Martsolf Syndrome

A number sign (#) is used with this entry because of evidence that some cases of Martsolf syndrome are caused by homozygous mutation in the gene encoding the noncatalytic subunit of RAB3 GTPase-activating protein (RAB3GAP2; 609275) on chromosome 1q41.

Warburg Micro syndrome-2 (WARBM2; 614225), a clinically overlapping but more severe disorder, is also caused by mutation in the RAB3GAP2 gene.

Clinical Features

Martsolf et al. (1978) described a family in which 2 brothers had severe mental retardation, cataracts, short stature, primary hypogonadism, and minor digital and cephalic abnormalities. The parents were first cousins of Polish-Jewish descent and had 1 normal daughter. There are several mental retardation syndromes associated with cataracts, with or without short stature. These were reviewed by Cuendet et al. (1976). The association of mental retardation, cataracts, and primary hypogonadism is more rare.

Sanchez et al. (1985) described this syndrome in 2 brothers of Sephardic Jewish ancestry.

Strisciuglio et al. (1988) reported a non-Jewish case.

Hennekam et al. (1988) described an affected brother and sister of Dutch or Belgian ancestry.

Harbord et al. (1989) described a syndrome of microcephaly, mental retardation, cataracts, and hypogonadism in a brother and sister with consanguineous parents of Pakistani origin. One sib had cardiomyopathy while the other had cardiac failure. Cardiac features had not previously been described in Martsolf syndrome.

Aligianis et al. (2006) described a consanguineous Pakistani family with 3 affected sibs. The first child had cataracts, microphthalmia, micropenis, and cryptorchidism at birth. Spastic diplegia was noted at the age of 3.5 years. At age 11 years, he had mild learning difficulties, was microcephalic, and walked with a walker. The sister of the proband likewise had dense bilateral cataracts, microphthalmia, and microcephaly at birth. Hypotonia was noted in infancy, and she later developed spastic diplegia. She had global developmental delay. At age 5 years, she had moderate learning difficulties and required special schooling, but she was bilingual in English and Punjabi. The third sib had congenitally corrected transposition of the great vessels with micropenis, bilateral cryptorchidism, congenital cataracts, and microphthalmia. Cardiac arrest of unknown cause occurred immediately after cataract surgery at the age of 2 months and, following resuscitation, he was found to have severe hypoxic ischemic encephalopathy with convulsions.

Ehara et al. (2007) reported a Japanese brother and sister with clinical features consistent with Martsolf syndrome. They were 31 and 24 years of age, respectively, at the time of the report. As children, both showed delayed motor development, short stature, cataracts, thoracic scoliosis, and severe mental retardation. Both also developed skeletal abnormalities of the femoral neck, including metaphyseal broadening and fragmentation consistent with Legg-Calve-Perthes disease (150600). The sister was found to have Klipper-Feil malformation (118100). Laboratory evaluations showed growth hormone deficiency and lack of response to GnRH stimulation suggesting hypothalamic-pituitary insufficiency. Brain MRI showed enlarged Sylvian fissures, mildly dilated ventricles, and mild cerebral atrophy. Other features included brachycephaly, short philtrum, low posterior hairline, scoliosis, talipes valgus, flat feet, and lax finger joints.

Bora et al. (2007) described a 7-year-old Turkish boy, born of first-cousin parents and whose great-grandparents were also first cousins, who had severe psychomotor retardation, microcephaly, microphthalmia with a myotic pupil, bilateral congenital cataracts (for which he had surgery in infancy), maxillary retrusion, dysplastic low-set ears, long philtrum, micropenis, cryptorchidism, and pes planus and equinovarus. Neurologic examination revealed hypotonia, 1- to 2-beat clonus, and diminished deep tendon reflexes; the boy had difficulties in walking and speaking, and his overall developmental age was 20 months. Laboratory studies were normal including cholesterol; cranial MRI showed high-intensity signals in the deep periventricular white matter.

Handley et al. (2013) studied 2 Gambian sisters and a Mexican Hispanic boy with Martsolf syndrome. All 3 were described as having postnatal growth retardation, postnatal microcephaly, axial hypotonia, and moderate mental retardation; speech was delayed in the boy, whereas both sisters had preserved speech and were bilingual. By 3 years of age, the boy exhibited spasticity of the lower limbs; the sisters, who were 14 and 17 years of age, showed general pyramidal signs with knee contractures, absence of knee reflex, and peripheral neuropathy. Nerve conduction studies in the sisters showed demyelinating polyneuropathy with motor predominance and distal secondary axonal neuropathy. Brain MRI in all 3 patients showed bilateral polymicrogyria, involving the parietal and occipital lobes in the sisters and the supratentorial cortex in the boy. All 3 exhibited bilateral microphthalmia, microcornea, and cataracts; the sisters had optic nerve atrophy, whereas the boy had pale optic nerves. Other features in the boy included cryptorchidism and micropenis.

Molecular Genetics

In a consanguineous Pakistani family with microphthalmia, congenital cataracts, hypogonadism, and mild mental retardation, Aligianis et al. (2006) identified a homozygous missense mutation in the noncatalytic subunit of RAB3GAP (RAB3GAP2) that resulted in abnormal splicing (609725.0001). Mutations in the catalytic subunit of RAB3GAP1 (602536) cause the Warburg micro syndrome (600118), a severe neurodevelopmental condition with clinical features overlapping those of Martsolf syndrome. RAB3GAP is a heterodimeric protein that consists of a catalytic subunit and a noncatalytic subunit encoded by RAB3GAP1 and RAB3GAP2, respectively. In mRNA expression studies of the orthologs of these 2 genes in zebrafish embryos, Aligianis et al. (2006) demonstrated that, whereas developmental expression of Rab3gap1 was generalized similar to that reported in mice, Rab3gap2 expression was restricted to the central nervous system. These findings were consistent with RAB3GAP2 having a key role in neurodevelopment.

In 2 Gambian sisters and a Mexican Hispanic boy with Martsolf syndrome, Handley et al. (2013) identified homozygosity for a missense mutation in the RAB3GAP2 gene (R426C; 609275.0003).

Heterogeneity

In the sibs with Martsolf syndrome reported by Hennekam et al. (1988), Aligianis et al. (2006) found no mutation in the RAB3GAP2 gene, indicating genetic heterogeneity.