striata. Because the disorder may resemble several other conditions, the differential diagnosis should include osteopoikilosis, the autosomal dominant form of osteopetrosis, and hyperostosis corticalis generalisata.