Recognizable type of pituitary,heart,kidney and skeletal dysplasia mostly caused

Fang Hu,Liao Sun

Fang Hu,Liao Sun,Department of Endocrinology and Metabolism,Fifth Affiliated Hospital Sun Yat-Sen University,Sun Yat-Sen University,Zhuhai 519000,Guangdong Province,China

Abstract

Key words:Pituitary dysplasia;Heart dysplasia;Kidney dysplasia;Short stature;Cryptorchidism;SEMA3A;Case report

INTRODUCTION

TheSEMA3Agene is located at 7q21.11 and has a length of 496947 bp.SEMA3Ais a member of the semaphorin family and encodes a protein with an Ig-like C2-type(immunoglobulin-like)domain,a PSI domain and a sema domain called semaphorin-3A.Semaphorin-3A is important in the development and migration of hypothalamic neurons.It is secreted by neurons and their surrounding tissue and guides migrating cells to their correct destination following very precise paths,sends out axons,and reacts to specific chemical environments.In addition,as a dual regulator of osteoclasts and osteoblasts,semaphorin 3A is involved in the balance of bone homeostasis by theSEMA3A/NRP1axis and the Wnt/β-catenin signaling pathway[1].Semaphorins are needed in kidney development because they regulate ureteric bud branching,vascular morphogenesis,and podocyte-endothelial crosstalk[2].SEMA3A-knockout mice exhibited an abnormal electrocardiograph pattern and were prone to ventricular arrhythmias and sudden cardiac death[3].Therefore,SEMA3Ais important in maintaining normal heart function.

SEMA3Amutations often appear in patients with Kallmann syndrome[4].In addition,patients with mutation of theSEMA3Agene exhibiting short stature,low gonadotropin,hypogonadism,thoracic deformity,high scapula,rib and lower limb deformity,facial deformity(long face,epicanthic folds,backwards ears),arterial malformation,and a normal sense of smell have been reported[5].We report a patient who exhibited pituitary,heart,kidney and skeletal dysplasia caused by new mutation of theSEMA3Agene.

CASE PRESENTATION

Chief complaints

A 26-year-old Chinese man complained of short stature.

History of present illness

The 26-year-old patient,who was his parents’ first child,was 50 cm in length and weighed 3.3 kg when he was born at 40 wk of gestation.His growth rate gradually slowed down beginning at the age of 12.Now,he is 133 cm tall(＜ -2.0 SD)with a 65 cm long upper half and 68 cm long lower half and weighs 35 kg(＜ -2.0 SD),with 130 cm finger spacing.

History of past illness

No disease in the past.

Personal and family history

His sister is of normal height and physical development.The patient was born normally without ischemia and hypoxia.His mother’s height is 156 cm,and hisfather’s height is 155 cm.The predicted height of the boy was calculated to be below the mid-parental height of 162 cm.

Physical examination upon admission

His abnormal symptoms are a short neck;facial moles;knee valgus;transverse palm;continuous grade 5/6 murmurs in the pulmonary auscultation area;no whiskers,or pubic hair;no Adam’s apple;a penis length of approximately 2 cm;a penis circumference of 3 cm and cryptorchidism(Figure 1A).

Laboratory examinations

The patient’s liver and kidney function,cortisol rhythm and thyroid function were normal.He completely lacked growth hormone,as shown through hypoglycemia challenge,a levodopa test and IGF-1 determination.His 25-hydroxyvitamin D was 11.3 ng/mL(low).Sex hormone assessment showed that the levels of luteinizing hormone(LH),follicle-stimulating hormone,testosterone and estrogen were all below normal.The peak LH level in a GnRH excitation test was 1.92 nmol/L(＜ 5 nmol/L).The peak testosterone level in a delayed human chorionic gonadotropin excitation test was 0.91 ng/mL(＜ 10 ng/mL).Conventional karyotyping after GTG-banding at a 500-band resolution showed a normal male karyotype(46,XY).Chromosomal microarray analysis showed no abnormalities.

Written informed consent for clinical whole-exome detection was obtained from the patient.All of the 3583 genes identified by the OMIM database were identified by high-throughput sequencing.Clinical whole-exome detection was offered by BGI in Shenzhen,Guangdong Province.

The results of clinical whole-exome detection are shown in Table 1.The diseases related to theLHCGR,HSPG2,andPKDIL1genes were autosomal recessive.ANCAgene-related exfoliative osteochondritis,short statue,early onset arthritis and vertebral hypoplasia exhibited autosomal dominant inheritance.SEMA3Agenerelated hypogonadotropic hypogonadism with or without olfactory loss exhibited autosomal dominant inheritance.

Imaging examinations

His bone age was 15 years old(Figure 1E).Dual-energy X-ray bone density assessment showed that the T(lumbar spine)was -5.3 SD below the mean and T(left hip joint)was -2.4 SD below the mean.Pelvic magnetic resonance imaging(MRI)(Figure 1C,D)showed the following:(A)Pelvic genitourinary dysplasia,in which(1)The prostate and bilateral seminal vesicles were not clearly shown;(2)The bilateral groin had soft tissue nodules and testicular hypoplasia;and(3)Penile dysplasia was observed;and(B)A pelvic bone that was not closed.In addition,abdominal ultrasound suggested left renal hypoplasia.Cardiac ultrasound suggested aortic dysplasia with moderate reflux.Pituitary MRI suggested pituitary dysplasia(Figure 1B).

FINAL DIAGNOSIS

LHCGR,HSPG2,PKDIL1,ANCAandSEMA3Aare all heterozygous mutation.SoANCA and SEMA3Agene mutations might be related to the symptom shown by our patient.However,ANCAgene mutation could not cause the previously reported gonadal and cardiac dysplasia.Therefore,we focused onSEMA3Aas the pathogenic gene.So final diagnosis isSEMA3Amutation,growth hormone deficiency,short stature,hypogonadotropic hypogonadism,heart dysplasia,kidney dysplasia and skeletal dysplasia.

TREATMENT

The patient was treated with recombinant human growth hormone injections(0.15 U/kg,GenSci,Changchun,Jilin Province).He refuses further treatment about gonad.

OUTCOME AND FOLLOW-UP

Now,his height has increased by 3 cm.In addition,he has a good appetite and reduced subcutaneous fat over 3 mo of recombinant human growth hormone injections therapy.We will continue to observe his height,bone density and gonads.

Figure 1 Clinical findings and radiographic abnormalities in a patient with a heterozygous SEMA3A gene mutation(c.950A＞G).

DISCUSSION

Two similar case reports have been published before.TheSEMA3Agenotype of the first case reported in 2013 included a compound-heterozygous de novo in-frame mutation in exon 9(c.945_949delinsTACATCTTCTAATG;p.Phe316_Lys317-delinsThrSerSerAsnGlu),a 150-kb deletion,the retention of intron 8,and a premature stop codon after 348 amino acids[6].TheSEMA3Agenotype of the second case reported in 2018 included a homozygous c.607C＞T [p.(Arg203*)] mutation in exon 6[5].All patients not only exhibited short statue,facial dysmorphism and skeletal system anomalies but also had cardiovascular,urogenital,hearing,olfactory,visual,motor development and cognitive development defects.There were some differences between our patient and the two patients presented previously(Table 2).First,theSEMA3Agenotype in our patient is c.950A＞G.Second,examination of our patient showed a complete lack of growth hormone,but this was not mentioned during the examination of the other two patients.Our patient’s short statue was perhaps caused by not only a lack of growth hormone but also vitamin D deficiency.Third,our patient has normal cognitive function and works in an electrical factory.Finally,he has kidney hypoplasia.Semaphorins are needed in kidney development because they regulate ureteric bud branching,vascular morphogenesis,and podocyte-endothelial crosstalk[5].Thus,SEMA3Agene mutation might result in kidney hypoplasia.In contrast,SEMA3Aoverexpression could promote foot process effacement,glomerular basement lamination,and endothelial damage in vivo and disrupt autonomous podocyte shape by downregulating nephrin and inhibiting αvβ3 integrin[7].ExcessSEMA3Aalso promoted severe diabetic nephropathy[8].No genes related to pituitary dysplasia were discovered in whole gene exome detection.Pituitary dysplasia might occur mainly because of defective hypothalamic neurons.

CONCLUSION

At present,short stature gets more and more attention.But we should make a clear diagnosis through gene detection if they have other simultaneous abnormal phenotypes.

Table 1 Clinical whole-exome detection results