ABSTRACT
Cell lineages of the early human gonad commit to one of the two mutually antagonistic organogenetic fates, the testis or the ovary. Some individuals with a 46,XX karyotype develop testes or ovotestes (testicular or ovotesticular disorder of sex development; TDSD/OTDSD), due to the presence of the testis-determining gene, SRY Other rare complex syndromic forms of TDSD/OTDSD are associated with mutations in pro-ovarian genes that repress testis development (e.g. WNT4); however, the genetic cause of the more common non-syndromic forms is unknown. Steroidogenic factor-1 (known as NR5A1) is a key regulator of reproductive development and function. Loss-of-function changes in NR5A1 in 46,XY individuals are associated with a spectrum of phenotypes in humans ranging from a lack of testis formation to male infertility. Mutations in NR5A1 in 46,XX women are associated with primary ovarian insufficiency, which includes a lack of ovary formation, primary and secondary amenorrhoea as well as early menopause. Here, we show that a specific recurrent heterozygous missense mutation (p.Arg92Trp) in the accessory DNA-binding region of NR5A1 is associated with variable degree of testis development in 46,XX children and adults from four unrelated families. Remarkably, in one family a sibling raised as a girl and carrying this NR5A1 mutation was found to have a 46,XY karyotype with partial testicular dysgenesis. These unique findings highlight how a specific variant in a developmental transcription factor can switch organ fate from the ovary to testis in mammals and represents the first missense mutation causing isolated, non-syndromic 46,XX testicular/ovotesticular DSD in humans.
Subject(s)
DNA-Binding Proteins/genetics , Disorder of Sex Development, 46,XY/genetics , Primary Ovarian Insufficiency/genetics , Sexual Development/genetics , Steroidogenic Factor 1/genetics , Adult , Androgen-Insensitivity Syndrome/genetics , Androgen-Insensitivity Syndrome/pathology , Cell Lineage/genetics , Child , Disorder of Sex Development, 46,XY/pathology , Female , Gonads/growth & development , Gonads/pathology , Humans , Karyotype , Male , Mutation, Missense , Ovary/growth & development , Ovary/pathology , Pedigree , Primary Ovarian Insufficiency/pathology , Sex Determination Processes , Testis/growth & development , Testis/pathologyABSTRACT
BACKGROUND: Obesity risk is increased for pediatric central nervous system tumor survivors. Hypothalamic involvement (HI) by tumor or treatment increases the risk. In healthy children, body mass index (BMI) normally declines until adiposity rebound (AR). We hypothesized that HI and diagnosis before AR would lead to increased BMI at follow-up. METHODS: A chart review of 114 brain tumor survivors diagnosed between 2001-2011 at the Children's Hospital of Wisconsin extracted tumor location, treatment and BMI z-scores at diagnosis and 2-year follow-up. Children were categorized based on age at diagnosis relative to AR and presence/absence of HI. RESULTS: Children diagnosed pre-AR and post-AR with HI had higher BMI z-scores at 2-year follow-up (pre-AR: 1.6, post-AR: 1.3) than at diagnosis (0.5, 0.6). All groups without HI showed no increase in BMI z-score from diagnosis to 2-year follow-up (pre-AR: 0.7-0.6, during AR: 0.7-0.8, post-AR: 0.7-0.8). The pre-AR and during-AR cohorts with HI had a higher BMI z-score at 2-year follow-up relative to those without HI, while the post-AR group did not. CONCLUSION: Except for the post-AR group, patients with HI have increased BMI at 2 years after diagnosis compared to those without HI. Diagnosis pre-AR is associated with greater follow-up BMI z-score.
Subject(s)
Body Mass Index , Brain Neoplasms , Hypothalamus , Age Factors , Age of Onset , Brain Neoplasms/diagnosis , Brain Neoplasms/physiopathology , Brain Neoplasms/therapy , Child , Child, Preschool , Follow-Up Studies , Humans , Hypothalamus/metabolism , Hypothalamus/physiopathology , SurvivorsABSTRACT
Langerhans cell histiocytosis (LCH) is a disorder of dendritic cell proliferation with subsequent tissue damage often requiring chemotherapy. Neurodegenerative LCH presents with neuromuscular, cognitive, and behavioral alterations typically occurring years after diagnosis of active LCH. We present a male child with a 4-year history of growth arrest, polyuria, polydipsia, recurrent otitis media, and seborrheic dermatitis. Cutaneous biopsies confirmed LCH and chemotherapy was initiated. During treatment for active LCH he developed neuropsychiatric decline. White matter changes on brain MRI were consistent with neurodegenerative LCH. Treatment was changed to cytarabine and intravenous immunoglobulin. After 1 year of therapy the patient experienced neuropsychological improvement.
Subject(s)
Histiocytosis, Langerhans-Cell/diagnosis , Histiocytosis, Langerhans-Cell/drug therapy , Neurodegenerative Diseases/diagnosis , Neurodegenerative Diseases/drug therapy , Child , Cytarabine/therapeutic use , Histiocytosis, Langerhans-Cell/complications , Humans , Immunoglobulins, Intravenous/therapeutic use , Magnetic Resonance Imaging , MaleABSTRACT
Genetic and pharmacological studies have shown that the melanocortin-4 receptor (MC4R) is an important regulator of food intake and energy homeostasis. Consistent with these studies, several mutations of the MC4R gene have been identified as being associated with early-onset severe obesity. We report here the first in-frame deletion mutation of the MC4R gene (delta88-92) in an obese female patient with onset of obesity at less than 5 yr of age. Functional analysis revealed that the mutant receptor is expressed well on the cell surface but completely devoid of ligand binding and cAMP generation in response to agonist stimulation. We conclude that this novel mutation is the cause of obesity of this patient.
