Rapamycin Treatment for a Child With Germline PTEN Mutation
Background: A 9-month-old boy with Proteus syndrome and a de novo germline mutation in the tumor suppressor PTEN was referred to a specialist centre for management. Over the first years of life, the patient developed life-threatening respiratory dysfunction and malnutrition because of progressive growth of hamartomas affecting the chest, mediastinum, abdomen and pelvis.
Investigations: Physical examination, CT scans of the mediastinum, pelvis and abdomen, measurement of serum insulin-like growth factor binding protein-2, and investigation of the effect of the PTEN mutation on phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling in an in vitro cell model.
Diagnosis: PTEN hamartoma tumor syndrome, specifically Proteus syndrome.
Management: Oral rapamycin.

A 9-month-old boy with Proteus syndrome was referred to a specialist center for the management of life-threatening complications of multiple hamartomas. At birth, the patient had an extensive epidermal nevus and over the first year of life he developed widespread subcutaneous and deep lipomata, multiple extensive epidermal nevi, generalized reduced subcutaneous fat, multiple gastrointestinal polyps, hypertrophy of the right leg and buttock, and scattered cutaneous capillary vascular malformations. His mother had been diagnosed with multiple fundic glandular polyps in the stomach and two small, hyperplastic distal rectal polyps at 33 years of age. CT scans of the patient at the age of 10 months demonstrated lobulated soft-tissue masses in the anterior mediastinum and the right side of the pelvis, multiple enlarged mesenteric lymph nodes and a widespread increase in fatty tissue in the axillae, chest, mediastinum, anterior abdominal wall, intraperitoneal and retroperitoneal spaces, pelvis and buttocks. A CT-guided biopsy of the anterior mediastinum 2 weeks later, demonstrated non-encapsulated mature fat tissue, hemangioma, and fibrous tissue. The patient's condition was compromised by progressive enlargement of lipomata, iron-deficiency anemia, hypoproteinemia and respiratory dysfunction. His clinical phenotype was consistent with a diagnosis of Proteus syndrome. Additionally, he showed poor linear growth-indicating an impaired response to growth hormone-repeatedly elevated concentrations of serum growth hormone (14-51 mU/l; normal range, <10 mU/l), undetectable serum insulin-like growth factor-1, and low concentrations of insulin-like growth factor binding protein (IGFBP)-3 (0.2-0.8 mg/l; normal range, 1.1-3.5 mg/l).

The patient was diagnosed with Proteus syndrome at the age of 16 months. Germline mutations in the tumor suppressor PTEN have been reported in patients with Proteus syndrome. The germline PTEN mutation c.507delC was identified in this patient, confirming the diagnosis of PTEN hamartoma tumor syndrome. This PTEN mutation was not identified in constitutive DNA from either parent. Loss of functional PTEN is known to provide a cellular survival advantage through the phosphatidylinositol 3-kinase (PI3-K)/mammalian target of rapamycin (mTOR) signaling pathway. Rapamycin, also known as sirolimus, opposes the survival advantage that results from activation of PI3-K/mTOR signaling and antagonizes mTOR signaling to downstream targets such as 4E-binding protein 1 and the ribosomal protein S6 kinase. At the age of 2 years and 2 months the patient received oral rapamycin at a dose of 0.1 mg/kg per day, divided into two doses. Serum rapamycin levels were maintained between 5-10 ng/ml. The off-label use of rapamycin was approved by the South Eastern Sydney Area Health Service ethics committee and institutional review board. The dose was chosen on the basis of the in vitro concentration of rapamycin required to inhibit cellular proliferation and to achieve a serum concentration known to be effective for immunosuppression in the management of solid organ transplantation.

Immediately before rapamycin treatment, the patient was tachypneic at rest and was fed by nasogastric tube. He was unable to sit, roll over or bear weight on his legs, and was receiving regular analgesics for recurrent abdominal pain. He had significant respiratory, gastrointestinal, and locomotor dysfunction due to large mediastinal, mesenteric and subcutaneous hamartomas. Rapamycin was well tolerated and caused no side-effects. Within 2 months of commencing treatment there was an increase in the patient's serum albumin levels-from 19 g/l to 35 g/l (normal range 35-45 g/l)-and within 4 months he had been taken off analgesics and nasogastric feeding. The patient started a normal diet, and from the age of 5 years and 6 months began walking independently. Comparisons of CT scans performed at the beginning of rapamycin treatment (Figure 1A, 1B, 1C) and 14 months later, revealed a marked reduction in soft-tissue masses in the anterior mediastinum (Figure 1D) and the right side of the pelvis (Figure 1E), as well as a reduction in the size of the mesenteric lymph nodes (Figure 1F). After 17 months of rapamycin therapy, treatment with this drug was ceased to determine whether the antitumor effects were reversible. Within 12 weeks of cessation, rapamycin was reinstated owing to increasing respiratory difficulty, hypoalbuminemia, reduced oral intake, and an increase in the size of soft-tissue masses and mesenteric lymphadenopathy (Figure 1G, 1H, 1I). There was little change in the size or appearance of the external subcutaneous lipomata during treatment. The regional absence of subcutaneous fat affecting his arms was unchanged and there was no increase in the measured skinfold thickness. Biochemical evidence showed that resistance to growth hormone was not affected by rapamycin. The patient continues to do well, without clinical evidence of respiratory or nutritional compromise. The treatment with rapamycin is ongoing and there are currently no plans to cease treatment. The patient is reviewed regularly by his primary and subspecialty pediatricians.


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Response to rapamycin therapy in anterior mediastinal and pelvic masses and mesenteric adenopathy. (A-C) CT scans of the mediastinum, pelvis and abdomen at the commencement of rapamycin treatment. (D-F) CT scans of the mediastinum, pelvis and abdomen after 14 months of treatment. (G-I) CT scans of the mediastinum, pelvis and abdomen after a 3-month cessation of rapamycin therapy. Regression of anterior mediastinal and pelvic masses and mesenteric adenopathy during rapamycin therapy and regrowth following a 3-month cessation of treatment are indicated by arrows.

(A-C) CT scans of the mediastinum, pelvis and abdomen at the commencement of rapamycin treatment. (D-F) CT scans of the mediastinum, pelvis and abdomen after 14 months of treatment. (G-I) CT scans of the mediastinum, pelvis and abdomen after a 3-month cessation of rapamycin therapy. Regression of anterior mediastinal and pelvic masses and mesenteric adenopathy during rapamycin therapy and regrowth following a 3-month cessation of treatment are indicated by arrows.