Andrew K. Poznanski

The Clinical and Genetic Spectrum of the Holt-Oram Syndrome (Heart-Hand Syndrome)

BACKGROUND The Holt-Oram syndrome is an autosomal dominant condition characterized by skeletal abnormalities that are frequently accompanied by congenital cardiac defects. The cause of these disparate clinical features is unknown. To identify the chromosomal location of the Holt-Oram syndrome gene, we performed clinical and genetic studies. METHODS Two large families with the Holt-Oram syndrome were evaluated by radiography of the hands, electrocardiography, and transthoracic echocardiography. Genetic-linkage analyses were performed with polymorphic DNA loci dispersed throughout the genome to identify a locus that was inherited with the Holt-Oram syndrome in family members. RESULTS A total of 19 members of Family A had Holt-Oram syndrome with mild-to-moderate skeletal deformities, including triphalangeal thumbs and carpal-bone dysmorphism. All affected members of Family A had moderate-to-severe congenital cardiac abnormalities, such as ventricular or atrial septal defects or atrioventricular-canal defects. Eighteen members of a second kindred (Family B) had Holt-Oram syndrome with moderate-to-severe skeletal deformities, including phocomelia. Twelve of the affected members had no cardiac defects; six had only atrial septal defects. Genetic analyses demonstrated linkage of the disease in each family to polymorphic loci on the long arm of chromosome 12 (combined multipoint lod score, 16.8). These data suggest odds greater than 10(16):1 that the genetic defect for Holt-Oram syndrome is present on the long arm of chromosome 12 (12q2). CONCLUSIONS Mutations in a gene on chromosome 12q2 can produce a wide range of disease phenotypes characteristic of the Holt-Oram syndrome. This gene has an important role in both skeletal and cardiac development.

Metacarpophalangeal Pattern Profiles in the Evaluation of Skeletal Malformations

Metacarpophalangeal pattern profile analysis is a graphic method of depicting lengthening and shortening of the tubular bones of the hand and their relationship to one another. The lengths of the tubular bones are plotted in terms of standard deviation units. These data are derived from simple measurements from hand radiographs and related to age and sex norms. Comparison of these patterns is a more sensitive index for detecting similarity of hand radiographs than is simple inspection of the radiograph. Since many congenital malformations have characteristic metacarpophalangeal pattern profiles, the method can be useful in the diagnosis and definition of these conditions.

Metacarpophalangeal Length in the Evaluation of Skeletal Malformation

Standards are presented for metacarpal and phalangeal lengths by row and ray (or digit) for 19 tubular bones of the hand, for both sexes separately from infancy through adulthood along with measurements of variability. Information on the 684 means and standard deviations is presented in relation to the relative size of bones within a row, and a comparison of the variabilities of males and females is discussed. The use of bone lengths in hand syndromes of chromosomal, genetic, and endocrine origin are described.

Bone Measurement in the Differential Diagnosis of Osteopenia and Osteoporosis

Increased or decreased bone formation and bone loss, resulting in the clinical appearance of deficient bone or reduced bone tissue, may be indicated by measurements of (a) total tubular bone width, (b) medullary cavity width, (c) cortical thickness, (d) cortical area, and (e) per cent cortical area. Such measurements are more useful than the general terms “osteopenia” and “osteoporosis.”

Arthropathy of neonatal onset multisystem inflammatory disease (NOMID/CINCA)

BackgroundNeonatal onset multisystem inflammatory disease (NOMID), an autoinflammatory disease, is characterized by fever, chronic urticarial rash, CNS manifestations, and arthropathy. Approximately 50% of patients with NOMID have de novo missense mutations in CIAS1, which is associated with modulation of the IL-1b and apoptotic pathways. Approximately 60% of NOMID patients have prominent arthropathy, most commonly involving the knees, the cause of which remains poorly understood.ObjectiveTo more fully describe the findings of NOMID arthropathy on MRI and radiography and to provide a better understanding of the origin of the bony lesions.Materials and methodsWe imaged 20 patients with NOMID to further investigate NOMID-associated bony lesions.ResultsBony abnormalities were seen in the knees of 11/20 patients. The knee findings included enlarged, deformed femora and patellae in all and tibiae in the majority, without evidence of synovitis. Some patients had other joint involvement. Most had short stature and valgus or varus knee deformities. No association was noted between bony abnormalities and CIAS1 mutations. The abnormalities appeared to be the result of a mass-producing process. The resulting heterogeneously calcified masses appeared to originate in the physis and deformed the adjacent metaphysis and epiphysis.ConclusionThese findings suggest that the arthropathy of NOMID is the result of abnormal endochondral bone growth. Further investigation is needed to determine whether this deformity is triggered by inflammation early in development or by CIAS1 mutations causing abnormal chondrocyte apoptosis.

Skeletal manifestations of the Holt-Oram syndrome.

The Holt-Oram syndrome is an autosomal dominant trait consisting of characteristic upper-limb abnormalities and congenital heart disease. Shoulder abnormalities are typical. Carpal abnormalities are distinctive and may be present even when the digits are normal. The most striking carpal abnormality is the presence of extra carpal bones. Carpal anomalies appear to be more specific for Holt-Oram syndrome than thumb changes. Prominent laterally and posteriorly protuberant medial epicondyles of the humeri are seen in many patients. The lower extremities are normal.

Genetic Heterogeneity of Heart-Hand Syndromes

BACKGROUND Heart-hand syndromes compose a class of combined congenital cardiac and limb deformities. The proto-typical heart-hand disorder is Holt-Oram syndrome, which is characterized by cardiac septation defects and radial ray limb deformity. We have recently mapped the Holt-Oram syndrome gene defect to the long arm of human chromosome 12 in two families. The role of this disease locus in the pathogenesis of related conditions such as heart-hand syndrome type III (cardiac conduction disease accompanied by skeletal malformations) or familial atrial septal defects is unknown. METHODS AND RESULTS Clinical evaluations and genetic linkage analyses were performed in five additional kindreds with Holt-Oram syndrome and also in one kindred with heart-hand syndrome type III and one kindred with familial atrial septal defect and conduction disease. Holt-Oram syndrome in all five kindreds mapped to chromosome 12q2. These studies and previous data provide odds of greater than 10(25):1 that the Holt-Oram syndrome disease gene is at chromosome 12q2. In contrast, neither the phenotypically similar disorder heart-hand syndrome type III nor the locus responsible for a familial atrial septal defect with atrioventricular block maps to chromosome 12q2. CONCLUSIONS We demonstrate that heart-hand syndromes are genetically heterogeneous. Conditions that clinically appear to be partial phenocopies of Holt-Oram syndrome arise from distinct disease genes.

The hand-foot-uterus syndrome: A new hereditary disorder characterized by hand and foot dysplasia, dermatoglyphic abnormalities, and partial duplication of the female genital tract**

A new hereditary syndrome is described in 13 living members of 4 generations in a single kindred. The syndrome is characterized by malformations and hypoplasia of the hands and feet, and by varying degrees of duplication of the female genital tract. Radiographic findings in the hands and feet, and associated dermatoglyphic patterns, are characteristic of the syndrome. It is transmitted as an autosomal dominant with full penetrance and variable expression.

Punctate epiphyses: A radiological sign not a disease

Punctate epiphyses are caused by a diverse group of conditions. They may be an inherited part of certain bone dysplasias or an incidental finding occurring occasionally in various disorders. The pattern of the puncta together with other radiologic findings aid in making the correct diagnosis.

Torg Syndrome Is Caused by Inactivating Mutations in MMP2 and Is Allelic to NAO and Winchester Syndrome

Torg syndrome is a multicentric osteolysis syndrome of unknown etiology. We identified mutations in the MMP2 gene in a patient with Torg syndrome that resulted in complete loss of MMP2 activity. MMP2 mutations were previously identified in patients with NAO and Winchester syndrome. Our findings suggest that Torg, NAO, and Winchester syndrome are allelic disorders.