A CASE of INCOMPLETE Digeorge SYNDROME ASSOCIATED with PARTIAL MONOSOMY 22Q11.1 DUE to MATERNAL 14;22 TRANSLOCATION

Jpn. J. Human Genet. 34, 235-241, 1989

A CASE OF INCOMPLETE DiGEORGE SYNDROME ASSOCIATED WITH PARTIAL MONOSOMY 22q11.1 DUE TO MATERNAL 14;22 TRANSLOCATION

Sadayuki NUKINA, 1 Yasutaka NISHIMURA, 1 Akihiko KINUGASA, 1 Tadashi SAWADA,1 Kenji HAMAOKA,2 Johji INAZAWA,3 Shoichiro TSUDA, ~ and Tatsuo ABE3

1Department of Pediatrics, Kyoto Prefectural University of Medicine, Kamigyu-ku, Kyoto 602, Japan 2Kyoto Children's Research Hospital, Kamigyu-ku, Kyoto 602, Japan 3Department of Hygiene, Kyoto Prefectural University of Medicine, Kamigyu-ku, Kyoto 602, Japan

Summary We report a boy with some clinical symptoms compatible with a diagnosis of incomplete DiGeorge syndrome. He had a dismorphic face, micrognathia, cleft palate, and heart anomalies similar to DiGeorge syndrome, but lacked aplasia of the thymus or hypoparathyroidism typical of the syndrome. High-resolution banding analysis revealed that his karyotype was 45,XY,- 14, - 22, + der(14)(14pter~ 14q32.32: :22q11.21--* 22qter), the consequence of a maternal reciprocal translocation between chromosomes 14 and 22. Precise localization of the gene responsible for the present DiGeorge syndrome was assigned to subband 22ql 1.1. Key Words translocation 14:22, monosomy 22q11.1, DiGeorge syndrome

INTRODUCTION In 1965 DiGeorge described a patient with hypoparathyroidism and cellular immune deficiency which was caused by aplasia of the parathyroid glands and thymus. Additional reports indicated that many patients of DiGeorge syndrome, as originally conceived which consists of aplasia of the parathyroid glands and thymus, had additional findings of cardiovascular anomalies (Robinson, 1975) and craniofacial anomalies characterized by hypertelorism, low-set ears, micrognathia, and cleft palate (Gatti et al., 1972). More recent reports reveal that there is more variability in DiGeorge syndrome than was initially thought (Conley et al., 1979).

Received May 1, 1989; revised version received June 5, 1989," Accepted June 15,B1989.

235 236 S. NUKINA et al.

For some patients that display a hypoplastic thymus, Lischner (1972) advocated the name "partial (or incomplete) DiGeorge syndrome." In 1981, de la Chapelle et af. reported an association between DiGeorge syndrome and a deletion in chromosome 22. Subsequently other reports of a similar association have been pub- lished (Kelley et al., 1982; Greenberg et al., 1984; Pong et al., 1985; Schwanitz and Zerres, 1987; Faed et al., 1987). Using high-resolution banding analysis, we report a patient with incomplete DiGeorge syndrome, who showed a deletion of 22ql 1.1 band.

CASE REPORT

The patient, a boy born in April 1988, was the third child of a 29-year-old mother and 31-year-old father. There was no consanguinity. There was no known ex- posure to radiation or drugs during the mother's pregnancy. The delivery at 34 weeks gestation was not eventful. The first child was a boy, born in 1984 with a heart anomaly, who died immediately after birth. No further information is avail- able about his heart anomaly. The second child, a girl born in 1985, is alive and phenotypically normal. The patient was admitted to our hospital with a low birth weight (2,054 g) and a heart murmur. Physical findings included dysmorphic facial features, hypertelorism, antimongoloid slant of the eyes, flat nasal bridge, low-set malformed ears, micrognathia, round doe-like eyes (Fig. 1), cleft palate, and abnormal location of the third toes. A chest X-ray revealed neither cardiomegaly nor any abnormal shadow. The thymus was detected faintly with roentogenography (Fig. 2). Elec- trocardiography was within normal limits. Echocardiography and cardiac digital subtraction angiography revealed a ventricular septal defect, a double-outlet right

Fig. la. Face of the patient, showing hypertelorism, antimongoloid slant, round eyes, and micrognathia. lb. Side view of the face of the patient, showing malformed low-set ear and micrognathia.

Jpn. J. Human Genet. INCOMPLETE DiGEORGE SYNDROME 237

Fig. 2. The thymus appears as a shadow in a chest X-ray film on admission. ventricle, a right-sided aortic arch, absence of the pulmonary valve, and dilatation of the pulmonary artery. Microcephaly, epicanthal fold, bifid uvula, hypotonia, tetani, and convulsions were not observed. The patient was not examined for a urinary tract malformation. Neither a pharyngeal atresia nor an imperforate anus was found. An avascular area was found in the bilateral peripheral retina at one month of age by fundoscopic examination. There were no other abnor- malities of the retina, the lens, or the iris. At two months of age the avascular area regressed without treatment. At three months of age, the patient developed respiratory deficiency. Atelec- tasis of the left lung was found on a chest X-ray film. Bronchography revealed compression of the left main bronchi by an aneurysm in the pulmonary artery. The patient was treated surgically (pulmonary banding and suspending). The atelectasis disappeared and the respiratory condition imporved after the operation; however, ten days later the patient died from heart failure. An autopsy was not performed. Laboratory data. A complete blood count at two months of age was as follows: hemoglobin, 10.6 g/dl; platelets, 343 x 103/mm~; and white blood cell count, 9,100/ram 3 with 1~ bands, 79~ segmented neutrophiies, 17~ lymphocytes and 3~ monocytes. Serum sodium, potassium, alkaline phosphatase, transaminases, bilirubin, urinary organic acid pattern and serum amino acid analysis were normal. Serum calcium was 9.7 mg/dl and phosphorus was 5.8 mg/dl. Immunoglobulin remained within the normal range as follows: IgG 168 mg/dl, IgA 9 mg/dl and lgM 39 mg/dl. Electroimmunophoresis of immunoglobulin showed a normal pattern. Neutrophils alkaline phosphatase (NAP) was normal (rate 95.5~, score 341.5). Parathyroid hormone (PTH) was 520 ng/ml (normal range, 230-560 ng/ml). There was no abnormal findings in a urinalysis.

Vol. 34, No. 3, 1989 238 S. NUKINA et al.

Both parents were phenotypicatly normal. His mother had no physical anomaly nor a history of frequent infection. Her serum immunoglobulin was within normal range as follows: IgG 1,715 mg/dl, lgA 311 mg/dl and IgM 179 mg/dl. Her lymphocytes showed a normal response to phytohaemagglutinin (PHA), concana- valin A (Con A), or pokeweed mitogen (PWM). No abnormality was detected in the proportion of lymphocytes identified by T3, T4, T8, or B markers.

CYTOGENETIC STUDIES

A chromosome analysis was done on the peripheral leukocytes of the propositus and his parents. Ethidium bromide was used for high-resolution banding analysis. The father had a normal karyotype. On the other hand, in the cells from the mother, each normal homologue of chromosomes 14 and 22 was deleted and replaced by a 14q+ and a minute chromosome. This minute chromosome

Fig. 3a. Partial karyotype of two cells from the mother.

Fig. 3b. Partial karyotype of two cells from the propositus.

Jpn. J. Human Genet. INCOMPLETE DiGEORGE SYNDROME 239 was found in all of 100 cells examined, and there was no cellular mosaisicm. High- resolution banding analysis of cells from the mother revealed a balanced reciprocal translocation between chromosomes 14 and 22, with breakpoints at 14q32.32 and 22q11.2100 (Fig. 3a). In the cells from propositus, the minute chromosome found in the mother was always lost. High resolution banding analysis demonstrated that breaks also occurred at 14q32.32 and 22q11.2100 or a certain portion within band 22q11.21 very close to the juxtaposition. Thus, the patient's karyotype was described as 45,XY,- 14,-22, + der(14)(14pter~ 14q32.32::22ql 1.21---,22qter) (Fig. 3b).

DISCUSSION

Patients with DiGeorge syndrome have craniofacial anomalies such as hypertelorism, low-set malformed ears, micrognathia, cleft palate, and cleft uvula (Conley et al., 1979). The craniofacial anomalies and cardiovascular malformations observed in our patient are compatible with a diagnosis of DiGeorge syndrome. Cardiovascular malformation is a major anomaly in DiGeorge syndrome. Conley et al. (1979) reported that 17 of 25 patients with the syndrome had cardiovascular malformations and Moerman et al. (1980) reported that all ten of their patients with the syndrome had heart anomalies. The majority of cardiovascular malformations found in DiGeorge syndrome are conotruncal anomalies, such as interrupted aortic arch plus ventricular septal defect (VSD), truncus arteriosus, tetralogy of Fallot (TOF), and right sided aortic arch. Our patient had a double outlet right ventricle (DORV) plus VSD, a right sided aortic arch, a hypoplastic pulmonary valve, and dilatation of the pulmonary artery. The blood movement of DORV+VSD is similar to that of TOF. The cardiovascular malformations observed in our patient were consistent with those described in the reported cases of DiGeorge syndrome. Although the cranial and heart anomalies were consistent with the diagnosis of DiGeorge syndrome, the thymus was seen, although indistinctly, in a chest X-ray and the serum parathyroid hormone was within normal limits. There are varia- tions in the clinical features for DiGeorge syndrome. Lischner (1972) proposed that a partial DiGeorge syndrome exists. In such cases there is evidence of some thymic tissue; however, (a) cell-mediated immunity is defective, attributable to the deficiency of thymic tissue, or (b) the total weight of the thymus is clearly below that expected from the degree of involution noted. Conley et al. (1979) defined DiGeorge syndrome to comprise any two of the following findings: (a) cellular immune deficiency or demonstrated absence of all or part of the thymus or both, (b) symptomatic hypocalcemia or anatomic deficiency of the parathyroids or both, and (c) congenital heart disease. In our case, symptoms of ceil-mediated immunodeficiency were not confirmed. The thymus was seen indistinctly in a chest X-ray, suggesting the possibility that the gland was hypoplastic. Robinson (1975) has suggested a possible mechanism for the syndrome. In

Vol. 34, No. 3, 1989 240 S. NUKINA et al. brief, there is a primary vascular malformation of the thyroideaima artery, the principal embryonic blood source to the third and fourth pharyngeal pouches; and aptasia of the parathyroid glands and thymus, which are developed from the third and fourth pouch, is secondary symptom caused by no blood supply. Consequently, the range of anomalies seen in patients with the syndrome is presented. So we con- sider our patient's disorder is closely related to DiGeorge syndrome. The cytogenetic studies on our family revealed that a translocation chromosome was transmitted from the mother to the patient. In a Robertsonian translocation, a minute translocation chromosome formed is usually lost. But there may be exceptions; we reported a case of G/G translocation Down's syndrome, in which both t(Gp21q) and t(Gq21p) were present (Mizukawa et al., 1974): In the present instance, the patient was found to be monosomic for chromosome segments, 14q 32.32~ 14qter and 22pter-~22ql 1.21. In our case, chromosome segment 14q32.32~14qter was also deleted. In chromosome 14q32.3 gene clusters for immunoglobulin heavy chain are located, but serum immunoglobulin was within normal range and electroimmunophoresis of immunoglobulin showed a normal pattern. Since the gene for DiGeorge syndrome is confirmed to be located at chromosome band 22ql 1 (Cannizzaro and Emanuel, 1985), the results of the present study reconfirmed this localization. High-resolution banding analysis enabled us to make more precise analysis. The locus for the present incomplete DiGeorge syndrome is thought to be located in the most proximal band of chromosome 22, i.e., 22q11.1.

Acknowledgments We are very grateful to Dr. James R. Miller for constructive comments on the manuscript.

REFERENCES

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