Mother to son transmission of del(1) (q42.1q42.3).

Familial transmission of cytogenetically visible autosome deletions is rare in humans. We describe here a case of mother to son transmission of an interstitial deletion of the distal long arm of chromosome one, breakpoints q42.1q42.3. This is the smallest described deletion of this region to date.

GeneClinics: a hybrid text/data electronic publishing model using XML applied to clinical genetic testing.

GeneClinics is an online genetic information resource consisting of descriptions of specific inherited disorders ("disease profiles") as well as information on the role of genetic testing in the diagnosis, management, and genetic counseling of patients with these inherited conditions. GeneClinics is intended to promote the use of genetic services in medical care and personal decision making by providing health care practitioners and patients with information on genetic testing for specific inherited disorders. GeneClinics is implemented as an object-oriented database containing a combination of data and semistructured text that is rendered as HTML for publishing a given "disease profile" on the Web. Content is acquired from authors via templates, converted to an XML document reflecting the underlying database schema (with tagging of embedded data), and then loaded into the database and subjected to peer review. The initial implementation of a production system and the first phase of population of the GeneClinics database content are complete. Further expansion of the content to cover more disease, significant scaling up of rate of content creation, and evaluation redesign are under way. The ultimate goal is to have an entry in GeneClinics for each entry in the GeneTests directory of medical genetics laboratories-that is, for each disease for which clinical genetic testing is available.

Two novel fibrillin-2 mutations in congenital contractural arachnodactyly.

Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder, comprising marfanoid habitus, flexion contractures, severe kyphoscoliosis, abnormal pinnae, and muscular hypoplasia. It is now known that mutations in the gene encoding fibrillin-2 cause CCA. Interestingly, mutations described to date cluster in the fibrillin-2 region homologous to the so-called neonatal Marfan syndrome region of fibrillin-1. Thus, it has been hypothesized that the relative infrequency of CCA compared with the Marfan syndrome is due to the limited region of the gene targeted for mutations. In support of the above hypothesis, we report here the finding of two additional FBN2 mutations in CCA, C1141F (exon 26) and C1252W (exon 29). In addition, a new 3' UTR polymorphism is also described.

Spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL): presentation in two unrelated patients in the United States.

This is a report of two North American patients with spondyloepimetaphyseal dysplasia with joint laxity, an uncommon autosomal recessive skeletal dysplasia rarely reported outside of South Africa. Patients with SEMDJL have vertebral abnormalities and ligamentous laxity that results in spinal misalignment and progressive severe kyphoscoliosis, thoracic asymmetry, and respiratory compromise resulting in early death. Nonaxial skeletal involvement includes elbow deformities with radial head dislocation, dislocated hips, clubbed feet, and tapered fingers with spatulate distal phalanges. Many affected children have an oval face, flat midface, prominent eyes with blue sclerae, and a long philtrum. Palatal abnormalities and congenital heart disease are also observed. Diagnosis in infancy may be difficult because many of the typical findings are not apparent early and only evolve over time. We review the physical and radiographic findings in two unrelated patients with this disorder in order to increase the awareness of this disorder, particularly for clinicians outside of South Africa.

Autosomal dominant inheritance of Barber-Say syndrome.

We report on a mother-to-son transmission of the Barber-Say syndrome, a finding that strongly supports dominant inheritance of this rare disorder. The characteristic facial changes, small ears, hirsutism, and redundant skin of our patients are consistent with the findings of five reported cases. The mother also had cleft palate and mild conductive hearing loss. Her son had a shawl scrotum, primary hypospadias, and mild hearing loss by report. The inheritance of this rare disorder has not been established. The parent-to-child transmission in this family suggests X-linked or autosomal dominant inheritance. The parents of the patient reported by Santana et al. [1993: Am. J. Med. Genet. 47:20-23] were consanguineous, suggesting autosomal recessive inheritance in other cases.

Phenotypic spectrum and management issues in Kabuki syndrome.

OBJECTIVE: To report the phenotypic spectrum and management issues of children with Kabuki syndrome (Niikawa-Kuroki syndrome) from North America. DESIGN: A case series of children (n = 18) with clinical findings of Kabuki syndrome. SETTING: Medical genetics clinics in Washington, Alaska, and Arizona. RESULTS: Most patients had postnatal growth retardation, and all had developmental delay and hypotonia. Feeding difficulties, with or without cleft palate, were common; 5 patients required gastrostomy tube placement. Developmental quotients/IQs in all but 2 were 60 or less. Seizures were seen in less than half of the patients, but ophthalmologic and otologic problems were common, particularly recurrent otitis media. Congenital heart defects were present in 7 (39%); 3 patients underwent repair of coarctation of the aorta. Other features included urinary tract anomalies, malabsorption, joint hypermobility and dislocation, congenital hypothyroidism, idiopathic thrombocytopenic purpura, and in one patient, autoimmune hemolytic anemia and hypogammaglobulinemia. All patients had negative family histories for Kabuki syndrome. CONCLUSIONS: Kabuki syndrome is a mental retardation-malformation syndrome affecting multiple organ systems, with a broad spectrum of neuromuscular dysfunction and mental ability. Given that 18 ethnically diverse patients were identified from 2 genetics programs, it appears that this syndrome is more common in North American non-Japanese patients than previously appreciated.

DAX1 mutations map to putative structural domains in a deduced three-dimensional model.

The DAX1 protein is an orphan nuclear hormone receptor based on sequence similarity in the putative ligand-binding domain (LBD). DAX1 mutations result in X-linked adrenal hypoplasia congenita (AHC). Our objective was to identify DAX1 mutations in a series of families, to determine the types of mutations resulting in AHC and to locate single-amino-acid changes in a DAX1 structural model. The 14 new mutations identified among our 17 families with AHC brought the total number of families with AHC to 48 and the number of reported mutations to 42; 1 family showed gonadal mosaicism. These mutations included 23 frameshift, 12 nonsense, and six missense mutations and one single-codon deletion. We mapped the seven single-amino-acid changes to a homology model constructed by use of the three-dimensional crystal structures of the thyroid-hormone receptor and retinoid X receptor alpha. All single-amino-acid changes mapped to the C-terminal half of the DAX1 protein, in the conserved hydrophobic core of the putative LBD, and none affected residues expected to interact directly with a ligand. We conclude that most genetic alterations in DAX1 are frameshift or nonsense mutations and speculate that the codon deletion and missense mutations give insight into the structure and function of DAX1.

Mutation analysis of UBE3A in Angelman syndrome patients.

Angelman syndrome (AS) is caused by chromosome 15q11-q13 deletions of maternal origin, by paternal uniparental disomy (UPD) 15, by imprinting defects, and by mutations in the UBE3A gene. UBE3A encodes a ubiquitin-protein ligase and shows brain-specific imprinting. Here we describe UBE3A coding-region mutations detected by SSCP analysis in 13 AS individuals or families. Two identical de novo 5-bp duplications in exon 16 were found. Among the other 11 unique mutations, 8 were small deletions or insertions predicted to cause frameshifts, 1 was a mutation to a stop codon, 1 was a missense mutation, and 1 was predicted to cause insertion of an isoleucine in the hect domain of the UBE3A protein, which functions in E2 binding and ubiquitin transfer. Eight of the cases were familial, and five were sporadic. In two familial cases and one sporadic case, mosaicism for UBE3A mutations was detected: in the mother of three AS sons, in the maternal grandfather of two AS first cousins, and in the mother of an AS daughter. The frequencies with which we detected mutations were 5 (14%) of 35 in sporadic cases and 8 (80%) of 10 in familial cases.

CHARGE association: an update and review for the primary pediatrician.

CHARGE association is a nonrandom pattern of congenital anomalies that occurs together more frequently than one would expect on the basis of chance. This common multiple anomaly condition has an estimated prevalence of 1:10,000. The number of children diagnosed with CHARGE association is increasing, owing presumably to greater awareness of this condition and advances in the care of complex, chronically ill children, resulting in improved survival and outcome. This review of CHARGE association presents diagnostic criteria that may define a concise, recognizable syndrome with a single pathogenetic basis. This review also summarizes our current understanding of the management for this complex and chronic multiple congenital anomaly condition and discusses the pathogenetic basis for this condition.

Brachydactyly type A1 with abnormal menisci and scoliosis in three generations.

We report a three-generation family in which four members had brachydactyly type A1, degenerative arthritis of the knee as a complication of abnormal menisci, and variable scoliosis. Nine of the 15 individuals in the two generations preceding the proband had brachydactyly. Three of these nine had degenerative arthritis of the knee including the proband's father who had meniscal degeneration with tears. One other had radiologically confirmed discoid menisci. Of those with brachydactyly, five also had scoliosis. Although autosomal dominant inheritance of brachydactyly A1 and discoid menisci have been reported separately, cosegregation of these features in one family has not previously been described and seems to comprise a unique autosomal dominant condition. The combination of brachydactyly, meniscal abnormalities including discoid meniscus, and scoliosis suggests that this disorder represents a new osteochondrodysplasia syndrome.

Development of the Critical Elements of Genetic Evaluation and Genetic Counseling for Genetic Professionals and Perinatologists in Washington State.

We present a method for the development of consensus documents describing the components of genetic evaluation and genetic counseling for various diagnoses. These documents were developed to encourage consistency among genetic professionals in Washington State. Other possible uses of these documents are to provide information regarding genetic evaluations for health care practitioners and payers, and to assist in quality assurance and genetic training programs. A working group of six genetic professionals developed two templates for the "critical elements of genetic evaluation and genetic counseling," for clinical (nonprenatal) and prenatal patients. The working group then completed prototype templates for several specific genetic disorders. The templates and prototypes were sent to interested genetic professionals and perinatologists who submitted a total of 76 draft "critical elements" (CE's) to the working group. At two statewide meetings, participating practitioners modified and unanimously approved the CE templates, then unanimously approved the 21 draft CEs that had been finalized in small group discussions. Approved CE's were distributed to genetic professionals and perinatologists within the state.

Creation and maintenance of Helix, a Web based database of medical genetics laboratories, to serve the needs of the genetics community.

Helix (healthlinks.washington.edu/helix) is a web accessible database that serves as the main U.S. directory of laboratories offering genetic testing. The database was designed to address the previously unmet need for a centralized, continuously updated source of information about clinical and research genetic testing to keep pace with the rapid rate of gene discovery resulting from the Human Genome Project. The Helix project began in 1992 at the University of Washington and Children's Hospital and Regional Medical Center. It has evolved from a single user stand alone relational database to a fully Web enabled database queried and maintained via the web and linked to other web accessible genomic databases. As of February, 1998 it lists more than 500 diseases and 290 laboratories, with over 5,200 registered users making approximately 250 queries/day (90% via the Internet). We describe the iterative design, implementation, population and assessment of the database over a six year period.

Digital anomalies, microcephaly, and normal intelligence: new syndrome or Feingold syndrome?

We present four patients-two boys and their mother and an unrelated girl-with microcephaly, normal intelligence, and digital abnormalities. The hand abnormalities are characterized by brachydactyly with radial clinodactyly of the fourth and fifth fingers, ulnar clinodactyly of the second fingers, and an increased space between the second and third fingers associated with an abnormal palmar crease that extends to the ulnar border. The foot abnormalities include short toes with syndactyly of the fourth and fifth toes. The mother has normal intelligence, and her sons and the unrelated girl have normal development. Although similar digital abnormalities, microcephaly, and normal intelligence were described by Feingold in patients with gastrointestinal atresia, we think that our patients' findings represent a different condition. The most likely mode of inheritance is autosomal dominant. The clinical recognition of this syndrome will allow for appropriate genetic counseling as well as provision of information on natural history, i.e., normal intelligence.

Facio-oculo-acoustico-renal (FOAR) syndrome: case report and review.

We report on an 11-year-old boy with distinct facial anomalies, iris coloboma, iris hypoplasia, cataract, high myopia, retinal detachment, moderate sensorineural hearing loss, and proteinuria. He appears to have the facio-oculo-acoustico-renal (FOAR) syndrome, a rare familial disorder reported only 4 times previously. In contrast to the other patients, he has normal intellect.