Refinement of the Region for Split Hand/Foot Malformation 5 on 2q31.1.

Background: Deletions that encompass 2q31.1 have been proposed as a microdeletion syndrome with common clinical features, including intellectual disability/developmental delay, microcephaly, cleft palate, growth delay, and hand/foot anomalies. In addition, several genes within this region have been proposed as candidates for split hand-foot malformation 5 (SHFM5). Methods: To delineate the genotype-phenotype correlation between deletions of this region, we identified 14 individuals with deletions at 2q31.1 detected by microarray analysis for physical and developmental disabilities. Results: All subjects for whom detailed clinical records were available had neurological deficits of varying degree. Seven subjects with deletions encompassing the HOXD cluster had hand/foot anomalies of varying severity, including syndactyly, brachydactyly, and ectrodactyly. Of 7 subjects with deletions proximal to the HOXD cluster, 5 of which encompassed DLX1/DLX2, none had clinically significant hand/foot anomalies. In contrast to previous reports, the individuals in our study did not display a characteristic gestalt of dysmorphic facial features. Conclusion: The absence of hand/foot anomalies in any of the individuals with deletions of DLX1/DLX2 but not the HOXD cluster supports the hypothesis that haploinsufficiency of the HOXD cluster, rather than DLX1/DLX2, accounts for the skeletal abnormalities in subjects with 2q31.1 microdeletions.

Reproductive fitness in maternal homocystinuria due to cystathionine beta-synthase deficiency.

Early diagnosis and improved treatment are leading to the potential for increased reproductive capability in homocystinuria due to cystathionine beta-synthase (CbetaS) deficiency, but information about reproductive outcome and risk of thromboembolism in pregnancy is limited. To provide further information, clinical and biochemical information was obtained on women with maternal homocystinuria, on their pregnancies and on the offspring. This information included blood sulphur amino acids and total homocysteine, CbetaS gene mutations and developmental and cognitive scores in the offspring. The study involved 15 pregnancies in 11 women, of whom 5 were pyridoxine-nonresponsive and 6 were pyridoxine-responsive. Complications of pregnancy included pre-eclampsia at term in two pregnancies and superficial venous thrombosis of the leg in a third pregnancy. One pregnancy was terminated and two pregnancies resulted in first-trimester spontaneous abortions. The remaining 12 pregnancies produced live-born infants with normal or above-normal birth measurements. One offspring has multiple congenital anomalies that include colobomas of the iris and choroid, neural tube defect and undescended testes. He is also mentally retarded and autistic. A second offspring has Beckwith-Wiedemann syndrome. The remaining 10 offspring were normal at birth and have remained normal. There was no relationship between the severity of the biochemical abnormalities or the therapies during pregnancy to either the pregnancy complications or the offspring outcomes. The infrequent occurrences of pregnancy complications, offspring abnormalities and maternal thromboembolic events in this series suggest that pregnancy and outcome in maternal homocystinuria are usually normal. Nevertheless, a cautious approach would include careful monitoring of these pregnancies with attention to metabolic therapy and possibly anticoagulation.

An unusual type of combined aortic coarctation due to fibromuscular dysplasia.

A 3-year-old patient is described with an unusual form of co-arctation due to hypoplasia of the transverse arch and fibromuscular dysplasia involving a long segment of the thoracic aorta. Surgical repair required resection of the aorta from the distal transverse arch to the mid-descending thoracic aorta, and replacement with a 16-mm Dacron interposition graft. This case demonstrates the importance of preoperative evaluation of the entire aorta in the presence of co-arctation due to fibromuscular dysplasia.

Unilateral retinoblastoma with acquired monosomy 7 and secondary acute myelomonocytic leukemia.

Patients with a nongenetic form of retinoblastoma are not particularly at high risk of developing second malignant neoplasms. We report here a case of treatment-related leukemia (secondary leukemia) with acquired monosomy 7, in a child with unilateral retinoblastoma.

Neonatal encephalopathy in two boys in families with recurrent Rett syndrome.

Rett syndrome (RTT) has been described in its classic form only in females. Although the majority of cases are sporadic, familial cases give valuable insight into the genetic basis and phenotypic variability of the disorder. The exclusive occurrence of classic Rett syndrome in females led to the hypothesis that the Rett syndrome locus is likely to be X-linked and mutations are lethal in hemizygous males. We identified two boys in families with recurrent Rett syndrome who had encephalopathies with neonatal onset and who may represent the phenotype of males harboring Rett syndrome mutations. The difference in severity of disease in these males and their female relatives supports the location of Rett syndrome locus on the X-chromosome.

Toward quality assurance for metaphase FISH: a multicenter experience.

Although fluorescent in situ hybridization (FISH) is rapidly becoming a part of clinical cytogenetics, no organization sponsors multicenter determinations of the efficacy of probes. We report on 23 laboratories that volunteered to provide slides and to use a probe for small nuclear ribonucleoprotein polypeptide N (SNRPN) and a control locus. Experiences with FISH for these laboratories during 1994 ranged from 0 to 645 utilizations (median = 84) involving blood, amniotic fluid, and bone marrow. In an initial study of hybridization efficiency, the median percentage of metaphases from normal individuals showing two SNRPN and two control signals for slides prepared at each site was 97.0 (range = 74-100); for slides prepared by a central laboratory, it was 97.8 (range = 81.6-100). In a subsequent blind study, each laboratory attempted to score 5 metaphases from each of 23 specimens [8 with del(15)(q11.2-->q12) and 15 with normal #15 chromosomes]. Of 529 challenges, the correct SNRPN pattern was found in 5 of 5 metaphases in 457 (86%) and in 4 of 5 in 33 (6%). Ambiguous, incomplete, or no results were reported for 32 (6%) challenges. Seven (1%) diagnostic errors were made, including 6 false positives and 1 false negative: 1 laboratory made 3 errors, 1 made 2, and 2 made 1 each. Most errors and inconsistencies seemed due to inexperience with FISH. The working time to process and analyze slides singly averaged 49.5 min; slides processed in batches of 4 and analyzed singly required 36.9 min. We conclude that proficiency testing for FISH by using an extensive array of challenges is possible and that multiple centers can collaborate to test probes and to evaluate costs.

Toward quality assurance for metaphase FISH: a multi-center experience.

Although fluorescent in situ hybridization (FISH) is rapidly becoming a part of clinical cytogenetics, no organization sponsors multi-center determinations of the efficacy of probes. We report on 23 laboratories that volunteered to provide slides and to use a probe for SNRPN and a control locus. Experiences with FISH for these laboratories during 1994 ranged from 0 to 645 utilizations (median = 84) involving blood, amniotic fluid and bone marrow. In an initial study of hybridization efficiency, the median percentage of metaphases from normal individuals showing two SNRPN and 2 control signals for slides prepared at each site was 97.0 (range = 74-100); for slides prepared by a central laboratory, it was 97.8 (range = 81.6-100). In a subsequent blind study, each laboratory attempted to score 5 metaphases from each of 23 specimens [8 with del(15) (q11.2-->q12) and 15 with normal 15 chromosomes]. Of 529 challenges, the correct SNRPN pattern was found in 5 of 5 metaphases in 457 (86%) and in 4 of 5 in 33 (6%). Ambiguous, incomplete or no results were reported for 32 (6%) challenges. Seven (1%) diagnostic errors were made including 6 false positives and 1 false negative: 1 laboratory made 3 errors, 1 made 2, and 2 made 1 each. Most errors and inconsistencies seemed due to inexperience with FISH. The working time to process and analyze slides singly averaged 49.5 minutes; slides processed in batches of 4 and analyzed singly required 36.9 minutes. We conclude that proficiency testing for FISH using an extensive array of challenges is possible and that multiple centers can collaborate to test probes and to evaluate costs.

Monozygotic twins with congenital acute lymphoblastic leukemia (ALL) and t(4;11)(q21;q23).

Congenital acute lymphoblastic leukemia (CALL) is a rare disorder and is frequently associated with t(4;11)(q21;q23). To our knowledge this is the first case report of monozygous twins with CALL and t(4;11)(q21;q23).

Painful fingers, heat intolerance, and telangiectases of the ear: easily ignored childhood signs of Fabry disease.

Generalized anhidrosis with heat collapse, painful fingers, and angiokeratomas were the presenting signs in a 23-year-old man who was shown by enzyme studies and electron microscopy to have Fabry disease. His 6-year-old brother had the early diagnostic findings of episodic painful fingers, heat intolerance, and retroauricular telangiectasia. Both had an absence of alpha-galactosidase. Over 6 years of observation, the older brother developed progressive renal failure and the younger one developed acrodynia and anhidrosis. Their mother had diminished alpha-galactosidase activity and several angiomatous papules on one breast. A review of Fabry disease emphasizes the need for skin inspection for angiomas and telangiectasia, and enzyme assay in patients with inexplicable complaints or findings. Carrier females are most easily recognized by the presence of unique corneal opacities.

Clinical, cytogenetic, and molecular characterization of seven patients with deletions of chromosome 22q13.3.

We have studied seven patients who have chromosome 22q13.3 deletions as revealed by high-resolution cytogenetic analysis. Clinical evaluation of the patients revealed a common phenotype that includes generalized developmental delay, normal or accelerated growth, hypotonia, severe delays in expressive speech, and mild facial dysmorphic features. Dosage analysis using a series of genetically mapped probes showed that the proximal breakpoints of the deletions varied over approximately 13.8 cM, between loci D22S92 and D22S94. The most distally mapped locus, arylsulfatase A (ARSA), was deleted in all seven patients. Therefore, the smallest region of overlap (critical region) extends between locus D22S94 and a region distal to ARSA, a distance of > 25.5 cM.

Head-upright tilt table testing in evaluation of recurrent, unexplained syncope.

Recurrent syncope is one of the most common problems referred to the pediatric neurologist for evaluation. Traditional evaluations are time consuming and expensive, and leave 40% of patients without a precise diagnosis. Vasovagal syncope has been believed to be a common cause of syncope; however, no reliable diagnostic modality has been available to confirm this theory. Head-upright tilt table testing has recently emerged as a useful tool in the evaluation and management of recurrent, unexplained syncope. In this review, we present the pathophysiologic mechanisms of vasovagal syncope and relate them to the reflexes triggered during head-upright tilt table testing. Additionally, we review the clinical data on the uses of this test in unexplained syncope, suggest a practical testing protocol, and elaborate potential therapeutic modalities that can be employed to prevent further episodes. Head-upright tilt table testing will likely become a standard test employed by both adult and child neurologists.

Autosomal recessive neurodegenerative disorder with trichorrhexis invaginata and ectodermal dysplasia.

Two siblings are reported with an autosomal recessive syndrome characterized by hair and skin abnormalities, hypoplastic nails, generalized hypotonia, absent reflexes, and progressive neurologic deterioration. Although this disorder shares clinical features with an ectodermal dysplasia syndrome with neurodegenerative changes, no specific neuropathologic findings were present. Instead, trichorrhexis invaginata was found in some hair shafts. Hair analysis may be helpful in classifying clinically confusing neurologic conditions.

Evaluation of the Health Belief Model and decision making regarding amniocentesis in women of advanced maternal age.

The Health Belief Model (HBM) was developed as an attempt to explain an individual's decision regarding obtaining preventive health care. This model was applied to predict the decisions of women of advanced maternal age regarding their obtaining amniocentesis in a one-year study conducted in Toledo, Ohio. A questionnaire based on the HBM was administered to a sample of 98 pregnant women of advanced maternal age. A total of 96 questionnaires were eligible for inclusion in the study. Sixty-one women reported that they would have amniocentesis, 22 would not, and 13 were unsure. A multivariate analysis of variance among amniocentesis decision groups was performed using the health belief components (perceived susceptibility, perceived seriousness, perceived benefit, perceived barrier) and knowledge as variables. There was a significant difference (Wilks' criterion, p less than .0001) among the three decision groups, but the differences were in the health belief components and not in knowledge. A stepwise discriminant function analysis was used to classify subjects on the amniocentesis decision. Of the variables examined, only the HBM component perceived benefit factor was a significant discriminant (p = .0001). It is not necessarily the lack of knowledge that prevents women who are at risk because of advanced maternal age from having amniocentesis but their perceptions regarding amniocentesis. Genetic counselors need to focus more on exploring the perceptions of amniocentesis benefits in this population to facilitate the decision making process.

Congenital lung herniation.

Congenital lung herniation is a rare condition. It is usually associated with a costal cartilage defect. We report on a newborn boy with a partial lung herniation through the parietal pleura and skin associated with a sternal malformation. We propose the herniation occurred around the fifth month of fetal life and interfered with sternal ossification.

Carnitine deficiency associated with ornithine transcarbamylase deficiency.

An infant with X-linked recessive ornithine transcarbamylase deficiency is described who also had severe deficiency of plasma and liver carnitine during normoammonemic periods. Treatment with L-carnitine (100 mg/kg/day) for 12 months decreased the frequency of hospitalizations for hyperammonemia, although it did not alter his neurologic status. This report demonstrates that persistent carnitine deficiency may be present in patients with ornithine transcarbamylase deficiency even when plasma ammonia is normal. Carnitine evaluation and supplementation may be important in the treatment of patients with this metabolic disorder.

Long-term L-carnitine treatment in isovaleric acidemia.

A 5-year-old girl with isovaleric acidemia was treated with long-term L-carnitine and no supplemental glycine. Clinical and laboratory data are presented. Following diagnosis and treatment at age 2 years, the frequency of acute exacerbations of metabolic acidosis was reduced and she resumed normal growth and development. L-carnitine supplementation and protein restriction may be sufficient for effective therapy of isovaleric acidemia.

Marfanoid children. Etiologic heterogeneity and cardiac findings.

The clinical, cardiac, and echocardiographic test results of 20 children with marfanoid features are reviewed. Fifteen were diagnosed as having Marfan syndrome, two had "possible" Marfan syndrome, and three had other diagnoses. On first evaluation, eight patients with Marfan syndrome (53%) had mitral regurgitation and none had aortic regurgitation. Echocardiography showed aortic root enlargement in 12 (80%) of 15 patients and mitral valve prolapse in 12 (80%) of 15. None had a normal echocardiogram. At follow-up examination, one patient had developed aortic root enlargement, and one patient, mitral valve prolapse. Thus, although aortic root enlargement is usually present in early childhood in patients with Marfan syndrome, it is not considered specific because in this study it also occurred in one child with Alport's syndrome and in one with marfanoid features. Four patients with aortic root enlargement were treated with propranolol and their echocardiograms showed no further increase in the aortic root diameter for several years. We recommend echocardiography in the diagnosis and routine management of children in whom Marfan syndrome is suspected.

Prenatal diagnosis of autosomal dominant microcephaly and postnatal evaluation with magnetic resonance imaging.

A case of fetal autosomal dominant microcephaly was prenatally diagnosed with ultrasonography in a woman with previously undiagnosed microcephaly. At the time of initial ultrasonographic assessment, the mother was identified to have a markedly small cranium, consistent with maternal microcephaly. The ultrasonographic examination showed the fetal head size to be four standard deviations below the mean for gestational age. Gestational dating from the other biometric parameters and from the last menstrual period was consistent with 31 weeks' gestation. Neurosonographic evaluation of the fetus revealed no obvious structural abnormalities. Serial ultrasonographic examinations at 35 and 38 weeks' gestation showed no changes in the fetal head size. A 2.64 kg male fetus was delivered at term. Neonatal assessment showed the fetal head circumference to be less than the second percentile for gestational age. Neurologic assessment of the neonate with magnetic resonance imaging showed abnormal development of the brain, with small cerebellar and cerebral hemispheres, and pachygyria. These images are compared with the magnetic resonance images of the mother. Our findings of maternal and fetal microcephaly are consistent with autosomal dominant microcephaly. To our knowledge, this is the first report of the prenatal diagnosis of autosomal dominant microcephaly.

Agnathia malformation complex associated with a cystic distention of the oral cavity and hydranencepahly.

A fetus with a severe variant of the agnathia malformation complex (AMC) was delivered following prenatal diagnostic evaluation with ultrasonography. The constellation of anomalies that accompanied the agnathia included holoprosencephaly, hydranencephaly, situs inversus, and polysplenia. Recently, several authors have reported the association between the agnathia, holoprosencephaly, and situs inversus. We present evidence which suggests that, when hydranencephaly is also present, this may represent the most severe variant of the AMC. Our case is presented, the literature is reviewed, and a hypothesis regarding the embryopathologic mechanism is discussed.