Steroid Resistant Nephrotic Syndrome
Das Portal für seltene Krankheiten und Orphan DrugsGalloway-Mowat syndrome GMS is an autosomal recessive disorder with a steroid resistant nephrotic syndrome definition prognosis that was first defined as a triad of central nervous system involvement, hiatal hernia, and nephrotic syndrome. However, this syndrome is now known to have a heterogeneous clinical presentation. The nephrotic syndrome is steroid resistant and is responsible for the outcome. The combination of collapsing glomerulopathy and GMS is very rare. A month-old resixtant presented with steroid-resistant nephrotic syndrome associated with neurologic tamoxifen clomiphene testosterone, including microcephaly, psychomotor retardation, and nystagmus.
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Galloway-Mowat syndrome GMS is an autosomal recessive disorder with a poor prognosis that was first defined as a triad of central nervous system involvement, hiatal hernia, and nephrotic syndrome. However, this syndrome is now known to have a heterogeneous clinical presentation. The nephrotic syndrome is steroid resistant and is responsible for the outcome. The combination of collapsing glomerulopathy and GMS is very rare. A month-old boy presented with steroid-resistant nephrotic syndrome associated with neurologic findings, including microcephaly, psychomotor retardation, and nystagmus.
Magnetic resonance imaging showed marked cerebral atrophy, optic atrophy, and hypomyelination. A renal biopsy was consistent with collapsing glomerulopathy. If collapsing glomerulopathy is associated with neurological abnormalities, especially with microcephaly, clinicians should consider GMS as a possible underlying cause. Galloway-Mowat syndrome GMS; MIM is a rare autosomal recessive disease characterized by the combination of nephrotic syndrome NS and central nervous system involvement [ 1 ].
Since Galloway and Mowat first reported two siblings with early-onset NS, microcephaly, and hiatal hernia in , more than 60 cases of GMS have been reported, with an expanding spectrum of phenotypic findings [ 2 , 3 ]. Galloway-Mowat syndrome is a clinically heterogeneous disorder, and although included in the initial definition, hiatal hernia is no longer necessary for the diagnosis [ 2 , 4 — 6 ].
Although some authors have tried to classify GMS according to the clinical presentation, no classification of the disease is currently accepted [ 7 ]. We report a boy with NS in whom a renal biopsy showed typical collapsing glomerulopathy associated with neurological findings consistent with GMS.
A month-old boy presented to our hospital with periorbital edema and ascites. The patient was being followed up at another center for nystagmus and microcephaly. He was the only child of a nonconsanguineous healthy couple.
The family history was negative for renal diseases. The patient was a full-term product of an uncomplicated pregnancy with normal birth growth parameters birth weight 3. When the patient was brought to us, psychomotor retardation was apparent. He had been able to keep his head upright since being 6 months of age but could not walk or speak at presentation.
There was no facial dysmorphism. The abdominal examination showed gross ascites. The baseline investigations showed hemoglobin, Ultrasound showed normal-sized kidneys with increased cortical echotexture and loss of corticomedullary differentiation. Coenzyme Q10 was also administered because of the psychomotor retardation. The urine organic acid screening and tandem mass spectrometry results were normal.
Brain magnetic resonance imaging revealed cerebral atrophy, bilateral hypomyelination in the periventricular white matter, and optic atrophy Figure 1. The metabolic peak was not available on brain magnetic resonance spectroscopy. A renal biopsy was performed after the patient did not respond to 4 weeks of steroid treatment, and the treatment shifted to cyclosporine. The kidney biopsy showed 11 glomeruli and revealed that the glomerular capillary lumens were occluded by global wrinkling and collapse of the glomerular basement membranes with hypertrophy and hyperplasia of the overlying podocytes forming pseudocrescents, without inflammatory cells and Bowman capsule rupture Figure 2 a.
Hypertrophied and hyperplastic podocytes contained numerous intracytoplasmic vesicles and protein resorption droplets. In addition, focal mild tubular degeneration, regeneration, and dilatation were observed, with mild to moderate interstitial inflammation. Some tubules contained red resorption droplets.
On electron microscopic examination, semithin sections stained with toluidine blue revealed collapse of the glomerular basement membranes, with hypertrophy and hyperplasia of the overlying podocytes, forming pseudocrescents.
Thin sections stained with lead citrate and uranyl acetate revealed wrinkling, irregular thinning, and thickening of the glomerular basement membranes, accompanied by diffuse foot process effacement of markedly hypertrophied and swollen podocytes with electron-lucent transport vesicles, increased organelles, and a disrupted actin cytoskeleton Figures 2 b and 2 c.
The glomerular basement membranes had a radiolucent fibrillary appearance, and the lamina densa, which consists mainly of collagen type IV and laminin, had disappeared or was disrupted in many areas in the glomerular basement membrane Figure 2 c. No electron-dense deposits or tubuloreticular inclusion bodies were observed in the glomeruli.
These findings supported a diagnosis of collapsing glomerulopathy. Brain magnetic resonance images: Genetic testing for the podocin mutation analysis revealed no mutation. We did not achieve clinical or laboratory improvement with cyclosporin therapy. However, after 2 months in the hospital, the patient died of Candida septicemia despite appropriate supportive care and antimycotic treatment. The kidney involvement in GMS comprises a broad spectrum ranging from mild nonnephrotic proteinuria to steroid-resistant NS with rapid progression to end-stage renal disease [ 8 , 9 ].
Nephrotic syndrome often develops within the first months of life, at an average of 3 months, although later onset during childhood 44— months has been reported [ 5 , 10 — 12 ].
If the renal findings occur at less than 3 months of age, the brain formation and migration anomalies become more severe, and the patient usually dies early. If the renal findings occur later, both the renal disease and brain development anomalies are less severe [ 7 , 13 ]. Pathologically, the renal involvement in GMS can be similar to calcineurin inhibitor toxicity, with striped fibrosis and tubular atrophy; other renal lesions include mesangial proliferation, microcystic dysplasia, minimal change NS, diffuse mesangial sclerosis, and focal segmental glomerulosclerosis [ 2 — 4 , 9 , 10 , 14 — 16 ].
Altered renal histology has been reported in the same patient [ 15 ]. There is no typical age-specific renal histological pattern regardless of whether the renal failure is seen at early or older ages.
Only two cases of collapsing glomerulopathy have been reported in GMS [ 8 , 17 ]. Severe collapsing glomerulopathy was present in both patients and progressed rapidly to death. Our patient is the third reported GMS patient with collapsing glomerulopathy, and he died 2 months after developing NS.
However, this finding has not been discussed in subsequent studies [ 17 ]. In our case, these two findings were present Figure 2 b. Another important feature of GMS nephropathology is tubular atrophy associated with tubulointerstitial inflammation; this was present to a mild to moderate degree in our case [ 17 ].
In GMS, the most frequently reported vascular change is arteriolar medial hypertrophy [ 14 , 18 ]. However, our patient, like most GMS cases, had normal arteries.
Neurological findings are universal in children with GMS and often precede renal abnormalities. The consistent morphological hallmark of the disease is microcephaly, which is often present at birth but can develop postnatally, as in our patient. In addition to microcephaly, severe developmental delay and structural brain abnormalities such as malformations of cortical development, hypomyelination, nystagmus, and cerebellar atrophy may occur in some patients [ 5 , 19 ].
Severe, intractable seizures, not mentioned in early reports, have been increasingly recognized, being involved in more than half of recently reported cases [ 3 , 9 , 13 ].
Our patient did not have epilepsy but had cortical especially frontal atrophy, widespread hypomyelination, and optic atrophy. Although no facial dysmorphism is seen in some patients, others may exhibit dysmorphic features such as a sloping narrow forehead, low-set large floppy ears, a high palate, abnormally shaped skull, micrognathia, arachnodactyly, and coarse hair [ 3 , 9 , 14 , 18 , 20 ].
Our patient did not have a dysmorphic appearance. The molecular basis of GMS is currently unknown. In , Cohen and Turner examined kidney tissues of the patients using antibodies against glomerular basal membrane, tubular basal membrane, type IV collagen, and laminin along with different stains in an attempt to understand the pathophysiology of the syndrome but did not find any abnormality [ 18 ].
In , Srivastava et al. Very recently, however, WDR73 deficiency was identified in five individuals with GMS presenting with childhood-onset NS, postnatal microcephaly, severe intellectual disability, and homogenous brain magnetic resonance imaging features including cerebellar atrophy [ 8 , 22 ]. WDR73, which is present in brain and kidney tissue, encodes a WDrepeat-containing protein and plays a role in cell survival and the organization of neuronal and axonal microtubule regulation [ 8 , 23 ].
They concluded that the WDR73 mutation is much more common in cerebellar atrophy associated with neurodegenerative diseases and this mutation may not always be associated with renal involvement. Moreover, glomerulopathy associated with the WDR73 mutation occurs in later years 5—12 years of age [ 1 , 8 , 22 ]. We did not detect any WDR73 mutations in our case. It is likely that GMS is genetically heterogeneous, given the clinical heterogeneity of the syndrome.
As a result, our case is the third reported collapsing glomerulopathy case with GMS, and our patient died rapidly. Galloway-Mowat syndrome should be considered in collapsing glomerulopathy patients with neurological findings, especially with microcephaly. The authors declare that there are no competing interests regarding the publication of this paper.
National Center for Biotechnology Information , U. Journal List Case Rep Nephrol v. Published online Jun Received Mar 7; Accepted May This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract Galloway-Mowat syndrome GMS is an autosomal recessive disorder with a poor prognosis that was first defined as a triad of central nervous system involvement, hiatal hernia, and nephrotic syndrome.
Introduction Galloway-Mowat syndrome GMS; MIM is a rare autosomal recessive disease characterized by the combination of nephrotic syndrome NS and central nervous system involvement [ 1 ]. Case Presentation A month-old boy presented to our hospital with periorbital edema and ascites. Open in a separate window. Discussion The kidney involvement in GMS comprises a broad spectrum ranging from mild nonnephrotic proteinuria to steroid-resistant NS with rapid progression to end-stage renal disease [ 8 , 9 ].
Competing Interests The authors declare that there are no competing interests regarding the publication of this paper. WDR73 mutations cause infantile neurodegeneration and variable glomerular kidney disease. Congenital microcephaly with hiatus hernia and nephrotic syndrome in two sibs.
Journal of Medical Genetics. Galloway-Mowat syndrome of abnormal gyral patterns and glomerulopathy. American Journal of Medical Genetics. Late-onset nephrotic syndrome and severe cerebellar atrophy in Galloway-Mowat syndrome.
Nephrotic syndrome, microcephaly, and developmental delay: Loss-of-function mutations in WDR73 Are responsible for microcephaly and steroid-resistant nephrotic syndrome: The American Journal of Human Genetics. Two novel cases and review of literature. Late-onset nephrotic syndrome in galloway-mowat syndrome: Saudi Journal of Kidney Disease and Transplantation.
Orphanet: Familial steroid resistant nephrotic syndrome with sensorineural deafness
Mai Steroidresistentes nephrotisches Syndrom (SRNS) bei Kindern hereditary and non-hereditary steroid-resistant nephrotic syndrome (SRNS). Download Citation on ResearchGate | On Feb 1, , D Oechslen and others published [Cytostatic treatment of the steroid-resistant nephrotic syndrome. (Long . On Jan 1, , K. Schärer published the chapter: Nephrotisches Syndrom in the book: Cyclophosphamide treatment of steroid dependent nephrotic syndrome: Steroid-Resistant Idiopathic Nephrotic Syndrome and Ciclosporin. Article.