#153480
ICD+
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| BANNAYAN-RILEY-RUVALCABA SYNDROME; BRRS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BANNAYAN-ZONANA SYNDROME; BZS RILEY-SMITH SYNDROME RUVALCABA-MYHRE-SMITH SYNDROME; RMSS MACROCEPHALY, PSEUDOPAPILLEDEMA, AND MULTIPLE HEMANGIOMATA MACROCEPHALY, MULTIPLE LIPOMAS, AND HEMANGIOMATA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because of evidence that this disorder results from mutations in the PTEN gene (601728). Cowden disease (CD; 158350) and macrocephaly/autism syndrome (605309) are allelic disorders with overlapping clinical features. Approximately 60% of BRRS patients have PTEN mutations (Blumenthal and Dennis, 2008). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Blumenthal and Dennis (2008) provided a detailed review of PTEN-related tumor syndromes. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Riley and Smith (1960) described a mother and 2 of 7 children with macrocephaly, pseudopapilledema, and multiple hemangiomata. Two other sibs had macrocephaly and pseudopapilledema. Intellect and vision were unimpaired. Bannayan (1971) first described the triad of macrocephaly, lipomatosis, and angiomatosis in a single child observed at autopsy at the Johns Hopkins Hospital. Zonana et al. (1975, 1976) described the triad in a father and 2 sons, suggesting autosomal dominant inheritance. One son had overgrowth of the right index finger and involvement of the small bowel mesentery by hamartoma with angiomatous, lipomatous, and lymphangiomatous components. Miles et al. (1981) documented the syndrome in 11 persons in 4 additional families. Clinical features included high palate, scaphocephaly, lipomas of the anterior abdominal wall, thigh, perineum, scapula area, etc., hemangiomas of the anterior abdominal wall, wrist, knee, and foot, bleeding from intracranial hemangioma, and arteriovenous malformation leading to leg amputation. Some children had pectus excavatum. Most of the lipomas spontaneously regressed with age. In some patients, seizures resulted from intracranial hemorrhage. Despite macrocephaly, computerized axial tomography showed no enlargement of the cerebral ventricles, and there was no pseudopapilledema. Affected persons had increased birth weight and length, but growth leveled off at age 6 or 7 years. There was delayed motor development with incoordination, delayed speech development, and mild mental retardation. Drooling was a problem in children. The disorder appeared to be autosomal dominant, but the authors noted that about 80% of affected persons have been male. In 1 instance, the disorder was transmitted by a man with a head of normal size. Miles et al. (1984) used the moniker 'Bannayan-Zonana syndrome.' Ruvalcaba et al. (1980) described 2 unrelated patients with macrocephaly, intestinal polyposis, and pigmented macules of the penis, and suggested that they had Sotos syndrome (117550). However, Smith (1982) subsequently suggested that these patients had a disorder different from Sotos syndrome. Higginbottom and Schultz (1982) described the syndrome in 3 generations of an American black kindred. They concluded that affected persons may have an increased risk of intracranial tumors: a woman in their family had meningothelial meningioma removed at age 28. DiLiberti et al. (1983) described a 7.5-year-old boy with macrocephaly, hamartomatous intestinal polyps, and cafe-au-lait spots on the penis, and referred to the disorder as 'Ruvalcaba-Myhre-Smith syndrome.' The patient's mother had macrocephaly, a facial appearance similar to the son's, and a hamartomatous intestinal polyp. DiLiberti et al. (1983) also identified prominent Schwalbe lines, which are a frequent normal finding but a consistent feature of 'anterior chamber cleavage syndromes,' prominent corneal nerves, and lipid storage myopathy as features of the disorder. DiLiberti et al. (1984) reported an association of a lipid storage myopathy with Ruvalcaba-Myhre-Smith syndrome, based on 4 patients with the disorder. The patients had delayed psychomotor development and/or hypotonia in childhood. Electromyography in 3 patients showed evidence of a myopathic process. Muscle biopsy in all 4 showed a lipid storage myopathy with increased numbers of neutral lipid droplets, predominantly in type 1 fibers. Type 2 fibers were consistently smaller than expected. In the sporadic cases of Bannayan (1971) and of Okumura et al. (1986), death occurred as a result of severe visceral lipomatosis at ages 3.5 years and 5.75 years, respectively. Dvir et al. (1988) reported a 4.5-year-old boy with macrocephaly, pseudopapilledema, enlarged penis, lipoangiomatosis, and spotted pigmentation of the glans penis. The patient's father and a brother had macrocephaly; the father had enlarged penis. Dvir et al. (1988) noted that the findings were consistent with features reported by Riley and Smith (1960), Bannayan (1971), and Ruvalcaba et al. (1980), and concluded that they all referred to the same syndrome. Dvir et al. (1988) proposed to unify the main features into 1 hereditary syndrome and name it 'macrocephaly-hamartomas-papilledema.' Gorlin (1988) also suggested that Ruvalcaba-Myhre-Smith syndrome was the same as the Bannayan-Zonana syndrome. He referred to the case of an 8-year-old male who had 50 or more hamartomas of the bowel through which he lost serum protein. The diagnosis of BZS had been made, but Gorlin found that the patient also had speckled penis, consistent with RMSS. In a 38-year-old man with macrocephaly, multiple lipomas, and vascular anomalies, Pyeritz (1988) observed 'unstable angina,' dilated aortic root, and ascending aorta. Halal and Silver (1989) described an 8.5-year-old boy with slowly progressive macrocephaly, psychomotor retardation, multiple subcutaneous angiolipomas, hypertelorism, exotropia, prolonged drooling to age 5 years, cutis marmorata, telangiectases over the shoulders, atrial septal defect repaired at age 4 years, broad thumbs and great toes, and muscle wasting. The angiolipomas were bluish subcutaneous nodules scattered all over his body. The parents were second cousins. The father was thought to have minor manifestations of the disorder, i.e., mild hypertelorism and broad thumbs and great toes, as well as mild cutis marmorata over the inner aspect of the forearms and a cluster of telangiectases and dilated vessels on the anterior aspect of both legs. Halal and Silver (1989) concluded that the proband and his father may have had the BZ syndrome, with previously undescribed additional anomalies, overlapping with the syndrome of cutis marmorata telangiectatica congenita (CMTC; 219250). Alternatively, the disorder in the father and son may have represented a new syndrome of macrocephaly and hamartomas with overlapping manifestations with the BZ and CMTC syndromes. Moretti-Ferreira et al. (1989) commented on the variability of severity in Bannayan-Zonana syndrome, which may represent different allelic mutations or genetic heterogeneity. DiLiberti (1992) extended the boundaries of this entry further to include benign familial macrocephaly (153470, 248000). He examined the muscle biopsy results from 14 children with macrocephaly and hypotonia/weakness and correlated them with clinical findings. Of the 14, 13 had evidence of lipid storage myopathy, either generalized or focal. All 13 had examinations consistent with benign familial macrocephaly, Ruvalcaba-Myhre-Smith syndrome, or Bannayan-Zonana syndrome. Gorlin et al. (1992) reported a kindred with 12 members affected with Bannayan-Riley-Ruvalcaba syndrome. The clinical features showed overlap between Bannayan-Zonana syndrome, Riley-Smith syndrome, and Ruvalcaba-Myhre syndrome. Gorlin et al. (1992) expanded the phenotypic spectrum to include Hashimoto thyroiditis, which occurred in 7 of the patients. Powell et al. (1993) reported 27 children, aged 14 months to 9 years, who had megalencephaly, hypotonia, proximal muscle weakness, speech and motor delay, and increased intracellular lipid (myoliposis) in needle muscle biopsy specimens. The patients had many features of the Ruvalcaba-Myhre-Smith syndrome, and in 17 families the authors confirmed the autosomal dominant inheritance pattern previously suggested. Muscle carnitine content was low in all 11 patients and all 4 affected relatives tested. All 27 probands were treated with oral L-carnitine; a clinical response was noted in 17. Powell et al. (1993) speculated that myoliposis may be found in other disorders with megalencephaly and muscle symptoms. Fryburg et al. (1994) suggested that a defect in long-chain fatty acid oxidation resulting from deficiency of long-chain-L-3-hydroxyacyl-CoA dehydrogenase (LCHAD; 143450) may be responsible for the lipid myopathy in the Bannayan-Riley-Ruvalcaba syndrome. Their patient had macrocephaly with prominent frontal bossing and low-set ears, hypertelorism, and hemangiomas. Boccone et al. (2006) reported a Sardinian boy with BRRS confirmed by genetic analysis. In addition to the classic features of macrocephaly, downslanting palpebral fissures, joint hypermobility, and pigmented macules on the penis, the boy also had autism and reactive nodular lymphoid hyperplasia of the small and large intestinal mucosa. Boccone et al. (2006) recommended screening for lymphomas as well as other malignancies in patients with BRRS. By a review of available imaging studies, Tan et al. (2007) identified vascular anomalies in 14 (54%) of 26 patients with BRRS or Cowden syndrome. The anomalies presented clinically as cutaneous discoloration, swelling, or pain. Eight (57%) of 14 patients had multiple lesions, and 11 (85%) of 13 with cross-sectional imaging had intramuscular vascular lesions. Radiographic studies showed that 12 (86%) of 14 were fast-flow vascular anomalies with focal segmental dilatation of draining veins. Excessive ectopic fat was present in 11 (92%) of 12 patients examined by MRI. Intracranial developmental venous anomalies were found in 8 (89%) of 9 patients who had brain MRI with contrast. Histology of some cases showed disordered growth of blood vessels, adipose, and fibrous tissue, with a low level of proliferation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Zigman et al. (1997) localized the gene for the Bannayan-Riley-Ruvalcaba syndrome to chromosome 10q23 by study of 2 patients with intestinal juvenile polyposis and karyotypic abnormalities involving 10q. Patient 1 was a boy who displayed cognitive and developmental delay, macrocephaly, subcutaneous hamartoma, and hypotonia, in addition to multiple intestinal juvenile polyps. He ultimately underwent a total abdominal colectomy for refractory anemia and failure to thrive. Patient 2 was a girl who had features consistent with Bannayan-Riley-Ruvalcaba syndrome, including hypotonia, cognitive and developmental delay, and multiple intestinal juvenile polyps. This patient also had additional features not typical of BRRS, including atrial and ventricular septal defects, dysplastic pulmonic valve, left superior vena cava draining into a dilated coronary sinus, and bilateral clubfoot. Patient 1 had an unbalanced translocation between chromosomes 10 and 9; patient 2 has an interstitial deletion of 10q23.1-q24.2. In each case, DNA markers allowed localization of the defect to 10q23. Three other unrelated patients with the diagnosis of BRRS but without karyotypic abnormalities were also studied; 2 of the 3 patients had pigmentary changes of the penis. Arch et al. (1997) described an 18-month-old patient originally thought to have the BRR syndrome. She had an interstitial deletion of chromosome 10q23.2-q24.1, the region to which Cowden disease and the PTEN gene had been mapped. Because of the considerable phenotypic overlap between the BRR syndrome and Cowden disease and because of a demonstration in their patient that the PTEN gene was deleted on chromosome 10, Arch et al. (1997) suggested that these are allelic disorders. The 18-month-old patient had macrocephaly, facial dysmorphism with prominent forehead and hypertelorism, a lipoma on the right abdomen and on the right thumb, 2 small hemangiomas on the back and shoulder, and 2 skin tags at the base of the spine and in the groin area. Psychomotor development was delayed. Ophthalmologic examination showed pseudopapilledema bilaterally. Neither parent had any features of either Cowden disease or BRR syndrome. Hematochezia prompted upper and lower gastrointestinal endoscopy, which showed multiple sessile polyps throughout the duodenum and large intestine. Histology showed that these were hamartomatous. Tsuchiya et al. (1998) described a 6-year-old African American boy with mental retardation, dysmorphic features, and juvenile polyposis coli. A cytogenetically visible interstitial deletion of 10q23 was identified and characterized by fluorescence in situ hybridization. Five YACs that span an 11- to 15-cM region within the deletion were identified. The patient's deletion contained the putative locus for Cowden syndrome and the PTEN gene. The patient first had rectal bleeding at 2 years of age. Polyps were identified extending from the duodenum to the rectum. Dysmorphic features included macrocephaly with a head circumference of 53.6 cm, frontal bossing, hypertelorism, flat nasal bridge, hyperpigmentation at the corners of the mouth, thickened gingiva, bilateral preauricular pits, and a flat midface. He had a large penis with a hyperpigmented macule on the dorsal shaft. Multiple other hyperpigmented macules as well as a large area of hypopigmentation were identified. The distal phalanges of all fingers and toes were strikingly bulbous and nail clubbing was noted. This was clearly a case of the Bannayan-Riley-Ruvalcaba syndrome. Ahmed et al. (1999) reported a boy with features consistent with BRR who had a novel de novo balanced translocation, 46,XY, t(10;13)(q23.2;q33), and a malignant intracranial hCG-secreting tumor, resulting in precocious puberty. The pathology of such tumors can vary, but none had yet been associated with the Cowden disease or BRRS phenotype or with PTEN mutations. Although previous reports provided evidence that germline intragenic mutations and gross deletion of PTEN can lead to BRRS, the authors postulated that a germline balanced translocation incorporating PTEN could also lead to the BRRS phenotype. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Marsh et al. (1997) identified germline mutations in the PTEN gene in patients with Bannayan-Zonana syndrome, demonstrating that Cowden disease and BZS are allelic disorders. One of the mutations that Marsh et al. (1997) identified, R233X (601728.0002), had previously been reported in patients with Cowden disease. The identical mutation occurred in 2 unrelated families with 2 distinct syndromes on 2 different 10q22-q23 haplotypes, arguing against a common ancestor or a founder effect. Longy et al. (1998) identified 4 mutations in the PTEN gene in 6 patients from 4 unrelated families with Bannayan-Riley-Ruvalcaba syndrome. In 1 family, 1 individual had features more suggestive of Cowden disease, whereas the overall family phenotype was that of Bannayan-Riley-Ruvalcaba syndrome. Celebi et al. (1999) reported a further family with a single PTEN mutation (601728.0021) in which 2 female members had phenotypic findings of Cowden disease and 2 males had phenotypic findings of BZS. Genetic Heterogeneity Carethers et al. (1998) failed to find PTEN germline mutations in 3 sporadic cases of Bannayan-Riley-Ruvalcaba syndrome in males. One patient presented with macrocephaly, hypotonia, cognitive and developmental delays, cutaneous lipomas, and a 2-cm intestinal metaplastic polyp located in the ascending colon. The second patient presented with macrocephaly, multiple intestinal juvenile polyps, pigmentation of the genitalia, cutaneous and visceral lipomas, cutaneous hemangiomas, and hyporeflexia. The third patient presented with macrocephaly, multiple rectal juvenile polyps, pigmentary spotting of the penis, cutaneous lipomas, and cognitive and developmental delay. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genotype/Phenotype Correlations | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Marsh et al. (1999) screened for PTEN mutations in constitutive DNA samples from 43 Bannayan-Riley-Ruvalcaba syndrome individuals comprising 16 sporadic and 27 familial cases, 11 of which were families with both Cowden disease and BRRS. Mutations were identified in 26 of 43 (60%) BRRS cases. Genotype-phenotype analyses within the BRRS group suggested a number of correlations, including the association of PTEN mutations and cancer or breast fibroadenoma in any given CD, BRRS, or BRRS/CD overlap family (p = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family (p = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in BRRS patients (p = 0.028). In contrast to the report of Carethers et al. (1998), in which no PTEN mutations or deletions were found in sporadic cases of BRRS, Marsh et al. (1999) found that identification of germline PTEN mutations was equally likely in sporadic and familial BRRS (p = 0.113). Comparisons between BRRS and a previously studied group of 37 CD families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CD alone or both CD and BRRS when compared with BRR alone (p = 0.002). Among CD, BRRS and BRRS/CD overlap families that were PTEN mutation positive, the mutation spectra appeared similar. Thus, PTEN mutation-positive CD and BRRS may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance. Lachlan et al. (2007) were unable to find a genotype/phenotype correlation among 42 patients from 26 families with PTEN mutations and clinical features of either Cowden syndrome or BRRS. The earliest features of the PTEN-related phenotype were macrocephaly and hamartomas, with mucocutaneous features and sometimes malignancies developing over time in the same patients. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Nomenclature | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cohen (1990) suggested the designation 'Bannayan-Riley-Ruvalcaba syndrome' to unify 3 previously recognized syndromes (Bannayan, 1971; Riley and Smith, 1960; Ruvalcaba et al. (1980)) as a single entity. DiLiberti (1990) questioned the evidence that these syndromes were the same. However, DiLiberti (1992) later suggested that Ruvalcaba-Myhre-Smith syndrome and Bannayan-Zonana syndrome represent phenotypic variability resulting from mutation at a single genetic locus. DiLiberti (1998) proposed a new nomenclature reflecting the unification of multiple syndromes that are now known to be caused by mutations in the PTEN gene. He proposed that it be called the PTEN MATCHS syndrome; MATCHS was derived from macrocephaly, autosomal dominant, thyroid disease, cancer, hamartomata, and skin abnormalities. Marsh et al. (1999) suggested that the spectrum of disorders be referred to as PTEN hamartoma tumor syndrome (PHTS). Lachlan et al. (2007) concluded that the BRRS and Cowden syndrome represent 1 condition with variable expression and age-related penetrance, which is common in tumor-suppressor disorders, and suggested that it is not helpful to split PTEN-related disorders into separate clinical syndromes. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| History | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a child with a Bannayan-Zonana phenotype, Israel et al. (1991) found a 19;Y translocation in circulating lymphocytes: 46X,t(Y;19)(q11;q13). They raised the possibility that a small deletion or position effect of chromosome 19q was responsible for this syndrome. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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