Mend Syndrome

A number sign (#) is used with this entry because of evidence that MEND syndrome (MEND) is caused by hemizygous mutation in the EBP gene (300205) on chromosome Xp11.

Mutation in the EBP gene can also cause the X-linked dominant disorder chondrodysplasia punctata-2 (CDPX2; 302960), which shows some overlapping features. CDPX2 in males almost always results from postzygotic mosaicism for an EBP mutation.

Description

Male EBP disorder with neurologic defects is an X-linked recessive disorder representing a continuous phenotypic spectrum with variable manifestations associated with a defect in sterol biosynthesis. Features include intellectual disability, short stature, scoliosis, digital abnormalities, cataracts, and dermatologic abnormalities. Not all patients show all features, and the severity is highly variable. Molecular studies indicate that affected males are hemizygous for a nonmosaic hypomorphic EBP allele. Carrier females are generally clinically asymptomatic, but may show biochemical abnormalities (summary by Arnold et al., 2012 and Barboza-Cerda et al., 2014).

Clinical Features

Milunsky et al. (2003) reported a 2.5-year-old Caucasian male with developmental delay, hypotonia, seizures, and patchy hypopigmentation of the skin. Multiple congenital anomalies included a unilateral cataract, esotropia, crossed renal ectopia, stenotic ear canals, and failure to thrive. The patient also had dysmorphic features, including excess nuchal fold with long neck, asymmetric 'crying mouth,' simple philtrum, micrognathia, high-arched palate, bulbous nasal tip, low-set posteriorly rotated ears with overfolded helices, and upslanting narrow palpebral fissures. He also had long fingers, broad halluces, a sacral dimple, overlapping fingers, and toes, and widely spaced nipples. Neurologic examination showed axial hypotonia and extremity hypertonia with opisthotonic posturing and persistent Moro response. No skeletal asymmetry or chondrodysplasia punctata was noted on skeletal survey at 6 weeks and 13 months of age. The levels of 8(9)-cholestenol and 8-dehydrocholesterol were mildly increased in plasma and in cultured fibroblasts. The patient's mother had normal stature, no asymmetry, and no cataracts, but did have a patch of hyperpigmentation on her chest, best visualized on Woods lamp examination, as well as otosclerosis, characteristic of a mild form of CDPX2. Happle (2003) and Ikegawa (2004) commented on the report of Milunsky et al. (2003).

Furtado et al. (2010) reported a male infant with multiple congenital anomalies first detected in utero, including polyhydramnios, agenesis of the corpus callosum, Dandy-Walker malformation, and cardiac malformations such as aortic stenosis, ventricular septal defect, and hypoplastic aortic arch. After birth, he was noted to have dysmorphic features, including waxy-appearing skin, cataracts, short-nasal root, micrognathia, cleft palate, single transverse palmar crease, syndactyly of the second and third toes, and undescended testes. Brain imaging showed ventriculomegaly, small nodular foci lining the subependymal region of the lateral ventricles, simplified gyral patterning, and hypoplasia of the corpus callosum. Radiographs did not show stippling of the epiphyses. Biochemical studies showed increased plasma 8(9)-cholestenol and 8-dehydrocholesterol, consistent with an enzymatic deficiency of EBP. The patient died of cardiac failure at 24 days of age. The maternal family history was strongly suggestive of an X-linked recessive disorder with several infant males demonstrating Dandy-Walker malformation, dysgenesis of the corpus callosum, hydrocephalus, cataracts, cryptorchidism, ichthyotic skin, septal defects, and high nasal bridge. Two infant brothers from an unrelated family had a similar disorder resulting in death by 13 months of age. Clinical features included Dandy-Walker malformation, agenesis of the corpus callosum, cryptorchidism, cataracts, collodian skin, 2,3-toe syndactyly, cardiovascular anomalies, and craniofacial anomalies including a prominent nasal bridge, small low-set ears, and microretrognathia. The mother in each family was unaffected.

Arnold et al. (2012) proposed that the phenotype described by Milunsky et al. (2003) and Furtado et al. (2010) be designated MEND syndrome (male EBP disorder with neurologic defects).

Barboza-Cerda et al. (2013) reported a 5-generation Mexican family in which 8 males had a similar multiple congenital anomaly disorder; 4 adult patients were examined clinically. All had variable delayed psychomotor development and intellectual disability. Facial dysmorphic features included narrow forehead, midface hypoplasia, broad nose, flat philtrum, thick lips, and low-set ears. Skeletal anomalies included short stature, scoliosis, variable polydactyly, brachydactyly, and syndactyly. Brain imaging of 1 patient showed cortical atrophy, olivopontocerebellar hypoplasia, and hypoplasia of the corpus callosum. The patients did not have cataracts or dermatologic abnormalities.

Hartill et al. (2014) reported a family in which 4 males had X-linked developmental delay and severe behavioral difficulties. Behavioral abnormalities included hyperactivity, aggression, attention-seeking behavior, outbursts, and self-harm. More variable features included scoliosis and 2-3 toe syndactyly; 2 patients had seizures. A 43-year-old patient had mild dysmorphic features, including long thin nose with high nasal bridge, long face, and deep-set eyes. Brain imaging performed in 2 patients was normal. Laboratory studies showed increased 8-dehydrocholesterol. Patient fibroblasts showed increased concentrations of 8(9)-cholestenol which could be suppressed when cells were incubated with simvastatin, and 2 of the patients were started on treatment with simvastatin. Hartill et al. (2014) noted the phenotypic differences in this family compared to previous reports of males with hemizygous nonmosaic EBP mutations.

Inheritance

The transmission pattern of MEND syndrome in the families reported by Furtado et al. (2010) was consistent with X-linked recessive inheritance.

Mapping

By linkage analysis of a Mexican family with X-linked recessive intellectual disability, short stature, and digital abnormalities, Barboza-Cerda et al. (2013) found linkage to a 15.74-Mb region on chromosome Xp11.4-p11.21 (lod scores of 3.6 to 4.8) between markers DXS8015 and DXS991.

Molecular Genetics

In a 2.5-year-old Caucasian male with developmental delay, hypotonia, seizures, and patchy hypopigmentation of the skin, Milunsky et al. (2003) described a hemizygous nonmosaic missense mutation in the EBP gene (L18P; 300205.0013). The patient's mother, who was adopted, also carried the L18P mutation. Happle (2003) suggested that this was a hypomorphic mutation, asserting that a nonmosaic male with a CDPX2-associated EBP mutation cannot survive.

In 2 unrelated male infants with MEND syndrome, Furtado et al. (2010) identified a hemizygous missense mutation in the EBP gene (W47C; 300205.0014). Each unaffected mother was heterozygous for the mutation; functional studies were not performed.

In affected members of a Mexican family with MEND syndrome, originally reported by Barboza-Cerda et al. (2013), Barboza-Cerda et al. (2014) identified a hemizygous missense mutation in the EBP gene (I75N; 300205.0016). The mutation was found by X-chromosome exome sequencing and confirmed by Sanger sequencing; it was present in 2 affected males tested and in the unaffected mother. Functional studies of the variant were not performed, but the mutation carriers had increased plasma 8(9)-cholestenol and 8-dehydrocholesterol, consistent with an enzymatic defect. Barboza-Cerda et al. (2014) concluded that this was a hypomorphic mutation.

In 4 affected males from a family with MEND syndrome, Hartill et al. (2014) identified a hemizygous missense mutation in the EBP gene (W47R; 300205.0017). In vitro functional expression studies showed that the mutant protein was hypomorphic. Obligate female carriers were unaffected.