American Journal of Medical Genetics 3673-75 (1990)

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Multiple Congenital Anomalies Associated With a 47,XXX Chromosome Constitution Opal J. Hood, Elizabeth A. Hartwell, Karen E. Shattuck, and Harvey S. Rosenberg Departments of Pediatrics (O.J.H.) and Pathology ( E A.H., H.S.R .), University of Texas Health Science Center, Houston; Department of Pediatrics (K.E.S.), University of Texas Medical Branch, Galveston, Texas An infant with a 47,XXX chromosome constitution, who died shortly after birth, had laryngeal atresia, p.ulmonary hypoplasia, craniofacial anomalies, urogenital malformations including unilateral renal agenesis, hydrometrocolpos and ovarian dysgenesis, and mildly abnormal endochondral ossification. Implications for genetic counseling are presented. KEY WORDS: triplo-X, laryngeal atresia, pulmonary hypoplasia,ovarian dysgenesis

INTRODUCTION The 47,XXX chromosome constitution, one of the more common aneuploid states in humans, occurs in an estimated 0.8/1,000 female births [de Grouchy and Turleau, 19841. Although most trip1o-X females have a n apparently normal phenotype, several have had multiple congenital anomalies [Barr et al., 1969; Spear and Porto, 19881. Here we report on a term female infant with a 47,XXX chromosome constitution who had laryngeal atresia, pulmonary hypoplasia, and other anomalies and died shortly after birth. CLINICAL REPORT A female infant was born a t term to a healthy 22-yearold G2P1 mother and an unrelated healthy 23-year-old father. Early oligohydramnios resolved by term. The infant, delivered by routine repeat cesarean section, was cyanotic and bradycardic a t birth. Despite visualization of the vocal cords, an endotracheal tube could not be passed. hsuscitation attempts, including surgical placement of a tracheostomy tube, were unsuccessful, and the infant died at age 35 minutes. Genetic consultation was sought because the infant had an unusual faReceived for publication June 14, 1989; revision received October 10, 1989. Address reprint requests to Dr. O.J. Hood, University of Texas Health Science Center, Department of Pediatrics Rm. 3.142A, 6431 Fannin, Houston, TX 77030.

0 1990 Wiley-Liss, Inc.

cia1 appearance suggestive of the Potter sequence and possible laryngeal atresia. The mother had a ventricular septa1 defect that did not require surgical correction, and the father had suspected pyloric stenosis. An older half sister (maternal) was healthy a t age 3 years.

Autopsy Findings The infant was appropriate for 40 weeks gestational age in all growth parameters. She had a “square” face, persistence of forehead hair, apparent hypertelorism, short philtrum, recessed chin, beaked nasal tip, and rudimentary formation of the upper helices of the ears (Figs. 1, 2). A midline pelvic mass distended the abdomen. The labia majora were hypoplastic, and a single perineal orifice was present. The oral cavity, pharynx, and esophagus were normal. Distal to hypoplastic vocal cords, the larynx was occluded by a band of cartilage, muscle, and connective tissue (Fig. 3). The trachea was patent below the occlusion. The lungs were hypoplastic. The ratio of lung weight: body weight was 0.013, with normal being equal to or greater than 0.015. Hydrometrocolpos with atresia of the distal vagina moved the bladder superiorly and anteriorly, displacing the urethra into the anterior vaginal wall. Both fallopian tubes and ovaries were compressed and elongated by the distended vagina. The right kidney was absent, and obstruction from the hydrometrocolpos led to hydroureter and hydronephrosis on the left. Pulmonary hypoplasia was confirmed histologically by the radial alveolar count. A persistent pharyngotracheal duct was identified posterior to the atretic larynx. The distended vagina had flattened epithelium, and the cervix and endometrium had a decidual reaction. In both ovaries, fibrous connective tissue enveloped occasional primordial follicles in the ovarian stroma (Fig. 4). Inhibited bone growth was evidenced by scant capillary penetration and ossification at the costochondral junction. The placenta had a mature configuration without abnormalities. Cytogenetic Results Chromosome analysis of peripheral leukocytes from blood obtained during the resuscitation showed 47,XXX

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Fig. 1. Frontal view of our patient’s face showing the “square”shape, apparent hypertelorism, and beaked nasal tip. The palpebral fissures do not appear short.

Fig. 2. Lateral view of the face showing the short philtrum and abnormal ear formation. The nasal bridge does not appear depressed,

in all cells. The sex chromosomes of the parents were normal in peripheral leukocytes.

DISCUSSION The 47,XXX chromosome constitution usually is seen in phenotypically apparently normal females who may have menstrual problems Lde Grouchy and Turleau, 19841. Some patients have had developmental delays, learning disabilities, or emotional problems [Linden et al., 19881. A small number of patients have congenital anomalies but without a consistent phenotype [Barr et al., 1969; Spear and Porto, 19881. Reported malformations have included defects of the urogenital tract, brain, skeleton, heart, and craniofacial region. A recent report suggests that certain facial changes including short palpebral fissures, midface hypoplasia, long philtrum, square chin, and abnormal ears may be characteristic of the 47,XXX phenotype, but the series was small [Ballesta and Zapata, 19891. To our knowledge, neither laryngeal atresia nor pulmonary hypoplasia have been reported in a 47,XXX patient. Laryngeal atresia, an uncommon developmental anomaly [Gatti et al., 19871, has been associated with tracheoesophageal fistula and urogenital, cardiac, and intestinal anomalies [Fox and Cocker, 19641. The lungs in patients with laryngeal atresia are characteristically large and filled with fluid, attributed to inhibited drainage across the occlusion, although normally developed lungs have also been reported [Fox and Cocker, 1964; Warkany, 19711. Laryngeal atresia has been associated with pulmonary hypoplasia as part of the broader tracheal agenesis sequence in which genitourinary, skele-

Fig. 3. A coronal section of the larynx shows occlusion (arrows)of the lumen a t a level inferior to the vocal cords.

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and the lack of a distinct phenotype in 47,XXX. The association of severe congenital anomalies and 47,XXX may be coincidental, e.g., the defects in our patient are consistent with the tracheal agenesis sequence [Evans et al., 19851.The laryngeal atresia in our patient may be an example of one of the rarer forms of tracheal agenesis, type G or short segment, which has been described [Faro et al., 19791.As an alternative to coincidence, a subset of 47,XXX patients may have anomalies etiologically related to the aneuploidy if the hypothesis that triplo-X females have a recognizable facies proves to be true. Our patient shared some of the facial anomalies described but differed in others. At this point we acknowledgethat such a relationship has not been established, and further clinical data are needed to resolve this question. Our patient does illustrate the difficulty encountered, especially in genetic counseling, when a common sex chromosome abnormality is associated with rare severe congenital anomalies.

ACKNOWLEDGMENTS The authors thank Mary Ann Crow and Thedaray Bailey for secretarial assistance. REFERENCES

Fig. 4. The ovaries contain few primordial follicles (large arrows) and cellular cords (small arrows) in a loose connective tissue stroma. Hematoxylin-eosin, X 100.

tal, cardiac, and gastrointestinal defects are also seen [Evans et al., 1985; Far0 et al., 19791. Hydrometrocolpos secondary to vaginal atresia often accompanies urogenital defects including renal agenesis, renal dysplasia, and imperforate anus [Hahn-Pedersen et al., 1984; Spencer and Levy, 19621, but only rarely tracheal stenosis [Hahn-Pedersen et al., 19841or laryngeal atresia [Fox and Cocker, 19641. Establishing a simple, direct etiologic relationship between congenital anomalies and 47,XXX remains difficult because of the rare association of severe anomalies

Ballesta F, Zapata M (1989): Phenotype in triple-X patients. Clin Genet 34:388-389. Barr ML, Sergovich FR, Carr DH, Shaver EL (1969): The triplo-X female: An appraisal based on a study of 12 cases and a review of the literature. Can Med Assoc J 101:247-258. de Grouchy J, Turleau C (1984): “Clinical Atlas of Human Chromosomes,” 2nd ed. New York: John Wiley and Sons, pp 384. Evans JA, Reggin J , Greenberg C (1985):Tracheal agenesis and associated malformations: A comparison with tracheoesophageal fistula and the VACTERL association. Am J Med Genet 21:21-34. Far0 RS, Goodwin CD, Organ CH, Hall RT, Holder TM, Ashcraft KW, Amoury RA (1979): Tracheal agenesis. Ann Thorac Surg 28:295-299. Fox H, Cocker J (1964): Laryngeal atresia. Arch Dis Child 39641-645. Gatti WM, MacDonald E, Orfei E (1987):Congenital laryngeal atresia. Laryngoscope 97:966-969. Hahn-Pedersen J, Kvist N, Nielsen OH (1984): Hydrometrocolpos: Current views on pathogenesis and management. J Urol 132:537-540. Linden MG, Bender BG, Harmon RJ,Mrazek DA, Robinson A (1988): 47,XXX What is the prognosis? Pediatrics 82:619-630. Spear GS, Porto M (1988): 47,XXX chromosome constitution, ovarian dysgenesis, and genito-urinary malformation. Am J Med Genet 29:511-515. Spencer R, Levy DM (1962):Hydrometrocolpos: Report of three cases and review of the literature. Ann Surg 155:558-571. Warkany J (1971): “Congenital Malformations.” Chicago: Yearbook Medical Publishers, pp 596-598.

Multiple congenital anomalies associated with a 47,XXX chromosome constitution.

An infant with a 47,XXX chromosome constitution, who died shortly after birth, had laryngeal atresia, pulmonary hypoplasia, craniofacial anomalies, ur...
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