Natural History of Thyroid Disease in Children with PTEN Hamartoma Tumor Syndrome

J Clin Endocrinol Metab. 2021 Mar 8;106(3):e1121-e1130. doi: 10.1210/clinem/dgaa944.


Context: Thyroid ultrasound screening is recommended in children with PTEN hamartoma tumor syndrome (PHTS) due to increased risk of thyroid neoplasia, but the natural history of thyroid disease in children with PHTS is unclear.

Objective: Determine the prevalence and natural history of thyroid disease in children with PHTS.

Methods: Retrospective cohort study (1998-2019) in an academic pediatric hospital of individuals with genetically confirmed PHTS diagnosed before age 19 years. Clinical, thyroid ultrasound, and laboratory characteristics are described. Primary outcomes were the prevalence of thyroid nodules ≥10 mm diameter and time course and risk factors for nodule development assessed by Cox regression analysis. Secondary outcomes included thyroid nodule requiring biopsy, other ultrasound findings, and prevalence of autoimmune thyroid disease.

Results: Among 64 subjects with PHTS, 50 underwent thyroid ultrasound. A thyroid nodule ≥10 mm was diagnosed in 22/50 (44%) subjects at median (range) age 13.3 (7.0-22.9) years. Nodules were diagnosed earlier in females than in males (10.8 [7.0-17.9] vs 14.2 [9.9-22.9] years, P = .009). In multivariate analysis, risk of thyroid nodules was significantly associated with female sex (hazard ratio 2.90, 95% CI 1.16-7.27, P = .02) and inversely associated with the presence of neurologic findings of PHTS (HR 0.27, 95% CI 0.10-0.69, P = .007). Abnormal-appearing lymph nodes with echogenic foci were observed by ultrasound in 20% of subjects, but these were not associated with malignancy. Autoimmune thyroid disease was present in 10/33 (30.3%) of subjects in whom it was assessed.

Conclusion: Thyroid disease is common in children with PHTS. This study supports current consensus recommendations for ultrasound screening.

Keywords: PTEN; hamartoma; pediatric; screening; thyroid; ultrasound.

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Cohort Studies
  • Disease Progression
  • Female
  • Hamartoma Syndrome, Multiple / complications
  • Hamartoma Syndrome, Multiple / epidemiology*
  • Hamartoma Syndrome, Multiple / genetics
  • Hamartoma Syndrome, Multiple / pathology*
  • Humans
  • Male
  • PTEN Phosphohydrolase / genetics
  • Prevalence
  • Retrospective Studies
  • Risk Factors
  • Thyroid Diseases / diagnosis
  • Thyroid Diseases / epidemiology*
  • Thyroid Diseases / etiology
  • Thyroid Diseases / pathology*
  • Ultrasonography
  • United States / epidemiology
  • Young Adult


  • PTEN Phosphohydrolase
  • PTEN protein, human