Sibylle Strenge

A missense mutation in the ZFHX1B gene associated with an atypical Mowat-Wilson syndrome phenotype.

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 2½‐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.

New Mutations of EXT1 and EXT2 Genes in German Patients with Multiple Osteochondromas

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.

Pulmonary artery sling and congenital tracheal stenosis in another patient with Mowat–Wilson syndrome

Sibylle Strenge,* Wolfram Heinritz, Christiane Zweier, Anita Rauch, Udo Rolle, Andreas Merkenschlager, and Ursula G. Froster Medical Faculty, Institute of Human Genetics, University of Leipzig, Leipzig, Germany Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany

Renal malformations in deletion 22q11.2 patients

DiGeorge anomaly (OMIM #188400) consists of hypoplasia of the thymus, T-Cell deficiency, hypoparathyroidism and structural heart defects [DiGeorge, 1965; Greenberg et al., 1984; Wilson et al., 1993]. Since establishment of fluorescence in situ hybridization (FISH), microdeletions in 22q11.2 were detectable in an increasing number of patients with DiGeorge anomaly, velocardiofacial syndrome (VCFS, syn. Shprintzen syndrome) and conotruncalanomaly-face syndrome [Scambler et al., 1991; Carey et al., 1992]. The 22q11.2 microdeletion syndrome occurs in 1/4,000 live births and constitutes the most frequent interstitial chromosomal aberration. A wide spectrum of clinical findings has been described in patients carrying the 22q11.2 deletion. The main symptoms are congenital heart defects, particularly conotruncal anomalies, immune deficiency and characteristic facial features. Congenital heart defects are present in over 70% of patients. Hearing loss, renal malformations, growth failure, and seizures are described less frequently. Also psychiatric disorders like schizophrenia are common in deletion 22q11.2 patients [Bassett et al., 2003]. We selected 31patientswith complete descriptions of their clinical phenotype. Patients with incomplete clinical data were excluded from this report. Of the 31 patients evaluated for microdeletion 22q11.2, 30 of them were referred to our clinic because of cardiovascular malformations and one because of velopharyngeal insufficiency and facial dysmorphisms. A complex heart defect associated with other malformations such as facial dysmorphisms, facial clefts and immune defects was reported in 27 patients at referral while in three patients an isolated heart defect was present. Routine cytogenetic analysis on Giemsa-banded chromosomes from cultured blood lymphocytes were performed on all 31 patients and were normal. FISH on metaphase chromosomes using DNA probes from the DiGeorge critical region, DGCR [TUPLE1, N25; Abbott/Vysis] for 22q11–13 deletion screening was performed. The clinical data of the patients were re-evaluated after cytogenetic and molecular cytogenetic investigations were completed to specify the phenotype. We found a microdeletion 22q11.2 in six out of the 31 selected patients (19%). Using the probes TUPLE1 and N25 (Abbott/Vysis) we found both loci to be deleted, spanning the complete DGCR. The affected patients showed typical facial features such as ear abnormalities and micrognathia. Two of these six patients were diagnosed with immune deficiencies and thymic hypoplasia. The clinical findings were summarized in Table I. In particular we noticed a high percentage of renal malformations in our group. In five out of six patients (80%) renal dysplasia, hydronephrosis and single kidney were recognized (seeTable I).Whileour sample size is small, this rateof renal anomalies in our group is higher than expected. Earlier studies demonstrated a percentage up to 40% for renal malformations in patients with a microdeletion 22q11 [Stewart et al., 1999; Wu et al., 2002]. Stewart et al. [1999] described an incidence of renal anomalies of 38.4% including bilateral duplex kidney, unilateral renal agenesis and dysplastic or small kidneys. The types of renal malformations noted in our study are similar to these of the European collaborative study [Ryan et al., 1997] and the study from Stewart et al. [1999]. However, Stewart et al. did not find a correlation between thymic and

Microcephaly‐lymphedema syndrome: Report of a family with short stature as additional manifestation

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.

Diaphragmatic hernia in 18p- syndrome.

A deletion of the short arm of chromosome 18 was first reported in 1963 [De Grouchy, 1963]. Today, more than 150 cases have been described in detail [Schinzel, 2001]. There is a broad variability in the phenotype. We present a case of congenital diaphragmatic hernia (CDH) in a girl with 18psyndrome. This is the first report of CDH associated with deletion 18psyndrome. The girl is the first and only child born to healthy, nonconsanguineous parents. At birth, the mother was 23 and fatherwas 27 years old. Therewas no exposure to alcohol, nicotine, drugs, or human teratogens during pregnancy.Diagnosis of diaphragmatic herniawasmade at the 30th week of gestation. Prenatal sonographic examination showed intrauterine growth retardation of the fetus. A left-sided CDH, intrathoracic position of the fetal stomach, and mediastinal shift were seen by highresolution ultrasound. Oligohydramnios was present. Amniocentesis was not performed. The girl was delivered at a gestational age of 37weeks by caesarean section. Apgar scores at 1, 5, and 10 min were 7, 8,and 9, respectively. Birth weight was 1,420 g (<3rd centile), length 41 cm (<3rd centile), and head circumference 29 cm (<3rd centile). Stomach, spleen, and parts of the small and large intestine were transferred into the chest. There was associated hypoplasia of the left lung. Two operations were necessary to correct the CDH succesfully. In the neonatal period, the girl suffered from breathing problems. Onphysical examination at the age of 5weeks (Fig. 1), multiple dysmorphic signs were present: high forehead, depressed nasal bridge, anteverted tip of the nose, wide mouth with downturning corners, low-set ears, atypical palmar furrows, and clinodactyly of 5th fingers. Other findings included widely spaced nipples, webbed neck, and relatively short arms. On physical examination at the age of 3months, lengthwas 53 cm (<3rd centile) and head circumference was 35.5 cm (<3rd centile). Cytogenetic study was performed on Giemsa-banded chromosomes from cultured peripheral blood lymphocytes. Chromosomal analysis revealed the karyotype 46,XX,del(18)(p11). The short arm of chromosome 18 (pter!p11) was deleted. The banding level was 550. Fluorescence in situ hybridization (FISH) analysis was performed onmetaphases to excludemore complex rearrangements. We used the commercially available Vysis TelVysion probe 18pSpectrumGreen (Abbott GmbH and Company, Wiesbaden-Delkenheim, Germany) specific for the subtelomeric locus D18S552. FISH yielded only one fluorescence signal at the terminal part of the short arm of the normal chromosome 18.No signal could be visualized on the deleted chromosome 18 or any other chromosome in all metaphases examined. There was no family history of chromosomal aberrations or congenital malformations. Chromosomal analyses of the parents showed the karyotype 46,XX and 46,XY, respectively. CDH is a relatively common malformation. The true incidence of CDH is difficult to establish as a number of affected fetuses die prenatally or at birth. Kaiser and Rosenfeld [1999] showed an incidence of 1/4,200 live births. Although CDH is a surgically correctable anatomical defect of the diaphragm, it is associated with high perinatal morbidity and mortality. CDH is often associated with additional malformations. The possibility of chromosomal abnormalities in CDH is well known. The incidence of chromosomal aberrations in fetuses with CDH was reported with a varying incidence from 2–34%. [Thorpe-Beeston et al., 1989; Nicolaides et al., 1993; Manni et al., 1994; Bollmann et al., 1995; Howe et al., 1996; Witters et al., 2001]. Manni et al. [1994] demonstrated the need for karyotyping, in particular when CDH is associated with multiple anomalies. In the study ofWitters et al. [2001], all cases of chromosomal anomalies in CDH were associated with evidence of additional problems. This case supports this observations. The prenatally detected diaphragmatic hernia was associated with intrauterine growth retardation and oligohydramnios. Chromosomal abnormalities described in cases of diaphragmatic hernia include numerical and structural aberrations. The most common chromosomal defects were trisomy 18 and 13 [Thorpe-Beeston et al., 1989; Nicolaides et al., 1993]. Howe et al. [1996] pointed out that a large proportion of fetuses with diaphragmatic hernia in association with chromosomal abnormalities had structural anomalies such as deletions, translocations, and additional marker chromosomes. The varying chromosomal aberrations detected in fetuses with diaphragmatic hernia suggest that there is no single chromosomal location for CDH (Table I). *Correspondence to: Sibylle Strenge, Institut für Humangenetik, Universität Leipzig, Philipp-Rosenthal-Str 55, D-04103 Leipzig, Germany. E-mail: strs@medizin.uni-leipzig.de

Different Phenotypes Including Gynecological Cancer in Three Female Patients with Peutz-Jeghers Syndrome and Mutations in the STK11 Gene

Background: 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. Patients and Results: 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. Conclusion: 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.

A microdeletion 22q11.2 can resemble Shprintzen-Goldberg omphalocele syndrome.

In the article entitled, ‘‘Shprintzen–Goldberg omphalocele syndrome: A new patient with an expanded phenotype,’’ Zelante et al. [2006] reported on a patient with Shprintzen–Goldberg omphalocele syndrome. Shprintzen and Goldberg [1979] described this malformation syndrome which includes dysmorphic facies, omphalocele, laryngeal and pharyngeal hypoplasia, scoliosis, and learning disabilities as major symptoms and is thought to be an autosomal dominant condition (OMIM 182210) (Table I). The patient of Zelante et al. [2006] had an expanded phenotype. We had the opportunity to evaluate a boy who showed resemblance to the Shprintzen–Goldberg omphalocele syndrome. Major symptoms were short stature, laryngeal abnormalities, an umbilical hernia, unilateral renal agenesis, highly pitched voice, and retarded motor and mental development. His facial features (Fig. 1) included a round face, brachycephaly, plagiocephaly, frontal bossing, hypertelorism, epicanthi, broad and high nasal bridge, downturned mouth, thin upper lip, micrognathia, and dysplastic low-set ears. Because of his unusual voice, a bronchoscopy was performed showing severe constrictions of the glottic airway. The height at age 2 6/12 years was 81 cm (5 cm <3rd centile) and the head circumference 50 cm (50th centile). The development was retarded: he started to walk at age 1 9/12 years and spoke the first few words at 2 years of age. Family history was unremarkable. Cytogenetic analysis of peripheral blood lymphocytes (G-banded chromosomes at 500 band resolution) showed a normal male karyotype 46,XY. FISH analysis (TUPLE1 and LSI DiGeorge N25 [Vysis, Abbott laboratories]) showed a deletion of the 22q11.2 region. Abnormalities associated with the 22q11 deletion syndrome are known to be extremely variable and are known to affect multiple body systems, including craniofacial and otolaryngeal structures, cardiovascular defects, skeletal, urogenital, and muscular abnormalities [Thomas and Graham, 1997]. Several features described in patients with Shprintzen– Goldberg omphalocele syndrome, such as laryngeal hypoplasia, membrane-like structures in the laryngeal lumen, anal atresia, and abnormal esophageal motility have been noted in patients with microdeletion 22q11.2. The diagnosis of Shprintzen–Goldberg omphalocele syndrome is based on the presence of omphalocele and pharynx/larynx hypoplasia as major diagnostic criteria. Further symptoms are unusual facies, abnormally high voice, scoliosis, hypotonia, and learning disabilities. Zelante et al. [2006] expanded the clinical phenotype, by describing a patient who had in addition an imperforate anus and dysphagia caused by an abnormal esophageal motility. These authors reported a normal male karyotype (46,XY) in their patient. Also FISH studies for subtelomeric rearrangements gave normal results, as did FISH analysis for del22q11.2. Chromosomal analysis is not mentioned in the original Shprintzen and Goldberg [1979] report. In conclusion, the present patient showed clinical features overlapping with Shprintzen–Goldberg omphalocele syndrome but in fact had a microdeletion of 22q11. Therefore, if Shprintzen–Goldberg omphalocele syndrome is considered in a patient, FISH studies to exclude a microdeletion 22q11.2 seem warranted.

Prenatal diagnosis of del(15)(q26.1) and del(18)(q21.3) due to an unbalanced de novo translocation: ultrasound, molecular cytogenetic and autopsy findings.

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. Copyright

Rezidivierende Muskellähmungen - HNPP als wichtige Differenzialdiagnose

Rezidivierende Muskellahmungen geben oft Anlass zu einer ausgedehnten apparativen Diagnostik. Ein 14-jahriger Junge wurde mit Paresen im Bizeps- und Fusheberbereich nach Bagatelltrauma vorgestellt. Familienanamnestisch fielen rezidivierende passagere Lahmungen beim Kindesvater auf. Die Elektroneuro- und Elektromyographie (EMG/ ENG) zeigten eine peripher-neurogene Schadigung. In der genetischen Untersuchung konnte mit dem Nachweis einer Deletion im Bereich des Peripheren Myelin Protein 22-Gens (PMP22) in der chromosomalen Region 17p11.2 der klinische Verdacht auf eine HNPP (hereditary neuropathy with liability to pressure palsies) bestatigt werden. Eine Duplikation des gleichen Gens verursacht eine HMSN 1A (hereditare motorisch-sensorische Neuropathie Typ 1A). Bei fehlender kausaler Therapie ist die Vermeidung traumatischer Nervenlasionen von groser Bedeutung. Bei akuter Symptomatik kann TENS (transkutane elektrische Nervenstimulation) angewendet werden.