Elisabeth G. Kaveggia

Studies of malformation syndromes of man XXXIII: The FG syndrome. An X-linked recessive syndrome of multiple congenital anomalies and mental retardation

Three brothers and two of their male first cousins were affected with a previously apparently undefined multiple congenital anomaly, mental retardation syndrome which was designated the FG syndrome and which consists of variable growth problems with a disproportionately large head, characteristic appearance and minor anomalies, imperforate anus, mild to severe mental retardation and congenital hypotonia; pyloric stenosis, hypoplastic left heart, generalized dilatation of the urinary tract, cutaneous syndactyly of third and fourth fingers, and severe craniosynostosis were seen each in 1 patient. Partial agenesis of the corpus callosum seen in 1 patient is suspected in another on the basis of EEG abnormalities. 1 boy died neonatally with congenital heart disease, and 2 others of pneumonia at 20 and 23 months. The FG syndrome is an X-linked recessive condition; heterozygotes appear grossly normal.

Analysis of etiologic factors in cerebral palsy with severe mental retardation

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 ≥35 and ≤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.

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.

Autosomal recessive syndrome of pseudogliomatous 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 oorpus 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 descendants. The condition has been designated craniofacial dyssynostosis.

The N syndrome, a “new” multiple congenital anomaly‐mental retardation syndrome:Studies of malformation syndromes in man XXVII

Two brothers are reported with a previously undescribed multiple congenital anomaly/ mental retardation (MCA/MR) syndrome consisting of characteristic appearance, severe mental and growth retardation with visual impairment and deafness, dolichocephaly, hypotelorism, a “scalloped”, laterally overlapping upper eyelid, large corneas, abnormal auricles, dental dysplasia, generalized skeletal dysplasia (which includes overtubulation of the long bones with the distal long bones being relatively shorter than the proximal long bones), high fingerprint ridge count, cryptorchidism, hypospadias and spasticity. They have an apparently normal karyotype. The older of the two, now 13 years old, is receiving total institutional care. The younger died of lymphosarcoma at the age of 5 8/12 years, and at autopsy was found to have markedly abnormal cerebral cortical cyto‐architecture. These cases are reported as a “provisionally private syndrome”, but with the possibility in mind that further studies may prove the N syndrome to be either an autosomal recessive or an X‐linked recessive trait.

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 empriric 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 persons 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: (unrecognized) environmental damage and/or maternal/fetal interaction; unrecognized chromosome abnormalities; the homozygous state of several different autosomal recessive genes; X-linked recessive mutations; autosomal dominant new mutations; and multifactorial 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.

Studies of malformation syndromes of man XXXVIII: the BD syndrome

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.

The N-syndrome. A “new” multiple congenital anomaly-mental retardation syndrome

Two brothers are reported with a previously undescribed multiple congenital anomaly/ mental retardation (MCNMR) syndrome consisting of characteristic appearance, severe mental and growth retardation with visual impairment and deafness, dolichocephaly, hypotelorism, a “scalloped”, laterally overlapping upper eyelid, large corneas, abnormal auricles, dental dysplasia, generalized skeletal dysplasia (which includes overtubulation of the long bones with the distal long bones being relatively shorter than the proximal long bones), high fingerprint ridge count, cryptorchidism, hypospadias and spasticity. They have an apparently normal karyotype. The older of the two, now 13 years old, is receiving total institutional care. The younger died of lymphosarcoma at the age of 5 8/12 years, and at autopsy was found to have markedly abnormal cerebral cortical cyto-architecture. These cases are reported as a “provisionally private syndrome”, but with the possibility in mind that further studies may prove the N syndrome to be either an autosomal recessive or an X-linked recessive trait.