Mental Retardation-Hypotonic Facies Syndrome, X-Linked, 1

A number sign (#) is used with this entry because X-linked mental retardation-hypotonic facies syndrome-1 (MRXFH1) is caused by mutation in the ATRX gene (300032) on chromosome Xq13.

Description

The term 'X-linked mental retardation-hypotonic facies syndrome' comprises several syndromes previously reported separately. These include Carpenter-Waziri, Holmes-Gang, and Smith-Fineman-Myers syndromes as well as 1 family with X-linked mental retardation with spastic paraplegia. All these syndromes were found to be caused by mutation in the XH2 gene and are characterized primarily by severe mental retardation, dysmorphic facies, and a highly skewed X-inactivation pattern in carrier women (Abidi et al., 2005). Other more variable features include hypogonadism, deafness, renal anomalies, and mild skeletal defects.

X-linked alpha-thalassemia/mental retardation syndrome (ATR-X; 301040) is an allelic disorder with a similar phenotype with the addition of alpha-thalassemia and Hb H inclusion bodies in erythrocytes.

Nomenclature

Juberg-Marsidi syndrome (see 309590) was previously thought to be the same as X-linked mental retardation-hypotonic facies syndrome; however, affected individuals from that original family were found to have a pathogenic mutation in the HUWE1 gene (300697).

Clinical Features

Smith et al. (1980) described 2 brothers with a combination of mental retardation, microcephaly, short stature, and unusual facial appearance, including slanted palpebral fissures, narrow face with maxillary overjet, alternating exotropia, and ptosis. Muscle tone was hypotonic, but 1 patient had hyperreflexia. The authors quoted Frota-Pessoa et al. (1968) as citing a prior probability of about 30% for autosomal recessive inheritance and about 70% for X-linked inheritance, when 2 brothers are affected. Stephenson and Johnson (1985) reported a third case of what they referred to as 'Smith-Fineman-Myers syndrome' in an unrelated male residing in the same institution as the 2 brothers of Smith et al. (1980). Ades et al. (1991) described 2 brothers who had findings similar to those in the patients of Smith et al. (1980) and Stephenson and Johnson (1985), including patulous lower lip and prominent, widely spaced upper central incisors. One of the brothers had asplenia, and both had bilateral cryptorchidism. Hypotonia was present early and hypertonia later. Hall (1992) suggested that these brothers in fact had the X-linked alpha-thalassemia/mental retardation syndrome. Ades (1992) responded that study of the blood of both boys, their phenotypically normal sister, and both parents showed absence of hemoglobin H inclusions in all specimens. Guion-Almeida et al. (1998) suggested that Smith-Fineman-Myers syndrome was the disorder in 2 boys thought to be monozygotic twins. Features were an unusual facial appearance, cortical atrophy, dolichocephaly, short stature, cleft palate, micrognathia, prominent upper central incisors, bilateral Sidney line, minor foot deformities, instability in walking, early hypotonia, hyperreflexia, hyperactivity, psychomotor retardation, and severe delay in language development.

Mattei et al. (1983) presented a family with a diagnosis of Juberg-Marsidi syndrome in which 7 males in 5 sibships were affected. The patients had deafness, severe mental retardation, facial dysmorphism, and genital abnormalities, including small penis, hypospadias, and cryptorchidism.

Holmes and Gang (1984) reported a family in which 3 males had an X-linked mental retardation syndrome with microcephaly, epicanthal folds, short nose with anteverted nostrils, short upper lip and equinovarus deformity. One patient had bilateral renal hypoplasia. The 3 affected boys died in infancy or early childhood, 1 of pneumonia, 1 of 'encephalitis,' and 1 of unknown cause during febrile illness.

Chudley et al. (1988) described a 3-year-old boy and his 2 maternal uncles with moderate to severe mental retardation, short stature, mild obesity, hypogonadism, a low total finger ridge count, and a distinctive face characterized by bitemporal narrowness, almond-shaped palpebral fissures, depressed nasal bridge, anteverted nares, short and inverted-V-shaped upper lip, and macrostomia. In this family, 2 other males with similar facial and other features had died in early infancy and mid-childhood. Preliminary studies with DNA probes were consistent with X-linkage, and permitted exclusion of distal Xp and Xq regions as the site of the mutation. Cole et al. (1991) suggested that the family reported by Chudley et al. (1988) might have the ATR-X syndrome. However, Chudley and Lowry (1992) reported that follow-up showed normal hematologic indices and no detectable hemoglobin H. Furthermore, their patients appeared to be less severely retarded than the patients reported by Cole et al. (1991). Because of the possibility of an X-chromosome contiguous gene syndrome with different sized deletions, they performed high resolution chromosome analyses but found no deletions.

Carpenter et al. (1988) reported a family in which 6 males were affected with X-linked mental retardation. Clinical features included short stature, prominent lips, bushy eyebrows, depressed nasal bridge with widening of the tip of the nose, widely-spaced teeth, and brachydactyly. Genetic analysis excluded fragile X syndrome, and radiographic analysis excluded Coffin-Lowry syndrome. Linkage studies identified a locus at Xq11-q22. In a follow-up study of the same family, Carpenter et al. (1999) found that obligate carrier females showed completely skewed X-inactivation. Carpenter et al. (1999) noted that the patients did not have alpha-thalassemia or genital abnormalities.

Villard et al. (1996) reported a male patient and maternal uncle with X-linked mental retardation-hypotonic face syndrome and a mutation in the XH2 gene (300032.0012). At age 4, the proband had severe mental retardation with hypotonia and absence of speech. Facial features included epicanthic folds, telecanthus, midface hypoplasia, flat nasal bridge, small triangular nose with anteverted nostrils and with columella not extending below the nasal alae, carp-shaped mouth, hypoplastic lower central incisors, apparently low-set and posteriorly angulated ears, and protrusion of the tongue. The fingers were short and tapering and the toes overlapping. There were no signs of hematologic abnormality. The maternal uncle was severely mentally retarded, could not speak, and died at 7 years of age. The authors stated that photographs of the uncle showed the same facial dysmorphism as was found in his nephew.

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

Mapping

In the kindred reported by Mattei et al. (1983) with a diagnosis of Juberg-Marsidi syndrome, Saugier-Veber et al. (1993) mapped the disease locus to Xq12-q21 by linkage to a probe at the DXS441 locus; maximum lod = 3.24 at theta = 0.0. Multipoint linkage analysis placed the JMS gene within the interval defined by DXS159 and DXYS1X.

By linkage analysis, Carpenter et al. (1988) found that the XLMR syndrome in the family they reported showed linkage to a locus at Xq11-q22. In a follow-up study of the same family, Carpenter et al. (1999) refined the disease locus to a region between Xp11.3 and Xq23 (maximum lod score of 2.53 at several markers).

Molecular Genetics

In 1 surviving affected member and many heterozygous carriers of a family with MRXHF1, previously reported by Mattei et al. (1983) as having Juberg-Marsidi syndrome, Villard et al. (1996) identified a mutation in the ATRX gene (300032.0011).

In affected males in the family reported by Carpenter et al. (1988, 1999), Abidi et al. (1999) identified a mutation in the ATRX gene (300032.0024). The authors referred to the disorder as the 'Carpenter-Waziri syndrome.'

Villard et al. (2000) found that the patients reported by Ades et al. (1991) as having Smith-Fineman-Myers syndrome had a mutation in the ATRX gene (300032.0017).

In 2 obligate carriers from the family reported by Holmes and Gang (1984), Stevenson et al. (2000) identified a mutation in the ATRX gene (300032.0025). Carriers in this family, who had no clinical manifestations, showed the typical marked skewing of X inactivation, consistent with a mutation in the ATRX gene. Stevenson et al. (2000) referred to this disorder as the 'XLMR-hypotonic face syndrome.'

In affected males in the original family with Chudley-Lowry syndrome (Chudley et al., 1988), Abidi et al. (2005) identified a mutation in the ATRX gene (300032.0022)

Leahy et al. (2005) reported a 3-year-old boy with mental retardation, dysmorphic facial features, early hypotonia followed by hypertonia, and asplenia, in whom they identified a missense mutation in the ATRX gene (300032.0026). They stated that this was the second reported patient with mental retardation and asplenia with a mutation in the ATRX gene, the first being the patient reported by Ades et al. (1991). Neither patient had HbH inclusion bodies on staining with brilliant cresyl blue.