Alpha-Thalassemia/mental Retardation Syndrome, X-Linked

A number sign (#) is used with this entry because X-linked alpha-thalassemia/mental retardation syndrome is caused by mutation in the ATRX gene (300032) on Xq21.

The 'deletion' type of alpha-thalassemia/mental retardation syndrome (141750) is a contiguous gene syndrome due to a deletion in chromosome 16p that involves the hemoglobin alpha-1 (HBA1; 141800) and alpha-2 (HBA2; 141850) genes.

The X-linked mental retardation-hypotonic facies syndrome (309580) is also caused by mutation in the ATRX gene.

Clinical Features

Weatherall et al. (1981) reported the association of hemoglobin H disease (Hb H; see alpha-thalassemias, 141800) and mental retardation in 3 unrelated patients of northern European descent.

Wilkie et al. (1990) reported 5 unrelated patients, 2 of whom were reported by Weatherall et al. (1981), with mental retardation and alpha-thalassemia without molecular abnormalities of the alpha-globin gene complex on chromosome 16p. The patients showed a strikingly uniform phenotype comprising severe mental handicap, characteristic dysmorphic facies, genital abnormalities, and an unusual, mild form of hemoglobin H disease. Facial features included microcephaly, hypertelorism, epicanthus, a small triangular upturned nose, and flat face. The degree of red blood cell hypochromia and Hb H levels, which varied from 0.7 to 6.7%, were milder than usually found in alpha-thalassemia. Although several approaches failed to find a defect in the alpha-globin genes, 3 patients tested had markedly reduced total mRNA levels of both HBA1 and HBA2. The authors suggested that the responsible locus encoded a trans-acting factor involved in the normal regulation of alpha-globin expression.

Harvey et al. (1990) described the syndrome in a 21-year-old male and his brother who had died earlier, suggesting X-linked inheritance. DNA analysis showed no deletions within the alpha-globin gene cluster. Hb H bodies were present at a low level (1.6%).

Porteous and Burn (1990) described a 6-year-old boy who had a maternal uncle with an X-linked mental retardation syndrome, and suggested that their case resembled 2 brothers previously thought to have an atypical form of the Coffin-Lowry syndrome (303600) (illustrated in Smith's Recognizable Patterns of Human Malformation, Jones, 1988). However, Wilkie et al. (1991) found that there were hematologic signs of the nondeletion ATR syndrome in the patient reported by Porteous and Burn (1990). In addition, Wilkie et al. (1991) reported that hematologic evaluation of 1 of the brothers reported in Smith's book showed that he had nondeletion ATR and that a male first-cousin through the maternal line had the same condition. Wilkie et al. (1991) suggested that this condition be called 'X-linked alpha-thalassemia/mental retardation' (ATR-X) to distinguish it from the deletion form.

In a review, Gibbons et al. (1991) noted that some patients with ATR-X syndrome have normal or only mildly abnormal hematologic indices; thus normal hemoglobin levels and red cell indices do not necessarily exclude the condition.

Cole et al. (1991) described an affected boy whose maternal uncle was also affected. The boy had right-sided renal agenesis with left-sided hydronephrosis and hydroureter. He had recurrent hypochromic, microcytic anemia. His otherwise unaffected sister had had recurrent urinary tract infections and persistent renal impairment in the absence of any identifiable renal tract anomaly. Kurosawa et al. (1996) described a boy with self-induced vomiting followed by rumination and noted that Cole et al. (1991) made the same observation in a man and his nephew.

Donnai et al. (1991) described 4 brothers with this syndrome in whom the diagnosis was first suspected because of their characteristic clinical features and was confirmed in each case by the demonstration of Hb H inclusions in a proportion of their red blood cells. Very rare Hb H inclusions were found in the red blood cells of the mother and one sister who both shared some facial features with the affected boys; they were presumed to be carriers of the disorder.

Gorlin (1993) examined patients with typical features of the ATR-X syndrome, but without hemoglobin H. The facies were identical and mapping studies in several families suggested location of the mutation in the site on the X chromosome involved in ATR-X. The facies of this syndrome, which is often confused with that of Coffin-Lowry syndrome, were marked by telecanthus, epicanthic folds, flat nasal bridge, midface hypoplasia, a carp-shaped mouth with full lips, and small triangular nose with anteverted nostrils. Gorlin (1993) noted that the alae of the nose extended lower than the columella and septum. All developmental milestones, especially walking, were delayed and speech was almost absent. On further investigation, Gibbons (1994) found that the patients of Gorlin (1993) did have alpha-thalassemia, as indicated by the presence of hemoglobin H inclusions after use of 1% brilliant cresyl blue staining overnight in buffered solution at room temperature. With the staining, the Hb H inclusions give the erythrocytes the appearance of golf balls.

Logie et al. (1994) reported a pedigree with 6 affected males in 4 sibships spanning 2 generations. Two affected cousins were described in detail, one of whom had an unusually mild hematologic phenotype. Hb H inclusions, the hallmark of the disorder, were detected in the peripheral red blood cells only after repeated observations. The cousins had strikingly similar facies with telecanthus, anteverted nares, carp-shaped mouth, and large tongue. Gibbons et al. (1995) showed that the hematologic findings in ATR-X may vary widely; indeed, in some cases, the manifestation of alpha-thalassemia may be subtle and missed without repeated examinations. McPherson et al. (1995) described a kindred with 4 affected members. The hematologic abnormality was not detected on routine hematologic studies, including hemoglobin electrophoresis, but the patients were found to have hemoglobin H inclusions on brilliant cresyl blue staining of peripheral smears.

Reardon et al. (1995) reported 2 phenotypic females with a 46,XY karyotype who had abnormalities of the external genitalia resulting in male pseudohermaphroditism. They pointed out that 1 of the 5 original patients described in defining the ATR-X syndrome was a phenotypic female with a 46,XY karyotype (Wilkie et al., 1990). McPherson et al. (1995) described genital anomalies that led to a female sex of rearing in 3 of 4 affected members of a family. Gibbons et al. (1995) emphasized the progressive coarsening of the facial appearance. Kuno et al. (1997) described a 5-year-old Japanese boy with this condition. He had an abnormal hemoglobin which was found to consist exclusively of a beta subunit. Severe mental retardation and hypoplastic penis and testes were present. Anemia was only mild (hematocrit 35.8%). The family history was unremarkable.

Martinez et al. (1998) reported 2 brothers and 1 maternal cousin with severe mental retardation, microcephaly, short stature, cryptorchidism, and spastic diplegia. Some facial dysmorphic features were present. Martinez et al. (1998) pointed out the similarity in phenotype between their family and that described by Sutherland et al. (1988) (see 309500). They suggested that the greater phenotypic severity in their family was due to allelic heterogeneity. X-inactivation analysis of 1 potential and 3 obligate carriers showed nonrandom inactivation of the disease-linked variant. On further analysis of this family, Lossi et al. (1999) found that 3% of the patients' erythrocytes showed Hb H inclusions, consistent with ATR-X. Lossi et al. (1999) also reported dysmorphic facial features, including 'carp-like' triangular mouth, hypertelorism, small triangular nose, and broad nasal root. The hypertonia and spasticity were unusual findings in this family. A mutation was found in the ATRX gene in affected individuals (300032.0016).

Gibbons and Higgs (2000) provided a review of the clinical spectrum of syndromes caused by mutation in the XH2 gene.

Martucciello et al. (2006) described male 3-year-old dizygotic twins with ATRX who exhibited gastrointestinal problems including severe regurgitation of food, vomiting, dysphagia, irritability, respiratory disorders, meteorism, and chronic constipation. Barium studies in both twins showed gastric pseudovolvulus, and 24-hour pH monitoring showed severe gastroesophageal reflux. Enzymo-histochemical studies of full-thickness colonic biopsies revealed a complex dysganglionosis: ultrashort Hirschsprung disease (see 142623) associated with hypoganglionosis. Martucciello et al. (2006) reviewed the gastrointestinal phenotype of 128 confirmed cases of ATRX and found that drooling was reported in 36% of cases, gastroesophageal reflux was present in 72%, and constipation in 30%. Fundoplication was performed in 10% of cases, and 9% were fed by gastrostomy. Upper GI bleeding was reported in 10% of cases. Fatal aspiration of vomitus occurred in 3 patients; volvulus was seen in 4 patients, 2 of whom died after intestinal infarction; and 4 patients had recurrent hospitalizations for ileus or pseudoobstruction. Martucciello et al. (2006) also noted that there were numerous anecdotal reports from parents describing prolonged episodes of patient distress with refusal to eat or drink.

Jezela-Stanek et al. (2009) reported a patient with ATRX confirmed by genetic analysis. He had hypertelorism, epicanthal folds, strabismus, short nose with flat bridge and triangular upturned tip, and tented upper lip with everted lower lip. Other features included hypotonia, psychomotor retardation, and hemoglobin H inclusions. The patient also had undescended testes and ambiguous genitalia, which the authors referred to as male pseudohermaphroditism. Laboratory studies showed increased FSH and decreased testosterone. A deceased sib was believed to have been affected and reportedly had ambiguous external genitalia. Jezela-Stanek et al. (2009) postulated that the distinctive facial features in ATRX result from facial hypotonia and can be confused with Coffin-Lowry syndrome (CLS; 303600) or SLO syndromes (SLOS; 270400).

Carrier Females

Studying 7 pedigrees that included individuals with the ATR-X syndrome, Gibbons et al. (1992) concluded that intellectually normal female carriers could be identified by the presence of rare cells containing Hb H inclusions in their peripheral blood and by an extremely skewed pattern of X inactivation in cells from a variety of tissues. McPherson et al. (1995) used a combination of skewed X inactivation and haplotype analysis at Xq12-q21.3 to establish carrier status.

Wada et al. (2005) found skewed X-inactivation patterns (greater than 90:10) in 6 of 7 unaffected Japanese female ATR-X carriers; the 1 carrier with non-skewed X inactivation (72:28) demonstrated moderate mental retardation. The woman did not have dysmorphic features or hemoglobin inclusions. Wada et al. (2005) concluded that mutations in the ATRX gene may cause mental retardation in females if the chromosome carrying the mutation is not properly inactivated.

Badens et al. (2006) reported a 4-year-old girl with typical features of the ATR-X syndrome. Molecular studies showed a totally skewed X-inactivation pattern, with the active chromosome carrying a heterozygous mutation in the ATRX gene (300032.0018). Neither parent had the mutation in peripheral blood leukocytes, but SNP analysis indicated that the mutation occurred on the maternal chromosome. The child was conceived with assisted reproduction technologies (ART) due to micropolycystic ovaries and endometriosis in the mother. Badens et al. (2006) suggested that some aspect of ART may have disturbed imprinting in this patient.


By linkage analysis of 7 affected pedigrees, Gibbons et al. (1992) mapped the ATR-X locus to an 11-cM interval on chromosome Xq12-q21.31 between markers DXS106 and DXYS1X (peak lod score of 5.4 at theta = 0 at DXS72).

In a 3-generation ATR-X family with 3 affected males, Houdayer et al. (1993) demonstrated a maximum lod score of 2.09 at a recombination fraction of zero for linkage with DXS453 located at the boundary Xq12-q13.1. The nearest flanking loci demonstrating recombination with the disease locus were the androgen receptor (AR; 313700) at Xq11.2-q12 on the centromeric side and DXS72 at Xq21.1 on the telomeric side. Houdayer et al. (1993) interpreted their results as compatible with a distal boundary at Xq21.1 instead of Xq21.31 as previously held.

Gibbons et al. (1995) performed linkage analysis in 9 families with ATR-X syndrome and identified key recombinants that reduced the area of interest to 1.4 cM (estimated to be 15 Mb) between DXS454 and DXS72 within Xq13.1-q21.1 (Wang et al., 1994).

Molecular Genetics

In patients with the ATR-X syndrome, Gibbons et al. (1995) identified mutations in the ATRX gene (300032.0001-300032.0009).

In affected members of a family with ATR-X syndrome, Villard et al. (1996) identified a splice site mutation in the ATRX gene (300032.0010). In 2 first cousins presenting the classic ATR-X phenotype with alpha-thalassemia and Hb H inclusions, only the abnormal transcript was expressed. In a distant cousin presenting with a similar dysmorphic mental retardation phenotype, but without thalassemia, they found that approximately 30% of the ATRX transcripts were normal. These data suggested that the mode of action of the ATRX gene product on globin expression is distinct from its mode of action in brain development and facial morphogenesis, and that the mutated splice site could be used with varying efficiency in different individuals.

Hendrich and Bickmore (2001) reviewed human disorders that share in common defects of chromatin structure or modification, including the ATR-X spectrum of disorders, ICF syndrome (242860), Rett syndrome (312750), Rubinstein-Taybi syndrome (180849), and Coffin-Lowry syndrome.

Partial Duplication of the ATRX Gene

Thienpont et al. (2007) reported 3 patients, including 2 sibs, with the ATRX syndrome due to partial duplications of the ATRX gene. In 1 family, the duplication included exons 2 to 35; in the other family, exons 2 to 29. Further analysis showed that both mothers carried the duplication and both had skewed X inactivation. In 1 patient, ATRX mRNA levels were about 3% of normal values. Thienpont et al. (2007) noted that the duplications were not identified by sequence analysis and suggested that quantitative analysis to detect copy numbers of the ATRX gene may be required in some cases.

Cohn et al. (2009) reported a family in which 3 males had ATRX syndrome due to a partial intragenic duplication of the ATRX gene that spanned exons 2 to 31. Northern blot analysis failed to identify a full-length transcript, but cDNA sequencing was consistent with some level of expression. The authors noted that complete loss of ATRX is most likely lethal, suggesting that the mutation was likely hypomorphic and associated with some residual protein function. Unaffected obligate carrier females in the family had highly skewed X inactivation. The phenotype was typical for the disorder, although the facial features were not as readily apparent in the 2 older affected individuals. The proband was identified from 2 larger cohorts comprising 300 males with mental retardation. Cohn et al. (2009) did not find ATRX duplications in 29 additional males with ATRX syndrome who were negative on sequence analysis, suggesting that duplications are a rare cause of the disorder.

Genotype/Phenotype Correlations

In a review article, Gibbons and Higgs (2000) noted that mutations in the ATRX gene resulting in the loss of the C terminal domain are associated with the most severe urogenital abnormalities. However, at other sites, there is no obvious link between genotype and phenotype, and there is considerable variation in the degree of abnormalities seen in individuals with the same mutation.

Among 22 ATRX patients from 16 families, Badens et al. (2006) found that those with mutations in the PHD-like domain of the ATRX protein had significantly more severe and permanent psychomotor retardation and significantly more severe urogenital anomalies compared to those with mutations in the helicase domain.

Animal Model

Medina et al. (2009) surveyed ATR-X syndrome clinical findings and noted that ocular defects were present in 47 (23%) of 202 patients. They showed that Atrx was expressed in the neuroprogenitor pool in embryonic mouse retina and in all cell types of adult mouse retina except rod photoreceptors. Conditional inactivation of Atrx in mouse retina during embryogenesis resulted in loss of only 2 types of neurons, amacrine and horizontal cells. This defect did not arise from a failure to specify these cells, but rather a defect in interneuron differentiation and survival postnatally. The timing of cell loss was concomitant with light-dependent changes in synaptic organization in mouse retina and with a change in Atrx subnuclear localization within these interneurons. The interneuron defects were associated with functional deficits as demonstrated by reduced b-wave amplitudes upon electroretinogram analysis. Medina et al. (2009) proposed a role for Atrx in interneuron survival and differentiation.