Background: 3-M syndrome is an autosomal recessive growth disorder characterised by severe prenatal and postnatal growth retardation caused by mutations in CUL7,OBSL1 or CCDC8.Clinical characteristics include dysmorphic facial features and skeletal abnormalities.
Aim: Evaluation of clinical and molecular findings and the effect of growth hormone (GH) threrapy in seven patients with 3-M syndrome from five different families.
Patients and Methods: Clinical and laboratory findings of seven patients(4males,3females) from 5 different families[Family(F)I(Patient(P)1,P2), FII(P3,P4),FIII(P5),FIV(P6),FV(P7)] were evaluated retrospectively. Pituitary function, GH stimulation and IGF generation tests were recorded.Growth and pubertal features were evaluated at follow-up.
Results: Median (range) age of the patients was 6.5(0.5-16.6) years,4 males(P1, P2,P6,P7), 3 females(P3,P4,P5). There was consanguinity in three families(FI, FII, FIV). Six cases(85.7%) were low birth-weight SDS was -3.1[(-1.4)-(-5.1)]. All patients presented with severe growth-retardation; median (range) height SDS was -5.3[(-3.9)(-7.9)],BMI SDS was -0.8[(-2.4)(1.5)], head-circumference SDS was 1.4[(-0.17)(-2.5)]. All patients had dysmorfic features related to 3-M syndrome. All patients' bone-age were delayed.CUL7 gene mutations were found in FI(homozygous;p.731insGlufs) and FV(novel, compound heterozygous;p.Pro1511Ser/p.Arg1528Ter),OBSL1 gene mutations (homozygous;p.Thr425Asp) were found in FII and FIII. Family IV's molecular analysis has not been completed yet. GH response in stimulation tests were normal in P4,P5,P7, high in P1,P2,P3 and low in P6. Five patients except(P1 and P7) were started GH treatment.Median of GH treatment duration was 1.9 years(0.1-4.3). Response to GH treatment was insufficient in all five patients. Patient 1 was 16.6 years-old at presentation while his pubertal-stage was Tanner-II and delayed. At recent evaluation he was 18.6 years-old and pubertal-stage was Tanner-III and puberty has not completed yet. Patient 6's puberty started at age 13.5 however progressing slowly, evaluation at age 17.1 his pubertal stage was Tanner-III and hormone levels were indicating partial primary hypogonadism. Recently, all female patients and P7 are below ten years of age and prepubertal. P2 is 13.1 years-old and prepubertal.
Conclusion: 3-M syndrome should be considered in differential diagnosis of patients with severe prenatal and postnatal growth retardation.Children with 3-M syndrome are treated with GH but there is lack evidence of efficacy in literature. Insufficient response to GH treatment and high levels of GH in tests might indicate GH resistance and IGF1 receptor resistance.3M syndrome might cause delayed puberty and partial primer gonadal insufficiency in boys.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology