Melissa Merideth

Phenotype and course of Hutchinson-Gilford progeria syndrome

BACKGROUND Hutchinson-Gilford progeria syndrome is a rare, sporadic, autosomal dominant syndrome that involves premature aging, generally leading to death at approximately 13 years of age due to myocardial infarction or stroke. The genetic basis of most cases of this syndrome is a change from glycine GGC to glycine GGT in codon 608 of the lamin A (LMNA) gene, which activates a cryptic splice donor site to produce abnormal lamin A; this disrupts the nuclear membrane and alters transcription. METHODS We enrolled 15 children between 1 and 17 years of age, representing nearly half of the worlds known patients with Hutchinson-Gilford progeria syndrome, in a comprehensive clinical protocol between February 2005 and May 2006. RESULTS Clinical investigations confirmed sclerotic skin, joint contractures, bone abnormalities, alopecia, and growth impairment in all 15 patients; cardiovascular and central nervous system sequelae were also documented. Previously unrecognized findings included prolonged prothrombin times, elevated platelet counts and serum phosphorus levels, measured reductions in joint range of motion, low-frequency conductive hearing loss, and functional oral deficits. Growth impairment was not related to inadequate nutrition, insulin unresponsiveness, or growth hormone deficiency. Growth hormone treatment in a few patients increased height growth by 10% and weight growth by 50%. Cardiovascular studies revealed diminishing vascular function with age, including elevated blood pressure, reduced vascular compliance, decreased ankle-brachial indexes, and adventitial thickening. CONCLUSIONS Establishing the detailed phenotype of Hutchinson-Gilford progeria syndrome is important because advances in understanding this syndrome may offer insight into normal aging. Abnormal lamin A (progerin) appears to accumulate with aging in normal cells. (ClinicalTrials.gov number, NCT00094393.)

A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare immunodeficiency disorder caused by gain-of-function mutations in the G protein-coupled chemokine receptor CXCR4. The CXCR4 antagonist plerixafor, which is approved by the US Food and Drug Administration (FDA) for stem cell mobilization in cancer and administered for that indication at 0.24 mg/kg, has been shown in short-term (1- to 2-week) phase 1 dose-escalation studies to correct neutropenia and other cytopenias in WHIM syndrome. However, long-term safety and long-term hematologic and clinical efficacy data are lacking. Here we report results from the first long-term clinical trial of plerixafor in any disease, in which 3 adults with WHIM syndrome self-injected 0.01 to 0.02 mg/kg (4% to 8% of the FDA-approved dose) subcutaneously twice daily for 6 months. Circulating leukocytes were durably increased throughout the trial in all patients, and this was associated with fewer infections and improvement in warts in combination with imiquimod; however, immunoglobulin levels and specific vaccine responses were not fully restored. No drug-associated side effects were observed. These results provide preliminary evidence for the safety and clinical efficacy of long-term, low-dose plerixafor in WHIM syndrome and support its continued study as mechanism-based therapy in this disease. The ClinicalTrials.gov identifier for this study is NCT00967785.

Female Long-Term Survivors After Allogeneic Hematopoietic Stem Cell Transplantation: Evaluation and Management

Female long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) incur a significant burden of late effects. Genital graft-versus-host disease (GVHD), human papillomavirus (HPV) reactivation, ovarian failure and infertility, sexual dysfunction, and osteoporosis are concerns that can significantly impact quality of life. This review examines the risk, pathogenesis, clinical presentation, and implications of these common complications. Recommendations are provided for evaluation and management of these late effects and other obstetric and gynecologic issues that may arise in this patient population.

High‐risk pregnancy and neonatal complications in the DNA repair and transcription disorder trichothiodystrophy: report of 27 affected pregnancies

To identify the frequency of pregnancy and neonatal complications in pregnancies carrying fetuses affected with trichothiodystrophy (TTD).

Human papillomavirus reactivation following treatment of genital graft-versus-host disease.

Vaginal chronic graft‐versus‐host disease (cGVHD) is a common complication of stem cell transplantation. Human papillomavirus (HPV) disease can reactivate after transplantation, presumably because of immune factors affecting systemic immunity, such as waning antibody titers, impaired T‐ and B‐lymphocyte responses, and the use of immunosuppressive therapies. However, a relationship between the use of local immunosuppressive agents and HPV reactivation and spread has not been previously described, to our knowledge. A 30‐year‐old woman, 2 years post transplant receiving systemic cyclosporine for cGVHD, was treated with vaginal dilators, topical corticosteroids, and estrogen for vaginal cGVHD. Colposcopy and biopsy for abnormal cytology revealed condylomatous cervicitis. Over the next 4 months, while continuing dilator therapy, linear verrucous lesions developed in the vagina and vulva, and were successfully treated with laser therapy. Use of local immunosuppression and dilators for genital GVHD can enhance spread of HPV infection. Integration of HPV screening and treatment into the care of women with genital cGVHD and development of strategies to manage both conditions simultaneously are warranted.

Effect of mutations in XPD(ERCC2) on pregnancy and prenatal development in mothers of patients with trichothiodystrophy or xeroderma pigmentosum

The XPD(ERCC2) gene encodes a DNA helicase involved in DNA repair and transcription. Patients with mutations in XPD may have different autosomal recessive phenotypes including trichothiodystrophy (TTD) or xeroderma pigmentosum (XP). TTD patients have sulfur-deficient, brittle hair, short stature and developmental delay. In contrast, XP patients have freckle-like pigmentation and a greatly increased risk of sun-induced skin cancers. Mothers of TTD patients have been reported to have a high frequency of pregnancy and neonatal complications. We performed a molecular epidemiological study of 15 mothers of 17 TTD patients and 13 mothers of 17 XP patients, all with XPD mutations. We found that 94% (16/17) of the TTD pregnancies had pre-term delivery, pre-eclampsia, hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, prematurity or low birth weight. None of the 17 XP pregnancies had these complications (P<0.001). As mutations in XPD may have differential effects on DNA repair and transcription, these observations should provide insights into the role of XPD in human pregnancy and fetal development.

Otologic and audiologic manifestations of Hutchinson-Gilford progeria syndrome.

To define the audiologic and otologic phenotype of Hutchinson‐Gilford progeria syndrome (HGPS).

Hermansky-Pudlak syndrome in two African-American brothers.

Hermansky–Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism, a bleeding disorder, and, in some patients, granulomatous colitis and/or a fatal pulmonary fibrosis. There are eight different subtypes of HPS, each due to mutations in one of eight different genes, whose functions are thought to involve intracellular vesicle formation and trafficking. HPS has been identified in patients of nearly all ethnic groups, though it has primarily been associated with patients of Puerto Rican, Northern European, Japanese and Israeli descent. We report on the diagnosis of HPS type 1 in two African‐American patients. Both brothers carried compound heterozygous mutations in HPS1: previously reported p.M325WfsX6 (c.972delC) and a novel silent mutation p.E169E (c.507G > A), which resulted in a splice defect. HPS may be under‐diagnosed in African‐American patients and other ethnic groups. A history of easy bruising or evidence of a bleeding disorder, combined with some degree of hypopigmentation, should prompt investigation into the diagnosis of HPS. Published 2009 Wiley‐Liss, Inc.

Treatment of Multifocal Bowen’s Disease in Immunocompromised Women With Surgery and Topical Imiquimod

BACKGROUND: In human immunodeficiency virus (HIV)-infected women, Bowens disease may be difficult to treat successfully with surgery alone. Imiquimod cream, effective in treating Bowens disease in healthy women, may be a useful postsurgical treatment in immunocompromised women. CASES: Two HIV-infected women had both Bowens disease and severe cervical dysplasia. In both cases, Bowens disease, but not cervical dysplasia, recurred after surgical treatment. When treated with topical 5% imiquimod cream twice weekly for 4 months, 70–80% reduction in lesions were observed in both patients. Follow-up biopsies of remaining lesions were vulvar intraepithelial neoplasia 1. CONCLUSION: Imiquimod cream, in combination with surgical treatment, may be an appropriate strategy for treatment of Bowens disease in HIV-infected and other immunocompromised women.

Natural killer cell activity and dysfunction in Hermansky‐Pudlak syndrome

Hermansky‐Pudlak syndrome (HPS) encompasses disorders with abnormal function of lysosomes and lysosome‐related organelles, and some patients who develop immunodeficiency. The basic mechanisms contributing to immune dysfunction in HPS are ill‐defined. We analysed natural killer (NK) cells from patients diagnosed with HPS‐1, HPS‐2, HPS‐4, and an unreported HPS subtype. NK cells from an HPS‐2 and an unreported HPS subtype share a similar cellular phenotype with defective granule release and cytotoxicity, but differ in cytokine exocytosis. Defining NK cell activity in several types of HPS provides insights into cellular defects of the disorder and understanding of mechanisms contributing to HPS pathogenesis.