The phosphatase and tensin homolog (PTEN) gene is one of the tumor suppressor genes (1) located in chromosome 10q23.31, encoding 403 amino acids of 47166 Da protein. Loss of heterozygosity and deletion of this gene was first reported in glioblastomas, and later in several malignant tumors (2). PTEN germline mutations cause a wide variety of phenotypic diseases, such as macrocephaly/autism syndrome (OMIM #605309) usually noticed in infants and PTEN hamartoma tumor syndrome (PHTS, OMIM #601728). PHTS includes Cowden syndrome (CS, OMIM#158350) and Bannayan-Riley-Ruvalcaba syndrome (BRRS, OMIM#153480) (3).

Macrocephaly/autism syndrome is an autosomal dominant disorder characterized by increased head circumference, abnormal facial features, and delayed psychomotor development resulting in autistic behavior or mental retardation (4). Varga et al (5) reported that PTEN mutations were detected in 5 of 60 (8.3%) patients with autism spectrum disorder (ASD) and 6 of 49 (12.2%) patients with developmental delay and macrocephaly without ASD.

CS is a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium in young adults and adults. Arteriovenous malformation, multiple lipomas, and other soft-tissue tumors are also reported (3,6). Affected individuals usually develop macrocephaly, trichilemmomas, and papillomatous papules by late 20s. On the other hand, BRRS is a congenital disorder characterized by macrocephaly, intestinal hamartomatous polyposis, lipomas, and pigmented macules of the glans penis (3). For PHTS patients, 2019.2 NCCN guideline (7) recommends that tumor follow-up involves annual physical examination and thyroid ultrasound, with colonoscopy every 5 years beginning at age 35 or earlier based on family colon cancer history and kidney ultrasound every 1-2 years starting at age 40.

We found a de novo PTEN germline mutation in a male infant with macrocephaly and lipomas by using NGS analysis. A rapidly growing lipoma was resected and examined for PTEN by immunostaining, since there have been few reports on PTEN inactivation, two hits or one hit, in tumors in PHTS patients.

We found a PTEN mutation by NGS analysis in a male infant with macrocephaly. Brain MRI examination showed simple macrocephaly consistent with PTEN macrocephaly/autism syndrome reported by Vanderver et al (14) and Bhargava et al (15).

Table I shows 30 patients of <3 years of age with macrocephaly or autism spectrum in whom PTEN mutations were detected (4,11,14-20). Clinical manifestations of these patients are presented in Table II. All cases showed developmental delay with 8 cases diagnosed as autism spectrum and 10 hypotonia. Ten of 30 cases showed frontal bossing with 8 exhibiting café-au-lait spots and skin features, and 5 diagnosed with tumors and hamartomas, such as gastrointestinal polyps and cutaneous lipomas. Our case, an only in infant patient with macrocephaly/autism syndrome reported, suggests that the PTEN mutation detected is responsible for the syndrome.

All the 30 patients with macrocephaly in Table I showed no apparent genotype-phenotype correlation nor malignant tumors that are frequently observed in patients with CS. The risk of developing malignant tumors in later years is not clear, without follow-up data.

Tan et al (21) reported lifetime cancer risks of individuals with PTEN germline mutation listing a variety of cancers (breast, thyroid, endometrial, colorectal, renal cell, and melanoma) found in a cohort of 368 children and adults aged 0.4-83 years (median age; 39 years). The earliest age of cancer onset reported was 3 years for melanoma. In this paper, no follow-up analysis from childhood to adulthood was reported. Consequently, it is not clear as to how many infant macrocephaly cases with PTEN mutation developed to CS in adulthood. Smpokou et al (22) reported that, in the case of a 7-year-old patient with a thyroid cancer, clinical description would allow better formulation of clinical guidelines in children with PHTS. For infant patients with PTEN mutation, pediatricians have tendency to focus attention on macrocephaly, developmental delay or autism. It is therefore important to conduct follow-up assessment for both developmental problem and cancer incidence, and carry out lifelong and total medical management.

On this basis, we conducted thyroid ultrasonography of our patient at the age of 2 years and 10 months, 4 years and 5 years of age and found no abnormality. Regarding gastrointestinal tract hamartomas, we did not perform endoscopic examination, since there have been no reports on the onset in childhood. We examined breasts only by inspection and palpation since the possibility of breast cancer was considered to be lower for male infant patients than female (23).

Lipomas and a café-au-lait spot on the skin were also found in our case. Our immunohistochemical examination revealed that lipoma tissue and the skin tissue obtained from a control subject showed very similar PTEN expression. No obvious differences in PTEN expression were detected among them, suggesting that two-hit in the PTEN gene by loss of heterozygosity was unlikely even in the rapidly growing lipoma. A previous report shows that loss of heterozygosity of markers in endometrial cancer, glioblastoma, and breast cancer (13). In our lipoma case, we are unable to do the immunohistochemical evaluation clearly.

To relieve psychosocial anxiety for PHTS patients and their parents with respect to cancer predisposition and developmental problems, genetic counseling is of need. Genetic counseling is also of use for family members who may feel at risk. Taken together, long-term follow-up plans for soft-tissue tumors, thyroid cancer, breast cancer and GI-hamartomas, as well as psychosocial problems are indispensable.