Fetal death associated with diffuse mesangial sclerosis combined with bilateral multicystic kidney

Introduction

The improvement of antenatal diagnostic techniques has led to an increasing number of children being diagnosed with kidney disease. However, differential diagnosis is sometimes difficult and both the short- and long-term prognoses as well as the counseling of parents are subjected to a great deal of uncertainty.

Renal dysplasia with cysts is a common finding on prenatal ultrasound examination as a cause of abnormally enlarged kidney; its frequency is as high as 1:1000 in the general population [21].

On ultrasonography, renal dysplasia typically presents as numerous cysts of various sizes with a reduced parenchyma and may be explained by an abnormal induction of metanephric blastema by the migrating ureteric bud [4]. The subsequent cystic dilatation of the dysplastic tissue is believed to compress and permanently damage the normal renal tissue.

We report here the highly unusual case of a fetus having diffuse mesangial sclerosis combined with bilateral cystic and dysplastic kidney which caused us considerable interpretive difficulties.

Diffuse mesangial sclerosis (DMS) is a rare histological feature associated with the onset of a nephrotic syndrome [3], often progressing to kidney failure which occurs either in isolation or as a feature of a number of syndromes [2, 15, 22]. In DMS, the glomerular lesions are characterized by increased fibrils in the mesangial matrix without mesangial cell proliferation [2], whereas the capillary walls are lined by hypertrophic podocytes [4].

Case report

A 36-year-old secundigravida was referred on the 28^th week for fetal renal evaluation.

The family history was positive for a duplicated collecting system with megaureter in a second cousin, a known disorder belonging to CAKUT (congenital anomalies of the kidney and urinary tract).

The patient had a normal pregnancy to 12 weeks of gestation when she was admitted for a vesical globe.

On the 16^th week, the patient underwent amniocentesis for karyotype analysis because of advanced maternal age. Cytogenetic analysis revealed normal male karyotype.

At the first ultrasound examination at 28⁺² weeks performed in our unit, fetal growth was regular, bilateral dysplastic kidneys with multiple cysts and anhydramnios were described.

Fetal echocardiography result was normal. The follow-up visits at 34⁺², 35⁺² and 37⁺¹ weeks showed progressive kidney enlargement without placental enlargement. At 37⁺¹ weeks, no fetal heartbeat could be detected and delivery was induced.

Findings at different stages of pregnancy and the progression of the disease from normal kidneys (16 weeks) to the fetal demise (37⁺¹ weeks) are summarized in Table 1, and Figure 1 shows the ultrasound result at 34⁺² weeks.

Figure 1

Antenatal ultrasound at 34⁺² weeks showing bilateral, enlarged, cystic kidneys filling the fetal abdomen. (A) Right kidney shows a 19.7-mm cyst. (B) Left kidney shows cysts with a maximum diameter of 33.23 mm.

At autopsy, on gross examination, the fetus (weight 2655 g) had diffuse areas of disepithelization, anhydramnios sequence with biparietal cephalohematoma and features of Potter’s facies that include prominent V-shaped epicanthic folds covering the inner canthus, flattening of the bridge of the nose with a turned down tip, a receding chin with a prominent depression below the lower lip, and low-set ears. Head circumference was 33 cm. Abdominal circumference was 30 cm. Pulmonary hypoplasia was present, and no congenital heart defects were detected. The kidneys were enlarged. Renal parenchyma showed multiple cysts with fibrous walls of various sizes, between 3 and 70 mm, mainly in the cortex (Figure 2). The medulla was slightly fibrotic and edematous. Early signs of renal obstructive dysplasia and arteriolar hypertrophy were found in the cortex.

Figure 2

Fetus autopsy shows markedly enlarged and asymmetric kidney, with multiple cysts of various sizes. Kidneys dimensions: left 9×5×2.5 cm, right 6×4.5×2.5 cm.

On microscopic examination, diffuse mesangial sclerosis was found (Figure 3).

Figure 3

(A) Renal cortex: the glomerulus shows an increase in mesangium and eosinophilic amorphous material between the blood capillaries [hematoxylin and eosin stain (H&E), 40×]. (B) Renal medulla: depletion of the tubules, increased intertubular stroma and edema (H&E, 10×). (C) Renal cortex: initial deposit of periodic acid-Schiff (PAS)-positive material in the renal glomeruli (PAS stain; 40×). (D) Renal cortex: subtotal sclerosis of the glomerulus, partly replaced by PAS-positive amorphous material. The same material is present in the renal tubules (PAS stain; 40×). (E) Renal cortex: intra-parenchymatous artery with wall hypertrophy (Masson’s trichrome stain, 40×). (F) Renal cortex: diffuse subtotal and advanced sclerosis of the glomeruli, partly replaced by fibrous amorphous material (Masson’s trichrome stain, 20×).

The liver and biliary tract were normal. No other relevant abnormalities were identified.

Genetic counseling to the family, in collaboration with the pediatric nephrologist, offered after the fetal demise, was helpful to elucidate fetal pathology and to communicate that a precise reproductive risk was impossible to define. An empirical increased risk was provided.

Discussion

Diffuse mesangial sclerosis (DMS) is a rare condition, probably with heterogeneous etiology [19], which is hereditary in some families [8], and it is a phenotypic expression of syndromic entities such as WAGR syndrome (Wilms’ tumor, aniridia, genitourinary anomalies and mental retardation) [20], Denys-Drash syndrome [13], Pierson syndrome [9], Frasier syndrome [5] and Galloway-Mowat syndrome [7].

The pathogenesis of DMS is unknown: a primary defect involving epithelial cells or one of the components of the glomerular extracellular matrix has been proposed [4].

Typically, DMS is diagnosed in infancy or early childhood, but patients appear normal at birth [3].

Scott and Rochefort [18], Parchoux et al. [17], Kristal and Lichtig [6] and Norio and Rapola [14] described fatal perinatal cases of DSM with probable onset in intrauterine life, but the only case of DSM described in a fetus is a prostaglandin-induced stillborn 18-week-old fetus because of oligohydramnios [19].

Nearly all affected children progress to nephrotic syndrome and end-stage renal failure. Nephrotic syndrome may be suspected in utero when placental hypertrophy [12] is noted or later in life because of severe proteinuria. The onset of proteinuria during the first month of life is associated with a poor prognosis [15].

Usually, nephropathy is the only manifestation of the disease, but various other signs have been reported in a few patients including nystagmus, cataract, myopia, mental retardation, microcephaly, myocarditis with cardiac arrhythmia, muscular dystrophy and dysmorphic facial features [3].

Moreover, the observation of DMS combined with bilateral dysplasia and enlarged cystic kidneys makes this case unique and difficult to interpret. A fetus with these findings seems never to have been reported previously.

Bilateral dysplasia is one of the well-recognized causes of congenitally enlarged kidney found by antenatal ultrasound examination as listed in Table 2 [8, 16]. All were evaluated during the differential diagnosis.

Ultrasound analysis, fetal autopsy, histology and family history have permitted us to exclude autosomal recessive polycystic kidney disease, autosomal dominant polycystic kidney disease (ADPKD) or multicystic dysplastic kidney disease (MCDKD) as the cause of the abnormalities.

Autosomal recessive polycystic disease is characterized by radially oriented, fusiform, multiple small cysts (1–2 mm of diameter), features not compatible with our case; ADPKD is not compatible either as the characteristics of cysts and negative family history make ADPKD less likely.

Multicystic dysplastic kidney is excluded, first of all, by the extremely rare bilateral involvement. Moreover, in our case, there is a late development of cysts and some normal parenchyma, found on histology, among cysts, which is incompatible with a diagnosis of MCDKD.

Approximately 10% of children with dysplasia have a positive history of a first-degree relative with renal or urinary tract disease; renal dysplasia with cysts appears to be transmitted as an autosomal recessive trait, and some cases are associated with syndromes [8]. But a clear genetic cause has not been discovered yet. This condition is a specific disorder included in the family of abnormalities (CAKUT) which constitute approximately 20%–30% of all anomalies identified in the prenatal period, and it is a well-known cause of renal oligohydramnios (ROH) [10].

Antenatally diagnosed ROH survival rate is 60%–90% [1, 10], but the presence of extrarenal comorbidities, such pulmonary hypoplasia in our case, is likely to worsen the prognosis [11].

CAKUT represents a broad range of disorders that result from three different abnormal renal developmental processes: malformation of the renal parenchyma resulting in failure of normal nephron development as seen in renal multicystic dysplasia, abnormalities of embryonic migration of the kidneys and abnormalities of the developing urinary collecting system [8].

For the first time, unusual bilateral renal damage due to progressive isolated diffuse mesangial sclerosis together with progressive dysplasia with multicystic formations is described, and a partial differential diagnosis is made. Despite these findings, the cause of fetal death remains unclear.

The defective gene(s) causing DMS is still unknown except for a few reports [2]: a mutation in WT1 in seven Japanese children with DMS is identified, whereas germline WT1 mutations in exon 8 or 9, coding for zinc fingers 2 or 3, are observed in children with Denys-Drash syndrome, characterized by the association of Wilms’ tumor, male pseudohermaphroditism and early nephritic syndrome with diffuse mesangial sclerosis.

Gbadegesin et al. [2] described LAMB2 and showed the possibly novel role of PLCE1/NPHS3 in the pathogenesis of DMS. The LAMB2 gene encodes lamin beta 2 (expressed in the glomerular basement membrane), and its mutations are associated with Pierson syndrome, an autosomal recessive disease characterized by congenital nephrotic syndrome with histological lesions of DMS and ocular malformations (microcoria, abnormal lens with cataracts and retinal abnormalities).

PLCE1 encodes phospholipase C epsilon 1 which plays a role in glomerulogenesis, and its mutations are associated with early-onset non-syndromic DMS.

The evidence for a genetic background for dysplasia with cysts and DMS leads to unclear definition of the reproductive risk.

The purpose of this case report was to describe the rarity of diffuse mesangial sclerosis combined with bilateral cystic and dysplastic kidney and to try to make the differential diagnosis of cystic renal masses. Our case demonstrated that more specific data about prenatal manifestation of rare conditions must be defined to increase our knowledge and ability to counsel parents appropriately.