Papillorenal Syndrome after Beta-Interferon Treatment in Pregnancy

Abstract

Papillo-Renal Syndrome (PRS, or Renal-Coloboma Syndrome) is an autosomal dominant disorder, characterized by colobomatous eye defects, abnormal vascular pattern of the optic disk, renal hypoplasia, vesicoureteral reflux, high-frequency hearing loss, and sometimes central nervous system (CNS) abnormalities. The syndrome is associated with mutations in the PAX2 gene. This 11-year-old girl's mother was treated with beta-interferon (IFNβ-1a) for multiple sclerosis (MS) during the pregnancy. The child failed to thrive in infancy and early childhood. The multicystic renal dystrophy, hypoplastic right kidney, and vesico-ureteral reflux (II–III grade) were diagnosed by ultrasound and radionucleotide renal scan. Subsequently, a morning glory anomaly and coloboma of the optic disc was discovered. Renal failure progressively followed. MRI of the head revealed a cyst of the right optic nerve. Genetic analysis revealed a mutation of the PAX2 gene (619 insG). The multicystic renal dystrophy and a cyst of the optic nerve in association with PRS syndrome have only rarely been described. The fact that this PRS patient stemmed from a pregnancy under beta-interferon treatment raises the question whether IFNβ-1a treatment during pregnancy has influenced the manifestation or the severity of the PAX2 mutant phenotype in this child.

Keywords:

• Papillo-Renal Syndrome
• beta-interferon treatment
• pregnancy
• multicystic renal dysplasia
• ophthalmic cyst

INTRODUCTION

The PAX2 gene is mutated in patients with ocular colobomas and kidney anomalies (papillo-renal syndrome, OMIM 120330). PAX2 encodes a transcription factor of the paired box class of DNA binding proteins. The gene is important for the development of the urogenital tract, optic nerve and adjacent retina, inner ear, and CNS. Because PAX2 mutations are not detected in patients with ocular colobomas, either in isolation or with associated abnormalities, except in patients with typical papillo-renal syndrome, PAX2 is considered to be the etiological cause of PRS. The diagnosis is typically made when renal disease is evident. The morphology of the optic disc allows an early diagnosis.[1]

There are limited data on pregnancy outcomes in women with MS receiving beta interferon during pregnancy.[2] Experiments in animals demonstrated that high doses were not teratogenic. So far, interferon administered prenatally was not shown to be teratogenic in humans. Nevertheless, it is recommended that interferon should be discontinued prior to initiating the pregnancy.[3]

CASE REPORT

The patient is an 11-year-old girl, the third child in the family. She was conceived at the mother's age of 24 years, who was treated with interferon beta for multiple sclerosis in the first trimester of her pregnancy. There was no use of tobacco, alcohol, over-the-counter drugs, or recreational drugs. There were no previous miscarriages. The proband was born after a pregnancy of 40 weeks with an uneventful vaginal delivery. Birth weight and length were normal, but exact measures are not available. The mother died at age of 26 years of causes related to MS (exact cause of death unavailable). TORCH was normal. The child was breastfed for the first three months. A small atrial septal defect was discovered after birth that spontaneously closed in the next couple of years. The skin is soft, and there is joint hypermobility. An ultrasound revealed left multicystic dysplastic kidney prenatally. It was also seen postnatally, but at the age of five years, the cysts resolved spontaneously. The right kidney is hypoplastic (see Figure 1). In addition, bilateral vesicoureteral reflux grade II–III was discovered. The diagnosis was confirmed by ultrasound and radionuclide scan. A chronic renal insufficiency installed (creatinine 129 micromol/L, clearance 58 mL/min/1.73m²). A renal biopsy was not performed.

Figure 1. Ultrasound of the kidneys: hypoplastic right kidney and multicystic left kidney.

The child has right esotropia, horizontal nystagmus and bilateral microphthalmos. An eye examination revealed partial coloboma, normal visual acuity, central optic disc excavation, multiple cilioretinal arteries, and circumscribed hypopigmented patch temporally. The left disk resembled a morning glory disk anomaly. Eye examination revealed bilateral foveal aplasia. TORCH serology was normal. The growth, intelligence, and hearing are normal. MRI of the brain and orbits demonstrated right orbital retrobulbar cystic mass (see Figure 2).

Figure 2. CT of the brain: right retroorbital cyst (sagital and transversal section).

The parents' DNA was not available. Informed consent was obtained prior to the DNA analysis. DNA screening was performed by direct sequencing. Mutational analysis revealed that a child is heterozygous with a mutation of the exon 2 of the PAX2 gene: 619 insG.

DISCUSSION

Papillo-renal syndrome (PRS; OMIM 120330) is an autosomal dominant disorder characterized by renal abnormalities and optic nerve defects.[4,5] Although PRS involves both ocular and renal anomalies, some patients are affected with vesico-ureteral reflux (VUR), high-frequency hearing loss, CNS anomalies (e.g., seizures, Arnold-Chiari malformation), and/or genital anomalies, consistent with the expression of PAX2 in these tissues during development.[6]

The PAX gene family comprises nine members and has an important role in mammalian development. The paired box transcription factor PAX2 plays a fundamental role in renal development. Heterozygous PAX2 mutants in mice are characterized by renal hypoplasia and retinal defects. In humans, PAX2 mutations have been described in the renal-coloboma syndrome. The majority of the mutations were insertions and deletions resulting in frameshift with a premature stop codon.[5,7–10] Therefore, the result is a haploinsufficiency of the functional PAX2 proteins in the process of development. It seems that heterozygous mutations of PAX2 are associated with increased apoptosis and reduced branching of the uteric bud, stemming from the reduction in PAX2 gene dosage during a critical period in the development of the kidneys.[11] The exon 2 of PAX2 is particularly prone to mutations, especially its sequence of seven Gs.[12] The most common PAX2 mutation, found also in this presented patient, is a G619-insertion mutation within a string of seven guanidines in exon 2.

The case presented in this article has a prominent renal history with the initial renal presentation of multicystic renal hypoplasia, with cysts disappearing on the subsequent ultrasound examinations. In addition, the child was found to have vesicoureteral reflux. Renal hypodysplasia is characterized by a reduced nephron number, small kidney size, and disorganized renal tissue. Weber et al.[13] found four different PAX2 mutations in six families. They also found a SIX1 sequence variant in two siblings with renal-coloboma syndrome as a result of a PAX2 mutation, suggesting an oligogenic inheritance. Interestingly PAX2 mutation has been also found in a isolated renal hypoplasia.[14]

Unilateral renal agenesis has been reported in two patients.[15,16] The case of Weaver et al.[15] was not recognized as PRS at the time of publication, but it obviously fits the frame of PRS. The case of Amiel et al.[16] had an n.832 del G PAX2 mutation, while the father of the proband had a less severe phenotype with renal insufficiency and reduced kidney size.

Multicystic dysplastic kidney has rarely been described in PRS.[17] A variable phenotype across three generations with a heterozygous 10-bp deletion in exon 2 of the PAX2 gene leading to a truncating mutation was reported. The authors suggested that PAX2 may play a role in early ureteric obstruction and subsequent renal maldevelopment.[17]

Oligomeganephronia, a rare congenital and usually sporadic anomaly, was also described in PRS.[18] It is characterized by bilateral renal hypoplasia, with a reduced number of enlarged nephrons. A limited optic nerve coloboma, a mild optic disk dysplasia in one patient, and no visual impairment in any of them were also reported.

Ocular defects in PRS include optic nerve head coloboma, optic disc pit, optic disc dysplasia, orbital cysts, and chorioretinal colobomas.[19] Serous retinal detachments were also described.[20] There is a great variation in the severity of those defects and their impact on visual acuity. Moreover, the degree of severity varies in patients with same mutation.

Optic nerve coloboma, found in PRS, is also present in Goltz's focal dermal hypoplasia, Rubinstein-Taybi syndrome, CHARGE association, COACH syndrome, Aicardi syndrome, and Walker-Warburg syndrome. Acro-renal-ocular syndrome can be presented with optic disc coloboma and renal disease, but can be easily discerned from PRS by the presence of polydactyly or thumb hypoplasia.

Optic nerve cyst was also described.[21] The authors reported a 47-year-old patient with two optic disk pits and an optic nerve cyst in the same eye. This well-circumscribed round cystic lesion compressed and displaced the nerve. This presented case also has a round cystic lesion on the left optical nerve, but no impaired vision.

Beta interferon (IFNβ-1a) during pregnancy in animals heightens the abortion rate. This information was the basis for the recommendation for a cessation of interferon treatment during pregnancy in humans. In contrast to this recommendation, only 15% of premature births, and one child with congenital anomaly (hydrocephalus), were reported among 69 MS pregnant patients.[22] The majority of women who chose to continue the pregnancies despite receiving interferon beta had favorable outcomes. It seems that the large molecular size of IFN preventing the transit across the placental barrier is chiefly responsible for the absence of major impact of IFN on pregnancy.[23] In contrast, a higher rate of miscarriages and stillbirths has been reported (39% vs. 5% in healthy controls).[24] The authors reported one case of Down syndrome (aborted electively after the prenatal diagnosis) and one anomaly of the X chromosome (spontaneous abortion).

At this moment, it is not possible to discern whether the PRS in this patient is linked to the eventual mutagenic effect of IFNβ-1a or to the parental disease itself, or if its occurrence is pure coincidence.

DECLARATION OF INTEREST

The authors of this manuscript do not have any conflict of interest. No funding was received.