Neck Mass in a 12-year-old Girl with Autism Spectrum Disorder

A 12-year-old girl with autism spectrum disorder (ASD) presents with a history of a mass in the center of the anterior neck increasing in size during the past 3 years. She recently immigrated from the Dominican Republic with her father and sister. Her birth was uneventful, but she has a history of global developmental delay and said her first words at age 7 years. Family history is significant for a maternal uncle with macrocephaly but not for thyroid diseases, malignancies, genetic conditions, ASD, or developmental delay. Physical examination reveals macrocephaly (head circumference, 22 in [56 cm] [>97th percentile]) and a yellowish firm nodular cutaneous swelling approximately 0.4 in (1 cm) in diameter at the left frontal region of the scalp, suggestive of a lipoma. Oropharyngeal papillomas and a nonfluctuant, nontender, mobile, 5 × 5-cm circular mass at the level of the thyroid in the mid-anterior cervical area are present. Dysmorphic features, cardiac murmur, lymphadenopathy, and hepatosplenomegaly are absent, and the rest of the examination findings are normal. Laboratory evaluation shows the following values (reference ranges are in parentheses): thyrotropin, 1.2 mIU/L (0.35–4.8 mIU/L); total thyroxine, 6.0 μg/dL (77.23 nmol/L) (4.6–12.0 μg/dL [59.21–154.45 nmol/L]); free thyroxine, 1.0 ng/dL (12.87 pmol/L) (0.90–1.90 ng/dL [11.58–24.45 pmol/L]); 25-hydroxyvitamin D3, 7.6 ng/mL (18.97 nmol/L) (30.0–80.0 ng/mL [74.88–199.68 nmol/L]); thyroglobulin, 1,283 ng/mL (1,283 µg/L) (1.60–59.90 ng/mL [1.60–59.90 µg/L]); and parathyroid hormone, 173 pg/mL (173 ng/L) (14.0–72.0 pg/mL [14.0–72.0 ng/L]). Initial computed tomography of the neck reveals a thyroid mass of unclear etiology. She undergoes left hemithyroidectomy with isthmectomy. The pathologic examination reveals follicular carcinoma of the thyroid with minimal capsular invasion. Hence, completion thyroidectomy is performed. We sought a genetic consult to address the previously mentioned clinical findings of macrocephaly, ASD, thyroid carcinoma, lipoma, and oropharyngeal papilloma.Several genetic syndromes are commonly associated with thyroid cancers, and each syndrome is associated with particular thyroid cancer subtypes. In this patient with macrocephaly, follicular thyroid carcinoma, and skin manifestations, we considered the differential diagnoses listed in the Table.The patient's clinical features are suggestive of Cowden syndrome (CS). The National Comprehensive Cancer Network has established major and minor criteria for diagnosing CS. A modified set of criteria tailored for children and adolescents has been developed by Plamper et al. (1) This patient had 3 major criteria (follicular thyroid carcinoma, macrocephaly, and oral mucosal papillomatosis) and 3 minor criteria (ASD, cognitive deficit, and lipoma). (1) Endocrine tumor panel analysis that includes sequencing and deletion/duplication analysis of 11 genes (AIP, APC, CASR, CDC73, CDKN1B, CHEK2, DICER1, MEN1, PRKAR1A, PTEN, and RET) revealed a heterozygous pathogenic variant in the PTEN gene c.712_713insCTGT(p.Phe238Serfsx6). The insertion of 4 nucleotides is predicted to cause a frameshift and premature chain termination in exon 7 of PTEN, confirming the diagnosis of CS. We also screened for 102 genes associated with ASD. The autism panel includes sequencing and deletion/duplication analysis, which also detected the same heterozygous PTEN pathogenic variant. Findings from blood chromosomal analysis, chromosomal microarray, and fragile X analysis were normal.CS is an autosomal dominant disorder estimated to affect 1 in 200,000 people. (2)(3)(4) Both males and females are affected, but there is a slight female predominance. The manifestations of CS can present between ages 4 and 75 years. (5) Most individuals are diagnosed in the third decade of life. A germline pathogenic variant in the PTEN tumor suppressor gene accounts for the various malignancies in CS. (6) The diagnostic cutaneous lesions in CS are trichilemmomas, acral keratoses, pits on palms and soles, lipomas, and papular lesions on the lips and oral mucosa (3)(4)(5); this patient had lipoma in her scalp and papular oral mucosal lesions in a cobblestone pattern. Facial features associated with CS are macrocephaly, high-arched palate, and adenoid facies. (4) Macrocephaly has been reported in 94% of the patients. (7) The patient reported herein also had ASD and brain malformations, which are among the neurologic manifestations associated with CS. Adult-onset Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum) is also a neurologic manifestation of CS. (8)(9)In patients with CS, the estimated lifetime risk of cancers is 85% for breast, 35% for thyroid, 34% for kidney, 28% for endometrium, 9% for colorectum, and 6% for melanoma. (10) The other common manifestations are polyps of the gastrointestinal tract, benign ovarian cysts, testicular lipomatosis, and immune dysfunction. (3)(8)(9) Thyroid disease is the most frequently reported extracutaneous manifestation of CS in 75% of patients. (3)(11) Benign manifestations are multinodular goiter, Graves' disease, lymphocytic thyroiditis, thyroid dysfunction, or adenomas. (3)(8) The youngest age of thyroid cancer in CS reported in the literature is 7 years. Hence, children presenting with thyroid cancers should be tested for PTEN pathogenic variants. (11)(12) In female patients with CS, breast cancer is the most prevalent cancer and the leading cause of mortality. (10)In children younger than 18 years, screening involves yearly thyroid ultrasonography from the time of diagnosis or 5 years before the youngest age of thyroid cancer diagnosis in the family. Jonker et al (13) recommend screening starting at 10 years of age as the incidence of thyroid cancer reaches 5% at age 10 years. A skin examination for melanoma and a detailed physical examination are recommended during each visit. Annual abdominal ultrasonography to screen for renal carcinoma at diagnosis and ultrasonography of the testes/uterus and ovaries to screen for testicular lipomatosis and endometrial cancer are also recommended. (1)(11) After a diagnosis of CS, a magnetic resonance image (MRI) of the brain and a psychomotor development evaluation are essential. (1) The pediatrician is pivotal in integrating the multidisciplinary team and coordinating care for patients with CS. Physicians must consider initiating cancer screening 5 to 10 years before the youngest age at diagnosis of a particular cancer in the family. (11)Her initial blood evaluation indicated that she was euthyroid, with elevated parathyroid hormone levels attributed to vitamin D deficiency. Elevated thyroglobulin level was caused by follicular thyroid carcinoma. The surgical team was uncertain whether she would tolerate a fine-needle aspiration without sedation. She underwent a partial thyroidectomy initially followed by a completion thyroidectomy once malignancy was confirmed. A whole-body radioactive iodine scan with I123 after surgery confirmed the absence of cancer metastasis in lymph nodes, lungs, and bones. She was started on a suppressive dose of thyroxine, and thyroid function is being periodically monitored with thyroid function tests, thyroid ultrasonography, and thyroglobulin levels. She receives calcium supplements and calcitriol due to hypoparathyroidism after thyroidectomy. She also had formal neuropsychological testing, which showed widespread cognitive impairment with low intellectual and adaptive functioning.The patient's father and 10-year-old sister tested negative for single-site molecular analysis of the PTEN pathogenic variant. The mother was not available for testing. The patient was scheduled for brain MRI to evaluate for brain malformations, but she developed seizures before it was performed. Emergency noncontrast computed tomography of the head showed a large arachnoid cyst centered in the suprasellar cistern with extension into the third ventricle and left middle cranial fossa and a partially absent hypothalamus. MRI of the brain revealed a Chiari type 1 malformation with no syrinx and a low-grade right temporal glioma. MRI of the spine was normal. She is on levetiracetam monotherapy for seizures and is being evaluated for surgical resection of the low-grade glioma.The patient is currently managed by a team comprising the primary care pediatrician, endocrinologist, developmental pediatrician, geneticist, gastroenterologist, hemato-oncologist, neurologist, neuro-oncologist, and neurosurgeon. Breast cancer screening is recommended and involves breast self-examination starting at age 18 years, a clinical breast examination every 6 to 12 months from age 25 years, and annual breast imaging beginning at age 30 to 35 years. (1)(10)(11) Recommendations also include screening for renal cancer, endometrial cancer (with ultrasonography and endometrial biopsy at age 35 years), and melanoma. Screening for colon cancer begins at age 35 years and is repeated every 5 years or sooner based on the patient's symptoms. (1)(10)(11)A high index of suspicion for Cowden syndrome (CS) is warranted when a pediatric patient presents with autism spectrum disorder and macrocephaly. Primary care physicians encountering children with these clinical manifestations must refer them for genetic evaluation.Pediatric patients presenting with thyroid cancers should undergo evaluation for PTEN pathogenic variants.Twenty-five percent to 80% of individuals with a clinical diagnosis of CS have a PTEN pathogenic variant (11); hence, clinical signs should dictate management.CS is inherited in an autosomal dominant manner; 10% to 50% of patients with CS have an affected parent. (11) Family members at risk should be evaluated for pathogenic variants of the PTEN gene.The most harmful consequence of CS is the development of malignancies in various organs. The International Cowden Consortium has recommended diagnostic evaluation and cancer surveillance in patients with PTEN pathogenic variants. Increased cancer surveillance, which enables early cancer diagnosis in the most treatable stages, forms the primary basis for managing CS.Early detection and screening for malignancies, patient education, genetic counseling, and regular surveillance are the key aspects of the management of CS.