Daughter and mother with orofaciodigital syndrome type 1 and glomerulocystic kidney disease

    Daughter and Mother with Orofaciodigital Syndrome Type 1 and Glomerulocystic Kidney Disease Takashi Iijima MD, Junichi Hoshino MD, Koki Mise MD, Keiichi Sumida MD, Tatsuya Suwabe MD, Noriko Hayami, Toshiharu Ueno MD,MD, Kenmei Takaichi MD, Takeshi Fujii MD, Kenichi Ohashi MD, Naoya Morisada MD, Kazumoto Iijima MD, Yoshifumi Ubara MD PII: DOI: Reference:

S0046-8177(16)30045-4 doi: 10.1016/j.humpath.2016.04.005 YHUPA 3882

To appear in:

Human Pathology

Received date: Revised date: Accepted date:

17 October 2015 11 March 2016 7 April 2016

Please cite this article as: Iijima Takashi, Hoshino Junichi, Mise Koki, Sumida Keiichi, Suwabe Tatsuya, Hayami Noriko, Ueno Toshiharu, Takaichi Kenmei, Fujii Takeshi, Ohashi Kenichi, Morisada Naoya, Iijima Kazumoto, Ubara Yoshifumi, Daughter and Mother with Orofaciodigital Syndrome Type 1 and Glomerulocystic Kidney Disease, Human Pathology (2016), doi: 10.1016/j.humpath.2016.04.005

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ACCEPTED MANUSCRIPT Daughter and Mother with Orofaciodigital Syndrome

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Takashi Iijima, MD,

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Keiichi Sumida, MD,

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Type 1 and Glomerulocystic Kidney Disease

Junichi Hoshino, MD, 1Koki Mise, MD,

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Fujii, MD,

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1+2

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Noriko Hayami,

Kenmei Takaichi, MD, 3Takeshi

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Toshiharu Ueno, MD, MD,

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Tatsuya Suwabe, MD,

Kenichi Ohashi, MD, 4Naoya Morisada, MD,

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1+2

Yoshifumi Ubara, MD

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Kazumoto Iijima, MD, and

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Nephrology Center, Toranomon Hospital Kajigaya, Kanagawa,

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Japan

Okinaka Memorial Institute for Medical Research and

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Department of Pathology, Toranomon Hospital, Tokyo, Japan Department of Pediatrics, Kobe University, Kobe, Japan

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Department of Pathology, Yokohama City University,

Graduate School of Medicine, Yokohama, Japan

Address for correspondence: Junichi Hoshino, MD, MPH Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, 20  20

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ACCEPTED MANUSCRIPT

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Short title: OFD 1 with glomerular cysts

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Kajigaya, Takatsu, Kawasaki, Kanagawa, 213-8587, Japan

Fax: 81-44-877-5333

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e-mail: [email protected]

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Phone: 81-44-877-5111

Key words: orofaciodigital syndrome type 1, glomerulocystic kidney disease, X-linked dominant

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inheritance, polycystic kidney disease

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Conflict of interest: The authors report no conflicts of

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interest.

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ACCEPTED MANUSCRIPT Abstract

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A 35-year-old woman was admitted to our hospital for

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evaluation of end-stage renal failure. Diagnostic imaging, including ultrasonography and MRI, showed polycystic

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kidneys and peribiliary hepatic cysts, but the renal cysts

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were isointense and her kidneys were smaller than the end-stage kidneys of patients with autosomal dominant polycystic kidney disease. Glomerulocystic kidney disease

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was diagnosed by renal biopsy. Clinical examination

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revealed findings such as a missing maxillary canine,

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lingual anomalies, and brachydactyly. Genetic testing gave a diagnosis of orofaciodigital syndrome type 1(OFD1) with

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5 oligonucleotide deletions indicating a frameshift mutation in exon 9. The patient’s mother had the same mutation and similar clinical findings. This case is useful for understanding kidney and liver involvement in OFD1.

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ACCEPTED MANUSCRIPT Introduction

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There are many causes of polycystic kidney disease

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other than autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease

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(ARPKD), including nephronophthisis, tuberous sclerosis,

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Caroli’s disease, and some types of glomerulocystic kidney disease (GCKD). Among them, GCKD was classified into five categories by Lennerz et al. [1]. Type 1 GCKD is a variant

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of ADPKD or ARPKD with glomerular cysts, while type 2 GCKD

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is a hereditary disease due to mutation of uromodullin,

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hepatocyte nuclear factor–1b (HNF1B), or other unspecified genes. Type 3 is defined as syndromic GCKD caused by

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various hereditary or acquired syndromes. Type 4 is due to urinary tract obstruction and type 5 is due to ischemia and/or drugs or other factors. Orofaciodigital syndrome type 1 is one of the type 3 GCKDs and has varying systemic manifestations [1]. The orofaciodigital syndromes (OFDs) are a group of at least 13 related conditions that affect development of the oral cavity (mouth and teeth), facial features, and 20  20

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ACCEPTED MANUSCRIPT digits (fingers and toes). OFD type 1 (OFD1) was first

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described by Papillon-Léage and Psaume in 1954. It is

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characterized by X-linked dominant inheritance, so almost all affected individuals are female. Renal involvement in

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OFD1 results in polycystic kidney disease [2]. The locus

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of OFD1 was first mapped by Feather et al., who used linkage analysis to identify a 19.8-cM interval in the Xp22 region flanked by crossovers with the markers DXS996

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and DXS7105 [3]. Ferrante et al. reported that analysis of

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familial cases of OFD1 revealed a missense mutation, a

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19-bp deletion, and a single base pair deletion leading to frameshift, while sporadic cases showed missense, nonsense,

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splice, and frameshift mutations [4]. The OFD1 gene is located on Xp22 and its product is related to formation of primary cilia and establishment of the left-right axis [5]. The relation between OFD1 and polycystic kidneys remains unclear [6-10]. We encountered a 35-year-old Japanese woman with clinical features of OFD1, including a missing maxillary canine, lingual anomalies, and brachydactyly, as well as 20  20

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ACCEPTED MANUSCRIPT polycystic kidney disease of the glomerulocystic type. The

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patient’s mother also had similar phenotypic

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characteristics. This report presents their imaging findings, renal histology, and gene analysis data, as well

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as discussing kidney involvement in OFD1.

Case presentation

In August 2013, a 35-year-old woman was admitted to

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our hospital for evaluation of end-stage renal failure.

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She had developed fatigue in March 2013, while dizziness,

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flu-like symptoms, and edema of the bilateral lower extremities were noted in May. At her local clinic, anemia

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(hemoglobin concentration: 6.6 g/dL) and renal dysfunction (serum creatinine: 10.2 mg/dl) were detected in June. Hemodialysis was started immediately, 2 units of red cell concentrate were transfused, iron and erythropoietin supplementation were initiated, and she was transferred to our hospital. On admission, the patient was 148 cm tall and weighed 41.3 kg. Her blood pressure was 118/73 mmHg. Her fingers 20  20

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ACCEPTED MANUSCRIPT (Figure 1a and 1b) and toes were short and she had mild

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edema of the lower legs. Her left maxillary canine was

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missing (Figure 1c). She had a history of frenotomy as an infant because of difficulty with nursing due to dense

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adhesions between the tongue and floor of the mouth.

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Laboratory parameters are shown in Table 1. There was mild anemia (hemoglobin concentration: 11.5 g/dL), hypoalbuminemia (serum albumin: 3.4 g/dL), elevation of

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serum urea nitrogen (85 mg/dL), and elevation of serum

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creatinine (10.2 mg/dL). Urinalysis showed moderate

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proteinuria (24-hr protein excretion: 1.2 g). Abdominal ultrasonography revealed numerous cysts in

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the bilateral kidneys and in the liver. The hepatic cysts were located parallel to the bile ducts (Figure 1d). MRI showed that both kidneys were largely replaced by isointense cysts and seemed smaller than ordinary end-stage kidneys of ADPKD patients (Figure 1e). Renal volume was calculated from MRI data using the formula for an ellipsoid (long axis × short axis × short axis × π/6), revealing that the left kidney volume was 427 cm3 20  20

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ACCEPTED MANUSCRIPT (12.1×5.4×6.4 cm) and the right kidney volume was 332 cm3

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(10.5×5.4×5.7 cm).

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Cystic kidney disease had previously been diagnosed in the patient’s mother, so she was also investigated. On

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examination, she had congenital absence of the right

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maxillary canine and her digits of both hands were short. The mother’s laboratory data are also shown in Table 1. Abdominal ultrasonography demonstrated peribiliary cysts

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in the liver, and MRI revealed numerous renal cysts

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similar to those in her daughter’s kidneys (Figure 1f).

Renal Biopsy

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Renal biopsy was performed because the time course of

renal failure was unknown. Of the 32 glomeruli in the biopsy specimens, 8 showed global sclerosis accompanied by severe interstitial fibrosis, tubular atrophy, and marked cellular infiltration. Several cystic lesions with thick fibrous walls and a flat epithelial lining were observed, and collapsed glomeruli with dilation of Bowman’s space and glomerular cysts could be seen around these cystic 20  20

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ACCEPTED MANUSCRIPT lesions. A few dilated proximal tubules with thickened

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basement membrane were noted, but dilation of distal

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tubules and collecting ducts was not observed. The residual glomeruli were intact. Based on these findings,

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the cystic lesions were considered to have originated from

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glomerular cysts (Figure 2a). Immunofluorescence microscopy and electron microscopy did not detect any immune deposits.

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Her mother had also previously undergone renal biopsy

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for diagnosis. The biopsy specimens contained 27 glomeruli,

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and all of them showed global sclerosis with severe interstitial fibrosis, tubular atrophy, and inflammatory

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cell infiltration. Some small cystic lesions with thick fibrous walls and flat epithelial lining were also noted, which resembled her daughter’s cystic lesions, but no glomerular cysts associated with collapsed glomeruli were found (Figure 2b).

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ACCEPTED MANUSCRIPT Gene analysis

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Because of the characteristic findings revealed by

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renal biopsy and the presence of brachydactyly, we considered analysis of several genes related to glomerular

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cysts. Among them, the OFD1 gene was the most plausible

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candidate because the patient’s history of frenotomy and her mother’s renal cystic disease were considered to suggest an X-linked systemic condition.

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We performed genetic analysis after obtaining written

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informed consent from the proband and her mother. All

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procedures were reviewed and approved by the Institutional Review Board of Kobe University School of Medicine and

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were in accordance with the ethical standards of the 1964 Declaration of Helsinki. Genomic DNA was extracted from peripheral blood mononuclear cells using a QuickGene whole blood kit S (Kurabo, Osaka, Japan) according to the manufacturer’s instructions. Twenty-two pairs of oligonucleotide primers were generated to amplify all 23 coding exons of OFD1. Then the polymerase chain reaction (PCR) was performed and the products were purified with a 20  20

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ACCEPTED MANUSCRIPT DNA purification kit (Qiagen Japan, Tokyo, Japan),

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followed by direct sequencing with a 3100 Genetic Analyzer

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(Life Technologies Japan, Tokyo, Japan). Sequence alignment was performed with CLC Main Workbench software

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(CLC-bio, Aarhus, Denmark). In both the proband and her

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mother, we identified 5 oligonucleotide deletions indicating a heterozygous frameshift mutation in exon 9 [NM_003611.2 (OFD1): c.840_844delAGAAA (p.Lys280AsnfsX27)],

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consistent with the genotype of OFD1 (Figure 2c). This

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mutation was considered to be causative in both patients.

Discussion

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Patients with OFD1 can develop polycystic kidney disease. Renal cysts are considered to arise from both the tubules and glomeruli, although previous reports have not provided sufficient information about the mechanism of renal involvement. There have been 3 reports about the incidence of polycystic kidneys in OFD1. Saal et al. investigated renal findings in 34 females with pathogenic mutation of the OFD1 gene. Polycystic kidneys were 20  20

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ACCEPTED MANUSCRIPT diagnosed in 12 patients by ultrasonography, while 10

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patients presented with renal impairment and 6 received

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kidney transplantation. The probability of developing renal failure was estimated as greater than 50% after the

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age of 36 years. While their data revealed a high

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incidence of renal impairment in OFD1 syndrome, they could not find any genotype-phenotype correlation that was predictive of renal failure [6].

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Bisschoff et al. studied 55 sporadic and six

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familial cases of suspected OFD-1. Comprehensive gene

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analysis revealed mutations in 37 women from 30 families. They also found cystic kidney diseases in 6 out of 23

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patients investigated (26.1%), but the details were not reported [7]. Prattichizzo et al. performed mutation analysis in a cohort of 100 unrelated affected individuals collected worldwide with a clinical diagnosis of OFDI syndrome. Most of the probands were from Europe (65%) and North America (21%), followed by Australia (6%), the Middle East (5%), and Asia (3%). Cystic kidney disease was 20  20

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ACCEPTED MANUSCRIPT demonstrated by renal scans in 24 out of 81 patients

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tested (29.6%). Renal cystic disease is present in 15 out

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of 25 patients (60%) >18 years old who were examined [8]. According to our literature search, there are only

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two case reports showing the development of renal cysts

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from the glomeruli in OFD1 patients. Feather et al. performed histological examination at autopsy of a woman in her 50s who had end-stage renal failure and polycystic

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kidneys with cysts < 1 cm in diameter. Cysts were not

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noted in any of her other organs. Most of the renal cysts

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were lined by flat epithelium and had fibrotic walls. Glomerular tufts were detected in the cyst lining and many

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of the tufts within cysts contained open capillary loops. Mildly dilated tubules up to 100–200 mm in size were also noted [3]. Stapleton reported an 11-year-old girl with OFD1 who underwent bilateral nephrectomy prior to renal transplantation. Examination of the resected kidneys showed that the cortex was largely replaced by numerous cysts lined by flattened epithelium, many of which contained glomerular tufts [9]. 20  20

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ACCEPTED MANUSCRIPT The imaging characteristics of renal cysts were

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reported by Scolari in two generations of a family with

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OFD1 (mother and daughter). CT of the abdomen revealed polycystic kidneys in both patients. Renal cysts were more

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numerous and smaller in the two OFD1 patients compared

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with those in ADPKD patients, and their kidneys showed less enlargement without gross deformity of the renal contour [10].

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Similarly, there have only been a few reports about

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hepatic cysts in patients with OFD1. Scolari reported the

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coexistence of multiple liver and pancreatic cysts in OFD1, with the liver containing peribiliary cysts along the

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principal branches of the biliary tree [10]. Topra reported a 20-year-old woman with polycystic kidneys and end-stage renal disease, who was diagnosed as having coexistence of OFD1 and Caroli’s disease [11]. Thus, it seems that hepatic cysts may be a rare manifestation of OFD1. OFD1 needs to be differentiated from "acquired cystic disease (ACD)" in ESRD patients. ACD can be diagnosed in 20  20

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ACCEPTED MANUSCRIPT patients on dialysis for more than 4 years. It features

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multiple cystic lesions that mainly originate from the

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proximal tubules and exist throughout cortex and medulla, along with intracystic hemorrhage and calcium oxalate

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crystal deposition (12).

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In conclusion, we encountered a 35-year-old woman with clinical features of OFD1 (missing maxillary canine, lingual anomalies, and brachydactyly) and polycystic

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kidney disease. Her mother also had similar clinical

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characteristics. In both women, gene analysis revealed 5

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oligonucleotide deletions of a frameshift mutation in exon 9, which was consistent with the diagnosis of OFD1. MRI

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showed that their kidneys contained isointense cysts and were smaller than the end-stage kidneys of ADPKD patients, while peribiliary cysts were noted in the livers of both women. Renal biopsy showed glomerulocystic polycystic kidney disease. This case suggests that OFD1 may be a possible alternative diagnosis in women with polycystic kidney disease and smaller cysts. Further clinical information about renal involvement in OFD1 may be 20  20

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obtained from detailed case series.

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ACCEPTED MANUSCRIPT References

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[1] Lennerz JK1, Spence DC, Iskandar SS, Dehner LP, Liapis

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H. Glomerulocystic kidney: one hundred-year perspective. Arch Pathol Lab Med 2010;134:583-605.

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[2] Toriello HV. Oral-facial-digital syndromes, Clin

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Dysmorphol 1993;2:95-105.

[3] Feather SA, Winyard PJ, Dodd S, Woolf AS. Oral-facial-digital syndrome type 1 is another dominant

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polycystic kidney disease: clinical, radiological and Nephrol

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histopathological features of a new kindred.

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Dial Transplant 1997;12:1354-61. [4] Ferrante MI1, Giorgio G, Feather SA et al.

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Identification of the gene for oral-facial-digital type I syndrome. Am J Hum Genet 2001;68:569-76. [5] Ferrante MI1, Zullo A, Barra A et al. Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification. Nat Genet 2006;38:112-7. [6] Saal S1, Faivre L, Aral B et al. Renal insufficiency, a frequent complication with age in oral-facial-digital 20  20

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ACCEPTED MANUSCRIPT syndrome type I. Clin Genet 2010;77:258-65.

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[7] Bisschoff IJ1, Zeschnigk C, Horn D et al. Novel

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mutations including deletions of the entire OFD1 gene in 30 families with type 1 orofaciodigital syndrome: a study

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of the extensive clinical variability. Hum Mutat

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2013;34:237-47.

[8] Prattichizzo C , Macca M, Novelli V, Giorgio G, Barra A, Franco B; Oral-Facial-Digital Type I (OFDI),

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Collaborative Group. Mutational spectrum of the

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oral-facial-digital type I syndrome: a study on a large

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collection of patients. Hum Mutat 2008;29:1237-46. [9] Stapleton FB, Bernstein J, Koh G, Roy S 3rd, Wilroy RS.

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Cystic kidneys in a patient with oral-facial-digital syndrome type I. Am J Kidney Dis 1982;1:288-93. [10] Scolari F1, Valzorio B, Carli O et al. Oral-facial-digital syndrome type I: an unusual cause of hereditary cystic kidney disease. Nephrol Dial Transplant 1997;12:1247-50. [11] Toprak O1, Uzum A, Cirit M et al. Franco B.Oral-facial-digital syndrome type 1, Caroli's disease 20  20

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ACCEPTED MANUSCRIPT and cystic renal disease. Nephrol Dial Transplant

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2006;21:1705-9.

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[12] Chang A, Vasilyev A. Acquired cystic disease. In: Chang A, Kambham N, Meehan AM, et al. Diagnostic pathology,

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Kidney Diseases; First edition. Amirsys Inc., 2011, Canada,

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pp 6.65-68

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ACCEPTED MANUSCRIPT ACKNOWLEDGEMENT

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This study was funded by the Okinaka Memorial

Figure legends

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1: Clinical and imaging finding

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Institute for Medical Research.

(a+b) The patient has short fingers (brachydactyly). (c) The left maxillary canine is missing (arrow).

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(d) Abdominal ultrasonography reveals hepatic cysts

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parallel to the bile ducts (peribiliary cysts) (arrows).

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(e) MRI shows that both kidneys (arrows) are largely replaced by isointense cysts and are smaller than the

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end-stage kidneys of ADPKD patients. (f) MRI also reveals numerous cysts in the mother’s kidneys (arrows). 2: Renal biopsy finding (a) Several cystic lesions with thick fibrous walls and flat epithelial lining were observed, and collapsed glomeruli with dilation of Bowman’s space and glomerular cysts (arrows) were seen around the cystic lesions. In 20  20

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ACCEPTED MANUSCRIPT some of the glomerular cysts, Bowman's capsule was

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connected to the cystic lesions. A few dilated proximal

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tubules with thickened basement membrane (large arrow)

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were noted.

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(b) The mother had similar cystic lesions (arrow) to those of her daughter. However, no glomerular cysts associated

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with collapsed glomeruli could be detected.

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(c) Gene analysis revealed 5 oligonucleotide deletions,

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indicating a frameshift mutation in exon 9 [NM_003611.2 (OFD1): c.840_844delAGAAA (p.Lys280AsnfsX27)], which was

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consistent with the genotype of OFD1.

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ACCEPTED MANUSCRIPT Table 1: Laboratory data of the patient and her mother. Moth er

Hematology 6700

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White blood cells

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hter

Normal

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Daug

11.5

167

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and Unit

3200-790 0 /mL

11.2

11.3-15. 0 g/dL

166

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Platelet count

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Hemoglobin

6000

Limit

155-350 x103/mL

Serum chemistry

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Total protein

6.3

7.7

6.7 -8.3 g/dl

Albumin

3.4

4.0

4.0 -5.0 g/dl

Aspartate

9

14

13-33

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ACCEPTED MANUSCRIPT aminotransferase

IU/L 12

12

170

gamma-glutamyltransfer

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ase

289

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Alkaline phosphatase

184

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Lactate dehydrogenase

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aminotransferase

15

85

239

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Uric acid

119-229 IU/L I8-42

10-46 IU/L

39

8-22 mg/dL

10.2

4.6

0.60.8

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Creatinine

IU/L

U/L

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Urea nitrogen

8-42

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Alanine

mg/dL 7.9

3.8

3.67.0 mg/dL

Sodium

138

144

135-145 mmol/L

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ACCEPTED MANUSCRIPT Potassium

5.2

4.7

3,5-

106

8.3

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Calcium

110

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Chloride

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4.9

5.3

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Ferritin

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C-reactive protein

Immunoglobulin G

96-108 mmol/L 8.7-10. 1 mg/dL

4.6

2.8 -4.6

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Phosphate

8.9

mmol/L

mg/dL 0.0

0.0

<0.3 mg/dL

120

19

<12.0 µg/L

937

1235

870-170 0 mg/dL

Immunoglobulin A

139.6

155.4

110-410 mg/dL

Immunoglobulin M

130.7

87

30-190

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tive

tive

1 to

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5 White blood cells

<1

1.2

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Protein excretion

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alpha-1 microglobulin

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beta-2 microglobulin

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M ptotein

<1

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Urinary analyses Red blood cells

1 to

/HPF

/HPF

4 0.63

103.1 49179

<40

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nega

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Antinuclear antibody

g/day g/day

56645

30-370 μ g/day

nega tive

negativ e

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25

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CE

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ED

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ED

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ED

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