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Xp21 contiguous gene deletion syndrome, sometimes called complex glycerol kinase deficiency, is associated with variable size Xp21 deletions that usually include the glycerol kinase gene and span multiple Xp21 disease gene loci in the region. The order of the potentially affected loci are as follows: Xpter-Aland Island eye disease (AIED), congenital adrenal hypoplasia (AHC), glycerol kinase deficiency (GKD), Duchenne muscular dystrophy (DMD), chronic granulomatous disease (CGD), McLeod phenotype (XK), retinitis pigmentosa (RP), ornithine transcarbamylase (OTC) and centromere.［1-3］ Clinically, Xp21 contiguous gene deletion syndrome is often misdiagnosed as only one of the multiple single-gene disorders affecting patients. In this report, we investigated the extent of gene deletion in a Chinese boy with Xp21 contiguous gene deletion syndrome involving the DMD, GKD, and AHC loci.
CASE REPORT
A 3-year and 6-month-old boy was admitted to the hospital with a 1-year history of nausea and vomiting and a worsening condition in the previous 5 to 6 days. At the time of his delivery, at term by cesarean section, turbid amniotic fluid had been observed. His birth weight was 3100 g and birth length was 52 cm. He was born to a G1P1 mother who had taken the traditional Chinese medicine “Gonghan” one week before pregnancy. Both mental and physical developmental delay was noted since infancy. The child could not walk independently until he was 2 years old. As of now, he is still unable to walk steadily or go upstairs independently. He cannot run fast or utter complete sentences. Pedigree analysis showed that there was no family history of a similar disease.
A physical examination revealed that the child's height was 95 cm, his weight was 14 kg, and his head circumference was 48 cm. He had a staggering gait and dark skin. Examinations of his heart, lung, abdomen, and external genitourinary region produced normal results. He had hypertrophy of the calves, positive Gower's sign, and diminished knee jerk reflexes.
Laboratory tests produced the following results (reference ranges in parentheses): serum sodium, 125.9 mmol/L (135-145 mmol/L); potassium, 6.59 mmol/L (3.5-4.5 mmol/L); cortisol, 3.5 ng/dl (5-25 ng/dl); triglyceride, 5.31 mmol/L (0.22-1.90 mmol/L); apolipoprotein-B, 0.46 g/L (0.55-1.05 g/L); HDL-cholesterol, 1.01 mmol/L (1.08-1.90 mmol/L); glutamic-oxaloacetic transaminase (GOT), 168 U/L (8-40 U/L); lactate dehydrogenase (LDH), 899 U/L (109-205 U/L); creatine kinase (CK), 5798 U/L (25-200 U/L); and α-hydroxybutyrate dehydrogenase (α-HBD), 873 U/L (80-220 U/L). Total-cholesterol, LOL-cholesterol, apolipoprotein-A1, and very-long-chain fatty acid levels were all within normal limits. The child's peripheral blood karyotype was 46, XY, without visible deletions. His IQ was estimated at 65. Adrenal computed tomography (CT) revealed that the bilateral adrenals were smaller than normal; a magnetic resonance image (MRI) of his head showed patchy low-signal-intensity shades on T1-weighted images and high-signal-intensity shades on T2-weighted images in the bilateral centrum semiovale and adjacent to the lateral ventricle with partial confluence. A thorough ophthal-mological examination found completely normal fundi.
The patient was diagnosed with Xp21 contiguous gene deletion syndrome. With prednisone treatment, the color of his skin became lighter and the levels of serum potassium and sodium returned to normal.
Genomic DNA was extracted from leukocytes by a standard method after informed consent was obtained from the patient's parents. Exons 59-66 of the DMD gene, the four microsatellite DNA markers A002S20, DXS1097, DXS1096, DXS992, the GKD gene, and the AHC gene were amplified by PCR using previously published primers［3-5］ (A002S20, DXS1097, DXS1096, and DXS992 were chosen from Genome Database, GDB) in 25 μl volumes containing 50 ng template DNA, 0.2 μmol/L each primer, 200 mmol/L dNTP, 1×Taq polymerase buffer, and 1 U Taq DNA polymerase. Cycling conditions were 94℃ for 10 minutes, followed by 30 cycles at 94℃ for 30℃ seconds, 55℃-58℃ for 30 seconds, and 72℃ for 30 seconds, with a final extension of 72℃ for 5 minutes. The products of amplification were visualized directly by electrophoresis of 10 μl of product on horizontal 2% agarose gels stained with 0.5 μg/ml ethidium bromide. The results ( Fig. and Table ) revealed the presence of appropriately sized amplicons up to and including DMD exon 61, but no products were detected for amplicons from exons 62 of the DMD gene to the AHC gene, with the exceptions of the GKD gene and the marker DXS992 between DMD and AHC.
DISCUSSION
The term “contiguous gene syndrome” was first used by Schmickel in 1986 to describe patients with multiple single-gene disorders originating from the deletion or duplication of a chromosomal segment that is not detected by routine karyotyping.［6］ Contiguous gene syndromes are characterized by the following: ① they are usually sporadic, but can be familial; ② the cytogenetic abnormalities may be detectable by high-resolution karyotyping or fluorescence in situ hybridization (FISH), although some may be too small to detect by either of these methods; ③ specific aspects of these syndromes are clearly recognizable as possessing single-gene Mendelian traits; and ④ the spectrum of abnormalities in affected patients can be deduced from the mutant phenotypes associated with the single-gene mutations involved.［7］
Xp21 contiguous gene deletion syndrome, also called complex glycerol kinase deficiency, is associated with variable size Xp21 deletions that usually include the glycerol kinase gene and that span multiple Xp21 disease gene loci in the following region: Xpter, AIED, AHC, GKD, DMD, CGD, XK, RP, OTC, and Xcen. Molecular analysis reveals that AHC is very close to the GKD locus and that they are both located within a 1-2 Mb region distal to the DMD locus, whereas XK and CGD lie in a 4-5 Mb region proximal to the DMD locus. Therefore, Xp21 contiguous gene deletion syndrome most frequently affects the X-linked AHC, DMD, and GKD loci.［8］
We diagnosed a patient with Xp21 contiguous gene deletion syndrome characterized by the spectrum of typical clinical and biochemical abnormalities associated with three single-gene mutations, at the AHC, GKD, and DMD loci. Molecular mapping of the Xp21 region in the patient revealed that the deletion encompassed nearly the whole region from a portion of the 3' end of the DMD gene to a site telomeric to the locus for X-linked AHC. The centromeric startpoint of the deletion was localized to the 3' end of the DMD gene, between exons 61 and 62; the telomeric deletion breakpoint mapped to a more distal region of the AHC locus. However, no evidence for the deletion of the GKD gene, located between DMD and AHC, was observed, perhaps the fortuitous effect of its pseudogene.［9］ Interestingly, no deletion of the marker DXS992 between DMD and GKD was detected, possibly indicating the presence of a separate double deletion or a complex paracentric inversion-deletion within this region. The exact mapping of the breakpoint in the patient remains to be determined.
Theoretically, the spectrum of abnormalities associated with Xp21 contiguous gene deletion syndrome should be composed of the mutant phenotypes associated with the single-gene mutations involved, but different single-gene disorders have different clinical characteristics. For example, AHC presents with salt wasting and hyperpigmentation during the neonatal period, so AHC is usually the first condition to be manifested in patients with Xp21 contiguous gene deletion syndrome. On the other hand, DMD is the most common of the constituent single-gene disorders, but it rarely manifests itself before age 3. Thus, Xp21 contiguous gene deletion syndrome may be clinically misdiagnosed as only one of the multiple single-gene disorders at the early stage of onset if some necessary biochemical and molecular analysis is ignored. Xp21 contiguous gene deletion syndrome should be considered in any infant with adrenal insufficiency irrespective of a normal karyotype. Measurement of serum triglycerides and creatine kinase activity are simple screening tests that may facilitate early diagnosis and prompt appropriate genetic counseling about the risks of recurrence in subsequent offspring. Analysis of molecular genetics would help in determining the extent of the deletion.
REFERENCES
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