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XXXXX Syndrome
49,XXXXX (pentasomy X) is a rare sex chromosome aneu- ploidy. The birth prevalence of pentasomy X is estimated to be 1 in 85,000 females.
GENETICS/BASIC DEFECTS
1. Etiology: Three extra X chromosomes are responsible for the pentasomy X syndrome.
2. Occurrence of a 49,XXXXX complement: secondary to sequential non-disjunctions in meiosis I and meiosis II in the mother
a. Involves the survival of both X chromosomes in a sin- gle oocytes through both meiotic divisions
i. Once between homologous X chromosomes at the first meiosis
ii. Twice between sister chromatids in both X chro- mosomes in the secondary oocytes at the second meiosis
b. Followed by the fertilization by a sperm contributing the 5th chromosome X
3. Formation of four Barr bodies a. Lyon hypothesis
i. Inactivation of all X chromosomes but one ii. Account for the viability of the X-chromosome
aneuploidies
b. Inactivation of four X chromosomes resulting in four Barr bodies
4. 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 increasing the severity
a. Affects somatic development most significantly i. Skeletal abnormalities
ii. Cardiovascular abnormalities b. Delays sexual development 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. Prenatal growth retardation b. Small birth weight
c. Low postnatal weight d. Failure to thrive e. Hypotonia
f. Short stature
g. Delayed psychomotor retardation h. Mental retardation
2. Craniofacial features a. Microcephaly b. Flattened occiput c. Epicanthus
d. Upslanting palpebral fissures e. Ocular hypertelorism
f. Uncoordinated eye movements g. Flat broad nose
h. Cleft palate i. Low-set ears j. Malformed teeth 3. Skeletal abnormalities
a. Short neck b. Lax joints
c. Multiple dislocations i. Shoulders ii. Elbows iii. Hips
d. Radioulnar synostosis e. Spinal abnormalities
f. Clinodactyly of the 5th fingers g. Lower leg abnormalities
i. Genu valgus ii. Talipes
iii. Metatarsus varus h. Delayed bone age 4. Congenital heart defects
a. Ventricular septal defect b. Patent ductus arteriosus 5. Abnormal lobulation of the lungs 6. Renal hypoplasia
7. Sexual development a. Delayed puberty
b. Incomplete secondary sexual development c. Small uterus
d. Hypoplastic/absent ovaries
i. Composed mainly of stroma and atrophic follicles ii. Absence of ova
iii. Unilateral absence of an ovary reported e. Reduced fertility
8. Normal external genitalia 9. Dermatoglyphics
a. Finger-dermal-ridge hypoplasia and a low total ridge count, consistent with the inverse proportion between the number of X chromosomes and the total ridge count (exceptions exist)
b. Transverse palmar creases
DIAGNOSTIC INVESTIGATIONS
1. Chromosome analysis a. 49,XXXXX karyotype
b. Fluorescence in situ hybridization (FISH), using DNA probe for α-satellite sequence in chromosome
XXXXX SYNDROME 1065
X (DXZ1), reveals five signals representing the pres- ence of XXXXX
2. Radiography
a. Dislocations of the elbows and/or hips b. Radioulnar synostosis
c. Clinodactyly
GENETIC COUNSELING
1. Recurrence risk
a. Patient’s sib: not increased
b. Patient’s offspring: not reported due to severe mental retardation
2. Prenatal diagnosis
a. Ultrasonography: bilateral radioulnar synostosis b. Amniocentesis and CVS
i. Chromosome analysis
ii. FISH using DNA probe (DXZ1) applied to uncultured amniocytes
3. Management
a. Physical/occupational therapy b. Speech therapy
REFERENCES
Archidiacono N, Rocchi M, Valente M, et al.: X pentasomy: A case and review.
Hum Genet 52:69–77, 1979.
Brody J, Fitzgerald MG, Spiers ASD: A female child with five X chromo- somes. J Pediatr 70:105–109, 1967.
Deng H-X, 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.
Dryer RF, Patil SR, Zellweger HU, et al.: Pentasomy X with multiple disloca- tions. Am J Med Genet 4:313–321, 1979.
Fryns JP, Kleczkowska A, Petit P, et al.: X-chromosome polysomy in the female: personal experience and review of the literature. Clin Genet 23:341–349, 1983.
Funderburk SJ, Valente M, Klisak I: Pentasomy X: report of patient and studies of X-inactivation. Am J Med Genet 8:27–33, 1981.
Kassai R, Hamada I, Furuta H, et al.: Penta X syndrome: A case report with review of the literature. Am J Med Genet 40:51–56, 1991.
Kesaree N, Woolley PV Jr: A phenotypic female with 49 chromosomes, pre- sumably XXXXX. J Pediatr 63:1099–1103, 1963.
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.
Martini G, Carillo G, Catizone F, et al.: On the parental origin of the X’s in a prenatally diagnosed 49,XXXXX syndrome. Prenat Diagn 13:763–766, 1993.
Monheit A, Francke U, Saunders B, et al.: The penta-X syndrome. J Med Genet 17:392–396, 1980.
Myles TD, Burd L, Font G, et al.: Dandy-Walker malformation in a fetus with pentasomy X (49,XXXXX) prenatally diagnosed by fluores- cence in situ hybridization technique. Fetal Diagn Ther 10:333–336, 1995.
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.
Sergovich F, Uilenberg C, Pozsony J: The 49,XXXXX chromosome constitu- tion: similarities to the 49,XXXXY condition. J Pediatr 78:285–290, 1971.
Silengo MC, Davi GF, Franceschini P: The 49XXXXX syndrome. Report of a case with 48XXXX/49XXXXX mosaicism. Acta Paediatr Scand 68:769–771, 1979.
Toussi T, Hala F, Lesage R, et al.: Renal hypodysplasia and unilateral ovarian agenesis in the penta-X syndrome. Am J Med Genet 6:153–162, 1980.
1066 XXXXX SYNDROME
Fig. 1. The first reported case of 49,XXXXX at infancy (A) and adult- hood (B) with 4 Barr bodies (C), two drumsticks in a polymorphonu- clear leukocyte (D), and a karyotype of 49,XXXXX (E).
Fig. 2. A girl with 49,XXXXX syndrome at birth (A), 6 month (B), and 2 years 4 months (C).
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