Neonatal Smith-Kingsmore syndrome: case report and literature review / 中国新生儿科杂志

Objective:To study the clinical and genetic features of neonatal Smith-Kingsmore syndrome (SKS).Methods:The clinical data of a newborn with SKS admitted to our hospital in November 2021 were reviewed. Using "Smith-Kingsmore", "rapamycin gene", "newborn", "premature infant", "the mammalian target of rapamycin", "MTOR", "mTOR", "Smith-Kingsmore syndrome", "megalencephaly", "macrocephaly" and "hemimegalencephaly" as keywords, databases including CNKI, Wanfang Database, VIP database, PubMed, Embase, Web of Science and the Cochrane Library were searched from the date of establishment to January 1, 2022. The clinical and genetic features of neonatal SKS from published literature were summarized.Results:The case admitted to our hospital was a male preterm infant. The presenting symptoms were groan and hypotonia. The facial abnormalities included macrocrania, ocular hypertelorism, depressed nasal bridge and low-set ears. Brain MRI showed lateral ventricle enlargement. Whole-genome sequencing (WGS) showed mTOR gene nonsense heterozygous mutation (NM_004958.4:c.7255G>A:p.Glu2419Lys). Neither father nor mother had any pathogenic gene mutations. The infant had seizure at 2-month and phenobarbital was effective reducing seizure. Gross motor delay was present at 3-month. Sixteen related articles were retrieved, including eight articles with 10 neonatal cases. Among them, 6 cases were male. The main clinical features were megalencephaly or hemimegalencephaly (9/10), facial developmental malformation (8/10), hypotonia (6/10), large-for-gestational age (LGA) infants (5/10), cerebral ventricle dilation (4/10) and abnormal corpus callosum (4/10). All the gene mutations were missense mutations, including c.5395G>A(p.Glu1799Lys) mutation in 5 cases, c.4448G>T(p.Cys1483Phe) mutation in 1 case, c.4448G>T(p.Cys1483Tyr) mutation in 1 case, c.7235A>T(p.Asp2412Val) mutation in 1 case, c.5663T>G(p.Phe1888Cys) mutation in 1 case, c.5390C>T(p.Thr1799IIe) mutation in 1 case.Conclusions:The clinical phenotypes of neonatal SKS are diverse, including megalencephaly, facial malformation, LGA and hypotonia. The brain MR findings included (hemi) megalencephaly, cerebral ventricle dilation and corpus callosum hypoplasia. Most of the gene mutations are missense mutations and c.5395G>A(p.Glu1799Lys) is the hotspot.

Smith-Kingsmore syndrome: The first report of a Korean patient with the MTOR germline mutation c.5395G>A p.(Glu1799Lys)

Smith-Kingsmore syndrome (SKS; OMIM 616638), also known as macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome (MINDS; ORPHA 457485), is a rare autosomal dominant disorder, the prevalence of which is not known. It is caused by a heterozygous germline mutation in MTOR (OMIM 601231). Ten different MTOR germline mutations in 27 individuals have been reported in the medical literature to date. These were all gain-of-function missense variants, and about half of the 27 individuals had c.5395G>A p.(Glu1799Lys) in MTOR. Here, I report for the first time a Korean patient with the heterozygous germline mutation c.5395G>A p.(Glu1799Lys) in MTOR. It was found to be a de novo mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing. The patient showed typical clinical features of SKS, including macrocephaly/megalencephaly; moderate intellectual disability; seizures; behavioral problems; and facial dysmorphic features of curly hair, frontal bossing, midface hypoplasia, and hypertelorism.