Mutations in the WT1 gene result in a spectrum of very rare congenital diseases characterized by abnormalities in gonadal and urinary tract development and are the cause of WAGR (Wilms-Aniridia-Genitourinary-mental Retardation) syndromes, Denys-Drash syndrome and Frasier syndrome. (3, 7, 12, 13) Initial manifestations of patients with nephropathy due to the WT1 gene mutation include edema, proteinuria, pseudo hermaphroditism, hypospadias or cryptorchidism at birth. (9) Frasier syndrome and Denys-Drash syndrome (DDS) share common features and are both characterized by a steroid-resistant nephrotic syndrome, which leads to renal failure, gonadal tumor (most often gonadoblastoma or dysgerminoma), and male pseudo hermaphroditism. (2, 12, 14) The main differences lie in the more prominent manifestation of renal symptomatology during childhood in DDS, contrasting FS which mostly manifests during the second decade, particularly during adolescence or young adulthood. (3, 7, 9, 12, 15, 16)Additionally, the risk of development Wilms' tumors is higher in DDS. (3, 6, 7, 12, 13, 16, 17). In our case, we eliminated DDS because the renal failure occurs mainly in the second decade (16–19 years), as mentioned in the literature (6, 7, 18, 19)
Frasier syndrome is defined by the presence of progressive glomerulopathy with proteinuria associated with male pseudo hermaphroditism (presence of female external genitalia in a male phenotype) (2, 3, 6–8). To our knowledge, this case is the first described in Haiti. Taking into account the appearance of the external genitalia, phenotype and sex chromosomes, Frasier syndrome is classified into 3 types (2):
a) Type 1: characterized by the presence of external female genitalia with sex chromosome 46, XY; the most common
b) Type 2 by the presence of male external genitalia with sex chromosome 46, XY
c) Type 3 presence of external female genitalia with sex chromosome 46, XX.
This case was closest to type 2 because of the male phenotype with predominant development of male sexual characteristics (no well-defined breasts or vagina). The mean age at diagnosis of Frasier syndrome was estimated to be 16.3 ± 2.3 years (2, 15, 20), which is also the age at which the diagnosis of end-stage renal disease is often made, although the onset of renal symptoms of proteinuria, edema and hypertension typically begins between 2–10 years of age. (1, 2, 6, 9, 10, 19, 20) This patient had a similar picture; since his childhood he was often in hospital for reasons of facial oedema and alteration of the renal function. This prompted the abdominal ultrasound revealing a decrease in kidney size of kidneys, and allowed the diagnosis of preterminal renal insufficiency at age 16.
Two elements are essential to confirm the diagnosis of Frasier syndrome: renal biopsy and cytogenetic study that identifies the WT1 gene mutation located on chromosome 11p13. (7) Renal biopsy performed before the stage of end-stage failure describes segmental and focal glomerulosclerosis (8, 18, 21) generally caused by the WT1 gene mutation leading to alterations in the podocytes with areas of proliferation (8, 9, 15). (8, 9, 15) It is due to point mutations in intron 9 of the WT1 gene, resulting in the loss of the lysine-threonine-serine (KTS) containing isoforms of the WT1 protein and result in deficiency of the usually more abundant KTS positive isoforms and reversal of the normal KTS positive/negative ratio from 2:1 to 1:2. (16). This has a great impact on tumor risk, because patients with Frasier syndrome have one normal copy of WT1 and one that can only produce the KTS negative isoform, this might explain why patients with Frasier syndrome do not develop Wilms’s tumor which also explains the observed external genitalia changes, because the KTS positive isoform might participate in another pathway required for normal male urogenital development. (2, 16, 19)There are extrarenal manifestations of the WT1 gene mutation such as the presence of cardiomyopathies (21), a finding that was identified in our patient at echocardiography showing dilated cardiomyopathy with slight alteration of the systolic ejection fraction (46, 4%). However, this could also be a complication of his chronic end-stage renal failure.
In our case, the renal biopsy was no longer appropriate since he had arrived at the nephrology unit very late and already had end-stage renal failure with hypotrophic kidneys. During his stay, we conducted genetic tests to confirm the presence of the mutations. Unfortunately, he died suddenly due to cardiac arrest after a dialysis session. As a result, the genetic tests were not performed to confirm mutations that would explain the clinical and paraclinical findings characteristic of Frasier syndrome.