Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance.

Diagnostic exome sequencing (DES) has aided delineation of the phenotypic spectrum of rare genetic etiologies of intellectual disability (ID). A SET domain containing 5 gene (SETD5) phenotype of ID and dysmorphic features has been previously described in relation to patients with 3p25.3 deletions and in a few individuals with de novo sequence alterations. Herein, we present additional patients with pathogenic SETD5 sequence alterations. The majority of patients in this cohort and previously reported have developmental delay, behavioral/psychiatric issues, and variable hand and skeletal abnormalities. We also present an apparently unaffected carrier mother of an affected individual and a carrier mother with normal intelligence and affected twin sons. We suggest that the phenotype of SETD5 is more complex and variable than previously presented. Therefore, many features and presentations need to be considered when evaluating a patient for SETD5 alterations through DES.

Fumaric aciduria: clinical and imaging features.

Fumaric aciduria (fumaric acidemia, fumarase deficiency) is a rare inborn error of metabolism caused by deficient activity of fumarate hydratase, one of the constituent enzymes of the Krebs tricarboxylic acid cycle. We describe the clinical and imaging features of this disease arising from a consanguineous pedigree in 8 patients in the southwestern United States. Thirteen patients have been previously described in the medical literature. Our patients presented with an early infantile encephalopathy with profound developmental retardation and hypotonia, and most experienced seizures. Previously unreported characteristics described here include structural brain malformations, dysmorphic facial features, and neonatal polycythemia. Magnetic resonance imaging showed multiple abnormalities, including diffuse polymicrogyria, decreased cerebral white matter, large ventricles, and open opercula. Fumaric aciduria should be included in the differential diagnosis of inborn errors of metabolism that cause cerebral malformations and dysmorphic features. The possibility that inborn errors of energy metabolism may cause structural malformations deserves increased recognition.

True hermaphroditism with partial duplication of chromosome 22 and without SRY.

We present the case of a patient with true hermaphroditism and partial duplication of chromosome 22. Cytogenetic evaluation showed no evidence of a Y chromosome in blood, skin, or gonadal tissue. Additional investigations using molecular probes showed no evidence of SRY. We conclude that there are genes on chromosome 22 that are involved in sex determination.

Different mutations in the same codon of the proteolipid protein gene, PLP, may help in correlating genotype with phenotype in Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2).

Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2) comprises a spectrum of diseases that range from severe to quite mild. The reasons for the variation in severity are not obvious, but suggested explanations include the extent of disruption of the transmembrane portion of the proteolipid protein caused by certain amino acid substitutions and interference with the trafficking of the PLP molecule in oligodendrocytes. Four codons in which substitution of more than one amino acid has occurred are available for examination of clinical and potential structural manifestations: Valine165 to either glutamate or glycine, leucine 045 to either proline or arginine, aspartate 202 to asparagine or histidine, and leucine 223 to isoleucine or proline. Three of these mutations, Val165Gly, Leu045Pro, and Leu223Ile have not been described previously in humans. The altered amino acids appear in the A-B loop, C helix, and C-D loop, respectively. We describe clinically patients with the mutations T494G (Val165Gly), T134C (Leu045Pro), and C667A (Leu223Ile). We discuss also the previously reported mutations Asp202Asn and Asp202His. We have calculated the changes in hydrophobicity of short sequences surrounding some of these amino acids and compared the probable results of the changes in transmembrane structure of the proteolipid protein for the various mutations with the clinical data available on the patients. While the Val165Glu mutation, which is expected to produce disruption of a transmembrane loop of the protein, produces more severe disease than does Val165Gly, no particular correlation with hydrophobicity is found for the other mutations. As these are not in transmembrane domains, other factors such as intracellular transport or interaction between protein chains during myelin formation are probably at work.

Opitz syndrome is genetically heterogeneous, with one locus on Xp22, and a second locus on 22q11.2.

Opitz syndrome (OS, McKusick 145410) is a well described genetic syndrome affecting multiple organ systems whose cardinal manifestations include widely spaced eyes and hypospadias (Fig. 1). It was first reported as two separate entities, BBB syndrome, and G syndrome. However, subsequent reports of families in which the BBB and G syndrome segregated within a single kindred suggested that they were a single clinical entity. Although the original pedigrees were consistent with X-linked and autosomal dominant inheritance, male-to-male transmission in subsequent reports suggested that OS was inherited as an autosomal dominant trait. Here we report that OS is a heterogeneous disorder, with an X-linked and an autosomal locus. Three families were linked to DXS987 in Xp22, with a lod score of 3.53 at zero recombination. Five families were linked to D22S345 from chromosome 22q11.2, with a lod score of 3.53 at zero recombination. This represents the first classic multiple congenital anomaly syndrome with an X-linked and an autosomal form.

Dominant inheritance of Wiedemann-Beckwith syndrome: further evidence for transmission of "unstable premutation" through carrier women.

We report on a 4-generation family in which the Wiedemann Beckwith syndrome (WBS) was transmitted as an autosomal dominant trait. The condition occurred in sibs born to carrier women and in children born to affected mothers. Presumptive carrier women were examined for microsigns of WBS in an attempt to determine whether extreme variability of the disorder, rather than an unaffected carrier state, was present. No minor stigmata of the WBS could be found in the presumptive carriers. Our study supports a previous hypothesis that in some families the WBS can be transmitted in a 2-step process involving first an unstable premutation and then a "telomutation." Because only females appear to be transmitters of the telomutation, an ovum-mediated sex-associated factor may be involved in the process of telomutation.

Familial Wiedemann-Beckwith syndrome and a second Wilms tumor locus both map to 11p15.5.

Wilms tumor of the kidney occurs with increased frequency in association with two clinically and cytogenetically distinct congenital syndromes, the Wiedemann-Beckwith syndrome (WBS) and the triad of aniridia, genitourinary anomalies, and mental retardation (WAGR). Constitutional deletions in the latter situation and similar alterations in sporadic Wilms tumors have implicated the chromosomal 11p13 region in neoplastic development. In contrast, some sporadic cases of WBS have been reported to have a constitutional duplication of chromosome 11p15. In order to resolve this seeming paradox, we have analyzed a family segregating WBS for linkage to DNA markers mapped to chromosome 11p. Consonant with the cytogenetic alterations in sporadic WBS cases, we obtained evidence for tight linkage of the mutation causing the syndrome to markers located at 11p15.5. Also consistent with this localization, we identified a subset of Wilms tumors, not associated with WBS, which have attained somatic homozygosity through mitotic recombination, with the smallest shared region of overlap being distal to the beta-globin complex at 11p15.5. These data provide evidence that familial WBS likely results from a defect at the same genetic locus as does its sporadic counterpart. Further, the data suggest there is another locus, distinct from that involved in the WAGR syndrome, which plays a role in the association of Wilms tumor with WBS.

In utero central nervous system damage in pyruvate dehydrogenase deficiency.

Pyruvate dehydrogenase deficiency is among the most common causes of congenital lactic acidosis. We describe siblings with congenital lactic acidosis due to a deficiency of pyruvate dehydrogenase complex. The findings of computed tomography and pathologic studies suggest that central nervous system damage had occurred in utero. These observations have implications for treatment and outcome in patients with enzymatic defects causing congenital lactic acidosis.

Congenital susceptibility to NIDDM. Role of intrauterine environment.

Non-insulin-dependent diabetes mellitus (NIDDM) during pregnancy in Pima Indian women results in offspring who have a higher prevalence of NIDDM (45%) at age 20-24 yr than in offspring of nondiabetic women (1.4%) or offspring of prediabetic women (8.6%), i.e., women who developed diabetes only after the pregnancy. These differences persist after taking into account paternal diabetes, age at onset of diabetes in the parents, and the offspring's weight relative to height. The findings suggest that the intrauterine environment is an important determinant of the development of diabetes and that its effect is in addition to effects of genetic factors.

Dyssegmental dysplasias: clinical, radiographic, and morphologic evidence of heterogeneity.

The dyssegmental dysplasias are lethal forms of neonatal short-limbed dwarfism in which vertebral segmentation defects and short, thick, bowed long bones are the prominent radiographic features. Clinically, unusual facies, short neck, narrow thorax, cleft palate, and reduced joint mobility are commonly seen. To date, 18 cases of dyssegmental dysplasia have been reported. Reports of three pairs of affected sibs suggest autosomal recessive inheritance. We have studied eight additional cases of dyssegmental dysplasia, including one pair of affected sibs. Clinical, radiographic, and histologic examination of these new cases and review of the literature demonstrates the presence of at least two distinct forms of dyssegmental dysplasia. The milder form, "dyssegmental dysplasia, type Rolland-Desbuquois," is characterized clinically by frequent survival beyond the newborn period and by distinct radiographic changes resembling Kniest dysplasia. The severe form, "dyssegmental dysplasia, type Silverman-Handmarker," is characterized by stillbirth or death within the first few days of life and by distinct and more severe radiographic changes. In addition, we have demonstrated chondro-osseous morphologic differences between the two disorders by light and electron microscopy. We conclude that there are at least two forms of dyssegmental dysplasia, each autosomal recessive, which can be delineated on clinical, radiographic and morphologic grounds.

Obesity in offspring of diabetic Pima Indian women despite normal birth weight.

The relationships of birth weight and maternal diabetes to the development of obesity were examined at 5-19 yr of age in the offspring of Pima Indian women. At each age, offspring of diabetic women, even those who were of normal birth weight, had a higher mean weight relative to height than offspring of nondiabetic and prediabetic women. Birth weight was predictive of relative weight in 5- to 9- and 10- to 14-yr-old offspring of nondiabetic women but not in the oldest group. In contrast, for offspring of prediabetic and diabetic women, birth weight was not predictive of subsequent obesity at any age studied. Offspring of diabetic women were heavier than offspring of nondiabetic and prediabetic women regardless of birth weight. Thus, maternal diabetes was important in predicting body size in the offspring even after accounting for the effects of the birth weight and maternal body size.

Mosaicism for ring and isopseudodicentric chromosome 13.

A three-month-old female infant with multiple malformations was noted on routine cytogenetic evaluation to have dicentric/ring mosaicism of chromosome 13. Additional cytogenic investigations indicated that the dicentric could be further defined as an isopseudodicentric. Unlike the double chromosome break in the more common ring 13 cases, the mechanism for isopseudodicentric/ring generation is attributed to chromosome and chromatid breaks with subsequent bridging, breaking and fusion. The phenotypic features are those of a combined duplication-deficiency of chromosome 13.

Gestational diabetes mellitus and impaired glucose tolerance during pregnancy. Long-term effects on obesity and glucose tolerance in the offspring.

The effects of disturbances in carbohydrate metabolism during gestation were studied in the offspring of 1049 Pima Indian women who had no previous diagnosis of diabetes. Rates of fetal and maternal complications of pregnancy among women with diabetes first diagnosed during the pregnancy were similar to those among women in whom diabetes was recognized before gestation. Offspring, aged 5-19 yr, of women with abnormal glucose tolerance during pregnancy had a higher mean percent desirable weight and a higher mean postchallenge plasma glucose concentration than did offspring of women with normal glucose tolerance. Percent desirable weight and glucose concentration, however, were both lower than found in offspring of women with diabetes diagnosed before the pregnancy. Thus, metabolic events during pregnancy, as indicated by the detection of abnormal glucose tolerance during gestation, appear to have long-term effects on obesity and glucose tolerance in the offspring.

Macrocephaly with hamartomas: Bannayan-Zonana syndrome.

Familial macrocephaly with mesodermal hamartomas is described as a distinct syndrome in nine individuals from four families. Constant manifestations include symmetrical macrocephaly without ventricular enlargement, mild neurological dysfunction, and postnatal growth deceleration. Speech and motor delays observed in all the children were usually well compensated by adulthood. Two children had mild mental retardation and seizures which may have been related to intracerebral hemorrhage in one. Mesodermal hamartomas were present in affected persons from all four families, with 60% of individuals manifesting only discrete lipomas and hemangiomas. More serious tumors, including intracerebral hemangiomas, hemangiomatous involvement of the bone, and aggressive lipomas occurred in 40%. Other findings that make it possible to delineate a recognizable syndrome include down-slanting palpebral fissures (66%), a high palate (67%), joint hyperextensibility (55%), pectus excavatum (22%), strabismus or amblyopia (33%), and prolonged drooling (44%). The Bannayan-Zonana syndrome is an autosomal-dominant trait with male predominance of affected individuals.

Familial porencephaly.

We studied familial porencephaly consistent with autosomal dominant or recessive inheritance in two families. The pathogenesis of the encephaloclastic and schizencephalic types was reviewed. Use of noninvasive neuroradiologic techniques, including computed tomography and ultrasonography, may help to delineate groups of children with smaller porencephalic cysts and to define further familial or genetic forms of this process.

Absence of intrauterine infection following Ross River virus infection during pregnancy.

An epidemic of Ross River virus (RRV) infection occurred in the Cook Islands in early 1980, and infected about 70% of the adult population of Rarotonga, the most populous island of the group. In July 1981, 80 mothers were identified as having been in the first trimester of pregnancy during the outbreak. Fifty-two of the at-risk mothers along with 63 of the offspring were ultimately examined. Of these 52 mothers, 39 (75%) were found to have serological evidence of RRV infection. Of the 63 infants located, 52 were examined serologically. None of the infants examined had serological evidence of RRV infection. There was no difference in age, size, or malformation rate in the offspring of the serologically positive or serologically negative mothers. These studies do not support an earlier report that RRV causes intrauterine infection.

Excessive obesity in offspring of Pima Indian women with diabetes during pregnancy.

We studied the relation in Pima Indians between obesity in children and diabetes during pregnancy in their mothers. Sixty-eight children of 49 women who had had diabetes during pregnancy had a higher prevalence of obesity than 541 children of 134 women who subsequently had diabetes (prediabetics) or than 1326 children of 446 women who remained nondiabetic. At 15 to 19 years of age, 58 per cent of the offspring of diabetics weighed 140 per cent or more of their desirable weight, as compared with 17 per cent of the offspring of nondiabetics and 25 per cent of those of prediabetics (P less than 0.001). Obesity in the offspring was directly related to maternal diabetes, since the association was not substantially confounded by maternal obesity. The findings strongly suggest that the prenatal environment of the offspring of diabetic women results in the development of obesity in childhood and early adulthood.

Metachromatic leukodystrophy without arylsulfatase A deficiency.

Two siblings of consanguinous parents were noted to have a neurologic syndrome marked by developmental delay, regression of psychomotor performance, marked spasticity and progressive central nervous system degeneration. Markedly delayed nerve conduction times and a sural nerve biopsy which demonstrated changes typical of metachromatic leukodystrophy (MLD) were evident. Impairment of sulfated glycolipid metabolism was documented by analysis of glycospingolipid in urinary sediment. In spite of these findings, activities of arylsulfatase A and cerebroside sulfatidase in white blood cells and cultured skin fibroblasts were near normal. However, when intact growing fibroblasts were loaded with 35SO4-sulfatide a clear defect in sulfatide cleavage, comparable to that seen in MLD patients, was observed. Thus, these patients represent a new form of sulfatide storage disease -- MLD characterized by intact enzyme activity in cell homogenates but defective sulfolipid metabolism in vivo and in intact fibroblasts.