Alpha-Thalassemia/mental Retardation Syndrome, Chromosome 16-Related

A number sign (#) is used with this entry because of evidence that the disorder represents a contiguous gene syndrome due to a deletion in chromosome 16p that involves the alpha-1 (HBA1; 141800) and alpha-2 (HBA2; 141850) genes, among others.

X-linked alpha-thalassemia/mental retardation syndrome (ATR-X; 301040) is a similar phenotypic disorder caused by mutation in the ATRX gene (300032).

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.

Hjelle et al. (1982) described a somewhat similar case in a male of northern European extraction. Hb H was associated with multiple congenital anomalies: spina bifida from T6 to the sacrum with a T10-L4 myelomeningocele, congenital cataracts, bilateral inguinal hernias, bilateral deformities of the femoral necks, and subluxation of the left hip. One of his 2 sibs also had congenital cataracts, but there was no family history of other congenital anomalies or of fetal wastage. According to restriction enzyme analyses, the father had 2 alpha-globin genes on one chromosome and only 1 gene on the homolog (i.e., was a silent alpha-thalassemia carrier), whereas the mother had cis alpha-thalassemia trait (i.e., 2 alpha genes on 1 chromosome and none on the homolog). The proband had the thalassemia chromosome of each parent. The restriction patterns were typical of Asian alpha-thalassemia. The brother with congenital cataracts carried the father's thalassemic chromosome.

Higgs et al. (1989) stated that they were aware of 13 individuals, 10 males and 3 females from a variety of racial groups, with this association. Nine of the patients had Hb H disease, with hypochromic microcytic anemia and 1 to 11% of Hb H in the peripheral blood. The other 4 had alpha-thalassemia trait with only occasional Hb H-containing cells. In all cases, family studies showed that alpha-thalassemia in the proband resulted entirely or in part from a de novo mutation affecting alpha-globin production.

Wilkie et al. (1990) reported 8 unrelated patients with mental retardation and alpha-thalassemia due to deletions of chromosome 16p, including patients previously reported by Weatherall et al. (1981), Borochovitz et al. (1970) and Bowcock et al. (1984), Hutz et al. (1986), and Buckle et al. (1988). Molecular genetic analysis of all 8 patients showed that each failed to inherit an alpha-globin allele from 1 of the parents and had deletions of variable size in band 16p13.3. In at least 4 cases, the deletion resulted from unbalanced chromosome translocation; hence aneuploidy of a second chromosome was also present. The clinical features varied widely and were relatively nonspecific.

Lindor et al. (1997) described a female infant of mixed northern European ancestry in which alpha-thalassemia was ascertained by newborn screening. Evaluation at 9 months of age showed minor anomalies and developmental delay. Chromosomal analysis demonstrated a de novo deletion of the most distal portion of 16p. By fluorescence in situ hybridization it was established that the anomaly was a terminal deletion with a breakpoint at 16p13.3, and not a translocation. This was said to have been only the fifth reported case of the ATR-16 chromosome that was not complicated by duplication or deletion in other chromosomes. They suggested that ATR-16 is underdiagnosed, since making the diagnosis is confounded by the mildness of the phenotype, the high frequency of alpha-thalassemia trait in many populations, the subtlety of cytogenetic findings, and the lack of altered Southern blot band sizes.

Holinski-Feder et al. (2000) reported a 5-generation family in which 10 individuals of both sexes had mild to moderate mental retardation and mild nonspecific dysmorphic features. The disorder was inherited in a seemingly autosomal dominant fashion with reduced penetrance. Standard clinical and laboratory screening protocols and extended cytogenetic analysis, including the use of high-resolution karyotyping and multiplex FISH, did not reveal the cause of the mental retardation. However, a genomewide scan showed linkage to chromosome 16p13.3, and a deletion of part of 16pter was demonstrated in patients, similar to the deletion observed in patients with ATR-16 syndrome. Subsequent FISH analysis demonstrated that the patients in this family inherited a duplication of terminal 3q in addition to the deletion of 16p. FISH analysis of obligate carriers revealed that a balanced translocation between the terminal parts of 16p and 3q segregated in this family. Affected individuals had hematologic parameters consistent with mild alpha-thalassemia. Holinski-Feder et al. (2000) emphasized the role of cryptic, cytogenetically invisible subtelomeric translocations in mental retardation, which has been estimated to be implicated in 5 to 10% of cases (Flint et al., 1995; Giraudeau et al., 1997; Slavotinek et al., 1999).

Gallego et al. (2005) described a child with ATR-16 syndrome who had been referred for genetic evaluation because of minor anomalies and developmental delay. Cytogenetic analysis showed a de novo complex rearrangement of chromosome 16. FISH analysis, using chromosome 16 subtelomeric probes, showed that the patient had a deletion of the distal short arm of chromosome 16 that contains the alpha-globin genes and a duplication of 16q. Southern blot analysis of the alpha-globin locus showed a half-normal dose of the alpha-globin genes. Microsatellite marker studies showed that the duplicated chromosome 16q region was maternal in origin. Hematologic studies showed anemia, hypochromia, and occasional cells with Hb H inclusion bodies. Gallego et al. (2005) concluded that a hematologic screening for alpha-thalassemia should be considered in patients with mild developmental delay and a suggestive phenotype of ATR-16 with microcytic hypochromic anemia and normal iron status. They suggested that the finding in this patient of a stellate pattern of the iris may be useful in the clinical delineation of ATR-16 and/or duplication of 16qter. Gallego et al. (2005) stated that approximately 15 cases of ATR-16 had been described and that 'only a handful of cases involving duplication of 16q22-qter' had been reported among liveborns.

Molecular Genetics

Pfeifer et al. (2000) stated that the SOX8 gene (605923) was found to be deleted in a patient with ATR-16 syndrome who carried a 2-Mb deletion on chromosome 16p13.3. Based on the high expression of SOX8 in the brain, they suggested that haploinsufficiency for the SOX8 protein could contribute to the mental retardation found in ATR-16 syndrome.

Lamb et al. (1993) restudied a South African Dutch patient with mental retardation who was originally reported by Borochovitz et al. (1970) to have a normal karyotype and was later found by Wilkie et al. (1990) to have a subtle shortening of band 16p13.3 of one chromosome 16 homolog. Lamb et al. (1993) showed that the patient had a truncation of the terminal 2 Mb of chromosome 16p and that the telomeric sequence (TTAGGG)n had been added at the site of breakage. The chromosomal break, which was paternal in origin and had probably arisen at meiosis, had apparently been stabilized in vivo by the direct addition of the telomeric sequence.

Harteveld et al. (2007) used multiplex ligation-dependent probe amplification (MLPA) to fine map deletions of chromosome 16p in 3 patients with ATR-16 and 1 patient with alpha-thalassemia without mental retardation. The region for which haploinsufficiency resulted in dysmorphic features and mental retardation was narrowed down to 800-kb on 16p between 0.9 and 1.7 Mb from the telomere.

Gibson et al. (2008) reported an 8-year-old Caucasian girl with ATR-16 syndrome associated with a do novo submicroscopic terminal deletion at chromosome 16p encompassing at least 1 Mb and including the SOX8 gene. Gibson et al. (2008) noted that isolated monosomy for chromosome 16p is rarely described, as most patients with this disorder have complex translocations or karyotypic abnormalities.