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A rare developmental defect during embryogenesis characterized by hamartomatous intestinal polyposis, lipomas, macrocephaly and genital lentiginosis.
ORPHA:109Classification level: Disorder
The prevalence is unknown, but Bannayan-Riley-Ruvalcaba syndrome (BRRS) is generally considered as a rare disease.
BRRS shares some of the clinical characteristics of Cowden syndrome (CS;) but with differing frequencies. Unlike CS, the classic presentation of BRRS occurs neonatally or shortly thereafter with macrocephaly, Hashimoto struma, lipomatosis, vascular malformations and speckled lentiginosis of the penis or vulva. Developmental delay and gastrointestinal hamartomatous polyposis occur in a subset of BRRS patients. There should be a low threshold to evaluate for autism spectrum disorder in BRRS, especially if a PTEN mutation is found. It is unclear if the case-based signs of myopathic processes in proximal muscles, pectus excavatum, joint hyperextensibility, scoliosis and high birth weight are truly components of BRRS. Although predisposition to cancer was not thought to be a feature of this syndrome, it is now believed that BRRS patients with a germline PTEN mutation share the same risk of cancer development as CS patients.
BRRS is caused (in 60% of cases) by a mutation in the phosphatase and tensin homolog (PTEN) gene (10q23) that encodes PTEN, a dual-specificity phosphatase. When BRRS is accompanied by germline PTEN mutations, it belongs to the PHTS group. Because the non-PTEN CS-related genes (ex. SDHB-D, AKT1, PIK3CA and KLLN) have not been formally studied in BRRS, it is not clear if they are also etiologic for non-PTEN-related BRRS.
There are no specific criteria for diagnosis of BRRS but it is usually determined by the clinical presentation. The pediatric criteria of the PTEN scoring systemcan be used and are heavily based on the presence or absence of macrocephaly and the presence of one of four sub-criteria (autism spectrum disorder, dermatologic features, vascular malformations and/or gastrointestinal polyposis). A germline PTEN mutation confirms that the BRRS patient belongs to the PHTS group.
Differential diagnoses include Lhermitte-Duclos syndrome, juvenile polyposis syndrome, Peutz-Jeghers syndrome (PJS), Birt-Hogg-Dube syndrome, Proteus syndrome, Cowden syndrome, Gorlin syndrome, and neurofibromatosis type 1.
Antenatal diagnosis is possible for at-risk pregnancies if the disease-causing mutation is discovered in an affected family member.
BRRS is inherited autosomal dominantly. Genetic counseling can be offered to patients with germline PTEN mutations and asymptomatic family members should also be tested for the mutation to identify those that need to be monitored before symptom onset.
Management and treatment
Management and treatment are multidisciplinary. Monitoring for symptoms of gastrointestinal hamartomatous polyposis is important as they can be more severe than those seen in CS. Once a germline PTEN mutation is identified, the patient should undergo a screening thyroid ultrasound exam, starting at the age of 7, and a low threshold for evaluation for autism spectrum disorder is strongly recommended. In patients over the age of 18, a yearly skin check is recommended. A colonoscopy and biennial renal imaging should begin between the ages of 35-40, unless symptomatic. Women should perform monthly breast self-examinations and yearly breast screenings as well as transvaginal ultrasounds (postmenopausal) or endometrial biopsies beginning at the age of 35. It is also important to pay attention to neurological and vascular malformations as well as GI symptoms.
The prognosis is unknown and is dependent on initial presentation and likely genotype.