A newly identified exonic mutation of the WT1 gene in a patient with Denys-Drash syndrome

An 11 month old boy with hypospadias and bilateral undescended testes developed renal failure. Denys-Drash syndrome was suspected and molecular analysis of the WT1 gene was performed, although no Wilms' tumor was identified. Direct sequencing analysis of genomic DNA from this patient revealed a G to A transition resulting in ³⁶⁶Arg to Leu substitution in exon 8 which has hitherto not been described. This newly identified mutation will help in the understanding of functional domains and in making a diagnosis of Denys-Drash syndrome.     

Association of partial gonadal dysgenesis, nephropathy and WT1 gene mutation without Wilms' tumor: incomplete Denys-Drash syndrome

The concurrence of ambiguous genitalia, nephropathy and predisposition to Wilms' tumor are characteristics of Denys-Drash syndrome. Some of the reported patients do not express the full spectrum of the syndrome, while the occurrence of nephropathy has become a generally accepted common feature of this syndrome. We report an infant with male pseudohermaphroditism due to partial gonadal dysgenesis and nephropathy without Wilms' tumor but with a Wilms' tumor suppressor gene (WT1) mutation. The high risk of Wilms' tumor mandates regular surveillance and the use of prophylactic bilateral nephrectomy as a treatment is not yet clear.     

Smith-Lemli-Opitz syndrome: in vivo and in vitro study of testicular function in a prepubertal patient with ambiguous genitalia

The pathogenesis of the development of ambiguous genitalia reported in some 46,XY patients with Smith-Lemli-Opitz syndrome is not understood. Presumably, it is related to the 7-dehydrocholesterol reductase deficiency present in these patients. In this study we have evaluated testicular function, both in vivo and in vitro, in a 46,XY patient with ambiguous genitalia, reared as a girl. The diagnosis was based on clinical features, low serum cholesterol and high serum 7-dehydrocholesterol levels. Serum hormone values, determined during the first month of age, showed normal basal testosterone (1.95 ng/ml), LH (0.91 U/l) and FSH (2.51 U/l). However, serum testosterone did not increase after hCG administration (1.98 ng/ml). On the other hand, the patient had a positive biological response to exogenous testosterone (decrease in sex hormone-binding globulin serum levels). She was orchidectomized at the age of 33 mo. Testicular cells were dispersed and maintained in culture for 6 d. These cells showed a very good capacity to secrete testosterone into the culture medium (X +/- SD, 26.1 +/- 11.7 vs. 4.36 +/- 1.70 pmol/10(6) cells/24 h in a control group of testicular cells prepared from testes collected at necropsy). The patient's cells failed to respond to LH stimulation (18.6 +/- 4.0 pmol/10(6) cells/24 h), although they did respond to other stimuli. It is concluded that the severe cholesterol deficiency of this patient did not impair the capacity of the testes to synthesize testosterone. However, the LH/hCG receptor or its subsequent message was activated neither in vivo nor in vitro. This finding suggests that the foetal testes might have failed to respond to placental hCG at the time of male external genital differentiation. This failure could have been responsible for the ambiguous genitalia present in this patient.     

Denys-Drash syndrome with neonatal renal failure in monozygotic twins due to c.1097G>A mutation in the WT1 gene

Denys-Drash syndrome, characterized by nephrosis, dysgenetic gonads and a predisposition to Wilms tumor, is due to germline mutations in the WT1 gene. We report the pathologic findings on monozygotic twins, both of whom presented with male pseudohermaphroditism, nephrotic syndrome, and progressed to renal failure and death within the first month of life. Sequence analysis of WT1 demonstrated a G-to-A substitution in exon 8 of the gene (c.1097G > A), resulting in an arginine-to-histidine (R366H) substitution in the second zinc finger domain. To the best of our knowledge, this is only the second set of monozygotic twins with Denys-Drash syndrome reported to date.     

Posterior sagittal transanorectal approach in patients with ambiguous genitalia: report of eight cases

The posterior sagittal transanorectal approach was used for reconstruction of the female genitalia (vaginoplasty) in eight girls with urogenital sinus, high vaginal implantation, and normal rectum, in all cases with a protective sigmoidostomy. These eight patients included four female and four male pseudohermaphrodites. They remain fecally continent, but only seven have urinary continence. One girl has a neuropathic bladder: umbilical discomfort during abdominal straining is present in one patient. One girl married and demonstrated satisfactory sexual intercourse. All patients are alive and healthy, physically and mentally. The transanorectal approach allows separation of the vagina from the urethra and bladder, provides good vaginal mobilization down to the perineum, avoids the utilization of perineal skin flaps and sometimes a laparotomy, and preserves defecation and urinary control. The cosmetic appearance of the genitalia seems to be better than that achieved in the past with other techniques. Accepted: 6 August 1998     

HCN1基因新生变异致Dravet综合征1例

目的探讨Dravet综合征临床及HCN1基因变异特征。方法回顾分析1例Dravet综合征患儿的临床资料及基因检测结果。结果 1岁11个月女性患儿,4月龄起病,表现为反复发热诱发的惊厥发作,发作时呈惊厥持续状态,发作形式多样。基因检测发现HCN1基因c.1199TC错义变异,导致第400号亮氨酸变异为脯氨酸(p.Leu400Pro);其父母该位点未见异常,为新生变异,尚未见报道。结论明确HCN1基因新生变异为致病基因,丰富了Dravet综合征的基因型。     

A patient with WT syndrome and Castleman disease

WT syndrome, an autosomal dominant condition, combines hematological abnormalities with mild lib defects. Anemia, pancytopenia, leukemia and lymphoma can occur at varying ages from childhood to middle age. Limb defects include ulnar and radial defects, bifid or hypoplastic thumbs and cutaneous syndactyly. Castleman disease is characterized by tumorous masses of lymphoid tissue showing plasma cell or hyaline vascular type changes in histological specimens. A 13 year old boy, diagnosed as WT syndrome with ulnar and radial deviation and 5th finger clinodactyly also had neutropenia, cervical and mediastinal lymphadenopathy. Histology of the cervical lymph node showed angiofollicular hyperplasia of the hyaline-vascular type (Castleman disease). This interesting patient is reported because Castleman disease, together with WT syndrome has not been previously described.     

Bardet-Biedl syndrome with syndrome X: a patient report

Bardet-Biedl syndrome (BBS) is an autosomal recessive condition with a wide spectrum of clinical features. The principal manifestations are rod-cone dystrophy (sometimes called atypical retinitis pigmentosa), postaxial polydactyly, central obesity, mental retardation, hypogonadism, and renal dysfunction. The clinical diagnosis of syndrome X defines a patient with abnormal glucose metabolism, hypertension, hyperlipidemia and obesity. We report here a 15 year-old girl with BBS presenting with syndrome X.     

Acute labio-scrotal pain in a patient with ovotesticular syndrome. Case report

Ovotesticular syndrome (OTS) belongs to the group of disorders of sex development (DSD). We present a case of a patient with OTS presenting with acute labioscrotal pain. A surgical exploration was indicated, and hemorrhage was identified. A gonadectomy was performed and the final pathology report revealed an ovotestis with a bleeding follicle, normal ovarian parenchyma and atrophic testicular parenchyma. After reviewing the literature there is scarce information on this complex topic, but conservative management could be an option if the risk of a gonadal malignancy is low.     

Robinow or “fetal face syndrome” in a male infant with ambiguous genitalia and androgen receptor deficiency

Typical features of the fetal face or Robinow syndrome are reported in a male infant who presented with ambiguous genitalia and persistence of the Mullerian ducts. Histology of the testes was normal whereas endocrinological studies showed partial deficiency of androgen receptors.Dedicated to Professor Dr. K. Stehr on the occasion of his 60th birthday     

Antenatally detected double prostatic utricle found in a neonate with ambiguous genitalia

Although enlarged prostatic utricle is usually seen in patients with hypospadias and disorders of sex development, double utricle has not been reported without unilateral renal dysplasia and Wolffian duct anomaly. We present an unusual case of antenatally detected large pelvic cyst, which turned out to be one of double prostatic utricles in a neonate with ambiguous genitalia. The possibility of enlarged utricle should be considered in the differential diagnosis of antenatally detected pelvic cysts in neonates with ambiguous genitalia.     

A child with isolated nephrotic syndrome and WT1 mutation presenting as a 46, XY phenotypic male

Mutations in the WT1 gene can lead to Denys-Drash syndrome or Frasier syndrome and can also cause isolated nephrotic syndrome (NS). Most patients with isolated NS caused by WT1 mutations present as 46, XX phenotypic females. There have been two cases with an onset age younger than 3 years with isolated NS caused by WT1 mutations presenting as 46, XY phenotypic males. We present a 46, XY phenotypic male patient with isolated NS and end-stage renal disease (ESRD) at the age of 6.3 years. He had normal male external genitalia with normal penis length and soft and normal volume of both testes. A mutation, 1051A>G (K351E), in exon 8 of WT1 was identified in the patient. After starting hemodialysis, manifestations of hypertension and renal failure improved, but he died at 6.8 years of age as a result of respiratory failure and heart failure. Our study supports the necessity of searching for mutations in WT1 in 46, XY phenotypic male patients with isolated NS and ESRD.     

Anakinra therapy for CINCA syndrome with a novel mutation in exon 4 of the CIAS1 gene

We report on a patient with chronic infantile neurological cutaneous and articular (CINCA) syndrome. Sequence analysis revealed a novel missense mutation in exon 4 of the CIAS1 gene. The patient was unresponsive to several treatments including prednisolone, immunosuppressants (azathioprine and cyclosporin), disease-modifying antirheumatic drugs (DMARDs: penicillamine, salazopyrin and methotrexate) and the tumour necrosis factor-alpha (TNF-a)-blocker infliximab. At 32 mo of age, administration of the recombinant human interleukin-1 receptor antagonist anakinra commenced, which caused an immediate and marked improvement in the clinical symptoms and laboratory test results. Continuous inhibition of the inflammation required a dose of 1.0 mg/kg every 12 h. CONCLUSION: Following the diagnosis of CINCA syndrome, anakinra treatment should be commenced as the first line of therapy.     

WT1 mutation as a cause of 46 XY DSD and Wilm's tumour: a case report and literature review

Aim: The Wilms’ Tumour gene is thought to have tumour suppressor activity and to play an important role in nephrogenesis, genitourinary development, haematopoiesis and sex determination. WT1 mutations will impair gonadal and urinary tract development and have been demonstrated to cause syndromes of WAGR, Denys–Drash and Fraiser. Methods: To elucidate the role of constitutional mutations of WT1, in the expression of the different clinical feature, we describe a 14‐year‐9‐month nonmosaic XY sex‐reversed woman with pure gonadal dysgenesis (46, XY karyotype, completely female external genitalia, normal Mullerian ducts, absence of Wolffian ducts, streak gonads) who had right kidney removed at 7 months of age because of Wilms’ tumour and was diagnosed as secondary thrombocytopenia (Plt 60–80 × 10⁹/L) since she was 4 years old. We sequenced the genomic DNA of all the 10 exons of the WT1 in which mutations may occur in proposita. Results: A new de novo insertion mutation in the first exon was found. A ‘GCCGCCTCACTCC’ is inserted between codon 138 and 139, resulting in the creation of a stop codon and a truncated protein. Conclusion: The present data provide further evidence to support the role of WT1 in diverse cellular functions.     

A novel mutation of the 5alpha-reductase type 2 gene in two unrelated Egyptian children with ambiguous genitalia

OBJECTIVE: To establish an etiological diagnosis in two unrelated Egyptian children with ambiguous genitalia through biochemical and molecular analyses. PATIENTS AND METHODs: Two XY patients were referred: one at the age of 14 years presenting with delayed puberty and menarche and the second at the age of 4 months with ambiguous genitalia. Basal and post-HCG stimulation plasma levels of testosterone (T) and dihydrotestosterone (DHT) were determined. Direct sequencing of the five exons of the 5alphaR type 2 gene and exons 2 to 8 of the androgen receptor gene was carried out. RESULTS: The high T/DHT value indicated 5alphaR deficiency in the first patient while the absence of parental consanguinity along with normal T/DHT value in the second patient suggested androgen insensitivity. In both patients, we identified a homozygous A --> G mutation in exon 3 that replaced the asparagine residue at position 160 by an aspartic acid. The parents of both patients were all heterozygotes for the N160D substitution. CONCLUSIONS: 1) We report a new mutation that enlarges the spectrum of genetic defects in 5alphaR deficiency. 2) Although the two patients were referred at very different ages, the clinical presentations raise the possibility of phenotypic variability for the same mutation. 3) These reports underline the difficulty of diagnosing 5alphaR deficiency based only on clinical and biochemical grounds. Molecular study remains the only definitive tool for diagnosis of ambiguous genitalia.     

Management of severe cervical kyphosis in a patient with Larsen syndrome. Case report

Larsen syndrome is a rare genetic disorder of the connective tissue that is characterized by multiple joint dislocations, distinctive deformities of the hands and feet, characteristic facial features, kyphoscoliosis, and segmentation anomalies of the vertebrae. Diverse treatment options, including conservative observation and surgical correction, have been reported for patients who present with cervical spine pathophysiology. Differences in surgical approaches, timing of the correction, and pre- or postoperative bracing have been reported. According to the authors, the present case is the first report of a pediatric patient with Larsen syndrome in whom an asymptomatic cervical instability was treated before neurological deterioration with synchronous anterior decompression and fixation, posterior fusion and fixation, and halo placement. A review of the literature on similar patients reveals the variety of practices associated with a diagnosis of Larsen syndrome.     

Association of ambiguous genitalia with VATER anomalies and its significance in management

Tracheo-oesophageal fistula, oesophageal atresia, and imperforate anus are known to be associated with renal anomalies — the VATER complex. The occurrence of ambiguous genitalia with this collection of anomalies has not previously been highlighted. We report two cases occurring 15 years apart; both had renal agenesis and neither was salvagealble from a renal or pulmonary viewpoint. Preoperative ultrasound examination of the renal tract should be performed in all babies born with the VATER complex and ambiguous genitalia; this will prevent unnecessary surgery.