Holoprosencephaly

Holoprosencephaly (HPE) is a complex brain malformation resulting from incomplete cleavage of the prosencephalon, occurring between the 18th and the 28th day of gestation and affecting both the forebrain and the face. It is estimated to occur in 1/16,000 live births and 1/250 conceptuses. Three ranges of increasing severity are described: lobar, semi-lobar and alobar HPE. Another milder subtype of HPE called middle interhemispheric variant (MIHF) or syntelencephaly is also reported. In most of the cases, facial anomalies are observed in HPE, like cyclopia, proboscis, median or bilateral cleft lip/palate in severe forms, ocular hypotelorism or solitary median maxillary central incisor in minor forms. These latter midline defects can occur without the cerebral malformations and then are called microforms. Children with HPE have many medical problems: developmental delay and feeding difficulties, epilepsy, instability of temperature, heart rate and respiration. Endocrine disorders like diabetes insipidus, adrenal hypoplasia, hypogonadism, thyroid hypoplasia and growth hormone deficiency are frequent. To date, seven genes have been positively implicated in HPE: Sonic hedgehog (SHH), ZIC2, SIX3, TGIF, PTCH, GLI2 and TDGF1. A molecular diagnosis can be performed by gene sequencing and allele quantification for the four main genes SHH, ZIC2, SIX3 and TGIF. Major rearrangements of the subtelomeres can also be identified by multiplex ligation-dependent probe amplification (MLPA). Nevertheless, in about 70% of cases, the molecular basis of the disease remains unknown, suggesting the existence of several other candidate genes or environmental factors. Consequently, a "multiple-hit hypothesis" of genetic and/or environmental factors (like maternal diabetes) has been proposed to account for the extreme clinical variability. In a practical approach, prenatal diagnosis is based on ultrasound and magnetic resonance imaging (MRI) rather than on molecular diagnosis. Treatment is symptomatic and supportive, and requires a multidisciplinary management. Child outcome depends on the HPE severity and the medical and neurological complications associated. Severely affected children have a very poor prognosis. Mildly affected children may exhibit few symptoms and may live a normal life

PTCH1 duplication in a family with microcephaly and mild developmental delay

With the exception of the X chromosome, genomic deletions appear to be more prevalent than duplications. Because of a lack of accurate diagnostic methods, submicroscopic duplications have been under-ascertained for a long period. The development of array CGH has enabled the detection of chromosomal microduplications with nearly the same sensitivity as deletions, leading to the discovery of previously unrecognized syndromes. Using a clinical targeted oligonucleotide array (CMA-V6.3 OLIGO), we identified an ∼360-kb duplication in 9q22.32 in a 21-month-old boy with developmental delay, failure to thrive, and microcephaly. The same duplication was identified in the patient's mother who is also microcephalic and mildly delayed. We have sequenced the chromosomal breakpoints and determined the duplication as tandem in orientation and 363 599 bp in size. The duplicated segment harbors the entire PTCH1 gene. Deletions or loss-of-function mutations of PTCH1 result in basal cell nevus syndrome (Gorlin syndrome), whereas gain-of-function mutations were proposed to lead to holoprosencephaly 7. We propose that patients with microcephaly or holoprosencephaly of unknown origin should also be screened for PTCH1 duplication