The TGF-beta superfamily comprises a number of functionally diverse growth factors/signalling molecules (1) which elicit their response upon binding to serine-threonine kinase receptors (2). We recently reported the isolation and characterization of two new members of the family, designated cartilage-derived morphogenetic protein (CDMP) 1 and 2 (ref. 3) which are closely related to the sub-family of bone morphogenetic proteins. CDMP-1 is predominantly expressed at sites of skeletal morphogenesis (3), and we now show that a mutation in hCDMP-1 is associated with a recessive human chondrodysplasia (acromesomelic chondrodysplasia, Hunter-Thompson type (4,5)). The disorder, characterized by skeletal abnormalities restricted to the limbs andlimb joints, is phenotypically similar to murine brachypodism (bp) which is due to mutations in growth/differentiation factor-5 (Gdf-5) (6), the mouse homologue of hCDMP-1. Affected individuals are homozygous for a 22-bp (tandem-duplication) frameshift mutation in the mature region of CDMP-1. The resulting phenotype provides direct evidence for the involvement of CDMP-1 in human skeletal development and represents the first human disorder attributable to a mutation in a TGF-beta superfamily member.

To determine the proportion and birth prevalence of "typical" orofacial clefts (cleft lip (CL), cleft palate (CP), cleft lip and palate (CLP)) and "atypical" clefts (median, transversal, or oblique facial clefts) and the conditions in which they occur, we analyzed a population-based sample of 4,433 cases ascertained from 2,509,881 California births. We classified cases into: isolated cleft anomalies, sequences of the primary defect, chromosomal aberrations, monogenic syndromes, results of known teratogens, associations, multiple congenital anomaly (MCA) of unknown etiology, or conjoined twins. The birth prevalence of isolated CL+/-P was 0.77 per 1,000 births (CL 0.29/1,000, CLP 0.48/1,000) and of isolated CP, 0.31 per 1,000 births. Non-Hispanic Whites had the greatest prevalence of isolated clefts, Asians slightly lower prevalences, and Blacks the lowest. Asians had the lowest prevalence of Robin sequence and nonHispanic Whites the highest, twice that of Hispanics. Hispanics, followed by Asians, had the highest prevalence of CL+/-P with MCA; non-Hispanic Whites had the lowest. Asians had the lowest prevalence of CP; in Whites and Hispanics it was almost twice as high. Blacks had the highest CL:CLP ratio, followed by non-Hispanic Whites and Asians; Hispanics had the lowest. Isolated anomalies constituted 61.67% of clefts. In the total sample there were 3.9% sequences, 8.79% chromosomal aberrations, 6.02% monogenic syndromes, 0.2% known teratogens, 0.79% associations, 18.55% MCA of unknown etiology, and 0.1% in conjoined twins. This study supports evaluation of each child on a "case" level, and provides a framework for genetic counseling and other studies focused on causes and prevention of these serious anomalies.

A five-month-old girl with autosomal-recessive osteopetrosis received a bone-marrow transplant from her five-year-old HLA-MLC-identical brother after preparation with cyclophosphamide and modified total-body irradiation. Engraftment was documented by chromosomal analysis. Anemia, thrombocytopenia, and leukoerythroblastosis corrected within 12 weeks of transplantation. Low serum calcium and elevated serum alkaline and acid phosphatase levels became normal. Serial x-ray studies revealed bony remodeling and new nonsclerotic bone formation. A pretransplantation bone biopsy revealed small marrow spaces, rare marrow elements, increased osteoclasts, and no bony resorption. After transplantation, osteoclasts were actively resorbing bone, and medullary cavities contained normal bone marrow. Fluorescent Y-body analysis after transplantation revealed donor (male) osteoclasts and recipient (female) osteoblasts. Monocyte bactericidal activity, markedly decreased before transplantation, became normal. Vision, hearing, growth, and development were progressively improving 16 months after transplantation. Allogeneic bone-marrow transplantation appears to be the treatment of choice in this fatal disorder.

To determine the proportion and birth prevalence of "typical" orofacial clefts (cleft lip (CL), cleft palate (CP), cleft lip and palate (CLP)) and "atypical" clefts (median, transversal, or oblique facial clefts) and the conditions in which they occur, we analyzed a population-based sample of 4,433 cases ascertained from 2,509,881 California births. We classified cases into: isolated cleft anomalies, sequences of the primary defect, chromosomal aberrations, monogenic syndromes, results of known teratogens, associations, multiple congenital anomaly (MCA) of unknown etiology, or conjoined twins. The birth prevalence of isolated CL+/-P was 0.77 per 1,000 births (CL 0.29/1,000, CLP 0.48/1,000) and of isolated CP, 0.31 per 1,000 births. Non-Hispanic Whites had the greatest prevalence of isolated clefts, Asians slightly lower prevalences, and Blacks the lowest. Asians had the lowest prevalence of Robin sequence and nonHispanic Whites the highest, twice that of Hispanics. Hispanics, followed by Asians, had the highest prevalence of CL+/-P with MCA; non-Hispanic Whites had the lowest. Asians had the lowest prevalence of CP; in Whites and Hispanics it was almost twice as high. Blacks had the highest CL:CLP ratio, followed by non-Hispanic Whites and Asians; Hispanics had the lowest. Isolated anomalies constituted 61.67% of clefts. In the total sample there were 3.9% sequences, 8.79% chromosomal aberrations, 6.02% monogenic syndromes, 0.2% known teratogens, 0.79% associations, 18.55% MCA of unknown etiology, and 0.1% in conjoined twins. This study supports evaluation of each child on a "case" level, and provides a framework for genetic counseling and other studies focused on causes and prevention of these serious anomalies.

We have analyzed chromosome breaks in 8 patients with Fanconi anemia (FA), 42 with "idiopathic" aplastic anema (AA), 15 first-degree relatives of FA patients, and 13 controls. Their lymphocytes were treated in culture with three concentrations of mitomycin-C (MMC). A 60-fold increase in breaks was observed in FA patients as compared to AA patients, regardless of severity of clinical signs. The MMC-stress test was standardized to clearly differentiate FA from other pancytopenias in doubtful cases. Also, the effect of storage of MMC in solution was investigated. The data on SCEs of 12 subjects tested, 10 mo apart, showed an inverse relationship between length of storage of MMC and chromosome damage. The 10-month-old solution induced only one half as many SCEs as it induced at 4 months. Further, the usefulness and power of diepoxybutane (DEB) in detection of FA heterozygotes was investigated in 12 first-degree relatives of patients with Fanconi anemia and 12 healthy controls. The mean number of chromosome breaks per mitosis by DEB stress in obligate heterozygotes was 0.08 in comparison to 0.06 in controls. Four of twelve control subjects showed proportions of breaks almost identical to or higher than those of FA heterozygotes, ie, 0.12, 0.10, 0.10, and 0.11 breaks per mitosis. The responses of healthy controls to DEB could be separated into two groups: one with mean chromosome breaks of 0.11 per mitosis, and a second with mean breaks of 0.04 per mitosis. Thus, it appears that heterozygote detection by DEB stress of cultured lymphocytes is not unequivocal.