Barbara F. Crandall

Neuroimaging findings in macrocephaly–capillary malformation: A longitudinal study of 17 patients

Here, we report the neuroimaging findings and neurological changes in 17 unpublished patients with Macrocephaly–Capillary Malformation (M–CM). This syndrome has been traditionally known as Macrocephaly–Cutis Marmorata Telangiectatica Congenita (M–CMTC), but we explain why M–CM is a more accurate term for this overgrowth syndrome. We analyzed the 17 patients with available brain MRI or CT scans and compared their findings with features identified by a comprehensive review of published cases. White matter irregularities with increased signal on T2‐weighted images were commonly observed findings. A distinctive feature in more than half the patients was cerebellar tonsillar herniation associated with rapid brain growth and progressive crowding of the posterior fossa during infancy. In four such cases, we confirmed that the tonsillar herniation was an acquired event. Concurrently, with the development of these findings, ventriculomegaly (frequently obstructive) and dilated dural venous sinuses were observed in conjunction with prominent Virchow–Robin spaces in many of those in whom cerebellar tonsil herniation had developed. We postulate that this constellation of unusual features suggests a dynamic process of mechanical compromise in the posterior fossa, perhaps initiated by a rapidly growing cerebellum, which leads to congestion of the venous drainage with subsequently compromised cerebrospinal fluid reabsorption, all of which increases the posterior fossa pressure and leads to acquired tonsillar herniation. We make a distinction between congenital Chiari I malformation and acquired cerebellar tonsil herniation in this syndrome. We also observed numerous examples of abnormal cortical morphogenesis, including focal cortical dysplasia, polymicrogyria which primarily involved the perisylvian and insular regions, and cerebral and/or cerebellar asymmetric overgrowth. Other findings included a high frequency of cavum septum pellucidum or vergae, thickened corpus callosum, prominent optic nerve sheaths and a single case of venous sinus thrombosis. One patient was found to have a frontal perifalcine mass resembling a meningioma at age 5 years. This is the second apparent occurrence of this specific tumor in M–CM.

Alpha-Fetoprotein: A Review

Alpha fetoprotein (AFP) is the major protein of fetal serum and most resembles albumen, which replaces it shortly after birth. It is produced by fetal liver and passes into the amniotic fluid (AF) via fetal urine. A small amount crosses the membranes into the maternal circulation. Excluding fetal blood contamination, elevated AF/AFP levels indicate fetal demise or one of several abnormalities. Maternal serum (MS) AFP measurement can be used as a screening procedure to identify neural tube defects providing a rigorous protocol is followed. This requires that a laboratory establish its normal range of MS/AFP levels between 15 and 20 weeks gestation, employ a reliable assay with adequate controls, and has recourse to genetic counseling as well as expert sonography, amniocentesis and amniography if necessary. Pregnancy is the only normal situation in which AFP is present after birth. It may be present in high levels in certain malignancies and has been useful in monitoring their recurrence. This article will review the history, biochemistry, and different assays of AFP in AF and blood as well as the indications and limitations for their use.

Risks associated with an elevated maternal serum a-fetoprotein level

Among 58,187 women tested, 1002 had a maternal serum alpha-fetoprotein measuring greater than or equal to 2.5 multiples of the median after correction for race, weight, and insulin-dependent diabetes. They were stratified into three groups: group 1, 2.5 to 2.9; group 2, 3.0 to 5.0; group 3, greater than or equal to 5.0 multiples of the median. The initial risk of a serious abnormality detected by ultrasonography or amniocentesis was 17% (5%, 12% and 65% in groups 1, 2, and 3, respectively). After correction for twins and dates, this risk became 23% (7%, 18%, and 71% in groups, 1, 2, and 3, respectively). Among the women with high maternal serum alpha-fetoprotein levels, 556 (77%) had normal ultrasonographic and amniocentesis studies, and the risk of adverse pregnancy outcome ws 27% (19%, 29%, and 70% in groups 1, 2, and 3, respectively). There was a statistically significant increase in late fetal and perinatal death, prematurity and growth retardation, oligohydramnios, abruptio placentae, preeclampsia, and congenital abnormalities. The overall risk for abnormality or adverse outcome was 24% in group 1, 41% in group 2, and 91% in group 3.

Common trisomy mosaicism diagnosed in amniocytes involving chromosomes 13, 18, 20 and 21: karyotype–phenotype correlations

Karyotype–phenotype correlations of common trisomy mosaicism prenatally diagnosed via amniocentesis was reviewed in 305 new cases from a collaboration of North American cytogenetic laboratories. Abnormal outcome was noted in 10/25 (40%) cases of 47,+13/46, 17/31 (54%) cases of 47,+18/46, 10/152 (6.5%) cases of 47,+20/46, and in 49/97 (50%) cases of 47,+21/46 mosaicism. Risk of abnormal outcome in pregnancies with less than 50% trisomic cells and greater than 50% trisomic cells were: 26% (4/15) versus 60% (6/10) for 47,+13/46, 52% (11/21) versus 75% (6/8) for 47,+18/46, 4.5% (6/132) versus 20% (4/20) 47,+20/46, and 45% (27/60) versus 59% (22/37) for 47,+21/46. Phenotypically normal liveborns were observed with mean trisomic cell lines of 9.3% for 47,+13/46, 8.6% for 47,+18/46, 27% for 47,+20/46, and 17% for 47,+21/46. Cytogenetic confirmation rates were 46% (6/13 cases) for 47,+13/46 mosaicism, 66% (8/12 cases) for 47,+18/46, 10% (10/97 cases) for 47,+20/46, and 44% (24/54 cases) for 47,+21/46. There were higher confirmation rates in pregnancies with abnormal versus normal outcome: 50% versus 44% for 47,+13/46 mosaicism, 100% versus 33% for 47,+18/46, 66% versus 7% for 47,+20/46, and 55% versus 40% for 47,+21/46. Repeat amniocentesis is not helpful in predicting clinical outcome. It may be considered when there is insufficient number of cells or cultures to establish a diagnosis. Fetal blood sampling may have a role in mosaic trisomy 13, 18, and 21 as the risk for abnormal outcome increases with positive confirmation: 1/5 (20%) normal cases versus 5/8 (62%) abnormal cases. High resolution ultrasound examination(s) is recommended for clinical correlation and to facilitate genetic counselling. Copyright

A familial syndrome of deafness, alopecia, and hypogonadism

Three male siblings are described, who had progressive neurosensory deafness, alopecia, and hypogonadism. Deafness with alopecia has been described previously as Bjornstads syndrome. Hypogonadism has not been a part of this syndrome and in this family it appeared to be secondary to a deficiency of luteinizing hormone associated with a deficiency of growth hormone. The normal stature found in this sibship may indicate a growth hormone deficiency of late onset. There have been no previous reports of deafness in association with growth hormone and luteinizing hormone deficiency. In contrast to Bjornstads syndrome, and autosomal dominant disorder, it appears that this syndrome is inherited as an autosomal recessive trait.

Chromosome findings in 700 children referred to a psychiatric clinic.

Chromosome analyses were performed on 700 consecutive children referred to a child psychiatric clinic. Seventy-seven per cent of these children were referred because of emotional problems and 23 per cent because of mental retardation, often accompanied by emotional problems. A chromosome change was found in 36 (5.1 per cent) of the whole group and in 4.62 per cent of the children with normal intelligence (I.Q.>70). There were 11 sex chromosome aneuploidies, 13 structural anomalies, and 12 chromosomal “variants.” This increased occurrence of chromosome changes in children with behavioral disorders emphasizes the need for further studies.

Maternal serum α-fetoprotein screening of fetal trisomies

Abstract Thirty-two trisomy pregnancies were retrospectively studied in which the maternal serum level of α-fetoprotein was determined prior to amniocentesis. Median levels of α-fetoprotein in serum (0.83 multiples of the median) and in amniotic fluid (0.72 multiples of the median) were lowered, but this was statistically significant only in the case of amniotic fluid.

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.

Infant hearing loss and connexin testing in a diverse population

Purpose: Previous studies of connexin-related hearing loss have typically reported on mixed age groups or adults. To further address epidemiology and natural history of connexin-related hearing loss, we conducted a longitudinal study in an ethnically diverse cohort of infants and toddlers under 3 years of age. Our study compares infants with and without connexin-related hearing loss to examine differences in the prevalence of connexin and non-connexin-related hearing loss by ethnic origin, detection by newborn hearing screening, phenotype, neonatal risk factors, and family history. This is the first study to differentiate infants with and without connexin-related hearing loss.Methods: We enrolled 95 infants with hearing loss from whom both exons of Cx26 were sequenced and the Cx30 deletion was assayed. Demographic, family history, newborn hearing screening data, perinatal, and audiologic records were analyzed.Results: Genetic testing identified biallelic Cx26/30 hearing loss-associated variants in 24.7% of infants with a significantly lower prevalence in Hispanic infants (9.1%). Eighty-two infants underwent newborn hearing screening; 12 infants passed, 3 had connexin-related hearing loss. No differences in newborn hearing screening pass rate, neonatal complications, or hearing loss severity were detected between infants with and without connexin-related hearing loss. Family history correlates with connexin-related hearing loss.Conclusions: Connexin-related hearing loss occurs in one quarter of infants in an ethnically diverse hearing loss population but with a lower prevalence in Hispanic infants. Not all infants with connexin-related hearing loss fail newborn hearing screening. Family history correlates significantly with connexin-related hearing loss. Genetic testing should not be deferred because of newborn complications. These results will have an impact on genetic testing for infant hearing loss.

Late replication studies in a human X/13 translocation: correlation with autosomal gene expression

Chromosome replication pattern was reevaluated in an unbalanced X/13 translocation carrier, 46,X,der (X),t(X;13)(q27;q12), using the BudR-acridine orange technique. The translocated chromosome, Xpter leads to q27::13q12 leads to 13qter, was late replicating in all analyzed cells. The autosomal segment showed a replication pattern comparable to the two normal, and presumably genetically active, chromosome 13s, with the exception of band 13q22, which was consistently late replicating. Measurements of red-cell levels of esterase D (ESD) (a marker assigned to 13q14) showed a 50% increase in ESD activity, compared to that in normal controls and parents of the patient. This suggests noninactivation of the ESD locus on the der(X) chromosome, a finding consistent with the late-replication data.