Hong-Wen Zhang, Bai-Ge Su, Yong Yao

Hong-Wen Zhang, Bai-Ge Su, Yong Yao, Department of Pediatrics, Peking University First Hospital, Beijing 100034, China

Abstract

Key words: Renal failure; Polycystic kidney disease; OFD1 mutation; China; Case report

INTRODUCTION

The humanOFD1gene is composed of 23 densely packed exons spanning about 35.59 kb of genomic DNA and maps to chromosome band Xp22.2.The OFD1 protein is located within the centrosomes and basal bodies of the primary cilia.Oral-facialdigital syndrome type 1 (OFD1) is caused byOFD1mutations with an X-linked dominant pattern of inheritance[1,2].It is reported that approximately 15%-50% cases of OFD1 progress to end-stage renal disease (ESRD) following the development of polycystic kidney diseases (PKD[3].The phenotypic spectrum associated withOFD1mutations has been recently extended with an X-linked recessive pattern of inheritance, such as Joubert syndrome type 10, mental retardation with macrocephaly,Simpson-Golabi-Behmel syndrome type 2, retinitis pigmentosa and so on[4-6].

There has been a report onOFD1mutation with an atypical presentation with ESRD without evidence of PKD[7].However, there has been no report on ESRD without any other phenotypes except PKD caused by anOFD1mutation.Here, we report a pair of childhood male twins with anOFD1mutation who presented ESRD and PKD but without any other phenotypes.

CASE PRESENTATION

Chief complaints

A pair of 14-year male twins were hospitalized with a complaint of abnormal renal function for nine days.

History of present illness

They both complained of ankle pain for 3 movs2 wk, respectively.They denied fever,abdominal pain, daytime or nighttime enuresis, urgency, dysuria, or hematuria.Laboratory tests at a local hospital showed renal failure (serum creatinine 485 μmol/Lvs442 μmol/L, blood urea nitrogen 14.7 mol/Lvs14.5 mol/L) and anemia(hemoglobin 88 g/Lvs98 g/L).

History of past illness

The twins are monozygotic.There was no abnormal birth, past medical, or family history.There was no family history of renal failure or PKD on their maternal side.

Physical examination

At admission, their blood pressure, weight, and height were all normal.Their physical examination showed no abnormal signs, especially no abnormal dysmorphic features.No neurodevelopmental or ophthalmologic deficits were observed.

Laboratory examinations

Laboratory tests at our hospital revealed Scr 433-486 μmol/Lvs382-425 μmol/L, BUN 20.2-24.4 mmol/Lvs17.1-19.9 mmol/L, serum calcium 1.39-1.80 mmol/Lvs1.62-1.80 mmol/L, serum phosphate 1.42-1.72 mmol/Lvs1.43-1.80 mmol/L, HCO3-23.6-26.1 mmol/Lvs23.0-26.3 mmol/L, intact parathyroid hormone 248.7-327.7 pg/mLvs256.2-298.5 pg/mL, hemoglobin 92-101 g/Lvs97-110 g/L, proteinuria 27.4 mg/kg per 24 hvs25.3 mg/kg per 24 h, urine specific gravity 1.008-1.010vs1.007-1.010, urine microalbumin 291 mg/Lvs128 mg/L, urine α1-microglobin 194 mg/Lvs180 mg/L,and low-molecular-weight proteinuria 35.7%vs42.1% in urine protein electrophoresis.Autoimmune profile was within the normal range, including antinuclear antibody, anti-double-stranded DNA antibody, complements C3and C4, and anti-neutrophil cytoplasmic antibodies (Table 1).

Imaging examinations

Ultrasonography and magnetic resonance imaging (MRI) showed that the renal body was small (7.3-7.5 cmvs7.2-7.6 cm in length and 3.7-3.8 cmvs3.5-3.8 cm in width), the border of the cortex and medulla was not clear, polycystic lesions were seen in both kidneys of the twins, and cysts were irregularly distributed and located within the cortex and the medulla.No cysts were found in the liver or pancreas.Brain MRI showed no abnormal findings.

FINAL DIAGNOSIS

Due to the presence of abnormal renal function, polycystic kidney diseases, and genetic history, an inherited renal cystic disease was suspected.

TREATMENT

Genetic analysis was performed using next generation sequencing[8]in the genetics laboratories of MyGenostics biotechnology companies in China, using “the polycystic kidney diseases panel” which covers genes strongly correlated with this disorder[9,10].The results showed that both the twins carried a hemizygous mutation in exon 19 c.2524G＞A (p.G842R) in theOFD1gene (Figure 1).Their mother heterozygously carried the same mutation as the twins.But the mother showed no anemia,proteinuria, or hematuria, and her renal function was normal.Neither polycystic lesions nor abnormal dysmorphic features were seen in her kidneys.X-inactivation was not analyzed in the mother.The mutation was found in the SNP databases(rs146047094, A = 0.0011/4, 0.007/65, and 0.006/6 in 1000Genomes, ExAC, and GOESP, respectively), but only found in females (18 homozygous and 29 heterozygous in ExAC, 2 heterozygous in 1000Genomes).Mutation testing analysis showed that amino acid sequence was changed and protein features (might be) affected.PolyPhen-2 and SIFT analysis showed that the mutation might be healthy or tolerated.However, it was not found in 100 normal Chinese controls.No variations were found inPKD1,PKD2,PKHD1,NPHPn(n= 1-18, 1 L and 2 L), or other related genes.

OUTCOME AND FOLLOW-UP

Within a follow-up period of 12 mo, renal functions of the twins continued to decline rapidly (Scr 589 μmol/Lvs564 μmol/L, BUN 28.2 mol/Lvs26.6 mol/L).Due to symptomatic uremia, they started on peritoneal dialysis and waited for transplant from appropriate living donors.

DISCUSSION

OFD1 is a rare ciliopathy with an X-linked dominant pattern of inheritance which involves multiple organs including the kidneys, tongue, nasal mucosa, oral mucosa,cranial cartilage, brain, and limbs[11].The incidence of OFD1 is 1/50000-1/250000 live births[12,13].PKD is the most common renal involvement[14].There is also a report ofOFD1mutation in a Chinese boy with Joubert syndrome[15].However, atypical presentation of OFD1 and ESRD caused byOFD1mutations without typical polycystic changes were also reported[7].

As for our twins, they both presented with low-molecular-weight proteinuria,hyposthenuria, anemia, renal failure, and renal polycystic changes, suggesting that they had an inherited renal cystic disease.Genetic tests showed that the twins both carried a hemizygous mutation in exon 19 c.2524G＞A (p.G842R) of theOFD1gene.The mutation was found in the SNP databases (ExAC, GO-ESP, and 1000Genomes)but only homozygous or heterozygous in females but not in males.Mutation testing analysis showed changed amino acid sequence and affected protein features (might be), and SIFT and PolyPhen-2 analysis showed that the mutation might be healthy ortolerated.Because no variations were found inPKD1,PKD2,PKHD1,NPHPn, or other related genes in our twins, and the mutation was not found in 100 normal controls in China, we suggested that it might be the genetic cause of our twins with an X-linked recessive pattern of inheritance.The mother heterozygously carried the same mutation as the twins but had no anemia, proteinuria, hematuria, abnormal dysmorphic features and her renal function was normal.Furthermore, our twins presented no malformation of the hands, feet, face, or oral cavity.And no CNS involvement was found.To our knowledge, these are the first two pediatric patients with anOFD1mutation that presented with renal failure and PKD with an X-linked recessive pattern of inheritance, without classic oral, facial, or digital features.However, it was a pity that we did not analyze fibroblasts from our twins to verify whether the p.G842R mutation affects cilia formation.Xianget al[16]reported a fetus with Joubert Syndrome terminated at 29+4wk of gestation, in which genetic analysis showed the c.2524G＞A (p.G842R) in theOFD1gene, and two compound heterozygous variants in theC5orf42gene (c.3599C＞T, p.A1200V in exon 20 and c.3857G＞A, p.R1286H in exon 22).They speculated that the later might be responsible for the disorder of the fetus because the 36-year-old normal father also carried the c.2524G＞A (p.G842R) in theOFD1gene.But it is a pity that there was no information on renal function and imaging examination of the father.The pathogenicity of c.2524G＞A (p.G842R) in theOFD1gene needs further studies especially in males in the future.

Table 1 Main clinical features of the twins

Figure 1 Genetic analysis of the OFD1 gene.

PKD affects approximately 15%-50% cases of OFD1 who have a higher likelihood of developing renal failure while those without PKD have normal renal function[1,11,14].Cystic changes can occur at any time point and are distributed and located irregularly within the cortex and the medulla.They are variable in size, multilocular, and thinwalled and contain serous fluid[17,18].These features are similar to those of our twins.The kidney size is normal or palpably large, but they maintain their reniform shape with minimal changes of renal contour[14].However, it is interesting that the kidneys of our twins were small in size, which is similar to the report of Sharmaet al[7], in which a boy aged 10 years and 6 mo with renal failure but without renal cystic changes had small kidneys (the right kidney 6.6 cm and the left kidney 7.8 cm)detected by renal ultrasound.Furthermore, it seems that the renal size can be small,normal, or large in PKD caused byOFD1mutations, the same as other renal cystic ciliopathies[19-21].

There were no different features between our monozygotic twins with the sameOFD1mutation.As for renal manifestations, our twins both presented low-molecularweight proteinuria, besides hyposthenuria, renal failure, and polycystic changes in the kidneys but without microscopic hematuria.This was contrary to other reports thatPKDcaused byOFD1mutations mainly presented with microscopic hematuria but no proteinuria[7,11].

CONCLUSION

We present a pair of twins with anOFD1mutation inherited in an X-linked recessive fashion.These are the first two childhood patients reported with this condition, who presented only renal failure and cystic kidneys but without classic oral, facial, or digital features of OFD1.Based on this unusual presentation, maybe the phenotypic spectrum ofOFD1-associated disorders is broader than previously anticipate.We suggest thatOFD1screening should be considered, especially in males, if the suspicion for ciliopathy remains high in patients with renal failure and polycystic changes.