9 Year Old Boy with Chromosomal Abnormality

Matthew Wise, MD Med‐Peds Endo September 13, 2012 HPI • Birth History: full‐term, uncomplicated, 5lb 15oz • Neonatal period: mom noticed 5th digits were bent inward, noticed widened space between his eyes, and small penis – pediatrician reassurance • Developmental Delays: ‐ walked at 17mo ‐ speech delayed until 4 years • Behavioral concerns ‐ sensitive to smells/textures ‐ anxiety, frequently frustrated

Pediatrician Eval

• 8 years, 5 months – karyotype:

48, XXYY Subsequent Evaluation

• Connected with developmental pediatrician in Denver, CO with expertise in 48,XXYY • Spent 1 week receiving further medical/neuropsychiatric evaluation • Anxiety  prescribed citalopram • Advised to establish care with a peds endocrinologist to discuss pubertal issues • Online support group Pubertal and Growth History

Peds endo clinic 9yr 6mo • No body odor • No growth spurt • No acne • No genital growth • Pubic hair noted 1 month prior PMH and ROS

PMH ROS • 48, XXYY chromosomal disorder • Transient improvement in • Developmental delay with speech anxiety, anger outbursts with citalopram, worsening again delays/learning disabilities • Anxiety disorder • Chronic constipation • Appendectomy age 5 • Chronic dry skin • Dental problems

MEDICATIONS • citalopram 10mg daily • hydrocortisone cream prn Family and Social History

Family • Mother 39yrs, 5’3”, 125lbs, menarche 13‐14, 1 miscarriage • Father 41yrs, 5’7”, 185lbs, HTN, dyslipidemia, ?early puberty • Mid‐parental height = 5’ 7.5” • Brother 12yrs, body odor x1yr, ? If other pubertal changes • Brother 7yrs, asthma Social • Suburban home • 3rd grade, public school, with IEP • Stay at home mother, father in health‐care • Therapeutic horse back riding Physical Exam

VSS Wt 54.1kg (95%ile), Ht 144.1cm (88%ile), BMI 26.1 (98%ile) Gen: Awake, alert, shy, poor eye contact Head/Face: Mild hypertelorism, epicanthal folds Neck: no thyromegaly, no acanthosis Resp: Clear bilaterally, unlabored CV: RRR no m/r/g Abd: Soft, scaphoid, non‐tender, no masses GU: No palpable breast tissue Few coarse pubic hairs at base (Tanner III), stretched penis 4.7cm Testes descended, pre‐pubertal 1cm R, 1cm L (volume ~1mL) No axillary hair Ext: clinodactyly of both 5th digits

Neuro:no focal neurologic signs Derm: no acne Assessment and Evaluation

48, XXYY male (9y6m) with pubarche ‐ LH ‐ FSH ‐ Total testosterone ‐ Free testosterone ‐ DHEA‐SO4 ‐ Bone Age

Evaluation and Recommendations

‐ LH <0.1 mIU/mL ‐ FSH 0.6 mIU/mL ‐ Total testosterone 7.1 ng/dL ‐ Free testosterone 0.2 ng/dL ‐ DHEA‐SO4 43 ug/dL ‐ Bone Age 11.4 years (+2.5 SD)  72.4 inches • Adrenarche, but no true puberty • Reviewed risk for hypogonadism, future need for testosterone • F/u in 6 months Clinical Questions

1) What clinical findings are typical in 48, XXYY?

2) What is known about the natural history of growth/puberty in patients with 48, XXYY?

3) How do clinical findings in 48, XXYY compare to Klinefelter syndrome?

48, XXYY

• First described 1964 • 1:18,000 – 1:40,000 (vs. 1:650 for 47,XXY) • Initially considered “variant” of 47, XXY • Now felt to have unique medical, neurodevelopmental, psychiatric characteristics 48, XXYY Cross‐Sectional Study

• 2008 • Multicenter, n=95 (US 66, Canada 5, Europe 23, Aus 1) • Mean age 14.9 (1.8‐55), 97% Caucasian

Mean age at Diagnosis 7.7 yrs Tartaglia et al 2008 Clinical Features

Age <10

Clinodactyly 80% Pes planus 79%

Hypertelorism 72% Poor dentition 71% Pectus excavatum 62%

Upslanting palpebral 58% fissures

Epicanthal folds 55%

Facial asymmetry 52%

Tartaglia et al 2008 Clinical Features

Tartaglia et al 2008 Associated Conditions

• Learning disability (100%) • Speech delay (92%) • Dental problems (88%) • Motor delay (75%) • ADHD (72%) • Intention tremor (61‐73%) • Asthma (60%) • Food allergies (56%) • Mood disorders (47%) • Constipation (40%) • Gynecomastia (25‐41%) • Cardiac (19%, VSD most common)

Tartaglia et al 2008 Associated Conditions

• Learning disability (100%) Age 11‐19 Prevalence • Speech delay (92%) • Dental problems (88%) DM2 0% • Motor delay (75%) Hypothyroidism 10.5% • ADHD (72%) • Intention tremor (61‐73%) Obesity 9.7% • Asthma (60%) • Food allergies (56%) Age >20 Prevalence • Mood disorders (47%) DM2 18.2% • Constipation (40%) • Gynecomastia (25‐41%) Hypothyroidism 9.1% • Cardiac (19%, VSD most common) Obesity 31.8%

Tartaglia et al 2008 Puberty in 48, XXYY patients

• Additional X in males leads to testicular dysgenesis and hypergonadotropic hypogonadism • All pts >20 yrs (n=22) had microorchidism, elevated LH with low/low‐nml Test • Avg age for initiation: 14.9yrs (11‐31) • Only 64% of pts in adult group were actively on testosterone 3 –previously treated, lost to f/u 3 –concern regarding worsening behavioral sx 1 – disliked the effects 1 –had elevated LH but low‐nml testosterone, not rx’d

Tartaglia et al 2008 Stature in 48, XXYY Patients

• Mean adult stature 6ft 3.7in (SD 3 inches) ‐ More variable in childhood ‐ Tall stature may be related to over‐expressed SHOX ‐ ? another growth control gene on Y chromosome

Tartaglia et al 2008 Klinefelter Syndrome vs 48, XXYY

47, XXY 48, XXYY Prevalence 1:650‐1000 1:18,000‐40,000 Age of Dx 3.6% before age 10 70% before age 10 Parent of origin 50% maternal 100% paternal 50% paternal Stature 188 cm = 6 ft 2 inches 192.4 cm = 6 ft 3 inches Congenital Clindodactyly common Clinodactyly common Malformations Other 18% Other 56%

Hypergonadotropic Yes Yes Hypogonadism Development Speech/Motor 40‐75% Speech/Motor 72‐92% Cognitive Learning disability 50‐75% Learning Disability 100% FS‐IQ 89‐102 FS‐IQ 70‐80 Verbal IQ > Performance IQ Verbal IQ > Performance IQ

Tartaglia et al 2008 Take Home

• 48, XXYY is a rare cause of hypergonadotropic hypogonadism in boys • Compared to 47 XXY, males with 48 XXYY have greater severity/frequency of neurodevelopmental disorders (including language‐based cognitive deficits and problems with adaptive functioning), dysmorphic features, and medical comorbidities, and tend to be taller • Testosterone replacement is indicated in 48 XXYY patients, and rarely may be associated with worsening behavioral symptoms References

Tartaglia et al. 48, XXYY, 48, XXXY, 49, XXXXY syndromes: not just variants of Klinefelter syndrome. Acta Paediatrica 2011; 100:851‐860.

Tartaglia et al. A new look at XXYY syndrome: medical and psychological features. Am J Med Genetics 2008; 146A(12): 1509‐1522.

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