Home About us Current issue Back issues Submission Instructions Advertise Contact Login   

Search Article 
  
Advanced search 
 
Saudi Journal of Kidney Diseases and Transplantation
Users online: 2191 Home Bookmark this page Print this page Email this page Small font sizeDefault font size Increase font size 
 

Table of Contents   
CASE REPORT  
Year : 2019  |  Volume : 30  |  Issue : 4  |  Page : 969-973
A rare association of pathological variant of Alport’s syndrome caused by hemizygous 5’ splice mutation in intron 10 of COL4A5 gene with metachondromatosis due to heterozygous missense variation in protein tyrosine phosphatase nonreceptor type 11 gene


Department of Nephrology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India

Click here for correspondence address and email

Date of Submission30-Jul-2018
Date of Acceptance03-Sep-2018
Date of Web Publication27-Aug-2019
 

   Abstract 


Metachondromatosis is a rare disorder of autosomal inheritance with incomplete penetrance, which is characterized by formation of osteochondroma and enchondroma, caused by loss of function of the protein tyrosine phosphatase nonreceptor type 11 (PTPN11) gene. Diagnosis is made based on the distribution and orientation of lesions with history of regression of lesions with time and confirmed by genetic mutation of PTPN11 gene. We report a rare case of a 24-year-old male with Alport’s syndrome with metachondromatosis due to missense variation in PTPN11 gene.

How to cite this article:
Sethi S, Mehta S, Makkar V, Kaur S, Sohal P M. A rare association of pathological variant of Alport’s syndrome caused by hemizygous 5’ splice mutation in intron 10 of COL4A5 gene with metachondromatosis due to heterozygous missense variation in protein tyrosine phosphatase nonreceptor type 11 gene. Saudi J Kidney Dis Transpl 2019;30:969-73

How to cite this URL:
Sethi S, Mehta S, Makkar V, Kaur S, Sohal P M. A rare association of pathological variant of Alport’s syndrome caused by hemizygous 5’ splice mutation in intron 10 of COL4A5 gene with metachondromatosis due to heterozygous missense variation in protein tyrosine phosphatase nonreceptor type 11 gene. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Nov 18];30:969-73. Available from: http://www.sjkdt.org/text.asp?2019/30/4/969/265476



   Introduction Top


Metachondromatosis is a rare genetic disease of osteochondroma and enchondroma formation, caused by loss of function of the protein tyrosine phosphatase nonreceptor type 11 (PTPN11) gene.[1],[2],[3],[4],[5],[6],[7] Loss of function of the PTPN11 tumor suppressor gene has been identified as a cause, and the condition is inherited in an autosomal-dominant pattern with incomplete penetrance unlike other enchondroma-toses, such as Ollier’s disease and Maffucci syndrome, which are sporadic in nature. It is distinct from multiple osteochondromatosis (MO), also known as hereditary multiple exocytosis, since the orientation of lesions in metachondromatosis is toward, rather than away from, the epiphysis, and there is a predilection for the hands and feet.[8] Diagnosis is made based on the distribution and orientation of lesions with history of regression of lesions with time and confirmed by genetic mutation of PTPN11 gene. Association of metachondromatosis with Alport’s syndrome has not been reported in the past. We report a rare case of a 24-year-old male with Alport’s syndrome having hemizygous 5’ splice mutation in intron 10 of COL4A5 gene with multiple bony swellings suggestive of metachon-dromatosis due to missense variation in PTPN11 gene.


   Case Report Top


Informed consent was obtained from the patient before presenting the report.

A 24-year-old male, born of nonconsangui-neous marriage with normal birth and developmental history, was admitted to us for evaluation of deranged renal function. The patient had a history of recurrent microscopic hema-turia since late childhood. He developed normally till the age of three years when the parents first noticed bony swelling over long bones of both upper and lower limbs, which gradually increased initially, but later on shown some regression in late second decade of life. These bony swellings never interfered with growth of child, and hence, no consultation was taken for this. He also had history of hearing loss since late childhood. Initial renal functions were normal. He was admitted with complaints of anorexia, nausea, vomiting, generalized fatigue, and pallor for the last four months. His first creatinine report was 11.86 mg/dL. His vitals were normal, and the blood pressure was 140/86 mm Hg. His height was normal and build was thin. The general physical examination showed pallor and mild pedal edema up to the ankle. There were bony swellings near the ends of long bones of approximately 3–4 cm of both upper and lower limbs [Figure 1], [Figure 2], [Figure 3]. The ocular examination was suggestive of lenticonus in both eyes. The ear–nose–throat evaluation was suggestive of bilateral sensor neural hearing loss. There were crepitations in both chest fields with the remaining systemic examination being normal. At presentation, his investigations were hemoglobin of 5.6 g/dL, total leukocyte count of 9300 (N 80%, L 12%, M 6%, E 1%, B 1%), platelet 1.53 lakh, blood urea 143, serum creatinine 11.8 mg/dL, sodium 137 mmol/L, potassium 5.5 mmol/L, total protein 7.8 mg/dL, albumin 3.9 mg/dL, total bilirubin 0.29 mg/dL, direct 3.9 mg/dL, oxalo-acetate transaminase 15 U/L, pyruvate trans-aminase 9 U/L, alkaline phosphate 101 U/L, calcium 8.5 mg/dL, phosphorus 4.9 mg/dL, uric acid 10.1 mg/dL, parathormone 21 pg/mL, serum iron 34.7 μg/dL, total iron binding capacity 249 μg/dL, and transferrin saturation of 13.9%. Viral markers were nonreactive. Urine routine showed 2+ proteinuria and 30–40 RBC/hpf and spot urine protein–creatinine ratio of seven. Patient was conservatively treated with hemodialysis (HD) sessions and symptomatic treatment. Ultrasonography of the abdomen was suggestive of small kidneys with increased echogenicity and loss of cortico-medullary differentiation suggestive of chronic kidney disease (CKD). Two-dimensional echo was suggestive of DCMP with ejection fraction of 26%. In view of positive findings of sensorineural hearing loss, bilateral lentic onus, and underlying CKD, possibility of Alport’s syndrome was made. His genetic analysis was done, which was suggestive of homozygous 5’ splice mutation in intron 10 of COL4A5 gene that affects invariant GT donor splice site exon 10. This was reported as pathological variant. There is another indel variation in exon 45 of COL4A3 gene that results in stop codon and premature truncation of the protein at codon 1331, but this variant was of uncertain significance. This was confirmed with Sanger sequencing. The patient was further evaluated for the bony swellings. His history and clinical findings were likely suggestive of metachondromatosis. The genetic analysis done was suggestive of heterozygous missense variation in PTPN11 gene. Literature was reviewed for metachondromatosis and its association, but no case report of metachon-dromatosis was found in association with Alport’s syndrome. This is probably the first reported case of metachondromatosis in association with Alport’s syndrome. The patient is now under regular follow-up and on regular maintenance HD thrice a week and doing well with good compliance.
Figure 1: Metachondromatosis near ends of long bones in bilateral lower limbs

Click here to view
Figure 2: Individual metachondromatosis over tibia.

Click here to view
Figure 3: Metachondromatosis in upper limb.

Click here to view



   Discussion Top


Metachondromatosis is a rare genetic disorder causing a combination of osteochondromas and enchondromas in the hands, feet, long bones, iliac crests, and spine. Diagnosis is made based on the distribution and orientation of lesions; however, a recently published case report describes a family with radiographic features of both metachondromatosis and MO and a mutation of EXT-2.[9] Lesions in meta-chondromatosis are reportedly not associated with axial deformity or disruption to the growth of bones; however, case reports have documented deformities in fingers and the distal tibia. Per articular soft tissue calcifications are often present and appear similar to those seen in Trevor’s disease, also known as dysplasia epiphysealis hemimelica. Lesions are typically present in the hands and feet; however, the iliac crest spine and long bones such as the proximal femur are also affected. The natural history of metachondromatosis is described as one of the spontaneous regressions during childhood although some lesions persist into adulthood.[10] As with other enchon-dromatoses and MO, new lesions do not appear after skeletal maturation.[11] Taking a thorough family history of spontaneously regressing lesions is, therefore, vital in the diagnosis of metachondromatosis. The differential diagnosis includes MO and multiple enchondromatosis (Ollier’s disease). The orientation of lesions toward rather than away from epiphyses helps distinguish metachon- dromatosis from MO. Lesions associated with Ollier’s disease are almost always unilateral, and there is no familial inheritance of the condition, unlike metachondromatosis. The prevalence of multiple osteochondromas is estimated to be 2/100,000 and Ollier’s disease 1/100,000.[12],[13] Both conditions are, therefore, significantly more prevalent than metachon-dromatosis. This condition is also considered to differ from other enchondromatoses due to its lack of potential for malignant transformation; however, a recent paper reports a grade two chondrosarcoma arising in an enchondroma in a patient with metachondro-matosis. Other reported complications of metachondromatosis include common pero-neal nerve palsy secondary to compression by exostoses near the fibular head, resulting in numbness and foot drop. Nerve function usually recovers completely with excision of the offending lesion. Avascular necrosis of the femoral head has also been described in patients with lesions around the femoral neck. This is thought to be due to the disruption of lateral epiphyseal vessels in the femoral neck. Necrosis of skin overlying a large lesion has occurred in at least one case. Two studies have independently identified loss of function of the PTPN11 gene as a cause of metachondro-matosis in 13 of 19 families, further distinguishing this disorder from MO and Ollier’s disease.[14],[15] Several other overlapping but phenotypically distinct disorders, including Noonan syndrome, Noonan-like disorder with multiple giant cell lesion syndrome, and  LEOPARD syndrome More Details, are caused by gain of function mutations of PTPN11. Histopatholo-gical findings differ between authors. Several papers found typical enchondromas and osteo-chondromas with cartilaginous caps; however, one paper reported lesions with fibrous caps overlying cartilaginous cores. The reason for the difference in these findings is unclear. Bowen et al reviewed the histopathologic features of 30 exostoses excised from patients with MO and compared them with 15 lesions excised from children with metachondroma-tosis.[15] They found lesions in MO to be comprised of cartilaginous caps overlying endochondral bone immediately beneath, whereas lesions in children with metachondro- matosis had a fibrous cap, a disorganized cartilaginous core, and surrounding trabecular bone. Two studies have attempted to identify the gene responsible for metachondromatosis. Sobreira et al studied two families, finding an 11 base pair deletion in one and a nonsense mutation in the other, both (100%) resulting in loss of function of the PTPN11 gene.[14] Bowen et al studied 17 families, of which frame shift, nonsense, deletion, and splice site mutations of PTPN11 were identified in 11 (65 %).[15] This is distinct from the EXT-1 and EXT-2 gene mutations that cause MO. Cells appear to undergo a “second hit,” as in MO, resulting in two nonfunctioning PTPN11 genes, leading to the absence of the production of the SHP2 protein. The mechanism by which SHP2 deficiency leads to the development of enchon-droma or osteochondroma is yet to be determined. Formal treatment and surveillance recommendations are difficult to make in the absence of a larger number of case reports in the literature. A conservative approach, however, appears to be warranted. Indications for surgical excision are predominantly symptomatic, relating to pain and nerve compression. Malignant transformation has only recently been described but should be considered an indication for intervention. Based on observations of other conditions causing the formation of enchondromas and osteochondromas, regular biannual clinical review, skeletal survey of regions not examinable clinically (chest, pelvis, and scapula), and repeat imaging of lesions that grow larger or become painful appear appropriate, with a view to minimizing unnecessary irradiation. Hence, the presence of multiple bony swellings near epiphysis of long bones with characteristic distribution pattern with history of regression should prompt the possibility of metachondro-matosis. The diagnosis should be confirmed by genetic analysis by mutation of PTPN11 gene. This is one of the rare case reports of metachondromatosis reported in the patient of genetically confirmed Alport’s syndrome.

Conflict of interest: None declared.



 
   References Top

1.
Maroteaux P. Metachondromatosis. Z Kinderheilkd 1971;109:246-61.  Back to cited text no. 1
    
2.
Lachman RS, Cohen A, Hollister D, Rimoin DL. Metachondromatosis. Birth Defects Orig Artic Ser 1974;10:171-8.  Back to cited text no. 2
    
3.
Kozlowski K, Scougall JS. Metachondro-matosis: Report of a case in a 6 year old boy. Aust Paediatr J 1975;11:42-5.  Back to cited text no. 3
    
4.
Beals RK. Metachondromatosis. Clin Orthop Relat Res 1982;169:167-70.  Back to cited text no. 4
    
5.
Vanek J. Metachondromatosis, 3 case reports with hereditary occurrence. Beitr Orthop Traumatol 1982;29:103-7.  Back to cited text no. 5
    
6.
Calabet A, Diard F, Ledosseur P, et al. Superior tibial epiphyseal osteochondroma with intra-articular development. Apropos of 2 cases in children. J Radiol 1984;65:389-92.  Back to cited text no. 6
    
7.
Hinkel GK, Rupprecht E, Harzer W. Meta-chondromatosis. Report of a family with 4 cases. Helv Paediatr Acta 1984;39:481-9.  Back to cited text no. 7
    
8.
Kennedy LA. Metachondromatosis. Radiology 1983;148:117-8.  Back to cited text no. 8
    
9.
Vining NC, Done S, Glass IA, et al. EXT2- positive multiple hereditary osteochondromas with some features suggestive of metachon-dromatosis. Skeletal Radiol 2012;41:607-10.  Back to cited text no. 9
    
10.
Giedion A, Kesztler R, Muggiasca F. The widened spectrum of multiple cartilaginous exostosis (MCE). Pediatr Radiol 1975;3:93- 100.  Back to cited text no. 10
    
11.
Bovée JV. Multiple osteochondromas. Orphanet J Rare Dis 2008;3:3.  Back to cited text no. 11
    
12.
Schmale GA, Conrad EU 3rd, Raskind WH. The natural history of hereditary multiple exostoses. J Bone Joint Surg Am 1994;76:986- 92.  Back to cited text no. 12
    
13.
Silve C, Jüppner H. Ollier disease. Orphanet J Rare Dis 2006;1:37.  Back to cited text no. 13
    
14.
Sobreira NL, Cirulli ET, Avramopoulos D, et al. Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene. PLoS Genet 2010;6:e1000991.  Back to cited text no. 14
    
15.
Bowen ME, Boyden ED, Holm IA, et al. Loss-of-function mutations in PTPN11 cause metachondromatosis, but not ollier disease or Maffucci syndrome. PLoS Genet 2011 ;7: e1002050.  Back to cited text no. 15
    

Top
Correspondence Address:
Sudhir Mehta
Department of Nephrology, Dayanan Medical College and Hospital, Ludhiana, Punjab
India
Login to access the Email id


DOI: 10.4103/1319-2442.265476

PMID: 31464257

Rights and Permissions


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

Top
   
 
 
    Similar in PUBMED
    Search Pubmed for
    Search in Google Scholar for
    Email Alert *
    Add to My List *
* Registration required (free)  
 


 
    Abstract
   Introduction
   Case Report
   Discussion
    References
    Article Figures
 

 Article Access Statistics
    Viewed337    
    Printed3    
    Emailed0    
    PDF Downloaded41    
    Comments [Add]    

Recommend this journal