Mulibrey Nanism

A number sign (#) is used with this entry because mulibrey (MUscle, LIver, BRain, and EYes) nanism ('dwarfism') is caused by homozygous or compound heterozygous mutation in the TRIM37 gene (605073), which encodes a peroxisomal protein, on chromosome 17q22.

Description

Mulibrey nanism is a rare autosomal recessive growth disorder with prenatal onset, including occasional progressive cardiomyopathy, characteristic facial features, failure of sexual maturation, insulin resistance with type 2 diabetes, and an increased risk for Wilms tumor (summary by Hamalainen et al., 2006).

Clinical Features

Perheentupa et al. (1973) first described and named this disorder in 23 patients in Finland, including 3 pairs of affected sibs born of consanguineous parents. Growth failure was evident at birth and was progressive. The patients had a characteristic triangular face often with hydrocephaloid skull, gracility and muscular hypotonia, peculiar voice, enlarged liver, raised venous pressure due to pericardial constriction, and yellowish dots and pigment dispersion in the ocular fundi. Two-thirds of the patients had cutaneous nevi flammei and one-third had cystic dysplasia of the tibia. The geographic accumulation of cases in a sparsely settled region of Finland and the observation of parental consanguinity in some cases supported autosomal recessive inheritance.

Thoren (1973) described an Egyptian patient. Cumming et al. (1976) reported affected sibs living in Canada. Voorhees et al. (1976) reported the first affected child from the United States whose parents were second cousins. In a review of published cases, the authors identified other clinical features, including fibrous dysplasia of the tibia in 7 of 25, hypoplasia of the choroid in 11 of 11, yellowish dots and pigment dispersion in the ocular fundi in 23 of 25, long shallow sella turcica in 25 of 26, muscular hypotonia in 20 of 25, small voice and triangular face in all, and low birth weight and length in most.

Haraldsson et al. (1993) found both immunoglobulin deficiency and isolated growth hormone (GH1; 139250) deficiency in a 6.7-year-old girl with constrictive pericarditis, pigmentary retinopathy, and other features of mulibrey nanism. Therapy with human growth hormone resulted in increased growth velocity but did not improve humoral immune functions. Lapunzina et al. (1995) reported 2 affected sibs from Argentina and another patient from Spain. All 3 had growth failure, short stature, abnormal pigmentary retinal changes, and a J-shaped sella turcica. Two had pericardial constriction. Pericardiectomy was performed in 1 patient at the age of 23 months with good results. The authors also reviewed the findings in 39 reported patients and grouped the anomalies into the very frequent (present in more than 66%), frequent (in at least 25%), and not frequent. Balg et al. (1995) reported a boy who had typical manifestations as well as hypoplastic corpus callosum and a localized intraretinal fibrosis of the left eye. He also had hepatomegaly; constrictive pericarditis was discovered only after mulibrey nanism was diagnosed.

Jagiello et al. (2003) reported a Turkish family in Germany in which 3 sibs, a boy and 2 girls, had mulibrey nanism. The parents were said not to be related but originated from small neighboring villages in Turkey. A 12-year-old girl was mentally retarded and had a high-pitched voice. She had obvious craniofacial dysmorphism, including a large skull with broad forehead, hypertelorism with broad nasal bridge, high palate, microgenia, and deep set ears. She had proportionate growth reduction and hypotonia of the trunk. Other symptoms included moderate adiposity, acanthosis nigricans, various hemangiomas, insulin-resistant diabetes mellitus, hepatosplenomegaly, liver cirrhosis, fibrosis of the lung, and cardiomyopathy. The 21-year-old affected brother had disproportionate growth reduction, mental retardation, moderate adiposity, acanthosis nigricans, signs of 'diabetic metabolism,' hypogonadotropic hypogonadism, and isolated fibroma of the tibia. The 17-year-old sister displayed similar symptoms as her sibs, but had no signs of mental retardation, indicating a milder phenotype. None of the sibs showed pronounced muscular hypotonia.

Karlberg et al. (2004) reviewed the clinical characteristics of the 85 known Finnish patients with mulibrey nanism, most of whom were homozygous for the major Finnish TRIM37 mutation (605073.0001), and proposed revised diagnostic criteria for the disorder. The authors suggested that the diagnosis should be considered in infants born small for gestational age who have poor weight gain postnatally, hepatomegaly, and characteristic craniofacial features.

Karlberg et al. (2004) stated that approximately 110 patients with mulibrey nanism had been described worldwide, of whom 85 were Finnish. They reviewed the hospital and autopsy reports of the 22 Finnish female postpubertal patients with the disorder; they found an association between the disorder and both premature ovarian failure and fibrothecomas (ovarian stromal tumors). Their study indicated that hypergonadotropic premature ovarian failure with spontaneous puberty, incomplete breast development, and early irregularity of menstrual periods with subsequent ovarian failure and infertility ultimately develops in female patients with mulibrey nanism. Furthermore, such patients are at a very high risk for ovarian fibrothecoma. Karlberg et al. (2004) concluded that TRIM37 is a putative tumor suppressor gene for ovarian stromal cells.

Hamalainen et al. (2006) reported an Australian girl with mulibrey nanism. She first presented at age 10 months with short stature and facial dysmorphism, including dolichocephaly, high broad forehead, low depressed nasal bridge, and small pointed chin. Skeletal survey showed slender long bones with overtubulation and J-shaped sella turcica. Developmental milestones were age-appropriate. Initial diagnostic considerations included 3M syndrome (273750) and Silver-Russell syndrome (SRS; 180860). At age 18 months, she presented with abdominal distention and a large Wilms tumor, which led to the diagnosis of mulibrey nanism.

Mapping

By linkage analysis in affected Finnish families, Avela et al. (1997) identified a 7-cM candidate region on chromosome 17q flanked by D17S1799 and D17S948 (maximum multipoint lod score of 5.01). Linkage disequilibrium analysis narrowed the critical disease region within approximately 250 kb of marker D17S1853. Because patients with mulibrey nanism commonly have hypoplasia of various endocrine glands and hormone deficiencies, Avela et al. (1997) analyzed a microsatellite-repeat polymorphism at the growth hormone locus (GH1; 139250). Recombination in 1 family excluded it as a candidate gene. Likewise, the homeobox B cluster was excluded by the absence of linkage disequilibrium with a microsatellite-repeat marker at HOX2B (142961). Avela et al. (1997) concluded that the most likely physical location of the markers linked to the MUL locus was 17q21-q24.

Paavola et al. (1999) studied the location of the genes for Meckel syndrome (MKS1; 249000) and mulibrey nanism, which had been mapped to the same region, 17q21-q24. They constructed a bacterial clone contig over the critical region for both disorders. Several novel CA-repeat markers were isolated from these clones, which allowed refined mapping of the MKS and MUL loci using haplotype and linkage disequilibrium analysis. The localization of the MKS locus was narrowed and the entire MKS region was found to fall within the MUL region. However, in the common critical region, the conserved haplotypes were different in Meckel syndrome and mulibrey nanism patients. A transcript map was constructed by assigning ESTs and genes, derived from the human gene map, to the bacterial clone contig. Altogether, 4 genes and a total of 20 ESTs were precisely localized.

Molecular Genetics

By positional cloning, Avela et al. (2000) identified the MUL gene and found 4 independent mulibrey nanism-associated mutations (605073.0001-605073.0004). A 5-bp deletion (605073.0001) was found to be the major Finnish mutation.

In a Turkish family studied in Germany, Jagiello et al. (2003) found that mulibrey nanism cosegregated with a mutation in the TRIM37 gene (605073.0005).

In an Australian girl with mulibrey nanism, Hamalainen et al. (2006) identified compound heterozygosity for 2 mutations in the TRIM37 gene (605073.0006 and 605073.0007).