Roifman Syndrome

A number sign (#) is used with this entry because of evidence that Roifman syndrome (RFMN) is caused by compound heterozygous mutation in the RNU4ATAC gene (601428) on chromosome 2q14.

Description

Roifman syndrome is a rare autosomal recessive disorder characterized by growth retardation, spondyloepiphyseal dysplasia, cognitive delay, facial dysmorphism, and antibody deficiency (summary by Merico et al., 2015).

Clinical Features

Roifman (1997, 1999) reported 4 boys, including 19- and 12-year-old brothers of Irish descent, a 7-year-old boy of Spanish and Italian descent, and a 4-year-old boy of Dutch and Maltese descent, who exhibited a syndrome consisting of humoral immunodeficiency involving the inability to produce specific antibodies, spondyloepiphyseal dysplasia, growth retardation, intellectual deficit, and retinal dystrophy. All had marked intrauterine growth retardation, and head circumference was -2 SD in 2 of the boys and in the third percentile in the other 2. All had hypotonia in early childhood, and all were short, primarily due to a short trunk. Skeletal survey revealed epiphyseal changes in multiple joints in all 4 patients, as well as irregular vertebral endplates and broadening of the femoral head and neck. Facial dysmorphism common to all included long prominent eyelashes, downslanting palpebral fissures, narrow and upturned nose, long philtrum, and thin upper lip. All had fifth-finger clinodactyly, hyperconvex nails, and transverse palmar creases. All 4 patients had eczema of variable severity, and blood eosinophils were increased, although IgE levels were normal. All had multiple ear infections, 2 had recurrent pneumonia, and 1 had septicemia and recurrent herpes reactivation. Immunologic analysis revealed that although immunoglobulin levels were normal, the patients exhibited a primary inability to produce specific antibodies. T cell levels were normal, but the proportion of antigen receptor-bearing B cells was low in all patients, suggesting a partial block of B cell maturation. In addition, responses to the B cell mitogen Staphylococcus aureus Cowan A (SAC) were markedly reduced in all patients.

Mandel et al. (2001) provided follow-up on the younger brother previously reported by Roifman (1999), who presented at age 14 years with vomiting, fatigue, tachycardia, and tachypnea. Chest x-ray showed cardiomegaly, pulmonary edema, and right pleural effusion, and echocardiography revealed severe global left ventricular dysfunction with left atrial thrombus and hypokinesis. The left ventricle was dilated with an ejection fraction of only 17%, and the wall showed marked noncompaction. Mandel et al. (2001) noted that the patient had shown no clinical evidence of cardiac dysfunction or enlargement on multiple previous examinations, chest radiographs, and CT scans. The authors stated that although the presence of noncompaction of the ventricular myocardium in a patient with Roifman syndrome might be a coincidence, the low prevalence of both diseases made the possibility unlikely.

Robertson et al. (2000) described a boy with similar features without retinal dystrophy but with coexistent hypogonadotropic hypogonadism. The patient of Robertson et al. (2000) had a height of 143.5 cm, with relative truncal shortening, at the age of 20 years. Recurrent bacterial pneumonia, sinusitis, and bacterial meningitis had led to a diagnosis of humoral immune deficiency, which was treated with intravenous immunoglobulin with good response. He had had persistent hepatosplenomegaly since early childhood. Dysmorphic facial features included narrow palpebral fissures, a long philtrum, and a thin upper lip. Hypotonia noted in infancy persisted into adulthood, and intellectual abilities were impaired. The SED was thought to be different from that in X-linked SED tarda (313400).

De Vries et al. (2006) reported the seventh case of a boy with Roifman syndrome. At age 11.5 years, he had significant intellectual disability with impaired attentional-executive, memory, and visuospatial abilities, although he appeared socially able and 'streetwise.' The authors suggested that Roifman syndrome may be an example of an X-linked mental retardation syndrome. Fairchild et al. (2011) provided follow-up of the patient reported by de Vries et al. (2006) at ages 13 and 16 years. The patient showed no decline in the neurocognitive profile after extensive testing. He had a full-scale IQ of 56, which remained stable. He showed some improvement in sustained attention, dual task performance, and visuospatial skills, but had poor performance in planning, attention, and executive skills. Brain MRI showed partial agenesis of the corpus callosum, with an absent posterior body and splenium. The hippocampi were hypoplastic. Fairchild et al. (2011) suggested that the relative strengths in emotion and face processing were consistent with the patient's social behavior and with intact amygdala function.

Gray et al. (2011) studied a Lebanese sister and brother, 5 years and 3 years old, respectively, who exhibited bone dysplasia and humoral immunodeficiency consistent with Roifman syndrome. The sister had skewed X inactivation and a milder phenotype, suggestive of an X-linked recessive condition. Gray et al. (2011) tabulated the features of these sibs and those of the 6 previously reported patients with Roifman syndrome.

Inheritance

Roifman (1997, 1999) reported 4 affected boys with Roifman syndrome and suggested X-linked recessive inheritance.

Molecular Genetics

In 2 brothers with Roifman syndrome, originally described by Roifman (1999), Merico et al. (2015) performed whole genome-sequencing and identified compound heterozygosity for point mutations in the minor spliceosomal snRNA gene RNU4ATAC (601428.0011, 601428.0012). Their unaffected parents were each heterozygous for 1 of the mutations. Sanger sequencing of RNU4ATAC in 4 additional Roifman patients from 3 unrelated families, including the Lebanese sibs reported by Gray et al. (2011), revealed compound heterozygosity for point mutations in all of them (601428.0001, 601428.0010-601428.0011, and 601428.0013-601428.0015).