Abbreviations: UPD-TR/GC: UPD(14)mat mediated by trisomy rescue or gamete complementation; UPD-MR/PE: UPD(14)mat mediated by monosomy rescue (MR)- orpostfertilization mitotic error; UPD-PE: UPD(14)mat mediated by postfertilization mitotic error; y, year; m, month, w, week; SDS, standard deviation score; OFC, occipitofrontalcircumference; GH, growth hormone; SGA-SS, small for gestational age-short stature; IQ/DQ, intellectual/developmental quotient; BMI, body mass index; ICSI, intracytoplasmic sperminjection; FET, frozen embryo transfer; IVF-ET, in vitro fertilization and embryo transfer; GHD, growth hormone deficiency; MP, micropenis; CO, cryptorchidism; and HS, hypospadias.* Birth OFC SDS ≥1.5 above birth length or weight SDS; present OFC SDS ≥1.5 above present height or weight SDS.† Including narrow forehead, almond-shaped eyes, and a triangular mouth.‡ Birth length and/or weight ≤ –2 SDS for gestational age; post-natal height (the latest height in childhood before the onset of pubertal growth spurt or the initiation of GH therapy, or in adulthood without GH therapy) ≤ –2 SDS for age).§ The actual latest present height data; thus, several patients show heights of the normal range (> –2 SDS) because of pubertal growth spurt or GH therapy, and this is not reflected by the assessment of post-natal growth failure.¶ Segmental isodisomy.# Mosaicism for 46,XX/46,XX,upd(14)mat.** Both of the parents were enrolled in special classes in childhood.†† Placed on levothyroxine supplementation therapy from 12 5/12 years of age.‡‡ Placed on hypoglycemic agent since adulthood.Footnote-1: weak integration of social, emotional, and communicative behaviors; difficulty in communication; being fascinated and stuck to details without noticing the whole; and unable to have a prospective view.Footnote-2: autistic tendency; abnormality of behavior and affection; compulsive adherence to specific matters; nonfunctional routines; and difficulty in social interactions.Footnote-3: excitement; self-injurious behaviors; aggressive behavior; restlessness; obstinate character; depression; and eating disorders.Footnote-4: stuck to details without noticing the whole; obstinate character; and poor communication skills.
References1. Goto M, Kagami M, Nishimura G, Yamagata T. A patient with Temple syndrome satisfying the clinical diagnostic criteria of Silver-Russell syndrome. Am J Med Genet A 2016;170:2483–2485.2. Tohyama J, Yamamoto T, Hosoki K et al. West syndrome associated with mosaic duplication of FOXG1 in a patient with maternal uniparental disomy of chromosome 14. Am J Med Genet A 2011;155A:2584–2588.3. Hosoki K, Kagami M, Tanaka T et al. Maternal uniparental disomy 14 syndrome demonstrates Prader-Willi syndrome-like phenotype. J Pediatr 2009;155:900–903.4. Kagami M, Mizuno S, Matsubara K, et al. Epimutations of the IG-DMR and the MEG3-DMR at the 14q32.2 imprinted region in two patients with Silver-Russell syndrome- compatible phenotype. Eur J Hum Genet 2015;23:1062–1067.5. Kagami M, Matsubara K, Nakabayashi K et al. Genome-wide multilocus imprinting disturbance analysis in Temple syndrome and Kagami-Ogata syndrome. Genet Med 2016 Sep 15. doi: 10.1038/gim.2016.123.6. Hosoki K, Ogata T, Kagami M, Tanaka T, Saitoh S. Epimutation (hypomethylation) affecting the chromosome14q32.2 imprinted region in a girl with upd(14)mat-like phenotype. Eur J Hum Genet 2008;16:1019–1023.7. Kagami M, Sekita Y, Nishimura G, et al. Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes. Nat Genet 2008;40:237–242.
Pt. 24 Pt. 25 Pt.26 Pt. 27 Pt. 28 Pt. 29 Median (Min ~ Max)*Initial Dx PWS SRS SRS PWS SRS PWSRe-assessed Dx in infancy PWS SRS SRS PWS & SRS PWS & SRS PWS<TS14- and KOS14-related DMRs>MEG3/DLK1 :IG-DMR CpG-1 24 34 25 31 22 22 58 (49 ~ 68)(Ch. 14q32.2) CpG-2 22 33 24 28 18 22 54 (40~ 62)
Reference This paper 1 (Pt. 2) 1 (Pt. 4) 1 (Pt.1) 1 (Pt. 3) This paper
* The reference data have been obtained from 50 control adults.Markedly low MIs highlighted with orange permit the diagnosis of Temples syndrome; the methylation indices, especially those for theMEG3:TSS-DMR , are relatively high in patient 25. Slightly low MIs and slightly high MIs are highlighted with yellow and blue, respectively.The values outside the normal ranges were confirmed by triplicated experiments, and the mean value of the three experiments are shown.The data of Pts. 25−28 have been adopted from Kagami et al.Reference1. Kagami M, Matsubara K, Nakabayashi K, et al. Genome-wide multilocus imprinting disturbance analysis in Temple syndrome and Kagami-Ogata syndrome. Genet Med 2016 Sep 15. doi: 10.1038/gim.2016.123. [Epub ahead of print]
Table S2. Methylation indices (MIs, %) for CpG dinucleotides determined by pyrosequencing analysis in patients with epimutations.
Table S3. Endocrine data and pubertal findings in 18 patients with Temple syndrome.Patient 8 Patient 10 Patient 11 Patient 12 Patient 13 Patient 14 Patient 15 Patient 16 Patient 18
Abbreviations: GH, growth hormone; IGH-1, insulin-like growth factor-1; LH, luteinizing hormone; FSH, follicle stimulating hormone; GnRH, gonadotropin releasinghormone; SGA-SS, small for gestational age-short stature; GHD, GH deficiency; G, genitalia; B, breast, and PH, pubic hair.* The peak values during GH provocation tests: arginine 0.5 g/kg [max. 30 g] i.v. over 30 minutes, insulin 0.05–0.1 U/kg bolus i.v., or clonidine 0.1–0.15 mg/m² [max. 0.15 mg] p.o.; blood sampling at 0, 30, 60, 90, and 120 minutes.† The peak values during GnRH stimulation tests: GnRH 100 μg/m² [max. 100 μg] bolus i.v.; blood sampling at 0, 30, 60, 90, and 120 minutes.‡ On GnRH analog therapy.The hormone values above and below the age- and sex-matched reference ranges are boldfaced and italicized, respectively.Tanner pubertal development earlier than the normal tempo are boldfaced.The diagnosis of GHD is made when all the serum GH values during ≥ two provocation tests are below 6 ng/mL.GH therapy for SGA-SS is performed for patients who are born small for gestational age (birth length and weight below 10 percentile plus birth length or weight < –2 SD), and remain short at 3 years of age (height velocity < 0 SD and height < –2.5 SD).GH therapy using recombinant GH is performed at a single fixed dosage of ~0.175 mg/kg/week for GHD since 1986, and its cost is fully covered by the Japanese government, whereas that is performed at variable dosages between 0.23 and 0.47 mg/kg/week (sometimes smaller dosages) for SGA-SS since 2008, and its cost is usually covered by the local government depending on the patient ages (usually <15 years of age).GnRH analog therapy (s.c. every 4 weeks) was performed with the initial dosage of 30 μg/kg and the maximum dosage of 90 μg/kg until 2010, and with larger dosages up to 180 μg/kg since 2011.Conversion factors to the SI unit: 1.0 for GH, IGF-1, LH, and FSH; 0.0347 for testosterone; and 3.67 for estradiol.
Classification of 32 patients with TS14 Group Subgroup Number UPD(14)mat TR/GC type 16 MR/PE type 4 PE type 3 Epimutations 6 Deletions DLK1 2 DLK1 & RTL1 1
Figure S1. Molecular approach and classification of identified TS14 patients. A. Schematic representation of the physical map of the chromosome 14q32.2 imprinted region.
PEGs are shown in blue, MEGs in red, a probably non-imprinted gene (DIO3) in black, and the DMRs in green.
B. Molecular approach for the identification of TS14 from 346 patients examined in this study. C. Classification of a total of 32 Japanese patients with TS14, consisting of 19 newly identified
patients and 13 previously reported patients. D. Methylation status of the MEG3/DLK1:IG-DMR and the MEG3:TSS-DMR, and expression
patterns of the imprinted genes. P: paternally derived chromosome; and M: maternally derived chromosome. Black and white circles represent methylated and unmethylated DMRs, respectively. The deleted regions are shown with stippled squares.
Figure S2. Body mass indices (BMIs) in Japanese patients with Temple syndrome and those with Silver-Russell syndrome. The data are plotted on the percentile BMI curves of Japanese children (3, 10, 25, 50, 75, 90, and 97 percentiles). The 50 percentile growth curves are boldfaced.
Figure S3. The developmental status. The orange, green, yellow, and blue bars represent the period beforehead control, that after head control and before sitting without support, that after sitting without support andbefore walking without support, and that after walking without support. The gray bars denote the periodwith no information. DQ: developmental quotient; IQ: intellectual quotient; N.E.: not examined; Age: age atthe last examination (year: month).
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Reference S1. A reference list of previously reported 65 patients with Temple syndrome
improving the recognition of an underdiagnosed chromosome 14 imprinting disorder: an analysis of 51 published cases. J Med Genet 2014;51:195–201. (The references for TS14 up to 2014 have been cited in this review article).
2. Azzi S, Salem J, Thibaud N, et al. A prospective study validating a clinical scoring system and demonstrating phenotypical-genotypical correlations in Silver-Russell syndrome. J Med Genet 2015;52:446–453.
3. Rosenfeld JA, Fox JE, Descartes M et al. Clinical features associated with copy number variations of the 14q32 imprinted gene cluster. Am J Med Genet A 2015;167A:345–353.
4. Kagami M, Mizuno S, Matsubara K et al. Epimutations of the IG-DMR and the MEG3-DMR at the 14q32.2 imprinted region in two patients with Silver-Russell Syndrome-compatible phenotype. Eur J Hum Genet 2015;23:1062–1067.
5. Dworschak GC, Draaken M, Hilger AC et al. Genome-wide mapping of copy number variations in patients with both anorectal malformations and central nervous system abnormalities. Birth Defects Res A Clin Mol Teratol 2015;103:235–242.
6. Severi G, Bernardini L, Briuglia S et al. New patients with Temple syndrome caused by 14q32 deletion: Genotype-phenotype correlations and risk of thyroid cancer. Am J Med Genet A 2016;170A:162–169.
7. Briggs TA, Lokulo-Sodipe K, Chandler KE, Mackay DJ, Temple IK. Temple syndrome as a result of isolated hypomethylation of the 14q32 imprinted DLK1/MEG3 region. Am J Med Genet A 2016;170A:170–175.
8. Goto M, Kagami M, Nishimura G, Yamagata T. A patient with Temple syndrome satisfying the clinical diagnostic criteria of Silver-Russell syndrome. Am J Med Genet A 2016;170A:2483–2485.
9. Sachwitz J, Strobl-Wildemann G, Fekete G et al. Examinations of maternal uniparental disomy and epimutations for chromosomes 6, 14, 16 and 20 in Silver-Russell syndrome-like phenotypes. BMC Med Genet 2016;17:20.
10. Shin EH, Cho E, Lee CG. Temple syndrome: A patient with maternal hetero-UPD14, mixed iso- and hetero-disomy detected by SNP microarray typing of patient-father duos. Brain Dev 2016;38:669–673.
Reference S2. A reference list of previously reported 16 patients with microdeletions
involving the 14q32.2 imprinted region of paternal origin Patients 30–32: Kagami M, Sekita Y, Nishimura G et al. Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes. Nat Genet 2008;40:237–242. Case 1: Mitter D, Buiting K, von Eggeling F et al. Is there a higher incidence of maternal uniparental disomy 14 [upd(14)mat]? Detection of 10 new patients by methylation-specific PCR. Am J Med Genet A 2006;140:2039–2049. Case 2: Béna F, Gimelli S, Migliavacca E et al. A recurrent 14q32.2 microdeletion mediated by expanded TGG repeats. Hum Mol Genet 2010;19:1967–1973. Case 3: Zada A, Mundhofir FE, Pfundt R et al. A Rare, Recurrent, De Novo 14q32.2q32.31 Microdeletion of 1.1 Mb in a 20-Year-Old Female Patient with a Maternal UPD(14)-Like Phenotype and Intellectual Disability. Case Rep Genet 2014;2014:530134. Case 4: Dworschak GC, Draaken M, Hilger AC et al. Genome-wide mapping of copy number variations in patients with both anorectal malformations and central nervous system abnormalities. Birth Defects Res A Clin Mol Teratol 2015;103:235–242. Case 5: Rosenfeld JA, Fox JE, Descartes M et al. Clinical features associated with copy number variations of the 14q32 imprinted gene cluster. Am J Med Genet A 2015;167A:345–353. Case 6: Severi G, Bernardini L, Briuglia S et al. New patients with Temple syndrome caused by 14q32 deletion: Genotype-phenotype correlations and risk of thyroid cancer. Am J Med Genet A 2016;170A:162–169. Case 7: Severi G, Bernardini L, Briuglia S et al. New patients with Temple syndrome caused by 14q32 deletion: Genotype-phenotype correlations and risk of thyroid cancer. Am J Med Genet A 2016;170A:162–169. Case 8: Severi G, Bernardini L, Briuglia S et al. New patients with Temple syndrome caused by 14q32 deletion: Genotype-phenotype correlations and risk of thyroid cancer. Am J Med Genet A 2016;170A:162–169. Case 9: Rosenfeld JA, Fox JE, Descartes M et al. Clinical features associated with copy number variations of the 14q32 imprinted gene cluster. Am J Med Genet A 2015;167A:345–353. Case 10: Kagami M, O'Sullivan MJ, Green AJ et al. The IG-DMR and the MEG3-DMR at human chromosome 14q32.2: hierarchical interaction and distinct functional properties as imprinting control centers. PLoS Genet 2010;6:e1000992. Case 11: Rosenfeld JA, Fox JE, Descartes M et al. Clinical features associated with copy number variations of the 14q32 imprinted gene cluster. Am J Med Genet A 2015;167A:345–353. Case 12: Rosenfeld JA, Fox JE, Descartes M et al. Clinical features associated with copy number variations of the 14q32 imprinted gene cluster. Am J Med Genet A 2015;167A:345–353. Case 13: Rosenfeld JA, Fox JE, Descartes M et al. Clinical features associated with copy number variations of the 14q32 imprinted gene cluster. Am J Med Genet A 2015;167A:345–353.
