An unusual presentation of acquired hypothyroidism: the Van Wyk–Grumbach syndrome

Abstract

The association in young females of long-standing primary hypothyroidism, isosexual precocious pseudopuberty and multicystic enlarged ovaries was first described in 1960 by Van Wyk and Grumbach. Since then, sporadic case reports have contributed to clarifying the key features of this syndrome. The unique elements that lead to this diagnosis are FSH-dominated sexual precocity combined with a delayed bone age in the presence of hypothyroidism. It is important to recognise this syndrome because initiating simple thyroid hormone replacement completely resolves symptoms and hormone abnormalities, avoiding unnecessary investigations for malignancies or surgical intervention. We describe an 8-year-old girl with autoimmune thyroiditis and severe long-standing hypothyroidism presenting with the clinical features of Van Wyk-Grumbach syndrome, a secondary TSH-secreting adenoma and hyperprolactinaemia. In addition, this girl presented with microcytic anaemia, elevated erythrocyte sedimentation rate (ESR) and two unusual features -a newly developed streaky hyperpigmented skin lesion and parathyroid hormone suppression despite vitamin D deficiency. Thyroxine replacement normalised all hormone abnormalities and shrunk the pituitary adenoma within 9 months, but the new skin lesion persisted. We review the literature and explore the pathophysiology of known and new features that give rise to speculation indicating stimulation of the FSH G protein-coupled receptor by excessive TSH, but LH suppression by hyperprolactinaemia.

Precocious Puberty with Primary Hypothyroidism due to Autoimmune Thyroiditis

“…The glycoproteins TSH, FSH, LH and hCG share a common alpha subunit but have a unique beta subunit that is specific to each hormone. They each act through transmembrane GPCRs to activate adenylate cyclase and stimulate c-AMP production 4 . Anasti et al 10 showed that recombinant human TSH elicited a dose-dependent response at the human FSH receptor.…”

“…In girls precocity menifests as breast enlargement, uterine bleeding and multicystic ovaries 3 . In 1960, Van Wyk and Grumbach first described a syndrome characterized by breast development, uterine bleeding and multicystic ovaries in the presence of long standing primary hypothyroidism 4 . Looking for hypothyroidism in girls with ovarian masses and precocious puberty is important in order to avoid surgery on the ovaries 5 .…”

“…Even with identical twins the concordance rate is only about 50% , emphasizing environment play a role in disease pathogenesis 6 . Most cases of syndrome in the literature are secondary to autoimmune thyroid disease but there are some case reports where the syndrome is secondary to unrecognized congenital hypothyroidism 4 . Although rare, the exact incidence of pseudoprecocious puberty attributable to hypothyroidism is unknown 7 .…”

A clue to diagnosis in a boy with short stature: Testicular enlargement

“…This condition is mostly manifested with ovarian cysts, early menstrual bleeding and galactorrhea in girls (1-3), while it is manifested with prominent penile enlargement and increased testicular size without increased testeosterone rarely in boys (4,5). Complete recovery is provided by administering thyroid hormone in both genders (6). In this article, we present an 8 year 9 month-old male patient who presented with short stature in whom increased testicular size found on physical examination directed us to the diagnosis.…”

“…Increased prolactin levels can have an inhibitory effect on pituitary gonodotropins by slowing down the gonodotropin releasing hormone pulse frequency (7). In Van Wyk-Grumbach syndrome, luteinizing hormone levels are low or normal and follicle stimulating hormone levels are increased (3)(4)(5)(6). The mechanism of this is based on the interaction of common alpha subunits included in the structures of TSH and follicle stimulating hormone (8).…”