Petra Muschke

Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome.

Craniofrontonasal syndrome (CFNS) is an X-linked craniofacial disorder with an unusual manifestation pattern, in which affected females show multiple skeletal malformations, whereas the genetic defect causes no or only mild abnormalities in male carriers. Recently, we have mapped a gene for CFNS in the pericentromeric region of the X chromosome that contains the EFNB1 gene, which encodes the ephrin-B1 ligand for Eph receptors. Since Efnb1 mutant mice display a spectrum of malformations and an unusual inheritance reminiscent of CFNS, we analyzed the EFNB1 gene in three families with CFNS. In one family, a deletion of exons 2-5 was identified in an obligate carrier male, his mildly affected brother, and in the affected females. In the two other families, missense mutations in EFNB1 were detected that lead to amino acid exchanges P54L and T111I. Both mutations are located in multimerization and receptor-interaction motifs found within the ephrin-B1 extracellular domain. In all cases, mutations were found consistently in obligate male carriers, clinically affected males, and affected heterozygous females. We conclude that mutations in EFNB1 cause CFNS.

Shprintzen-Goldberg syndrome: fourteen new patients and a clinical analysis.

The Shprintzen–Goldberg syndrome (SGS) is a disorder of unknown cause comprising craniosynostosis, a marfanoid habitus and skeletal, neurological, cardiovascular, and connective‐tissue anomalies. There are no pathognomonic signs of SGS and diagnosis depends on recognition of a characteristic combination of anomalies. Here, we describe 14 persons with SGS and compare their clinical findings with those of 23 previously reported individuals, including two families with more than one affected individual. Our analysis suggests that there is a characteristic facial appearance, with more than two thirds of all individuals having hypertelorism, down‐slanting palpebral fissures, a high‐arched palate, micrognathia, and apparently low‐set and posteriorly rotated ears. Other commonly reported manifestations include hypotonia in at least the neonatal period, developmental delay, and inguinal or umbilical hernia. The degree of reported intellectual impairment ranges from mild to severe. The most common skeletal manifestations in SGS were arachnodactyly, pectus deformity, camptodactyly, scoliosis, and joint hypermobility. None of the skeletal signs alone is specific for SGS. Our study includes 14 mainly German individuals with SGS evaluated over a period of 10 years. Given that only 23 other persons with SGS have been reported to date worldwide, we suggest that SGS may be more common than previously assumed.

SIL1 mutations and clinical spectrum in patients with Marinesco-Sjögren syndrome

Marinesco-Sjögren syndrome is a rare autosomal recessive multisystem disorder featuring cerebellar ataxia, early-onset cataracts, chronic myopathy, variable intellectual disability and delayed motor development. More recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum resident co-chaperone, were identified as the main cause of Marinesco-Sjögren syndrome. Here we describe the results of SIL1 mutation analysis in 62 patients presenting with early-onset ataxia, cataracts and myopathy or combinations of at least two of these. We obtained a mutation detection rate of 60% (15/25) among patients with the characteristic Marinesco-Sjögren syndrome triad (ataxia, cataracts, myopathy) whereas the detection rate in the group of patients with more variable phenotypic presentation was below 3% (1/37). We report 16 unrelated families with a total of 19 different SIL1 mutations. Among these mutations are 15 previously unreported changes, including single- and multi-exon deletions. Based on data from our screening cohort and data compiled from the literature we found that SIL1 mutations are invariably associated with the combination of a cerebellar syndrome and chronic myopathy. Cataracts were observed in all patients beyond the age of 7 years, but might be missing in infants. Six patients with SIL1 mutations had no intellectual disability, extending the known wide range of cognitive capabilities in Marinesco-Sjögren syndrome to include normal intelligence. Modestly constant features were somatic growth retardation, skeletal abnormalities and pyramidal tract signs. Examination of mutant SIL1 expression in cultured patient lymphoblasts suggested that SIL1 mutations result in severely reduced SIL1 protein levels irrespective of the type and position of mutations. Our data broaden the SIL1 mutation spectrum and confirm that SIL1 is the major Marinesco-Sjögren syndrome gene. SIL1 patients usually present with the characteristic triad but cataracts might be missing in young children. As cognitive impairment is not obligatory, patients without intellectual disability but a Marinesco-Sjögren syndrome-compatible phenotype should receive SIL1 mutation analysis. Despite allelic heterogeneity and many families with private mutations, the phenotype related to SIL1 mutations is relatively homogenous. Based on SIL1 expression studies we speculate that this may arise from a uniform effect of different mutations on protein expression.

Refinement of the deletion in 7q21.3 associated with split hand/foot malformation type 1 and Mondini dysplasia.

Split hand/foot malformation type I (SHFM1, OMIM *183600) is an autosomal dominant developmental disorder of limb formation that results in the absence of the central digital rays, deep median clefts, and syndactyly of the remaining digits. Patients with SHFM1 harbour deletions, translocations, and inversions in chromosomal region 7q21–q22.1 The deletions at 7q21–q22 encompass different genomic regions and probably result in a contiguous gene syndrome that includes growth impairment, microcephaly, craniofacial manifestations, hernias, hearing loss, and mental retardation.2,3 Cases with translocations do not show this broad pattern of abnormalities but are associated with hearing loss in most cases.4,5 Split hand/foot malformation type I is the only form of split hand/foot malformation associated with sensorineural hearing loss, and it has been designated SHFM1D (OMIM *605617).5,6 Recently, SHFM1D was shown to result from Mondini dysplasia in a boy with a de novo deletion of about 8.9–17 cM of the paternal chromosome 7q21.1–q21.3.7 So far, microdeletions at 7q21.3 have been described in only two cases: one in a boy with split hand/foot malformation plus mild mental retardation, growth retardation of post-natal onset, and hypotonia and another in a patient with ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome.8,9 Mapping of the deletion and translocation breakpoints in several patients showed a critical interval of about 1 Mb for the SHFM1 locus at 7q21.3.9 This interval included a 500 kb region that spanned five of seven known translocation breakpoints. In this region, the candidate genes DLX5 and DLX6 (human homologues of the Drosophila distal-less homeobox gene family) and DSS1 (deleted in the split hand/split foot SHFM1 region) were identified. No mutations were detected in patients with sporadic split hand/foot malformation with translocations or two families with split hand/foot malformation, sensorineural deafness, and normal chromosomes who …

Genotype/phenotype analysis in a patient with pure and complete trisomy 12p.

Reports on patients with pure and complete trisomy 12p are rare. Up to now, 12 cases have been described in the literature. Here, we report on the genotype/phenotype‐correlation of a female patient with a pure trisomy 12p. Conventional cytogenetic studies on peripheral blood chromosomes as well as molecular cytogenetic (fluorescence in situ hybridization, FISH) techniques including whole chromosome painting (WCP), comparative genomic hybridization (CGH), multicolor‐banding (MCB) detected a female karyotype with an abberant chromosome 12:46,XX,der(12).ish dup(12)(pter → q24.3::p11.2 → pter). In addition to the trisomy 12p specific clinical hallmarks, the patient showed some features of Pallister–Killian syndrome (PKS) such as sparse hair, macroglossia, and epilepsy. These findings contribute to the genotype/phenotype correlation in trisomy 12p patients.

Mapping of a further locus for X-linked craniofrontonasal syndrome

Craniofrontonasal syndrome is a rare dysostosis syndrome with an unusual pattern of X-linked inheritance, because males are usually not or less severely affected than females. Previously, a CFNS locus has been localised in Xp22. We report on a haplotype analysis in a German CFNS family, mapping the CFNS locus to the pericentromeric region of the X chromosome. This discrepancy can be explained by locus heter- ogeneity. Furthermore, random X inactivation could be demonstrated in affected females. The most plausible interpretation for this unusual pattern of X-linked inheritance is metabolic interference. Consequently, we propose that the CFNS gene escapes X inactivation.

Intrachromosomal triplication 12p11.22–p12.3 and gonadal mosaicism of partial tetrasomy 12p,**

Cases of tetrasomy 12p and trisomy 12p are known to be associated with specific phenotypic abnormalities well described in the literature. Here, we report on the unusual case of a partial tetrasomy 12p found in an affected patient and in a mosaic constellation in the patients mother, who showed no phenotypic abnormality. The index patient was a 16‐year‐old boy with clinical features similar to the “trisomy 12p syndrome” including mental retardation, macrocephaly, a short nose with anteverted nostrils, and a broad protruding lower lip. G‐banding analysis and fluorescence in situ hybridization (FISH) experiments using locus specific YAC DNA probes revealed a derivative chromosome 12 with a partial triplication of the short arm with an inverted copy, flanked by two direct copies. Chromosome analyses in parental lymphocytes showed a chromosomal mosaicism in the phenotypically normal mother, with 12% cells exhibiting the same partial tetrasomy 12p as detected in her son. The allelic pattern of short tandem repeats (STR) in the mothers blood DNA showed that a chimerism can be excluded with high probability. To our knowledge, this is the first report of intrachromosomal triplication on chromosome 12, as well as partial tetrasomy 12p mosaicism. Moreover, as a consequence of the chromosomal aberration in the son it can be concluded that a gonadal mosaicism is present in the mother.

Autosomal recessive non-immune hydrops fetalis caused by systemic lymphangiectasia

Non-immune hydrops fetalis is a heterogeneous disorder with more than 150 underlying diseases resulting in this condition. Four major pathogenetic factors can be delineated: fetal circulatory disorders, non-immune anemia, decreased oncotic pressure, and disorders of lymphatic circulation. Lymphatic diseases can be caused by space occupying lesions such as intrathoracic mass or diaphragmatic hernia, or they can be only a symptom of systemic disorders like Noonan or Turner syndrome. Lymphangiectasia as a primary cause of lymphedemas is mostly restricted to selective areas, as it has been described in congenital pulmonary lymphangiectasia.We report on two sibs affected by non-immune hydrops generalisatus that is caused by systemic lymphangiectasia. The probands, a 17-year-old woman and a 27-year-old man, are healthy and presented to our genetic counseling unit because of recurrent hydrops fetalis. Otherwise, the medical history of both families was inconspicuous. Consanguinity was denied. In the first pregnancy hydrops fetalis was detected in the 16th week of gestation. Amniocentesis revealed a normal male karyotype (46,XY). Because of the infaust prognosis pregnancywas terminated. Pathological examination revealed nomalformations. In the secondpregnancyhydrops fetaliswas obvious in the 15th week. Amniotic fluid volume was normal. Amniocentesis revealed a female karyotype (46,XX). Delivery occurred in the 24thweek of pregnancy.Birthweightwas 830 g (75 centile), height was 29 cm (10 centile). The girl affected by a severe hydrops died 1 hr after delivery. Pathological examination demonstrated a systemic lymphangiectasia including skin, lungs, pancreas, liver, kidneys, and the surrounding tissues (Figs. 1and2). Internal or externalmalformationswere not detectable. Non-immune hydrops fetalis is a diagnostic challenge and the etiology frequently remains unclear [Villaespesa et al., 1990]. Disorders of lymphatic circulation is one of the pathogenetic factors leading to lymphedemas and hydrops fetalis in severe cases.One of the causes of disturbed lymphatic circulation is lymphangiectasia that is mostly restricted to selected areas as it is the case in pulmonary lymphangiectasia (CPL). Most cases of CPL seem to be sporadic, but ScottEmuakpor et al. [1981] and Moerman et al. [1993] reported on the first familial cases suggesting autosomal recessive inheritance. All cases described by Moerman et al. [1993] were associated with polyhydramnios. Furthermore, Irons et al. [1996] described the familial occurrence of lymphedema, atrial septal defect (ASD), and characteristic facial changes in two brothers. The sister was affected by a severe hydrops fetalis, ASD, omphalocele, accessory spleens and significant extramedullary hematopoiesis, demonstrating the phenotypic variability of this syndrome.Njolstad et al. [1998] reported on three siblings with congenital pulmonary lymphangiectasia leading in two of them to subcutaneous edemas, hydrothorax, and ascites. Interestingly, pathological examination in one of these two patients revealed lymphangiectasia restricted to the lungs whereas in the other patient lymphangiectasia could not be demonstrated even in a retrospective analysis. The third sibling was affected by generalized subcutaneous edemas slowly decreasing after birth, but recurrent edemas of arms and face as well as bilateral congenital glaucoma. Jacquemont et al. [2000] confirmed this clinical entity in four cases. In three siblings there was a phenotypic variability extending from hydrops fetalis to lymphedema of the legs and the vulva aswell as pleural effusion. The fourth child was affected by a hydrothorax and a lymphedema of the lower limbs. Mental development of both living children was normal. Our cases are very similar to those described by Njolstad et al. [1998] and Jacquemont et al. [2000]. It is noteworthy that in the first fetus lymphangiectasia could be detected only in a retrospective analysis. Our report confirms autosomal recessive inheritance of this condition. The similarity to Hennekam syndrome is obvious. This autosomal recessive disorder first described by Hennekam et al. [1989] includes intestinal lymphangiectasia with protein-losing enteropathy, craniofacial dysmorphy, heart and genitourinary malformations, skeletal defects, mental retardation and seizures [VanBalkom et al., 2002]. In this context it is remarkable that inHennekam syndrome lymphangiectasia has been rarely described in different organs such as pleura, pericardium, thyroid gland, and kidneys [Scarcella et al., 2000; Sombolos et al., 2001]. Therefore, it is conceivable that Hennekam syndrome and the cases reported byNjolstad, Jacquemont andusmaybevariable manifestations of the same entity. This question can only become clear by the identification of the responsible gene. So

High incidence of familial breast cancer segregates with constitutional t(11;22)(q23;q11)

In a family with a high incidence of postmenopausal breast cancer and a case of glioblastoma, the constitutional translocation t(11;22)(q23;q11.2) was shown to segregate with the malignancies. The breakpoints in this family coincided with the common breakpoints in t(11;22) as shown by a translocation‐specific PCR assay. Loss of heterozygosity analysis of breast tumor tissue revealed deletion of the normal chromosome 22, but retention of der(22) in the tumor cells, suggesting a predisposing effect of the der(22) for breast and brain tumor development in this family.

The heterozygous LMNA mutation p.R471G causes a variable phenotype with features of two types of familial partial lipodystrophy.

We report on a novel LMNA mutation (p.R471G) in a proband affected by a syndrome comprising partial lipodystrophy, insulin‐resistant diabetes, acanthosis nigricans, liver steatosis, muscle weakness, and contractures. This phenotype has features of both types 1 and 2 familial partial lipodystrophy. The sister and father of the proband had the same mutation. The sister was more mildly affected and the father was apparently unaffected, demonstrating variable expressivity and reduced penetrance for this mutation.