Medical Litterature

SCHMID-FRACCARO SYNDROME

CHROMOSOME 22 PARTIAL TETRASOMY
INV DUP(22)(q11)

Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
22q11 Cat eye syndrome 115470

Clinical Synopsis

TEXT
A number sign (#) is used with this entry because a chromosomal abnormality is known in this syndrome. However, because in many of the reported cases the abnormality is in only a portion of the patients’ cells, and because the mosaicism is sometimes transmitted through several generations, mendelian factors may be important in its causation.

Description
Cat eye syndrome (CES) is characterized clinically by the combination of coloboma of the iris and anal atresia with fistula, downslanting palpebral fissures, preauricular tags and/or pits, frequent occurrence of heart and renal malformations, and normal or near-normal mental development. A small supernumerary chromosome (smaller than chromosome 21) is present, frequently has 2 centromeres, is bisatellited, and represents an inv dup(22)(q11).

Clinical Features
The variability of clinical features, particularly congenital malformations, is enormous (see Schachenmann et al., 1965, Schinzel et al., 1981, and Schinzel, 1994). Within a single family, a wide spectrum of features can be observed, ranging from marginally affected individuals in whom, unless other members are affected, no chromosome examination would be performed, to those with the full pattern of malformations and lethal outcome. Only mild prenatal growth retardation occurs. Minimal features include downslanting palpebral fissures and misshapen ears with a preauricular pit or tag or both. Other frequently encountered minor anomalies include hypertelorism, strabismus, inner epicanthic folds, flat nasal bridge, and small mandible.

The following major malformations may occur and are listed in order of decreasing frequency: anal atresia with a fistula from the rectum into the bladder, vagina, or vulva in females, and the bladder, urethra, or perineum in males; coloboma of the iris, either uni- or bilateral and total or (rarely) partial and coloboma of the choroid and/or optic nerve, microphthalmia (almost always unilateral); cleft palate; congenital heart malformations, particularly totally anomalous pulmonary venous return (TAPVR) and tetralogy of Fallot (TOF); various renal malformations, e.g., absence of 1 or both kidneys, hydronephrosis, supernumerary kidneys or renal hypoplasia; hernias; reduction of the auricles to several tags, mostly in combination with atresia of the external auditory canal and often unilateral.

Rarer malformations may affect almost every organ; the eyes are preferentially affected: aniridia (Weber et al., 1970), corneal clouding (Giraud et al., 1975), coloboma of eyelids (Carmi et al., 1980), cataract (Schinzel et al., 1981), and the Duane anomaly (Cullen et al., 1993). Craniofacial malformations include choanal atresia (Ginsberg et al., 1968), skin tags on the cheeks (Fryns et al., 1972); hypothalamic growth hormone deficiency (Pierson et al., 1975); cleft lip and palate (Loevy et al., 1977). Limb malformations include radial aplasia (Balci et al., 1974,; Guanti, 1981); duplication of the hallux (Carmi et al., 1980) absent toes and sirenomelia (Jensen and Hansen, 1981). Thoracic and abdominal malformations include absence or synostosis of ribs (Ginsberg et al., 1968; Balci et al., 1974; Pierson et al., 1975), vertebral fusions (Toomey et al., 1977; Schinzel et al., 1981), Eisenmenger complex (Schinzel et al., 1981), pulmonary segmentation defects; malrotation of the gut (Ginsberg et al., 1968; Hoo et al., 1986), Meckel diverticulum, Hirschsprung disease (Guanti, 1981; Mahboubi and Templeton, 1984; Ward et al., 1989), biliary atresia (Gerald et al., 1972; Johnson et al., 1974); spina bifida (Cory and Jamison, 1974) and MMC (Carmi et al., 1980), hypoplastic uterus and vaginal atresia (Schinzel et al., 1981), hypospadias (Guanti, 1981; Schinzel et al., 1981).

A few patients die from multiple malformations during early infancy; of the remainder, life expectancy is not significantly reduced. Growth retardation is a variable feature as is mental retardation. The majority of patients function in the borderline normal to mildly retarded range, a few are normal, and some are moderately to severely retarded, although the latter condition is rare. Behavioral problems have been reported in individual cases, but are not characteristic of the disorder (Schinzel et al., 1981).

Rosias et al. (2001) reported a case and reviewed the characteristics of 105 reported CES patients. They commented on the large phenotypic variability, ranging from near normal to severe malformations. Preauricular skin tags and/or pits constituted the most consistent features and suggested the presence of a supernumerary bisatellited marker chromosome 22 derived from duplication of the CES critical region.

Denavit et al. (2004) reported a female with a severe form of CES associated with a molecular type II chromosome (McTaggart et al., 1998). At birth, she had severe craniofacial abnormalities, including microcephaly, total absence of the external ears bilaterally, hypertelorism with downslanting palpebral fissures, bilateral coloboma of the iris, flat nasal bridge with prominent nose, thin upper lip, and micrognathia. Other features included anal stenosis, patent ductus arteriosus, and intra- and extrahepatic biliary atresia. She died at age 1 month of cardiac failure. Cytogenetic analysis showed a small de novo extra chromosome in all cells with a karyotype of 47,XX, +idic(22)(pter-q11.2::q11.2-pter) with the duplication breakpoints distal to 22q11.2. The marker could be classified as CES type II symmetrical.

Inheritance
The additional chromosome 22 generally arises de novo from one of the parents. Since CES is a rare chromosome disorder in which transmission is possible through both sexes, chromosome examination should be performed if one of the parents displays characteristic features such as a preauricular pit or downslanting palpebral fissures. Even in asymptomatic parents, mosaicism for an extra chromosome is possible. Direct transmission was reported by Schachenmann et al. (1965); Gerald et al. (1972); Darby and Hughes (1971); Krmpotic et al. (1971); Noel et al. (1976); Schinzel et al. (1981); and Luleci et al. (1989).

Recurrence Risk

There are no data available on the recurrence risk for sibs of a CES patient. However, because mosaicism for an extra inv dup(22)(q11) chromosome may produce a normal phenotype, chromosome examination of both parents is indicated after the birth of an affected child. Even if a lymphocyte chromosome study indicates a nonmosaic diploid karyotype, a hidden (including germline) mosaicism cannot fully be excluded, and a small recurrence risk will remain. For offspring of an affected who does not appear to have reduced fertility, the risk will be close to 50% (Noel et al., 1976; Schinzel et al., 1981; Luleci et al., 1989).

Cytogenetics
The additional marker is always dicentric, which can be demonstrated by centromere staining. By different stainings of heterochromatin and NORs it can be shown in most cases that the marker contains short arm material from acrocentrics on both arms (Schinzel et al., 1981; Petit et al., 1980). Differential staining can show that the chromosome is composed, thus far without exception, of material from the 2 different maternal chromosome 22 (Magenis et al., 1988). Secondary rearrangements can occur in the dicentric and hence unstable marker resulting in extra chromosomes of different appearance in a mother and daughter (Ing et al., 1987). The easiest and most elegant way to demonstrate the origin of the chromosome 22 marker is by FISH examination with a chromosome 22 library (Liehr et al., 1992).

A particular feature of familial CES is the frequent occurrence of mosaicism resulting from early loss of the marker during postzygotic divisions (Gerald et al., 1972; Luleci et al., 1989).

Wenger et al. (1994) evaluated the marker chromosome in a proband and his mother by cytogenetic banding techniques to verify the dicentric chromosomal rearrangement and by fluorescence in situ hybridization to confirm the involvement of chromosome 22. The mother also had an offspring with an unrelated aneuploidy, trisomy 21. At birth the proband showed coloboma of the iris, preauricular pits, and anal stenosis. Developmentally, he had short stature and was moderately mentally retarded. Diagnosis of biliary atresia was made in infancy. The mother was moderately mentally retarded and had stigmata of the cat eye syndrome which had been cytogenetically confirmed in the neonatal period. Anal atresia had been surgically corrected during childhood. She was 19 years old at the time of the birth of her son with CES.

Mapping
Among others, Zhang et al. (1990), Delattre et al. (1991), and Budarf et al. (1991) constructed restriction maps of chromosome 22, the latter authors with special attention to the critical cat eye region. Mears et al. (1994) investigated patients with cat eye syndrome and with DiGeorge syndrome with probes from proximal 22q and could show that the distal boundary of the critical cat eye segment (represented by probe D22S36) is proximal to the critical DiGeorge region.

McDermid et al. (1996) constructed a long-range restriction map of the region of 22q which is duplicated in the typical CES marker chromosome, the region extending from the centromere to locus D22S36. The map covered approximately 3.6 Mb. They also used 15 loci to construct a YAC contig that encompassed about half of the region critical to the production of the CES phenotype (from the centromere to D22S57).

Molecular Genetics
McDermid et al. (1986) isolated a single-copy DNA probe, D22S29, from a chromosome 22 library and localized it by in situ hybridization to the critical cat eye region. By dosage, this probe was present in 4 copies in all examined cat eye patients while patients with familial partial trisomy of the proximal 22q region contained 3 copies, and normal individuals, 2 copies of the critical region.

Mears et al. (1994) demonstrated 4 copies of the following probes in all 10 cat eye patients examined: D22S9, D22S43, D22S57; more distal sequences (D22S36 and D22S75) were duplicated only in a proportion of the patients. The observation that D22S36 was present in 3 copies in a few patients, the most distal marker, D22S75, was usually present in only 2 copies, and in a minority of patients in 3 copies, points toward both asymmetry of the extra chromosome and the variability of the duplicated/triplicated segment in different patients. Interestingly, no correlation between the length of the duplicated/triplicated segment and the severity of clinical features and the extent of mental handicap could be demonstrated.

Mears et al. (1995) described an individual who inherited a minute supernumerary double ring chromosome 22, resulting in expression of all the cardinal features of CES. The ATP6E gene (108746) and 2 anonymous probes were found to be present in 4 copies, whereas 2 other anonymous probes were present in 2 copies. This finding further delineated the distal boundary of the critical region of CES, with ATP6E being the most distal duplicated locus identified. The phenotypically normal father and grandfather of the patient each had a small supernumerary ring chromosome and demonstrated 3 copies of the 3 loci which were present in quadruplicate in the proband. Mears et al. (1995) hypothesized that, although 3 copies of this region had been reported in other cases with CES features, it is possible that the presence of 4 copies leads to greater susceptibility.

Hough et al. (1995) demonstrated that the supernumerary chromosome in CES contains none of the lambda immunoglobulin gene sequences (see 147220) as indicated by the fact that no increased copy number was found in the DNA from 10 CES individuals tested.

McTaggart et al. (1998) found that the duplication breakpoints that give rise to the CES dicentric supernumerary chromosome are clustered in 2 intervals. The more proximal, most common interval is the 450- to 650-kb region between D22S427 and D22S36, which corresponds to the proximal deletion breakpoint interval found in the 22q11 deletion syndrome (DiGeorge/velocardiofacial syndrome). The more distal duplication breakpoint interval falls between CRKL (602007) and D22S112, which overlaps with the common distal deletion interval of the 22q11 deletion syndrome. Therefore, McTaggart et al. (1998) classified CES chromosomes into 2 types based on the location of the 2 breakpoints required to generate them. The smaller type I CES chromosomes are symmetric, with both breakpoints located within the proximal interval. The larger type II CES chromosomes are either asymmetric, with 1 breakpoint located in each of the 2 intervals, or symmetric, with both breakpoints located in the distal interval. The colocalization of the breakpoints in these different syndromes, plus the presence of low-copy repeats adjacent to each interval, suggested the existence of several specific regions of chromosomal instability in 22q11.2 that are involved in the production of both deletions and duplications. Since the phenotype associated with the larger duplication does not appear to be more severe than that of the smaller duplication, determination of the type of CES chromosome does not have prognostic value.

Bridgland et al. (2003) reviewed the integration of duplicated fragments of DNA from elsewhere in the genome into the pericentromeric region of chromosomes. The resulting complex patchwork of fragments shows large segments of paralogous sequence with high identity to regions on nonhomologous chromosomes. Although the pericentromeric regions may appear to be junkyards for gene-containing fragments, it has been suggested that these regions may also be the birthplace of new genes with novel functions through a process similar to exon shuffling (Eichler et al., 1997; Jackson et al., 1999). Bridgland et al. (2003) characterized a chimeric transcription unit, which they designated cat eye syndrome critical region gene-7 (CECR7), formed from 3 duplicons in the pericentromeric region of 22q. CECR7 exons show similarity to sequences on 13 nonhomologous chromosomes and elsewhere on chromosome 22. Based on PCR analysis of CECR7 duplicon boundaries in various primate species, and the sequence divergence between the human duplicons and their putative ancestral loci, Bridgland et al. (2003) concluded that CECR7 was probably formed before the separation of macaque and is therefore older than most previously reported pericentromeric duplicons. Expression of CECR7 was detected by RT-PCR in humans and gorilla fibroblasts, but not orangutan, suggesting that expression did not result immediately from the formation of this novel transcription unit, or that expression was silenced in orangutan following its formation.

Heterogeneity
Cases with the characteristic clinical pattern occur in which examination of different tissue fails to detect a marker chromosome. Since these patients have thus far not been investigated molecularly, it is not possible to exclude tetrasomy of the small critical region on 22q11 which presumably causes all or most of the clinical findings of CES (Franklin and Parslow, 1972).

Diagnosis
Although CES was initially defined as the combination of an additional chromosome, with coloboma and anal atresia as primary features, it became evident from the patients reported by Schachenmann et al. (1965) that neither coloboma nor anal atresia were obligatory findings. In addition to the above features, the following are helpful for the diagnosis: heart malformations, renal malformations, downslanting palpebral fissures, preauricular pits and/or tags, and reduction of the auricles with atresia of the external auditory canal. The diagnosis nowadays, however, is based on the presence of an extra marker chromosome which, by FISH examination, is derived from chromosome 22 and contains 2 copies of the critical CES region in proximal 22q11.

Clinical Management
Surgery is required for anal atresia and complex cardiac malformations. With intestinal problems, malrotation, Meckel diverticulum, and biliary atresia have to be considered. Patients with very short stature might have additional hypothalamic growth hormone deficiency and thus be candidates for growth hormone therapy (Pierson et al., 1975).

Population Genetics
There are no estimates on the incidence of the marker. An incidence between 1:50,000 and 1:150,000 seems a reasonable estimate from patients observed in Northeastern Switzerland during the last 20 years.

History
The association between iridal coloboma and anal atresia was probably first noticed by Haab (1879). The first report on the association of coloboma and anal atresia with a small extra chromosome came from Schmid in Zurich and Fraccaro in Pavia (Schachenmann et al., 1965). These authors proposed the term cat eye syndrome, in analogy with the cat cry or cri-du-chat syndrome (123450). However, more than half of the patients with the chromosome aberration lack any coloboma.

(from http://omim.org/entry/115470)