1068
XXXXY Syndrome
49,XXXXY syndrome was first described by Fraccaro and Lindsten in 1960. The incidence is estimated to be approxi- mately 1 in 85,000 newborn males.
GENETICS/BASIC DEFECTS
1. Etiology: Three extra X chromosomes are responsible for the 49,XXXXY syndrome.
2. Mechanism
a. All four X chromosomes are of maternal in origin b. Resulting from successive nondisjunctions in maternal
meiosis I and II
c. Inactivation of three out of four X chromosomes results in three Barr bodies (Lyon hypothesis).
3. Effect of supernumerary X chromosomes: a direct rela- tionship between the number of supernumerary X chro- mosomes and phenotypic abnormalities and mental retardation, with each additional chromosome increas- ing the severity
a. Somatic development most significantly affected i. Skeletal abnormalities
ii. Cardiovascular abnormalities
b. Gonadal development in males: particularly suscepti- ble to extra genetic material
i. Addition of a single X chromosome to a 46,XY karyotype resulting in seminiferous tubal dysge- nesis rendering infertile as such males with Klinefelter syndrome
ii. Additional extra X chromosomes in polysomy X males such as 48,XXXY and 49,XXXXY can result in not only infertility but hypoplastic and malformed genitalia.
c. Affects cognitive development i. Severe mental retardation
ii. Language delay (both expressive and receptive language)
iii. Behavioral problems
CLINICAL FEATURES
1. Growth and development a. Growth retardation b. Severe speech impairment
c. Varying degree of mental retardation 2. Craniofacial features
a. Microcephaly b. A full, round face c. Ocular hypertelorism d. Upslanted palpebral fissures e. Epicanthus
f. Broad nasal bridge
g. Micrognathia h. Prognathism
i. High arched or cleft palate j. Irregular teeth implantation k. Malformed ears
3. Webbed and short neck 4. Congenital heart defects
a. Patent ductus arteriosus b. Atrial septal defect c. Pulmonic stenosis d. Tetralogy of Fallot 5. Skeletal abnormalities
a. Short stature
b. Proximal radio-ulnar dysostosis c. Vertebral anomalies
d. Clinodactyly of the 5th fingers e. Coxa valga
f. Genu valga g. Pes planus 6. Genital abnormalities
a. Hypoplastic male genitalia b. Micropenis
c. Hypospadias d. Small testes e. Hypogonadism
f. Infertility 7. Dermatoglyphics
a. Decrease in total finger ridge count b. Transverse palmar creases
8. Psychological profile a. Timid and shy
b. Emotional disturbances with low frustration level c. Strong reaction to minor changes
d. Adaptive function higher than cognitive function
DIAGNOSTIC INVESTIGATIONS
1. Chromosome analysis showing 49,XXXXY 2. Radiography
a. Elbows
i. Proximal radio-ulnar dysostosis
ii. Radio-ulnar dislocation without synostosis iii. Elongated upper radius
iv. Wide, club-shaped proximal ulna b. Wrists and hands
i. Elongated distal ulna ii. “Pseudoepiphyses”
iii. Clinodactyly of the 5th fingers iv. Brachymesophalangia V
v. Retarded bone age vi. Corner defect in capitate
vii. Poor modeling of the 5th metacarpals
XXXXY SYNDROME 1069
c. Pelvis and hips i. Coxa valga ii. Narrow iliac wings d. Knees
i. Shallow intercondylar fossa ii. Genu valgum
e. Ankles and feet
i. Gap between the 1st and 2nd toes
ii. Short wide distal phalanx of the great toes f. Skull
i. Sclerotic cranial sutures ii. Thick cranial vault iii. Ocular hypertelorism
iv. J-shaped sella v. Prognathism g. Spine
i. Scoliosis
ii. Thoracic kyphosis iii. Square vertebral bodies h. Sternum
i. Thick
ii. Abnormal segmentation
3. Echocardiography for congenital heart defects
4. Histology of testicular biopsies: dysgenesis of testicular germ cells and tubules leading to fibrosis
GENETIC COUNSELING
1. Recurrence risk
a. Patient’s sib: not increased
b. Patient’s offspring: no offspring due to infertility of the condition
2. Prenatal diagnosis
a. Ultrasonographic markers i. Polyhydramnios ii. Cystic hygroma iii. Clubfoot
iv. Micropenis
b. Amniocentesis and CVS i. Chromosome analysis
ii. FISH using DNA probe (DXZ1) applied to uncultured amniocytes
3. Management
a. Early intervention and stimulation programs i. Speech/language therapy
ii. Physical/occupational therapy b. Testosterone replacement therapy
REFERENCES
Chen C-P, Chern S-R, Chang C-L, et al.: Prenatal diagnosis and genetic analysis of X chromosome polysomy 49,XXXXY. Prenat Diagn 20:754–757, 2000.
Curfs LM, Schreppers-Tijdink G, Wiegers A, et al.: The 49,XXXXY syn- drome: clinical and psychological findings in five patients. J Ment Defic Res 34:277–282, 1990.
Deng HX, Abe K, Kondo I, et al.: Parental origin and mechanism of formation of polysomy X: an XXXXX case and four XXXXY cases determined with RFLPs. Hum Genet 86:541–544, 1991.
Galasso C, Arpino C, Fabbri F, et al.: Neurologic aspects of 49,XXXXY syn- drome. J Child Neurol 18:501–504, 2003.
Hecht F: Observations on the natural history of 49,XXXXY individuals. Am J Med Genet 13:335–336, 1982.
Houston CS: Roentgen findings in the XXXXY chromosome anomaly. J Can Assoc Radiol 18:258–267, 1967.
Karsh RB: Congenital heart disease in 49, XXXXY syndrome. Pediatrics 56:462–464, 1975.
Kleczkowska A, Fryns J-P, Van den Berghe H: X-chromosome polysomy in the male. The Leuven experience 1966–1967, 1988.
Kojima Y, Hayashi Y, Maruyama T, et al.: 49,XXXXY syndrome with hydronephrosis caused by intravesical ureterocele. Urol Int 63:212–214, 1999.
Leal CA, Belmont JW, Nachtman R, et al.: parental origin of the extra chromo- somes in polysomy X. Hum Genet 94:423–426, 1994.
Linden MG, Bender BG ,Robinson A: Sex chromosome tetrasomy and penta- somy. Pediatrics 96:672–682, 1995.
Lomelino CA, Reiss AL: 49,XXXXY syndrome: behavioural and developmen- tal profiles. J Med Genet 28:609–612, 1991.
Peet J, Weaver DD,Vance GH: 49,XXXXY: a distinct phenotype. Three new cases and review. J Med Genet 35:420–424, 1998.
Rehder H, Fraccaro M, Cuoco C, et al.: The fetal pathology of the XXXXY- syndrome. Clin Genet 30:213–218, 1986.
Schluth C, Doray B, Girard-Lemaire F, et al.: Prenatal sonographic diagnosis of the 49,XXXXY syndrome. Prenat Diagn 1177–1180, 2002.
Sepulveda W, Ivankovic M, Be C, et al.: Sex chromosome pentasomy (49,XXXXY) presenting as cystic hygroma at 16 weeks’ gestation.
Prenat Diagn 19:257–259, 1999.
Villamar M, Benitez J, Fernandez E, et al.: Parental origin of chromosomal nondisjunction in a 49,XXXXY male using recombinant-DNA tech- niques. Clin Genet 36:152–155, 1989.
Zaleski WA, Houston CS, Pozsonyi J, et al.: The XXXXY chromosome anom- aly: report of three new cases and review of 30 cases from the literature.
Can Med Assoc J 94:1143–1154, 1966.
1070 XXXXY SYNDROME
Fig. 1. An older boy with 49,XXXXY showing bilateral dislocation of the elbows, radio-ulnar synostosis and 3 Barr bodies (buccal smear).
Fig. 2. A younger boy with 49,XXXXY showing a full, round face. He also has incontinentia pigmenti achromians.
