Moyamoya Disease 4 With Short Stature, Hypergonadotropic Hypogonadism, And Facial Dysmorphism

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome on chromosome Xq28.

Description

This multisystem disorder is characterized by moyamoya disease, short stature, hypergonadotropic hypogonadism, and facial dysmorphism. Other variable features include dilated cardiomyopathy, premature graying of the hair, and early-onset cataracts. Moyamoya disease is a progressive cerebrovascular disorder characterized by stenosis or occlusion of the internal carotid arteries and the main branches, leading to the development of small collateral vessels (moyamoya vessels) at the base of the brain. Affected individuals can develop acute neurologic events due to stroke-like episodes (summary by Miskinyte et al., 2011).

For a general phenotypic description and a discussion of genetic heterogeneity of moyamoya disease, see MYMY1 (252350).

Clinical Features

Herve et al. (2010) reported an Algerian family in which 5 males were affected with a multisystem disorder characterized by moyamoya angiopathy, short stature, hypergonadotropic hypogonadism, facial dysmorphism, and early-onset cataracts. The proband developed repeated episodes of sudden right arm weakness at age 22 years, and was later found to have cortical and subcortical infarcts associated with moyamoya disease on brain imaging. He had facial dysmorphism, with mild congenital ptosis, long philtrum, retrognathia, and premature graying of the hair. He also had short stature, hypergonadotropic hypogonadism, decreased testicular volume, and azoospermia. Cardiac function was compromised due to dilated cardiomyopathy. He had recurrent episodes of heart failure and neurologic deficits, and died at age 34 years of heart failure.

Miskinyte et al. (2011) described the family reported by Herve et al. (2010) and 2 additional unrelated families with a similar disorder. There were 9 affected males in all. The age at onset of acute neurologic events ranged between 4 and 36 years of age, and both cerebral infarcts and hemorrhages occurred. All had short stature and facial dysmorphism, which variably included wide nose, deep-set eyes, low-set ears, hypertelorism, ptosis, long philtrum, and flared nares. Other features included hypergonadotropic hypogonadism (7/9 patients), hypertension (3/9 patients), partial growth hormone deficiency (4/9 patients), dilated cardiomyopathy (3/9 patients), premature coronary heart disease (1/9 patients), and premature hair graying (6/9 patients). Gonadal failure was associated with azoospermia. Four patients in 1 family had early-onset cataracts, and 2 patients from another family had developmental delay.

Inheritance

The transmission pattern of syndromic moyamoya disease in the families reported by Herve et al. (2010) and Miskinyte et al. (2011) was consistent with X-linked recessive inheritance.

Molecular Genetics

In affected members of 3 families with X-linked recessive syndromic moyamoya disease, Miskinyte et al. (2011) identified 3 different deletions on chromosome Xq28. The critical region of overlap was a 3.4-kb region including exon 1 of the MTCP1/MTCP1NB gene (300116) and the first 3 exons of the BRCC3 gene (300617), resulting in loss of BRCC3 and MTCP1NB expression in patient lymphoblastoid cell lines. Morpholino knockdown of Brcc3 in zebrafish resulted in defective angiogenesis that could be rescued by endothelial expression of Brcc3, suggesting that loss of BRCC3 function was responsible for the human disorder. Miskinyte et al. (2011) noted that some of the features of the disorder were reminiscent of chromosome breakage syndromes.