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Cover page of the Journal of Health Sciences

 Table of Contents  
Year : 2016  |  Volume : 9  |  Issue : 3  |  Page : 342-344

49, XXXXY syndrome: An infant presenting with ambiguous genitalia

1 Department of Urology, KLES Kidney Foundation, KLES Dr. Prabhakar Kore Hospital and M.R.C., Belagavi, Karnataka, India
2 Department of Biotechnology and Microbiology, Karnatak University, Dharwad, Karnataka, India

Date of Web Publication21-Dec-2016

Correspondence Address:
Dr. Rajendra B Nerli
Department of Urology, KLES Kidney Foundation, KLES Dr. Prabhakar Kore Hospital and M.R.C., Nehru Nagar, Belgaum - 590 010, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2349-5006.196341

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Presences of normal genes on the Y chromosome are essential for normal sex determination and sex differentiation of male genitalia. Several genes on the X chromosome and other autosomes have been shown to be anti-testes and have a detrimental effect on the development process of normal male genital system. The addition of X chromosomes to the 46, XY karyotype results in seminiferous tubules dysgenesis, hypogonadism, and malformed genitalia. We report an infant male with 49, XXXXY syndrome presenting with ambiguous genitalia and multiple extra-gonadal anomalies.

Keywords: 49 XXXXY syndrome, ambiguous genitalia, intrauterine growth restriction, sex chromosome aneuploidy

How to cite this article:
Nerli RB, Magdum PV, Mungarwadi AM, Ghagane SC, Hiremath MB. 49, XXXXY syndrome: An infant presenting with ambiguous genitalia. Indian J Health Sci Biomed Res 2016;9:342-4

How to cite this URL:
Nerli RB, Magdum PV, Mungarwadi AM, Ghagane SC, Hiremath MB. 49, XXXXY syndrome: An infant presenting with ambiguous genitalia. Indian J Health Sci Biomed Res [serial online] 2016 [cited 2020 Jul 11];9:342-4. Available from: http://www.ijournalhs.org/text.asp?2016/9/3/342/196341

  Introduction Top

The 49, XXXXY syndrome is a rare sex chromosome aneuploidy disorder, first reported in 1960 by Fraccaro et al., with an approximate incidence of 1 in 85,000–100,000 male births.[1] The “classical triad” of 49, XXXXY syndrome consists of mental retardation, radioulnar synostosis, and hypogonadism.[2] Other phenotypic features reported include low birth weight, slow growth with retarded bone age, craniofacial anomalies, abnormal genitals, multiple skeletal deformities with joint laxity, cardiac deformities, and mental retardation.[3] A few more than 100 cases with variable features have been reported in the world literature.[4] Previously, this syndrome was thought to be a variant of the Klinefelter syndrome (49, XXY). However, children with the 49, XXXXY syndrome have distinct facial features, body habitus, multiple skeletal anomalies, and cardiac defects that are not found in Klinefelter syndrome. Moreover, adults with the 49, XXXXY syndrome are known to be short, unlike Klinefelter syndrome.[5] We report an infant presenting to the pediatric urology services with ambiguous genitalia.

  Case Report Top

A 9-month-old infant was brought to the out-patient services with suspected ambiguous genitalia. The infant was born at term (gestational age 41 weeks, 5 days) to a 21-year-old primigravida following an uneventful pregnancy of nonconsanguineous marriage. The child's 28-year-old father appeared normal. The delivery was normal vaginal one. At birth, the neonate weighed 1700 g, length 46 cm, and head circumference was 30 cm. At birth, the neonate had asphyxia with APGAR score of 6. The neonate was also diagnosed to have congenital talipes equinus varus of the right foot (CTEV) [Figure 1] and ambiguous genitalia [Figure 2]. A cast was applied to the foot to treat the talipes equinovarus deformity. On examination of the infant at our center, it was noticed that the neonate had a developmental delay in milestones. The child psychologist after examination labeled the child's mental/physical age of 7½ months. Genital examination revealed penoscrotal hypospadias with prepenile scrotum, left undescended testes and normally descended right testes. The child had CTEV of the right foot. Hemoglobin levels were 10.2 g/dl; peripheral smear examination revealed dimorphic anemia with lymphocytosis and thrombocytosis. Serum creatinine was 0.4 mg%. Chest X-ray showed cardiomegaly and two-dimensional echocardiography revealed patent ductus arteriosus (0.1–0.2 cm) [Figure 3]. Karyotype analysis by G-banding showed 49, XXXXY chromosomes at a band resolution of 500 [Figure 4]. The child was assigned male gender. The parents were counseled regarding the child's health and prognosis. The genital reconstruction was planned after the child was to be of 12 months of age.
Figure 1: Congenital talipes equinus varus of right foot

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Figure 2: Hypospadiac and scrotalization of penis

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Figure 3: Two-dimensional-echocardiography showing patent ductus arteriosus

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Figure 4: Karyotype showing 49, XXXXY chromosomes

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  Discussion Top

The infants of 49, XXXXY syndrome commonly present with a variable combination of craniofacial dysmorphism, abnormal genitals, and delayed developmental milestones which are confirmed on chromosome karyotyping examination.[2],[3],[6],[7] However, many get diagnosed much later in life by chromosome screening studies in institutions for the mentally deficient. Infants present with multiple skeletal anomalies and in particular with radioulnar synostosis.[2],[6] Joint laxity and hypotonia are reported in approximately 33% of patients with the 49, XXXXY syndrome.[3],[6] The prevalence of congenital heart disease among patients with the 49, XXXXY syndrome is 14%.[8] Of these, patent ductus arteriosus is the most common.

The Y chromosome contains the SRY gene, which is essential for normal testicular organogenesis.[8] Several genes on the X chromosomes (e.g., DAX1 gene), as well as those from the autosomes, have been shown to have anti-testes property. This seems to have a detrimental effect on the process of testes development, resulting in dose-related severe gonadal dysgenesis, ambiguous genitalia, or even complete male-to-female sex reversal. Several studies have shown that the DAX1 gene on the X chromosome per se is not critical for either ovarian or testicular differentiation; however, a double dose of DAX1 gene acts as an anti-testes gene. The addition of an additional X chromosome to a 46, XY karyotype results in seminiferous tubules dysgenesis and infertility as seen in Klinefelter syndrome (47, XXY). The addition of more X chromosomes in polysomy X males results in not only infertility but also hypoplastic and undervirilized genitalia.[8] The majority of those with the 48, XXXY and 49, XXXXY syndromes are known to have small testes (94%), small penis and hypoplastic scrotum (80%), and some even with cryptorchidism (30%) and ambiguous genitalia.[8]

Mental retardation remains a major problem in these patients. A direct relationship between the number of supernumerary X chromosomes with phenotypic abnormalities and mental retardation has been well reported. The severity of mental retardation increases with each additional X chromosome.[4],[5] 49, XXXXY syndrome commonly present with various congenital anomalies which is confirmed on chromosome karyotyping. The severity of mental retardation, infertility, and genital malformation increases with each additional X chromosome. Mental retardation remains a major problem in these patients. Hence, proper counseling, gender reassignment and treatment of anomalies should be done with the help of multidisciplinary approach.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Fraccaro M, Kaijser K, Lindsten J. A child with 49 chromosomes. Lancet 1960;2:899-902.  Back to cited text no. 1
Peet J, Weaver DD, Vance GH. 49, XXXXY: A distinct phenotype. Three new cases and review. J Med Genet 1998;35:420-4.  Back to cited text no. 2
Sijmons RH, van Essen AJ, Visser JD, Iprenburg M, Nelck GF, Vos-Bender ML, et al. Congenital knee dislocation in a 49, XXXXY boy. J Med Genet 1995;32:309-11.  Back to cited text no. 3
Etemadi K, Basir B, Ghahremani S. Neonatal diagnosis of 49, XXXXY syndrome. Iran J Reprod Med 2015;13:181-4.  Back to cited text no. 4
Grumbach MM, Hughes IA, Conte FA. Disorders of sex differentiation. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, editors. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders; 2003. p. 842-62, 881-5, 961-2.  Back to cited text no. 5
Hayek A, Riccardi V, Atkins L, Hendren H. 49, XXXXY chromossomal anomaly in a neonate. J Med Genet 1971;8:220-1.  Back to cited text no. 6
Linden MG, Bender BG, Robinson A. Sex chromosome tetrasomy and pentasomy. Pediatrics 1995;96(4 Pt 1):672-82.  Back to cited text no. 7
Ng SF, Boo NY, Wu LL, Shuib S. A rare case of ambiguous genitalia. Singapore Med J 2007;48:858-61.  Back to cited text no. 8


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]


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