Bannayan-Riley-Ruvalcaba Syndrome

Clinical Features, Genes and Therapeutics

The signs and symptoms of Bannayan-Riley-Ruvalcaba syndrome are present from birth or become apparent in early childhood.

In a series of reports, Riley and Smith (1960) observed the association of macrocephaly, pseudopapilledema, and multiple hemangiomas.

Bannayan (1971) and Zonana et al (1976) described macrocephaly with multiple subcutaneous and visceral lipomas and hemangiomas. Ruvalcaba et al (1980) reported patients with macrocephaly, intestinal polyposis, and pigmented spotting of the penis.

Gorlin et al extended the syndrome to include Hashimoto thyroiditis and suggested a relationship to juvenile polyposis of infancy. At least 45 cases have been described. Cohen proposed the syndrome be named for the first authors of the three original reports.

Gene and Phenotypic Expression

The inheritance pattern Opens in new window of Bannayan-Riley-Ruvalcaba syndrome (BRRS) is autosomal dominant Opens in new window. More males than females have been reported. The syndrome, mapping to 10q23, is due to mutations Opens in new window in a tumor suppressor gene, PTEN, a dual specificity phosphatase.

BRRS is allelic to Cowden syndrome Opens in new window. Phenotypic and molecular overlap have been reported. Germline mutations have been found in almost 60% of cases, none within the PTPase core motif as yet. In fact, there are examples of overlapping phenotypes, and families in which the two phenotypes exist. Translocation causing the syndrome has been noted. The PTEN gene is expressed in the embryo in areas other than those affected by the syndrome.

Clinical Manifestations

Birth weight is usually in excess of 4000 g, with birth length above the 97th centile. Postnatal growth decelerates, older children and adults both being well within the normal range.

Hypotonia, gross motor delay, mild-to-severe mental deficiency, and cognitive speech delay have been reported in approximately 70%. About 25% exhibit seizures. DiLiberti and Budden and Powell et al reported asymmetric motor development. These minor motor asymmetries were transient and improved with age. Deep tendon reflexes are diminished.

1. Craniofacial Features

Head circumference is at least 4.5 SD above the mean in nearly all affected. A few patients have exhibited delayed closure of the anterior fontanel. Ocular hypertelorism has been noted in some instances.

Downslanting palpebral fissures and strabismus or amblyopia are frequently noted. Examination of the eyes under slit lamp has demonstrated prominent Schwalbe lines and clearly visible corneal nerves in approximately 35% of patients. Pseudopapilledema has been found in some cases.

2. Skin Features

Pigmented macules are found on the penile gland and shaft in 25% of affected males. This spotting is often subtle and may be missed if not specifically looked for. The macules may not appear until mid-childhood or later.

Cutaneous angliolipomas with a vascular component that vary in number, size, and location have been observed in over half the patients. About 25% have a small number of café-au-lait spots on the trunk and lower limbs. One patient had acanthosis nigricans-like lesions of the face. Another patient had accessory nipples.

3. Hashimoto Thyroiditis

Gorlin et al expanded the syndrome to include Hashimoto thyroidism, an autoimmune disorder of delayed hypersensitivity and characterized by euthyroid or mildly hypothyroid goiter. It occurs predominantly in middle-age females, although it may be seen in adolescent or preadolescent females.

Goiter or fullness in the throat with mild dysplasia is usually present. Onset is insidious. The gland is 2–5 times normal size, firm to rubbery in consistency, and painless. Asymmetric enlargement is noted in about 35%.

Microscopically there is diffuse involvement of the entire gland marked by a dense infiltration of lymphocytes throughout the parenchyma and in focal collections with true germinal centers. Fibrous connective tissue is not significantly increased.

The acinar lining cells are swollen with granular, eosinophilic (oncocytic) cytoplasm and large hypochromatic nuclei. The acini are small with slitlike lumina containing almost no colloid.

4. Gastrointestinal System

Hamartomatous (juvenile) polyps, usually multiple and limited to the distal ileum and colon, may be associated with intussusception and/or rectal bleeding Opens in new window.

Polyps have been found in 45% of all patients. Polyps other than juvenile type have been found. While some become manifested in childhood, others have not become evident until middle age. Protein-losing enteropathy has been observed.

5. Musculoskeletal System

At least 60% of patients had a myopathic process in the proximal muscles which manifests as delayed motor development. There is exercise intolerance. Muscle biopsy has shown intracellular lipid accumulation, predominantly in enlarged type I muscle fibers.

Type II fibers are smaller than normal and contain less fat. Metacarpophalangeal profile patterns show accelerated growth of the first metacarpal and first and second middle phalanges. Joint hyperextensibility, pectus excavatum, and scoliosis have been reported in about 50%.

6. Neoplams

Mesodermal hamartomous masses are usually discrete lipomas. Capillary or venous malformations (10%) and lymphatic malformations (10%) are seen. In 20% of patients, the vascular malformations are of the combined type. Most of the hamartomas are subcutaneous, but may be intracranial (20%) or osseus (10%).

Some lipomas may be aggressive and can cause serious complications. The puzzling patient of Okumura et al had manifestations of Bannayan-Riley-Ruvalcaba syndrome, Klippel-Trenaunay syndrome, and Proteus syndrome. A Proteus-like syndrome was noted by Zhou et al. Hamartomatous polyposis has already been discussed in the section on the gastrointestinal system.

Malignant tumors have been noted in some patients. One adult male had a thyroid tumor and two other affected males had thyroidectomies at a young age. One affected female has had rapid onset of bilateral invasive breast cancer at age 34 (DiLiberti, personal communication, 1986).

7. Other Abnormalities

Adult males had enlarged testes. A patient seen by one of the reporters (RJG) had a painful testis due to fatty infiltration. They have also noted hemihyperplasia in a few patients.

Differential Diagnosis

An exhaustive discussion of conditions associated with macrocephaly is that of Gorlin et al. The most common cause is autosomal dominant macrocephaly.

Other syndromes are those of Sotos Opens in new window, Weaver Opens in new window, Marshall-Smith Opens in new window, and macrocephaly-cutis marmorata Opens in new window. Lipomas, hemangiomas, and lymphangiomas may also occur in Proteus syndrome.

The combination of macrocephaly, angiomatosis, and limb asymmetry in sporadic cases has been discussed by Stephan et al. Hashimoto thyroiditis has been reported in association with familial adenomatous polyposis and with generalized hypertrophic myopathy and chorioretinal dystrophy.

Familial juvenile polyposis, an autosomal dominant disorder which maps to 18q21.1, placed the affected at increased risk for gastrointestinal adenocarcinoma. Hereditary mixed polyposis maps to 6q. There has been considerable argument whether the gene for some patients with juvenile polyposis is the PTEN gene.

Therapy: Laboratory Aids

Electromyography, muscle biopsy, and mutational analysis should be performed on all infants with macrocephaly, normal CT scans, and hypotonia. Patients with Bannayan-Riley-Ruvalcaba syndrome should be monitored for gastrointestinal polyposis and thyroid neoplasms. Muscle-free carnitine levels have been reduced.