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A rare developmental defect during embryogenesis characterized by growth delay and multiorgan manifestations.
ORPHA:2576Classification level: Disorder
The exact prevalence is unknown. Worldwide, around 150 cases have been reported. Most cases described are from Finland where a birth prevalence of 1/37,000 has been reported.
Mulibrey nanism (MUL) manifests neonatally and during infancy. It is characterized by pre- and postnatal growth restriction, relative macrocephaly, thin extremities and typical craniofacial features (scaphocephaly, facial triangularity, broad forehead and low nasal bridge). Psychomotor development is mainly normal. Feeding difficulties are common in infants. Children are prone to respiratory problems. Characteristic features also include yellowish dots in the retinal mid peripheral region, a high-pitched voice and cutaneous naevi flammei. Radiologic findings include slender long bones with thick cortex, narrow medullary channel and fibrous dysplasia, J-shaped sella turcica and a small thoracic cage. A restrictive, perimyocardial heart disease is the most serious element of the disorder. Hepatomegaly and fatty liver are common. Insulin resistance is an important metabolic finding. More than 90% of the adults show abnormally high fasting insulin levels resulting in type 2 diabetes in half of the patients. Tumors have been detected in several internal organs. The most frequent malignant tumor is Wilms' tumor. Females are at high risk of developing ovarian fibrothecomas. Primary hypogonadism, both male and female, as well as infertility, are central clinical characteristics.
MUL is caused by mutations in the TRIM37 gene (17q22) encoding the peroxisomal TRIM37 protein of unknown function. Worldwide, around 110 Finnish and 30 non-Finnish patients have a molecularly confirmed diagnosis. In Finland, one major founder mutation is seen in all patients with less than 10% of them being compound heterozygous combined with another mutation. Private mutations account for the non-Finnish cases. To date around 30 different disease associated mutations are known.
The diagnosis relies on the clinical signs. Major and minor signs for clinical diagnosis have been established. Molecular diagnostics does confirm the diagnosis. Molecular genetic testing for the two most common mutations of the TRIM37 gene is available in Finland. However, sequencing of the whole TRIM37 gene is necessary particularly for non-Finnish patients. The TRIM37 gene is usually well covered by exome sequencing and targeted next-generation sequencing (NGS)-based panels.
Differential diagnosis includes dysmorphic growth disorders with prenatal onset growth failure, namely Silver-Russell syndrome and 3M-syndrome.
Prenatal molecular genetic testing is possible but is rational only in families known to be affected with the disease.
MUL is an autosomal recessive disorder. A genetic counseling should be offered to affected couples.
Management and treatment
Early recognition and management of feeding-, respiratory- or cardiac problems are of major importance. Regular cardiovascular follow-up is central, as well as assessment of growth and puberty. Abdominal ultrasound is well-grounded as the risk for tumors, namely Wilms' tumor, and organ abnormalities is elevated. From adolescence, the glucose metabolism should be monitored, and females need regular gynecological follow-up.
The severity of the heart disease is the main prognostic factor. The average survival is clearly shortened but a normal life span is not excluded.
A summary on this disease is available in Deutsch (2019) Español (2019) Français (2019) Italiano (2019) Nederlands (2019) Hebrew (2021, pdf) Polski (2007, pdf) Polski (2007)