The Clinical Features and Effect of Growth Hormone Treatment in 3-M Syndrome Cases with Severe Growth Retardation

Abstract

Background: 3-M syndrome is an autosomal recessive growthdisorder characterised by severe prenatal and postnatal growth retardationcaused by mutations in CUL7,OBSL1 or CCDC8.Clinicalcharacteristics include dysmorphic facial features and skeletalabnormalities.Aim: Evaluation of clinical and molecular findings and the effectof growth hormone (GH) threrapy in seven patients with 3-Msyndrome from five different families.Patients and Methods: Clinical and laboratory findings of sevenpatients(4males,3females) from 5 different families[Family(F)I(Patient(P)1,P2), FII(P3,P4),FIII(P5),FIV(P6),FV(P7)] wereevaluated retrospectively. Pituitary function, GH stimulation andIGF generation tests were recorded.Growth and pubertal featureswere 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 wasconsanguinity in three families(FI, FII, FIV). Six cases(85.7%)were low birth-weight SDS was -3.1[(-1.4)-(-5.1)]. All patientspresented 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 patientshad dysmorfic features related to 3-M syndrome. All patients’bone-age were delayed.CUL7gene mutations were foundin FI(homozygous;p.731insGlufs) and FV(novel, compoundheterozygous;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. GHresponse in stimulation tests were normal in P4,P5,P7, high inP1,P2,P3 and low in P6. Five patients except(P1 and P7) werestarted GH treatment.Median of GH treatment duration was 1.9years(0.1-4.3). Response to GH treatment was insufficient in allfive patients. Patient 1 was 16.6 years-old at presentation while hispubertal-stage was Tanner-II and delayed. At recent evaluationhe was 18.6 years-old and pubertal-stage was Tanner-III and pubertyhas not completed yet. Patient 6’s puberty started at age 13.5however progressing slowly, evaluation at age 17.1 his pubertalstage was Tanner-III and hormone levels were indicating partialprimary hypogonadism. Recently, all female patients and P7 arebelow ten years of age and prepubertal. P2 is 13.1 years-old andprepubertal.Conclusion: 3-M syndrome should be considered in differentialdiagnosis of patients with severe prenatal and postnatal growthretardation.Children with 3-M syndrome are treated with GH butthere is lack evidence of efficacyin literature. Insufficient response to GH treatment and high levels of GH in tests might indicate GHresistance and IGF1 receptor resistance.3M syndrome might causedelayed puberty and partial primer gonadal insufficiency in boys