9 year old boy chromosomal abnormality

9 Year Old Boy with Chromosomal Abnormality

Matthew Wise, MDMed‐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 ROSPMH

• 48, XXYY chromosomal disorder

• Developmental delay with speech

delays/learning disabilities

• Anxiety disorder

• Appendectomy age 5

ROS

• Transient improvement in

anxiety, anger outbursts with

citalopram, worsening again

• Chronic constipation

• 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 ExamVSS Wt 54.1kg (95%ile), Ht 144.1cm (88%ile), BMI 26.1 (98%ile)Gen: Awake, alert, shy, poor eye contactHead/Face: Mild hypertelorism, epicanthal

folds

Neck: no thyromegaly, no acanthosisResp:

Clear bilaterally, unlabored

CV: RRR no m/r/gAbd: Soft, scaphoid, non‐tender, no massesGU: No palpable breast tissue

Few coarse pubic hairs at base (Tanner III), stretched penis 4.7cmTestes descended, pre‐pubertal 1cm R, 1cm L (volume ~1mL)No axillary

hair

Ext: clinodactyly

of both 5th

digitsNeuro: no focal neurologic signsDerm: 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

Tartaglia et al 2008Mean age at Diagnosis 7.7 yrs

Clinical Features

Clinodactyly 80%

Pes

planus 79%

Hypertelorism 72%

Poor dentition 71%

Pectus

excavatum 62%

Upslanting

palpebral

fissures

58%

Epicanthal

folds 55%

Facial asymmetry 52%

Age <10

Tartaglia et al 2008

Clinical Features


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)


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)

Age 11‐19 Prevalence

DM2 0%

Hypothyroidism 10.5%

Obesity 9.7%

Age >20 Prevalence

DM2 18.2%

Hypothyroidism 9.1%

Obesity 31.8%


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


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


Klinefelter

Syndrome vs

48, XXYY47, 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% maternal50% paternal

100% paternal

Stature 188 cm = 6 ft 2 inches 192.4 cm = 6 ft 3 inches

CongenitalMalformations

Clindodactyly

common

Other 18%

Clinodactyly

commonOther 56%

HypergonadotropicHypogonadism

Yes Yes

DevelopmentCognitive

Speech/Motor 40‐75%Learning disability 50‐75%FS‐IQ 89‐102Verbal IQ > Performance IQ

Speech/Motor 72‐92%Learning Disability 100%FS‐IQ 70‐80Verbal IQ > Performance IQ


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.

xxyysyndrome.org

xxyysyndrome.org

9 year old boy chromosomal abnormality

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