Faculty Bibliography

The 45,X disorder of sexual differentiation (DSD) is a rare disorder. We report long-term follow-up of a 5-year-old African-American male whose evaluation for short stature revealed a karyotype of 45,X der(X)t(X;Y)(p22.3;p11.2)(SRY+). Presence of the SRY (sex-determining region Y) gene resulted in his male development. His chromosome abnormality also resulted in a deletion of the SHOX (short stature homeobox-containing) gene, which partly contributed to his short stature and skeletal features. He underwent normal spontaneous pubertal development, but his final height remained compromised due to advanced bone age, non-optimal response to recombinant human growth hormone (rhGH) treatment during the period of compliance and ultimately non-compliance with rhGH therapy. To our knowledge, this is the first case report describing long-term follow-up of a 45,X male DSD which highlights the similarities and differences from Turner syndrome females.

Angiotensin receptor blockers (ARBs) are a group of anti-hypertensive drugs that are widely used to treat pediatric hypertension. Recent application of ARBs to treat diseases such as Marfan syndrome or Alport syndrome has shown positive outcomes in animal and human studies, suggesting a broader therapeutic potential for this class of drugs. Multiple studies have reported a benefit of ARBs on adult bone homeostasis; however, its effect on the growing skeleton in children is unknown. We investigated the effect of Losartan, an ARB, in regulating bone mass and cartilage during development in mice. Wild type mice were treated with Losartan from birth until 6 weeks of age, after which bones were collected for microCT and histomorphometric analyses. Losartan increased trabecular bone volume vs. tissue volume (a 98% increase) and cortical thickness (a 9% increase) in 6-weeks old wild type mice. The bone changes were attributed to decreased osteoclastogenesis as demonstrated by reduced osteoclast number per bone surface in vivo and suppressed osteoclast differentiation in vitro. At the molecular level, Angiotensin II-induced ERK1/2 phosphorylation in RAW cells was attenuated by Losartan. Similarly, RANKL-induced ERK1/2 phosphorylation was suppressed by Losartan, suggesting a convergence of RANKL and angiotensin signaling at the level of ERK1/2 regulation. To assess the effect of Losartan on cartilage development, we examined the cartilage phenotype of wild type mice treated with Losartan in utero from conception to 1 day of age. Growth plates of these mice showed an elongated hypertrophic chondrocyte zone and increased Col10a1 expression level, with minimal changes in chondrocyte proliferation. Altogether, inhibition of the angiotensin pathway by Losartan increases bone mass and accelerates chondrocyte hypertrophy in growth plate during skeletal development.

OBJECTIVE: The objective of this study is to study if involuntary detention criteria in legal certificates filed by psychiatry residents and faculty psychiatrists are consistent with observations in clinical documentation. METHODS: Eighty-nine involuntarily hospitalized patients were retrospectively selected from medical records; eight patients were excluded due to change in involuntary status or immediate discharge on clinical grounds. Medical certificates filed by the residents and faculty psychiatrists were compared with clinical documentation of the same day for consistency in criteria for detention (substantial risk of harm to self or others and/or inability to care for self). RESULTS: Of 81 included patients, 38.3 % lacked sufficient documentation of clinical justification for involuntary hospitalization. The rate of inconsistency of documented clinical justification showed a greater trend among psychiatry residents compared to faculty psychiatrists (p = 0.069, not statistically significant). CONCLUSIONS: Inconsistency of documented clinical justification for involuntarily detention was higher among residents compared to faculty. There is a need for structured training and supervision of psychiatry residents as well as updated training for faculty psychiatrists with regard to involuntary detention procedures.

Osteogenesis imperfecta (OI) is typically caused by mutations in type 1 collagen genes, but in recent years new recessive and dominant forms caused by mutations in a plethora of different genes have been characterized. OI type V is a dominant form caused by the recurrent (c.-14C > T) mutation in the 5'UTR of the IFITM5 gene. The mutation adds five residues to the N-terminus of the IFITM5, but the pathophysiology of the disease remains to be elucidated. Typical clinical features present in the majority of OI type V patients include interosseous membrane calcification between the radius and ulna and between the tibia and fibula, radial head dislocation, and significant hyperplastic callus formation at the site of fractures. We report a 5-year-old child with clinical features of OI type III or severe OI type IV (characteristic facies, gray sclerae, typical fractures) and absence of classical features of OI type V with a de novo recurrent IFITM5 mutation (c.-14C > T), now typical of OI type V. This highlights the variability of OI caused by IFITM5 mutations and suggests screening for mutations in this gene in most cases of OI where type 1 collagen mutations are absent.

In a large cohort of osteogenesis imperfecta type V (OI type V) patients (17 individuals from 12 families), we identified the same mutation in the 5' untranslated region (5'UTR) of the interferon-induced transmembrane protein 5 (IFITM5) gene by whole exome and Sanger sequencing (IFITM5 c.-14C > T) and provide a detailed description of their phenotype. This mutation leads to the creation of a novel start codon adding five residues to IFITM5 and was recently reported in several other OI type V families. The variability of the phenotype was quite large even within families. Whereas some patients presented with the typical calcification of the forearm interosseous membrane, radial head dislocation and hyperplastic callus (HPC) formation following fractures, others had only some of the typical OI type V findings. Thirteen had calcification of interosseous membranes, 14 had radial head dislocations, 10 had HPC, 9 had long bone bowing, 11 could ambulate without assistance, and 1 had mild unilateral mixed hearing loss. The bone mineral density varied greatly, even within families. Our study thus highlights the phenotypic variability of OI type V caused by the IFITM5 mutation.

This report identifies human skeletal diseases associated with mutations in WNT1. In 10 family members with dominantly inherited, early-onset osteoporosis, we identified a heterozygous missense mutation in WNT1, c.652T-->G (p.Cys218Gly). In a separate family with 2 siblings affected by recessive osteogenesis imperfecta, we identified a homozygous nonsense mutation, c.884C-->A, p.Ser295*. In vitro, aberrant forms of the WNT1 protein showed impaired capacity to induce canonical WNT signaling, their target genes, and mineralization. In mice, Wnt1 was clearly expressed in bone marrow, especially in B-cell lineage and hematopoietic progenitors; lineage tracing identified the expression of the gene in a subset of osteocytes, suggesting the presence of altered cross-talk in WNT signaling between the hematopoietic and osteoblastic lineage cells in these diseases.

Pediatric hematology oncology nurses face a variety of stressors while working in this specialty field. Through hematology oncology staff group discussions, nurses identified a myriad physical and emotional stressors they experienced, and expressed concern regarding possible burnout. They described facing stressors related to experiencing loss, grief, moral and ethical dilemmas, and administering complex treatment regimens. To address these concerns, a hematology oncology nursing supportive care committee envisioned and implemented 3 off-site self-care retreats. The committee's primary purpose was to create a therapeutic and supportive environment for all participants, while allowing time for relaxation, reflection, and serenity. The primary goals for the retreats were to heal nurses from their reported past trauma and stress and to provide them effective coping strategies for the ongoing stressors they will inevitably face. In a collaborative effort, the committee members developed an agenda including presentations, group discussions, and relaxation activities. Written evaluations were completed by each participant to assess the benefit of the retreat. Overall feedback was extremely positive, with the majority of the participants finding great value in this experience.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with skeletal involvement. It is caused by mutations in fibrillin1 (FBN1) gene resulting in activation of TGF-beta, which developmentally regulates bone mass and matrix properties. There is no consensus regarding bone mineralization in children with MFS. Using dual-energy X-ray absorptiometry (DXA), we evaluated bone mineralization in 20 children with MFS unselected for bone problems. z-Scores were calculated based on age, gender, height, and ethnicity matched controls. Mean whole body bone mineral content (BMC) z-score was 0.26+/-1.42 (P=0.41). Mean bone mineral density (BMD) z-score for whole body was -0.34+/-1.4 (P=0.29) and lumbar spine was reduced at -0.55+/-1.34 (P=0.017). On further adjusting for stature, which is usually higher in MFS, mean BMC z-score was reduced at -0.677+/-1.37 (P=0.04), mean BMD z-score for whole body was -0.82+/-1.55 (P=0.002) and for lumbar spine was -0.83+/-1.32 (P=0.001). An increased risk of osteoporosis in MFS is controversial. DXA has limitations in large skeletons because it tends to overestimate BMD and BMC. By adjusting results for height, age, gender, and ethnicity, we found that MFS patients have significantly lower BMC and BMD in whole body and lumbar spine. Evaluation of diet, exercise, vitamin D status, and bone turnover markers will help gain insight into pathogenesis of the reduced bone mass. Further, larger longitudinal studies are required to evaluate the natural history, incidence of fractures, and effects of pharmacological therapy.