Cleft palate and hypopituitarism in a patient with Noonan-like syndrome with loose anagen hair-1.

Noonan syndrome (NS), the most common of the RASopathies, is a developmental disorder caused by heterozygous germline mutations in genes encoding proteins in the RAS-MAPK signaling pathway. Noonan-like syndrome with loose anagen hair (NSLH, including NSLH1, OMIM #607721 and NSLH2, OMIM #617506) is characterized by typical features of NS with additional findings of macrocephaly, loose anagen hair, growth hormone deficiency in some, and a higher incidence of intellectual disability. All NSLH1 reported cases to date have had an SHOC2 c.4A>G, p.Ser2Gly mutation; NSLH2 cases have been reported with a PPP1CB c.146G>C, p.Pro49Arg mutation, or c.166G>C, p.Ala56Pro mutation. True cleft palate does not appear to have been previously reported in individuals with NS or with NSLH. While some patients with NS have had growth hormone deficiency (GHD), other endocrine abnormalities are only rarely documented. We present a female patient with NSLH1 who was born with a posterior cleft palate, micrognathia, and mild hypotonia. Other findings in her childhood and young adulthood years include hearing loss, strabismus, and hypopituitarism with growth hormone, thyroid stimulating hormone (TSH), and gonadotropin deficiencies. The SHOC2 mutation may be responsible for this patient's additional features of cleft palate and hypopituitarism.

T Follicular Helper Cell-Dependent Clearance of a Persistent Virus Infection Requires T Cell Expression of the Histone Demethylase UTX.

Epigenetic changes, including histone methylation, control T cell differentiation and memory formation, though the enzymes that mediate these processes are not clear. We show that UTX, a histone H3 lysine 27 (H3K27) demethylase, supports T follicular helper (Tfh) cell responses that are essential for B cell antibody generation and the resolution of chronic viral infections. Mice with a T cell-specific UTX deletion had fewer Tfh cells, reduced germinal center responses, lacked virus-specific immunoglobulin G (IgG), and were unable to resolve chronic lymphocytic choriomeningitis virus infections. UTX-deficient T cells showed decreased expression of interleukin-6 receptor-α and other Tfh cell-related genes that were associated with increased H3K27 methylation. Additionally, Turner Syndrome subjects, who are predisposed to chronic ear infections, had reduced UTX expression in immune cells and decreased circulating CD4(+) CXCR5(+) T cell frequency. Thus, we identify a critical link between UTX in T cells and immunity to infection.

Prevalence of pilomatricoma in Turner syndrome: findings from a multicenter study.

IMPORTANCE: The absence of data on the prevalence of pilomatricoma among patients with Turner syndrome served as the catalyst for this multicenter investigation. OBJECTIVES: To ascertain the prevalence of pilomatricoma among patients with Turner syndrome and to determine any association between the development of pilomatricomas and the use of exogenous hormones in patients with Turner syndrome. DESIGN: A retrospective medical record review from January 1, 2000, through January 1, 2010, was performed of all patients with Turner syndrome. Data on pilomatricomas and the use of hormone therapy were collected. SETTING: University of California-Davis Medical Center, University of Nebraska Medical Center, and The University of North Carolina at Chapel Hill. PARTICIPANTS: Patients with a diagnosis of Turner syndrome. MAIN OUTCOME MEASURES: Prevalence of concomitant pilomatricoma and diagnosis of Turner syndrome. Secondary outcome measures included the use of the exogenous hormones estrogen or recombinant human growth hormone (rhGH). RESULTS: In total, 311 patients with Turner syndrome were identified from these 3 institutions. Among them, 8 patients (2.6%) were diagnosed as having pilomatricomas. Before the development of pilomatricomas, 5 patients had been treated with rhGH but not estrogen, 1 patient had received estrogen but not rhGH, and 2 patients did not receive either therapy. CONCLUSIONS AND RELEVANCE: Although the prevalence of pilomatricoma among the general population is unknown, this study demonstrates a high prevalence (2.6%) of pilomatricomas among patients with Turner syndrome. No apparent relationship was noted among our patients or in the literature between the use of rhGH and the development of pilomatricomas.

Growth hormone therapy in Turner syndrome.

Short stature is the single most common physical abnormality in Turner syndrome (TS) with adult stature averaging 20 cm shorter than that of the general population. Randomized, placebo-controlled studies to final adult height have proven that GH therapy is effective in increasing stature in TS. Recently, randomized, controlled studies have demonstrated that adjunctive therapies with low-dose estrogen or low-dose oxandrolone enhance stature further. These therapies may provide benefits beyond height augmentation.

Moving toward an understanding of hormone replacement therapy in adolescent girls: looking through the lens of Turner syndrome.

Turner syndrome (TS) is a relatively common disorder of phenotypic females caused by loss of all or part of the second sex chromosome. Most individuals with TS have short stature and gonadal dysgenesis and are at risk for many other medical and learning problems. In the 45,X ovary, germs cells multiply quite normally during fetal development, but there is accelerated atresia of oocytes in the second half of pregnancy that produces gonadal insufficiency by birth. In girls with other karyotypes, especially those mosaic for 45,X/46,XX, gonadal function may be normal or near-normal. In this chapter, management goals for gonadal insufficiency in girls with TS are presented. The effects of estrogen deficiency and its replacement on three specific problems associated with TS-short stature, cardiovascular disease, and developmental differences in brain structure and function-are explored. General guidelines for estrogen replacement therapy using transdermal estrogen, the most physiologic option, are provided and future research goals are outlined.

Evidence for early initiation of growth hormone and transdermal estradiol therapies in girls with Turner syndrome.

Results from the first randomized, controlled trial of growth hormone (GH) therapy in girls with Turner syndrome (TS) followed to final height firmly establish that GH increases final adult stature. It is widely believed that the efficacy of GH is dependent upon the duration of therapy and dosing (longer duration and higher dose give taller final height). In a recent observational study involving more than 1500 French girls with TS, multivariate analyses demonstrated that the age at initiation of GH therapy accounted for a large percentage of the variance (44%) in response. Age at initiation of estrogen therapy was the second most important factor in determining GH effect (later initiation, taller final height), accounting for 22% of the variance. Overall, 0.3 cm in adult height was gained for every year that estrogen therapy was delayed. However, analyses of the French data restricted to patients with induced puberty revealed that those treated with percutaneous estradiol attained a height 2.1cm taller than those using oral estradiol or other estrogen preparations. In another study, girls receiving GH therapy (n=14) who were randomized to receive intramuscular (IM) depot estradiol early (12.0-12.9 years) attained at least as much height as those who initiated it late (14.0-14.9 years). These results are consistent with the observations in adult women that oral estrogens decrease IGF-I serum levels and suppress the IGF-independent metabolic effects of GH, while transdermal estrogens do not. Taken together, these studies suggest that girls with TS should begin GH therapy as soon as growth failure is demonstrated and that puberty should be induced with transdermal or IM estradiol. Girls for whom height is normalized with GH therapy in early childhood have the opportunity to undergo puberty at an age-appropriate time and still achieve a normal adult stature.

Central obesity, the metabolic syndrome, and plasminogen activator inhibitor-1 in young adults.

PURPOSE: To determine the association of central obesity with the components of the metabolic syndrome (i.e., hyperinsulinemia, hypertension, hypertriglyceridemia, low levels of high-density lipoprotein cholesterol [HDL-C]) and plasma levels of plasminogen activator inhibitor-1 (PAI-1) in young adults. We hypothesized that central obesity as determined by waist circumference would be predictive of components of the metabolic syndrome and of PAI-1. DATA SOURCES: Participants in this descriptive study consisted of 85 healthy young adults aged 19-22 years, 62% women who fasted for 12 h prior to data collection in the General Clinical Research Center at a major university hospital medical center in the southeastern United States. CONCLUSIONS: The majority of the participants had one or more components of the metabolic syndrome (n= 43, 51%). Central obesity was present in 14.1% and was more common in women than men (chi(2)= 5.11; p= 0.021). Central obesity was significantly and positively correlated with elevated blood pressure (BP) and levels of insulin and PAI-1 while being negatively correlated with HDL-C. In multiple regression analyses, diastolic BP, insulin, and HDL-C were predictors of waist circumference (R(2)= 0.615). In a separate multiple regression, PAI-1 was predicted by waist circumference (R(2)= 0.331). IMPLICATIONS FOR PRACTICE: Many otherwise healthy young adults have one or more components of the metabolic syndrome. Assessment and institution of preventative measures for obesity and the components of the metabolic syndrome should begin in childhood. Furthermore, determination of waist circumference especially in young women may aid the practitioner to identify those at risk for the metabolic syndrome earlier in their disease trajectory. Furthermore, insulin resistance is believed to occur initially in the trajectory of the metabolic syndrome, making it a principal contender for suitable interventions to reduce risk for both type 2 diabetes and cardiovascular disease (CVD). Homeostatic model assessment for insulin resistance was used to assess for insulin resistance among the euglycemic participants. Recording the presence of insulin resistance will aid the practitioner in determining if a low-risk patient is in peril for development of type 2 diabetes and/or CVD. Early cardiovascular risk recognition is vital to clinical practice as it allows more time for the practitioner to counsel patients for the essential planning needed to make lifestyle changes.