RESUMO
Several aspects of clinical management of 46,XX congenital adrenal hyperplasia (CAH) remain unsettled and controversial. The North American Disorders/Differences of Sex Development (DSD) Clinician Survey investigated changes, over the last two decades, in clinical recommendations by specialists involved in the management of newborns with DSD. Members of the (Lawson Wilkins) Pediatric Endocrine Society and the Societies for Pediatric Urology participated in a web-based survey at three timepoints: 2003-2004 (T1, n = 432), 2010-2011 (T2, n = 441), and 2020 (T3, n = 272). Participants were presented with two clinical case scenarios-newborns with 46,XX CAH and either mild-to-moderate or severe genital masculinization-and asked for clinical recommendations. Across timepoints, most participants recommended rearing the newborn as a girl, that parents (in consultation with physicians) should make surgical decisions, performing early genitoplasty, and disclosing surgical history at younger ages. Several trends were identified: a small, but significant shift toward recommending a gender other than girl; recommending that adolescent patients serve as the genital surgery decision maker; performing genital surgery at later ages; and disclosing surgical details at younger ages. This is the first study assessing physician recommendations across two decades. Despite variability in the recommendations, most experts followed CAH clinical practice guidelines. The observation that some of the emerging trends do not align with expert opinion or empirical evidence should serve as both a cautionary note and a call for prospective studies examining patient outcomes associated with these changes.
Assuntos
Hiperplasia Suprarrenal Congênita , Humanos , Feminino , Masculino , Inquéritos e Questionários , Recém-Nascido , América do Norte , Adolescente , Padrões de Prática Médica , Transtornos do Desenvolvimento Sexual/cirurgia , AdultoRESUMO
Clinical decision-making for individuals with 46,XY disorders/differences of sex development (DSD) remains unsettled and controversial. The North American DSD Clinician Survey examines the recommendations of a large group of clinical specialists over the last two decades. Active members of the (Lawson Wilkins) Pediatric Endocrine Society and the Societies for Pediatric Urology were invited to respond to a web-based survey at three different timepoints: 2003-2004 (T1), 2010-2011 (T2), and 2019-2020 (T3). Data from 429 participants in T1, 435 in T2, and 264 in T3 were included in this study. The participants were presented with three XY newborn clinical case scenarios-micropenis, partial androgen insensitivity syndrome, and iatrogenic penile ablation-and asked for clinical management recommendations. The main outcomes assessed included the recommended gender of rearing, surgical decision-maker (parent or patient), timing of genital surgery, and age at which to disclose medical details and surgical history to the patient. For all scenarios, the overwhelming majority recommended rearing as male, including a significant increase across timepoints in those recommending a male gender of rearing for the infant with penile ablation. The proportions recommending female gender of rearing declined significantly across timepoints. In general, most recommended parents (in consultation with the physician) serve as surgical decision-makers, but these proportions declined significantly across timepoints. Recommendations on the timing of surgery varied based on the patient's gender and type of surgery. There has been a shift in recommendations away from the "optimal gender policy" regarding gender of rearing and surgical interventions for patients with XY DSD.
Assuntos
Transtorno 46,XY do Desenvolvimento Sexual , Humanos , Masculino , Feminino , Endocrinologistas , Urologistas , América do Norte , Recém-Nascido , Tomada de Decisão Clínica , Adulto , Padrões de Prática Médica/estatística & dados numéricos , Inquéritos e Questionários , CriançaAssuntos
Febre Suína Africana/epidemiologia , Animais Selvagens/virologia , Suínos/virologia , Febre Suína Africana/prevenção & controle , Animais , Animais Selvagens/classificação , Bornéu/epidemiologia , Espécies em Perigo de Extinção/estatística & dados numéricos , Extinção Biológica , Floresta Úmida , Suínos/classificação , Vacinas ViraisRESUMO
PURPOSE OF REVIEW: In this review, we outline the usage and formulations of gonadotropin-releasing hormone analogs (GnRHas) in central precocious puberty (CPP), short stature, and gender diverse individuals, as well as adverse effects, long-term outcomes, and monitoring of therapy. There is a particular focus on citing references published within the last 24âmonths. RECENT FINDINGS: Long-acting formulations of GnRHa now include Federal Drug Administration approval for subcutaneous injections. Significant adverse events continue to be rarely reported; extremely rare events include arterial hypertension and pseudotumor cerebri. There continue to be no significant long-term consequences including the impact upon body mass index and bone mineral density, which appear to be transient. GnRHas have been used in differences of sexual development (DSD) and increasingly in the treatment of adolescent transgender individuals. SUMMARY: GnRHas remain as the only fully efficacious therapy for CPP and effectively suppress pubertal hormones in other situations. The use of GnRHa therapy in gender incongruent individuals has proven beneficial and has become a standard of care, whereas use in those with DSDs should still be considered experimental. VIDEO ABSTRACT: http://links.lww.com/MOP/A62.
Assuntos
Nanismo , Puberdade Precoce , Adolescente , Estatura , Densidade Óssea , Criança , Hormônio Liberador de Gonadotropina , Humanos , Puberdade Precoce/tratamento farmacológicoRESUMO
This review suggests a central theme: that the treatment of each patient presenting with evidence consistent with central precocious puberty (CPP) needs to be individualized. This pertains to multiple factors relating to growth and growth potential, monitoring patients on treatment with gonadotropin-releasing hormone analogue (GnRHa), evaluating psychological issues with CPP and therapy, and concerns about weight gain during GnRHa therapy. Individual cases are presented. New data on adult height and rate of bone age advance are included. GnRHa treatment is effective in improving adult height in children with precocious onset of puberty, rapid progression, and good growth potential. Monitoring suppression adequacy involves a random LH level < 0.6 IU/L or a GnRHa-stimulated peak LH level < 4 IU/L as long as physical exam, growth rate, and rate of bone age progression, are also consistent with suppression. Abnormal psychosocial issues are rare with concerns primarily being related perceptions, real or perceived by others.
Assuntos
Puberdade Precoce , Estatura , Hormônio Liberador de Gonadotropina , Humanos , Aumento de PesoRESUMO
The understanding, care and treatment of patients born with intersex or disorders of sex development conditions has evolved considerably over the last five decades. Regarding those who require evaluation before gender assignment is made, each "generation" of approach has been based upon and reflects the contemporary biological, social and psychological understanding. The most recent generation needs to consider the dramatically changed societal viewpoints regarding the acceptance and expansion beyond a binary perception of sexuality. This together with advances in genetic etiologies, surgical refinements and psychological support should result in better care and quality of life (QoL) outcomes for patients with these conditions. This paper reviews the successive generations of approach and discusses the multiple challenges facing the multidisciplinary teams caring for these patients today.
Assuntos
Transtornos do Desenvolvimento Sexual/psicologia , Transtornos do Desenvolvimento Sexual/terapia , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/psicologia , Hiperplasia Suprarrenal Congênita/terapia , Adulto , Congressos como Assunto , Feminino , História do Século XX , História do Século XXI , Humanos , Recém-Nascido , Masculino , Procedimentos de Cirurgia Plástica/ética , Procedimentos de Cirurgia Plástica/legislação & jurisprudência , Procedimentos de Cirurgia Plástica/psicologia , Procedimentos de Cirurgia Plástica/tendências , Procedimentos de Readequação Sexual/ética , Procedimentos de Readequação Sexual/psicologia , Procedimentos de Readequação Sexual/tendências , Sexualidade/fisiologia , Sexualidade/psicologiaRESUMO
PURPOSE: Cryptorchidism is one of the most common pediatric disorders of the male endocrine glands and the most common genital disorder identified at birth. This guideline is intended to provide physicians and non-physician providers (primary care and specialists) with a consensus of principles and treatment plans for the management of cryptorchidism (typically isolated non-syndromic). MATERIALS AND METHODS: A systematic review and meta-analysis of the published literature was conducted using controlled vocabulary supplemented with key words relating to the relevant concepts of cryptorchidism. The search strategy was developed and executed by reference librarians and methodologists to create an evidence report limited to English-language, published peer-reviewed literature. This review yielded 704 articles published from 1980 through 2013 that were used to form a majority of the guideline statements. Clinical Principles and Expert Opinions were used for guideline statements lacking sufficient evidence-based data. RESULTS: Guideline statements were created to inform clinicians on the proper methods of history-taking, physical exam, and evaluation of the boy with cryptorchidism, as well as the various hormonal and surgical treatment options. CONCLUSIONS: Imaging for cryptorchidism is not recommended prior to referral, which should occur by 6 months of age. Orchidopexy (orchiopexy is the preferred term) is the most successful therapy to relocate the testis into the scrotum, while hormonal therapy is not recommended. Successful scrotal repositioning of the testis may reduce but does not prevent the potential long-term issues of infertility and testis cancer. Appropriate counseling and follow-up of the patient is essential.
Assuntos
Criptorquidismo/diagnóstico , Criptorquidismo/cirurgia , Humanos , MasculinoRESUMO
BACKGROUND: Hormonal indicators could be useful for detecting early pubertal onset, but there is little research on how they are related to puberty in U.S. girls. We determined median age at hormonal onset of puberty based on luteinizing hormone (LH) and inhibin B (InB) and explored the extent to which body composition moderates this timing process. METHODS: We analyzed anthropometric and hormone data of 698 US peri-pubertal girls ages 6-11.99 y who had participated in the Third National Health and Nutrition Examination Survey (NHANES III), 1988-1994. RESULTS: Median age of hormonal onset of puberty was 10.43 y by LH and 10.08 y by InB cut-offs (1.04 mIU/ml for LH and 17.89 pg/ml for InB). Postnatal weight gain modulated onset, making it earlier by 10-11 mo among the highest (greater than +1 SD) relative to normal weight gainers. Onset occurred first in non-Hispanic black (NHB) girls, 10.08 y (95% confidence interval (CI): 10.07-10.09), followed by Mexican-American (MXAM) at 10.64 y (95% CI: 10.63-10.65), and at 10.66 y (95% CI: 10.66-10.67) for non-Hispanic white (NHW) girls using LH. With InB, onset occurred first in MXAM girls at 9.9 y, and at 10.3 y and 10.4 y for their NHB and NHW peers, respectively. CONCLUSION: Preadolescent weight gain lowers the age at hormonal onset as defined by LH concentrations. Preventing obesity in childhood may also avert the earlier initiation of the maturation process even at the hormonal level.
Assuntos
Composição Corporal , Inibinas/sangue , Hormônio Luteinizante/sangue , Puberdade/sangue , Fatores Etários , Biomarcadores/sangue , Peso ao Nascer , Criança , Feminino , Humanos , Recém-Nascido , Inquéritos Nutricionais , Puberdade/etnologia , Fatores Sexuais , Estados Unidos/epidemiologia , Aumento de PesoRESUMO
The treatment of adolescent males with hypogonadism using testosterone is dependent on the underlying diagnosis as well as the patient's and family's preferences. Those with testicular failure, always a pathologic condition, begin lifelong therapy, while short-term therapy is often begun for those who have a delayed puberty. There is a wide variety of testosterone formulations available, with differences in adverse events sometimes associated with the method of administration. The goals of treatment involve stimulating physical puberty, including achievement of virilization, a normal muscle mass and bone mineral density for age, and improvement in psychosocial wellbeing. While androgen therapy results in physical changes of puberty, the potential for fertility must be considered for those with permanent gonadotropin deficiency. in this population, therapy with gonadotropins or gonadotropin releasing hormone may be effective. For those with testicular failure, fertility may be possible but requires assisted reproductive procedures.
Assuntos
Hipogonadismo/tratamento farmacológico , Puberdade Tardia/tratamento farmacológico , Testosterona/análogos & derivados , Adolescente , Androgênios/uso terapêutico , Criança , Humanos , Masculino , Testosterona/uso terapêuticoRESUMO
Varicoceles are the most common cause of infertility in men. Despite the high prevalence of varicoceles, only a small percentage of men with varicoceles have subfertility or infertility. In adolescents, the prevalence of varicoceles increases dramatically during puberty to reach adult prevalence rates. The development of varicoceles during puberty can impair testicular growth and function. Data on hormonal and semen parameters in adolescents with varicoceles are limited, making it harder to determine which varicoceles are associated with infertility and which may benefit from surgery. The main indications for varicocelectomy in adolescents with varicoceles include a volume differential between unaffected and affected testes or abnormality in semen analysis.
Assuntos
Infertilidade Masculina , Varicocele , Procedimentos Cirúrgicos Vasculares , Adolescente , Humanos , Infertilidade Masculina/epidemiologia , Infertilidade Masculina/patologia , Infertilidade Masculina/cirurgia , Masculino , Prevalência , Espermatogênese/fisiologia , Varicocele/epidemiologia , Varicocele/patologia , Varicocele/cirurgiaRESUMO
A rarely reported phenomenon of rapid-tempo puberty in which the physical changes of puberty and testosterone levels increase very rapidly has not been reported outside apart from in two reviews. The resulting rapid advancement of skeletal age causes early completion of growth with shorter adult stature than expected. This appears to be genetic given its occurrence in the present report in two families, one with three brothers, one with two. We also describe potential treatments and found for the youngest that early initiation of standard therapy preserved or reclaimed adult height (AH) potential. The foreshortened AH in this situation involves rapidly advancing puberty resulting from high circulating testosterone levels leading to rapid advance in skeletal age. This was recognized earlier among younger brothers and treatment with gonadotropin-releasing analogues, growth hormone (GH) and/or aromatase inhibitor therapy (AIT) was tried. Two brothers in family A and family B were treated. Case 5 started treatment early enough so his AH was within target height (mid-parental height) range. Cases 2, 3, 4 were tried on GH and/or AIT with outcomes suggesting benefit. The prevalence and mechanism of rapid-tempo puberty requires further study. Furthermore, as illustrated by two of the current cases, this phenomenon may have a heightened prevalence, or at least may occur, in children previously diagnosed with constitutional delay of growth, underscoring the need to be cautious in assurance of a normal AH outcomes in this population, based on data from a single assessment.
Assuntos
Estatura , Puberdade , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Inibidores da Aromatase/uso terapêutico , Estatura/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/análogos & derivados , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Hormônio do Crescimento Humano/administração & dosagem , Puberdade/efeitos dos fármacos , Puberdade/fisiologia , Puberdade Precoce/tratamento farmacológico , Testosterona/uso terapêutico , Testosterona/sangue , Testosterona/administração & dosagemRESUMO
This patient, now in her 40s, was evaluated because of genital ambiguity and diagnosed with pAIS in infancy based upon elevated testosterone and gonadotropin levels and significantly reduced binding affinity of the androgen receptor. Such reduced binding is consistent with a structural abnormality of the receptor protein precluding expected activity of the androgen receptor. Based on this information and counseling, her parents chose a female sex assignment. She had clitoral recession and testes removal as an infant and neovaginal surgery using a distal ileum segment at age 11 years and was begun on estrogen therapy at age 12 years. She is being reported now to point out that the data known at her birth provided as specific information to guide sex assignment and genital surgery as is currently available. More importantly, long-term outcome data is very positive showing clear female gender identity, successful marriage of more than 20 years, excellent social relationships including family and friends, an active social life. Since this diagnosis is lifelong, it is inevitable that there will be reminders, hopefully rare, that may be traumatizing. Unfortunately, in this patient, such reminders have been related to access to health care.
RESUMO
Breast development in a girl 3 years of age or younger is a commonly encountered scenario. Nearly all of these cases will either regress or fail to progress during follow-up, confirming a diagnosis of premature thelarche (PT). Studies show that these girls will have onset of true puberty and menses at a normal age. The authors present evidence that laboratory testing, particularly basal and gonadotropin hormone-releasing hormone -stimulated gonadotropin levels, will show overlap between girls with PT and the rare patients with the onset of central precocious puberty before age 3, mainly of whom have hypothalamic hamartomas.
Assuntos
Mama , Puberdade Precoce , Pré-Escolar , Feminino , Humanos , Lactente , Mama/crescimento & desenvolvimento , Puberdade Precoce/diagnóstico , Puberdade Precoce/sangue , Puberdade Precoce/etiologiaRESUMO
46,XX individuals born with severely masculinized genitals due to congenital adrenal hyperplasia (CAH) who have been assigned male at birth and reared male can successfully establish a male gender identity/role, find employment, marry, function sexually with a female partner, and develop positive mental health status. While there were a few individuals who reportedly did not fare well or who changed gender to female, the majority of those identifying as males appear to have an overall good quality of life. Parental/family support, along with the support of others, appears essential to a positive outcome as a male, or as a female. This paper suggests that serious consideration should be given to male gender assignment and rearing and, in certain situations, is justified. Disorders of sex differentiation teams should inform parents about the option for male assignment and rearing in 46,XX CAH infants with severe genital masculinization, which is a rare condition. To provide this option is concordant with the principles of ethics, transparency and with the Endocrine Society Guidelines and the American Academy of Pediatrics' policy of fully informed consent.
Assuntos
Hiperplasia Suprarrenal Congênita , Humanos , Masculino , Recém-Nascido , Feminino , Identidade de GêneroRESUMO
Central precocious puberty (CPP) among males is less frequent than among females but more likely to have an underlying pathologic cause. Diagnosis of CPP is often straightforward among males because increased testicular volume, the first sign of puberty, can be verified although careful central nervous system (CNS) assessment is generally necessary. Treatment with gonadotropin-releasing hormone agonist (GnRHa) is indicated, given in conjunction with any therapy needed for CNS lesions. Monitoring of treatment usually can consist of evaluating growth and physical puberty and with testosterone levels as the only lab data. Short-term and long-term outcome data indicate efficacy and safety, although data are limited. Such data need to be reported.
Assuntos
Puberdade Precoce , Humanos , Puberdade Precoce/diagnóstico , Puberdade Precoce/tratamento farmacológico , Puberdade Precoce/etiologia , Puberdade Precoce/terapia , Masculino , Hormônio Liberador de Gonadotropina/agonistas , Criança , Resultado do TratamentoRESUMO
This review discusses issues and concerns in the management of aphallia, updating status of a post-pubertal individual who required further surgery after having initial surgery for aphallia as an infant. Through this case, which discusses an 18-year-old young adult who had penile agenesis, who desired further phalloplasty involving glanuloplasty and implantation of an erectile device, we highlight the importance of periodic evaluation and close follow up. Surgery during infancy or early childhood to create a penis is important for gender development in a boy, especially if there were functional testes during fetal life, even if this surgery would only be the first stage. There is a strong probability of subsequent surgery after initial phalloplasty before puberty, even with the use of currently refined techniques. Here we discuss the changing techniques that document the ongoing, continued refinement of these procedures, highlighting that further outcome data are needed to identify ways to further optimize current techniques.
Assuntos
Doenças do Pênis , Procedimentos de Cirurgia Plástica , Masculino , Lactente , Adulto Jovem , Humanos , Pré-Escolar , Adolescente , Doenças do Pênis/cirurgia , Pênis/cirurgia , Pênis/anormalidades , Ereção Peniana , Desenvolvimento SexualRESUMO
OBJECTIVES: To understand possible predictors of the onset of menses after gonadotropin-releasing hormone agonist treatment cessation in girls with central precocious puberty (CPP). METHODS: This exploratory post hoc analysis of a phase 3 and 4 trial of girls with CPP treated with once-monthly intramuscular leuprolide acetate examined onset of menses after treatment completion using a time-to-event analysis. Pretreatment and end-of-treatment chronologic age (CA), bone age (BA)/CA ratio, and Tanner breast stage; pretreatment menses status; and end-of-treatment BA and body mass index (BMI) were studied as potential factors influencing the onset of menses. RESULTS: Median time to first menses after stopping treatment was 18.3 months among 35 girls (mean age at onset of treatment, 6.8 years) examined. Of 26 girls experiencing menses, 11 (42â¯%) menstruated at 16-21 months after stopping treatment. Most girls with pretreatment BA/CA≥1.4 started menstruating very close to 18 months after stopping treatment; those with less advanced BA/CA experienced menses at 9-18 months. End-of-treatment BA/CA≥1.2 was associated with a quicker onset of menses (14.5 vs. 18.5 months for BA/CA<1.2, p=0.006). End-of-treatment BA≥12 years predicted longer time to menses. No relationship with time to menses was observed for pretreatment menarche status, pretreatment or end-of-treatment Tanner breast stage (<3/≥3) or CA (<6/≥6 or ≤11/>11), or end-of-treatment BMI percentiles (<85.6/≥85.6 and <92.6/≥92.6). CONCLUSIONS: Pretreatment menarche status or CA do not appear to predict onset of menses, but pre- and end-of-treatment BA/CA may be helpful in anticipating time to first menses after stopping treatment.
Assuntos
Hormônio Liberador de Gonadotropina , Leuprolida , Menstruação , Puberdade Precoce , Criança , Feminino , Humanos , Determinação da Idade pelo Esqueleto , Índice de Massa Corporal , Seguimentos , Hormônio Liberador de Gonadotropina/agonistas , Leuprolida/uso terapêutico , Leuprolida/administração & dosagem , Menarca/efeitos dos fármacos , Menstruação/efeitos dos fármacos , Prognóstico , Puberdade Precoce/tratamento farmacológico , Fatores de TempoRESUMO
PURPOSE OF REVIEW: Gender identity development is poorly understood but impacted by central nervous system (CNS) factors, genes, gonadal hormones and receptors, genitalia, and social/environmental factors. Gender identity disorder (GID) is the diagnostic term to describe persons discontent with the sex they were assigned at birth and/or the gender roles associated with that sex. It is crucial that the diagnosis be verified as persistent, since gender confusion among those young persists among only a portion. RECENT FINDINGS: Recent publications do not yet provide an overall perspective but involve observations regarding outcome information, unusual variables, incidence of cross-gender behavior, and CNS differences related to GID and bi-gender descriptions. Approaches to therapy for GID and task force guidelines are noted. SUMMARY: Although the concept of gender identity is a relatively new paradigm and remains an area of active and exciting investigation, findings reported here provide items of information for understanding and treatment of GIDs and illustrate the need for further research.
Assuntos
Transtornos do Desenvolvimento Sexual/diagnóstico , Transexualidade/diagnóstico , Transtornos 46, XX do Desenvolvimento Sexual/diagnóstico , Adolescente , Criança , Transtorno 46,XY do Desenvolvimento Sexual/diagnóstico , Transtornos do Desenvolvimento Sexual/etiologia , Transtornos do Desenvolvimento Sexual/psicologia , Transtornos do Desenvolvimento Sexual/terapia , Feminino , Identidade de Gênero , Predisposição Genética para Doença , Humanos , Masculino , Transexualidade/etiologia , Transexualidade/psicologia , Transexualidade/terapiaRESUMO
Intersex/Disorders/Differences of sex development conditions have been recognized for millennia. An organized approach was adopted in the 1960-70s using the philosophy that gender identity was fluid and malleable. Consequences of this approach were the lack of disclosure, stigmatization, and excessive surgery to "normalize" the genitalia. Often this led to quality of life issues for those patients. There have been many modifications in approach since then to avoid the problems noted. There is consensus on many of these changes (e.g. disclosure) but continued controversy on others (e.g. the benefits of early surgery). This review summarizes the historical context and the current areas of consensus and controversy.
Assuntos
Transtornos do Desenvolvimento Sexual , Identidade de Gênero , Humanos , Masculino , Feminino , Qualidade de Vida , Transtornos do Desenvolvimento Sexual/cirurgia , Consenso , GenitáliaRESUMO
Differences of sex development (DSDs) are a spectrum of congenital clinical conditions involving the development of gonadal, chromosomal, and anatomical sex. The physical presentation provides incomplete clues because underlying etiologies may present with similar findings. We describe an 8-year-old boy from the Dominican Republic originally diagnosed with congenital adrenal hyperplasia (CAH). He was prescribed oral hydrocortisone and fludrocortisone, with irregular adherence. During infancy, he had human chorionic gonadotropin injections to stimulate phallic growth. After migrating to the United States, medications became depleted but without adrenal crisis. Laboratory testing with high-dose adrenocorticotropin stimulation study ruled out CAH. Careful examination noted an underdeveloped bifid scrotum, bilaterally undescended testicles, a 2-cm phallus, severe penoscrotal hypospadias, and chordee. Subsequently, he had a 2-stage bilateral orchiopexy and surgical repair of penoscrotal hypospadias and chordee. Genetic testing for 46,XY DSD revealed a novel, dominant, heterozygous, likely pathogenic variant (c.102 + 1G > C) in the NR5A1 gene associated with severe phenotype of undervirilized male. This case illustrates the crucial role of molecular genetic testing for the diagnosis of 46,XY DSDs and a novel NR5A1 gene variant.