David J. Aughton

Evaluation of mental retardation: Recommendations of a consensus conference

A Consensus Conference utilizing available literature and expert opinion sponsored by the American College of Medical Genetics in October 1995 evaluated the rational approach to the individual with mental retardation. Although no uniform protocol replaces individual clinician judgement, the consensus recommendations were as follows: 1. The individual with mental retardation, the family, and medical care providers benefit from a focused clinical and laboratory evaluation aimed at establishing causation and in providing counseling, prognosis, recurrence risks, and guidelines for management. 2. Essential elements of the evaluation include a three-generation pedigree: pre-, peri-, and post-natal history, complete physical examination focused on the presence of minor anomalies, neurologic examination, and assessment of the behavioral phenotype. 3. Selective laboratory testing should, in most patients, include a banded karyotype. Fragile X testing should be strongly considered in both males and females with unexplained mental retardation, especially in the presence of a positive family history, a consistent physical and behavioral phenotype and absence of major structural abnormalities. Metabolic testing should be initialed in the presence of suggestive clinical and physical findings. Neuroimaging should be considered in patients without a known diagnosis especially in the presence of neurologic symptoms, cranial contour abnormalities, microcephaly, or macrocephaly. In most situations MRI is the testing modality of choice. 4. Sequential evaluation of the patient, occasionally over several years, is often necessary for diagnosis, allowing for delineation of the physical and behavioral phenotype, a logical approach to ancillary testing and appropriate prognostic and reproductive counseling.

Further delineation of Kabuki syndrome in 48 well-defined new individuals†

Kabuki syndrome is a multiple congenital anomaly/mental retardation syndrome. This study of Kabuki syndrome had two objectives. The first was to further describe the syndrome features. In order to do so, clinical geneticists were asked to submit cases—providing clinical photographs and completing a phenotype questionnaire for individuals in whom they felt the diagnosis of Kabuki syndrome was secure. All submitted cases were reviewed by four diagnosticians familiar with Kabuki syndrome. The diagnosis was agreed upon in 48 previously unpublished individuals. Our data on these 48 individuals show that Kabuki syndrome variably affects the development and function of many organ systems. The second objective of the study was to explore possible etiological clues found in our data and from review of the literature. We discuss advanced paternal age, cytogenetic abnormalities, and familial cases, and explore syndromes with potentially informative overlapping features. We find support for a genetic etiology, with a probable autosomal dominant mode of inheritance, and speculate that there is involvement of the interferon regulatory factor 6 (IRF6) gene pathway. Very recently, a microduplication of 8p has been described in multiple affected individuals, the proportion of individuals with the duplication is yet to be determined.

Detection of deletions in de novo balanced chromosome rearrangements: Further evidence for their role in phenotypic abnormalities

Purpose: The purpose of this study was to test the hypothesis that deletions of varying sizes in de novo apparently balanced chromosome rearrangements are a significant cause of phenotypic abnormalities.Methods: A total of fifteen patients, with seemingly balanced de novo rearrangements by routine cytogenetic analysis but with phenotypic anomalies, were systematically analyzed. We characterized the breakpoints in these fifteen cases (two of which were ascertained prenatally), using a combination of high-resolution GTG-banding, fluorescence in situ hybridization (FISH) with bacterial artificial chromosomes (BACs), and data from the Human Genome Project.Results: Molecular cytogenetic characterization of the 15 patients revealed nine with deletions, ranging in size from 0.8 to 15.3 Mb, with the number of genes lost ranging from 15 to 70. In five of the other six cases, a known or putative gene(s) was potentially disrupted as a result of the chromosomal rearrangement. In the remaining case, no deletions were detected, and no known genes were apparently disrupted.Conclusions: Our study suggests that the use of molecular cytogenetic techniques is a highly effective way of systematically delineating chromosomal breakpoints, and that the presence of deletions of varying size is an important cause of phenotypic abnormalities in patients with “balanced” de novo rearrangements.

X-linked dominant chondrodysplasia punctata (CDPX2) caused by single gene mosaicism in a male

X‐linked dominant chondrodysplasia punctata (CDPX2; Happle syndrome) is recognized almost exclusively in females, who display mosaic and asymmetric features, presumed to arise secondary to random X‐inactivation. CDPX2 results from mutation of an X‐linked gene coding for sterol‐Δ8‐Δ7 isomerase (emopamil binding protein). We describe a boy with clinical features of CDPX2 (including those presumed to arise usually secondary to functional mosaicism in females). Biochemical and molecular studies demonstrate that he is mosaic for a sterol‐Δ8‐Δ7 isomerase gene mutation. He is the first reported example of single gene mosaicism giving rise to CDPX2 in a male.

Delineation of complex chromosomal rearrangements: evidence for increased complexity

There is an assumption of parsimony with regard to the number of chromosomes involved in rearrangements and to the number of breaks within those chromosomes. Highly complex chromosome rearrangements are thought to be relatively rare, with the risk for phenotypic abnormalities increasing as the number of chromosomes and chromosomal breaks involved in the rearrangement increases. We report here five cases of de novo complex chromosome rearrangements, each with a minimum of four breaks. Deletions were found in four cases, and in at least one case, a number of genes or potential genes might have been disrupted. This study highlights the importance of the detailed delineation of complex rearrangements, beginning with high-resolution chromosome analysis, and emphasizes the utility of fluorescence in situ hybridization in combination with the data available from the Human Genome Project as a means to delineate such rearrangements.

Clinical outcome of fetuses with sonographic diagnosis of isolated micrognathia.

OBJECTIVE To describe the clinical outcome of fetuses with the prenatal sonographic diagnosis of isolated micrognathia. METHODS A retrospective review of fetuses and infants with the prenatal diagnosis of isolated micrognathia for April 1990 to August 2001 was undertaken. Isolated micrognathia was considered if no other anatomic, growth, or amniotic fluid abnormalities were detected by a detailed ultrasound examination. Sources of outcome data included maternal and neonatal medical records, prenatal genetics records, and karyotype results. RESULTS Fifty-eight fetuses with the diagnosis of micrognathia were identified. Fifteen fetuses (26%) had isolated micrognathia by prenatal sonogram. After neonatal examination, 14 of 15 were found to have at least one additional abnormality. Eleven had a cleft of the soft and/or hard palate. Seven (54%) of 13 live-born neonates had mild to severe airway obstruction that required intervention. Four (31%) of 13 experienced feeding difficulties of varying duration. Follow-up data were available for 1 to 10 years. Eight (62%) of 13 children are reported to be doing well. Five (38%) of 13 children are reported to have mild to severe developmental delay. CONCLUSION If micrognathia is the only sonographic finding identified, physicians and families should be prepared for possible respiratory difficulty at delivery, the presence of a cleft palate, and/or developmental delay.

Biochemical and molecular analyses of infantile free sialic acid storage disease in North American children

The differential diagnosis of developmental delays and growth retardation in early childhood includes the allelic lysosomal sialic acid storage disorders, Salla disease and infantile free sialic acid storage disease (ISSD). These diseases, due to defective free sialic acid transport out of lysosomes, derive from mutations in the SLC17A5 gene coding for the protein sialin. We present two patients with clinical, biochemical, and molecular data indicative of lysosomal free sialic acid storage disorders. One patient, with a severe clinical course typical of ISSD, had 86‐fold elevated levels of fibroblast free sialic acid, with 62% in the lysosomal fraction. His SLC17A5 mutations include a 148‐bp deletion of exon 9, due to a G > A splice site mutation in position 1 of intron 9, and a 15‐bp deletion (del 801–815) in exon 6. Another patient, with “intermediate severe” Salla disease, had 9‐fold elevated levels of free sialic acid in cultured fibroblasts, of which 87% resided in the lysosomal fraction. This girl is compound heterozygous for the SLC17A5 mutation commonly found in Finnish Salla disease patients (R39C) and a 15‐bp deletion found in ISSD patients (del 801–815). These observations emphasize the importance of considering free sialic acid disorders in infants with developmental delays and growth retardation, regardless of whether they are of Finnish ancestry.

Diploid/tetraploid mosaicism in a liveborn infant demonstrable only in the bone marrow: case report and literature review

A case of a multiply malformed liveborn infant with mosaic tetraploidy on examination of bone marrow but not of peripheral lymphocytes or skin fibroblasts is presented. The literature is reviewed and the clinical features of our patient are compared with those of the nine previously reported cases. We suggest that when the clinical suspicion of polyploidy is strong, it may be prudent to expand the search for the abnormality to include cytogenetic studies of the bone marrow, despite a normal karyotype in peripheral blood.

Cholelithiasis in Infants with Down Syndrome Three Cases and Literature Review

Only four cases of cholelithiasis have been reported in patients with Down syndrome and none in Down syndrome infants. The cases of three Down syndrome infants (all males) with cholelithiasis are reported. Each exhibited different fetal complications, and in each, Down syndrome was diagnosed at birth. Gallstones apparently were congenital (a rarity) in one infant, since they were detected on the first day of life. Cholelithiasis was an incidental finding in another of the infants when, at 12 weeks old, he had renal ultrasonography because of a urinary tract infection. The third infant was 4 months old when sonographic studies revealed a gallstone. Despite the confirmation of cholelithiasis in all three infants, none has since had any signs or symptoms that suggest the need for intervention. Cholelithiasis is probably more common in Down syndrome infants than has been supposed, but whether Down syndrome infants with gastrointestinal (GI) malformations are more likely to have gallstones than are children with similar GI malformations but with normal karyotypes is unknown.

Dizygotic twins concordant for truncus arteriosus.

Persistent truncus arteriosus (TA) is an uncommon congenital cardiovascular malformation, which comprises between 0.4% and 4% of all congenital heart defects. Occurrence of TA in siblings has been reported infrequently. Twins concordant for isolated TA appear to have been reported only once previously. In this paper, we describe dizygotic twin females who were concordant for isolated TA.