Subject(s)
Aromatase , Gynecomastia , Humans , Gynecomastia/genetics , Male , Child , Aromatase/genetics , Anastrozole , Exome Sequencing , Nitriles , Triazoles/therapeutic use , Phenotype , Mutation , Breast/abnormalities , Breast/pathology , PedigreeABSTRACT
INTRODUCTION: The recommendations for annual mammography for male carriers with gynecomastia are controversial. This study investigated the potential link between gynecomastia and breast cancer in male carriers. PATIENTS AND METHODS: The database of a tertiary medical center was retrospectively searched for all male patients who underwent at least 1 digital mammography study from 2016 to 2023. Known carriers of a pathogenic variant in a high-risk breast-cancer gene were identified. Patients were stratified by carrier status, diagnosis of breast cancer, and diagnosis of gynecomastia. Data on demographics, hormone profile, and pathology results were compared. RESULTS: The cohort included 446 men of whom 82 were known carriers. Gynecomastia was diagnosed by mammography in 251 patients: 239/364 noncarriers (66%) and 12/82 carriers (15%) (P < .0001). Breast cancer was found in 21/364 noncarriers (6%) and 6/82 carriers (7%) (P < .6), and in 10/251 patients with gynecomastia (4%) and 17/193 (9%) without gynecomastia (P < .05). Among patients without gynecomastia, the number of breast cancer cases was similar in carriers and noncarriers (P = .3). Among patients with gynecomastia, the rate of breast cancer was higher in carriers (P < .08). On logistic regression analysis, the effect of gynecomastia on carriers was significant (P = .02). The odds ratio for a breast cancer diagnosis was 5.8 in the presence of gynecomastia (95% CI, 1.1-31, P < .04) and 0.52 in the absence of gynecomastia (95% CI, 0.2-1.7, P < .3). CONCLUSION: Gynecomastia may be associated with an increased risk of breast cancer in carriers. Larger studies are needed to determine whether and when to screen male carriers.
Subject(s)
Breast Neoplasms, Male , Early Detection of Cancer , Gynecomastia , Mammography , Mutation , Humans , Gynecomastia/genetics , Gynecomastia/diagnostic imaging , Male , Retrospective Studies , Breast Neoplasms, Male/genetics , Breast Neoplasms, Male/diagnostic imaging , Breast Neoplasms, Male/pathology , Middle Aged , Adult , Early Detection of Cancer/methods , Aged , Heterozygote , Genetic Predisposition to Disease , BRCA1 Protein/genetics , BRCA2 Protein/geneticsABSTRACT
Androgen insensitivity syndrome (AIS) is a rare disorder with X-linked recessive inheritance in 46 XY patients. The clinical manifestations vary between patients, especially regarding external genitalia development. Herein, the case of AIS in a 13-year-old male, who was born with hypospadias and presented to the hospital with gynaecomastia that had developed from 8 years of age, is reported. No micropenis, cryptorchidism or bifid scrotum were found. Testis volume was 12 ml on both sides. His testosterone and luteinizing hormone levels were normal compared with sex- and age-adjusted reference range. His bone age was approximately 13 years according to Greulich-Pyle assessment. Sequence analysis of the androgen receptor (AR) gene revealed a mutation (c.2041A>G) in exon 4, a novel mutation site in the AR gene. Prediction analysis suggested this to be a disease-causing variant. A milder clinical presentation and normal hormone levels in cases of partial AIS might differ from the usually reported signs and symptoms. A diagnosis of AIS should not be ignored in teenage patients who present with gynaecomastia and hypospadias, but normal hormone levels.
Subject(s)
Androgen-Insensitivity Syndrome , Gynecomastia , Hypospadias , Male , Adolescent , Humans , Androgen-Insensitivity Syndrome/diagnosis , Androgen-Insensitivity Syndrome/genetics , Gynecomastia/diagnosis , Gynecomastia/genetics , Receptors, Androgen/genetics , Hypospadias/diagnosis , Hypospadias/genetics , Mutation , TestosteroneABSTRACT
Peutz-Jeghers Syndrome (Peutz-Jeghers Syndrome, PJS) refers to syndromes of hereditary tumor predisposition and is caused by pathological variants of the STK11 gene, leading to a defect in the synthesis of serine/threonine kinase 11 protein, which acts as a tumor suppressor.Clinical symptoms of the syndrome are combination of hamartomatous polyposis of the gastrointestinal tract and specific skin-mucosal hyperpigmentation. Also, this disease is characterized by a high risk of developing gastrointestinal and extra-intestinal tumors, including benign or malignant tumors of the reproductive system.One of the first signs of the disease in male patients may be prepubertal gynecomastia associated with large-cell calcifying Sertoli cells tumors expressing aromatase. In contrast to from pubertal gynecomastia, prepubertal is extremely rare, and it is often based on pathological causes. Early diagnosis of patients with pre-pubertal gynecomastia, including Peitz-Jaegers syndrome, defines the tactics of gynecomastia management and protocols for monitoring the development of other components of the disease in the future.This article describes two patients with pre-pubertal gynecomastia and Peitz-Jaegers syndrome with different molecular genetic defects: in one case associated with duplication of the STK11 gene site, in the other - with microdeletion of the short arm of chromosome 19 containing this gene.
Subject(s)
Charadriiformes , Gynecomastia , Hyperpigmentation , Neoplastic Syndromes, Hereditary , Peutz-Jeghers Syndrome , Humans , Male , Animals , Peutz-Jeghers Syndrome/complications , Peutz-Jeghers Syndrome/genetics , Gynecomastia/genetics , Genotype , Genetic Predisposition to DiseaseABSTRACT
Aromatase deficiency (AD) is a rare autosomal recessive genetic disease caused by loss-of-function mutations in aromatase gene (CYP19A1), leading to congenital estrogen deficiency syndrome. Both mothers of AD patients during pregnancy and female AD fetus show virilization, while male patients are usually diagnosed in adulthood due to continued height increase and metabolic abnormalities. In 2019, a patient with AD was admitted in the Second Xiangya Hospital. The patient was a 37-year-old adult male who continued to grow linearly after adulthood. His estradiol was below the measurable line, the follicle-stimulating hormone (FSH) increased, bone age delayed, epiphysis unfused, and the bone mass reduced. CYP19A1 gene detection showed that c.1093C>T, p.R365W was homozygous mutation. This disease is rare in clinic. Clinicians need to raise awareness of the disease for early diagnosis and treatment to improve the long-term prognosis of patients.
Subject(s)
46, XX Disorders of Sex Development , Gynecomastia , 46, XX Disorders of Sex Development/genetics , Adult , Aromatase/deficiency , Aromatase/genetics , Aromatase/metabolism , Female , Gynecomastia/genetics , Humans , Infertility, Male , Male , Metabolism, Inborn Errors , Mutation , PregnancyABSTRACT
OBJECTIVE: To explore the clinical and genetic basis for a patient with isolated 17,20 lyase deficiency presenting with pubertal gynecomastia. METHODS: Clinical manifestation, steroid analysis as well as genetic testing were carried out for a 14-year-old boy featuring puberty gynecomastia. RESULTS: The patient was admitted due to puberty gynecomastia for 2 years. Physical examination showed Tanner B5, G2 and normal blood pressure. Laboratory examination showed normal range of serum potassium and blood gas. Steroid analysis revealed extremely high pregnenolone, progesterone, 17-hydropregnenolone and 17-hydroprogesterone, Correspondingly, the DHEA, androstenedione, testosterone and dihydrotestosterone were low. He was found to harbor compound heterozygous variants of CYP17A1 gene (c.1304T>C/p.F435S and c.1346G>A/p.R449H), among which the R449H variant may result in isolated 17,20 lyase deficiency by altering the structure of redox-partner binding site. CONCLUSION: Isolated 17,20 lyase is a rare cause for puberty gynecomastia. The p.R449H variant of the CYP17A1 gene can result in isolated 17,20 lyase deficiency.
Subject(s)
Gynecomastia , Steroid 17-alpha-Hydroxylase , Adolescent , Genetic Testing , Gynecomastia/genetics , Humans , Male , Steroid 17-alpha-Hydroxylase/geneticsABSTRACT
OBJECTIVES: Gynecomastia may be due to aromatase excess in several diseases such as obesity and cancer. Aromatase excess syndrome (AEXS) is an autosomal dominant disorder caused by overexpression of CYP19A1. Germinal mutations occurring in AEXS include various genomic rearrangements including duplication, deletion, and inversion identified in the upstream region of CYP19A1. Aromatase overexpression caused by a CYP19A1 somatic mutation has been rarely described. METHODS: Breast adipose tissue biopsies or surgical specimens were obtained from 19 subjects with gynecomastia. Aromatase quantification was performed by digital PCR and CYP19A1 sequencing by RACE PCR products. RESULTS: We observed localized aromatase overexpression (>10 fold greater than normal) in breast adipose tissue from three prepubertal males with gynecomastia out of the 19 cases. One carried a chromosomal rearrangement between CYP19A1 and DMXL2, consistent with AEXS. In the 2 others, the first exon of CYP19A1 contained 11 different tissue-specific promoter subtypes, specifically I.4 or I.3 normally expressed by adipose tissue, but also the placental I.2 promoter and the more ubiquitous I.7 which is usually expressed in breast cancer, uterine, and endothelial tissues. No differences in clinical or biochemical characteristics were observed between these 3 subjects and 16 others without aromatase overexpression. CONCLUSIONS: We describe two cases of aromatase overexpression in breast adipose tissue associated with nonspecific promoter recruitment. Further investigations are necessary to understand the mechanisms involved in aberrant promoter selection.
Subject(s)
Aromatase , Gynecomastia , Aromatase/genetics , Aromatase/metabolism , Female , Gynecomastia/genetics , Gynecomastia/pathology , Humans , Male , Metabolism, Inborn Errors , Pregnancy , Promoter Regions, Genetic/geneticsABSTRACT
OBJECTIVES: Androgen receptor gene CAG repeat, AR (CAG)n, polymorphism is thought to have an effect on male reproductive functions and a relationship between long AR (CAG)n and decreased androgenic activity has been shown. Therefore, we hypothesized that in adolescents with long AR CAG repeat the prevalence of pubertal gynecomastia (PG) will be higher and we aimed to investigate the association between AR (CAG)n polymorphism and PG in Turkish adolescents. METHODS: Adolescents with PG between 11 and 19 years of age were enrolled as the study group and healthy individuals without a history of PG, who were at least 14 years of age and Tanner 4 or 5 were enrolled as the control group. The AR (CAG)n length was detected by direct DNA sequencing analysis and reproductive hormones were measured by standardized analyses. RESULTS: The mean AR (CAG)n was 22.3 ± 2.6 (mean ± SD) in the PG group (n=101) and 21.9 ± 3.1 (mean ± SD) in the control group (n=88) (p=0.276). The adolescents with short AR (CAG)n had lower body mass index standard deviation scores (BMI SDS) compared to the adolescents with intermediate and long repeat numbers (p=0.029). CONCLUSIONS: The results of this study showed a lack of direct association between AR (CAG)n and PG. However, the significant relationship between the AR (CAG)n quartiles and BMI SDS suggests that long AR (CAG)n might cause PG indirectly. Further studies are needed to better clarify this relationship.
Subject(s)
Gynecomastia , Receptors, Androgen/genetics , Adolescent , Body Mass Index , Gynecomastia/genetics , Humans , Male , Polymorphism, Genetic , Trinucleotide Repeats/geneticsABSTRACT
Estrogens regulate pubertal development and reproductive function in women, spermatogenesis in men, and bone turnover and metabolic conditions in individuals of both sexes. Estradiol, the major estrogen in humans, is synthesized from testosterone by the action of aromatase and exerts its effects though binding to estrogen receptors. Germline loss- and gain-of-function variants in CYP19A1, the gene encoding aromatase, lead to aromatase deficiency and aromatase excess syndrome, respectively. Germline loss-of-function variants in ESR1, the gene encoding estrogen receptor α, are known to cause of estrogen insensitivity/resistance. In addition, rare variants in ESR1 and ESR2 have been implicated in various disease phenotypes. Clinical studies on these rare endocrine disorders provided clues to understand the biological functions of estrogens in the human body. This review introduces the genetic basis, phenotypes, and current management procedures of congenital disorders in estrogen biosynthesis and action.
Subject(s)
46, XX Disorders of Sex Development , Gynecomastia , Metabolism, Inborn Errors , 46, XX Disorders of Sex Development/genetics , 46, XX Disorders of Sex Development/metabolism , Aromatase/genetics , Aromatase/metabolism , Estrogen Receptor alpha/genetics , Estrogen Receptor alpha/metabolism , Estrogens/physiology , Female , Gynecomastia/genetics , Gynecomastia/metabolism , Humans , Male , Metabolism, Inborn Errors/geneticsABSTRACT
Aromatase deficiency (AD) is a rare autosomal recessive genetic disease caused by loss-of-function mutations in aromatase gene (CYP19A1), leading to congenital estrogen deficiency syndrome. Both mothers of AD patients during pregnancy and female AD fetus show virilization, while male patients are usually diagnosed in adulthood due to continued height increase and metabolic abnormalities. In 2019, a patient with AD was admitted in the Second Xiangya Hospital. The patient was a 37-year-old adult male who continued to grow linearly after adulthood. His estradiol was below the measurable line, the follicle-stimulating hormone (FSH) increased, bone age delayed, epiphysis unfused, and the bone mass reduced. CYP19A1 gene detection showed that c.1093C>T, p.R365W was homozygous mutation. This disease is rare in clinic. Clinicians need to raise awareness of the disease for early diagnosis and treatment to improve the long-term prognosis of patients.
Subject(s)
Adult , Female , Humans , Male , Pregnancy , 46, XX Disorders of Sex Development/genetics , Aromatase/metabolism , Gynecomastia/genetics , Infertility, Male , Metabolism, Inborn Errors , MutationABSTRACT
CONTEXT: 17α-Hydroxylase/17,20-lyase deficiency (17OHD) caused by mutations in the CYP17A1 gene is a rare form of congenital adrenal hyperplasia typically characterised by cortisol deficiency, mineralocorticoid excess and sex steroid deficiency. OBJECTIVE: To examine the phenotypic spectrum of 17OHD by clinical and biochemical assessment and corresponding in silico and in vitro functional analysis. DESIGN: Case series. PATIENTS AND RESULTS: We assessed eight patients with 17OHD, including four with extreme 17OHD phenotypes: two siblings presented with failure to thrive in early infancy and two with isolated sex steroid deficiency and normal cortisol reserve. Diagnosis was established by mass spectrometry-based urinary steroid profiling and confirmed by genetic CYP17A1 analysis, revealing homozygous and compound heterozygous sequence variants. We found novel (p.Gly111Val, p.Ala398Glu, p.Ile371Thr) and previously described sequence variants (p.Pro409Leu, p.Arg347His, p.Gly436Arg, p.Phe53/54del, p.Tyr60IlefsLys88X). In vitro functional studies employing an overexpression system in HEK293 cells showed that 17,20-lyase activity was invariably decreased while mutant 17α-hydroxylase activity retained up to 14% of WT activity in the two patients with intact cortisol reserve. A ratio of urinary corticosterone over cortisol metabolites reflective of 17α-hydroxylase activity correlated well with clinical phenotype severity. CONCLUSION: Our findings illustrate the broad phenotypic spectrum of 17OHD. Isolated sex steroid deficiency with normal stimulated cortisol has not been reported before. Attenuation of 17α-hydroxylase activity is readily detected by urinary steroid profiling and predicts phenotype severity. SIGNIFICANCE STATEMENT: Here we report, supported by careful phenotyping, genotyping and functional analysis, a prismatic case series of patients with congenital adrenal hyperplasia due to 17α-hydroxylase (CYP17A1) deficiency (17OHD). These range in severity from the abolition of function, presenting in early infancy, and unusually mild with isolated sex steroid deficiency but normal ACTH-stimulated cortisol in adult patients. These findings will guide improved diagnostic detection of CYP17A1 deficiency.
Subject(s)
Steroid 17-alpha-Hydroxylase/genetics , Adolescent , Adrenal Hyperplasia, Congenital/genetics , Amenorrhea/genetics , Computer Simulation , Corticosterone/urine , Failure to Thrive/enzymology , Failure to Thrive/genetics , Female , Gas Chromatography-Mass Spectrometry , Gonadal Steroid Hormones/deficiency , Gynecomastia/etiology , Gynecomastia/genetics , HEK293 Cells , Humans , Hydrocortisone/deficiency , Infant , Infant, Newborn , Male , Mineralocorticoids/metabolism , Mutation/genetics , Phenotype , Steroids/urine , Young AdultABSTRACT
OBJECTIVES: Aromatase deficiency is a rare autosomal recessive disease that results in the absence of aromatase. In females it presents with ambiguous genitalia and lack of secondary sexual characteristics during puberty. Aromatase deficiency is not attributed to any specific population, but it is more commonly seen in consanguineous parents. Herein, we report the first Old Order Mennonite family with that diagnosis. CASE PRESENTATION: Our proband is an Old Order Mennonite female born with ambiguous genitalia who was identified to carry novel homozygous variant in the CYP19A1 gene c.1304G>A (p. Arg435His). Her older brother was later confirmed with the same genetic diagnosis. CONCLUSIONS: Recognizing the cultural sensitivity, unrecognized affected cases, and late presentation of males affected with aromatase deficiency, this condition may be more prevalent than believed in that population.
Subject(s)
46, XX Disorders of Sex Development/diagnosis , Aromatase/deficiency , Gynecomastia/diagnosis , Infertility, Male/diagnosis , Metabolism, Inborn Errors/diagnosis , Mutation , 46, XX Disorders of Sex Development/enzymology , 46, XX Disorders of Sex Development/genetics , Adult , Aromatase/genetics , Female , Gynecomastia/enzymology , Gynecomastia/genetics , Homozygote , Humans , Infant, Newborn , Infertility, Male/enzymology , Infertility, Male/genetics , Male , Metabolism, Inborn Errors/enzymology , Metabolism, Inborn Errors/genetics , VirilismABSTRACT
We have produced RNA sequencing data for 53 primary cells from different locations in the human body. The clustering of these primary cells reveals that most cells in the human body share a few broad transcriptional programs, which define five major cell types: epithelial, endothelial, mesenchymal, neural, and blood cells. These act as basic components of many tissues and organs. Based on gene expression, these cell types redefine the basic histological types by which tissues have been traditionally classified. We identified genes whose expression is specific to these cell types, and from these genes, we estimated the contribution of the major cell types to the composition of human tissues. We found this cellular composition to be a characteristic signature of tissues and to reflect tissue morphological heterogeneity and histology. We identified changes in cellular composition in different tissues associated with age and sex, and found that departures from the normal cellular composition correlate with histological phenotypes associated with disease.
Subject(s)
Transcription, Genetic , Cell Line , Endothelial Cells/metabolism , Epithelial Cells/metabolism , Female , Gene Expression Profiling , Gynecomastia/genetics , Gynecomastia/metabolism , Humans , Male , Mesoderm/cytology , Mesoderm/metabolism , Neoplasms/genetics , Organ Specificity , Sequence Analysis, RNAABSTRACT
BACKGROUND: Aromatase deficiency (AD) caused by cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1) variants is characterized by a deficiency in androgen-to-oestrogen conversion. OBJECTIVE: To investigate the clinical characteristics and accurate management of aromatase-deficient children. PATIENTS AND METHODS: We described three 46, XX aromatase-deficient children, searched PubMed with "(aromatase deficiency) AND (46, XX OR ovaries)" and manually searched citations in identified studies for the literature review. RESULTS: Two girls and one boy (3.4-9.2 years) with the 46, XX karyotype presented ambiguous genitalia and maternal antenatal virilization, normal-low height, delayed bone age, normal glucose and lipid profiles, markedly elevated follicle-stimulating hormone (FSH) levels and poor oestradiol responses to human menopausal gonadotropin stimulation. Ultrasound revealed normal-sized uterus and ovaries with undetectable follicles. Histopathology revealed primordial follicles and few primary follicles in ovaries. One patient presented granulosa and follicular membrane cell proliferation and interstitial sclerosis. We identified four CYP19A1 variants; c.146_158del and c.344G >A were unreported. We reviewed available data from thirty 46, XX patients (0.2-32 years). Some patients were not diagnosed until puberty/adulthood; three were initially misdiagnosed with congenital adrenocortical hyperplasia. The main characteristics were maternal antenatal virilization (21/29), ambiguous genitalia (mainly Prader IV or III, 19/23), delayed bone age (16/17), low bone mass (5/8), markedly elevated FSH levels and ovarian cysts (13/30). CONCLUSIONS: 46, XX AD is easily neglected or misdiagnosed. Ambiguous genitalia, maternal antenatal virilization and markedly elevated FSH levels are important diagnostic indicators. We described two novel variants, new histopathological features of ovaries and an early management strategy.
Subject(s)
46, XX Disorders of Sex Development , Gynecomastia , 46, XX Disorders of Sex Development/genetics , Adult , Aromatase/deficiency , Aromatase/genetics , Child , China , Female , Follicle Stimulating Hormone , Gynecomastia/genetics , Humans , Infertility, Male , Male , Metabolism, Inborn Errors , PregnancyABSTRACT
Aromatase deficiency rarely causes a 46,XX sexual differentiation disorder. The CYP19A1 gene encodes the aromatase enzyme which catalyses the conversion of androgens to oestrogens. In cases with 46,XX karyotype, mutations in the CYP19A1 gene can lead to disorders of sex development. Clinical findings in aromatase deficiency vary depending on the degree of deficiency. The effect of increased androgens, including acne, cliteromegaly and hirsutism, can be observed in mothers with placental aromatase deficiency. A decrease in maternal virilisation symptoms is observable in the postpartum period. It is rarely reported that there is no virilization in pregnancy. In this study, two 46,XX sibling having the p.R115X (c.343 C>T) novel pathogenic variant in the CYP19A1 gene and raised as different genders, with no maternal virilisation during pregnancy, are presented. In conclusion, 46,XX virilised females should be examined in terms of aromatase deficiency once congenital adrenal hyperplasia has been excluded, even if there is no history of maternal virilisation during pregnancy.
Subject(s)
46, XX Disorders of Sex Development/genetics , Aromatase/deficiency , Gynecomastia/genetics , Infertility, Male/genetics , Metabolism, Inborn Errors/genetics , 46, XX Disorders of Sex Development/complications , 46, XX Disorders of Sex Development/etiology , Adolescent , Aromatase/genetics , Child , Female , Gynecomastia/complications , Humans , Infertility, Male/complications , Male , Metabolism, Inborn Errors/complications , SiblingsABSTRACT
Prolactin (PRL) levels can usually be controlled by PRL-inhibiting psychiatric drugs that include anti-dopamine agents. However, the use of dopamine (DA) antagonists may lead to hyperprolactinemia under certain clinical conditions. The aim of this study was to investigate postmortem PRL levels as potential markers of drug abuse, especially that of DA antagonists, in autopsy cases. We examined 121 autopsy cases, excluding cases involving acute hypoxia/ischemia, such as asphyxia, because PRL concentrations are reportedly increased under acute hypoxic conditions. Detected drugs were classified as either DA antagonists, stimulants, psychotropic drugs other than DA antagonists, or other non-psychotropic drugs, and many cases had no detected drugs. Samples comprised blood collected from the right heart chamber and cerebrospinal fluid (CSF). PRL protein level was measured by chemiluminescent immunoassay, and PRL gene expression in the anterior pituitary of autopsy cases was analyzed by reverse transcription-polymerase chain reaction. The PRL-positive cell ratio in the anterior pituitary gland was also measured by immunohistochemical analysis. The results indicated that PRL levels in the serum and CSF were higher in DA antagonist cases than in other cases. PRL levels in the serum and CSF also correlated with the PRL gene expression in cases with abuse of DA antagonists. However, no significant difference in the PRL-positive cell ratio in the anterior pituitary gland was evident between any of the classes of drug-detected and drug-undetected cases. These results suggest that postmortem measurements of PRL transcription levels may be useful for diagnosing cases of DA antagonist use.
Subject(s)
Dopamine Antagonists , Prolactin/genetics , Substance-Related Disorders/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Autopsy , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Child , Child, Preschool , Dopamine/blood , Female , Gene Expression , Gynecomastia/blood , Gynecomastia/cerebrospinal fluid , Gynecomastia/diagnostic imaging , Gynecomastia/genetics , Humans , Infant , Male , Middle Aged , Myocardium/metabolism , Prolactin/blood , Prolactin/cerebrospinal fluid , Psychotropic Drugs , RNA, Messenger/metabolism , Substance-Related Disorders/blood , Substance-Related Disorders/cerebrospinal fluid , Young AdultABSTRACT
Background Aromatase excess syndrome (AEXS) is a rare autosomal dominant disorder caused by CYP19A1 overexpression. Clinical manifestations of AEXS include pre- or peri-pubertal gynecomastia, advanced bone age and compromised adult height. Case presentation Here we report an 8-year-old boy diagnosed with AEXS by chromosomal array that revealed a 1.1 Mb novel de novo duplication at 15q21.2, with a predicted final height of 157.4 cm. We prescribed letrozole and growth hormone (GH) to maximize his linear growth. Without further bone age advancement, his height increased from 137.7 cm to 144 cm after an 8-month treatment period. Conclusions We identified a novel duplication at 15q21.2 in AEXS, and found that aromatase inhibitor (AI) plus GH might provide a better growth-promoting approach for AEXS patients.
Subject(s)
46, XX Disorders of Sex Development/genetics , 46, XX Disorders of Sex Development/pathology , Aromatase/genetics , Chromosomes, Human, Pair 15/genetics , Gene Duplication , Gynecomastia/genetics , Gynecomastia/pathology , Infertility, Male/genetics , Infertility, Male/pathology , Metabolism, Inborn Errors/genetics , Metabolism, Inborn Errors/pathology , 46, XX Disorders of Sex Development/drug therapy , Aromatase/chemistry , Aromatase Inhibitors/therapeutic use , Child , Gynecomastia/drug therapy , Humans , Infertility, Male/drug therapy , Male , Metabolism, Inborn Errors/drug therapy , PrognosisABSTRACT
Aromatase deficiency is a rare, autosomal recessive disorder in which affected patients fail to synthesize normal estrogen. Herein, we report a 46, XX patient born with virilised external genitalia. A novel homozygous mutation in the CYP19A1 gene, causing aromatase deficiency, was detected. A 30-day infant registered as a male was referred to pediatric endocrinology because of a uterus detected on ultrasonography. The infant was born at 23 gestational weeks by C-section because of preeclampsia and premature membrane rupture. The parents were consanginenous. There was no evidence of virilisation, such as acne, hirsutism, deep voice or clitoral enlargement in the maternal history. Physical examination of the infant revealed complete scrotal fusion and a single urogenital meatus, consistent with Prader stage-3. A standard dose adrenocorticotropic hormone (ACTH) test revealed an inadequate cortisol response and high 17-hydroxy progesterone levels, suggesting simple virilising congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. However, no mutation in the CYP21A2 gene was detected. At age 2.5 years the ACTH test was repeated, after suspension of hydrocortisone treatment for 48 hours, when resulting cortisol and androgen levels were normal. The patient was re-evaluated in terms of 46, XX disorders of sex development (DSD), especially with a suspicion of aromatase deficiency. A novel, homozygous, exon 6 deletion was identified in the CYP19A1 gene. Aromatase deficiency may be confused with CAH in the newborn period. In this case 46, XX DSD aromatase deficiency was present in the absence of a history of maternal virilisation or large and multicystic ovaries.
Subject(s)
46, XX Disorders of Sex Development/genetics , Adrenal Hyperplasia, Congenital/genetics , Aromatase/deficiency , Gynecomastia/genetics , Homozygote , Infertility, Male/genetics , Metabolism, Inborn Errors/genetics , Mutation , Virilism/genetics , 46, XX Disorders of Sex Development/pathology , Adrenal Hyperplasia, Congenital/pathology , Aromatase/genetics , Exons , Female , Gynecomastia/pathology , Humans , Infant, Newborn , Infertility, Male/pathology , Male , Metabolism, Inborn Errors/pathology , PrognosisABSTRACT
Aromatase deficiency is a rare autosomal recessive genetic disorder with an unknown incidence. Aromatase converts androgens into estrogen in the gonadal and extra-gonadal tissues. Aromatase deficiency causes ambiguous genitalia in the female fetus and maternal virilization (hirsutism, acne, cliteromegaly, deep voice) during pregnancy due to increased concentration of androgens. A 19 months old girl patient was assessed due to presence of ambiguous genitalia. There were findings of maternal virilization during pregnancy. The karyotype was 46,XX. Congenital adrenal hyperplasia was not considered since adrenocorticotropic hormone, cortisol, and 17-hydroxyprogesterone levels were within normal ranges. At age two months, follicle-stimulating hormone and total testosterone levels were elevated and estradiol level was low. Based on these findings, aromatase deficiency was suspected. A novel homozygous mutation IVS7-2A>G (c.744-2A>G) was identified in the CYP19A1 gene. Pelvic ultrasound showed hypoplasic ovaries rather than large and cystic ovaries. We identified a novel mutation in the CYP19A1 gene in a patient who presented with ambiguous genitalia and maternal virilization during pregnancy. Presence of large and cystic ovaries is not essential in aromatase deficiency.
Subject(s)
46, XX Disorders of Sex Development/genetics , Aromatase/deficiency , Genetic Predisposition to Disease/genetics , Gynecomastia/genetics , Infertility, Male/genetics , Metabolism, Inborn Errors/genetics , Mutation , 46, XX Disorders of Sex Development/diagnosis , Aromatase/genetics , Disorders of Sex Development/genetics , Female , Gynecomastia/diagnosis , Homozygote , Humans , Infant , Infertility, Male/diagnosis , Metabolism, Inborn Errors/diagnosisABSTRACT
17-beta hydroxysteroid dehydrogenase type 3 (17ßHSD-3) enzyme catalyzes the conversion of androstenedione (Δ4) to testosterone (T) in the testes of the developing fetus, thus playing a crucial role in the differentiation of the gonads and in establishing the male sex phenotype. Any mutation in the encoding gene (HSD17B3) can lead to varying degrees of undervirilization of the affected male, ranging from completely undervirilized external female genitalia to predominantly male with micropenis and hypospadias. We present here an infant who was referred to our clinic because of ambiguous genitalia at birth. Gonads were palpable in the inguinal canal bilaterally and no Müllerian structures were identified on pelvic ultrasound. Because of a low T/Δ4 ratio after a human chorionic gonadotropin stimulation test, a tentative diagnosis of 17ßHSD-3 deficiency was made which was confirmed after genetic analysis of the HSD17B3 gene of the patient. The molecular analysis identified compound heterozygosity of two previously described mutations and could offer some further validation for the idea of a founder effect for 655-1;GâA mutation in the Greek population.