Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 
  • Users Online: 635
  • Home
  • Print this page
  • Email this page

 Table of Contents  
Year : 2018  |  Volume : 4  |  Issue : 3  |  Page : 299-302

ZNF469 mutation in a case of Ehlers–Danlos syndrome presenting with glomerulonephritis

1 Department of Medicine, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India
2 CSIR Institute of Genomics and Integrative Biology, New Delhi, India

Date of Submission14-Apr-2018
Date of Acceptance10-May-2018
Date of Web Publication24-Dec-2018

Correspondence Address:
Dr. Smita Nath
Department of Medicine, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJAM.IJAM_11_18

Rights and Permissions

Ehlers Danlos syndrome is the term applied to a group of rare genetic disorders charactersised by joint hypermobility, skin fragility and hyperextensibility. However the syndrome includes patients with rare distinctive features like severe muscle hypotonia, marfanoid habitus, kyphoscoliosis, osteopenia, keratoconus and eye globe rupture. We present a case of Ehlers-Danlos Syndrome Type VI, with ZNF 469 mutation affecting two siblings born out of consanguineous marriage.
The following core competencies are addressed in this article: Medical knowledge, Patient care, Systems-based practice.

Keywords: Glomerulonephritis, hereditary collagen vascular disorder, keratoconus, ZNF469 mutation

How to cite this article:
Nath S, Parmar P, Shadab S, Garg S, Kumar S, Scaria V, Shivasubu S. ZNF469 mutation in a case of Ehlers–Danlos syndrome presenting with glomerulonephritis. Int J Acad Med 2018;4:299-302

How to cite this URL:
Nath S, Parmar P, Shadab S, Garg S, Kumar S, Scaria V, Shivasubu S. ZNF469 mutation in a case of Ehlers–Danlos syndrome presenting with glomerulonephritis. Int J Acad Med [serial online] 2018 [cited 2021 Dec 2];4:299-302. Available from: https://www.ijam-web.org/text.asp?2018/4/3/299/248324

  Introduction Top

Ehlers–Danlos syndrome (EDS) is a rare connective tissue disorder, which affects collagen metabolism, resulting in deficiency and disordered deposition of collagen in tissues.[1] The disease is characterized by a distinct array features such as joint hypermobility, skin hyperextensibility, and fragility.[2] The Villefranche classification scheme adopted in 1998 categorizes EDS into six subtypes based on clinical features, mode of inheritance, and biochemical and genetic analysis.[3] This syndrome affects 1 in 5000 people.[3] We describe a case of EDS Type VIB associated with ZNF469 mutation and membranous glomerulonephritis in two siblings, born out of consanguineous marriage.

  Case Report Top

Our patient presented to us with chief complaints of periorbital puffiness followed by progressive, generalized swelling of whole body for 1 month and intermittent low-grade fever with dry cough for 5 days. There was no history of decreased urination, hematuria, jaundice, fever, altered bowel habits, hemoptysis, and hematemesis or melena. The patient was afebrile. She had pallor, B/L pitting pedal edema, bluish sclera, keratoconus with corneal scarring, and thyromegaly. Scoliosis was present. There were no icterus, cyanosis, and clubbing lymphadenopathy. Juglar venous pressurewas not raised. There was no neurocutaneous marker or hernias. Blood pressure at the time of examination was 110/70 mmHg in the right upper limb in supine position, and pulse rate was 100/min with regular rhythm and character. Her respiratory rate was 16/min. Systemic examination was normal except for the presence of coarse crepitations in the left infraaxiallary area. Laboratory examination revealed a hemoglobin level of 12.6 gm% and total Leukocyte count of 8600 with 45% lymphocytes and 55% polymorphs. At this stage, her blood urea was 44 mg/dl and serum creatinine was 1.2 mg/dl. She had a total serum protein of 6.5 mg/dl and albumin of 3.9 mg/dl. Total bilirubin was 0.9 mg/dl, SerumGlutamicOxaloacetic T ransaminase was 14, SerumGlutamicPyruvicTransaminase was 20, and alkaline phosphatase was 111. Lipid profile revealed a total serum cholesterol of 122 mg/dl and serum triglycerides of 232 mg/dl. Urine R/M revealed the presence of albumin (4+) and red blood cell (RBC) (20–30/HPF). Urine for active sediments revealed dysmorphic RBC. C3 levels were within normal limits. Chest X-ray revealed homogenous opacity in left lower lung fields suggestive of pneumonitis. Based on the above clinical and laboratory findings, a diagnosis of left lower zone pneumonia with acute glomerulonephritis was made. She was treated with antibiotics after which her fever subsided. Her liver and kidney functions remained stable. However, her systolic blood pressure showed elevation and settled in the range of 150–160 mmHg. Further history and examination revealed that the patient had history of recurrent corneal lesions since the age of 3 years for which she underwent keratoplasty 8 years back. The patient also had B/L sensory neural hearing loss for which she was using hearing aid for the past 10 years. She gave a history of easy bruising after trivial trauma. She was a newly diagnosed case of hypothyroidism and was started on thyroid supplementation about 1 month back. During her current hospital admission, thyroid-stimulating hormone (TSH) was within normal limits.

The patient has a younger male sibling with marfanoid habitus and keratoconus. He has no hearing loss and no history of anasarca. Their parents have a consanguineous marriage and are first cousins. With proper consent, the male sibling was examined. He had keratoconus. No joint hypermobility was detected on Beighton scale. Both the siblings had no joint hypermobility or skin hyperextensibility. His hematological and biochemical parameters were normal. Urine routine microscopy was normal. However, urine for active sediments revealed 20% dysmorphic RBC.

  • Further investigation for the female sibling revealed 24-h urine protein 4.65 g/day. Ultrasound examination of abdomen and pelvis was normal. Two-dimensional echo revealed mild Mitral Regurgitation, mild Tricuspid Regurgitation, mild Pulmonary Arterial Hypertension and Ejection Fraction = 60%. Anti Nuclear Antibody/Extracted nuclear Antigen profile and Anti Neutrophilic Cytoplasmic Antibody serology were negative. TSH was 4.2. Kidney biopsy shows seven glomeruli which appear enlarged and show increased mesangial matrix and cellularity with lobular accentuation [Figure 1]. The basement membrane thickening shows focal splitting on silver methenamine stain [Figure 2]. Tubule shows focal injury in the form of lowering of epithelium [Figure 3]. The interstitium shows edema and marked inflammatory cell. Immunofluorescence revealed two glomeruli which show linear deposits of IgG (2+), IgM (2+), C1q (2–3+), Kppa2+, and lambda2+ along the peripheral capillary wall. There is also granular deposition C3 (2+) along peripheral capillary wall. The inference was immune complex mediated, receding phase of diffuse proliferative glomerulonephritis. The kidney biopsy of the male sibling was normal
  • After the kidney biopsy, our patient was started on steroids and Angiotensin Converting E nzyme inhibitors in accordance with the KIDGO guidelines for diffuse proliferative glomerulonephritis. She responded to the treatment, and steroids were subsequently tapered
  • However, the diagnostic conundrum regarding the syndrome afflicting the two siblings born out of consanguineous marriage remained unresolved. Taking into consideration the family history and clinical presentation, our provisional diagnosis was hinged between EDS (occuloscoliotic variety) and Alport syndrome. Hence, an exome sequencing and sanger validation were done at CSIR institute of genomic and integrative biology. The study included both the siblings along with their parents. Apart from them, their maternal and paternal grandmothers and four other first-degree relatives were part of the study. The siblings were found to have ZNF469 mutation which is the putative and novel disease-associated variant and is considered highly pathogenic [Figure 4]. This was confirmed by the fact that the homozygous variant was previously associated with brittle cornea disease-1/EDS VIB (OMIM 229200).
Figure 1: Kidney biopsy of female sibling showing increased mesangial matrix and cellularity with lobular accentuation

Click here to view
Figure 2: The basement membrane thickening shows focal splitting on silver methenamine stain of glomeruli on kidney biopsy. Tubule shows focal injury in the form of lowering of epithelium. The interstitium shows edema and marked inflammatory cell

Click here to view
Figure 3: Kidney biopsy of female sibling showing tubular injury on hematoxylin stain

Click here to view
Figure 4: Sanger sequence validation of ZNF469 mutation in Ehlers–Danlos syndrome

Click here to view

  Discussion Top

EDS comprises clinically and genetically heterogeneous group of disorders that results from defect in the synthesis of fibrillar collagen.[1] It is inherited as an autosomal recessive or dominant trait and is also associated with X chromosome.[2] Depending on the type of collagen affected, the disorder has a wide range of expressivity, giving rise to distinctive phenotypes.[3] Mutation in ZNF469 has been reported as causative factor for brittle cornea syndrome/EDS VIB.[4] ZNF469 gene is located on 16q24.2 and encodes for zinc finger protein. Low percentage homology suggests that it may function as transcription factor for synthesis or organization of collagen fibers.[4] Rare missense mutations in ZNF469, predicted to be pathogenic, occurred heterozygously, at a frequency of 23% in patients suffering from keratoconus. The pathogenic changes lead to predisposition toward a “thin” cornea, which then becomes keratoconic.[5],[6] A review of literature suggests that EDS VI is caused by homozygous or compound heterozygous mutation in PLOD1 gene, which encodes for procollagen-lysine 5-dioxygenase, which is an enzyme involved in the formation of stable crosslinks in collagen fibers. These patients apart from features of classic EDS have severe muscle hypotonia after birth, progressive kyphoscoliosis, marfanoid habitus, and osteopenia, with brittle cornea and rupture of great arteries.[7]

In our case, the female sibling presented to use with nephrotic range proteinuria and pneumonia. Although features of classic EDS such as joint hypermobility and skin hyperextensibility were absent in the siblings, both of them had history recurrent corneal ulcers and had underwent keratoplasty. Male sibling had marfanoid habitus, and scoliosis was observed in the female sibling along with sensorineural hearing loss. Both the parents were carriers of mutation, but asymptomatic otherwise. Five other first-degree relative underwent clinical examination and genomic sequencing. However, they did not carry the ZNF469 mutation.

The other perplexing feature was the presence of nephrotic syndrome, which is not documented in association with EDS. The kidney biopsy of the female sibling was suggestive of membranous glomerulonephritis. The biopsy of male sibling, although normal, was associated with active urinary sediments.

Our case combined the feature of EDS to a variable degree along with the presence of rare genetic mutation and kidney involvement. It opens up new avenues for study of association between renal involvement and EDS in patients with ZNF469 mutation.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

Ethical conduct of research

The requisite consent was obtained from appropriate Institutional Ethics Committee.

  References Top

Badauy CM, Gomes SS, Sant'Ana Filho M, Chies JA. Ehlers-Danlos syndrome (EDS) type IV: Review of the literature. Clin Oral Investig 2007;11:183-7.  Back to cited text no. 1
Castori M, Dordoni C, Morlino S, Sperduti I, Ritelli M, Valiante M, et al. Spectrum of mucocutaneous manifestations in 277 patients with joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type. Am J Med Genet C Semin Med Genet 2015;169C: 43-53.  Back to cited text no. 2
Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: Revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos support group (UK). Am J Med Genet 1998;77:31-7.  Back to cited text no. 3
Karolak JA, Gambin T, Rydzanicz M, Szaflik JP, Polakowski P, Frajdenberg A, et al. Evidence against ZNF469 being causative for keratoconus in Polish patients. Acta Ophthalmol 2016;94:289-94.  Back to cited text no. 4
Davidson AE, Borasio E, Liskova P, Khan AO, Hassan H, Cheetham ME, et al. Brittle cornea syndrome ZNF469 mutation carrier phenotype and segregation analysis of rare ZNF469 variants in familial keratoconus. Invest Ophthalmol Vis Sci 2015;56:578-86.  Back to cited text no. 5
Vincent AL, Jordan CA, Cadzow MJ, Merriman TR, McGhee CN. Mutations in the zinc finger protein gene, ZNF469, contribute to the pathogenesis of keratoconus. Invest Ophthalmol Vis Sci 2014;55:5629-35.  Back to cited text no. 6
Yeowell HN, Walker LC. Mutations in the lysyl hydroxylase 1 gene that result in enzyme deficiency and the clinical phenotype of Ehlers–Danlos syndrome type VI. Mol Genet Metab 2000;71:212-24.  Back to cited text no. 7


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]


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

  In this article
Case Report
Article Figures

 Article Access Statistics
    PDF Downloaded20    
    Comments [Add]    

Recommend this journal