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Background
This syndrome is very closely related to Cowden's syndrome with multiple hamartomas. Individuals with this syndrome frequently present with macrocephaly with developmental delay and hypotonia, which are recognized during the first few years of life. Hamartomatous growths such as intestinal polyposis, subcutaneous and visceral lipomas, and vascular malformations are common findings. Skin findings include pigmented macules of the penis.
Because of recently discovered genetic findings, there is evidence that Cowden's syndrome and this disease share a common genetic abnormality. Prior to this discovery, there was no increased risk of malignancy in kindreds. However, in light of this new discovery, it has been suggested that there may be an increased risk of malignancy.
OUTLINE
DISEASE ASSOCIATIONS CHARACTERIZATION COWDEN SYNDROME LONG CHAIN FATTY ACID DEFICIENCY
- Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (L-CHAD) deficiency in a patient with the Bannayan-Riley-Ruvalcaba syndrome.
Fryburg JS, Pelegano JP, Bennett MJ, Bebin EM.
Department of Pediatrics, University of Virginia Health Sciences Center, Charlottesville 22908.
Am J Med Genet. 1994 Aug 1;52(1):97-102. Abstract quote
Bannayan-Riley-Ruvalcaba syndrome (BRRS) is an autosomal dominant condition of macrocephaly in combination with lipomas/hemangiomas, hypotonia, developmental delay, and a lipid myopathy. The etiology of the lipid storage myopathy has been unclear.
We describe a black boy with findings of BRRS who also has a defect in long-chain fatty acid oxidation expressed in cultured skin fibroblasts as a deficiency of long-chain-L-3-hydroxyacyl-CoA dehydrogenase (L-CHAD). He also has an abnormal brain MRI and increased size of both lower limbs.
We present this child because of his unusual combination of findings, and postulate that L-CHAD deficiency may be the cause of the lipid myopathy in BRRS.LYMPHAGNIOMYOMA Bannayan-Zonana syndrome associated with lymphangiomyomatous lesions.
Klein JA, Barr RJ.
Department of Dermatology, California College of Medicine, University of California-Irvine.
Pediatr Dermatol 1990 Mar;7(1):48-53 Abstract quote
Bannayan-Zonana syndrome is an autosomal dominant condition that has not been well described in the dermatology literature. The typical case is characterized by macrocephaly, multiple angiomas, and multiple encapsulated or infiltrating lipomas. As in other autosomal dominant hamartoneoplastic syndromes, the degree of expression within one family frequently varies widely.
Our patient had macrocephaly and angiomas, as well as lipomas with peculiar histologic features similar to lymphangiomyomas. Her father had a large nevus flameus on his leg, and lipomas with normal histologic appearance. The paternal grandfather had multiple encapsulated lipomas with normal histologic appearance. Neither father nor grandfather had macrocephaly.
PATHOGENESIS CHARACTERIZATION PTEN MUTATIONS
- Identification of a PTEN mutation in a family with Cowden syndrome and Bannayan-Zonana syndrome.
Wanner M, Celebi JT, Peacocke M.
Department of Dermatology, Columbia University, College of Physicians and Surgeons, New York, NY, USA.
J Am Acad Dermatol. 2001 Feb;44(2):183-7. Abstract quote
Cowden syndrome (CS) and Bannayan-Zonana syndrome (BZS) are two inherited hamartoma syndromes characterized by distinct phenotypic features. Mutations in the PTEN gene have been identified in patients with CS and BZS, suggesting the presence of a common genetic basis.
We describe a single kindred with individuals manifesting both CS and BZS phenotypes (CS/BZS overlap family) in which we have identified a novel mutation in PTEN by DNA sequencing. We have confirmed these results by means of restriction enzyme analysis. The presence of individuals with CS and BZS within the same family, and moreover the identification of identical PTEN gene mutations in these individuals, suggest that these two syndromes represent different phenotypic expressions of one disease.
Furthermore, these findings imply that, like patients with CS, individuals with BZS should be monitored for the onset of malignancy.
- Phenotypic findings of Cowden syndrome and Bannayan-Zonana syndrome in a family associated with a single germline mutation in PTEN.
Celebi JT, Tsou HC, Chen FF, Zhang H, Ping XL, Lebwohl MG, Kezis J, Peacocke M.
Department of Dermatology, Columbia Presbyterian Hospital, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
J Med Genet. 1999 May;36(5):360-4 Abstract quote
Cowden syndrome (CS) and Bannayan-Zonana syndrome (BZS) are two hamartoma syndromes with distinct phenotypic features. Although partial clinical overlap exists between CS and BZS, they are considered to be separate entities. PTEN has been identified as the susceptibility gene for both disorders, suggesting allelism.
We have identified a germline mutation, R335X, in PTEN in a family consisting of two female members with the phenotypic findings of CS and two male members with the phenotypic findings of BZS.
To our knowledge, this is the first report that shows the presence of separate subjects with CS and with BZS in a single family associated with a single germline PTEN mutation.
- Identification of PTEN mutations in five families with Bannayan-Zonana syndrome.
Tok Celebi J, Chen FF, Zhang H, Ping XL, Tsou HC, Peacocke M.
Department of Dermatology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Exp Dermatol. 1999 Apr;8(2):134-9 Abstract quote.
Germline mutations in PTEN, a putative tumor suppressor gene, has been identified in 2 autosomal dominant inherited hamartoma syndromes, Cowden syndrome (CS) and Bannayan-Zonana syndrome (BZS). While both diseases exhibit distinct phenotypic features, there seems to be a partial clinical overlap between the 2 diseases.
To date, 9 families with BZS have been screened for PTEN mutations, of which 5 were found to exhibit mutations in this gene. We report 5 novel germline mutations in the PTEN coding sequence from 5 unrelated families with the BZS phenotype. While all the mutations we identified are novel in BZS, 1003C-->T (nonsense mutation) and 209+5G-->A (putative splice site mutation) have been previously reported in unrelated families with CS and Lhermitte Duclos disease. Interestingly, 1 of the families has an individual with BZS and 1 with CS phenotype, associated with a single PTEN mutation, 885insA.
These data support the notion that CS and BZS may be within the spectrum of the same primary disorder.
- Carney complex, Peutz-Jeghers syndrome, Cowden disease, and Bannayan-Zonana syndrome share cutaneous and endocrine manifestations, but not genetic loci.
Stratakis CA, Kirschner LS, Taymans SE, Tomlinson IP, Marsh DJ, Torpy DJ, Giatzakis C, Eccles DM, Theaker J, Houlston RS, Blouin JL, Antonarakis SE, Basson CT, Eng C, Carney JA.
Unit on Genetics and Endocrinology, Section on Pediatric Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1862, US.
J Clin Endocrinol Metab. 1998 Aug;83(8):2972-6. Abstract quote
Carney complex (CC), Peutz-Jeghers syndrome (PJS), Cowden disease (CD), and Bannayan-Zonana syndrome (BZS) share clinical features, such as mucocutaneous lentigines and multiple tumors (thyroid, breast, ovarian, and testicular neoplasms), and autosomal dominant inheritance.
A genetic locus has been identified for CC on chromosome 2 (2p16), and the genes for PJS, CD, and BZS were recently identified; genetic heterogeneity appears likely in both CC and PJS. The genes for PJS and CD/BZS, STK11/LKB1 and PTEN, respectively, may act as tumor suppressors, because loss of heterozygosity (LOH) of the PJS and CD/BZS loci has been demonstrated in tumors excised from patients with these disorders.
We studied 2 families with CC in whom the disease could not be shown to segregate with polymorphic markers from the 2p16 locus. Their members presented with lesions frequently seen in PJS and the other lentiginosis syndromes. We also tested 16 tumors and cell lines established from patients with CC for LOH involving the PJS and CD/BZS loci. DNA was extracted from peripheral blood, tumor cell lines, and tissues and subjected to PCR amplification with primers from microsatellite sequences flanking the STK11/LKB1 and PTEN genes on 19p13 and 10q23, respectively, and a putative PJS locus on 19q13. All loci were excluded as candidates in both families with LOD scores less than 2 and/or by haplotype analysis. LOH for these loci was not present in any of the tumors that were histologically identical to those seen in PJS. The overall rate of LOH for the PJS and CD/BZS loci in tumors from patients with CC was less than 10%.
We conclude that despite substantial clinical overlap among CC, PJS, CD, and BZS, LOH for the STK11 and PTEN loci is an infrequent event in CC-related tumors. Linkage analysis excluded the PJS and CD/BZS loci on chromosomes 19 (19p13 and 19q13) and 10 (10q23) from harboring the gene defect(s) responsible for the phenotype in these 2 families.
LABORATORY/
RADIOLOGYCHARACTERIZATION
- Arteriovenous malformation in a patient with Bannayan--Zonana syndrome.
Naidich JJ, Rofsky NM, Rosen R, Karp N.
Department of Radiology, NYU Medical Center, 550 First Avenue, New York NY 10016, USA.
Clin Imaging. 2001 Mar-Apr;25(2):130-2. Abstract quote
Bannayan-Zonana syndrome (BZS) is a genetic disorder with autosomal dominant inheritance characterized by macrocephaly and multiple hamartomas of mesodermal origin.
Here we present a patient with BZS manifested by many of the classic features, as well as a high-flow upper extremity arteriovenous malformation (AVM).
Although this rare syndrome was initially described in 1971, to our knowledge, this is the first report showing an association of AVM with BZS and the first report of this syndrome in the radiologic literature.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION GENERAL
Surg Neurol. 1998 Aug;50(2):164-8 Abstract quote.
BACKGROUND: Bannayan-Zonana syndrome is a rare hamartomatous disorder, characterized by macrocephaly, multiple lipomas, and hemangiomas. Inheritance is by autosomal dominant transmission with few reported sporadic cases. Male predominance is also reported.
METHODS: We describe a patient who presented with multiple subcutaneous lipomas, mild macrocephaly, and an extradural spinal hemangioma. Other affected family members and 24 other previously reported cases are discussed.
RESULTS: Spinal hemangiomas have not been described previously with this syndrome. The patient also had a "malignant bone tumor" removed from his humerus 20 years ago. Two of the patient's siblings also had lymphoma, which is an unusual accompaniment not reported previously. Only the male members in the family showed multiple subcutaneous lipomas.
CONCLUSION: Some patients with Bannayan-Zonana syndrome may have hamartomatous lesions producing cord compression or intracerebral hemorrhage, or they may rarely have other malignant tumors; therefore it is important that neurosurgeons are aware of the entity. The early diagnosis of BZS is also important for genetic counseling.
J Pediatr Surg. 1992 Jun;27(6):722-3 Abstract quote.
Bannayan-Zonana syndrome is a rare disorder characterized by macrocephaly and multiple soft tissue and visceral hamartomas.
This report presents a sporadic patient with macrocephaly, lipomas, hemangiomas, and lymphangiomas who died of cardiac and respiratory failure due to progressive cervicomediastinal arteriovenous fistulous hemangiomas at the age of 9 years.
- Macrocephaly with hamartomas: Bannayan-Zonana syndrome.
Miles JH, Zonana J, Mcfarlane J, Aleck KA, Bawle E.
Am J Med Genet. 1984 Oct;19(2):225-34. Abstract quote
Familial macrocephaly with mesodermal hamartomas is described as a distinct syndrome in nine individuals from four families. Constant manifestations include symmetrical macrocephaly without ventricular enlargement, mild neurological dysfunction, and postnatal growth deceleration. Speech and motor delays observed in all the children were usually well compensated by adulthood.
Two children had mild mental retardation and seizures which may have been related to intracerebral hemorrhage in one. Mesodermal hamartomas were present in affected persons from all four families, with 60% of individuals manifesting only discrete lipomas and hemangiomas. More serious tumors, including intracerebral hemangiomas, hemangiomatous involvement of the bone, and aggressive lipomas occurred in 40%.
Other findings that make it possible to delineate a recognizable syndrome include down-slanting palpebral fissures (66%), a high palate (67%), joint hyperextensibility (55%), pectus excavatum (22%), strabismus or amblyopia (33%), and prolonged drooling (44%).
The Bannayan-Zonana syndrome is an autosomal-dominant trait with male predominance of affected individuals.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
- Clinicopathologic findings in the Bannayan-Riley-Ruvalcaba syndrome.
Fargnoli MC, Orlow SJ, Semel-Concepcion J, Bolognia JL.
Department of Dermatology, Yale University School of Medicine, New Haven, Conn, USA.
Arch Dermatol. 1996 Oct;132(10):1214-8. Abstract quote
BACKGROUND: The term Bannayan-Riley-Ruvalcaba syndrome has been proposed to reflect the clinical overlap of 3 conditions previously described as separate entities, each inherited in an autosomal dominant fashion. They are the Riley-Smith, Bannayan-Zonana, and Ruvalcaba-Myhre-Smith syndromes.
OBSERVATIONS: We studied 2 kindreds with the Bannayan-Riley-Ruvalcaba syndrome. Characteristic cutaneous findings included multiple subcutaneous lipomas and vascular malformations, lentigines of the penis and vulva, verrucae, and acanthosis nigricans. Macrocephaly with normal ventricular size, mental retardation, central nervous system vascular malformations, intestinal polyposis, skeletal abnormalities, and thyroid tumors were the most common systemic featues. A striking clinical finding in 1 patient was widespread verrucous changes of both lips that histologically showed epidermal hyperplasia with papillomatosis and hyperkeratosis. Biopsy specimens of facial papules demonstrated the histological features of both syringomas and trichilemmomas. Lentiginous hyperplasia of the epidermis with increased pigment in the basal layer and a slight increase in the number of melanocytes were seen in biopsy specimens of the penile lentigines.
CONCLUSIONS: The histologic findings of both the facial lesions and the pigmented macules of the penis in the Bannayan-Riley-Ruvalcaba syndrome have not, to our knowledge, been reported previously. The similarities between the Bannayan-Riley-Ruvalcaba syndrome and Cowden disease raise the possibility of a common genetic pathogenesis for these 2 diseases.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES PROTEUS SYNDROME
Eur J Pediatr. 1988 Nov;148(2):122-5 Abstract quote.
The Proteus syndrome (PS) and the Bannayan-Zonana syndrome (BZS) both have multiple hamartomata as prominent features. Hemihypertrophy, macrodactyly, exostoses, skin lesions, scoliosis, and sporadic occurrence are seen in PS, whereas patients with BZS have macrocephaly and related craniofacial findings. BZS has been observed in families as an autosomal dominant trait. Although the two syndromes can be distinguished in most patients, there are features in common to both that may pose a diagnostic dilemma in an isolated case.
We report the case of a 3-year-old girl with macrocephaly, macrodactyly, and superficial and intra-abdominal hamartomata who illustrates the problem of differentiating between PS and BZS. We compare this patient and another recently reported patient with other published cases of PS and BZS. Patients with PS, in general, show more extensive systemic involvement, including skeletal and cutaneous manifestations. Macrocephaly, seen in all reported patients with BZS, is also found in 14% of patients with PS.
Overlap among syndromes which include hamartomata as prominent features suggests that they might be etiologically or pathogenetically related. The present case also illustrates the usefulness of imaging techniques in the diagnosis of mixed mesodermal hamartomata.
PROGNOSIS CHARACTERIZATION GENERAL Potentially increased risk of malignant transformation for some of the soft tissue tumors
TREATMENT CHARACTERIZATION GENERAL Complete removal of lesional tissue Pediatrics 1982;69:632-4.
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Am J Med Genet 1984;19:225-34.
Arch Dermatol 1996;132:1214-8.
J Am Acad Dermatol 2001;44:183-7
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