Abstracts

INTRODUCTION

Bannayan-Riley-Ruvalcaba Syndrome is a rare condition manifested with multiple lipomas, macrocephaly, hemangiomas, hamartomatous intestinal polyposis, developmental delay and speckled pigmented maculae on the male genitalia.¹1. Lynch NE, Lynch SA, McMenamin J, Webb D. Bannayan-Riley-Ruvalcaba syndrome: a cause of extreme macrocephaly and neurodevelopmental delay. Arch Dis Child. 2009;94:553-4.^,22. Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Hum Genet. 2008;16:1289-300.

CASE REPORT

We describe the case of a nine-month-old male child, who had fast growing and progressive lesions on the trunk and abdomen since the age of 6 months. A previous evaluation by a pediatrician diagnosed first degree malnutrition and absence of psychomotor development deficit. At the examination, the child was thinner, presented macrocephaly, voluminous abdomen with multiple masses of soft consistency, affecting also the back and thorax, the larger of the lesions being located on his right flank (Figure 1). He also presented brownish, round macules on the penis, measuring around three millimeters in diameter (Figure 2).

General physical examinations included lipid profile, without any alterations. Computerized tomography of the abdomen and pelvis revealed extensive lipomatosis in the right postero-lateral thorax-abdomen region at the T8 level, extending downward until the perineal region with signs of controlateral paraspinal muscle invasion starting at T12. Lesional infiltration of vertebral, retrodural and psoas muscle epidural regions of the spinal canal could also be bilaterally observed (Figure 3). Magnetic resonance of the thoracic column revealed lipomatous dorsal lesion associated with enlargement of the spinal canal and spinal cord compression in the low thoracic column, as well as nonenhanced lumbosacral medullary compression after contrast.

The child underwent surgery for partial removal of the larger lesion, thus avoiding progression of medullary compression and functional deficit; examination of the sample confirmed the lipoma diagnosis (Figure 4). After the surgery, growth of the other lesions was observed, although without functional deficit (Figure 5). In order to detect chromosomal alterations in the adipocytic lesion, DNA was extracted, followed by CGH array. Loss of approximately 1MB of the long arm of chromosome 10, the region where the PTEN gene is located, was revealed. The same alteration was confirmed in the peripheral blood of the patient.

The authors present this case because of its exuberance and rarity. The child should be followed for early detection of intestinal polyps and possible neoplasms.

DISCUSSION

Bannayan-Riley-Ruvalcaba Syndrome (BRRS) is a rare disorder, caused by mutations in the PTEN gene. It occurs both in an autosomal dominant and in a sporadic manner.¹1. Lynch NE, Lynch SA, McMenamin J, Webb D. Bannayan-Riley-Ruvalcaba syndrome: a cause of extreme macrocephaly and neurodevelopmental delay. Arch Dis Child. 2009;94:553-4.^,22. Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Hum Genet. 2008;16:1289-300. PTEN gene mutations are detected in 60% of the patients with SBRR.³3. Marsh DJ, Kum JB, Lunetta KL, Bennett MJ, Gorlin RJ, Ahmed SF, et al. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet. 1999;8:1461-72. It is manifested by the presence of multiple lipomas, hemangiomas, intestinal hamartomatous polyposis, arteriovenous malformations, developmental delay, macrocephaly and speckled pigmented maculae on the male genitalia.²2. Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Hum Genet. 2008;16:1289-300.^,44. Parisi MA, Dinulos MB, Leppig KA, Sybert VP, Eng C, Hudgins L. The spectrum and evolution of phenotypic findings in PTEN mutation positive cases of BannayanRiley-Ruvalcaba syndrome. J Med Genet. 2001;38:52-8.^,55. Eng C. PTEN Hamartoma Tumor Syndrome (PHTS). In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. Gene Reviews. Seattle (WA): University of Washington; 1993-2001.^,66. Perriard J, Saurat JH, Harms M. An overlap of Cowden's disease and Bannayan-Riley-Ruvalcaba syndrome in the same family. J Am Acad Dermatol. 2000;42:348-50. Penile maculae are possibly the most marked and valuable characteristic for diagnosis of the syndrome; they may be present at birth or appear during infancy or puberty and persist in adulthood.⁴4. Parisi MA, Dinulos MB, Leppig KA, Sybert VP, Eng C, Hudgins L. The spectrum and evolution of phenotypic findings in PTEN mutation positive cases of BannayanRiley-Ruvalcaba syndrome. J Med Genet. 2001;38:52-8. Some authors recommend investigation of PTEN mutations in children who present extreme macrocephaly with normal neurological images, specially when one of the parents has macrocephaly and also when older children present extreme macrocephaly and motor development delay or learning difficulties.¹1. Lynch NE, Lynch SA, McMenamin J, Webb D. Bannayan-Riley-Ruvalcaba syndrome: a cause of extreme macrocephaly and neurodevelopmental delay. Arch Dis Child. 2009;94:553-4.

Other characteristics of BRRS include thyroid abnormalities, high-arched palate, frontal bone protuberance, hypertelorism, strabismus, macrosomia, hypotonia, joint hyperextensibility, hypoglycemia, convulsions, café-au-lait spots, wide mouth and relative micrognathia.²2. Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Hum Genet. 2008;16:1289-300.^,77. Latiff ZA, Atmawidjaja RW, RajaLope RJ, Syed Omar SA, Syed Zakaria SZ, Jamal RA. Bannayan Riley Ruvalcaba syndrome. Ann Acad Med Singapore. 2010;39:578-2.

Marsh et al defined the clinical diagnosis of BRRS as the presence of three of four characteristics: macrocephaly, lipomatosis, hemangiomas and speckled pigmented maculae on the penis.⁸8. Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia PL, Zheng Z, et al. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet. 1998;7:507-15. Parisi et al used less rigorous criteria, defining the syndrome as the presence of two of the three characteristics: macrocephaly, hamartomas (including at least one lipoma, hemangioma or intestinal polyp) and maculae on the penis.⁴4. Parisi MA, Dinulos MB, Leppig KA, Sybert VP, Eng C, Hudgins L. The spectrum and evolution of phenotypic findings in PTEN mutation positive cases of BannayanRiley-Ruvalcaba syndrome. J Med Genet. 2001;38:52-8.

Lipomas and vascular malformations are manifested as soft lesions on the trunk and extremities; they may grow fast and become painful, with aggressive local behavior, without tendency for spontaneous resolution.⁷7. Latiff ZA, Atmawidjaja RW, RajaLope RJ, Syed Omar SA, Syed Zakaria SZ, Jamal RA. Bannayan Riley Ruvalcaba syndrome. Ann Acad Med Singapore. 2010;39:578-2.^,99. Erkek E, Hizel S, Sanlý C, Erkek AB, Tombakoglu M, Bozdogan O, et al. Clinical and histopathological findings in Bannayan-Riley-Ruvalcaba syndrome. J Am Acad Dermatol. 2005;53:639-43. Intestinal hamartomatous polyposis occurs in 35-45% of BRRS cases, but without association with a greater risk for malignancy.⁹9. Erkek E, Hizel S, Sanlý C, Erkek AB, Tombakoglu M, Bozdogan O, et al. Clinical and histopathological findings in Bannayan-Riley-Ruvalcaba syndrome. J Am Acad Dermatol. 2005;53:639-43. The polyps may be located along the entire gastrointestinal tract, more frequently in the colon and rectum. During infancy, they may present with diarrhea, abdominal pain, painless rectal bleeding, anemia, intussusception and intestinal obstruction. Considering the fact that hamartomatous polyposis may not manifest before middle age, routine yearly hemoglobin and fecal occult blood test may be useful for early diagnosis.⁷7. Latiff ZA, Atmawidjaja RW, RajaLope RJ, Syed Omar SA, Syed Zakaria SZ, Jamal RA. Bannayan Riley Ruvalcaba syndrome. Ann Acad Med Singapore. 2010;39:578-2.^,99. Erkek E, Hizel S, Sanlý C, Erkek AB, Tombakoglu M, Bozdogan O, et al. Clinical and histopathological findings in Bannayan-Riley-Ruvalcaba syndrome. J Am Acad Dermatol. 2005;53:639-43.

The PTEN (phosphatase and tensin homologue) is a tumor suppressor gene that has a significant role in the molecular pathway of cellular proliferation, migration and apoptosis. Mutations result in uncontrolled cellular proliferation and failure in programmed cellular death.⁹9. Erkek E, Hizel S, Sanlý C, Erkek AB, Tombakoglu M, Bozdogan O, et al. Clinical and histopathological findings in Bannayan-Riley-Ruvalcaba syndrome. J Am Acad Dermatol. 2005;53:639-43. The main clinical consequence is the onset of hamartomas derived from all three germinative layers,⁹9. Erkek E, Hizel S, Sanlý C, Erkek AB, Tombakoglu M, Bozdogan O, et al. Clinical and histopathological findings in Bannayan-Riley-Ruvalcaba syndrome. J Am Acad Dermatol. 2005;53:639-43. as well as increase in risk for certain types of tumors in adulthood.

Mutations of this gene cause Cowden Syndrome (CS), characterized by facial trichilemmomas, acral keratosis, papillomatous papules, benign hamartomas, macrocephalia and increased risk for breast, thyroid and endometrium cancer, colorectal adenocarcinoma, non-Hodgkin lymphoma and melanoma, among others.²2. Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Hum Genet. 2008;16:1289-300.^,99. Erkek E, Hizel S, Sanlý C, Erkek AB, Tombakoglu M, Bozdogan O, et al. Clinical and histopathological findings in Bannayan-Riley-Ruvalcaba syndrome. J Am Acad Dermatol. 2005;53:639-43.^,1010. Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012;18:400-7. These may occur also in a variant, Lhermitte-Duclos disease, characterized by dysplastic cerebellar gangliocytomas, which may evolve with hydrocephaly, ataxia and convulsions.²2. Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Hum Genet. 2008;16:1289-300.

Identical mutations were demonstrated in patients with BRRS.²2. Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Hum Genet. 2008;16:1289-300. There are common characteristics also in CS and BRRS, like hamartomas, macrocephaly and thyroid abnormalities²2. Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Hum Genet. 2008;16:1289-300.^,88. Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia PL, Zheng Z, et al. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet. 1998;7:507-15. Families have reported that the same mutation is found in different individuals with phenotypes more consistent with CS or BRRS.²2. Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Hum Genet. 2008;16:1289-300.

Due to these clinically and genetically overlapping disorders, BRRS and CS are considered different phenotypical expressions of the same allelic syndrome, collectively named PTEN Hamartoma Tumor Syndrome (PHTS).²2. Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Hum Genet. 2008;16:1289-300.^,55. Eng C. PTEN Hamartoma Tumor Syndrome (PHTS). In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. Gene Reviews. Seattle (WA): University of Washington; 1993-2001.^,88. Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia PL, Zheng Z, et al. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet. 1998;7:507-15.^,99. Erkek E, Hizel S, Sanlý C, Erkek AB, Tombakoglu M, Bozdogan O, et al. Clinical and histopathological findings in Bannayan-Riley-Ruvalcaba syndrome. J Am Acad Dermatol. 2005;53:639-43. Screening, vigilance and prevention of possible malignancies are the base of treatment of patients with PHTS, particularly those with CS.⁵5. Eng C. PTEN Hamartoma Tumor Syndrome (PHTS). In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. Gene Reviews. Seattle (WA): University of Washington; 1993-2001. Such screening should be done in the following manner:⁹9. Erkek E, Hizel S, Sanlý C, Erkek AB, Tombakoglu M, Bozdogan O, et al. Clinical and histopathological findings in Bannayan-Riley-Ruvalcaba syndrome. J Am Acad Dermatol. 2005;53:639-43.

Patients younger than 18 years of age: Annual thyroid ultrasound, dermatological, neurological and psychological examination

Patients older than 18 years of age: Annual thyroid ultrasound, annual mammography, biopsy of the endometrium or annual transvaginal ultrasound starting at 40 years of age, biannual colonoscopy, biannual renal ultrasound or MRI

Although an increased risk of malignancies in BRRS has not been documented, due to the clinical and genetic similarities between Cowden and BannayanRiley-Ruvalcaba Syndromes and because patients with PTEN mutations have increased risk for cancer, some authors recommend that BRRS patients be advised to comply with the same malignancy screening recommendations for patients with CS.²2. Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Hum Genet. 2008;16:1289-300.^,55. Eng C. PTEN Hamartoma Tumor Syndrome (PHTS). In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. Gene Reviews. Seattle (WA): University of Washington; 1993-2001.^,88. Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia PL, Zheng Z, et al. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet. 1998;7:507-15.^,99. Erkek E, Hizel S, Sanlý C, Erkek AB, Tombakoglu M, Bozdogan O, et al. Clinical and histopathological findings in Bannayan-Riley-Ruvalcaba syndrome. J Am Acad Dermatol. 2005;53:639-43.

REFERENCES

Publication Dates

History