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      3-M syndrome: a novel CUL7 mutation associated with respiratory distress and a good response to GH therapy

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          Summary

          3-M syndrome is a rare autosomal recessive disorder caused by mutations in the CUL7, OBSL1 and CCDC8 genes. It is characterised by growth failure, dysmorphic features and skeletal abnormalities. Data in the literature show variable efficacy of GH in the treatment of short stature. We report four Emirati siblings with the condition. The index case is a 10-year-old boy with characteristic features, including prenatal and postnatal growth failure, a triangular face, a long philtrum, full lips and prominent heels. Genetic testing confirmed a novel mutation (p.val88Ala) in the CUL7 gene. The parents are healthy, first-degree cousins with nine children, of whom two died in the first year of life with respiratory failure. Both had low birth weight and growth retardation. The boy's older sibling reached an adult height of 117 cm (−6.71 SDS). She was never treated with GH. He was started on GH treatment at 7 years of age, when his height was 94 cm (−5.3 SDS). 3-M syndrome should be considered in children with short stature who have associated dysmorphism and skeletal abnormalities. The diagnosis is more likely to occur in families that have a history of consanguinity and more than one affected sibling. Death in early infancy due to respiratory failure is another clue to the diagnosis, which might have a variable phenotype within a family. Genetic testing is important for confirming the diagnosis and for genetic counselling. GH treatment might be beneficial in improving stature in affected children.

          Learning points

          • 3-M syndrome should be considered in families that have more than one sibling with short stature, particularly if there is consanguinity.

          • Syndrome phenotype might be variable within a family with the same mutation.

          • Genetic analysis is helpful in confirming diagnosis in the presence of variable siblings' phenotype.

          • GH treatment might be useful in improving stature in 3-M syndrome.

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          Most cited references5

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          Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia.

          In total, 43 patients having short stature syndrome in 37 Yakut families with autosomal recessive prenatal and postnatal nonprogressive growth failure and facial dysmorphism but with normal intelligence have been identified. Because Yakuts are considered as a population isolate and the disease is rare in other populations, genomewide homozygosity mapping was performed using 763 microsatellite markers and candidate gene approach in the critical region to identify the causative gene for the short stature syndrome in Yakut. All families shared an identical haplotype in the same region as the identical loci responsible for 3-M and gloomy face syndromes and a novel homozygous 4582insT mutation in Cullin 7 (CUL7) was found, which resulted in a frameshift mutation and the formation of a subsequent premature stop codon at 1553 (Q1553X). Yakut patients with short stature syndrome have unique features such as a high frequency of neonatal respiratory distress and few bone abnormalities, whereas the clinical features of the other Yakut patients were similar to those of 3-M syndrome. Furthermore, abnormal vascularisation was present in the fetal placenta and an abnormal development of cartilage tissue in the bronchus of a fetus with CUL7 mutation. These findings may provide a new understanding of the clinical diversity and pathogenesis of short stature syndrome with CUL7 mutation.
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            The 3M syndrome.

            3M syndrome (MIM 273750) is an autosomal recessive disorder characterized by pre- and post-natal growth retardation (<-4 SD), facial dysmorphism, large head circumference, normal intelligence and endocrine function. Skeletal changes include long slender tubular bones and tall vertebral bodies. There is no specific treatment. Up till now, mutations in either CUL7 or OBSL1 genes have been identified in this rare disorder. There are no clinical or radiological differences between patients with CUL7 or OBSL1 mutations. CUL7 appears to be the major gene responsible for 3M syndrome accounting for 77.5% of cases while OBSL1 mutations accounts for 16.3%. A few patients have no mutations in these genes suggesting the involvement of a third gene.
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              The 3-M syndrome: a heritable low birthweight dwarfism.

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                Author and article information

                Journal
                Endocrinol Diabetes Metab Case Rep
                Endocrinol Diabetes Metab Case Rep
                edm
                EDM Case Reports
                Endocrinology, Diabetes & Metabolism Case Reports
                Bioscientifica Ltd (Bristol )
                2052-0573
                1 April 2015
                2015
                : 2015
                : 150012
                Affiliations
                [1]Paediatric Endocrinology Department, Mafraq Hospital , PO Box 2951, Abu Dhabi, United Arab Emirates
                [1 ]Medical School, Gulf University , Ajman, United Arab Emirates
                [2 ]Biochemistry Laboratory Department, Shaikh Khalifa Medical Center, Mafraq Hospital , Abu Dhabi, United Arab Emirates
                Author notes
                Correspondence should be addressed to A Deeb Email: adeeb@ 123456mafraqhospital.ae
                Article
                EDM150012
                10.1530/EDM-15-0012
                4418346
                25945256
                9daccee0-abb3-426a-ab84-ee984d34917c
                © 2015 The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.

                History
                : 11 March 2015
                : 1 April 2015
                Categories
                Unique/Unexpected Symptoms or Presentations of a Disease

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