Chromosome Xp21 Deletion Syndrome

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome on chromosome Xp21.

Description

Infantile or complex glycerol kinase deficiency is a contiguous gene syndrome caused by microdeletion of GK (300474) and its neighboring genes, dystrophin (300377), which causes Duchenne muscular dystrophy (DMD; 310200), and NR0B1 (300473), which causes congenital adrenal hypoplasia (AHC; 300200). Patients present with hyperglycerolemia and glyceroluria, associated with DMD and/or AHC (summary by Stanczak et al., 2007).

Clinical Features

McCabe et al. (1977) described 2 brothers, aged 2 and 5 years, with an elevated urinary excretion of glycerol, poor growth, mental retardation, nonparalytic esotropia, and osteoporosis with pathologic fractures. Follow-up of these brothers by Guggenheim et al. (1980) noted that they also had adrenal insufficiency (300200). Other features included psychomotor retardation, spasticity, growth failure, myopathy, and osteoporosis. Glycerol kinase activity in leukocytes and cultured fibroblasts was less than 5% of controls. The younger brother died unexpectedly at 30 months of age within a day of onset of a febrile illness. At autopsy, the adrenals were small and the zona glomerulosa was encroached on by a nodular, hyperplastic zona fasciculata, indicating congenital adrenal hypoplasia. A maternal uncle was probably affected also.

Bartley et al. (1982) described 4 persons from 2 unrelated families with coincidence of X-linked GKD and X-linked congenital adrenal hypoplasia. All had psychomotor retardation. Renier et al. (1983) reported 3 male sibs with glycerol kinase deficiency, congenital adrenal hypoplasia, and Duchenne muscular dystrophy.

Toyofuku et al. (1981, 1986) reported 2 brothers with Duchenne muscular dystrophy and cytomegalic congenital adrenal hypoplasia. There was also a possibly affected maternal uncle. The authors suggested that a small deletion of the X chromosome may be responsible for the 2 disorders. Renier et al. (1983) reported 3 brothers with DMD, cytomegalic congenital adrenal hypoplasia, glycerol kinase deficiency, and mental retardation. Although all 3 of the disorders are X-linked, there were no microscopically visible abnormalities of Xp in prometaphase chromosomes.

Ginns et al. (1984) identified infantile and juvenile (see 307030) forms of GK deficiency. The infantile form is characterized by adrenal hypoplasia, psychomotor retardation, growth delay, osteoporosis, and in some patients myopathy histologically similar to that of Duchenne muscular dystrophy.

Baranzini et al. (1997) reported a 10-year-old boy with hyperglycerolemia and glyceroluria, congenital adrenal hypoplasia, and Duchenne muscular dystrophy, who also had agenesis of the corpus callosum with subtle ventricular dilation on CT scan. Dysmorphic features included wideset eyes with alternating strabismus, drooping mouth, and clinodactyly of the hands. Baranzini et al. (1997) stated that this was the first report of agenesis of the corpus callosum in a patient with complex GKD.

Mapping

Wieringa et al. (1985, 1985) reported that in a family (Renier et al., 1983) in which males had a combination of Duchenne muscular dystrophy, adrenal hypoplasia, and glycerol kinase deficiency, use of a DNA probe known to be closely linked to DMD indicated a deletion on the X chromosome, as did examination of extended chromosomes which showed deletion of part of the Xp21 band. Patil et al. (1985) also described studies of families in which affected males had combined GK deficiency and adrenal hypoplasia, sometimes with myopathy as well, and had deletion of the Xp21.3-p21.2 region.

Hammond et al. (1985) suggested that the locus for glycerol kinase and that for X-linked adrenal hypoplasia are in the segment Xp21-p11.2. The suggestion was based on the finding of an interstitial Xp deletion with breakpoints at p11.2 and p21 in the phenotypically normal mother of a male infant who died at 36 hours of cytomegalic adrenal hypoplasia with glyceroluria (indicating glycerol kinase deficiency) and deficiency of ornithine carbamoyltransferase (OTC; 300461) in the liver. The infant also showed hypoglycemia, hyperammonemia, and gross orotic aciduria. The mother showed excessive orotic acid excretion after an orotic acid-free protein load. Cytogenetic studies in the baby were technically unsatisfactory. Linkage of primary adrenal hypoplasia and glycerol kinase deficiency is supported by description of coincidence of the 2 disorders in 2 brothers (McCabe, 1983).

Investigations of glycerol kinase deficiency by Seltzer et al. (1985) suggested that primary adrenal hypoplasia seen in association with glycerol kinase deficiency in cases of Xp deletion is not due to loss of a separate, closely linked locus but rather is a pleiotropic effect of the glycerol kinase deficiency. In the infantile form of GK deficiency, adrenocortical hypoplasia with insufficiency is a consistent feature (in 12 patients in 6 families). Seltzer et al. (1985) proposed that deficiency of outer mitochondrial membrane-bound GK restricts glycerophospholipid synthesis and hence the activation of steroidogenesis.

In a case reported by Saito et al. (1986), the mother was a carrier of the deletion of Xp21 that caused GK deficiency, adrenal hypoplasia, progressive muscular dystrophy, and mental retardation in the son.

Using Xp DNA probes, Dunger et al. (1986) demonstrated deletion in the Xp21 region in 1 of 2 unrelated boys with adrenal hypoplasia, GKD, DMD, and mental retardation. Conventional G banding did not show the deletion. The authors thought that the other boy probably had an undetected deletion. The authors suggested that the syndrome is likely due to deletion of several closely linked genes, comparable to the cause of the WAGR syndrome (194070) on 11p and perhaps the Langer-Giedion syndrome (150230) on chromosome 8 and other 'contiguous gene' syndromes (Schmickel, 1986). Dunger et al. (1986) favored separate loci for AHX, GK, and DMD. They pointed out that congenital adrenal hypoplasia has been reported with DMD and with GKD without muscle disease. Bartley et al. (1986) likewise found deletion in Xp (Xp21.3-p21.2) in a 6-year-old boy with adrenal insufficiency discovered at age 11 days and with evidence of Duchenne muscular dystrophy. An older brother diagnosed as having DMD was not known to have electrolyte imbalance or hypoglycemia but adrenal function was never evaluated and he died suddenly at age 5 years without autopsy. The mother and sister of these boys had the Xp21 deletion.

Francke et al. (1987) did mapping studies with various DNA probes in a search for deletions of GK deficiency either in isolation or in association with congenital adrenal hypoplasia and developmental delay with or without congenital dystrophic myopathy. Four of 7 such patients were found to have deletions of different sizes within Xp21. No deletions were detected in 2 patients with isolated GK deficiency. Patients with progressive muscular dystrophy tended to have larger deletions that included markers known to derive from the DMD locus. The findings in the patients with isolated GK deficiency suggested that the AH and GK loci are separate and distinct.

Goonewardena et al. (1987) found no cytogenetically detectable deletion in a 26-year-old man suffering from glycerol kinase deficiency, adrenal aplasia, and hypogonadism; however, DNA markers showed deletion. The presence of hypogonadism suggested the existence of a locus for hypogonadism in that region of Xp. The hypogonadism was of the hypogonadotropic type. Kallmann syndrome (308700), a form of hypogonadotropic hypogonadism, maps to the distal portion of Xp.

Borresen et al. (1987) studied amniocytes from a pregnant woman who previously had given birth to a boy who had died at 12 months with a diagnosis of glyceroluria and adrenal insufficiency. A high amount of glycerol (9.0 SD above the mean for controls) was found in the amniotic fluid. The activity of glycerol kinase in cultured amniocytes was very low. For that reason, the pregnancy was terminated. Examination of DNA isolated from the male fetus demonstrated deletion of 2 out of 16 probes mapped to Xp, i.e., DXS28 and DXS68, both of which map to Xp21.3, distal to the Duchenne locus. On prometaphase chromosomes, Marlhens et al. (1987) found an interstitial deletion involving Xp21.2, and possibly Xp21.3, in a boy with both congenital adrenal hypoplasia and glycerol kinase deficiency, as well as in his mother. Duchenne muscular dystrophy was excluded on the basis of normal serum creatine kinase and normal muscle biopsy; further, molecular hybridization of DNA from DMD probes was normal.

Davies et al. (1988) proposed that AHC, GK, and DMD are located in that order from pter to centromere. The conclusion was based on the finding of patients who suffered from DMD and GK deficiency without AHC and other patients who suffered from all 3 disorders. The conclusion was further supported by the work of Love et al. (1990), who reported a new locus designated JC-1, which mapped between AHC and GK. (JC were the initials of the patient suffering from DMD and GK deficiency but not AHC.) Love et al. (1990) pointed out that there appears to be a paucity of HTF islands in the DMD--GK--AHC region, suggesting that, unlike the fragile X region, the Xp21 region is relatively AT-rich and contains few genes.

Darras and Francke (1988) studied DNA samples from 9 previously reported patients with complex GK deficiency by probing with the entire cDNA for the dystrophin protein (300377). All 5 patients with associated myopathy, including 2 in whom no deletions had been detected before, were found to have variable-sized deletions extending through the 3-prime end of the dystrophin gene. A correlation was found between severity and progression of the muscular dystrophy phenotype and the size of the gene deletion. In cases with the GKD/adrenal hypoplasia microdeletion syndrome without myopathy, no deletion was found in the dystrophin gene.

Matsumoto et al. (1988) described 5 unrelated Japanese males and reviewed 20 previously reported patients (1 of them female) with a contiguous gene syndrome including GK deficiency. They pointed out that at least 6 of the 25 patients were known to have had gonadotropin deficiency and/or cryptorchidism, and suggested that a gene responsible for gonadotropin deficiency (GTD; 306190) is located in the Xp21 region and is situated in the following linear order: Xpter--GTD--AHC--GK--DMD--OTC--Xcen. Molecular genetic analysis of DNA from a patient with glycerol kinase deficiency, adrenal hypoplasia, mental retardation, and hypogonadotropic hypogonadism, reported by Goonewardena et al. (1989), was consistent with this gene order. They further suggested that the anonymous marker DXS41 is distal to the GTD locus.

In a 2-year-old boy with Duchenne muscular dystrophy, GK deficiency, and congenital adrenal hypoplasia, Stuhrmann et al. (1991) found a microscopically visible deletion within Xp21 that was also demonstrated in the mother. Their findings with DNA markers supported the order pter--AHC--GK--DMD--cen.

In 12 patients who had GKD with AHC and/or DMD, Muscatelli et al. (1994) detected variable-sized deletions that all encompassed the DAX1 gene (NR0B1; 300473).

Balducci et al. (1995) used the designation 'complex glycerol kinase deficiency' for the form of GK deficiency due to microdeletion involving not only the GK1 locus but also the locus for congenital adrenal hypoplasia and/or that for Duchenne muscular dystrophy. They described a case in which there was marked salt wasting which could not be attributed to congenital adrenal hyperplasia. GK deficiency was demonstrated by evaluating plasma triglycerides by a routine clinical method that measures glycerol released after lipolysis. High resolution cytogenetic investigation of blood cells showed a small interstitial deletion within Xp21; the same deletion was found in the patient's mother but not in his maternal grandmother.

Using high-resolution cytogenetic analysis and molecular techniques in a 10-year-old boy who had complex GKD associated with agenesis of the corpus callosum, Baranzini et al. (1997) identified a 46,del(X)(p21.1-p21.3),Y karyotype, involving a deletion that spanned at least 3 million base pairs.

In 2 sibs with AHC-GKD and in 2 unrelated patients with AHC-GKD-DMD, Peter et al. (1998) detected an approximately 650-kb deletion that included the AHC-GKD locus and an approximately 1-Mb deletion involving the entire AHC-GKD-DMD locus, respectively.

Asghar et al. (1999) described a child who presented with failure to thrive and was found to have glycerol kinase deficiency and Duchenne muscular dystrophy due to deletion of Xp21.2.