Fragile X Syndrome

Epidemiology and Genetics

Epidemiology

• Most common inherited cause of intellectual disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment and 2nd-most common genetic cause (behind Down’s syndrome)
• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency of classic Fragile X syndrome:
  • 1 in 4,000–7,000 live births in boys 
  • In girls, the prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency is two-thirds to one-half of that in boys.

Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics

Fragile X syndrome (FXS) occurs due to a loss of function Loss of Function Inflammation mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the fragile X mental retardation 1 (FMR1) gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics on the X chromosome X chromosome The female sex chromosome, being the differential sex chromosome carried by half the male gametes and all female gametes in human and other male-heterogametic species. Basic Terms of Genetics. FMR1 codes for fragile X mental retardation protein (FMRP), which is important in brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification and gonadal ( testes Testes Gonadal Hormones and ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries: Anatomy) development.

More than 99% of cases are due to unstable trinucleotide (CGG) repeat expansion in the promoter region of the FMR1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics:

• Classic fragile X phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics (full mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations) results from > 200 repeats → abnormal methylation Methylation Addition of methyl groups. In histo-chemistry methylation is used to esterify carboxyl groups and remove sulfate groups by treating tissue sections with hot methanol in the presence of hydrochloric acid. . Glucocorticoids → silencing of the FMR1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics → reduced/loss of FMRP
• Approximately 50–200 repeats is considered a premutation (normal < 40 repeats) → leads to a functional FMR1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics with production of FMRP, although not fully normal
  • Less severe clinical manifestations present.
  • Allele Allele Variant forms of the same gene, occupying the same locus on homologous chromosomes, and governing the variants in production of the same gene product. Basic Terms of Genetics is unstable and may become a full mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in future offspring/generations.
  • The prеmսtаtiоո rate is approximately 1 in 750–850 males.
  • The prеmսtаtiоո rate is approximately 1 in 250–300 females.
• Length/size of the repeat expansion correlates with the severity of clinical manifestations (↑ expansion repeat → higher severity of condition)

The inheritance pattern is X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) dominant:

• Boys more severely affected than girls due to boys only having 1 X chromosome X chromosome The female sex chromosome, being the differential sex chromosome carried by half the male gametes and all female gametes in human and other male-heterogametic species. Basic Terms of Genetics
• Girls may have > 200 repeats on 1 allele Allele Variant forms of the same gene, occupying the same locus on homologous chromosomes, and governing the variants in production of the same gene product. Basic Terms of Genetics on 1 X chromosome X chromosome The female sex chromosome, being the differential sex chromosome carried by half the male gametes and all female gametes in human and other male-heterogametic species. Basic Terms of Genetics but not the other
• In girls’ cells, 1 X chromosome X chromosome The female sex chromosome, being the differential sex chromosome carried by half the male gametes and all female gametes in human and other male-heterogametic species. Basic Terms of Genetics is inactivated, potentially limiting the effects of the mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations.

Clinical Presentation

Girls and those with premutations have variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables and often less severe clinical manifestations. The following are the clinical features of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with classic FXS (full mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations).

Clinical phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics in boys

• Outer appearance: 
  • Tall stature
  • Macrocephaly Macrocephaly Cowden Syndrome (large head) with increased brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification volume
  • Prominent facial features: long face, prominent forehead Forehead The part of the face above the eyes. Melasma, prominent chin Chin The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. Melasma
  • Large ears
  • High arched palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy 
  • Flat feet
  • Macroorchidism (enlarged testes Testes Gonadal Hormones, albeit with normal function) occurs after onset of puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty.
  • Hyperextensible joints, particularly thumbs and finger
  • Low muscle tone Muscle tone The state of activity or tension of a muscle beyond that related to its physical properties, that is, its active resistance to stretch. In skeletal muscle, tonus is dependent upon efferent innervation. Skeletal Muscle Contraction in infancy
  • Noticeable motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology delay
• Cognition/intelligence:
  • Global developmental delay
  • Intellectual disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment: IQ worsens with increase in age.
  • Learning disabilities Learning disabilities Conditions characterized by a significant discrepancy between an individual’s perceived level of intellect and their ability to acquire new language and other cognitive skills. These may result from organic or psychological conditions. Relatively common subtypes include dyslexia, dyscalculia, and dysgraphia. DiGeorge Syndrome, particularly with math/quantitative skills and visuospatial abilities
  • Delay in language development
    • More difficulty with expressive than receptive language skills
    • Articulation poor, speech repetitive 
    • Approximately 10% remain nonverbal.
  • Decline in executive functioning and memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment compared with peers worsens over time.
• Behavioral abnormalities:
  • Attention Attention Focusing on certain aspects of current experience to the exclusion of others. It is the act of heeding or taking notice or concentrating. Psychiatric Assessment deficit hyperactivity Hyperactivity Attention Deficit Hyperactivity Disorder disorder ( ADHD ADHD Attention deficit hyperactivity disorder is a neurodevelopmental disorder characterized by a pattern of inattention and/or hyperactivity-impulsivity that occurs in at least 2 different settings for more than 6 months. Although the patient has normal intelligence, the disease causes functional decline. Attention Deficit Hyperactivity Disorder)–like symptoms
    • Hyperactivity Hyperactivity Attention Deficit Hyperactivity Disorder/ impulsivity Impulsivity Attention Deficit Hyperactivity Disorder
    • Inattention Inattention Attention Deficit Hyperactivity Disorder/short attention Attention Focusing on certain aspects of current experience to the exclusion of others. It is the act of heeding or taking notice or concentrating. Psychiatric Assessment span
  • Anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder symptoms
    • Social anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder
    • Panic attacks
    • Obsessive-compulsive disorder Obsessive-compulsive disorder Obsessive-compulsive disorder (OCD) is a condition characterized by obsessions (recurring and intrusive thoughts, urges, or images) and/or compulsions (repetitive actions the person is compelled to perform) that are time-consuming and associated with functional impairment. Obsessive-compulsive Disorder (OCD)–like activities/ obsessions Obsessions Recurrent thoughts, images, or urges that are intrusive and recognized as unwanted, causing significant anxiety and distress . Obsessive-compulsive Disorder (OCD)
  • Autism spectrum disorder Autism spectrum disorder Autism spectrum disorder (ASD) is a neurodevelopmental disorder marked by poor social skills, restricted interests/social interactions, and repetitive/stereotyped behaviors. The condition is termed a “spectrum” because of the wide variability in the severity of symptoms exhibited. Autism Spectrum Disorder
    • 18%–67% meet criteria for autism spectrum disorders.
    • Boys with FXS and autism have greater cognitive and behavioral disabilities than those with FXS alone.
    • Characterized by:
      • Difficulty with social interactions, understanding social cues, and forming peer relationships
      • Gaze aversion and poor eye contact
      • Repetitive motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology patterns (e.g., hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand: Anatomy flapping, rocking, toe walking Toe Walking Becker Muscular Dystrophy)
      • Echolalia echolalia Involuntary (‘parrot-like’), meaningless repetition of a recently heard word, phrase, or song. This condition may be associated with transcortical aphasia; schizophrenia; or other disorders. Schizophrenia/repetition of words and sounds
      • Hypersensitivity to environmental stimuli
      • Self-injurious behaviors (e.g., head banging, nail-biting)

Clinical phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics in girls

• Approximately 50% with full mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations have normal intellect Intellect Psychiatric Assessment, remainder have borderline to mild intellectual disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment.
• Approximately 50% have similar yet milder physical and behavioral features to boys, as seen above.

Associated conditions

• Vision Vision Ophthalmic Exam: refractive errors Refractive errors By refraction, the light that enters the eye is focused onto a particular point of the retina. The main refractive components of the eye are the cornea and the lens. When the corneal curvature, the refractive power of the lens, does not match the size of the eye, ametropia or a refractive error occurs. Refractive Errors, strabismus Strabismus Strabismus is the misalignment of the eyes while fixating the gaze on an object. Strabismus can be idiopathic, but it may also be caused by cerebral palsy, uncorrected refractive errors, and extraocular muscle or cranial nerve dysfunction. Strabismus, and amblyopia Amblyopia A nonspecific term referring to impaired vision. Major subcategories include stimulus deprivation-induced amblyopia and toxic amblyopia. Stimulus deprivation-induced amblyopia is a developmental disorder of the visual cortex. A discrepancy between visual information received by the visual cortex from each eye results in abnormal cortical development. Strabismus and refractive errors may cause this condition. Toxic amblyopia is a disorder of the optic nerve which is associated with alcoholism, tobacco smoking, and other toxins and as an adverse effect of the use of some medications. Strabismus
• Neurological:  Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures occur in 10%–20% of FXS cases.
  • Most common types: simple or complex partial seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Most common in early childhood, with a peak between 6 months and 4 years of age
• Cardiac: mitral valve Mitral valve The valve between the left atrium and left ventricle of the heart. Heart: Anatomy prolapse, mitral regurgitation Regurgitation Gastroesophageal Reflux Disease (GERD)

Diagnosis

Prenatal diagnosis

• Amniocentesis Amniocentesis Percutaneous transabdominal puncture of the uterus during pregnancy to obtain amniotic fluid. It is commonly used for fetal karyotype determination in order to diagnose abnormal fetal conditions. Polyhydramnios
• Chorionic villus sampling

Postnatal diagnosis

• History and clinical examination
• Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies:
  • Count CGG repeats on the X chromosome X chromosome The female sex chromosome, being the differential sex chromosome carried by half the male gametes and all female gametes in human and other male-heterogametic species. Basic Terms of Genetics: > 200 repeats on 1 allele Allele Variant forms of the same gene, occupying the same locus on homologous chromosomes, and governing the variants in production of the same gene product. Basic Terms of Genetics marks the diagnosis in girls.
  • Recommended in children who have characteristic physical or behavioral features and present with the following:
    • Developmental delay
    • Borderline intellectual abilities/ disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment
    • Diagnosis of autism without specific etiology
  • Recommended in adults who present with the following:
    • Physical features and unspecified intellectual disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment
    • Women with premature ovarian failure Premature ovarian failure Primary ovarian insufficiency (POI) is a condition resulting from the depletion or dysfunction of the ovarian follicles, leading to cessation of ovulation and menses before age 40. Primary ovarian insufficiency is primarily idiopathic. Patients present with signs and symptoms of menopause prior to age 40, including oligo- or amenorrhea, vaginal dryness (often leading to dyspareunia), and infertility. Primary Ovarian Insufficiency ( ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries: Anatomy stop working before 40 years of age)
    • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship > 50 years of age with progressive cerebellar ataxia Cerebellar ataxia Incoordination of voluntary movements that occur as a manifestation of cerebellar diseases. Characteristic features include a tendency for limb movements to overshoot or undershoot a target (dysmetria), a tremor that occurs during attempted movements (intention tremor), impaired force and rhythm of diadochokinesis (rapidly alternating movements), and gait ataxia. Cerebellar Disorders and intention tremor Intention Tremor Cerebellar Disorders
• Additional testing: echocardiogram Echocardiogram Transposition of the Great Arteries (echo) to evaluate for mitral valve Mitral valve The valve between the left atrium and left ventricle of the heart. Heart: Anatomy prolapse

Management

There is no curative treatment for FXS. Treatment is tailored to the symptoms present. Supportive therapy includes the following:

Educational treatment

• Early intervention
• Special education
• Speech and language therapy
• Vocational training
• Avoidance of stimulants Stimulants Stimulants are used by the general public to increase alertness and energy, decrease fatigue, and promote mental focus. Stimulants have medical uses for individuals with ADHD and sleep disorders, and are also used in combination with analgesics in pain management. Stimulants, which trigger Trigger The type of signal that initiates the inspiratory phase by the ventilator Invasive Mechanical Ventilation hypersensitivity and specific behaviors

Medical treatment

• Stimulants Stimulants Stimulants are used by the general public to increase alertness and energy, decrease fatigue, and promote mental focus. Stimulants have medical uses for individuals with ADHD and sleep disorders, and are also used in combination with analgesics in pain management. Stimulants for ADHD ADHD Attention deficit hyperactivity disorder is a neurodevelopmental disorder characterized by a pattern of inattention and/or hyperactivity-impulsivity that occurs in at least 2 different settings for more than 6 months. Although the patient has normal intelligence, the disease causes functional decline. Attention Deficit Hyperactivity Disorder, under strict monitoring (effective in approximately 70% of cases)
• Selective serotonin reuptake inhibitors Selective Serotonin Reuptake Inhibitors Serotonin Reuptake Inhibitors and Similar Antidepressants ( SSRIs SSRIs Serotonin Reuptake Inhibitors and Similar Antidepressants) for anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder and mood swings (effective in approximately 50% of cases)
• Anticonvulsants to control seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures and alleviate mood issues
• Antidepressants and antipsychotics to treat self-injurious and aggressive behaviors

Other

• Strabismus Strabismus Strabismus is the misalignment of the eyes while fixating the gaze on an object. Strabismus can be idiopathic, but it may also be caused by cerebral palsy, uncorrected refractive errors, and extraocular muscle or cranial nerve dysfunction. Strabismus correction
• Genetic counseling Genetic Counseling An educational process that provides information and advice to individuals or families about a genetic condition that may affect them. The purpose is to help individuals make informed decisions about marriage, reproduction, and other health management issues based on information about the genetic disease, the available diagnostic tests, and management programs. Psychosocial support is usually offered. Myotonic Dystrophies

Clinical Relevance

Differential diagnosis

The following conditions are differential diagnoses of FXS:

• Prader-Willi syndrome Prader-Willi syndrome Prader-Willi syndrome (PWS) is a rare autosomal neurodevelopmental genetic disorders mapped to a specific region of chromosome 15 attributed to genomic imprinting. A paternally derived chromosome 15 with this deletion results in 15q11-13 paternal deletion syndrome, or PWS. Prader-Willi Syndrome and Angelman Syndrome ( PWS PWS A vascular malformation of developmental origin characterized pathologically by ectasia of superficial dermal capillaries, and clinically by persistent macular erythema. In the past, port wine stains have frequently been termed capillary hemangiomas, which they are not; unfortunately this confusing practice persists: hemangioma, capillary is neoplastic, a port-wine stain is non-neoplastic. Port-wine stains vary in color from fairly pale pink to deep red or purple and in size from a few millimeters to many centimeters in diameter. The face is the most frequently affected site and they are most often unilateral. Sturge-Weber Syndrome (SWS)): a genetic condition that is rarely inherited and is caused by a loss of functional genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure on chromosome 15 Chromosome 15 Marfan Syndrome. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship have similar physical, cognitive, and behavioral features as FXS; however, these patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship display hyperphagia (overeating) and obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity. Approximately 10% of boys with FXS have a Prader-Willi phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics, but not the genetic changes seen with PWS PWS A vascular malformation of developmental origin characterized pathologically by ectasia of superficial dermal capillaries, and clinically by persistent macular erythema. In the past, port wine stains have frequently been termed capillary hemangiomas, which they are not; unfortunately this confusing practice persists: hemangioma, capillary is neoplastic, a port-wine stain is non-neoplastic. Port-wine stains vary in color from fairly pale pink to deep red or purple and in size from a few millimeters to many centimeters in diameter. The face is the most frequently affected site and they are most often unilateral. Sturge-Weber Syndrome (SWS). Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies aids in diagnosis. Treatment is supportive.  
• Klinefelter syndrome Klinefelter syndrome Klinefelter syndrome is a chromosomal aneuploidy characterized by the presence of 1 or more extra X chromosomes in a male karyotype, most commonly leading to karyotype 47,XXY. Klinefelter syndrome is associated with decreased levels of testosterone and is the most common cause of congenital hypogonadism. Klinefelter Syndrome: a genetic condition affecting boys, characterized by the presence of 1 or more extra X chromosomes Chromosomes In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. DNA Types and Structure, most commonly leading to the karyotype Karyotype The full set of chromosomes presented as a systematized array of metaphase chromosomes from a photomicrograph of a single cell nucleus arranged in pairs in descending order of size and according to the position of the centromere. Congenital Malformations of the Female Reproductive System 47, XXY XXY Klinefelter syndrome is a chromosomal aneuploidy characterized by the presence of 1 or more extra X chromosomes in a male karyotype, most commonly leading to karyotype 47,XXY. Klinefelter syndrome is associated with decreased levels of testosterone and is the most common cause of congenital hypogonadism. Klinefelter Syndrome. Klinefelter syndrome Klinefelter syndrome Klinefelter syndrome is a chromosomal aneuploidy characterized by the presence of 1 or more extra X chromosomes in a male karyotype, most commonly leading to karyotype 47,XXY. Klinefelter syndrome is associated with decreased levels of testosterone and is the most common cause of congenital hypogonadism. Klinefelter Syndrome is associated with decreased levels of testosterone Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens and is the most common cause of congenital hypogonadism Congenital hypogonadism Klinefelter Syndrome. Affected persons are typically tall and have small testes Testes Gonadal Hormones, decreased body hair, gynecomastia Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Gynecomastia, and infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility. Treatment consists of life-long testosterone Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens replacement therapy. 
• Sotos syndrome: also known as cerebral gigantism Gigantism The condition of accelerated and excessive growth in children or adolescents who are exposed to excess human growth hormone before the closure of epiphyses. It is usually caused by somatotroph hyperplasia or a growth hormone-secreting pituitary adenoma. These patients are of abnormally tall stature, more than 3 standard deviations above normal mean height for age. Acromegaly and Gigantism, a rarely familial genetic condition typically caused by a sporadic Sporadic Selective IgA Deficiency gene mutation Gene Mutation Myotonic Dystrophies. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship have similar facial features as well as cognitive and behavioral abnormalities as in FXS. However, they have extreme growth in early childhood followed by premature Premature Childbirth before 37 weeks of pregnancy (259 days from the first day of the mother’s last menstrual period, or 245 days after fertilization). Necrotizing Enterocolitis epiphyseal fusion (growth plate closure) and advanced bone age Bone Age Short Stature in Children. Diagnosis is made through genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies. Treatment is supportive. 
• Autism spectrum disorder Autism spectrum disorder Autism spectrum disorder (ASD) is a neurodevelopmental disorder marked by poor social skills, restricted interests/social interactions, and repetitive/stereotyped behaviors. The condition is termed a “spectrum” because of the wide variability in the severity of symptoms exhibited. Autism Spectrum Disorder: a neurodevelopmental disorder with early-childhood onset, characterized by poor communication Communication The exchange or transmission of ideas, attitudes, or beliefs between individuals or groups. Decision-making Capacity and Legal Competence and social skills as well as repetitive and stereotyped behaviors. Intellect Intellect Psychiatric Assessment is variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables and may even be advanced. No association with specific physical features. Diagnosis is clinical based on history and behaviors. Testing may be done to evaluate for underlying or coexisting conditions. Early diagnosis and supportive therapies are important to improve the outcome. May occur with or without concurrent diagnosis of FXS.
• ADHD ADHD Attention deficit hyperactivity disorder is a neurodevelopmental disorder characterized by a pattern of inattention and/or hyperactivity-impulsivity that occurs in at least 2 different settings for more than 6 months. Although the patient has normal intelligence, the disease causes functional decline. Attention Deficit Hyperactivity Disorder: a mental health disorder characterized by hyperactivity Hyperactivity Attention Deficit Hyperactivity Disorder/ impulsivity Impulsivity Attention Deficit Hyperactivity Disorder and inattentiveness that affects cognitive, behavioral, and social functioning. The disorder is not associated with any specific physical features. Diagnosis is clinical with extensive multifaceted medical, behavioral, emotional, and educational evaluations. Treatment involves stimulant medications, psychotherapy Psychotherapy Psychotherapy is interpersonal treatment based on the understanding of psychological principles and mechanisms of mental disease. The treatment approach is often individualized, depending on the psychiatric condition(s) or circumstance. Psychotherapy, and behavioral and educational interventions. May occur with or without concurrent diagnosis of FXS.

Related conditions

The following are conditions of concern for those with premutations for FXS.

• Premature ovarian failure Premature ovarian failure Primary ovarian insufficiency (POI) is a condition resulting from the depletion or dysfunction of the ovarian follicles, leading to cessation of ovulation and menses before age 40. Primary ovarian insufficiency is primarily idiopathic. Patients present with signs and symptoms of menopause prior to age 40, including oligo- or amenorrhea, vaginal dryness (often leading to dyspareunia), and infertility. Primary Ovarian Insufficiency: hypogonadotropic hypogonadism Hypogonadotropic Hypogonadism Hypogonadism in women before the age of 40. Associated with menstrual irregularities, symptoms of estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy deficiency (e.g., hot flashes, vaginal dryness, and osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis), and, possibly, difficulty conceiving. Laboratory testing of hormone levels aids in diagnosis. As premature ovarian failure Premature ovarian failure Primary ovarian insufficiency (POI) is a condition resulting from the depletion or dysfunction of the ovarian follicles, leading to cessation of ovulation and menses before age 40. Primary ovarian insufficiency is primarily idiopathic. Patients present with signs and symptoms of menopause prior to age 40, including oligo- or amenorrhea, vaginal dryness (often leading to dyspareunia), and infertility. Primary Ovarian Insufficiency is associated with an FXS premutation, genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies for FXS premutation is warranted. Management involves hormone replacement therapy Hormone Replacement Therapy Hormone replacement therapy (HRT) is used to treat symptoms associated with female menopause and in combination to suppress ovulation. Risks and side effects include uterine bleeding, predisposition to cancer, breast tenderness, hyperpigmentation, migraine headaches, hypertension, bloating, and mood changes. Noncontraceptive Estrogen and Progestins and addressing reproductive and associated mental health issues. 
• Tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies/ ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia syndrome: a progressive neurodegenerative disorder seen in individuals over 50 years of age with a premutation for FSX. Men are affected more than women. Clinical features include early-onset dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders or cognitive decline, late-onset ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia (difficulty with movements such as walking), postural tremors, proximal lower limb weakness, and peripheral neuropathy Neuropathy Leprosy. Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies confirms the diagnosis. Treatment is supportive, with medications and therapy. There is no cure for the syndrome.