Canadian Health&Care Mall: Congenital Heart Disease in a Tetra-X Woman

congenital heart diseaseTetra-X is a rare abnormality of the sex chromosomes; only 20 cases have been reported previously. It is thought to result from nondisjunctions during the first and second meiotic divisions of oogenesis. The clinical features are nonspecific and have included mental retardation reduction of dermal ridges, behavioral disturbances, hypertelorism with epicanthal folds, eye anomalies (myopia, squints, nystagmus, iridoschisis), skeletal abnormalities (clinodactyly, radioulnar synostosis, dislocation of the hip, tall stature), menstrual irregularities with reduced fertility, and congenital heart disease.

The patient to be presented is the first case of tetra-X to be studied at autopsy and the first with documented congenital heart disease. Read more about congenital heart disease on Canadian Health&care Mall –

Case Report

The patient was a mentally retarded woman with an IQ of 50, cardiomegaly, a systolic ejection murmur in the pulmonary area, and accentuation of the second heart sound with wide splitting (60 msec). Menses and menopause (at 42 years) were unremarkable.

The clinical picture of congestive heart failure appeared when the patient was 52 years of age and progressed inexorably.

Chest x-ray examinations revealed cardiomegaly, dilatation of the main pulmonary artery and proximal branches, “pruning” of the smaller pulmonary arteries, and reduced peripheral pulmonary vascularity—findings consistent with pulmonary vascular obstruction. Electrocardiograms revealed atrial fibrillation, right axis deviation, and marked right ventricular hypertrophy.

Buccal smear showed that 28 percent of the cells examined were chromatin positive, 18 percent having two Barr bodies and 10 percent having three Barr bodies. Karyotype (Fig 1) indicated a 48, XXXX chromosomal constitution: of 60 cultured peripheral leukocytes examined, there were 56 ( 93.3 percent) with 48, XXXX, two (3.3 percent) with 47, XXX, and two (3.3 percent) with 46, XX.

The patient died at 58 years from congestive heart failure.

Autopsy showed cardiomegaly (530/270 gm), with hypertrophy and enlargement of the right atrium and right ventricle, and dilatation of the main pulmonary artery (Fig 2a-c). Three atrial septal defects of the ostium secundum type measured 2.2 x 1.7,1.3 X 0.8, and 0.6 X 0.3 cm (Fig 2b, d). The pulmonary valve was bicuspid, calcified and regurgitant. Grade 2 pulmonary vascular obstructive changes were found histologically. Antemortem mural thrombi were found in both atria (chronic atrial fibrillation) and organized throm-boemboli were present in two small brandies of the right pulmonary artery.

The brain was underweight (1050/1250 gm), without obvious external abnormality. However, coronal sections revealed a generalized deficiency of hemispheral white matter (Fig 3a) compared with normal controls (Fig 3b). Paucity of white matter was least marked in the temporal lobes. Inter-hemispheral association pathways such as die corpus callosum were thin. The ventricles were mildly enlarged (Fig 3a). The pyramidal system was small bilaterally. The only histologic abnormality was widespread fibrillary gliosis of hemispheral white matter (Fig 3c, d).


Our patient is the first case of tetra-X in whom congenital heart disease has been documented. However, a clinical diagnosis of patent ductus arteriosus, not confirmed by catheterization, was made in one previously reported patient. Available data suggest that congenital heart disease is not characteristic of the tetra-X woman (2 of 21 cases, 9.5 percent).

The widespread deficiency of cerebral white matter found in this patient, while not specific for tetra-X, appears to be a basis for her mental retardation by reducing association pathways (corticocortical, thalamocortical, and interhemispheral).

Figure 1. Chromosomal preparation showing two extra pairs of С group chromosomes indicating a 48, XXXX chromosomal constitution.
Figure 2. Specimen of heart and left lung. a. External frontal view showing the normally interrelated right atrium (RA), left atrium (LA), right ventricle (RV), left ventricle (LV), dilated main pulmonary artery (MPA) and left pulmonary artery (LPA). b. Interior of the RA showing the three secundum type of atrial septal defects (ASD II), with the superior vena cava (SVC), right atrial appendage (RAA) and tricuspid valve (TV) for orientation, c. Opened RV and MPA. Note the hypertrophy and enlargement of RV and the dilatation of the MPA. The right pulmonary artery (RPA) is unopened. The pulmonary valve is bicuspid, calcified, and regurgitant, but not stenotic, d. Interior of LA showing the deficiency and fenestrations of septum primum, the flap valve of the foramen ovale, resulting in three ASD II. Left pulmonary veins (LPV), right pulmonary veins (RPV), and left atrial appendage (LAA) provide orientation. Ruler is marked in cm and mm.
Figure 3. Brain, a. Coronal sections of tetra-X female’s brain showing a generalized reduction of hemispheral white matter, b. A control, sectioned similarly, c. Low power, and d, high power histologic sections (Holzer method) showing glial fibrils spread diffusely throughout hemispheral white matter.


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