The MIller-Dieker syndrome.

Four unrelated children with the Miller-Dieker syndrome, previously referred to as the lissencephaly syndrome, have been evaluated, bringing to ten the number of patients reported with that disorder. We wish to emphasize that lissencephaly is etiologically non-specific and represents only one feature in this malformation syndrome. Other features, such as the craniofacial, neurologic, and growth abnormalities, are more helpful in diagnosing this autosomal recessive disorder.

Sporadic case of apparent aprosencephaly.

We report a sporadic case of apparent aprosencephaly, ie, apparent absence of forebrain with the facial anomalies of the (alobar) holoprosencephaly field complex. The infant lived-14 months, manifested temperature variations between 34.5 and 41.7 degrees C, and suffered at least one episode of severe hyponatremia suggesting hypoaldosteronism of brain or adrenal origin. Eye changes were suggestive of Rieger mesodermal dysgenesis.

Decreased maternal age with hydranencephaly.

We studied parental ages of institutionalized children with hydranencephaly. Mothers under age 20 years and under age 18 years were, respectively, 5 and 10 times as frequent as in the general population, and 3 and 4 times more frequent than for institutionalized control patients. Unwed mothers were also common, but may reflect high rates in younger mothers combined with institutionalization bias. Thus, hydranencephaly appears to show a decreased maternal age effect, similar to that seen with other conditions presumably due to prenatal vascular disruptions.

"ADAM complex" (amniotic deformity, adhesions, mutilations)--a pattern of craniofacial and limb defects.

We report eight patients with the craniofacial defects and limb anomalies of the (amniotic deformity, adhesions, mutilations) ADAM complex. Facial abnormalities comprise clefts and distortion and dislocation of craniofacial structures; limbs show various combinations of amputation, secondary syndactyly, and constriction. From previous reports and our cases it is obvious that the clinical picture of the ADAM complex varies enormously; a less severe type combines cleft lip and palate with amputations or amniotic bands. Clinical and experimental data suggest that these malformations are of symptomatic (exogenous) origin. Nosologic differentiation from other conditions phenotypically similar but of genetic etiology is important for genetic counseling. Observation of the ADAM complex in two members of a family suggests that genetic factors might operate in some cases.

Studies of malformation syndromes of humans XXXIIIC: the FG syndrome - further studies on three affected individuals from the FG family.

The brain findings at autopsy of an 18-year-old male with FG syndrome were megalencephaly, midline fusion of mammillary bodies, heterotopia of neuroglial tissue in the 7th and 8th nerves, and ependymal cell replacement by neuroglial tissue as well as a diffuse defect of neuronal cell migration evidenced from pachygyria of many gyri, dysgenesis of cerebral cortex, and heterotopia of neurons in the white matter of the centrum ovale. A cousin, studied at 20 weeks' gestational age, had gross turridolichocephaly with enlarged cranium and also multiple minor external and internal anomalies. An affected brother of this fetus died at 17 months of complications of a congenital heart defect and CNS dysfunction. X-linked inheritance of the FG syndrome is confirmed.

The dup(3q) syndrome: report of eight cases and review of the literature.

Clinical and cytogenetic examinations were performed on eight unrelated infants with duplication of part of the long arm of chromosome 3. A review of published cases shows a clinical syndrome characterized by statomotoric retardation, shortened life span, and a multiple congenital anomalies (MCA) syndrome of abnormal head configuration, hypertrichosis, hypertelorism, ocular anomalies, anteverted nostrils, long philtrum, maxillary prognathia, down-turned corners of the mouth, highly arched or cleft plate, micrognathia, malformed auricles, short, webbed neck, clinodactyly, simian crease, talipes, and congenital heart disease. The dup(3q) syndrome is a clinically easily recognizable entity.

Studies of malformation syndromes of man XXXVIII: The BD syndrome. A "new" multiple congenital anomalies/mental retardation syndrome with athetoid cerebral palsy.

Two patients with a virtually identical physical examination syndrome are reported. Both had severe microbrachycephaly, profound mental retardation and athetoid cerebral palsy. The anomalies include prominence of forehead, hypoplastic midface, mandibular prognathism, apparent midline "cleft" of mandible with absence of lower central incisors, ear and eye anomalies, growth failure, and various similar secondary anomalies due to hypotonia, cerebral palsy and immobilisation. The patients probably represent a "new" MCA/MR syndrome, the etiology of which is still unknown. A genetic cause, i.e., a gene mutation with pleiotropic effects, is suggested. This may involve an autosomal recessive trait, an autosomal dominant new mutation, or an X-linked dominant-hemizygous lethal trait.

Autosomal recessive syndrome of pseudogliomantous blindness, osteoporosis and mild mental retardation.

We report a sibship of three sisters and two brothers who showed osteoporosis of variable severity; the propositus has incapacitating deformities following numerous fractures. Four of the sibs, including three with frequent fractures, were blind from infancy ("pseudogliomatous blindness"). In addition, two were mentally retarded. The osteoporosis-pseudoglioma syndrome is inherited as an autosomal recessive trait; similar reports from the literature support this assumption.

Studies of malformation syndromes of man XXXIX: a craniosynostosis-craniofacial dysostosis syndrome with mental retardation and other malformations: "craniofacial dyssynostosis".

We report clinical findings in 2 sisters and 5 sporadic cases with a "new" type of craniosynostosis/craniofacial dysostosis and shortness of stature. Premature closure of lambdoid sutures and posterior part of sagittal suture causes a posteriorly narrow, dolichocephalic skull with small, flat or bulging occiput and protuberance of the forehead; disturbance of the growth of basal skull structures leads to craniofacial dysostosis and (secondary) anomalies of the face. In one patient the coronal suture was also involved. One of the patients had a congenital heart defect. Four untreated patients had mental retardation; 3 had craniosynostectomy with more or less normal psychomotor development afterwards. Some patients had hydrocephalus and 1 had a brain malformation (agenesis of the corpus callosum with presumed interventricular lipoma). The observation of sisters with the same condition suggests autosomal recessive inheritance. This etiologic hypothesis is supported by the fact that 4 of 7 patients are of Spanish, Mexican, or Puerto Rican ancestry; this population probably has a rather high gene frequency and the trait should be relatively common in areas occupied by this population and their descendents. The condition has been designated craniofacial dyssynostosis.

Syndrome of mental retardation, seizures, hypotonic cerebral palsy and megalocorneae, recessively inherited.

A previously apparently undescribed "syndrome" is reported in which megalocornea and iris anomalies are accompanied by minor facial and skeletal anomalies, severe mental retardation, hypotonia, and seizures. The condition was found in 3 siblings of one family and in 4 sporadic cases; it is thought to be recessively inherited.

A biologic and genetic study of 40 cases of severe pure mental retardation.

The family history of 40 patients with severe "pure" mental retardation (MR) was studied to determine the incidence of mental retardation and dull-normal intelligence among relatives, probable etiologies and an empiric recurrence risk. Significant findings include: (1) an increased sex ratio (69% males) of propositi, (2) a significant proportion of patients with clinical manifestations besides MR, (3) virtually no consanguinity among parents, (4) a "positive" family history for over 1/2 of the propositi--about 37% of all children in the sibships were affected; about 21% of the full sibs were affected, (5) a higher number of offspring produced by dull persons and a lower number of offspring from retarded persons compared to two normal persons (6) a proportionately large number of affected children produced from matings involving one or two dull persons, (7) a tendency for dull to have additional dull children and mentally retarded parents to have further retarded children while normal parents with more than one affected child usually had further retarded children, (8) an incidence of affected parents of about 32%, and (9) an overall empiric recurrence risk of 14%. Several etiologies were discussed as possible causes of the condition(s) in this group: (unrecongized) environmental damage and/or maternal/fetal interaction; unrecognized chromosome abnormalities; the homozygous state of several different autosomal recessive gees: X-linked recessive mutations; autosomal dominat new mutations; and mutifactoral inheritance. It was concluded that the group was etiologically heterogeneous and although none of the probable etiologies could be excluded, it seemed reasonable to assume that autosomal recessive inheritance plays an important role in the etiology of severe "pure" mental retardation.

Fatal CNS dysgenesis with severe microencephaly, mental retardation, seizures and paucity of myelin, autosomal recessive trait?

Siblings are reported with severe mental retardation, spastic cerebral palsy and seizures; in addition they had progressive or intermittent jaundice and recurrent infections; they died at 3 and 4 years respectively. Neuropathological studies in one showed a small brain with an almost complete lack of myelin in cerebral white matter, brain stem, cerebellum and anterolateral parts of the spinal cord. The condition most likely represents a dysgenesis of myelin (dysmyelination), possibly due to an inability of oligodendrocytes to form myelin and/or metabolic defects in the process of myelination. This mental retardation condition is probably inherited as an autosomal recessive trait and may represent a special type of a primary CNS developmental defect.

Analysis of etiologic factors in cerebral palsy with severe mental retardation. I. Analysis of gestational, parturitional and neonatal data.

We analyzed the gestational, parturitional, neonatal (GPN) histories of 281 severely mentally retarded patients with cerebral palsy to define the etiology or pathogenesis of cerebral palsy in each patient. No association between type of cerebral palsy and GPN histories was found except for an increase in spastic-athetoid patients in the breech delivery subgroup. Significant findings include: increased incidence of prematurity and postmaturity, small and large for-gestational age (GA) fetal size, a normal birthweight for GA distribution of patients with diabetic mothers, an excess of mothers greater than or equal to 35 and less than or equal to 20 years old, an increased immediately-previous sib interval of 2.59 years suggestive of an "infertility factor", an unremarkable GPN history in one third of the cases, in another one third GPN problems not usually associated with a high risk of CNS damage, and in one third gross complications which were probably responsible for the CP, including: an increased incidence of breech deliveries, twinning, prolonged and precipitous labor and placental complications; no increased association of athetosis and Rh incompatibility or incidence of toxemia was found. Disseminated intravascular coagulation due to prenatal death of a twin may have been the cause of brain damage in several patients.

Generalized gangliosidosis type II (juvenile GM1 gangliosidosis). A pathological, histochemical and ultrastructural study.

Pathological, histochemical and ultrastructural studies on 3 siblings with GM1 gangliosidosis type II are reported. These studies support a biochemical defect with profound deficiency of beta-galactosidases which results in widespread accumulation of the GM1 ganglioside and its asialo derivative in brain and to a lesser extent in viscera, as well as in storage of a keratan sulphate-like mucopolysaccharide. Striking valvular changes in the heart without myocardial involvement were seen in all cases. The histochemical and ultrastructural changes are similar to those seen in GM1 gangliosidosis type I, though less severe. Autosomal recessive inheritance without apparent ethnic predilection seems likely.

Studies of malformation syndromes in man XXXVI: the Pfeiffer syndrome, association with Kleeblattschädel and multiple visceral anomalies. Case report and review.

This paper reports sporadic occurrence of the Pfeiffer syndrome with Kleeblattschädel (KS) in a male infant who died at 6 months of pneumonia with signs of increased intracranial pressure and who was found to have hydrocephalus, polymicrogyria, cerebellar herniation, bicuspid aortic valve, a common mesentery, absence of lesser omentum, hypoplasia of gallbladder, a single umbilical artery, and multiple eye defects. This case is presumed to represent a new mutation: in other families the Pfeiffer syndrome has been dominantly inherited. The Pfeiffer syndrome is a form of acrocephalosyndactyly and impresses clinically as a mild form of the Apert syndrome. The Kleeblattschädel is an etiologically non-specific developmental field defect (DFC); about two fifths of 51 known cases have apparent thanatophoric dwarfism and about one fifth are probable or possible examples of the Pfeiffer syndrome. The KS-DFC has also been seen in the syndromes of Carpenter, Apert and Crouzon.

Heterogeneity of nonlethal severe short-limbed dwarfism.

The Grebe syndrome is a nonlethal form of severe short-limbed dwarfism which was previously called "achondrogenesis-Brazilian or Grebe type". We have studied three patients with severe short-limbed dwarfism originally considered to have this syndrome. On re-evaluation of their clinical and radiographic features, only one of them had the typical features of the Grebe chondrodysplasia, whereas the other two appear to have clearly distinct, previously unreported skeletal dysplasias. These patients illustrate the heterogeneity that exists among the nonlethal forms of severe short-limbed dwarfism.