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An abnormal head shape is an uncommon finding on prenatal ultrasound, associated most commonly with spina bifida, aneuploidy or oligohydramnios. In other cases diagnosis can be difficult. The objective of this study was to define management pathways for the investigation of fetuses with an abnormal head shape. Fetuses with an abnormal skull shape seen over a 10-year period in our unit were identified by searching the computerised database. Sonographic findings, diagnosis and outcome were reviewed. Three hundred and thirty-one cases were identified, the majority being associated with spina bifida (30%, lemon-shaped), aneuploidy (12%, strawberry-shaped) or dolicocephaly (18%) secondary to fetal position or oligohydramnios. Of the remainder, eight had craniosynostosis, three of which had a skeletal dysplasia. There was also one fetus each with Aperts syndrome, Saethre Chotzen syndrome and I-cell disease and two with an as yet undefined craniosynostosis sydrome.

Saethre-Chotzen syndrome (SCS) is an autosomal dominant craniosynostosis syndrome with variable expression. Analysis of chromosome translocations found in patients with SCS played an important role in mapping the SCS gene to 7p21 and the subsequent identification of the TWIST gene. SCS has been associated with point mutations within the TWIST gene as well as deletion of the entire gene. The purpose of this report is to present a patient with severe craniofacial features of SCS who has a complex chromosome anomaly. The patient was a product of a term gestation complicated by fetal ventriculomegaly and oligohydramnios. Physical examination in the neonatal period revealed cranial and facial asymmetry, brachycephaly, low posterior and anterior hairlines, midface hypoplasia, ptosis, broad thumbs and toes, and cryptorchidism. Imaging demonstrated bilateral coronal suture fusion, dilated lateral ventricles, partial agenesis of the corpus callosum, and a large cisterna magna. An echocardiogram revealed a VSD and ASD. At two months of age the infant had a bifrontal craniotomy and bilateral orbito-zygomatico-temporal osteotomies. At three months of age he appears to be developmentally delayed. The infant has a balanced four-way translocation between 1q, 2q, 7p, and 18p and a separate translocation between 7q and 18q. Parental karyotypes are normal. Successive FISH analyses using dual color whole chromosome paints, centromeric alpha satellite probes, and a telomeric probe for 18p confirmed these findings. The breakpoint on the short arm of chromosome 7p is assigned to 7p 15.3 and does not appear to interrupt band 7p21. Sequencing of the TWIST gene and FISH analysis using a probe specific for the TWIST region were normal. Southern blot analysis to assess dosage of the TWIST gene is pending. Mutation analysis of the FGFR genes and comparative genomic hybridisation are planned. It is possible that this infant's phenotype is the result of position effect on the TWIST gene or disruption of other genes associated with craniosynostosis This expanded cytogenetic and molecular armamentarium may allow us to determine the pathogenesis of this infant's condition and may provide further insight into the mechanisms for SCS.

A male patient with brachycephalosyndactyly syndrome associated with ocular and skin anomalies is reported and it is suggested that this patient has a previously undescribed disorder.

The occurrence among 13 siblings of a malformation-mental retardation syndrome and diverse malignancies was investigated for etiologic relationship by clinical, genetic, immunologic, and virologic techniques. Three sisters and their father had Saethre-Chotzen syndrome, an autosomal dominant trait with craniosynostosis and asymmetric facies. One affected sister also had nasopharyngeal carcinoma; tow nondysmorphic brothers had Hodgkin's disease, and another had seminoma with teratocarcinoma of the testis. Decreased in vitro lymphocytic proliferation to various mitogens was observed in both available siblings with tumor, one sibling with Saethre-Chotzen syndrome, and two clinically normal siblings and their father. Both parents and all siblings had normal karyotypes and no increase of antibodies to Epstein-Barr virus. The malformation syndrome and the various neoplasias segregated independently of each other and of 47 genetic markers, including histocompatibility antigens (HLA). This study illustrates an approach to defining etiology when rare disorders cluster in a family and suggests that the occurrence of malignancies in this family may be related to subclinical immune dysfunction. Whether the Saethre-Chotzen syndrome predisposed to malignancy, perhaps through impaired immunity, awaits additional observations.

The possibility of plastic surgery in acrocephalosyndactylia syndrome during infancy is shown. Due to her main signs and symptoms and the mode of inheritance the patient suffered from an acrocephalosyndactylia syndrome type III (Saethre-Chotzen). Craniofacial surgery with frontal craniotomy, turn of frontal bone and frontal orbital advancement were performed at the age of eight months, using bone plates developed by Luhr. The reconstruction gave an aesthetically satisfactory result, and further development was normal. The condition for a good result is the cooperation between plastic surgeons, neurosurgeons, anaesthesiologists and paediatricians in specialised centres.

Acrocephalosyndactyly (ACS) is an inherited syndrome of premature synostosis of the cranial sutures and abnormalities in the distal segments of the limbs. Several forms of ACS have been described. ACS type III (or Saethre-Chotzen syndrome) is characterized by microcephaly, skull asymmetry, mild syndactyly, and facial abnormalities. We describe an Italian family with ACS III in which two sibs are clearly affected; the mother and the maternal grandmother show some features of the syndrome.

A 4.5-year-old girl with clinical features of both the Pfeiffer and Saethre-Chotzen syndromes is described. She was severely mentally retarded, had brachycephaly, craniosynostosis, prominent forehead, proptosis, midface hypoplasia, low-set and small ears, a high arched palate, broad thumbs and great toes, short phalanges of the third toes, and soft tissue syndactyly between the second and third fingers and between the second and third toes. In addition, she showed several clinical features characteristic of the Saethre-Chotzen syndrome, including a low-set frontal hairline, mild ptosis, a deviated nasal septum, and a cleft soft palate. Thus, the disease in the patient may represent a transitional form between the Pfeiffer and Saethre-Chotzen syndromes. Her father and paternal grandmother each had a few clinical features of the disease, indicating that the disease was inherited in an autosomal dominant fashion.

Specific anomalies of the skull in eight family members affected with Saethre-Chotzen syndrome were documented by cephalometric analysis of standardized skull radiographs. The most severe deviations included reduced length and abnormal position of the posterior cranial base, low position of the sella turcica, reduced mandibular ramus length, steep mandibular plane angle, and, in adults, reduced facial depth. A feature of the syndrome may be the absence or reduced size of cranial sinuses.

A father and son with Saethre-Chotzen syndrome and parietal foramina are described, to draw attention to this little known feature of the syndrome.

A family is described in which 15 persons in five generations are affected with a complex of skeletal malformations which variably includes peculiar asymmetric facies, delayed closure of large fontanels, brachycephaly, acrocephaly, brachydactyly, cutaneous syndactyly, broad great toes, and mild shortness of stature. Although craniosynostosis is either lacking or relatively mild in the members of this family, their features are otherwise strikingly similar to those of patients with the Saethre-Chotzen syndrome. We believe the findings in this family indicate that the Saethre-Chotzen syndrome comprises a broad pattern of carniofacial and other skeletal malformations in which craniosynostosis may sometimes occur.

Five individuals in four generations affected with the Saethre-Chotzen syndrome are reported. Serial roentgencephalometric data obtained pre- and postoperatively on the proband were compared with similar measurements on the affected mother and maternal uncle, both of whom had not had operative corrections. Similarity in skull form among the affected individuals was demonstrated. Head circumference, as an index of cranial growth or intracranial capacity, was misleading in assessing the intellectual potential of the affected adults. In contrast, cranial capacity, as measured by the modulus, was found to be more reliable.

Summary Thirty-two unrelated patients with features of Saethre-Chotzen syndrome, a common autosomal dominant condition of craniosynostosis and limb anomalies, were screened for mutations in TWIST,FGFR2, and FGFR3. Nine novel and three recurrent TWIST mutations were found in 12 families. Seven families were found to have the FGFR3 P250R mutation, and one individual was found to have an FGFR2 VV269–270 deletion. To date, our detection rate for TWIST or FGFR mutations is 68% in our Saethre-Chotzen syndrome patients, including our five patients elsewhere reported with TWIST mutations. More than 35 different TWIST mutations are now known in the literature. The most common phenotypic features, present in more than a third of our patients with TWIST mutations, are coronal synostosis, brachycephaly, low frontal hairline, facial asymmetry, ptosis, hypertelorism, broad great toes, and clinodactyly. Significant intra- and interfamilial phenotypic variability is present for either TWIST mutations or FGFR mutations. The overlap in clinical features and the presence, in the same genes, of mutations for more than one craniosynostotic condition—such as Saethre-Chotzen, Crouzon, and Pfeiffer syndromes—support the hypothesis that TWIST and FGFR s are components of the same molecular pathway involved in the modulation of craniofacial and limb development in humans.

A mother and son are reported with bilateral, symmetrical syndactyly of the third, fourth, and fifth toes, mild craniosynostosis of the coronary sutures, and small pinnae. The same combination of malformations was recently described as a new syndrome by Kurczynsky and Casperson in a mother and her daughter. In addition, in the present family, the mother had fusion of two cervical vertebrae and a partial duplication of the first metatarsal. The child had a bilateral cleft lip and palate. The question is raised whether these patients represent a new syndrome or a variant of the Saethre-Chotzen syndrome.

The authors describe three cases of familial acrocephalosyndactyly (ACS) in two boys (9 and 3 years of age) and in their 7.5-year old sister. In addition, irregularities in skull and limbs were found in the 46-year old father as well as in two other children, i.e., two girls, 14 and 4 years of age. The mother (46 years-old) and the remaining four 4 boys (12-, 9-, and 7-years-old), as well as the youngest child, a son, (1-year-old) did not show any deviations. The diagnosis of the Saethre-Chotzen syndrome in six members of one family was based on the finding of a typical skull deformation (oxybrachycephalia), low hairline, flattened nasofrontal angle, lateral deviation of the nasal septum, facial dysmorphy, prolapse of upper eyelids, antomongoloid placement of palpebral fissures, protruding eyes, hypertelorism, dysmorphy of auricles, imperfect hearing, highly arched palate, improper dentition, and characteristic skin syndactyly of hands and feet. In addition, deformed chest, weight and height deficiency, significant mental retardation, as well as, in the boys, true cryptorchidism were found. Radiological examination showed, in all affected members of the family, intensified digitate impressions within the whole fornix of the skull, large and deep sella turcica, underdeveloped frontal bone and upper jaw bone, untypical syndactyly of hands and feet, and the partial bifid of distal phalanges of the great toes, not described previously in the Saethre-Chotzen syndrome. In the differential diagnosis, other forms of ACS, i.e., Apert, Vogt, Pfeiffer, Summitt, and Herrmann-Opitz syndromes, were not found. Manifestation of the described symptoms transferred autosomally, dominantly, and with a similar degree of expression in 6 of 11 members of one family, leads us to think that they are the consequence of a fresh mutation revealed in the father.