The Miller-McKusick-Malvaux (3M) syndrome is a primordial growth disorder characterized by low birth weight, reduced birth length, severe postnatal growth restriction, a spectrum of skeletal anomalies, facial dysmorphism and normal intelligence. Mutations in the CUL7 gene (6p21.1) are most often responsible for 3M syndrome (67% of cases). Other causal mutations include those in the OBSL1 gene (2q35), in 28% of cases, or the CCDC8 gene (19q13.33), in 5% of cases. The precise mechanisms leading to growth failure in 3M syndrome remain unclear. Recurrent mutation in Maghreb patients was reported. It is a frameshift deletion (c.4451_4452delTG) in exon 24. We report two Tunisian 3M syndrome patients. The first patient is a 4 year-old girl. She is born from two healthy cousin parents from induced twin pregnancy. She had an intrauterine growth restriction with low birthweight (1820<3p) and length (40 cm:<3P) and normal head circumference pc (34 cm). Her face was triangular with pointed chin, prominent forehead and malar hypoplasia. The nose was short with upturned nares. She had full fleshy lips, long philtrum, dysplastic ears, prominent heels, unique transverse palmer crease and short neck and thorax. Molecular analysis confirmed the diagnosis showing the Maghreb mutation in homozygous state. The results of her endocrine evaluation, which included thyroid function, GH (2.2 ng/ml), IGF1 (90 ng/ml) and catapressan stimulation test were normal. Nevertheless, she have received recombinant human GH (rhGH) treatment from the age of 2 years. She gained 19 cm and 4 kg in 2 years. The second patient is a 3-year-old boy. He was referred to us for pre and postnatal growth restriction. He had already have prenatal caryotype because of intrauterine growth restriction. No chromosomal anomalies were diagnosed. At birth he had low birth weight and lengh, bilateral hip dysplasia, hyperextensible joints, proeminent heels and a short chest. He showed facial dimorphism: a triangular face and a hypoplasic midface and proeminent forehead. At the age of three years, he is 74 cm (-4DS) tall. He has growth normal mental development. The bone x ray showed a distal phalange hypoplasia. Molecular investigation for the maghreb mutation was normal. Endocrinological investigations: IGF1=92 ng/ml (13143 ng/ml), GH=3.62 ng/ml and the hypoglycemic GH stimulation revealed a total GH deficiency. The patient received (rhGH).
Conclusion: Nowadays GH treatment outcomes for 3M syndrome appear controversial, but based on the successful height increase in our case significant individual variation in relation to GH response in 3M syndrome should be considered.
18 - 21 May 2019
European Society of Endocrinology