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GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism

Idiopathic hypogonadotropic hypogonadism (IHH) is a condition characterized by failure to undergo puberty in the setting of low sex steroids and low gonadotropins. IHH is due to abnormal secretion or action of the master reproductive hormone gonadotropin-releasing hormone (GnRH). Several genes have been found to be mutated in patients with IHH, yet to date no mutations have been identified in the most obvious candidate gene, GNRH1 itself, which encodes the preprohormone that is ultimately processed to produce GnRH. We screened DNA from 310 patients with normosmic IHH (nIHH) and 192 healthy control subjects for sequence changes in GNRH1. In 1 patient with severe congenital nIHH (with micropenis, bilateral cryptorchidism, and absent puberty), a homozygous frameshift mutation that is predicted to disrupt the 3 C-terminal amino acids of the GnRH decapeptide and to produce a premature stop codon was identified. Heterozygous variants not seen in controls were identified in 4 patients with nIHH: 1 nonsynonymous missense mutation in the eighth amino acid of the GnRH decapeptide, 1 nonsense mutation that causes premature termination within the GnRH-associated peptide (GAP), which lies C-terminal to the GnRH decapeptide within the GnRH precursor, and 2 sequence variants that cause nonsynonymous amino-acid substitutions in the signal peptide and in GnRH-associated peptide. Our results establish mutations in GNRH1 as a genetic cause of nIHH.

GnRH-Deficient Phenotypes in Humans and Mice with Heterozygous Variants in KISS1/Kiss1

CONTEXT KISS1 is a candidate gene for GnRH deficiency. OBJECTIVE Our objective was to identify deleterious mutations in KISS1. PATIENTS AND METHODS DNA sequencing and assessment of the effects of rare sequence variants (RSV) were conducted in 1025 probands with GnRH-deficient conditions. RESULTS Fifteen probands harbored 10 heterozygous RSV in KISS1 seen in less than 1% of control subjects. Of the variants that reside within the mature kisspeptin peptide, p.F117L (but not p.S77I, p.Q82K, p.H90D, or p.P110T) reduces inositol phosphate generation. Of the variants that lie within the coding region but outside the mature peptide, p.G35S and p.C53R (but not p.A129V) are predicted in silico to be deleterious. Of the variants that lie outside the coding region, one (g.1-3659C→T) impairs transcription in vitro, and another (c.1-7C→T) lies within the consensus Kozak sequence. Of five probands tested, four had abnormal baseline LH pulse patterns. In mice, testosterone decreases with heterozygous loss of Kiss1 and Kiss1r alleles (wild-type, 274 ± 99, to double heterozygotes, 69 ± 16 ng/dl; r(2) = 0.13; P = 0.03). Kiss1/Kiss1r double-heterozygote males have shorter anogenital distances (13.0 ± 0.2 vs. 15.6 ± 0.2 mm at P34, P < 0.001), females have longer estrous cycles (7.4 ± 0.2 vs. 5.6 ± 0.2 d, P < 0.01), and mating pairs have decreased litter frequency (0.59 ± 0.09 vs. 0.71 ± 0.06 litters/month, P < 0.04) and size (3.5 ± 0.2 vs. 5.4 ± 0.3 pups/litter, P < 0.001) compared with wild-type mice. CONCLUSIONS Deleterious, heterozygous RSV in KISS1 exist at a low frequency in GnRH-deficient patients as well as in the general population in presumably normal individuals. As in Kiss1(+/-)/Kiss1r(+/-) mice, heterozygous KISS1 variants in humans may work with other genetic and/or environmental factors to cause abnormal reproductive function.

Mutations in KCTD1 Cause Scalp-Ear-Nipple Syndrome

Scalp-ear-nipple (SEN) syndrome is a rare, autosomal-dominant disorder characterized by cutis aplasia of the scalp; minor anomalies of the external ears, digits, and nails; and malformations of the breast. We used linkage analysis and exome sequencing of a multiplex family affected by SEN syndrome to identify potassium-channel tetramerization-domain-containing 1 (KCTD1) mutations that cause SEN syndrome. Evaluation of a total of ten families affected by SEN syndrome revealed KCTD1 missense mutations in each family tested. All of the mutations occurred in a KCTD1 region encoding a highly conserved bric-a-brac, tram track, and broad complex (BTB) domain that is required for transcriptional repressor activity. KCTD1 inhibits the transactivation of the transcription factor AP-2α (TFAP2A) via its BTB domain, and mutations in TFAP2A cause cutis aplasia in individuals with branchiooculofacial syndrome (BOFS), suggesting a potential overlap in the pathogenesis of SEN syndrome and BOFS. The identification of KCTD1 mutations in SEN syndrome reveals a role for this BTB-domain-containing transcriptional repressor during ectodermal development.

Outcomes in pediatric atypical spitz tumors treated without sentinel lymph node biopsy.

Abstract:  The diagnosis of atypical Spitz tumor (AST) in a pediatric patient conveys an uncertain potential for malignancy. Although pediatric melanoma is rare, AST may be treated aggressively with sentinel lymph node biopsy (SLNB) and subsequent completion lymphadenectomy. These procedures have unclear therapeutic benefit and potential morbidity. We aimed to collect outcomes on children with AST treated with excision alone to assist in the management of these lesions. We queried our institution’s pathology database for AST specimens submitted between 1994 and 2009. A dermatopathologist reviewed pathology slides to confirm AST diagnosis. Clinical information was obtained from medical records, and outcomes surveys were administered to children with AST. Twenty‐nine patients met AST diagnostic criteria and were included in this study. Mean age at first excision was 9.0 ± 4.2 (range 2.3–17.5), and 19 patients underwent more than one excision procedure to achieve clear margins. No patient had SLNB. Fourteen patients (48%) with mean follow‐up time of 8.4 years (range 3.5–15.8) completed clinical outcomes surveys. Outcomes with mean follow‐up time of 2.8 years (range 0.02–8.1 years) were obtained for 10 additional patients from medical records. There were no reports of recurrence, additional lesions, or metastases in these 24 patients. We report one of the largest series of children with AST treated using excision alone and who remain disease free after a significant follow‐up period. Our data suggest that SLNB is not warranted in the routine management of pediatric AST. We recommend complete excision with clear margins and careful clinical follow‐up.

The Impact of Macromastia on Adolescents: A Cross-Sectional Study

OBJECTIVE: To determine the physical and psychosocial impact of macromastia on adolescents considering reduction mammaplasty in comparison with healthy adolescents. METHODS: The following surveys were administered to adolescents with macromastia and control subjects, aged 12 to 21 years: Short-Form 36v2, Rosenberg Self-Esteem Scale, Breast-Related Symptoms Questionnaire, and Eating-Attitudes Test-26 (EAT-26). Demographic variables and self-reported breast symptoms were compared between the 2 groups. Linear regression models, unadjusted and adjusted for BMI category (normal weight, overweight, obese), were fit to determine the effect of case status on survey score. Odds ratios for the risk of disordered eating behaviors (EAT-26 score ≥20) in cases versus controls were also determined. RESULTS: Ninety-six subjects with macromastia and 103 control subjects participated in this study. Age was similar between groups, but subjects with macromastia had a higher BMI (P = .02). Adolescents with macromastia had lower Short-Form 36v2 domain, Rosenberg Self-Esteem Scale, and Breast-Related Symptoms Questionnaire scores and higher EAT-26 scores compared with controls. Macromastia was also associated with a higher risk of disordered eating behaviors. In almost all cases, the impact of macromastia was independent of BMI category. CONCLUSIONS: Macromastia has a substantial negative impact on health-related quality of life, self-esteem, physical symptoms, and eating behaviors in adolescents with this condition. These observations were largely independent of BMI category. Health care providers should be aware of these important negative health outcomes that are associated with macromastia and consider early evaluation for adolescents with this condition.

Human genetics of GPR54.

Idiopathic hypogonadotropic hypogonadism (IHH) is a condition characterized by absence of sexual maturation in the setting of low sex steroids and low/normal gonadotropins. Despite its rarity, considerable genetic heterogeneity and phenotypic variability exists in this disorder. Loss of function mutations in a G protein coupled receptor, GPR54, have been shown to cause IHH. Although mutations in GPR54 are not a common cause of this condition, patients bearing mutations are critical to explore genotype-phenotype correlations and gene function. In this review, we will examine the human genetics studies of GPR54, the phenotypic implications of mutations in this gene, and the emerging roles of the kisspeptin/GPR54 pathway.

The effect of obesity on early outcomes in adolescents undergoing reduction mammaplasty.

It is not known whether obesity portends poorer outcomes following reduction mammaplasty in adolescent macromastia patients. We review symptoms in obese and nonobese adolescent macromastia patients and describe early outcomes following reduction mammaplasty. Demographics, operative details, and postoperative follow-up data were collected on 67 patients seen at our institution between 1997 and 2008. Variables were compared using 2-sample t tests or Pearson &khgr;2/Fisher exact tests. Mean age at surgery was 17.1 ± 1.6 years. Mean body mass index was 27.9 ± 4.5 kg/m2, and 32.8% were obese. Thirty-four patients (50.7%) experienced minor complications; 1 patient experienced a major complication. Of patients with complications, obese patients reported a greater number than nonobese patients (P = 0.013). There were no differences in the type of complication or self-reported satisfaction between obese and nonobese patients 34.4 ± 25.7 weeks after surgery. Our findings suggest that reduction mammaplasty is well-tolerated in obese and nonobese adolescents with macromastia and that obesity is not an absolute contraindication to reduction mammaplasty in adolescents.

Diagnosis and Management of Fibroadenomas in the Adolescent Breast

Fibroadenomas are benign breast masses that can present a management challenge in adolescent populations. Most fibroadenomas may be managed conservatively without surgery, but those masses that are symptomatic or increasing in size may require surgical excision. In adolescents, the implications of surgical intervention in the breast are unclear, and there is little outcomes data. In this article, the authors discuss the presentation, diagnosis, and management of fibroadenoma in adolescents. Key considerations for physicians in treating these masses in this population are reviewed.

Psychosocial impact of adolescent gynecomastia: a prospective case-control study.

Background: The purpose of this study was to determine the physical and psychosocial impact of gynecomastia and its severity on adolescents seeking treatment as compared with healthy adolescent males. Methods: The following surveys were administered to adolescents with gynecomastia and healthy male controls, aged 12 to 21 years: Short Form-36 Version 2, the Rosenberg Self-Esteem Scale, and the Eating Attitudes Test-26. Demographic variables were compared between the two groups, and controls were administered a short chest symptoms survey. Linear regression models, unadjusted and adjusted for body mass index category, were fit to determine the effect of case status and graded severity of gynecomastia on survey score. Results: Forty-seven patients with gynecomastia and 92 male control subjects participated in this study. There was no difference in mean age between the groups, although patients with gynecomastia had a significantly higher body mass index. Gynecomastia subjects had three lower Short Form-36 domain and Rosenberg Self-Esteem Scale scores independent of body mass index category as compared with controls, although there was no difference in Eating Attitudes Test-26 scores between the groups. Graded gynecomastia severity had no effect on survey scores, all independent of body mass index category. Conclusions: Gynecomastia has a significant negative impact on primarily the psychosocial well-being of affected adolescent patients, specifically in regard to social functioning, mental health, and self-esteem. Psychosocial impact was not affected by graded severity of disease. Health care providers and patients should be aware of the psychosocial impairments associated with gynecomastia and consider early treatment for adolescents suffering from this condition, regardless of severity. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Psychological impact of breast asymmetry on adolescents: a prospective cohort study.

Background: This study measures the impact of adolescent breast asymmetry compared with macromastia and female controls. Methods: The following surveys were given to patients with breast asymmetry, macromastia, and controls aged 12 to 21 years: Short Form Health Survey, Version 2 (Short Form-36), the Rosenberg Self-Esteem Scale, and the Eating Attitudes Test. Demographics were compared, and linear regression models, adjusted for body mass index category and age, were fit to determine the effect of case status on survey score. Results: Fifty-nine adolescents with asymmetry, 142 controls, and 160 macromastia patients participated. After controlling for differences in body mass index category, asymmetry patients scored lower on psychological Short Form-36 domains and the Rosenberg Self-Esteem Scale than controls (p < 0.05), but did not differ in physical health. When compared with macromastia adolescents, asymmetry patients scored significantly better on Short Form-36 physical health domains (p < 0.05), but had similar decrements in emotional functioning, mental health, self-esteem, and eating behaviors/attitudes, after accounting for differences in age. Age and asymmetry type and severity had no effect on survey scores, independent of body mass index category (p > 0.05). Asymmetry patients had a higher mean body mass index percentile than controls (83.36 versus 73.52) but did not differ from that of macromastia patients (83.39). Conclusions: Breast asymmetry may negatively impact the psychological quality of life of adolescents similar to macromastia. Breast asymmetry is not just a cosmetic issue. Providers should be aware of the psychological impairments associated with asymmetry and provide proper support. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.