The Haspeslagh syndrome (MIM 177980) is caused by an unbalanced reciprocal 6q/9p translocation

To the Editor: In 1985, Haspeslagh et al. [1] reported in this journal a family where 3 individuals related as first or second cousins showed a strikingly similar phenotype with severe mental retardation, a distinct facial phenotype and pterygia. At that time, the etiology was unknown, and the possibility of either an autosomal dominant disorder with variable expressivity or the segregation of a chromosome abnormality was suggested. Karyotype analysis was normal. Since the original description, individuals with a similar phenotype were observed in two additional families [2,3], and this syndrome became known as the Haspeslagh syndrome (MIM 177980). In view of the recent development of techniques allowing the detection of cryptic reciprocal chromosomal translocations, this family was re-examined recently, after 15 years. High resolution karyotype after G- and T-banding now revealed the presence of a chromosomal aberration. In the 3 patients, a partial monosomy for distal chromosome 9p and partial trisomy for distal chromosome 6q were present. This was the unbalanced result of a balanced reciprocal translocation of distal 9p-6q ( Fig. 1). These cytogenetic findings were confirmed by FISH, using subtelomeric probes for chromosomes 9p and 6q. FISH using subtelomeric probes for chromosomes 6q left panel and 9p (right panel), showing unbalanced translocation with partial monosomy 6q and trisomy 9p in one of the patients. On this occasion, we learned of two additional affected children in this family. The first child, a boy of 6.5 years, is the first child of healthy, unrelated parents. The mother had one miscarriage. The father of this patient is a cousin of patient 3 from the original publication by Haspeslagh et al. [1]. At birth, facial dysmorphism was already evident, especially the trigonocephaly. He had bilateral club feet. At the age of 4 months, he presented convulsions and a CT scan of the brain revealed a hypoplastic corpus callosum and an abnormal gyration of the right temporal lobe. Now, at the age of 6.5 years, his weight is at the 3rd percentile, length at the 10th percentile and head circumference at the 3rd–10th percentile. He is severely mentally retarded with a full-scale IQ of 35 and follows special education. Physically, he presented the same facial features as the previously reported family members, with trigonocephaly, dysplastic ears, epicanthal folds, retognathia, small mouth and maxillary hypoplasia ( Fig. 2). He has hypoplastic nipples, a pectus excavatum and a grade 1 hypospadias. The hands and feet are slender. His phenotype strikingly resembles his female affected relatives and karyotype analysis confirmed the presence of the same unbalanced reciprocal translocation, inherited from the father. Another child in this family, a girl aged 2.5 years, was found to carry the complementary reciprocal translocation, with partial monosomy of distal chromosome 6q and partial trisomy of distal chromosome 9p, inherited from her mother. Her mother is a sister of patient 1 in the report of Haspeslagh et al. [1]. She could not yet be examined physically. Several additional carrier females and males were identified, but in contrast to the initial report, no consistent phenotype was present in these individuals. Phenotype of patient with partial monosomy 9p and partial trisomy 6q at age 6.5 years. A, frontal view; B, hands The Haspeslagh syndrome is therefore caused by a partial trisomy for distal chromosome 6q and monosomy for distal chromosome 9p, resulting from a familial balanced reciprocal translocation. In the initial report, it was noted that the physical features were reminiscent of two aneuploidy syndromes, the trigonocephaly in 9p2 monosomy and the flat face with short neck in 6q2 trisomy [1]. However, at that time, the available techniques did not allow further confirmation. This observation confirms previous reports that small chromosomal aberrations, difficult to detect by standard cytogenetic techniques, may cause familial ‘private’ syndromes, especially those where transmission occurs through unaffected individuals and where multiple miscarriages are present [4,5].