Evaluation of genotype–phenotype relationships in patients referred for endocrine assessment in suspected Pendred syndrome

DesignPatients with Pendred syndrome have genotypic and phenotypic variability, leading to challenges in definitive diagnosis. Deaf children with enlarged vestibular aqueducts are often subjected to repeated investigations when tests for mutations in SLC26A4 are abnormal. This study provides genotype and phenotype information from patients with suspected Pendred syndrome referred to a single clinical endocrinology unit.MethodsA retrospective analysis of 50 patients with suspected Pendred syndrome to investigate the correlation between genetic, perchlorate discharge test (PDT) and endocrine status.ResultsEight patients with monoallelic SLC26A4 mutations had normal PDT. Of the 33 patients with biallelic mutations, ten of 12 patients with >30% discharge developed hypothyroidism. In our cohort, c.626G>T and c.3-2A>G result in milder clinical presentations with lower median perchlorate discharge of 9.3% (interquartile range 4–15%) compared with 40% (interquartile range 21–60%) for the remaining mutations. Eight novel mutations were detected. All patients with PDT <30% remained euthyroid to date, although the majority are still under the age of 30. There was a significant correlation between PDT and goitre size (R=0.61, P=0.0009) and the age of onset of hypothyroidism (R=−0.62, P=0.0297). In our population, the hazard of becoming hypothyroid increased by 7% per percentage point increase in PDT (P<0.001).ConclusionThere is a correlation between SLC26A4 genotype and thyroid phenotype. If results hold true for larger patient numbers and longer follow-up, then for patients with monoallelic mutations, PDT could be unnecessary. Patients with biallelic mutations and PDT discharge >30% have a high risk of developing goitre and hypothyroidism, and should have lifelong monitoring.

Clinical and laboratory features of children and adolescents with congenital hypothyroidism due to dyshormonogenesis in southern Brazil

OBJECTIVE: To characterize the phenotype of patients with congenital hypothyroidism (CH) due to dyshormonogenesis, and to hypothesize on the degree of genetic defect. SUBJECTS AND METHODS: Patients with dyshormonogenesis were subdivided into G1 (radioactive iodine uptake, RAIU > 15%; n = 62) and G2 (RAIU < 15%; n = 32). Thyroglobulin (TG) was measured in all patients; perchlorate discharge test (PDT) was performed in G1; and saliva-to-plasma radioiodine ratio (I- S/P) in G2. RESULTS: Levels of TSH, TT4, and FT4 before treatment and upon diagnosis confirmation were significantly different in both groups, but not between groups. In G1, 27 patients developed goiter; 17 had positive PDT (14%-71% discharge), 11 had TG < 2.5 ng/dL (one with high TSH), and one developed thyroid carcinoma. In G2, four patients developed goiter, and three had low I- S/P. CONCLUSION: These data suggest an iodide organification defect in 17 cases; an iodide transport defect (NIS defect) in three, probable TSH resistance in 10, and a TG synthesis defect in two cases.

Concurrence of Pendred Syndrome, Autoimmune Thyroiditis, and Simple Goiter in One Family

Pendred syndrome is the autosomal recessively transmitted association of familial goiter and congenital deafness. There is no specific biochemical marker of this disease, and the diagnosis depends upon the demonstration of the triad of congenital sensorineural hearing loss, goiter, and abnormal perchlorate discharge test. Pendred syndrome is caused by mutations within the putative ion transporter gene (PDS gene), located on chromosome 7q. A wide variation in the clinical presentation of this condition, and its well documented phenotypic overlap with other thyroid disorders (such as Hashimoto’s thyroiditis), can lead to diagnostic difficulties. The potential for misdiagnosis increases when these disorders occur coincidentally in the same family. We describe a kindred in which Pendred syndrome, autoimmune thyroiditis, and simple goiter coexisted, to highlight these diagnostic pitfalls and to illustrate the use of mutational analysis in resolving diagnostic confusion.

Pendred's Syndrome: A Study of Patients and Relatives

Four families, 29 members, with Pendred's syndrome were studied to clarify hearing loss and hormonal status. The ages ranged fro 3 to 50 years. Complete Pendred's syndrome was found in 9 patients. They had bilateral profound hearing loss with residual hearing low frequencies. Goiter was diagnosed at the age of 1 to 14 years with a positive perchlorate discharge test. Twelve of the patient relatives showed partial Pendred's syndrome. Mild sensorineural hearing losses occurred in the low- and medium-range frequencies wi normal perchlorate discharge test results in 6 cases. The other 6 had a slight drop in the perchlorate discharge test results with norm hearing. Five subjects were normal and 3 had normal hormonal and normal perchlorate discharge test results, but were not teste audiologically. This paper shows that patients with Pendred's syndrome may have goiter at birth or develop it between 8 and 14 year that their deafness is bilateral and profound, and that their perchlorate discharge tests are positive. Relatives of Pendred's syndrorr patients showed mild low-frequency sensorineural hearing loss without goiter and normal perchlorate discharge test results in half tl cases, and a slight drop in the perchlorate discharge test results with normal hearing and without goiter in the other half. A correlatic between these findings and genetic studies needs further investigation.

Primary hypothyroidism manifested in childhood with special reference to various types of reversible hypothyroidism

Okamura K, Sato K, Ikenoue H, Nakagawa M, Kuroda T, Yoshinari M, Fujishima M. Primary hypothyroidism manifested in childhood with special reference to various types of reversible hypothyroidism. Eur J Endocrinol 1994;131:131–7. ISSN 0804–4643 The clinical courses of 15 patients with overt primary hypothyroidism manifested in childhood were studied. Nine female patients with goitrous hypothyroidism due to chronic thyroiditis showed almost normal height and became euthyroid spontaneously during iodine restriction. The other 6 non-goitrous patients (3M and 3F) (atrophic thyroiditis in 2, lingual goiter in 2 and probable hypoplastic thyroid in 2) showed physical growth retardation and remained irreversibly hypothyroid requiring replacement therapy. In the reversible group, the characteristic findings were high thyroidal radio-active iodine uptake (58 ± 19%/24 h, N = 8) and positive perchlorate discharge test. Serum non-hormonal iodine levels were high in 4 of 6 patients measured. During the long-term follow-up period of 6 years in 6 patients, 2 patients remained euthyroid with normal growth and regular menstrual cycle and 4 patients became hypothyroid again (after eating seaweed in 1, despite iodine restriction in 2 and after the episode of painless thyroiditis in 1). Transient retardation of growth was observed during the second episode of hypothyroidism. In the irreversible group, one patient with blocking type TSH binding inhibitor immunoglobulin (TBII) became thyrotoxic 4 years later with the decrease in activity of blocking type TBII. These results suggested that reversible recovery of the thyroid function could be expected in patients with juvenile hypothyroidism due to chronic thyroiditis after (1) iodine restriction, (2) improvement of immunological perturbation, or (3) disappearance of blocking type TBII. However, careful follow-up is necessary, because hypothyroidism would recur again with transient retardation of growth in children. Ken Okamura, Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812, Japan