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Peutz-Jeghers syndrome (PJS), a rare hereditary disorder, is characterized by the occurrence of gastrointestinal hamartomatous polyps associated with mucocutaneous pigmentation. Patients are at an increased cancer risk not only for gastrointestinal but also for extraintestinal neoplasms.We report on the clinical and molecular findings in 3 young female patients with PJS; 2 of them suffered from severe gynecological cancer. One patient died at the age of 29 years of an incurable mucin-producing cervical adenocarcinoma. Another patient had a papillary serous carcinoma of the ovary. In all patients, we identified corresponding mutations in the STK11 gene, 2 of them novel.PJS should be considered in differential diagnosis in young women with gynecological malignancies. Identification of STK11 mutations in patients and their relatives can help to improve the clinical management.

ZusammenfassungDie genetische Beratung ist integraler Bestandteil in der Abklärung genetisch bedingter und mitbedingter Entwicklungsstörungen im Kindesalter. Wichtige Elemente der genetischen Beratung sind die Stammbaumerhebung sowie die klinisch-genetische Untersuchung. Dabei gilt es, das Auftreten von einzelnen Merkmalen, Dysmorphiezeichen und klinischen Manifestationen zu einem Gesamtbild zusammenzuführen. Bereits ab dem frühen Kleinkindesalter ist die Diagnosefindung für die Eltern außerordentlich wichtig – einerseits, um einen Namen für die Entwicklungsstörung zu finden und damit auch eine Ursache benennen zu können und andererseits, um die Entwicklung der Kinder zu unterstützen. Ein weiterer Aspekt in der Arbeit der Humangenetik ist die Bestimmung des Wiederholungsrisikos.

ZusammenfassungAls Ursache einer großen Zahl von MCA/MR-Syndromen (multiple kongenitale Anomalien/mentale Retardierung) wurden Mikrodeletionen identifiziert. Wir veranschaulichen häufige Mikrodeletionssyndrome unter Berücksichtigung der zugrunde liegenden genetischen Faktoren, der klinischen Aspekte und diagnostischen Möglichkeiten. Patienten mit Prader-Willi-Syndrom, Angelman-Syndrom, Williams-Beuren-Syndrom sowie Patienten mit einer Mikrodeletion 22q11.2 werden vorgestellt.

Prenatal diagnosis of Duchenne and Becker muscular dystrophy (DMD) is performed as a routine procedure in many laboratories. The major potential problem is an incorrect diagnosis that could be obtained due to contamination with maternal tissue. We report a case of mosaicism of the X-chromosomes confined to the placenta as a possible source of confusing results in prenatal diagnosis of DMD. To the best of our knowledge, this is the first reported case of this problem in a prenatal DMD diagnosis.

Patients with the rare autosomal dominant microcephaly-lymphedema syndrome have apparently normal intelligence. We report on a boy with microcephaly, lymphedema, and short stature as an additional manifestation. The family history of our patient suggests autosomal dominant inheritance with reduced penetrance and variable expressivity. However, X-linked inheritance cannot be excluded.

Es wird ein 15jahriges Madchen mit einer hypohidrotischen ektodermalen Dysplasie vorgestellt. Die Patientin wies eine Oligodontie und Zahnformanomalien auf. Das Behaarungsmuster war generell stark reduziert, der Minor-Schweistest pathologisch. Das histologische Bild der Haut lies keine Schweisdrusen und nur rudimentare Adnexstrukturen erkennen. Die Mutter und die Schwester der Patientin wiesen hingegen lediglich eine Hypodontie auf. Diskussion: Bei rezidivierendem Fieber unklarer Ursache mit gleichzeitig vorhandenen Zahn- und Haaranomalien sollte auch an die hypohidrotische ektodermale Dysplasie gedacht werden.

Mutations in the Notch3 gene in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) usually involve cysteine residues.1 We report a cysteine-sparing mutation (A1020P) in association with a CADASIL-compatible phenotype in two German families. ### Case histories. The index patient 1 is a 49-year-old woman with a medical history of sensorineural hearing loss of adolescent onset. At the age of 34, arterial hypertension was diagnosed. Since her 40s she reported episodes of unilateral headache, vertigo, and nausea. In addition, the patient had intermittent paresthesias and weakness of the left extremities, reduced fine motor skills, cognitive slowing, and impaired memory. MRI in 2003 revealed widespread T2-hyperintense white matter lesions (WMLs) (figure, A). Electron microscopic examination of a skin biopsy showed deposits of osmiophilic material between the smooth-muscle cells of small arteries (figure e-1 on the Neurology ® Web site at www.neurology.org), and immunostaining with a Notch3 monoclonal antibody showed granular labeling of vascular smooth-muscle cells (figure e-2). Figure Axial T2-weighted (A, C, E) and fluid-attenuated inversion recovery MRIs (B, D) of the index patient (A), the index patient’s mother (B), and patient 2 (D), compatible with widespread ischemic leukoaraiosis Note especially the absence of white matter lesions (WMLs) in the anterior temporal lobes in all three individuals. The MRI of the index patient’s uncle (C), although characterized as a mutation carrier, only showed a slight pallor of the white matter and dilated Virchow Robin spaces. (E) MRI of the father of the …

Item does not contain fulltext Mutations in either the EXT1 or EXT2 genes lead to Multiple Osteochondromas (MO), an autosomal dominantly inherited disorder. This is a report on clinical findings and results of molecular analyses of both genes in 23 German patients affected by MO. Mutation screening was performed by using denaturing high performance liquid chromatography (dHPLC) and automated sequencing. In 17 of 23 patients novel pathogenic mutations have been identified; eleven in the EXT1 and six in the EXT2 gene. Five patients were carriers of recurrent mutations in the EXT2 gene (p.Asp227Asn, p.Gln172X, p.Gln258X) and one patient had no detectable mutation. To demonstrate their pathogenic effect on transcription, two complex mutations in EXT1 and EXT2 and three splice site mutations were characterized by mRNA investigations. The results obtained provide evidence for different aberrant splice effects - usage of new cryptic splice sites and exon skipping. Our study extends the mutational spectrum and understanding of pathogenic effects of mutations in EXT1 and EXT2.

Mowat-Wilson syndrome (MWS) is a rare mental retardation-multiple congenital anomalies syndrome associated with typical facial dysmorphism. Patients can show a variety of other anomalies like short stature, microcephaly, Hirschsprung disease, malformations of the brain, seizures, congenital heart defects and urogenital anomalies. Mutations leading to haploinsufficiency of the ZFHX1B gene have been described as the underlying cause of this condition. We report on the clinical findings in a 2(1/2)-year-old boy with some aspects out of the MWS-spectrum in addition to unusual anomalies and a novel missense mutation in the ZFHX1B gene.

A case of partial deletion of the distal parts of chromosomes 15 and 18 [(15)(q26.1)(18)(q21.3)] due to a de novo translocation is reported. Cordocentesis and fetal karyotyping was done because of severe oligohydramnios and bilateral absence of kidneys. Renal defects are a frequent finding in fetuses with different chromosomal anomalies; this particular chromosomal rearrangement however has not been reported yet in a fetus with bilateral renal agenesis. FISH was performed for detailed clarification of the chromosomal anomaly. Prenatal karyotyping appears to be important in fetuses with renal agenesis.

Greig cephalopolysyndactyly syndrome, characterized by craniofacial and limb anomalies (GCPS; MIM 175700), previously has been demonstrated to be associated with translocations as well as point mutations affecting one allele of the zinc finger gene GLI3. In addition to GCPS, Pallister-Hall syndrome (PHS; MIM 146510) and post-axial polydactyly type A (PAP-A; MIM 174200), two other disorders of human development, are caused by GLI3 mutations. In order to gain more insight into the mutational spectrum associated with a single phenotype, we report here the extension of the GLI3 mutation analysis to 24 new GCPS cases. We report the identification of 15 novel mutations present in one of the patient's GLI3 alleles. The mutations map throughout the coding gene regions. The majority are truncating mutations (nine of 15) that engender prematurely terminated protein products mostly but not exclusively N-terminally to or within the central region encoding the DNA-binding domain. Two missense and two splicing mutations mapping within the zinc finger motifs presumably also interfere with DNA binding. The five mutations identified within the protein regions C-terminal to the zinc fingers putatively affect additional functional properties of GLI3. In cell transfection experiments using fusions of the DNA-binding domain of yeast GAL4 to different segments of GLI3, transactivating capacity was assigned to two adjacent independent domains (TA 1 and TA 2 ) in the C-terminal third of GLI3. Since these are the only functional domains affected by three C-terminally truncating mutations, we postulate that GCPS may be due either to haploinsufficiency resulting from the complete loss of one gene copy or to functional haploinsufficiency related to compromised properties of this transcription factor such as DNA binding and transactivation.