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.[2] 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).[2][3] 47,XYY patients are also more likely than the general population to have a diagnosis of asthma, seizure disorder, and tremors.[3] Adult males may present with a history of infertility as well as decreased libido.[2] Physical examination results may vary, as phenotypic expressions of 47,XYY syndrome is quite diverse.[2] The most common physical exam findings include tall stature, macrocephaly, hypertelorism, hypotonia, and clinodactyly.[3] Tremors may be observed on the neurological exam.[3] Atrophic testicles may be observed, but external genitalia may also appear normal.[2] 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.[3]

Diagnosis of 47,XYY syndrome may occur as early as the prenatal period using cell-free fetal DNA.[10][11][12] This technique is known as non-invasive prenatal testing and has been found to be highly accurate for detecting sex chromosome aneuploidies.[11] In this type of testing, a pregnant woman's peripheral blood is drawn, and fetal DNA is isolated and analyzed.[11] Amniocentesis is a more-invasive method of prenatal diagnosis and is therefore no longer the preferred method.[11] 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.[2] Many who do so are able to father children successfully with these methods.[2]

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.[13] 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.[13] 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.[13] 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.[14] Hallmark features include excessive growth during childhood, macrocephaly, learning disabilities, hypotonia, and seizure disorders.[14] 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.[15] Key features include tall stature, gynecomastia, small testes, learning disabilities, and, at times, infertility.[15] 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.[2] 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.[2][7] It is hypothesized that this shorter lifespan may be partly due to the increased risk of these comorbid conditions.[2] 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.[2][3]

Patients with Jacob's syndrome have been found to have an increased incidence of certain diseases. These include asthma, seizure disorders, and tremors.[3] Some 47,XYY patients have been noted to have genitourinary abnormalities such as microphallus, hypoplastic scrotum, cryptorchidism, and hypospadias.[3] There is a possibility that these men may be diagnosed with infertility due to oligospermia or sperm chromosomal abnormalities.[2] Some psychological studies have shown that these patients may have problems with impulse control and emotional regulation.[7] Early studies done on incarcerated males with 47,XYY syndrome showed increased testosterone levels that were linked to an increased risk of aggressive behavior.[3] 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.[3] These patients are also at an increased risk for learning disabilities, ADHD, autism spectrum disorder, and speech difficulties.[1]

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.[3] 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.[2]

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.[3] While the average age at diagnosis is 17 years, many patients may benefit from educational interventions earlier than that.[2] [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.[2] [Level 5]