Methods

The subjects enrolled in the present study provided formal consent in accordance with the guidelines of the local institutions. All family members underwent a complete examination, including cardiac, endocrine, and otorhinolaryngologic evaluation. Laboratory studies included ECGs, audiograms, cervical echography, serum determination of thyroid-stimulating hormone (TSH), free thyroxine (FT4), thyroglobulin, antithyroperoxidase, and anti-TSH auto-antibodies, and chromosome analyses. At least one 12-lead ECG was obtained from all patients. The QT and QTc intervals were measured in all leads using Bazett’s formula by 2 physicians who were unaware of the patients’ status. U waves were not included in the measurements. The reported QTc intervals are the values obtained in lead II. The LQTS phenotype assignment was made according to the criteria of Keating et al. Patients were coded as affected if their QTc interval was ≥0.45 second with symptoms or ≥0.47 second without symptoms. Unaffected patients were those with a QTc interval of ≤0.41 second, and borderline patients were those in whom the QTc interval was >0.41 but <0.47 second without symptoms or ≤0.44 second with symptoms. Symptoms included syncope and/or aborted cardiac arrest, triggered or not by physical and/or emotional stress.

Results

The proband (VI-2, Figure 1 ) came to our attention at age 36 years as an emergency patient owing to cardiac arrest. She was resuscitated. A subsequent examination revealed deafness with a palpable goiter. The ECG showed sinus rhythm with a conspicuous lengthening of the QT interval measured in lead II: QT = 0.560 second and QTc = 0.603 second ( Figure 2 ). The findings from chest radiography, echocardiography, and abdominal ultrasonography were normal. Thyroid ultrasonography confirmed the goiter by showing a hypertrophic and multinodular thyroid. The ophthalmic examination ruled out optic atrophy and abnormal retinal pigmentation. The standard serum tests results, as well as TSH, FT4, and thyroglobulin, were all within normal ranges. A hemogram showed mild microcytic anemia. The tympanic membranes and vestibular function were normal, but she had profound bilateral deafness with pure tone audiometry. Brainstem-evoked response testing confirmed the deafness. The findings from temporal bone computed tomography and magnetic resonance imaging were normal. The parents were first cousins once-removed. The proband was born after an uneventful pregnancy and delivery. The deafness was discovered by 5 months of age. She experienced her first syncopal episode at 6 months of age with a seizure and without an obvious triggering event. Subsequently, she experienced about 10 syncopal episodes/year, associated with emotion and/or stress, such as vaccination. Cardiac arrest occurred while she was ascending the stairs. She was considered to have LQTS associated with euthyroid (nontoxic) multinodular goiter and sensorineural deafness and was discharged with propranolol (3 mg/kg/day). No suppressive thyroid hormone therapy was undertaken. She recently experienced a syncope that lasted, according to her entourage, >5 minutes without an evident triggering event. She had a cardiac defibrillator installed. At the last follow-up visit, she continued to take propranolol but still had complaints of important palpitations.

Family pedigree. Females are denoted by circles and males by squares. To illustrate phenotype variations, symbol was divided into quadrants, indicating presence of LQTS and/or goiter and/or deafness. Open symbols denote normal phenotype. Dotted symbols denote “thyroid status unknown” in 7 patients who died from sudden death, 6 unavailable patients, and 40 patients aged <21 years (cutoff). The 2 latter groups underwent cervical examination, FT4 and thyroid-stimulating hormone measurements, and thyroid ultrasound examination, all of which were normal.

Proband’s 12-lead ECG showing important QT interval prolongation. QTc was determined by Bazett’s formula. In lead II, QT was 0.560 second and QTc was 0.603 second.

A 7-generation family from Tunisia, part of a large tribe, consisting of 113 persons were studied. Of these 113 family members, 28 were deceased, 5 were not available, and 80 were enrolled in the present study ( Figure 1 ). Of the latter group, 41 were female and 39 were male. Their age range was 2 to 80 years (mean age 27.81 ± 17.14), and 40 were affected. The phenotype was complete (ie, LQTS, goiter, and deafness) in 2 patients, the proband and patient VI-4. In the remaining 38 patients, the 3 manifestations were present variably: 18 had 2 traits and 20 only 1 ( Table 1 ).

Sudden death occurred in 7 subjects (4 females and 3 males) aged 9 days to 19 years. In these patients, the fainting attacks were of neonatal or infantile onset, stress-induced, and repeated (several episodes monthly or daily), leading to death in early childhood, before 8 years of age in all except for patient VI-14, who died at 19 years of age while walking. Fatal episodes associated with physical stress (dancing, swimming, or running) occurred in 4 patients. In 2 others, death occurred without evident physical stress, during sleep or while walking. In 1 patient, death occurred immediately after syncope associated with seizures. The syncopes varied in duration. None of the victims had been medicated, and none of the living family members reported any history of syncope or cardiac arrest, except for the proband and a 15-year-old female adolescent (VI-30). The latter reported one episode of syncope that occurred while working. When the 7 victims of sudden death were taken into account, 11% of the family members had experienced syncope. Of the 80 subjects enrolled in the study, 17 had a prolongation of the QT and QTc interval (all of them had a QTc interval of ≥0.47 second without symptoms), with 18 LQTS-affected patients when the symptomatic proband was included ( Table 1 ). Also, 46 were coded as borderline (45 with a QTc interval >0.41 but <0.47 second without symptoms and 1 [VI-30] with a QTc interval of 0.380 second with symptoms). Finally, 16 patients were coded as unaffected (QTc interval of ≤0.41 second). Their age range was 4 to 65 years (mean age 34.55 ± 16.88). A female predominance was found (12 females and 6 males; Table 1 ). Of the 80 subjects, 25 (31%) complained of repeated episodes of palpitations. Recurrent near-syncope was reported by 2 patients coded as normal (VI-18 and VII-1) and 1 coded as borderline (VI-19; Figure 1 ). None of the family members had conduction defects or a low heart rate. Echocardiograms of the deaf patients failed to detect any congenital heart malformations. No history of medication or disorders known to prolong the QT interval was present in the family.

All 80 family members were clinically euthyroid. A palpable goiter was noticed in 6 patients. Ultrasonography confirmed a multinodular goiter in these and revealed thyroid nodules in 15 additional patients, for a total of 21 patients, with a female predominance (12 females and 9 males; Table 1 ). Multiple nodules were found in 13 patients and a single nodule in 8 others ( Table 1 ). Their age range was 21 to 80 years (mean age 40.9 ± 15.27; Table 1 ). Because the actual age at which these nodules developed might have been lower than the age at ascertainment, 53 subjects (40 who were <21 years of age, 6 who were not available for a thyroid examination, and 7 who had died from sudden death) were coded as “thyroid status unknown” and dotted in the pedigree ( Figure 1 ). In 2 patients (VI-4 and V-22), in whom the nodules were >3 and >4.5 cm, respectively, thyroid scintigraphy showed cold nodules. They underwent partial thyroidectomy and were prescribed 50 μg/day l -thyroxine as suppressive therapy. Pathologic examination showed macrovesicular adenoma and no signs of malignancy in both patients. The serum levels of TSH, FT4, and thyroglobulin were within the normal range in the 80 study participants, except for 1 patient (V-13) with subclinical hyperthyroidism (low TSH, normal FT4). No thyroid auto-antibodies were found in any of the 80 study participants. The 2 operated patients, together with patient V-9, who was treated with l -thyroxine only, had had a relapse of their thyroid nodules found at a recent checkup. The family lives in an area without known endemic goiter or iodine deficiency.

No family members had vertigo by history or examination. The 7 patients who died from sudden death had documented bilateral sensorineural deafness. Pure tone audiometry revealed 7 additional deaf patients, of whom 4 had bilateral cophosis (VI-2, VI-42, VI-53, and VI-55), 1 had mild bilateral deafness (VI-20) in the 500 to 4,000 Hz range, and 2 had unilateral cophosis, in the right ear (IV-7) or the left (VI-4; Table 1 ). These results were confirmed by brainstem-evoked response testing, which showed no response at all in the 6 patients with cophosis. Deafness was congenital in all 14 patients, prelingual in 11 of them, and predominating in women (9 females and 5 males). Inner ear computed tomography and magnetic resonance imaging were performed for 7 deaf patients (14 temporal bones analyzed). No abnormalities were found in any of them, in particular neither a Mondini malformation nor an enlarged vestibular aqueduct was found.