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PubMed2000

Mutations in MKKS cause Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder with locus heterogeneity. None of the 'responsible' genes have previously been identified. Some BBS cases (approximately 10%) remain unassigned to the five previously mapped loci. McKusick-Kaufma syndrome (MKS) includes hydrometrocolpos, postaxial polydactyly and congenital heart disease, and is also inherited in an autosomal recessive manner. We ascertained 34 unrelated probands with classic features of BBS including retinitis pigmentosa (RP), obesity and polydactyly. The probands were from families unsuitable for linkage because of family size. We found MKKS mutations in four typical BBS probands (Table 1). The first is a 13-year-old Hispanic girl with severe RP, PAP, mental retardation and obesity (BMI >40). She was a compound heterozygote for a missense (1042GA, G52D) and a nonsense (1679TA, Y264stop) mutation in exon 3. Cloning and sequencing of the separate alleles confirmed that the mutations were present in trans. A second BBS proband (from Newfoundland), born to consanguineous parents, was homozygous for two deletions (1316delC and 1324-1326delGTA) in exon 3, predicting a frameshift. An affected brother was also homozygous for the deletions, whereas an unaffected sibling had two normal copies of MKKS. Both the proband and her affected brother had RP, PAP, mild mental retardation, morbid obesity (BMI >50 and 37, respectively), lobulated kidneys with prominent calyces and diabetes mellitus (diagnosed at ages 33 and 30, respectively). A deceased sister (DNA unavailable) had similar phenotypic features (RP with blindness by age 13, BMI >45, abnormal glucose tolerance test and IQ=64, vaginal atresia and syndactyly of both feet). Both parents and the maternal grandfather were heterozygous for the deletions. Genotyping with markers from the MKKS region confirmed homozygosity at 20p12 in both affected individuals.

Adolescent↗
PubMed2003

Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein.

Fraser syndrome (OMIM 219000) is a multisystem malformation usually comprising cryptophthalmos, syndactyly and renal defects. Here we report autozygosity mapping and show that the locus FS1 at chromosome 4q21 is associated with Fraser syndrome, although the condition is genetically heterogeneous. Mutation analysis identified five frameshift mutations in FRAS1, which encodes one member of a family of novel proteins related to an extracellular matrix (ECM) blastocoelar protein found in sea urchin. The FRAS1 protein contains a series of N-terminal cysteine-rich repeat motifs previously implicated in BMP metabolism, suggesting that it has a role in both structure and signal propagation in the ECM. It has been speculated that Fraser syndrome is a human equivalent of the blebbed phenotype in the mouse, which has been associated with mutations in at least five loci including bl. As mapping data were consistent with homology of FRAS1 and bl, we screened DNA from bl/bl mice and identified a premature termination of mouse Fras1. Thus, the bl mouse is a model for Fraser syndrome in humans, a disorder caused by disrupted epithelial integrity in utero.

Animals↗
PubMed2004

A direct functional link between the multi-PDZ domain protein GRIP1 and the Fraser syndrome protein Fras1.

Cell adhesion to extracellular matrix (ECM) proteins is crucial for the structural integrity of tissues and epithelial-mesenchymal interactions mediating organ morphogenesis. Here we describe how the loss of a cytoplasmic multi-PDZ scaffolding protein, glutamate receptor interacting protein 1 (GRIP1), leads to the formation of subepidermal hemorrhagic blisters, renal agenesis, syndactyly or polydactyly and permanent fusion of eyelids (cryptophthalmos). Similar malformations are characteristic of individuals with Fraser syndrome and animal models of this human genetic disorder, such as mice carrying the blebbed mutation (bl) in the gene encoding the Fras1 ECM protein. GRIP1 can physically interact with Fras1 and is required for the localization of Fras1 to the basal side of cells. In one animal model of Fraser syndrome, the eye-blebs (eb) mouse, Grip1 is disrupted by a deletion of two coding exons. Our data indicate that GRIP1 is required for normal cell-matrix interactions during early embryonic development and that inactivation of Grip1 causes Fraser syndrome-like defects in mice.

Adaptor Proteins, Signal Transducing↗
PubMed2005

MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome.

Feingold syndrome is characterized by variable combinations of esophageal and duodenal atresias, microcephaly, learning disability, syndactyly and cardiac defect. We show here that heterozygous mutations in the gene MYCN are present in Feingold syndrome. All mutations are predicted to disrupt both the full-length protein and a new shortened MYCN isoform, suggesting that multiple aspects of early embryogenesis and postnatal brain growth in humans are tightly regulated by MYCN dosage.

Brain↗
PubMed2003

Clinical and molecular analysis of nine families with Adams-Oliver syndrome.

Adams-Oliver syndrome (AOS) is defined by the combination of limb abnormalities and scalp defects, often accompanied by skull ossification defects. We studied nine families affected with AOS, eight of which have not been clinically described before. In our patients, scalp abnormalities were most often found, followed by limb and skull defects. The most common limb abnormalities appeared to be brachydactyly, syndactyly of toes 2 and 3 and hypoplastic toenails. Additional features observed were cutis marmorata telangiectatica congenita, cryptorchidism and cardiac abnormalities. In an attempt to identify the disease-causing mutations in our families, we selected two genes, ALX4 and MSX2, which were considered serious candidates based on their known function in skull and limb development. Mutation analysis of both genes, performed by direct sequencing, identified several polymorphisms, but no disease-causing mutations. Therefore, we can conclude that the AOS in our set of patients is not caused by mutations in ALX4 or MSX2.

DNA Mutational Analysis↗
PubMed2003

A new locus for postaxial polydactyly type A/B on chromosome 7q21-q34.

Postaxial polydactyly (PAP) is the occurrence of one or more extra ulnar or fibular digits or parts of it. In PAP-A, the extra digit is fully developed and articulates with the fifth or an additional metacarpal/metatarsal, while it is rudimentary in PAP-B. Isolated PAP usually segregates as an autosomal dominant trait, with variable expression. Three loci are known for PAP in humans. PAPA1 (including PAP-A/B in one patient) on 7p13 caused by mutations in the GLI3 gene, PAPA2 on 13q21-q32 in a Turkish kindred with PAP-A only, and a third one (PAPA3) in a Chinese family with PAP-A/B on 19p13.1-13.2. We identified a fourth locus in a large Dutch six-generation family with 31 individuals including 11 affecteds. Their phenotype varied from either PAP-A, or PAP-B to PAP-A/B with or without the co-occurence of partial cutaneous syndactyly. We performed a whole-genome search and found linkage between PAP and markers on chromosome 7q. The highest LOD score was 3.34 obtained at D7S1799 and D7S500 with multipoint analysis.

Chromosomes, Human, Pair 7↗
PubMed2000

Case report: orthodontic and dentofacial orthopedic considerations in Apert's syndrome.

Apert's syndrome is a developmental malformation characterized by: craniosynostosis, a cone-shaped calvarium, midface hypoplasia, pharyngeal attenuation, ocular manifestations, and syndactyly of the hands and feet. The prodromal characteristic for the typical craniofacial appearance is early craniosynostosis of the coronal suture, the cranial base, and an agenesis of the sagittal suture. These craniofacial characteristics predispose the patient to maxillary transverse and sagittal hypoplasia with concomitant dental crowding, a maxillary pseudocleft palate, and a skeletal and dental anterior open bite. This is a case report of an Apert's syndrome patient with a discussion of the orthodontic and dentofacial orthopedic considerations that influenced the treatment plan.

Acrocephalosyndactylia↗
PubMed2000

Cutis marmorata telangiectatica congenita: report of 18 cases.

We report 18 patients with cutis marmorata telangiectatica congenita (CMTC) who visited the University Hospital Nijmegen between 1982 and 1999. In 11 patients (61%), associated abnormalities of varying severity were observed. Three of these patients had a previously described distinct syndrome comprising CMTC, a naevus flammeus at the upper lip/philtrum, macrocephaly and syndactyly, among other abnormalities. Findings in the other eight patients with associated abnormalities included hydrocephalus, hyperplasia/hypoplasia (body asymmetry), anal atresia, hearing loss, cardiovascular abnormalities, strabismus hypothyroidism, haemangioma, naevus anaemicus, café-au-lait spot, lipoma and an elevation of the right diaphragm. All cases were sporadic.

Abnormalities, Multiple↗
PubMed2000

A Japanese case of Kindler syndrome.

A 25-year-old Japanese woman presented with contracture of the fingers and toes, and difficulty in opening her mouth. Her grandparents are first cousins, but none of the other members of the family are affected. Bulla formation started at birth on areas of the skin that received pressure, and in infancy and early childhood the lesions were limited only to the acral areas. She also had bilateral, incomplete syndactylies involving all web spaces (Fig. 1a). The formation of blisters ceased after the age of 15 years, but a generalized progressive poikiloderma then appeared with accompanying cutaneous atrophy of the skin of the neck, trunk, and extremities (Fig. 1b). The patient experienced mild photosensitivity of the face and neck. At age 18 years, surgical removal of the webbing of all her fingers was performed. Oral examination showed atrophy of the buccal mucosa, and an inability to fully open the mouth. The patient also suffered from poor dentition and easily bleeding gums, but had no symptoms of esophageal dysfunction. Histology of separate biopsy specimens, taken from the poikilodermatous pretibial and trunk skin, showed classical features of poikiloderma, namely epidermal atrophy with flattening of the rete ridges, vacuolization of basal keratinocytes, pigmentary incontinence, and mild dermal perivascularization (Fig. 2a). Interestingly, dyskeratotic cells (Fig. 2b) and eosinophilic rounded bodies (colloid bodies) (Fig. 2c) were frequently found at the basal keratinocyte layer and in the upper dermis, respectively. Pigment was also present in the upper epidermis. To rule out the possibility of a congenital epidermolysis bullosa, ultrastructural and immunofluorescence studies were performed. Ultrastructural studies demonstrated the reduplication of the basal lamina with branching structures within the upper dermis and cleavage between the lamina densa and the cell membrane of the keratinocytes (Fig. 3a). The numbers of associated anchoring fibrils did not seem to be reduced, and colloid bodies and dyskeratotic cells were detected. Immunofluorescence studies with the antibody against type VII collagen (LH 7 : 2) were subsequently carried out. The results showed extensive broad bands with intermittently discontinuous and reticular staining at the dermo-epidermal junction (DEJ) (Fig. 3b), whereas a linear distribution is typically seen in healthy tissue (data not shown). Interestingly, direct immunofluorescence studies revealed intracellular accumulation of immunoglobulin G (IgG), IgM, IgA, and C3 in colloid bodies under the basement membrane (Fig. 3c).

Adult↗
PubMed2003

Chromosome 2 deletion encompassing the MAP2 gene in a patient with autism and Rett-like features.

We present here a unique case of a 14-year-old female with autism and some features similar to Rett syndrome (RTT). Genetic analysis demonstrated a large deletion of chromosome 2q instead of a MECP2 mutation. Like a Rett patient, she is dyspraxic and shows frequent hand-washing stereotypic activities, hyperpnea, and bruxism. Like a preserved speech variant (PSV) of RTT, she is obese, able to speak in second and third persons, frequently echolalic, and has final normal head circumference and autistic behavior. In addition, she has dysmorphic features such as down-slanting palpebral fissures, low set ears without lobuli, bilateral flat feet, and bilateral syndactyly of the second and third toes, which do not belong to the Rett spectrum. She has a de novo chromosomal deletion in 2q34 of paternal origin. Gene content analysis of the deleted region showed the presence of 47 genes (14 putative and 33 known genes). This region contains some interesting genes such as ADAM23/MDC3, CREB1, KLF7, and MAP2. Because alteration of neuronal maturation, dendritic anomalies, and a decrease in MAP2 immunoreactivity in white matter neurons are well documented in RTT patients, we propose MAP2 gene as a good candidate for the generation of PSV phenotype in this case.

Adolescent↗
PubMed2001

Respiratory complications during anaesthesia in Apert syndrome.

BACKGROUND: Clinical experience with anaesthesia for a series of patients with Apert syndrome (craniosynostosis, midface hypoplasia and syndactyly) has not been reported previously. METHODS: In this review, 10 years of experience was examined at our hospital. There were 145 anaesthetics administered to 18 individuals. RESULTS: There were 16 complications (15 were perioperative wheezing) which occurred in seven patients. In four cases, surgery was cancelled due to intractable wheezing. CONCLUSIONS: We could not demonstrate any benefit from preoperative administration of nebulized albuterol. Paediatric anaesthetists should be aware of this high incidence of respiratory complications in Apert syndrome.

Acrocephalosyndactylia↗
PubMed2002

A review of the literature of Bardet-Biedl disease and report of three cases associated with metabolic syndrome and diagnosed after the age of fifty.

Bardet-Biedl syndrome (BBS) is a genetic autosomal-recessive disease (formerly grouped with Laurence-Moon-Biedl syndrome but considered today as a separate entity) characterized by abdominal obesity, mental retardation, dysphormic extremities (syndactyly, brachydactyly or polydactyly), retinal dystrophy or pigmentary retinopathy, hypogonadism or hypogenitalism (limited to male patients) and kidney structural abnormalities or functional impairment. The expression and severity of the various clinical BBS features show inter- and intrafamilial variability. This study focuses on three cases of familial BBS--two sisters and one brother (66, 64 and 51 years of age, respectively)--with the main cardinal findings of the disease plus a classic 'metabolic syndrome' (characterized by abdominal obesity, atherogenic dyslipidaemia, raised blood pressure, insulin resistance with or without glucose intolerance, and prothrombotic risk and proinflammatory states). One female patient (not affected by reproductive dysfunction) had three healthy offspring, while the other two patients were unmarried. Another severely affected brother died at 70 years of age; two other brothers are lean but affected by nephropathy, retinopathy, slight mental retardation, polydactyly, hypertension and thrombotic diseases, and had healthy offspring. BBS is a rather rare but severe syndrome that is often mis- or undiagnosed. Ophthalmologists, endocrinologists and nephrologists should be aware of BBS because of its adverse prognosis--early onset of blindness, associated findings of metabolic syndrome and increased vascular risk, and severe renal impairment (the most frequent cause of reduced survival and death early in life).

Abnormalities, Multiple↗
PubMed1991

Screening for fetal anomalies during the first trimester of pregnancy: transvaginal versus transabdominal sonography.

Ultrasound is a sensitive tool for the diagnosis of fetal anomalies during the prenatal period. Most knowledge about the ultrasound images of such anomalies is based on abdominal scanning during the second trimester of pregnancy. The value of transvaginal sonography for evaluating fetal anomalies and a comparison with transabdominal sonography in the first trimester has, to our knowledge, so far not been studied. During a 12-month period, 800 pregnant women between 9 and 13 weeks of gestation, underwent first a transabdominal scan followed by a transvaginal examination, in order to compare the value of the two techniques. Eight cases of fetal abnormality, including anencephaly, exencephaly, cervical myelomeningocele, cystic hygroma, omphalocele, posterior fossa cyst and syndactyly, were diagnosed by using the transvaginal sonographic approach. The standard abdominal technique failed to detect four of these anomalies, while in the other four only vague and non-specific fetal abnormalities could be demonstrated. All women with normal abdominal and vaginal sonograms in the first trimester were rescreened transabdominally at mid-gestation. Five patients with a variety of fetal anomalies, including hydrocephalus, agenesis of corpus callosum, bilateral ureteropelvic junction obstruction, right heart hypoplasia and tetralogy of Fallot, were identified in the rescreening procedure. One case of ventricular septal defect and coarctation of the aorta was not detected at either of the first or second screening procedures. Our findings show that transvaginal sonography is more sensitive than transabdominal sonography in the detection of first-trimester anomalies. However, since not all fetal anomalies are manifest so early in pregnancy, standard abdominal sonography in the second trimester is still recommended.

Journal Article↗
PubMed1999

Second-trimester molecular prenatal diagnosis of sporadic Apert syndrome following suspicious ultrasound findings.

Apert syndrome, an autosomal dominant disorder characterized by craniosynostosis, mid-facial malformations, symmetric bony syndactyly of hands and feet, and varying degrees of mental retardation, is most frequently caused by a de novo mutation. Two missense mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have been found to account for the disorder in approximately 98% of affected patients. Seven cases of prenatal ultrasound diagnosis have been reported. Although one earlier diagnosis has been made in a familial case, sporadic cases have not been definitively diagnosed until the third trimester when craniosynostosis is usually detected. We report a second-trimester molecular diagnosis of a sporadic case, based on the ultrasound observation of fetal 'mitten hands' and craniosynostosis. We discuss the approach to such ultrasound features, given the current availability of molecular diagnosis for Apert syndrome.

Abortion, Therapeutic↗
PubMed2001

Prenatal diagnosis of Bardet-Biedl syndrome by targeted second-trimester sonography.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by mental retardation, obesity, retinal degeneration, polydactyly and syndactyly, diabetes mellitus, hypogenitalism, renal dysplasia and short stature. Definitive molecular diagnosis for BBS is not currently available and counseling of affected families is based on the 25% recurrence risk consistent with autosomal recessive inheritance. Our case presents the first successful use of second trimester targeted sonographic anatomy scanning to prospectively identify a fetus affected with BBS, and indicates that ultrasound can be of critical importance in providing precise as well as timely prenatal diagnosis for families at risk for this serious disorder.

Adult↗
PubMed2002

Prenatal diagnosis of de novo mosaic deletion 13q associated with multiple abnormalities.

A case of prenatal diagnosis of de novo mosaic deletion of the long arm of chromosome 13 (del(13)(q13.3)) is presented. Routine scanning in a 27-year-old primigravida at 25 weeks' gestation showed fetal bilateral hydronephrosis. Detailed anomaly scanning in our tertiary referral center further demonstrated posterior meningoencephalocele, sloping forehead, microcephaly, syndactyly and hypoplastic thumbs. Both genetic amniocentesis and cordocentesis revealed a mosaic karyotype, 46,XY/46,XY,del(13)(q13.3). Sonographic findings were confirmed by postmortem autopsy and additional abnormalities such as agenesis of corpus callosum, hypoplastic cerebellum and macroglossia were diagnosed. Detailed sonography in this case thus revealed multiple malformations that prompted fetal karyotyping at 25 weeks' gestation.

Abnormalities, Multiple↗
PubMed2003

Sonic hedgehog: restricted expression and limb dysmorphologies.

Sonic hedgehog, SHH, is required for patterning the limb. The array of skeletal elements that compose the hands and feet, and the ordered arrangement of these bones to form the pattern of fingers and toes are dependent on SHH. The mechanism of action of SHH in the limb is not fully understood; however, an aspect that appears to be important is the localized, asymmetric expression of Shh. Shh is expressed in the posterior margin of the limb bud in a region defined as the zone of polarizing activity (ZPA). Analysis of mouse mutants which have polydactyly (extra toes) shows that asymmetric expression of Shh is lost due to the appearance of an ectopic domain of expression in the anterior limb margin. One such polydactylous mouse mutant, sasquatch (Ssq), maps to the corresponding chromosomal region of the human condition pre-axial polydactyly (PPD) and thus represents a model for this condition. The mutation responsible for Ssq is located 1 Mb away from the Shh gene; however, the mutation disrupts a long-range cis-acting regulator of Shh expression. By inference, human pre-axial polydactyly results from a similar disruption of Shh expression. Other human congenital abnormalities also map near the pre-axial polydactyly locus, suggesting a major chromosomal region for limb dysmorphologies. The distinct phenotypes range from loss of all bones of the hands and feet to syndactyly of the soft tissue and fusion of the digits. We discuss the role played by Shh expression in mouse mutant phenotypes and the human limb dysmorphologies.

Embryonic Induction↗
PubMedDate not supplied

Prevalence and new phenotypic and radiologic findings in congenital onychodysplasia of the index finger.

Congenital onychodysplasia of the index finger (COIF) is a rare condition characterized by dysplastic changes in the nail with variable phenotypic manifestations. Its prevalence is unknown. We describe three newborn patients with various clinical and radiologic expressions of this entity. The first, born to a mother treated with multiple antidepressant drugs, had bilateral nail dysplasia of the index finger without bony involvement. The second presented with bilateral hypoplastic nail of the index finger and bilateral symphalangism of the fifth finger; aplastic distal phalanges of the second finger was also noted radiologically. The third baby (born to a diabetic mother treated with insulin), had micronychia and brachydactyly of the right index finger and syndactyly of the second and third fingers; the radiologic finding was bilateral brachymesophalangia of the index finger. It would seem that, besides the nail dysplasia of the index finger, COIF may also be associated with bone dysplasia of the same finger.

Female↗