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Key Clinical Message This case report describes a patient with a 22q11.2 duplication. His features, which include VACTERL association with an esophageal atresia/tracheo‐esophageal fistula and a vascular ring, expand the previously described phenotype for this duplication.

Transplantation of whole bone marrow (BMT) as well as ex vivo–expanded mesenchymal stromal cells (MSCs) leads to striking clinical benefits in children with osteogenesis imperfecta (OI); however, the underlying mechanism of these cell therapies has not been elucidated. Here, we show that non–(plastic)–adherent bone marrow cells (NABMCs) are more potent osteoprogenitors than MSCs in mice. Translating these findings to the clinic, a T cell–depleted marrow mononuclear cell boost (> 99.99% NABMC) given to children with OI who had previously undergone BMT resulted in marked growth acceleration in a subset of patients, unambiguously indicating the therapeutic potential of bone marrow cells for these patients. Then, in a murine model of OI, we demonstrated that as the donor NABMCs differentiate to osteoblasts, they contribute normal collagen to the bone matrix. In contrast, MSCs do not substantially engraft in bone, but secrete a soluble mediator that indirectly stimulates growth, data which provide the underlying mechanism of our prior clinical trial of MSC therapy for children with OI. Collectively, our data indicate that both NABMCs and MSCs constitute effective cell therapy for OI, but exert their clinical impact by different, complementary mechanisms. The study is registered at [www.clinicaltrials.gov][1] as [NCT00187018][2]. [1]: http://www.clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00187018&atom=%2Fbloodjournal%2F120%2F9%2F1933.atom

Aim: Mitochondrial function studies in autism spectrum disorders (ASD) have detected skeletal muscle mitochondrial enzyme deficiencies in respiratory complex (RC) activities. As a muscle biopsy is expensive and invasive, we assessed RC-I and RC-IV activities in buccal swabs. Methods: 92 children with ASD and 68 controls were studied with immunocapture for RC-I and microspectrophotometry for RC-IV. Results: Significant RC activity deficiencies were found in 39 (42%) ASD patients (p < 0.01) and more prevalent in more severe cases. Aberrant RC overactivity was seen in 9 children. RC-I/RC-IV activity ratio was significantly increased in 64% of the entire ASD cohort including 76% of those more severely affected (p < 0.05). Conclusion: Buccal swab analysis revealed extensive RC abnormalities in ASD providing a noninvasive biomarker to assess mitochondrial function in ASD patients.

We report on a patient with Noonan syndrome due to SHOC2 missense mutation predicting p.Ser2Gly, recently described in association with Noonan syndrome. The male infant presented with fetal distress requiring premature delivery at 32 weeks and was noted to have dysmorphic features, edema, hepatosplenomegaly, leukocytosis, thrombocytopenia, and respiratory distress following birth. An echocardiogram revealed hypertrophic cardiomyopathy with left ventricular outflow tract obstruction. The infant's cardiac lesion rapidly progressed, and he was discharged home for palliative care. Clinical testing of genes causative of Noonan syndrome and related disorders detected the previously reported, pathogenic, de novo SHOC2 missense mutation predicting p.Ser2Gly. The patient's cardiac findings and features were not typical for those individuals previously reported with this SHOC2 mutation and thus expand the clinical phenotype.

BACKGROUND To the authors' knowledge, national-level population-based data regarding prostate carcinoma incidence and detection currently are not available. The availability of such data could identify those regions with a disproportionately high cancer incidence as well as the population-level association between prostate carcinoma detection and incidence. METHODS Inpatient, hospital outpatient, and physician/supplier Medicare claims from 1997 were used to identify incident cases of prostate carcinoma in men age ≥ 65 years and to calculate state and county-level incidence rates. The 1991 and 1997 claims data were used to determine small area rates of prostate-specific antigen (PSA) testing and prostate biopsy and to determine their correlation with incidence. RESULTS The calculated incidence rates for 1997 were 890 per 100,000 and 1196 per 100,000, respectively, in white males and African-American males and varied substantially between counties (i.e., 25–75th percentile, 676–1124 per 100,000). Rates of PSA and prostate biopsy increased markedly from 1991 to 1997 in both white men (1580 per 100,000 to 24,286 per 100,000) and African-American men (1277 per 100,000 to 15,190 per 100,000), and considerable variation in detection between counties was observed. Counties that had higher rates of prostate biopsy also had higher age-adjusted incidence rates, and county-level PSA testing was found to be associated with incidence in African-American patients, but not in white patients. CONCLUSIONS Medicare claims may provide an alternative source of population-based data, particularly for areas in which registry data are not readily available or are of limited scope. In addition, claims provide otherwise unavailable national data concerning cancer detection. Cancer 2001;92:102–9. © 2001 American Cancer Society.

We describe a family illustrating the diagnostic difficulties occurring when pyridoxine-responsive cystathionine beta-synthase (CBS) deficiency presents with thrombotic disease without associated ocular, skeletal, or CNS abnormalities, a situation increasingly recognized. This family had several thromboembolic episodes in two generations with apparently inconstant elevations of plasma total homocysteine (tHcy). When taking (sometimes even low amounts) of pyridoxine, the affected family members had low-normal tHcy and normal values for cystathionine, methionine, and cysteine. Withdrawal of vitamin therapy was necessary before lower cystathionine, elevated methionine, and decreased cysteine became apparent, a pattern suggestive of CBS deficiency, leading to the finding that the affected members were each compound heterozygotes for CBS p.G307S and p.P49L. To assist more accurate diagnosis of adults presenting with thrombophilia found to have elevated tHcy, the patterns of methionine-related metabolites in CBS-deficient patients are compared in this article to those in patients with homocysteine remethylation defects, including inborn errors of folate or cobalamin metabolism, and untreated severe cobalamin or folate deficiency. Usually serum cystathionine is low in subjects with CBS deficiency and elevated in those with remethylation defects. S-Adenosylmethionine and S-adenosylhomocysteine are often markedly elevated in CBS deficiency when tHcy is above 100 umol/L. We conclude that there are likely other undiagnosed, highly B6-responsive adult patients with CBS deficiency, and that additional testing of cystathionine, total cysteine, methionine, and S-adenosylmethionine will be helpful in diagnosing them correctly and distinguishing CBS deficiency from remethylation defects.

Bone marrow transplantation (BMT) has changed the course of treatment for an array of diseases, including disorders of bone. Hematopoietic stem cells (HSC) within the marrow are known to be the precursors of osteoclastic bone cells, and trials of BMT in osteopetrosis, a disorder characterized by a deficiency of osteoclasts, have resulted in significant clinical improvement in patients. The origin of the other major bone cell, the osteoblast, remains uncertain, although studies have identified osteoprogenitor cells within the marrow, leading to further investigation of both mesenchymal stromal cells (MSC) and HSC as candidates for this role. A better understanding of the source of osteoblasts and normal bone metabolism is crucial to efforts to develop effective cell therapy for bone disorders characterized by deficient or abnormal osteoblast function. This review focuses on systemic and local cell therapy in the treatment of several genetic bone disorders and osteoporosis, an acquired disorder caused by abnormal bone metabolism, with the intent of presenting both the progress and challenges associated with this emerging form of therapy. Although the risks of systemic transplantation must be carefully considered, cell therapy for disorders of bone carries the potential for long-term and potentially curative benefits, justifying further intensive research on this important treatment option.

Correction of a short cardiac PR interval in a 12-year-old girl with late-onset Pompe disease following enzyme replacement therapy