TABLE 1.

Pediatric Evaluation and Treatment Recommendations for XXY/Klinefelter syndrome

Neurodevelopmental/Psychological Risk	Recommendation for Follow-Up and Further Evaluation
Developmental delay (Age 0–3)	Developmental and ASD Screening by PCP per AAP recommendations, and Referral for comprehensive developmental assessments for all children, with evaluation of cognitive, speech-language, motor, social, and adaptive functioning domains using standardized measures. If prenatal diagnosis: Evaluations at 9–15 months, 18–24 months, and 30–36 months. Sooner or more frequent if any developmental concerns. If postnatal diagnosis: Evaluation at diagnosis, and then at ages recommended above. If indicated, initiation of early interventions including developmental, speech, occupational, physical, or behavioral therapies.
Learning Disabilities	Monitoring of learning and academic performance from preschool throughout education. Psychological evaluations to assess cognitive functioning, learning disabilities (reading and/or math) at key times during education and transitions: early elementary, late elementary, middle school, high school, transition to post-secondary programming/education. Special education supports (504 plans or Individual Education Plans) as needed. Evidence-based interventions for learning disabilities if identified. Consideration of additional academic supports, tutoring, options for schools/educational settings
ADHD/Executive functioning (EF) problems	Education of parents/caretakers about EF and manifestations of symptoms of EF deficits. Screening by school system and PCP with input from family and school as presentation may vary in different environments. Recognition that ADHD-Inattentive symptoms are more common in XXY. Formal evaluation of executive functioning and attention by psychologist or neuropsychologist beginning at 7–8 years of age, and at key times during education: late elementary, middle school, high school, transition to post-secondary programming. Implementation of educational strategies and supports for EF and ADHD symptoms at school and home if present. Consideration of medication treatment for attention disorders/ADHD if present.
Speech-Language disorders	Assessment with an experienced pediatric speech and language pathologist with evaluation of expressive-receptive language abilities, higher-order language skills, pragmatic/social use of language, and disorders of speech production (developmental dyspraxia/apraxia) or hypernasality due to possible velopharyngeal insufficiency (VPI). Recommended yearly from birth to 4 years, then every 2–3 years depending on presence or severity of impairment. Referral to ENT if concerns of hypernasality, VPI Speech-language therapy through early intervention, school system and/or privately if indicated. Consideration of role of speech difficulties in behavior/frustration.
Motor skills	Beyond age 3, monitoring of fine and gross motor skills, balance, coordination, motor planning. Occupational and/or physical therapy interventions if motor deficits causing difficulties with handwriting, play or recreational activities, dressing, eating or other self-care skills.
Social skills difficulties	Social Development and ASD Screening by PCP per AAP recommendations, and Evaluation by developmental pediatrician, child psychiatrist and/or psychologist for evaluation if concerns of social functioning or ASD Consideration of whether social immaturity and/or language deficits contribute to social difficulties Therapy/counseling, school supports and/or medication treatment if indicated. Consideration of social skills therapy/groups in academic setting or privately Involvement in clubs/activities of interest where peers share interests If ASD, evidence-based and individualized Applied Behavior Analysis (ABA) therapies such as ESDM
Emotional/Behavioral Difficulties, Anxiety	Evaluation by developmental pediatrician, child psychiatrist and/or psychologist for evaluation and treatment if concerns. Involvement of school psychology/counseling team, incorporation of behavioral supports in school environment, consideration of contributions of bullying Consideration of behavioral responses relative to developmental level Adaptations should be made in therapy approach if language deficits are present, parental involvement in therapy Consideration of medication treatment as indicated for anxiety, emotional lability, depression, mood dysregulation, irritability Consideration of OT/Sensory-based approaches to address self-regulation, especially in younger ages or for if difficulties with self-expression during therapy Consideration of complementary therapies including equine therapy, art/music therapy, yoga, etc.
Adaptive functioning problems	Evaluation of adaptive functioning using standardized measures including domains of self-care, communication, social, community use, safety and self-direction should be included as part of the psychological or educational evaluations recommended above. Consideration of OT or other therapies for support throughout childhood and adolescence
Medical Features/Risks	Recommendation for Follow-Up and Further Evaluation
Cardiovascular
Congenital anomalies	Cardiology consultation and/or Echocardiogram/EKG for all new diagnoses or after birth in a prenatal diagnosis.
Dyslipidemia	Cholesterol screening with lipid panel at age 9–11 and then again after puberty per AAP. Sooner and/or more frequent if family history and/or noted abnormalities.
Abdominal obesity, fatty liver disease, insulin resistance, Metabolic syndrome	Anticipatory guidance for establishing a healthy diet and active lifestyle in childhood. If obesity is present, screening should include ALT and HbA1C. Referral to weight management programs if indicated.
Dental
Enamel defects/caries Taurodauntism	Dental evaluation beginning at age 1, followed by dental visits twice per year or per dentist recommendation.
Endocrinologic
Hypogonadism/Testosterone deficiency	Consider consultation with Pediatric Endocrinology around 2 months of age. Pubertal examination with every annual physical exam. Referral to Pediatric Endocrinology at first sign of puberty or by age 10 years. Monitoring of serum gonadotropins and testosterone every 6 months when pubertal. Consideration of testosterone supplementation based on provider assessment and family preference. The goal of treatment is to replace deficient endogenous testosterone production and support development of secondary sex characteristics, bone health, metabolic function, psychosocial health, and prevent consequences of hypogonadism including gynecomastia and tall stature. Over treatment should be avoided.
Gynecomastia	Palpation for breast tissue with every annual physical exam. Early referral to Endocrinology for any gynecomastia. Consideration of treatment with testosterone, aromatase inhibitors, and anti-estrogens, and/or surgical resection if medical management fails.
Subfertility	Consider semen analysis in adolescence if developmentally appropriate. Consider referral to Reproductive Urologist with experience in TESE in KS if desired.
Osteopenia/Osteoporosis	Ensure adequate dietary intake of calcium and vitamin D. Consider measurement of vitamin D stores and replacement if deficient. No role for routine bone density measurement in pediatrics.
Genetics	If a prenatal diagnosis, postnatal confirmatory genetic testing is recommended, including FISH testing for mosaicism. Consultation with genetic counselor and/or clinical genetics upon diagnosis. Consultation in early adulthood; consider preimplantation genetic testing if paternity is pursued.
Genitourinary
Undescended testes, inguinal hernia, hypospadias	Referral to Urology if present. Consider testicular tissue biopsy and preservation if surgery is indicated.
Microphallus	Referral to Pediatric endocrinology or Urology if present in infancy. Short course of testosterone can be discussed.
GI/Feeding
Newborn feeding difficulties	Lactation specialist, feeding therapy through occupational (OT) or speech therapist if indicated. Weight/growth monitoring by PCP.
Reflux/Constipation/Abdominal complaints	Evaluation and treatment with primary care provider if present. Referral to GI if indicated. Consideration of Eosinophilic esophagitis.
Hematology/Oncology
Hypercoaguability	Awareness of increased hypercoagulable risk and symptoms (DVT, PE). Prophylaxis in high-risk clinical situations (orthopedic surgery, central lines, etc) Hypercoaguability evaluation and/or referral to Hematology if blood clot diagnosed
Malignancy risk	Palpation for breast tissue with every annual physical exam. Evaluation of any discrete masses. CXR to rule out mediastinal mass if symptoms of cough, dyspnea, or chest pain. Immediate evaluation/endocrine referral for precocious puberty. Eval to include serum β-HCG and alpha-fetoprotein.
Immunology
Autoimmune diseases	Discussion and monitoring of symptoms autoimmune disease with PCP. Thyroid function screening every 1–2 years starting at age 10, sooner or more frequent if symptoms of hypo or hyperthyroidism are present.
Musculoskeletal
Pes Planus (Flat feet)/Ankle pronation	Referral to PT or orthopedics for consideration of orthotics if causing pain, limiting activities, or affecting motor coordination or motor skills.
Tall stature	Considerations of adaptations if needed at home and school (i.e. larger chairs/desks) Recognition that tall stature can lead to expectations of more mature behavioral functioning, when social maturity in KS may be average or slightly delayed relative to peers
Neurologic
Seizures	Neurologic history, including questions about staring spells or atypical movements. Neurology consultation and/or EEG and brain MRI may be indicated. Anticonvulsant medication(s) if indicated.
Tremor	Monitoring for intention and/or postural tremor, most commonly in upper extremities Referral to Neurology and consideration of medication as needed or for daily use if interfering with school (handwriting), work tasks, daily living skills (dressing, eating)
Pulmonary
Allergies/Reactive Airways/Respiratory Infections	Management through PCP, referral if needed.
Sleep Apnea	Sleep study if symptoms of sleep apnea present (i.e. daytime fatigue, short sleep latency, difficulty with morning awakening, snoring, apnea)