Received: 10 April 2003Published online: 14 June 2003© Springer-Verlag 2003

Abstract Introduction: Cerebralmalformations can be genetically de-termined and/or part of complex syn-dromes. When the defect is detectedduring pregnancy, it important torule out an associated genetic condi-tion. Family history and detailed ex-amination of fetal anatomy are need-ed. Discussion: Intrauterine growthretardation, as well as limb abnor-malities (especially polydactyly) arestrong indicators of a genetic condi-tion in the context of a fetal cerebralmalformation. A standard chromo-somal analysis is needed in all cases.Fluorescent in situ hybridization(FISH) techniques using locus-spe-cific probes that permit the detectionof subtle chromosomal rearrange-ments and metabolic analyses may

be indicated when a specific condi-tion is suspected. As for molecularanalyses, they have so far beenmainly applicable to pregnancies atrisk of a known disorder because offamily history. The diagnosis con-sists of determining whether the fe-tus has inherited the causative muta-tion identified in the index case.When termination of pregnancy iselicited, a careful prenatal and post-natal examination is needed in orderto give accurate genetic counselingfor further pregnancies. Storage offetal material allowing further mo-lecular analyses is strongly recom-mended.

Keywords Fetus · Genetic · Karyotype · Amniocentesis

Childs Nerv Syst (2003) 19:436–439DOI 10.1007/s00381-003-0779-0 O R I G I N A L PA P E R

Nicole Philip Screening for genetic disorders

Introduction

The recent progress of prenatal ultrasound imaging haseased the diagnosis of fetal malformations. Fetal MRI,used as a complementary approach to US screening hasproven to be particularly useful in the characterization ofcerebral malformations. In many cases, when a CNS ab-normality is detected antenatally, the prognosis is mainlydependent on the severity of the malformation and thepresence or absence of other defects. However, most ce-rebral malformations can be part of complex syndromes.When termination of pregnancy is elicited, a careful pre-natal and postnatal examination, including cytogeneticanalyses and molecular studies when indicated, is neededin order to give accurate genetic counseling for furtherpregnancies. On the other hand, when the defect is com-

patible with a normal life, it is important to rule out anassociated genetic condition.

General assessment of a pregnancy in the contextof cerebral malformation

Family history

Family history is an important step of genetic evaluationand can bring interesting clues to the diagnosis. An ade-quate family history comprises information from at leastboth parents, previous children, parents’ siblings, andgrandparents. Parental consanguinity brings argumentsfor an autosomal recessive disorder. Advanced paternalage is frequent in cases of de novo dominant mutations.

N. Philip (✉)Département de Génétique Médicale,Hôpital d’Enfants de la Timone,13385 Marseille Cedex 5, Francee-mail: nicole.philip@ap-hm.frTel.: +33-4-91386734Fax: +33-4-91386630

Recurrent miscarriages suggest a balanced parental chro-mosomal rearrangement. In some cases, a careful exami-nation of both parents can evidence a minor sign as thesole manifestation of a phenotypically variable dominantdisorder (e.g., single maxillary incisor in a subtle form ofholoprosencephaly, dermatologic abnormalities in theparent of a fetus suspected of tuberous sclerosis).

The syndromic approach

In all cases, a detailed examination of fetal anatomy isneeded. Intrauterine growth retardation, as well as limbabnormalities (especially polydactyly) is a strong indica-tor of a genetic condition in the context of a fetal cere-bral malformation. The use of databases for syndromicdelineation can be useful. However, suggestions must beinterpreted with caution and re-evaluated by postnatal orpostmortem examination. When fetal autopsy is impossi-ble or not permitted by the parents, these findings canserve as a basis for syndromic evaluation in geneticcounseling.

Cytogenetic analyses

A standard chromosomal analysis is needed in all cases[4].

Fluorescent in situ hybridization (FISH) techniquesusing locus-specific probes permit the detection of subtlechromosomal rearrangements that are not visible in stan-dard procedures. These techniques are widely used incases of cryptic or complex chromosomal translocationsand identification of marker chromosomes [12]. In rarecases, a specific malformation can be preferentially asso-ciated with a microdeletion syndrome that can be diag-nosed by FISH when not visible on standard chromo-somal analyses (e.g., microdeletion 17p in lissencephalytype I, monosomy 18p in holoprosencephaly).

FISH methods using chromosome-specific DNAprobes can be performed on interphase nuclei of uncul-tured amniocytes [8]. Probes specific for chromosomes21, 13, 18, X, and Y are generally used. The results areobtained within 24 to 48 h. This rapid and valuablemethod detects the most common chromosomal aneu-ploidies, which represent the majority of clinically sig-nificant chromosomal disorders. It is particularly indicat-ed in pregnancies at a high risk of chromosomal disorderor when fetal anomalies are detected at an advanced ge-stational age.

Quantitative fluorescent PCR is an alternative methodthat has been recently proposed for the rapid detection ofaneuploidies, with a result within a few hours of sam-pling [3].

Molecular analyses

DNA-based diagnosis of hundreds of genetic disorders isnow available [4]. Chorionic villus sampling (CVS) isthe method of choice, since the amount of DNA extract-ed from CV is much larger than that obtained from cul-tured amniocytes. Nevertheless, it is important to bear inmind that most monogenic disorders are genetically het-erogeneous. In single gene disorders, mutations are oftenwidespread along the gene (allelic heterogeneity). In ad-dition, mutations in different genes (locus heterogeneity)can produce the same phenotype. Therefore, when amonogenic disorder is suspected on ultrasound findings,a complete molecular screening of the gene(s) known tobe related to this condition is rarely possible. With thecurrent technologies, DNA-based prenatal diagnosis ismainly applicable to pregnancies at risk of a known dis-order because of family history. The diagnosis consistsof determining whether the fetus has inherited the caus-ative mutation(s) identified in the index-case and/or theparents. It is likely that further development of new tech-nologies, especially using the DNA microarrays tech-nique will considerably improve the availability of DNAtechniques.

Metabolic screening

It is now acknowledged that several metabolic disordershave a prenatal onset [7]. In utero metabolic disturbancescan produce brain dysgenesis. Peroxisomal disorders anddefects in cholesterol metabolism may be suspectedwhen associated malformations are detected. Biochemi-cal analyses of amniotic fluid are required to confirm thediagnosis.

Storage of fetal material

When termination of pregnancy is elicited on the basis ofa severe malformation in the absence of precise etiology,storage of fetal material is strongly recommended. Frozenamniotic fluid is easily conservable for biochemical ana-lyses. Samples of DNA extracted from chorionic villi ofcultured amniotic cells allow further molecular studies.When a metabolic disorder is suspected, conservation offrozen amniotic cells that can be used for enzymatic stud-ies is more strongly advocated. In any case, the pregnantwoman, or preferably both parents, must be kept aware ofthe procedure and give their informed consent.

Genetics of some CNS malformations

CNS malformations can be associated with hundreds ofsyndromes. Each condition has a very low prevalence

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and making the diagnosis in utero is rather difficult inthe absence of the family history of an affected sibling orrelative. Furthermore, some syndromes have overlappingclinical pictures and different brain malformations areoften associated in complex syndromes. Our purposewas not to establish a list of syndromes associated withCNS malformations. Instead, we focused on four malfor-mations and described some of the most recognizableconditions.

Hydrocephalus

Ventriculomegaly is the most common CNS anomaly de-tected by ultrasonography during pregnancy. It has beenshown that the prognosis correlated more with the pres-ence of associated anomalies than the degree of ventricu-lar dilatation. Apparently isolated mild ventriculomegalymay be the only antenatal manifestation of various syn-dromes and chromosomal disorders [9]. Fetal karyotypeis therefore indicated in all cases. Genetic conditions as-sociated with multiple and characteristic malformationscan be recognized whereas those characterized by subtledysmorphic syndromes may not. Hydrocephalus-congen-ital stenosis of the aqueduct of Sylvius is an X-linkeddisorder due to mutations in the L1-CAM gene. In theabsence of family history, the diagnosis can be suspectedin a male fetus presenting with macrocephaly, dilatedventricles, hypo/aplasia of the corpus callosum, and ad-ducted thumbs. The thumb anomaly is already present inthe first trimester of pregnancy [10].

Cystic malformations of the posterior fossa

Dandy-Walker malformation is associated with other de-velopmental anomalies of the CNS in 50% of cases [2].Numerous chromosomal abnormalities and up to 40 syn-dromes have been reported in association with this mal-formation. The presence of distal limb abnormalities(polydactyly) is highly suggestive of a genetic condition[1].

Lissencephaly

During the past few years, lissencephaly was demon-strated to be associated with a growing number of genet-ic syndromes. Several genes have been identified [5].Some conditions are characterized by a spectrum of de-fects that may be diagnosed in utero: classical or type Ilissencephaly is related to heterozygous mutations in ei-ther LIS1 (on 17p) or DCX (on Xq) genes. Submicro-scopic deletions represent up to 40% of mutations ofLIS1 and can be easily detected by FIH using an LIS1probe. In Miller-Dieker syndrome, which is caused by

deletion of several contiguous genes on 17p, associatedmalformations and facial dysmorphism are present. Therecently described XLAG syndrome (X-linked lissen-cephaly with abnormal genitalia) is due to mutations inthe ARX gene [6]. Walker-Warburg syndrome, a reces-sive disorder due to mutations in the O-mannosyltrans-ferase 1 gene is characterized by lissencephaly type II,cerebellar malformations, retinal dysplasia, and musculardystrophy. Encephalocele is occasionally associated. Thecharacteristic ocular anomaly may be detected on carefulUS examination [11].

Holoprosencephaly

Chromosomal anomalies account for one-third to one-half of all cases of holoprosencephaly (HPE). Besidestrisomy 13, which represents three-quarters of abnormalkaryotypes, chromosomal regions 2p, 13q, 18p, and 7qare frequently involved. The phenotype is due to haplo-insufficiency of developmental genes located in these re-gions (SIX3; SHH; ZIC2; TIGF). Point mutations inthese genes give rise to isolated forms of HPE [13]. Themode of inheritance is dominant with a variable pene-trance and expressivity. The risk of recurrence after afirst affected child is 13 to 14%. Among the syndromesassociated with HPE, some may be suspected in utero onthe basis of associated findings. Young-Madders (orpseudo trisomy 13) is characterized by HPE, polydacty-ly, congenital heart defect, and normal chromosomes.The mode of inheritance is autosomal recessive. HPE isalso seen in association with severe forms of another au-tosomal recessive syndrome, Smith-Lemli-Opitz syn-drome. The diagnosis, based on intrauterine growth re-tardation, polydactyly, severe micrognathia, and sex re-versal in males, can be confirmed by measuring 7-dehy-drocholesterol in chorionic villus sampling or amnioticfluid.

Conclusion

In summary, a growing number of DNA-based diagnosesare available. The improvement of cytogenetic analysesallows the detection of subtle chromosomal rearrange-ments. To date, most of these techniques have been ap-plicable to the detection of recurrences in families with apreviously affected child. In the absence of a positivefamily history, a close collaboration between the echog-raphist and the geneticist is the best way to optimize theetiologic investigations.

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