Agnathia-holoprosencephaly: a midline malformation association.
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Abnormalities, Multiple↗
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Prenatal diagnosis and fetopathological findings in five fetuses with trisomy 9.
Five male fetuses with trisomy 9 are discussed. Three were detected prenatally and terminated, 1 aborted spontaneously, and the fifth delivered prematurely and died soon after. Multiple congenital abnormalities characteristic of trisomy 9 were detected in all 5 cases and are compared to those of previous reports.
Abnormalities, Multiple↗
Malignant hematological disorders in children with Wolf-Hirschhorn syndrome.
Wolf-Hirschhorn syndrome (WHS) is a rare chromosomal disorder attributable to a deletion at the short arm of chromosome 4. This syndrome is associated with characteristic facial appearance, multiple congenital abnormalities, mental retardation, feeding difficulties and failure to thrive. We report two girls with WHS who developed myelodysplastic syndrome (MDS). According to the "Category, Cytology, Cytogenetic (CCC)"classification of childhood MDS, patient 1 had refractory cytopenia with ring sideroblasts at the age of 6 years, while patient 2 had refractory cytopenia with dysplasia at the age of 5-1/2 years. Patient 1 progressed to refractory cytopenia with excess blasts within a year, while patient 2 progressed to acute lymphoblastic leukemia within 1 month of presentation. It is possible that allelic loss of a tumor suppressor gene such as WHSC1 and/or FGFR3 from the deleted segment 4p16.3 plays a critical role in the process of malignant transformation. To our knowledge, this is the first report of severe hematological complications like MDS and leukemia in children with WHS and may be an important genetic model for understanding malignant hematological transformation. This report also underscores the importance of evaluating children with WHS for hematopoietic dysfunction.
Abnormalities, Multiple↗
Epithelial reorganization and irregular growth following carbendazim-induced injury of the efferent ductules of the rat testis.
Occlusions of the rat efferent ductules were induced by an oral gavage of carbendazim and the capacity for regeneration or recanalization of the ductules was histologically evaluated between 2 and 70 days post-treatment. At 2 days post-treatment, the efferent ductules were occluded by sloughed materials and showed various degrees of inflammation. Severely damaged epithelium showed few regenerative features at later intervals. On the other hand, epithelia with medium inflammation often exhibited irregular epithelial growth along the luminal contents or the formation of multiple abnormal ductules. These abnormal ductules were formed by migrated and original epithelia at the periphery of the occluded lumen at 16 days post-treatment, indicating attempted recanalization. At later time periods, 32 and 70 days post-treatment, the occluded original lumen was filled in by fibrotic connective tissue and surrounded by a series of abnormal ductules. These abnormal ductules were characterized by cuboidal epithelia, a small luminal diameter, fewer cilitated cells than normal, less developed organelles in the epithelial cells, and basal laminae of irregular thickness. However, there was no evidence that occluded ductules formed patent re-connections via abnormal ductules. The results suggest that occluded efferent ductules have the ability to initiate epithelial regrowth and to form new ductules, but the newly formed ductules are abnormal and are not adequate to recover from azoospermia at least at 70 days post-treatment.
Animals↗
The allopurinol hypersensitivity syndrome. Unnecessary morbidity and mortality.
Patients receiving allopurinol are at risk of developing the allopurinol hypersensitivity syndrome, an immunologic reaction to the drug, characterized by multiple abnormalities such as fever, rash, decreased renal function, hepatocellular injury, leukocytosis, and eosinophilia. The records of 8 patients with the allopurinol hypersensitivity syndrome evaluated at the Downstate Medical Center hospitals and an additional 72 patients described in the literature were reviewed. All were seriously ill. Three of the 8 patients at the Downstate Medical Center hospitals died as a result of allopurinol hypersensitivity; 19 of the 72 previously described patients also died from consequences of taking the drug. Only 1 of our 8 patients with allopurinol hypersensitivity was given allopurinol for an appropriate reason. Eight of the 59 previously described patients on whom there was adequate information had legitimate indications for allopurinol therapy. Severe, often fatal iatrogenic disease occurred unnecessarily in the others.
Aged↗
Management of pineal non-germinoma germ cell tumor with residual teratoma and normal alpha-fetoprotein.
A 16-year-old white male presented with multiple abnormal extraocular movements secondary to an enhancing pineal tumor. Subtotal resection of the lesion revealed a mixed malignant germ cell tumor. The preoperative serum alpha-fetoprotein (AFP) was markedly elevated at 155 IU/L. The patient subsequently received radiotherapy and adjuvant chemotherapy consisting of cisplatin rotating monthly with vincristine and cyclophosphamide, with dramatic tumor regression and return of AFP to normal. Eighteen months later the persistence of a substantial tumor mass despite a normal AFP raised concern for residual active tumor. Histological examination of the resected lesion revealed benign teratoma and fibrous tissue. Repeat management of mixed malignant germ cell tumors, which demonstrate a persistent mass following an initial response to treatment.
Adolescent↗
Non-mosaic trisomy 22: a report of 2 cases.
Non-mosaic trisomy 22 is a common cause of first trimester miscarriage and has a livebirth incidence of 1 in 30,000-50,000. Consequently there is a paucity of information for counselling parents. Detection in the second trimester is rare. It is commonly associated with severe growth retardation and multiple structural abnormalities. Oligohydramnios is frequently seen and can make detection of other abnormalities difficult. The outlook is uniformly poor and survival beyond the first trimester may present management dilemmas. A thorough fetal assessment including high-resolution cytogenetics with or without FISH is required for counselling. Careful plans for intrapartum and neonatal management may be necessary. The recurrence risk is thought to be low but information is very limited as there have been no reported cases of recurrence. We present two case of non-mosaic trisomy 22 including the first to be diagnosed subsequent to investigation for a high serum screening Down's risk.
Abnormalities, Multiple↗
Amniotic band disruption syndrome associated with elevated amniotic AFP and normal acetylcholinesterase gel test.
Ultrasonography in an 18 week pregnancy selected for detailed scanning because of a single elevated maternal serum AFP result suggested the presence of anencephaly. Amniocentesis at 19 weeks yielded a clear AF with an elevated AFP result (5.4 MOM) and no evidence of an acetylcholinesterase band of neural origin on PAG electrophoresis. At termination, the fetus had cephalo-amniotic fusion and multiple abnormalities including bilateral cleft lip and palate and digital amputations characteristic of the amniotic band syndrome. The cranial defect was completely sealed by attachment of the amniotic surface of the placenta to the skull.
Acetylcholinesterase↗
Teratogenicity and carcinogenicity in a twin exposed in utero to cyclophosphamide.
A 29-year-old pregnant woman diagnosed with acute lymphocytic leukemia maintained remission with daily cyclophosphamide and intermittent prednisone treatment. She delivered a male twin with multiple congenital abnormalities who was diagnosed with papillary thyroid cancer at 11 years of age and stage III neuroblastoma at 14 years of age. The female twin was unaffected and has exhibited normal development to date. First trimester exposure to cyclophosphamide has been associated with major malformations. Metabolites of cyclophosphamide have been demonstrated to be teratogens and carcinogens in animals. Differences in placental or fetal hepatic cytochrome P-450 may account for the variability in response between the twins. In addition, disparity between the twins may be the result of differences in metabolite inactivating enzymes present either in fetal liver or placenta. The risk of second malignancies caused by alkylating agents such as cyclophosphamide has been well documented in adults and children but to the best of our knowledge this is the first description of transplacental second cancer.
Abnormalities, Drug-Induced↗
A gene producing symmelia in the mouse.
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Abnormalities, Multiple↗
The acardiac anomaly.
Karyotype analysis of a premature human acardiac twin disclosed normal chromosomes. A review of previous cytogenetic, placental and animal studies suggests that chromosomal errors are not the cause of the acardiac anomaly. Rather, they point to the placental vascular anastomoses as the principal pathogenetic event.
Abnormalities, Multiple↗
Teratogenicity of cytochalasin D in the mouse.
Cytochalasin D, a mold metabolite identified in food, was injected intraperitoneally in doses of 0.4 to 0.9 mg per kilogram on gestational days 7 through 11 and produced evidence of teratogenicity in two out of three strains of mice. Exencephaly, hypognathia and axial skeletal defects were found in strains C57BL/6J and BALB/c while no increase in defects was observed in the Swiss Webster strain. In all three strains, a significantly increased resorption rate was found. Oral doses of approximately 7.0 mg per kg on days 7 through 11 in the BALB/c produced exencephaly in the offspring. Autoclaved cytochalasin D retained its teratogenic potential.
Abnormalities, Drug-Induced↗
Anencephaly with incomplete twinning (diprosopus).
A case of diprosopus with anencephaly is presented. It is suggested that such concurrence of neural tube defects and incomplete twinning corroborates the notion that a single pathogenetic mechanism may be common to both neural tube defects and monozygotic twinning.
Abnormalities, Multiple↗
Cyclopia: an anatomic and histologic study of two specimens.
The craniofacial complex of two neonatal, human, cyclopic specimens was studied in detail. Both specimens exhibited a single ocular opening and one had a prominent probosics positioned in the midline directly superior to the ocular aperture. No external nasal development was noted in the other specimen. The most remarkable finding was the lack of development of all skeletal derivatives of the ethmoidal cartilage(cribriform plate, perpendicular plate, superior and middle nasal conchae, medial orbital walls, and nasal septal cartilage) in both specimens. Since these bones normally form the medial, lateral, and superior walls of the nasal passage, this cavity was also absent. The two posterior halves of the maxillae were directed superiorly, medially, and with the vomer merged in the midline as a thick mass of bone. As a result the right and left alveolar portions of the maxillae were joined superiorly in the midline. With the absence of the nasal cavity, the right and left medial pterygoid plates merged medially with the palatal and pyramidal processes of the palatine bone to obstruct the junction between the oropharynx and nasopharynx(choanal atresia). The role of the skeletal parts of the ethmoid during maxillofacial growth and development is discussed.
Abnormalities, Multiple↗
Atelencephalic microcephaly: craniofacial anatomy and morphologic comparisons with holoprosencephaly and anencephaly.
This is the first detailed report of the craniofacial anatomy of atelencephaly. Comparisons were made with a control specimen and others with holoprosencephaly, anencephaly, and anencephaly with holoprosencephalic facial features. In the atelencephalic fetus, severe microcephaly, flattened calvaria, and partial synostosis of the metopic suture were apparent. The cranial fossae were much smaller than usual; lesser wings of the sphenoid were folded into a rounded basal mass. Facial features were pronounced, and orbits were hyperteloric, lowset, and rounded. Ethmoidal cartilages, nasal bones, and maxillary structures were distorted and elongated. The secondary palate was displaced inferiorly and cleft. Because major components of the craniofacial complex were generally present, although misshapen, changes in the atelencephalic skull seem to be deformations rather than malformations. Differences in the cranial morphology of associated disorders--holoprosencephaly and anencephaly--can be construed as aberrations of separate developmental fields. Relationships between atelencephaly and these fields are unclear.
Abnormalities, Multiple↗
Occurrence of embryotoxicity in mouse embryos following in utero exposure to 2'-deoxycoformycin (pentostatin).
Previous investigations had shown that i.p. injection of 2'-deoxycoformycin (dCF; pentostatin; 5 mg/kg) on either E7 or E8 into pregnant mice results in a 61-81% resorption rate at E17. The incidence of visible gross malformations among the surviving conceptuses was exceptionally low (3%) at the time of necropsy on E17 and was unrelated to dCF dose (Knudsen et al., Teratology, 40:5-626, '89; Teratology, 45:91-103, '92). These findings demonstrated the embryotoxicity of dCF but provided no clues as to the site(s) of dCF action. To define the lesion site(s), we have now examined embryos at 72 h (E10), 96 h (E11), and 120 h (E12) following administration of a highly embryotoxic dose of 5 mg dCF/kg to dams on E7. Deoxycoformycin caused multiple abnormalities and growth retardation, and the temporal sequence between maximal abnormal embryo incidence and resorption frequency was established. The quantitative data show that the maximal occurrence of abnormal embryos on E10 (71%) was followed by a maximal resorption rate on E12 (78%). There was a strong correlation (r = -0.82; P < 0.05) between the rapid decline of percent abnormal embryos over E10-E12 and the simultaneous increase in resorption rate, with linear regression analysis showing nearly equal but opposite slopes (-31.2% vs. +35.8% per gestational day, respectively). This suggests that one or more of the abnormalities seen at E10 is associated with the death and resorption of the embryo at E12. The dCF treatment perturbed a wide spectrum of developmental events, including neural tube closure, craniofacial and limb development, turning of the embryo, and growth retardation. None of the individual abnormalities, however, can quantitatively account for the high percentage of dead and resorbed embryos. Therefore, the specific cause of dCF-induced embryolethality is not clear. There is evidence both for direct dCF toxicity at specific embryonic sites as well as for a generalized retardation in the rate of development.
Abnormalities, Drug-Induced↗
A case of X-linked agammaglobulinemia diagnosed in adulthood.
X-linked agammaglobulinemia (XLA), caused by mutations in Bruton's tyrosine kinase (BTK), typically presents in early childhood. We report here the case of a male diagnosed at age 23 years with hypogammaglobulinemia, originally classified as common variable immunodeficiency (CVID). On further analysis at age 40, flow cytometric analysis of lymphocytes showed only 0.1% B cells and Western blot analysis showed a deficiency of BTK protein in peripheral blood mononuclear cells, indicating the patient has XLA. BTK cDNA and genomic DNA analysis revealed a splice site mutation at the 3' end of intron 13. Multiple abnormally spliced mRNA species were identified, one of which was predicted to produce a protein with a 24-amino-acid insertion between the SH2 and kinase domains. In vitro kinase assay of this product showed weak kinase activity, perhaps resulting in milder than usual disease. XLA can present in adult males, and sporadic cases may be misdiagnosed as CVID.
Adult↗
Identification of a putative regulatory subunit of a calcium-activated potassium channel in the dup(3q) syndrome region and a related sequence on 22q11.2.
Duplication of a segment of the long arm of human chromosome 3 (3q26.3-q27) results in a syndrome characterized by multiple congenital abnormalities and neurological anomalies in some patients. We have identified a novel gene (KCNMB3) that maps to this region. KCNMB3 has significant sequence similarity to the regulatory subunit of the large-conductance calcium-activated potassium channel. Due to the significance of potassium channels in neuronal functions, the overexpression of this gene may play a role in the abnormal neurological functions seen in some of these patients. A related sequence corresponding to the second and third exons of this gene resides in the pericentromeric region of 22q11, where a number of other unprocessed pseudogenes are known to map.
Abnormalities, Multiple↗