Down syndrome--an update and review for the primary pediatrician.
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Down Syndrome↗
Biomedical subjects
J M Graham
Publications and source records attributed to J M Graham.
Analysis of the chondroitin sulfate proteoglycan core protein (CSPGCP) gene in achondroplasia and pseudoachondroplasia.
Achondroplasia and pseudoachondroplasia are autosomal dominant skeletal dysplasias resulting in short-limbed dwarfism. Histologic and ultrastructural studies of the cartilage in pseudoachondroplasia and in homozygous achondroplasia have suggested a structural abnormality in chondroitin sulfate proteoglycan (CSPG), a major structural protein in the extra-cellular matrix. The gene encoding CSPG core protein (CSPGCP) is thus a logical "candidate gene" for analysis in these conditions. cDNA probes encoding CSPGCP were used to identify restriction fragment length polymorphisms (RFLPs) in DNA from a panel of control individuals. No gross alterations at the CSPGCP locus were noted in DNA from 37 individuals with achondroplasia and 5 individuals with pseudoachondroplasia. In addition, allelic frequencies of the RFLPs were not significantly different among controls and patients with either condition. In one three-generation family with achondroplasia, close linkage of the CSPGCP locus and the skeletal dysplasia was excluded using a Bgl II polymorphism. Similarly, in a three-generation family with pseudoachondroplasia, the CSPGCP gene was not tightly linked to the disease phenotype. These results indicate that mutations at the chondroitin sulfate proteoglycan core protein locus do not cause achondroplasia or pseudoachondroplasia in these families.
Achondroplasia↗
Localization of the gene encoding the GABAA receptor beta 3 subunit to the Angelman/Prader-Willi region of human chromosome 15.
Deletions of the proximal long arm of chromosome 15 (bands 15q11q13) are found in the majority of patients with two distinct genetic disorders, Angelman syndrome (AS) and Prader-Willi syndrome (PWS). The deleted regions in the two syndromes, defined cytogenetically and by using cloned DNA probes, are similar. However, deletions in AS occur on the maternally inherited chromosome 15, and deletions in PWS occur on the paternally derived chromosome 15. This observation has led to the suggestion that one or more genes in this region show differential expression dependent on parental origin (genetic imprinting). No genes of known function have previously been mapped to this region. We show here that the gene encoding the GABAA (gamma-aminobutyric acid) receptor beta 3 subunit maps to the AS/PWS region. Deletion of this gene (GABRB3) was found in AS and PWS patients with interstitial cytogenetic deletions. Evidence of beta 3 gene deletion was also found in an AS patient with an unbalanced 13;15 translocation but not in a PWS patient with an unbalanced 9;15 translocation. The localization of this receptor gene to the AS/PWS region suggests a possible role of the inhibitory neurotransmitter GABA in the pathogenesis of one or both of these syndromes.
Amino Acid Sequence↗
Identification of fetal problems associated with anticonvulsant usage and maternal epilepsy.
This article reviews the general approach for assessing teratogenic risks related to fetal exposure, concentrating on the specific patterns associated with anticonvulsant usage and maternal epilepsy. Major anomalies that might be detected prenatally are presented, as well as the patterns of minor anomalies (syndromes) that might be detected at birth or later. Each of the specific drugs used in the treatment of epilepsy is reviewed in detail. In addition, recent information concerning genetically determined variations in the metabolism of antiepileptic drugs is discussed in light of how genetic factors might relate to teratogenicity.
Abnormalities, Drug-Induced↗
Clinical approach to human structural defects.
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Congenital Abnormalities↗
Reactions of mothers and medical professionals to a film about Down syndrome.
Parents, genetic counselors, and nurses were shown an 18-minute video-taped discussion involving parents of persons with Down syndrome and were asked to complete an evaluation. Some of the statistically significant differences were as follows: 89% of mothers believed that the film was an accurate portrayal of parental attitudes compared with 14% of the genetic counselors and 40% of the nurses; 48% of genetic counselors believed that problems outweigh the benefits in parenting a child with Down syndrome, but 94% of mothers and 83% of nurses thought that the benefits predominated; and 56% of genetic counselors believed that parents of a child with Down syndrome would choose to abort a subsequent affected fetus while only 8% of parents and 10% of nurses agreed. It is important that medical professionals have a balanced and accurate view of the impact of Down syndrome on families.
Abortion, Induced↗
Atelosteogenesis type III: a distinct skeletal dysplasia with features overlapping atelosteogenesis and oto-palato-digital syndrome type II.
We present 5 cases of a short-limb dwarfism syndrome whose manifestations overlap those of atelosteogenesis and oto-palato-digital syndrome Type II. Clinical, radiographic, genetic, and histologic data are presented which demonstrate differences between our patients and previously reported cases of these other conditions. We conclude that the disorder seen in these children represents a distinct chondrodysplasia for which we propose the name atelosteogenesis Type III.
Bone and Bones↗
Microphthalmia and chorioretinal lesions in a girl with an Xp22.2-pter deletion and partial 3p trisomy: clinical observations relevant to Aicardi syndrome gene localization.
We present a 4-year-old girl with a maternally derived, unbalanced X;3 translocation resulting in partial Xp monosomy and partial 3p trisomy. She had chorioretinal defects, developmental delay, infantile seizures, and microphthalmia. These findings initially suggested a diagnosis of Aicardi syndrome. However, she had a normal-appearing corpus callosum on CT and magnetic resonance imaging scans of the brain and her retinal findings were not typical for Aicardi syndrome. This represents the 6th reported example of microphthalmia associated with an Xp22 chromosome abnormality. Four of these individuals also had features suggestive of focal dermal hypoplasia (FDH), which was not evident in our patient. The available evidence supports the hypothesis that gene disruption at Xp22 may lead to findings similar to those seen in Aicardi syndrome and FDH, both of which are believed to be X-linked dominant male lethal conditions.
Child, Preschool↗
Central nervous system malformations in the CHARGE association.
Of 144 patients with the CHARGE association (literature 136, new patients 8), 47 (33%) had either a postmortem examination (30) or computerized axial tomography scan (17) of the head. Twenty-six of 47 (55%) had definite central nervous system (CNS) malformations; arhinencephaly, with or without other defects (11), holoprosencephaly (2), holoprosencephaly with arhinencephaly (1), other forebrain defects (3), hindbrain defects (3), or other defects (6). The presence of CNS malformation was most strongly associated with choanal atresia. This review demonstrates a predominance of forebrain anomalies, particularly arhinencephaly and holoprosencephaly, which may provide a clue to the mechanism of abnormal morphogenesis involved in CHARGE association.
Abnormalities, Multiple↗
The achondroplasia gene is not linked to the locus for neurofibromatosis 1 on chromosome 17.
We have investigated genetic linkage of von Recklinghausen neurofibromatosis (NF1) and achondroplasia (ACH) using chromosome-17 markers that are known to be linked to NF1. Physical proximity of the two loci was suggested by the report of a patient with mental retardation and the de novo occurrence of both NF1 and ACH. Since the chance of de novo occurrence of these two disorders in one individual is 1 in 600 million, this suggested a chromosomal deletion as a single unifying molecular event and also that the ACH and NF1 loci might be physically close. To test this, we performed linkage analysis on a three-generation family with ACH. We used seven DNA probes that are tightly linked to the NF1 locus, including DNA sequences that are known to flank the NF1 locus on the centromeric and telomeric side. We detected two recombinants between the ACH trait and markers flanking the NF1 locus. In one recombinant, the flanking markers themselves were nonrecombinant. Multi-point linkage analysis excluded the ACH locus from a region surrounding the NF1 locus that spans more than 15 cM (lod score less than -2). Therefore, analysis of this ACH pedigree suggests that the ACH locus is not linked to the NF1 locus on chromosome 17.
Achondroplasia↗
Isolation of the major subcellular organelles from mouse liver using Nycodenz gradients without the use of an ultracentrifuge.
Commonly, subcellular organelles such as nuclei, mitochondria, lysosomes, and Golgi membranes are isolated first by differential centrifugation in low-speed or high-speed centrifuges and then purified by gradient centrifugation in ultracentrifuges. We have prepared these organelles using a new high-speed centrifuge (28,000 rpm max) which allows the generation of higher radial centrifugal forces (rcfs) than are available in standard machines. We have shown that most subcellular organelles can be purified by using low-viscosity Nycodenz gradients at rcfs lower than those normally used in ultracentrifuges, without increasing the time of centrifugation. Use of Nycodenz also allows rapid harvesting of material from gradients and we have adapted a number of enzyme assays to facilitate gradient analysis.
Animals↗
Studies of type I collagen in osteogenesis imperfecta.
We used the results of skin fibroblast type I collagen analysis to improve the accuracy of diagnosis and genetic counseling for six patients with osteogenesis imperfecta. The fibroblasts of two patients with osteogenesis imperfecta type I synthesized a reduced quantity of qualitatively normal type I procollagen. Another patient with osteogenesis imperfecta type I had two populations of type I collagen molecules, one apparently normal and the other with a substitution of cysteine for glycine in the triple helical domain. Three sporadic cases with osteogenesis imperfecta types II, III, and IV were studied; in each proband a normal and an abnormal overmodified population of type I collagen molecules were demonstrated, and parental collagens were normal in the two available patients. These results indicated that the probands were heterozygous for new dominant mutations and assisted our genetic counseling, especially in osteogenesis imperfecta types II and III, which were formerly believed to be inherited in an autosomal recessive fashion. The results could not exclude parental germ line mosaicism for a new dominant mutation, which has resulted in recurrence in siblings of some patients with osteogenesis imperfecta, so prenatal diagnosis was therefore offered for future pregnancies. Analysis of chorionic villus cell collagen may facilitate antenatal diagnosis in selected cases, and the study of a larger number of patients may allow correlation of the biochemical defects with the natural history and prognosis.
Adult↗
Angelman syndrome: three molecular classes identified with chromosome 15q11q13-specific DNA markers.
Angelman syndrome (AS) and Prader-Willi syndrome (PWS) share a cytogenetic deletion of chromosome 15q11q13. To determine the extent of deletion in AS we analyzed the DNA of 19 AS patients, including two sib pairs, with the following chromosome 15q11q13--specific DNA markers: D15S9-D15S13, D15S17, D15S18, and D15S24. Three molecular classes were identified. Class I showed a deletion of D15S9-D15S13 and D15S18; class II showed a deletion of D15S9-D15S13; and in class III, including both sib pairs, no deletion was detected. These molecular classes appear to be identical to those observed in PWS. High-resolution cytogenetic data were available on 16 of the patients, and complete concordance between the presence of a cytogenetic deletion and a molecular deletion was observed. No submicroscopic deletions were detected. DNA samples from the parents of 10 patients with either a class I or a class II deletion were available for study. In seven of the 10 families, RFLPs were informative as to the parental origin of the deletion. In all informative families, the deleted chromosome 15 was observed to be of maternal origin. This finding is in contrast to the paternal origin of the deletions in PWS and is currently the only molecular difference observed between the two syndromes.
Abnormalities, Multiple↗
Chlamydial infections.
Chlamydia causes many human infections and should be treated aggressively. Tetracycline or doxycycline are the drugs of choice, but erythromycin can be used if a drug allergy is present or if tetracyclines are contraindicated. In the pregnant woman, aggressive treatment can improve neonatal outcome. In the United States, each year 155,000 infants are exposed to Chlamydia trachomatis during the birth process, and more than 100,000 will be infected. Of these, 75,000 will get conjunctivitis, and 30,000 will get pneumonia. In pregnancy, erythromycin is the drug of choice, with treatment recommended after initial culture and at term if repeat cultures are positive. If erythromycin is not tolerated, or the patient has an allergy to it, ampicillin or clindamycin may be effective alternatives.
Anti-Bacterial Agents↗
Clinical approach to prenatal detection of human structural defects.
Tremendous advances in prenatal diagnosis have allowed clinicians to recognize a variety of structural defects in the developing fetus. Guidelines for fetal ultrasonography and an approach to fetal evaluation are outlined. The developmental morphologic approach is emphasized as a way of categorizing congenital anomalies whether they are detected during prenatal or postnatal life. The use of this approach for diagnosing and managing fetal malformation syndromes is illustrated.
Congenital Abnormalities↗
Posterior nuchal cystic hygroma.
When cystic hygroma is detected antenatally, the prognosis is usually poor, and intrauterine or neonatal death are common. This seems especially true for Turner syndrome (the largest etiologic group associated with cystic hygroma) and the lethal multiple pterygium syndromes. However, some fetuses with Turner syndrome, and also with certain other diagnoses, had a good outcome, and further study of these conditions is required before more definite prognostic indicators and risk figures will be available. Increasing numbers of syndromes are being reported in association with fetal cystic hygroma, and lymphedema may be a common element in their pathogenesis. Mild, short-lived, or otherwise uncomplicated jugular lymphatic obstruction may be a cause of the neck webbing seen in the Noonan, familial pterygium colli, and distichiasis-lymphedema syndromes. With earlier and more widespread fetal ultrasonography, and more sensitive techniques, a greater number of resolving fetal cases may be reported. This may clarify the natural history and provide prospective criteria for the conditions that have better prognoses. The associated conditions include autosomal dominant and recessive genetic traits. Careful ultrasound study for other malformations, polyhydramnios and fetal growth parameters, a fetal karyotype, and, if appropriate, pathologic examination are required to determine the etiology and recurrence risk. The parents should be asked about exposure to alcohol or other agents and should be examined for signs of pterygium colli or Noonan syndrome. If the decision is made to continue the pregnancy, and there is doubt about the natural history and prognosis, multi-disciplinary supervision should include social services, neonatology, pediatric surgery, cardiology, and genetics specialties when indicated.
Female↗
Diagnosis and management of infantile marfan syndrome.
Marfan syndrome is infrequently diagnosed early in infancy. The experience of the authors with 22 severely affected infants diagnosed as having Marfan syndrome in the first 3 months of life is described and the literature on 32 additional infants with Marfan syndrome is reviewed. It was found that serious cardiac pathology (82% of the patients described in the article, 94% of those described in the literature) may be present at birth, and that congenital contractures (64% of our cases, 47% of literature cases) are often an associated finding. Other useful clinical findings included arachnodactyly, dolichocephaly, a characteristic facies, a high-arched palate, micrognathia, hyperextensible joints, pes planus, anterior chest deformity, iridodenesis, megalocornea, and dislocated lenses. Echocardiography was useful as a noninvasive method for defining the extent of cardiovascular involvement and following its course. Characteristic cardiac findings in early life included mitral valve prolapse, valvular regurgitation, and aortic root dilation. Cardiac function ranged from normal to poor, with a tendency to worsen. Of the 22 cases 3 infants died during the first year of life. Morbidity and mortality may be high when Marfan syndrome is diagnosed during infancy, and prompt recognition of this phenotype can facilitate management and counseling. Most such severe cases appear to be due to a sporadic mutation in a single germ cell of one parent. Many familial cases may have milder manifestations, be more difficult to detect during infancy, and have a better prognosis.
Heart Defects, Congenital↗
A modified cystourethropexy in the management of incontinence and dyspareunia.
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Adult↗