Jacob's syndrome, also known as 47,XYY syndrome, is a rare genetic condition that occurs in about 1 out of 1000 male children. It belongs to a group of conditions known as "sex chromosome trisomies", with Klinefelter's syndrome being the more common type. This condition was initially discovered in the 1960s. Early studies performed on institutionalized men found that 47,XYY males were more likely to exhibit antisocial tendencies than those without this genotype. The median age of diagnosis is approximately 17 years, with many patients presenting due to infertility concerns. Patient presentations may vary greatly, and in fact, many patients have relatively few, if any, phenotypic abnormalities. Those who do, however, may display macroorchidism, tall stature, macrocephaly (abnormally large head), and hypertelorism (increased distance between two body parts, typically the eyes), among other features. These patients are also more likely than the general population to be diagnosed with asthma, autism spectrum disorder, and seizures. While some 47,XYY individuals are infertile, those who are able to reproduce often produce offspring that have normal karyotypes.
Jacob's syndrome is not an inherited condition. It most commonly arises during meiosis II in the father, at which time an extra Y chromosome is attributed to the resultant sperm. An alternate and less common form of this condition is 46,XY/47,XYY mosaicism, which arises during early embryonic development. In this scenario, the postzygotic mitotic nondisjunction is responsible for the disease. These mutations seem to occur randomly, and it is unknown if there are any parental causes for these mutations.
Jacob's syndrome is relatively rare, occurring in approximately 1 out of 1000 newborn males. This incidence appears to be relatively constant among men worldwide. Diagnosis is often delayed, with the average age of diagnosis being approximately 17 years. Phenotypic presentations may vary greatly and are often mild. It is estimated that approximately 85% of 47,XYY men are never actually diagnosed.
The pathophysiology of this disease normally begins with erroneous spermatogenesis in the patient's father, resulting in an extra Y chromosome in the patient. Disease symptoms may be quite vague during childhood, and for this reason, most children go undiagnosed. Men with Jacob's syndrome who do display symptoms are most likely to exhibit tall stature, macrocephaly, hypotonia, clinodactyly (medial curvature of a digit, i.e., 5th finger toward the 4th), and hypertelorism. Developmental delays and behavioral issues have been noted, as well. The incidence of asthma and autism spectrum disorder also appears to be increased in these individuals.
When obtaining a history of a patient with Jacob's syndrome, it would not be unusual to elicit a history of mild learning disabilities and behavioral disturbances. Patients may also have had delayed speech onset as children, as well as a diagnosis of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). 47,XYY patients are also more likely than the general population to have a diagnosis of asthma, seizure disorder, and tremors. Adult males may present with a history of infertility as well as decreased libido. Physical examination results may vary, as phenotypic expressions of 47,XYY syndrome is quite diverse. The most common physical exam findings include tall stature, macrocephaly, hypertelorism, hypotonia, and clinodactyly. Tremors may be observed on the neurological exam. Atrophic testicles may be observed, but external genitalia may also appear normal. About half of these patients may have flat feet, and dental abnormalities such as underbites and macrodontia have been noted in a minority of patients.
Diagnosis of 47,XYY syndrome may occur as early as the prenatal period using cell-free fetal DNA. This technique is known as non-invasive prenatal testing and has been found to be highly accurate for detecting sex chromosome aneuploidies. In this type of testing, a pregnant woman's peripheral blood is drawn, and fetal DNA is isolated and analyzed. Amniocentesis is a more-invasive method of prenatal diagnosis and is therefore no longer the preferred method. After birth, diagnosis is made using karyotype analysis from a sample of the patient's blood. 47,XYY men who are being seen for infertility should receive a semen analysis, testicular ultrasound, and bloodwork to measure reproductive hormones.
Families who receive a prenatal diagnosis of 47,XYY syndrome should receive genetic counseling to aid in their understanding of the disease. Treatment of this syndrome is generally only supportive, with attention given to the comorbidities of the patient. Boys who are diagnosed with Jacob's syndrome may benefit from speech therapy and behavioral interventions from qualified professionals. Occupational therapy may be needed if hypotonia is present. Patients may benefit from supplemental or special educational resources if learning disabilities exist. Appropriate medical treatment for any comorbid condition such as asthma or seizure disorder should be elicited from a licensed clinician. Men with infertility should receive a comprehensive evaluation from a qualified reproductive endocrinologist. Hormonal imbalances, if found, may need to be corrected. Patients who are having difficulty achieving pregnancy due to low sperm counts may need to undergo in-vitro fertilization or intracytoplasmic sperm injection. Many who do so are able to father children successfully with these methods.
As boys with Jacob's syndrome are often tall for their age, another condition that should be ruled out is Marfan syndrome, a disease that also presents with tall stature. Marfan syndrome is a connective tissue disorder which, in contrast to Jacob's syndrome, often presents with cardiac abnormalities such as aortic root dilatation and mitral valve prolapse. A full cardiac workup, including EKG and echocardiogram, will confirm the presence of these conditions, thereby ruling in or out Marfan syndrome, as the case may be. Genetic analysis to determine the presence of a fibrillin-1 gene mutation may be helpful as well, as this mutation often occurs with Marfan syndrome. Sotos syndrome is another condition that should be considered and ruled out. Sotos syndrome, also known as cerebral gigantism, is a rare genetic condition caused by a mutation in the NSD1 gene on chromosome 5. Hallmark features include excessive growth during childhood, macrocephaly, learning disabilities, hypotonia, and seizure disorders. This condition may be ruled out via genetic analysis. Klinefelter's syndrome should also be considered and ruled out. This disease is another sex chromosome abnormality in which the patient's genotype is 47,XXY. Key features include tall stature, gynecomastia, small testes, learning disabilities, and, at times, infertility. This condition may also be ruled out via genetic analysis.
Studies have shown that the lifespan of a patient with Jacob's syndrome may be approximately 10 years less than that of age-controlled peers without the disease. Men with 47,XYY syndrome are at increased risk for pulmonary and neurological conditions such as asthma and seizure disorders, as well as behavioral problems and difficulties with impulse control. It is hypothesized that this shorter lifespan may be partly due to the increased risk of these comorbid conditions. Regardless, many men with Jacob's syndrome go on to live normal lives as adult males. Most boys go through puberty normally, and many men are fertile despite increased risk for sperm abnormalities.
Patients with Jacob's syndrome have been found to have an increased incidence of certain diseases. These include asthma, seizure disorders, and tremors. Some 47,XYY patients have been noted to have genitourinary abnormalities such as microphallus, hypoplastic scrotum, cryptorchidism, and hypospadias. There is a possibility that these men may be diagnosed with infertility due to oligospermia or sperm chromosomal abnormalities. Some psychological studies have shown that these patients may have problems with impulse control and emotional regulation. Early studies done on incarcerated males with 47,XYY syndrome showed increased testosterone levels that were linked to an increased risk of aggressive behavior. More recent studies have found these men to be at an increased risk for criminal activity, although testosterone levels have not consistently been found to be elevated or associated with this increased risk. These patients are also at an increased risk for learning disabilities, ADHD, autism spectrum disorder, and speech difficulties.
Patients with Jacob's syndrome should be reassured that most patients with this disease go on to live long and fulfilling lives. The fact that up to 85% of these patients are never diagnosed is a testament to how mild symptoms often are and the wide range of phenotypic presentations possible. Families of children with Jacob syndrome should be aware that their sons may benefit from special education or speech therapy resources due to the possibility of mild learning impairment and speech delays. Men with Jacob's syndrome who are trying to conceive may benefit from an early sperm analysis to screen for low sperm counts or sperm abnormalities. Patients should be informed that many men with this condition are able to father children, and that reproductive technology may be of assistance if a difficulty does arise.
Jacob's syndrome is a rare genetic disorder that often presents with mild symptoms. It is grossly underdiagnosed, with up to 85% of these patients never receiving a diagnosis. While the average age at diagnosis is 17 years, many patients may benefit from educational interventions earlier than that. [Level 3]. Diagnosis requires a working knowledge of the subtle signs and symptoms of the diseases that present themselves during history-taking and physical exam. In order to improve the identification of this disease, it is essential that all members of a healthcare team be aware of what to look for. Management of this disease also requires collaboration and effective communication within the patient's interprofessional team. Patients with Jacob's syndrome are at an increased risk of a variety of comorbid conditions such as asthma, tremors, seizure disorders, infertility, and psychological problems such as autism spectrum disorder, and ADHD. All of these conditions are generally managed by different specialists, all of whom should communicate with one another in an effort to coordinate care and improve patient outcomes. [Level 5]
|||van Rijn S, A review of neurocognitive functioning and risk for psychopathology in sex chromosome trisomy (47,XXY, 47,XXX, 47, XYY). Current opinion in psychiatry. 2019 Mar; [PubMed PMID: 30689602]|
|||Kim IW,Khadilkar AC,Ko EY,Sabanegh ES Jr, 47,XYY Syndrome and Male Infertility. Reviews in urology. 2013; [PubMed PMID: 24659916]|
|||Bardsley MZ,Kowal K,Levy C,Gosek A,Ayari N,Tartaglia N,Lahlou N,Winder B,Grimes S,Ross JL, 47,XYY syndrome: clinical phenotype and timing of ascertainment. The Journal of pediatrics. 2013 Oct; [PubMed PMID: 23810129]|
|||Zhang X,Liu X,Xi Q,Zhu H,Li L,Liu R,Yu Y, Reproductive outcomes of 3 infertile males with XYY syndrome: Retrospective case series and literature review. Medicine. 2020 Feb; [PubMed PMID: 32118782]|
|||Wilson AC,King J,Bishop DVM, Autism and social anxiety in children with sex chromosome trisomies: an observational study. Wellcome open research. 2019; [PubMed PMID: 31231689]|
|||Bloy L,Ku M,Edgar JC,Miller JS,Blaskey L,Ross J,Roberts TPL, Auditory evoked response delays in children with 47,XYY syndrome. Neuroreport. 2019 May 1; [PubMed PMID: 30896674]|
|||Jo HC,Lee SW,Jung HJ,Park JE, Esthesioneuroblastoma in a boy with 47, XYY karyotype. Korean journal of pediatrics. 2016 Nov; [PubMed PMID: 28018456]|
|||Stochholm K,Juul S,Gravholt CH, Diagnosis and mortality in 47,XYY persons: a registry study. Orphanet journal of rare diseases. 2010 May 29; [PubMed PMID: 20509956]|
|||Liu ZH,Zhou SC,Du JW,Zhang K,Wu T, A patient with 46,XY/47,XYY karyotype and female phenotype: a case report. BMC endocrine disorders. 2020 Mar 24; [PubMed PMID: 32209072]|
|||Margiotti K,Cesta A,Dello Russo C,Cima A,Barone MA,Viola A,Sparacino D,Mesoraca A,Giorlandino C, Cell-free DNA screening for sex chromosomal aneuploidies in 9985 pregnancies: Italian single experience. BMC research notes. 2020 Mar 18; [PubMed PMID: 32188487]|
|||Kypri E,Ioannides M,Touvana E,Neophytou I,Mina P,Velissariou V,Vittas S,Santana A,Alexidis F,Tsangaras K,Achilleos A,Patsalis P,Koumbaris G, Non-invasive prenatal testing of fetal chromosomal aneuploidies: validation and clinical performance of the veracity test. Molecular cytogenetics. 2019; [PubMed PMID: 31338126]|
|||Zheng Y,Wan S,Dang Y,Song T,Chen B,Zhang J, Non-invasive prenatal testing for detection of trisomy 13, 18, 21 and sex chromosome aneuploidies in 8594 cases. Ginekologia polska. 2019; [PubMed PMID: 31165466]|
|||Yuan SM,Jing H, Marfan's syndrome: an overview. Sao Paulo medical journal = Revista paulista de medicina. 2010 Dec; [PubMed PMID: 21308160]|
|||Baujat G,Cormier-Daire V, Sotos syndrome. Orphanet journal of rare diseases. 2007 Sep 7; [PubMed PMID: 17825104]|
|||Groth KA,Skakkebæk A,Høst C,Gravholt CH,Bojesen A, Clinical review: Klinefelter syndrome--a clinical update. The Journal of clinical endocrinology and metabolism. 2013 Jan; [PubMed PMID: 23118429]|