Midface Hypoplasia, Hearing Impairment, Elliptocytosis, And Nephrocalcinosis

A number sign (#) is used with this entry because of evidence that midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis (MFHIEN) is caused by hemizygous mutation in the AMMECR1 gene (300195) on chromosome Xq22.

Description

Midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis is an X-linked recessive disorder with onset of features in early childhood. Anemia is sometimes present. Some patients may show mild early motor or speech delay, but cognition is normal (summary by Andreoletti et al., 2017).

Clinical Features

Andreoletti et al. (2017) reported 2 maternal half brothers with MFHIEN. Both boys had dysmorphic features, including large forehead, midface hypoplasia, small mouth with crowded teeth, downslanting palpebral fissures, thin upper lip, micrognathia, short neck, subcutaneous cleft palate, bifid uvula, square hands, fifth finger clinodactyly, and short stature. The dysmorphic facial features lessened with time. Both patients also had mild nephrocalcinosis apparent on imaging. One patient had intermittent hypercalciuria, and the other had renal dysplasia. The boys had mildly delayed early motor and speech development but both attended mainstream schools at ages 11 and 5 years. The older patient had mixed conductive and sensorineural hearing loss beginning around age 3, whereas the younger patient had borderline but progressive conductive hearing loss. Both had joint hypermobility. More variable features included hypotonia, patent foramen ovale, cataracts, talipes, congenital dysplasia of the hip, strabismus, esotropia, and delayed eruption of primary dentition. Peripheral blood smear showed elliptocytes only in the older boy at age 10 years, and not in the younger boy at age 4, suggesting variable penetrance of this feature.

Basel-Vanagaite et al. (2017) reported a 4-year-old boy, born to unaffected nonconsanguineous parents of Libyan, Yemenite, and Turkish Jewish origin, with MFHIEN. He had clubfeet, short stature, cleft hard palate, and dysmorphic features, including flat facies, midface hypoplasia, synophrys, small mouth, and thin upper lip. He also had a small patent ductus arteriosus and patent foramen ovale. He had mild early motor and speech delay, but cognitive development was normal. Other features included conductive hearing loss, mild hydronephrosis on imaging, and anemia with basophilic stippling and elliptocytosis requiring blood transfusion. The patient's maternal uncle had similar dysmorphic features, including malar flattening, small mouth, and thin lips, as well as broad distal phalanges, lateral deviation of the fingers, and flat feet. He had postlingual moderate to severe sensorineural hearing loss and used hearing aids. Peripheral blood smear showed elliptocytosis; he did not have anemia. He had normal cognitive development and he worked as forklift driver.

Inheritance

The transmission pattern of MFHIEN in the family reported by Andreoletti et al. (2017) was consistent with X-linked recessive inheritance.

Molecular Genetics

In 2 Caucasian maternal half brothers with MFHIEN, Andreoletti et al. (2017) identified a hemizygous missense mutation in the AMMECR1 gene (G177D; 300195.0001). The mutation, which was found by X-chromosome exome sequencing and confirmed by Sanger sequencing, was present in the unaffected mother. Expression of the mutation in HEK293, COS7, and HeLa cells showed nonuniform expression patterns in the nucleus, which was distinct from the wildtype pattern. The number of immunopositive cells was also decreased compared to wildtype. Andreoletti et al. (2017) concluded that the altered expression pattern of in the nucleus was consistent with the mutant protein being targeted for proteasomal degradation.

In a 4-year-old boy, born of unrelated parents of Libyan, Yemenite, and Turkish Jewish descent, with MFHIEN, Basel-Vanagaite et al. (2017) identified a hemizygous truncating mutation in the AMMECR1 gene (R45X; 300195.0002). The mutation, which was found by X-chromosome exome sequencing and confirmed by Sanger sequencing, was present in the unaffected mother and in an affected maternal uncle, demonstrating segregation within the family.