Van Wyk Grumbach Syndrome in Juvenile Hypothyroidism

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Abstract and Introduction

Abstract

Context: Prolonged hypothyroidism in children commonly causes short stature with delayed bone maturation, and delayed puberty. However, a paradoxical occurrence of peripheral precocious puberty and pituitary enlargement in chronically untreated juvenile hypothyroidism was first reported by Van Wyk and Grumbach in 1960.

Objective: To create increased awareness and a better understanding of this clinical entity among emergency room physicians, pediatricians, surgeons, gynecologists and oncologists.

Methods: Case records of children diagnosed with Van Wyk–Grumbach syndrome (VWGS) were analyzed retrospectively.

Results: Twenty-six girls and 4 boys were identified (2005–2020). All had profound primary hypothyroidism (total thyroxine [T4]: 2.5–33.5 nmol/L, thyrotropin: > 75–3744 μIU/mL). Hypothyroidism was not the referral diagnosis in any of the girls. Among them, 17 were referred for precocious puberty, 5 with a diagnosis of pituitary tumor on magnetic resonance imaging, and others for acute surgical abdomen in 7 girls (painful abdominal mass—2, ovarian tumor—2, ovarian torsion—2, ruptured ovarian cyst—1), acute myelopathy in 1, and menorrhagia with headache in another. All girls were successfully managed with levothyroxine replacement alone, except for the 2 with ovarian torsion, who required surgery. Menstruation ceased promptly with T4 therapy in all girls, occurring at an age-appropriate later date. All boys had testicular enlargement at presentation that regressed partially after T4 treatment. Catch-up growth was remarkable during the first treatment year, but the final height was compromised in all.

Conclusion: Increased awareness of varied presentations of VWGS is vital among pediatricians to facilitate early diagnosis and targeted investigations, and to help in the initiation of the simple yet highly rewarding T4 replacement therapy to avoid all possible complications.

Introduction

The principal manifestations of untreated hypothyroidism in children are hindered growth and maturation. Delay in skeletal maturity caused by low thyroxine (T4) levels is often associated with delayed pubertal development. However, in 1960, Van Wyk and Grumbach reported 3 girls with untreated, long-standing juvenile hypothyroidism presenting with the seemingly unusual combination of precocious menstruation, galactorrhea, early breast development, a conspicuous absence of pubic hair along with delayed bone age, and an enlarged sella turcica. All the abnormal clinical features including pituitary enlargement improved dramatically after thyroid hormone replacement therapy.^[1] By giving a logical explanation to these and 4 other similar isolated cases reported earlier, Van Wyk and Grumbach grouped them all under the same umbrella term.

Over the years, a greater understanding of the phenotype of this syndrome emerged in several case reports, with the description of a diverse range of clinical manifestations varying from isolated breast development to premature menstrual bleeding, enlarged pituitary gland, multicystic ovaries resembling cystic ovarian tumor, or acute surgical abdomen due to ovarian torsion.^[2–8] Although predominantly seen in older children with long-standing acquired hypothyroidism, cases were reported in association with congenital hypothyroidism as well.^[9] Ovarian hyperstimulation syndrome (OHSS), seen in pubertal girls and young women with chronic untreated hypothyroidism, was considered to result from a similar pathophysiological process.

We analyzed the clinical, biochemical, and imaging findings of a series of children who presented with features of Van Wyk–Grumbach syndrome (VWGS) to survey the varied presenting manifestations. The underlying pathophysiology is also reviewed.

Table 1. Referral diagnosis and clinical features at presentation in girls (n = 26)
Clinical features			At presentation	At last follow-up
History of early vaginal bleeding			21/26	—
Age at onset of vaginal bleed, y^a			7.3 (4–10.5)	—
Median age of girls, y (n = 26)			9.0 (4.75 to 17.92)	14.5 (7.8 to 20.8)
Weight SDS^a			−0.94 (−3.77 to +2.01)	NA
Height SDS^a			−2.83 (−6.67 to +1.07)	−2.06 (−6.4 to −0.21)
BMI^a			17.45 (14.3 to 34.6)	NA
Bone age delay, y^a			2.9 (0.2 to 5)	NA
Referral diagnosis and clinical features at presentation		No. of cases	Response to thyroxine monotherapy
Precocious puberty	Idiopathic Pituitary enlargement Pituitary enlargement associated with -Monocular temporal hemianopsia -Galactorrhea -Kocher-Debré-Sémélaigne syndrome	12 1 1 1 2	Breast size regressed in 3 mo Normal puberty started later appropriately Visual field defects improved in 6 mo Galactorrhea resolved in 2 wks Calf muscle hypertrophy and tendon reflexes improved by 9–12 mo	Further menstrual cycles ceased promptly in those with early menarche
Paraparesis with short stature and pituitary enlargement		1	Lower limb weakness showed improvement in 1 wk; resolved fully in 1 mo
Ovarian torsion		2	Enlarged ovarian cysts regressed in 1 girl The other required emergency unilateral salpingo-oophorectomy at initial presentation Contralateral ovary showed regression of enlarged follicles
Ruptured ovarian cyst with hemoperitoneum		1	Acute abdominal symptoms resolved in 1 wk Ovaries regressed to normal volume within 6 mo
Ovarian "malignancy" (CA-125 positive)		1
Ovarian tumor (? Cystadenoma)		1
Painful mass per abdomen		2
Menorrhagia with headache and pituitary enlargement		1	Resolved in next few mo

Abbreviations: BMI, body mass index; NA, not available; SDS, SD score.
^aMedian (range).

Table 2. Referral diagnosis and clinical features at presentation in boys (n = 4)
Clinical features	At presentation	At last follow-up
Median age of boys, y (n = 4)	8.83 (2.42 to 12.42)	9.85 (3.7 to 20)
Weight SDS^a	−0.24 (−3.66 to +0.24)	NA
Height SDS^a	−2.63 (−6.00 to −1.14)	−2.05 (−4.77 to −0.71)
BMI^a	19.95 (15.9 to 22.7)	NA
Bone age delay, y^a	1.95 (1.4 to 6.4)	NA
Referral diagnosis and clinical features at presentation	No. of cases	Response to thyroxine therapy
Recurrent headaches with "pituitary macroadenoma" in a boy diagnosed with hypothyroidism and poor compliance to therapy	1	Headaches resolved in 3 mo when regular thyroxine therapy was ensuredMRI at 6-mo follow-up showed normal pituitary gland
Developmental delay, short stature with enlarged testes (4–6 mL) on examination	1	Thyroxine replacement improved stature; developmental milestones are advancingTesticular size regressed to 3 mL by 6 mo
Short stature with enlarged testes (4–6 mL) on examination	1
Short stature with "pituitary macroadenoma"	1

Abbreviations: BMI, body mass index; MRI, magnetic resonance imaging; NA, not available; SDS, SD score
^aMedian (range).

Table 3. Investigation results at diagnosis and etiology of hypothyroidism
Laboratory investigation	Result
TT4, nmol/L, range	2.5–33.5
TSH, μIU/mL, range	> 75 to 3744
LH^a, IU/L, median and range	0.01 (0.01–0.1)
FSH^a, IU/L, median and range	5.55 (4.2–16.2)
Etiology of hypothyroidism^b	AITD: 80% (n = 24)
Etiology of hypothyroidism^b	CH: 20% (n = 6)
Ultrasonogram of pelvis	Bulky, multicystic ovaries in all girls
MRI brain	Pituitary macroadenoma/hyperplasia n = 10 (8 girls, 2 boys)

TT4 reference range: 85 to 170 nmol/L, TSH reference range: 0.7 to 5.5 μIU/mL.
Abbreviations: AITD, autoimmune thyroid disorder; CH, congenital hypothyroidism; FSH, follicle-stimulating hormone; LH, luteinizing hormone; MRI, magnetic resonance imaging; TSH, serum thyrotropin; TT4, serum total thyroxine.
^aData available for only 5 girls.
^bTwo girls had trisomy 21 and one girl had idiopathic thrombocytopenic purpura as associated conditions.

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Van Wyk Grumbach Syndrome and Ovarian Hyperstimulation in Juvenile Primary Hypothyroidism

Lessons From a 30-Case Cohort

Abstract and Introduction

Abstract

Introduction

Van Wyk Grumbach Syndrome and Ovarian Hyperstimulation in Juvenile Primary Hypothyroidism

Lessons From a 30-Case Cohort

Abstract and Introduction

Abstract

Introduction

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Tables

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Authors and Disclosures

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