Van Wyk and Grumbach Syndrome

Overview

Van Wyk and Grumbach syndrome is a rare endocrine disorder characterized by the unusual combination of long-standing untreated hypothyroidism, delayed bone age, and isosexual precocious puberty in children, particularly girls. First described in 1960 by Van Wyk and Grumbach, the syndrome presents a paradox where hypothyroidism, typically associated with delayed puberty, instead causes early onset of secondary sexual characteristics. It is considered a form of pseudoprecocious puberty because the changes are not due to gonadotropin stimulation from the pituitary, but rather a result of excessive thyroid-stimulating hormone (TSH) and its interaction with other hormonal pathways.

Causes

The primary cause of Van Wyk and Grumbach syndrome is prolonged, untreated primary hypothyroidism during childhood. The hypothyroid state results in elevated levels of TSH and thyrotropin-releasing hormone (TRH), which can cross-react with other receptors and lead to abnormal hormonal activity. Contributing factors include:

• Autoimmune thyroiditis (Hashimoto’s thyroiditis) – the most common cause in children

• Congenital hypothyroidism – if inadequately treated or diagnosed late

• Iodine deficiency or other causes of thyroid dysfunction

Symptoms

The clinical presentation of Van Wyk and Grumbach syndrome typically includes a mix of hypothyroid symptoms and signs of precocious puberty. Common features include:

• Hypothyroid signs: Fatigue, constipation, weight gain, cold intolerance, dry skin, delayed growth, and coarse facial features

• Precocious puberty: Breast development, menstrual bleeding (in girls), and sometimes ovarian cysts despite prepubertal levels of gonadotropins

• Delayed bone age: Bone maturation lags behind chronological age, which is unusual in true precocious puberty

• Galactorrhea: In some cases due to elevated prolactin caused by increased TRH

Diagnosis

Diagnosis of Van Wyk and Grumbach syndrome involves clinical suspicion in children showing both hypothyroid symptoms and early puberty signs. Diagnostic steps include:

• Thyroid function tests: Low free T4 and elevated TSH levels confirm hypothyroidism

• Bone age assessment: X-rays of the hand and wrist show delayed bone maturation

• Pelvic ultrasound: May reveal multicystic enlarged ovaries or uterine enlargement

• Hormonal profile: Typically shows low or normal gonadotropins (LH and FSH), supporting a diagnosis of pseudoprecocious puberty

Treatment

The treatment of Van Wyk and Grumbach syndrome centers on correcting the underlying hypothyroidism. This is achieved with:

• Levothyroxine therapy: Oral thyroid hormone replacement normalizes TSH and resolves symptoms

• Monitoring and dose adjustment: Regular thyroid function tests to ensure appropriate dosing and response

• Supportive care: Management of any ovarian cyst complications or other endocrine issues if present

Once euthyroidism is restored, signs of precocious puberty typically regress, and normal growth and pubertal development resume.

Prognosis

The prognosis for Van Wyk and Grumbach syndrome is excellent with timely diagnosis and adequate thyroid hormone replacement. Most children experience regression of pseudo-pubertal signs, normalization of growth rate, and catch-up growth. Long-term outcomes are favorable, and complications are rare if hypothyroidism is properly managed. Early treatment also prevents permanent developmental or reproductive sequelae.