Balkan Journal of Medical Genetics

MUSCLE HEMANGIOMATOSIS PRESENTING AS A SEVERE FEATURE IN A PATIENT WITH THE PTEN MUTATION: EXPANDING THE PHENOTYPE OF VASCULAR MALFORMATIONS IN BANNAYAN-RILEY-RUVALCABA SYNDROME
Soysal Y, Acun T, Lourenço CM, Marques W Jr, Yakıcıer MC
*Corresponding Author: Assistant Professor Yasemin Soysal, Department of Medical Genetics, Afyon Kocatepe University, Faculty of Medicine, Ali Çetinkaya Kampüsü, Afyonkarahisar, 03100, Turkey; Tel.: +90-5423463576; Fax: +90-2722463300; E-mail: yasemin_soysal@yahoo.com
page: 45

DISCUSSION

The PTEN mutation is related to hamartoma syndromes, displaying partial clinical overlap. The determination of germline mutations in PHTS can allow the identifi cation of new genotype-phenotype correlations, particularly in BRRS. However, it was reported that males are more frequently affected than females but our female patient was in the group of lower penetrance group [9]. We have identifi ed a de novo mutation, R335X, in the PTEN coding sequence in a child with the phenotypic fi ndings of BRRS. Although this truncating PTEN mutation is common in CS, the R335X mutation is rarely reported in BRRS [2]. The R335X mutation at nucleotide 1003 (C>T) in exon 8 results in a truncated protein lacking the C-terminal portion that is needed for phosphatase function [2]. Destabilization of the predicted secondary structure by point mutations on the C-terminal has been shown to result in haploinsuffi ciency and to affect phosphatase function [10]. Since we did not analyze the DNA of affected tissues, we speculate that a single PTEN hit resulting in PTEN haploinsuffi ciency may be causative of the patient’s clinical features, such as macrocephaly, verrucae vulgares, café-au-lait spots, seizures and hemangiomas. Çelebi et al. [2] described for the fi rst time a family with two female members fulfi lling the criteria for CS and two male members with the phenotypic fi ndings of BRRS associated with PTEN R335X mutation. Marsh et al. [11] reported a CS patient with the PTEN gene R335X mutation with malignancy. Parisi et al. [10] reviewed their experience in three families with BRRS and PTEN mutations. Similarly, we encountered common phenotypic features identifi ed in approximately one-third of their patients, who had downwardslanting palpebral fi ssures, high-arched palates, macrocephaly, frontal bossing, vascular malformations, café-au-lait macules, seizures, and some degree of learning impairment [10]. Fifty-six to 70% of BRRS patients also exhibited high-arched palates [10]. Zhou et al. [12] intended to defi ne whether other syndromes of overgrowth and hamartomas are part of PHTS. They also studied six unrelated individuals who had minimal features of lipomas, hamartomas, and overgrowth but did not meet the diagnostic criteria of CS and BRRS; they subjected these patients to PTEN mutation analysis. In their study, a germline PTEN R335X mutation and a second “hit” germline mosaic R130X mutation, were detected in affected tissues of a boy with clinical features of marked hemihypertrophy, macrocephaly, epidermoid nevi, and lipomas. The patient had been diagnosed with an undefi ned Proteus-like syndrome. The patient had arteriovenous malformations in all tissues, including muscle, nerve, and bone. The malformations progressively worsened, and after a series of embolizations, a right hip amputation was performed. Since he did not have any gastrointestinal symptoms, this patient did not meet the criteria for a diagnosis of CS or BRRS [12]. Another small series of Proteus syndrome patients was examined for PTEN mutations [13-15]. Interestingly, R335X was found in two of fi ve Proteuslike individuals and the same mutation has also been found in CS and BRRS patients [15]. Vascular abnormalities, arteriovenous malformations, vascular hamartomas, or hemangiomas, have been reported in some BRRS and CS patients [16-18]. These vascular anomalies are typically multifactorial intramuscular combinations of fast-fl ow channels and ectopic fat in patients with PTEN mutations [19]. Nevertheless, monitoring for vascular anomalies is not a standard diagnostic procedure for BRRS patients [19]. Erkek et al. [1] reported tender and painful arteriovenous hemangiomas that were misdiagnosed as angiolipomas in their patients. In this report, the patient’s most striking features were the limitation of vascular hamartomas, myopathy, axonal neuropathy and enostosis to the right lower extremity. Tan et al. [19] identifi ed vascular anomalies in 54% of their patients positively identifi ed as having a PTEN mutation, although none of them had found the R335X mutations in two male patients, one with vascular anomalies and one without. They concluded in this research that macrocephalic patients with fast-fl ow vascular anomalies or multiple intracranial developmental venous anomalies should be tested for PTEN mutation [19]. Although a few cases have been reported with the association of CS, hemangiomas and arteriovenous malformations are reported features of BRRS [20]. Electromyography may refl ect the myopathic process [21]. We showed the presence of myopathic potential units in our patient. Bannayan-Riley-Ruvalcaba syndrome is also associated with muscular abnormalities [1]. Our patient had weakness in her left leg with moderate degree of muscle atrophy and aqueous aquileus retraction. Hamartomatous polyposis occurs in 35-45% of BRRS cases, mainly in the colon and rectum [5,8,22]. The results of our patient’s colonoscopy showed a few polyps in the sigmoid colon; a biopsy showed that the polyps were compatible with a hamartomatous type. Timely identifi cation of PTEN mutations, regardless of clinical presentation, would redefi ne a diagnosis. Severe arteriovenous malformations/ hemangiomas may be a particular presentation of BRRS patients carrying the R335X mutation and can be a debilitating feature of the disease. We aimed to evaluate genetic features of BRRS, demonstrating clinical correlations in a demonstrated case. Our study has contributed to the knowledge of vascular anomalies in patients with a PTEN mutation. This case report reminds the clinicians to consider a PTEN gene mutation testing for diagnosis of patients with vascular anomalies and other clinical features of CS and BRRS. Declaration of Interest. The authors report no confl icts of interest. The authors alone are responsible for the content and writing of this article.

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