Case report: WT1 exon 6 truncation mutation and ambiguous genitalia in a patient with Denys-Drash syndrome

Denys-Drash syndrome is a rare genetic disorder featuring the triad of congenital nephropathy, Wilms tumor, and intersex disorders (XY under-virilization or XY female). Denys-Drash syndrome is associated with constitutional mutations in the Wilms tumor suppressor gene WT1. Unlike WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome, with its complete deletion of one copy of WT1, Denys-Drash syndrome is generally caused by a dominant-negative mutation. We present a new case of Denys-Drash syndrome in a patient initially diagnosed with XY ambiguous genitalia/partial androgen insensitivity syndrome, who was found to have a novel nonsense mutation in exon 6 leading to a stop codon and hence a truncated protein. Based on lessons learned from this patient, the diagnosis of Denys-Drash syndrome should be considered in the presence of ambiguous genitalia and partial androgen insensitivity.     

Penoscrotal inversion, hypospadias, imperforate anus, facial anomalies, and developmental delay: definition of a new clinical syndrome

 We describe a 2-month-old boy with penoscro- tal inversion, hypospadias, imperforate anus, facial anomalies, developmental retardation, and a subtelomeric deletion of chromosome 13q. His phenotype with anogenital malformations and characteristic facies closely resembled two unrelated patients with minute deletions of chromosome 13q who we reported earlier. In addition, he had unilateral renal agenesis. We propose that these patients represent a clinically recognizable, novel chromosomal microdeletion syndrome. The findings indicate the presence of a major gene(s) on chromosome 13q33.2qter that regulate(s) the migration and development of ano-reno-genital cells and organs. We speculate that mutations of this developmental gene(s) may also result in more frequent congenital malformations (isolated hypospadias, uterus bicornis, unilateral renal agenesis). Additional studies are needed to further delineate the genetic defect. Accepted: 15 September 1999     

Reproductive failure in a carrier of inv dupl l(q21.4----q12)

High resolution analysis of the early metaphase and prometaphase chromosomes of the father of a child with malformations and mental retardation revealed inv dupl l(q21.4----q12). Almost the same was the aberration in the propositus but with a deletion of the band lq11.2 : 46,XX, inv dupl l(q21.4----q12)del lq11.2. This suggested that the malformations and mental retardation in the child were probably due to the microchromosome anomaly in the euchromatin, connected with the heterochromatin block in the father.     

DELETION MAPPING OF CRITICAL REGION FOR HYPOSPADIAS, PENOSCROTAL TRANSPOSITION AND IMPERFORATE ANUS ON HUMAN CHROMOSOME 13

BACKGROUND: The 13q-deletion syndrome causes human congenital birth defects due to the loss of regions of one long arm of human chromosome 13. A distal critical region for severe genitourinary and anorectal birth defects in the region of 13q32.2-34 has been suggested; we sought to narrow this critical region. METHODS: From patients with karyotypes revealing haploinsufficiency for distal chromosome 13q and their parents, peripheral blood was obtained and lymphocytes were immortalized for DNA isolation. Genetic and molecular cytogenetic methods were used to map deletions. Patient and parental samples were genotyped with a panel of 20 microsatellite markers spanning 13q31.3 qter and deletions identified by loss of heterozygosity. Deletions were also mapped using a panel of 35 BAC clones from the same region as probes for fluorescence in-situ hybridization on patient lymphoblastoid metaphase preparations. The data were synthesized and a deletion map defining the critical region was generated. RESULTS: Eight patients with known deletions around 13q32qter and their parents were analyzed, and categorized into three groups: three patients with anorectal and genitourinary anomalies (hypospadias, penoscrotal transposition), four male patients without anorectal and genitourinary anomalies, and one XY patient with ambiguous genitalia without anorectal anomalies. We mapped the critical region for anorectal and genitourinary anomalies to a approximately 9.5-Mb interval of 13q33.3-q34 delineated by markers D13S280-D13S285; this spans approximately 8% of the chromosome and contains 20 annotated genes CONCLUSION: The critical region of chromosome 13q mediating genitourinary/anorectal anomalies has been mapped, and will be narrowed by additional patients and further mapping. Identification of the gene(s) mediating these syndromic genitourinary defects should further our knowledge of molecular mediators of non-syndromic hypospadias, penoscrotal transposition and anorectal malformations.     

Monosomy 7qter: 2 new cases of chromosomal pathology with aspecific disorders of pre- and post-natal development

Many cases of 7q deletion associated with mental retardation and multiple malformations have been described, nevertheless it is quite different to recognize common features among these infants. In this paper the cases of two female infants with uncommon facial features and 7q deletion are described. We also try to recognize the phenotypic features of this chromosomal disorder.     

Defective sexual development in an infant with 46, XY, der(9)t(8;9)(q23.1;p23)mat

We report on a male infant with ambiguous genitalia (scrotal hypospadias, sinus urogenitalis) trisomic for 8q23-ter and monosomic for 9p23-ter, who shared craniofacial and other abnormalities with either phenotype. Gonadal histology was nearly normal for age. Normal endocrinological findings and exclusion of mutations in SRY, androgen receptor and alpha-reductase genes point to supplementary gene(s) located in 9p2305-ter, haplo-insufficiency (by deletion) of which is expected to cause defective male morphogenesis. Conclusion This observation lends further support to the hypothesis that genetic factors are located at 9p23-ter which are involved in normal sex determination. Received: 26 February 1998 / Accepted: 28 May 1998     

PRIMARY HYPOTHYROIDISM, GROWTH HORMONE DEFICIENCY AND CONGENITAL MALFORMATIONS IN A CHILD WITH THE KARYOTYPE 46, XY, del(l)(q25q32)

Abstract. Primary thyroidal hypothyroidism, growth hormone deficiency, congenital malformations and mental retardation occurred in a child with an interstitial deletion of one of the No. 1 chromosomes. Two bands were missing, so that the karyotype could be written: del(l)(pter→q25::q32→qter). The possible relationship between the clinical features and chromosomal deletion are discussed.     

Prepubertal XX male with profound physical and mental deficiency, retinitis pigmentosa and multiple congenital anomalies

A unique case of a prepubertal XX male with profound mental and physical retardation, retinitis pigmentosa, ambiguous genitalia and multiple congenital anomalies is reported. His clinical, genetic, dermatoglyphic and histological findings are presented. This case could represent a new multiple congenital malformation syndrome. Theories on XX male aetiology are briefly discussed.     

Clinical characteristics and diagnosis of Smith-Lemli-Opitz syndrome and tentative phenotype-genotype correlation: report of 45 cases]

INTRODUCTION: SLO (Smith-Lemli-Opitz) syndrome is an autosomal recessive multiple congenital malformations syndrome, including mental retardation, failure to thrive, craniofacial abnormalities, incomplete development of male genitalia, limb anomalies and various internal organ abnormalities. This syndrome is caused by a deficiency of cholesterol biosynthesis at the distal step of 7-dehydrocholesterol reductase (7DHCR). PATIENTS AND METHODS: We have reviewed 45 cases of SLO syndrome and showed the large clinical spectrum of this syndrome. RESULTS: The prenatal diagnosis should be considered when dealing with antenatal growth retardation and visceral malformations. At birth, a normal weight does not systematically exclude the diagnosis. Diagnosis was more difficult for older children especially for girls and should be suspected on the association of mental retardation, autism, short stature and microcephaly. We found a correlation between low plasmatic cholesterol measurement and clinical severity. Phenotype-genotype correlation was difficult to establish. However, homozygosity for IVS8-1G > C splice site mutation was associated with severe phenotype. CONCLUSION: Better understanding of the 7DHCR gene regulation factors and of the compensatory mechanism of foeto-maternal cholesterol transfer are necessary to explain the wide clinical spectrum of the SLO syndrome.     

Fraser syndrome: recurrence in a family

Fraser syndrome is a rare, autosomal recessive condition with classical features of cryptophthalmos, syndactyly, ambiguous genitalia, genitourinary mal-formations and mental retardation. We report a family with affected child where the pregnant woman was referred at 24 weeks of gestation for termination of pregnancy. The aborted fetus showed typical findings suggestive of Fraser syndrome.     

49, XXXXY syndrome: an Italian child

The 49, XXXXY syndrome is a rare sex chromosome polysomy, first described by Fraccaro and colleagues in 1960. The approximate incidence of this disorder is 1 in 85,000 male births. To date, >100 cases had been published in the literature. Patients with 49, XXXXY syndrome show some peculiar clinical features, such as mental retardation, facial dysmorphism, ambiguous genitalia, and multiple skeletal and cardiac defects. We report a new case of 49, XXXXY syndrome; the first Italian case to our knowledge.     

Severe feeding problems and congenital laryngostenosis in a patient with 3q23 deletion

Common clinical features of patients with 3q23 deletion include the phenotype of BPES (blepharophimosis, ptosis, epicanthus inversus and telecanthus syndrome), growth and mental retardation, microcephaly, ear and nose dysmorphism and joint and digit abnormalities. We report on a 3-year-old girl with the phenotype of BPES, mental retardation, facial dysmorphism and camptodactyly. In addition, she had a congenitally small larynx and severe, chronic feeding difficulties. Chromosome studies revealed an interstitial deletion in the long arm of chromosome 3: del(3)(q23-q25) Conclusion Congenital laryngostenosis and severe feeding problems may be part of the clinical syndrome caused by chromosome 3q23 deletion. Received: 28 January 1997 / Accepted: 25 February 1997     

A case of Antley-Bixler syndrome caused by compound heterozygous mutations of the cytochrome P450 oxidoreductase gene

Antley-Bixler syndrome (ABS) is a skeletal malformation syndrome primarily affecting the skull and limbs. Although causal mutations in the FGFR2 gene have been found in some patients, mutations in the electron donor enzyme P450 oxidoreductase gene (POR) have recently been found to cause ABS in other patients. In addition to skeletal malformations, POR deficiency also causes glucocorticoid deficiency and congenital adrenal hyperplasia with ambiguous genitalia in both sexes. Here, we report on a 7-month-old Korean girl with ABS and ambiguous genitalia who was confirmed by POR gene analysis. Our patient showed typical skeletal findings with brachycephaly, mid-face hypoplasia, and radiohumeral synostosis. She also had partial labial fusion and a single urogenital orifice, as well as increased 17α-hydroxyprogesterone levels, suggesting a 21-hydroxylase deficiency. Cortisol and DHEA-sulfate response to rapid adrenocorticotropic hormone (ACTH) stimulation was inadequate. Direct sequencing of the POR gene revealed compound heterozygous mutations (I444fsX449 and R457H). This is the first report of a Korean patient with ABS caused by POR gene mutations.     

Interstitial deletion of a chromosome nr. 13: a new syndrome? (author's transl)

We report on a 7-year-aged girl with severe mental and physical retardation, short stature and malformations of the face and limbs. In the karyogramm an interstitial deletion of the long arm of a chromosome Nr. 13 was found. The karyotypes of the parents, the girl's brother and of three of her sisters were normal. In the discussion the symptoms of the few hitherto published cases with interstitial or terminal deletion of the chromosome 13 are compared. Till now, however, it is not possible to attach particular symptoms of 13q- -- syndromes to certain bands of the chromosome Nr. 13.     

The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): one gene leads to many phenotypes

PURPOSE OF REVIEW: Infantile spasms, mental retardation, autism, and dystonia represent disabling diseases for which little etiologic information is available. Mutations in the Aristaless related homeobox gene (ARX) have been found in patients with these conditions. This discovery provides important genetic information and may ultimately offer treatment options for these patients. RECENT FINDINGS: Recent work has demonstrated that mutations in ARX cause X-linked West syndrome, X-linked myoclonic epilepsy with spasticity and intellectual disability, Partington syndrome (mental retardation, ataxia, and dystonia), as well as nonsyndromic forms of mental retardation. Patients with these aforementioned diseases and ARX mutations were not reported to have brain imaging abnormalities. In contrast, mutations in ARX mutations have also been found in X-linked lissencephaly with abnormal genitalia, which typically includes severe brain malformations (lissencephaly, agenesis of the corpus callosum, and midbrain malformations), intractable seizures, and a severely shortened lifespan. ARX knockout mice manifest defects in overall neuroblast proliferation as well as selective abnormalities in gamma-aminobutyric acid-ergic interneuron migration. Consistent with these findings in mice, phenotype/genotype studies in humans suggest that truncating mutations cause X-linked lissencephaly with abnormal genitalia, and insertion/missense mutations result in epilepsy and mental retardation without cortical dysplasia. SUMMARY: Mutations in the homeobox gene, ARX, cause a diverse spectrum of disease that includes cognitive impairment, epilepsy, and in another group of patients severe cortical malformations. Although the precise prevalence of ARX mutations is unclear, ARX may rival Fragile X as a cause of mental retardation and epilepsy in males.     

The Rieger syndrome and a chromosome 13 deletion

The Rieger syndrome, characterized by a prominent Schwalbe line, iris strands to the cornea, iris hypoplasia, dental abnormalities, facial malformations, and umbilical defects, is inherited in an autosomal dominant pattern. We studied a boy with the ocular features of the Rieger syndrome, micrognathia, and redundancy of the periumbilical skin. Chromosome analysis revealed an interstitial deletion of the long arm of chromosome 13 involving the distal region of band q14 through band q31. As there was a previous report of the Rieger syndrome in a child with an interstitial deletion of chromosome 13 (q12,q22), we suggest that a gene for this disorder may be located in the segment q14 to q22.     

Unique maternal deletion of 15q in a patient with some symptoms of Prader-Willi syndrome

BACKGROUND: Human chromosome 15q11-q13 is a critical region for Prader-Willi syndrome (PWS) and Angelman syndrome (AS) and most of the genes are under the condition of imprinting mechanism. PWS results from the loss of expression of paternally expressed genes and AS of maternally expressed genes. In this study molecular studies about a patient with congenital anomalies and mental retardation are analyzed. METHODS: Highly polymorphic microsatellite markers were analyzed by PCR. These markers exist within 15q11-q13 and distal to 15q13. RESULTS: Only the maternal D15S986 locus within 15q11-q13 was deleted and other markers were biallelic. CONCLUSIONS: The result of maternal small region deletion in this patient is different from the typical PWS with paternal chromosome deletion and it suggests that nearby the deleted region there exists a gene (genes) which is not imprinted but needs biallelic expression.     

True hermaphroditism with characteristics of Klinefelter's syndrome: a rare presentation

True hermaphroditism, a very rare cause of intersex, is usually diagnosed during the newborn period in the course of evaluating ambiguous genitalia. As an exception we report an unusual case of a 14.5 year-old boy with phenotypically near-normal male genitalia and bilaterally descended gonads, who was seen for evaluation of gynecomastia and hematuria. His eunuchoid body habitus and mild mental retardation were compatible with Klinefelter's syndrome. He had a low level of free testosterone (15.2 pmol/l), and high level of estradiol (264.3 pmol/l) for his age. The patient was diagnosed as true hermaphroditism with 46,XX /47,XXY karyotype causing an ovotestis with inguinal uterus hernia in the left scrotum and a dysgenetic testis in the right scrotum.     

Report of a deletion 11 (qter→q23.3) and short review of the literature

A male child is described with short stature, mental retardation and unusual facial appearance. Cytogenetic analysis revealed a partial deletion of the long arm of chromosome 11: 46,XY,del (11)(qterq23.3:). A short review of previously reported cases of del 11q is presented. A comparison of the main clinical characteristics and the extent of the 11q deletion is given.     

Hearing impairment in a female infant with interstitial deletion of 2q24.1q24.3

Patients with interstitial deletions in 2q24.1q24.3 are rarely reported. These patients manifest a variety of clinical features in addition to intellectual disability, depending on the size and location of the deletion. We report a female patient with interstitial deletion of 5.5 Mb in 2q24.1q24.3, who showed intrauterine growth retardation, hypotonia, global developmental delay, microcephaly, and characteristic facial appearance. In addition, she had hearing impairment, with no auditory brainstem response. Case of 2q24.1q24.3 deletion with hearing impairment is quite rare. We suspect that hearing impairment is caused by bilateral cochlear nerve deficiency due to cochlear nerve canal stenosis. Further studies are necessary to evaluate hearing impairment as a clinical feature in patients with de novo heterozygous 2q24.1q24.3 deletion.