Studies of malformation syndromes VID: The G syndrome. Further observations

An anatomic study of the organs of a 2-day-old female infant with severe repiratory manifestations of the G syndrome is presented. This case represents the third affected infant and first affected female of the J family. The first 2 male siblings were reported in previous communications. The developmental defects in this case include: failure of closure of the laryngotracheal groove, a high carina, hypoplasia of the left main stem bronchus, complete absence of the left lung, lack of major fissures of the right lung, a tracheo-esophageal fistula, agenesis of the gallbladder, and a stricture of the duodenum.     

Chondrodysplasia punctata — Rhizomelic form

Pathologic, ultrastructural and radiologic studies are described on 3 infants with the rhizomelic form of chondrodysplasia punctata. Radiologic criteria in the young infant include radiolucent coronal clefts dividing all or most of the thoracic and lumbar vertebral bodies, short humeri with flared metaphyses and punctate calcifications commonly present adjacent to the ossified ischial and pubic bones and less commonly in other locations. In late infancy and childhood the radiologic criteria include demineralization in all bones with slow maturation, flat vertebral bodies, short humeri and femora, metaphyseal flaring, especially in the distal humerus, proximal femur and proximal tibia, immature shape of pelvis, and disappearance of the punctate calcifications with advancing age. The histologic changes of the resting cartilage include areas of degenerating cartilage which had become partially calcified, cystic changes with severe disturbance of the maturation of the cartilage at the physeal plate, and the formation of cancellous bone directly on resting cartilage. Ultrastructural changes are characterized by degeneration of chondrocytes, delicate collagenous fibrils without visible periodicity, and the presence of flocculent material within greatly distended endoplasmic reticulum.Supported in part by USPHS/NIH Grants GM 15422, GM 20130, and 5 K04 HD 18982. Submitted as Paper No. 1977 from the University of Wisconsin Laboratory of Genetics.     

Abundant REM sleep in a patient with Alzheimer's disease

In patients with Alzheimer's disease (AD), greatly diminished REM sleep might be expected because of the cholinergic deficit in this disease and because cholinergic agonists stimulate REM sleep in humans and animals. We present here an unusual case of neuropathologically verified AD with abundant REM sleep. We suggest 4 possible explanations for this phenomenon: (1) selective cell loss in caudal midbrain/rostral pontine structures known to control sleep; (2) development of narcolepsy; (3) unrecognized affective disorder; (4) disruption of circadian timekeeping system.     

Opioids and non-opioid enantiomers selectively attenuate N-methyl-D-aspartate neurotoxicity on cortical neurons

Addition of 1 microM-1 mM methadone to the bathing medium produced a concentration-dependent reduction in the neurotoxicity of exogenously applied N-methyl-D-aspartate (NMDA) in murine cortical cell culture (EC50 about 100 microM); the reduction persisted at intense NMDA exposure, consistent with non-competitive inhibition. Methadone also protected against exposure to quinolinate but not quisqualate or kainate. Concentrations (100 microM-3 mM) of several other opioids - morphine, fentanyl, codeine, meperidine, dextropropoxyphene, and naltrexone - were additionally found to produce concentration-dependent reductions in NMDA neurotoxicity. This novel neuron-protective effect of opioids was not mediated by conventional opioid receptors: the non-opioid enantiomer of methadone and morphine exhibited a potency equal to or greater than that of the opioid enantiomer, and 1 mM naloxone did not act as an antagonist. The possibility that opioids, or especially non-opioid enantiomers of opioids, might provide a useful therapeutic approach in diseases states involving NMDA receptor-mediated neurotoxicity, warrants further study.     

The clinical spectrum of congenital contractural arachnodactyly

A case of congenital contractural arachnodactyly with severe cardiovascular malformations is described. This case and two other reports of CCA with congenital heart disease from the literature indicate a wider spectrum of clinical manifestations in CCA than generally assumed. The pattern of abnormalities suggests that the underlying connective tissue abnormality in CCA is “spotty” and not generalized as in such disorders as the Marfan syndrome, Stickler syndrome and arthro-dento-osteo dysplasia.     

Neonatal intracranial choriocarcinoma

A 1-month-old infant died from extensive intracerebral hemorrhage due to a metastatic choriocarcinoma to the brain that presumably originated in the placenta. The clinical course was characterized by hyperbilirubinemia, repeated episodes of seizures, and intracranial hemorrhage. A computed tomographic scan revealed a large vascular mass in the left parieto-occipital region and a small lesion in the left frontal lobe. The placenta was expelled during the delivery and was not examined. In view of the high level of maternal human chorionic gonadotropic hormone and the autopsy finding of metastasis, we presumed that the mass was a metastatic choriocarcinoma that had originated in the maternal placenta. To our knowledge, only one previous instance of this phenomenon has been reported.     

Idiopathic hydrops fetalis report of 4 patients including 2 affected sibs

We report four patients with idiopathic hydrops fetalis (IHF), two being affected sibs; the latter represent the first reported familial occurrence. A review identified 45 additional cases that seem to represent 1/3 to 2/3 of all cases of hydrops fetalis of nonimmunologic origin (NIHF). Our patients and the other adequately documented cases permit delineation of “idiopathic” fetal hydrops; ie, that form of the condition which is not associated with any detectable fetal or maternal disorders. These fetuses are usually premature, often the product of a gestation complicated by pre-eclampsia, occasional maternal anemia, and most often polyhydramnios. The fetuses have striking edema of most tissues with effusions into serous cavities, but no other specific anatomic abnormalities. They are often hypoproteinemic, but not anemic and do not manifest signs of accelerated hematopoiesis. Results of fetal and maternal immunohematological examination are normal. Fetal mortality rates approach 100% but recent data suggest that salvage rates can be significantly improved with early diagnosis. This requires accurate diagnosis and all factors and conditions known to be associated with other types of NIHF should be excluded. A relationship between fetal hypoalbuminemia and IHF may exist and needs further investigation. IHF is sporadic in most instances; however, recessive inheritance may be indicated by occurrence in two sibs. IHF represents a distinct, frequently unrecognized and relatively common entity in need of further study and increased recognition.     

Studies of malformation syndromes of man XXIX: The Wiedemann-Beckwith syndrome

This report describes 12 patients with the Wiedemann-Beckwith syndrome (WBS), including 6 familial cases from 2 families. The clinical manifestations do not allow for a differentiation between familial and sporadic cases. Consistent morphologic features include organomegaly, cytomegaly nd nucleomegaly. The pathogenetic process may involve few or many organs and tissues and may represent a nuclear/mitotic dysfunction. Clinically, the manifestations are hyperplasia, hypoplasia, dysplasia, neoplasia and defects in differentiation. Secondary functional disturbances are at times prominent.The differential diagnosis of the WBS includes 1) the Wilms' tumor (WT)-aniridia syndrome; 2) the tumor-hypertrophy syndrome which includes WT, adrenocortical tumors or hepatoblastoma; 3) the WT-pseudohermaphroditism syndrome; and 4) the tumor-nevus syndrome with or without malformations (particularly duplications) of the urinary tract. The latter two conditions are apparently not associated with hemihypertrophy.Familial occurrence suggests that some cases of the WBS may be due to delayed mutation. Carriers of the premutated allele appear to belong to two classes: those with a high risk of producing affected offspring and those who transmit the premutated allele but have no affected offspring.Supported in part by PHS/NIH grants GM 15422, 5-KO4-HD 18 982 and GM 20 130. Paper No. 1703 from the University of Wisconsin Genetics Laboratory.     

X-linked hydrocephalus. Further observations

The neuropathologic findings in a case of hydrocephalus of the X-linked recessive aqueductal stenosis type have been studied and compared with those previously reported from the same pedigree as well as with other cases from the literature. Additional pathological findings not previously recorded included: absence of the septum pellucidum and corpus callosum with malformation of the corpora quadrigemina and partial midline fusion of the fornices and thalami and fusion of thalamus with basal ganglia. These new findings indicate a broader phenotypic spectrum of this form of congenital X-linked recessive aqueductal stenosis than was previously known. Additional data from a diagnostic/genetic study of severely mentally retarded individuals are cited to show that 4 out of 5 familial cases of hydrocephalus without spina bifida are compatible with X-linked inheritance.Supported by USPHS Grants GM15422, GM20130 and 5KO4 HD18982. Paper No. 1785 from the University of Wisconsin Genetics Laboratory.