Goiter, Multinodular 1, With Or Without Sertoli-Leydig Cell Tumors

A number sign (#) is used with this entry because susceptibility to multinodular goiter-1 (MNG1) with or without Sertoli-Leydig cell tumors is caused by heterozygous mutation in the DICER1 gene (606241) on chromosome 14q32.

See also pleuropulmonary blastoma (PPB; 601200), which is a tumor predisposition syndrome, also caused by heterozygous mutation in the DICER1 gene.

Description

Multinodular goiter (MNG) is a common disorder characterized by nodular enlargement of the thyroid gland. In MNG1, some individuals may also develop Sertoli-Leydig cell tumors, usually of the ovary (summary by Rio Frio et al., 2011).

Genetic Heterogeneity of Multinodular Goiter

Other MNG loci map to chromosome Xp22 (MNG2; 300273) and chromosome 3q26 (MNG3; 606082).

Clinical Features

Murray et al. (1966) described a family in which members of 5 generations had nontoxic goiter appearing in the early teens. Calcification and firm, nodular consistency were unusual features. None of the known defects in thyroid hormonogenesis could be demonstrated. Radioactive iodine studies showed increased thyroid avidity and rapid turnover. No certain male-to-male transmission was observed.

Jensen et al. (1974) described ovarian tumors in a mother and 2 daughters. The tumor proved to be arrhenoblastoma, secreting androgens, in the 2 daughters. Thyroid adenomas occurred in several members of the family and were found to be associated frequently with ovarian arrhenoblastoma in young women surveyed separately.

O'Brien and Wilansky (1981) described a family in which the 16-year-old proband had a nodular thyroid and a functioning ovarian arrhenoblastoma. Males and females to a total of 6 in 4 generations were known to have nodular thyroids. The disorder was apparently transmitted through an unaffected male. The authors raised the question of testicular tumors in males with the gene.

Couch et al. (1986) observed a Canadian family in which 18 members had a form of euthyroid adolescent multinodular goiter. Histologic study showed multiple adenomata with areas of epithelial hyperplasia, hemorrhage, and calcification. In 2, there were focal areas of epithelial hyperplasia reminiscent of low-grade papillary carcinoma (see 188550). The family was later studied by Bignell et al. (1997) (see MAPPING).

Druker et al. (1997) reported a family of Ashkenazi Jewish descent in which 7 individuals had benign and/or malignant thyroid tumors. The proband was diagnosed with nodular hyperplasia and superimposed well-differentiated localized follicular carcinoma of the thyroid at age 17. Her father also had multinodular goiter and was later diagnosed with well-differentiated follicular carcinoma. Three of the proband's sibs had thyroid conditions, including 2 with multinodular goiter and 1 with an enlarged thyroid; 1 of the sibs died of an alveolar rhabdomyosarcoma at age 20 years.

Niedziela (2008) reported a 14-year-old girl with an ovarian Sertoli-Leydig cell tumor and high serum testosterone. She presented with intermittent abdominal pain, deepening of voice, and amenorrhea for 4 months. She had a personal and family history of multinodular goiter. After surgery and treatment of both, the patient remained disease-free for 6 years.

Inheritance

In the family reported by Couch et al. (1986) and Bignell et al. (1997), transmission was consistent with autosomal dominant inheritance with reduced penetrance in males; in 3 instances, unaffected males had daughters with multinodular goiter. One example of male-to-male transmission was noted.

Brix et al. (1999) studied the relative contributions of genetic and environmental factors causing simple goiter in a well-defined population of Danish twins. They performed a historical cohort study of 5,479 same-sex twin pairs born between 1953 and 1972. Concordance rates, tetrachoric correlations, and heritability were determined. The crude probandwise concordance rates were 0.42 (95% confidence interval (CI), 0.26 to 0.59) and 0.13 (95% CI, 0.06 to 0.24) for female monozygotic and female dizygotic pairs, respectively. The age-adjusted cumulative probandwise risk for simple goiter from birth to age 43 years was 0.53 (95% CI, 0.23 to 0.83) for female monozygotic twins and 0.18 (95% CI, 0.05 to 0.35) for female dizygotic twins (P of 0.003). The tetrachoric correlations were substantially higher in monozygotic (0.82; SE, 0.007) than in dizygotic twins (0.47; SE, 0.12). Model-fitting analysis suggested that the heritability of the liability to the development of simple goiter in women is approximately 82%. Brix et al. (1999) concluded that the etiology of clinically overt simple goiter is multifactorial. Genetic factors play a major role in the etiology of simple goiter in females, but environmental factors are also of importance.

Mapping

Bignell et al. (1997) performed a genomewide linkage scan in a large Canadian family originally reported by Couch et al. (1986) with 18 cases of nontoxic multinodular goiter. They identified a locus on chromosome 14q, designated MNG1 for 'multinodular goiter-1,' with a maximum 2-point lod score of 3.8 at D14S1030 and a multipoint lod score of 4.88, defined by D14S1062 (proximally) and D14S267 (distally). The gene encoding thyroid-stimulating hormone receptor (TSHR; 603372), which is located at 14q31, was considered a possible candidate gene but was found to be outside the linked region and could be excluded by recombination and sequencing. To determine the role of the MNG1 gene in familial nonmedullary thyroid cancer (NMTC), Bignell et al. (1997) studied 37 smaller pedigrees, each containing at least 2 cases of NMTC. Analysis by both parametric and nonparametric methods indicated that only a very small proportion of familial NMTC is attributable to MNG1.

Neumann et al. (1999) investigated a patient with a relapsing euthyroid goiter and her family, in which several members had undergone thyroidectomy for euthyroid goiter. Sequence analysis of thyroid peroxidase (TPO; 606765) and TSHR cDNAs revealed several previously reported polymorphisms. The markers for the thyroglobulin (TG; 188450), TPO, and sodium-iodide symporter (SLC5A5; 601843) genes gave 2-point and multipoint lod scores that were negative or less than 1 for all assumed recombination fractions. Neumann et al. (1999) concluded that these candidate genes could be excluded as a major cause of the euthyroid goiters in this family. A maximum 2-point lod score of 1.5 at theta of 0.0 was obtained with marker D14S1030, which is close to the MNG1 locus. The authors concluded that the haplotype of markers TSHR, D14S1054, and D14S1030 cosegregates with familial euthyroid goiter, confirming that the MNG1 locus is a positional candidate for nontoxic goiter.

Molecular Genetics

In affected members of 5 unrelated families with autosomal dominant multinodular goiter with or without Sertoli-Leydig cell tumors, Rio Frio et al. (2011) identified 5 different heterozygous mutations in the DICER1 gene (see, e.g., 606241.0007-606241.0010). Four of the families had previously been reported by O'Brien and Wilansky (1981), Niedziela (2008), Bignell et al. (1997), and Druker et al. (1997). Studies of both types of tumors from several families showed no loss of heterozygosity at the DICER1 locus. Goiter tissue showed mixed immunostaining results, with some tissues showing no DICER1 protein staining and other tissues showing clear cytoplasmic staining. RNA studies from patient lymphoblasts showed perturbations of miRNA compared to controls, suggesting a dysregulation of gene expression patterns. In particular, LET7A (605386) and miR345 were both decreased in DICER1-related goiter tissue.