Molecular Genetics and Genomics

, Volume 291, Issue 1, pp 1–15 | Cite as

Primordial dwarfism: overview of clinical and genetic aspects

  • Preeti Khetarpal
  • Satrupa Das
  • Inusha Panigrahi
  • Anjana MunshiEmail author


Primordial dwarfism is a group of genetic disorders which include Seckel Syndrome, Silver–Russell Syndrome, Microcephalic Osteodysplastic Primordial Dwarfism types I/III, II and Meier–Gorlin Syndrome. This genetic disorder group is characterized by intra-uterine growth retardation and post-natal growth abnormalities which occur as a result of disorganized molecular and genomic changes in embryonic stage and, thus, it represents a unique area to study growth and developmental abnormalities. Lot of research has been carried out on different aspects; however, a consolidated review that discusses an overall spectrum of this disorder is not accessible. Recent research in this area points toward important molecular and cellular mechanisms in human body that regulate the complexity of growth process. Studies have emerged that have clearly associated with a number of abnormal chromosomal, genetic and epigenetic alterations that can predispose an embryo to develop PD-associated developmental defects. Finding and associating such fundamental changes to its subtypes will help in re-examination of alleged functions at both cellular and developmental levels and thus reveal the intrinsic mechanism that leads to a balanced growth. Although such findings have unraveled a subtle understanding of growth process, we further require active research in terms of identification of reliable biomarkers for different subtypes as an immediate requirement for clinical utilization. It is hoped that further study will advance the understanding of basic mechanisms regulating growth relevant to human health. Therefore, this review has been written with an aim to present an overview of chromosomal, molecular and epigenetic modifications reported to be associated with different subtypes of this heterogenous disorder. Further, latest findings with respect to clinical and molecular genetics research have been summarized to aid the medical fraternity in their clinical utility, for diagnosing disorders where there are overlapping physical attributes and simultaneously inform about the latest developments in PD biology.


Primordial dwarfism Subtypes Clinical Genetics 



Author gratefully acknowledges the funding received from UGC, New Delhi under UGC-BSR Research Start-Up-Grant.

Compliance with ethical standards

Conflict of interest

The authors declare that no conflict of interest exists.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. Abdelhedi F, El Khattabi L, Cuisset L, Tsatsaris V, Viot G, Druart L, Lebbar A, Dupont JM (2014) Neonatal Silver–Russell syndrome with maternal uniparental heterodisomy trisomy 7 mosaicism and dysplasia of the cerebellum. Am J Clin Pathol 142:248–253PubMedCrossRefGoogle Scholar
  2. Abdel-Salam GM, Miyake N, Eid MM, Abdel-Hamid MS, Hassan NA, Eid OM, Effat LK, El-Badry TH, El-Kamah GY, El-Darouti M, Matsumoto N (2011) A homozygous mutation in RNU4ATAC as a cause of microcephalic osteodysplastic primordial dwarfism type I (MOPD I) with associated pigmentary disorder. Am J Med Genet A 155A:2885–2896PubMedCrossRefGoogle Scholar
  3. Agha Z, Iqbal Z, Azam M, Siddique M, Willemsen MH, Kleefstra T, Zweier C, de Leeuw N, Qamar R, van Bokhoven H (2014) A complex microcephaly syndrome in a Pakistani family associated with a novel missense mutation in RBBP8 and a heterozygous deletion in NRXN1. Gene 538:3–35CrossRefGoogle Scholar
  4. Alderton GK, Joenje H, Varon R, Børglum AD, Jeggo PA, O’Driscoll M (2004) Seckel syndrome exhibits cellular features demonstrating defects in the ATR-signalling pathway. Hum Mol Genet 13:3127–3138PubMedCrossRefGoogle Scholar
  5. Al-Dosari MS, Shaheen R, Colak D, Alkuraya FS (2010) Novel CENPJ mutation causes Seckel syndrome. J Med Genet 47:411–444PubMedCrossRefGoogle Scholar
  6. Barolo S, Posakony JW (2002) Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling. Gene Dev 16:1167–1181PubMedCrossRefGoogle Scholar
  7. Bicknell LS, Bongers EM, Leitch A, Brown S, Schoots J, Harley ME, Aftimos S, Al-Aama JY, Bober M, Brown PA, van Bokhoven H, Dean J, Edrees AY, Feingold M, Fryer A, Hoefsloot LH, Kau N, Knoers NV, Mackenzie J, Opitz JM, Sarda P, Ross A, Temple IK, Toutain A, Wise CA, Wright M, Jackson AP (2011a) Mutations in the pre-replication complex cause Meier–Gorlin syndrome. Nat Genet 43:356–359PubMedPubMedCentralCrossRefGoogle Scholar
  8. Bicknell LS, Walker S, Klingseisen A, Stiff T, Leitch A, Kerzendorfer C, Martin CA, Yeyati P, Al Sanna N, Bober M, Johnson D, Wise C, Jackson AP, O’Driscoll M, Jeggo PA (2011b) Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier–Gorlin syndrome. Nat Genet 43:350–355PubMedCrossRefGoogle Scholar
  9. Birkebaek NH, Wolthers OD, Heuch C, Balslev T, Flyvbjerg A, Frystyk J (2011) Growth hormone treatment, final height, insulin-like growth factors, ghrelin, and adiponectin in four siblings with Seckel syndrome. J Pediatr Endocrinol Metab 24:995–1000PubMedCrossRefGoogle Scholar
  10. Bobabilla-Morales L, Corona-Rivera A, Corona-Rivera JR, Buenrostro C, García-Cobián TA, Corona-Rivera E, Cantú-Garza JM, García-Cruz D (2003) Chromosome instability induced in vitro with mitomycin C in five Seckel syndrome patients. Am J Med Genet A 123A:148–152PubMedCrossRefGoogle Scholar
  11. Bober MB, Khan N, Kaplan J, Lewis K, Feinstein JA, Scott CI Jr, Steinberg GK (2010) Primordial dwarfism type II (MOPD II): expanding the vascular phenotype. Am J Med Genet A 152A:960–965PubMedCrossRefGoogle Scholar
  12. Bober MB, Niiler T, Duker AL, Murray JE, Ketterer T, Harley ME, Alvi S, Flora C, Rustad C, Bongers EM, Bicknell LS, Wise C, Jackson AP (2012) Growth in individuals with Majewski osteodysplastic primordial dwarfism type II caused by pericentrin mutations. Am J Med Genet A 158A(11):2719–2725PubMedCrossRefGoogle Scholar
  13. Boles RG, Teebi AS, Schwartz D, Harper JF (1994) Further delineation of the ear, patella, short stature syndrome (Meier–Gorlin Syndrome). Clin Dysmorphol 3:207–214PubMedCrossRefGoogle Scholar
  14. Bonaldi A, Mazzeu JF, Costa SS, Honjo RS, Bertola DR, Albano LM, Furquim IM, Kim CA, Vianna-Morgante AM (2011) Microduplication of the ICR2 domain at chromosome 11p15 and familial Silver–Russell syndrome. Am J Med Genet A 155A:2479–2483PubMedCrossRefGoogle Scholar
  15. Bongers EM, Opitz JM, Fryer A, Sarda P, Hennekam RC, Hall BD, Superneau DW, Harbison M, Poss A, van Bokhoven H, Hamel BC, Knoers NV (2001) Meier–Gorlin syndrome: report of eight additional cases and review. Am J Med Genet 102:115–124PubMedCrossRefGoogle Scholar
  16. Borglum AD, Balslev T, Haagerup A, Birkebaek N, Binderup H, Kruse TA, Hertz JM (2001) A new locus for Seckel syndrome on chromosome 18p1131-q112. Eur J Hum Genet 9:753–757PubMedCrossRefGoogle Scholar
  17. Brackeen A, Babb-Tarbox M, Smith J (2007) Pigmentary changes and atopic dermatitis in a patient with Seckel syndrome. Pediatr Dermatol 24:53–56PubMedCrossRefGoogle Scholar
  18. Bruce S, Hannula-Jouppi K, Puoskari M, Fransson I, Simola KO, Lipsanen-Nyman M, Kere J (2010) Submicroscopic genomic alterations in Silver–Russell syndrome and Silver–Russell-like patients. J Med Genet 47:816–822PubMedCrossRefGoogle Scholar
  19. Butler MG, Hall BD, Maclean RN, Lozzio CB (1987) Do some patients with Seckel syndrome have hematological problems and/or chromosome breakage? Am J Med Genet 27:645–649PubMedCrossRefGoogle Scholar
  20. Casper AM, Durkin SG, Arlt MF, Glover TW (2004) Chromosomal instability at common fragile sites in Seckel syndrome. Am J Hum Genet 75:654–660PubMedPubMedCentralCrossRefGoogle Scholar
  21. Codd PJ, Scott RM, Smith ER (2009) Seckel syndrome and moyamoya. J Neurosurg Pediatr 3:320–324PubMedCrossRefGoogle Scholar
  22. Cousens S, Blencowe H, Stanton C, Chou D, Ahmed S, Steinhardt L, Creanga AA, Tunçalp O, Balsara ZP, Gupta S, Say L, Lawn JE (1995) National, regional and worldwide estimates of stillbirth rates in 2009 with trends since 1995: a systematic analysis. Lancet 377:1319–1330CrossRefGoogle Scholar
  23. Coutton C, Devillard F, Vieville G, Amblard F, Lopez G, Jouk PS, Satre V (2012) 17p131 microduplication in a boy with Silver–Russell syndrome features and intellectual disability. Am J Med Genet A 158A:2564–2570PubMedCrossRefGoogle Scholar
  24. Crickmore MA, Mann RS (2008) The control of size in animals: insights from selector genes. BioEssays 30:843–853PubMedPubMedCentralCrossRefGoogle Scholar
  25. Daniel M, Kleis L, Cemeroglu AP (2008) Etiology of failure to thrive in infants and toddlers referred to a pediatric endocrinology outpatient clinic. Clin Pediatr (Phila) 47:762–765CrossRefGoogle Scholar
  26. Darrigo LG, Rodrigues MC Jr, Pieroni F, Stracieri AB, Moraes DA, Grecco CE, Dias JB, Sobral AC, Simões BP (2014) Successful outcome of allogeneic stem cell transplantation in Seckel syndrome. Pediatr Transplant 18:E93–E95PubMedCrossRefGoogle Scholar
  27. Dauber A, Lafranchi SH, Maliga Z, Lui JC, Moon JE, McDeed C, Henke K, Zonana J, Kingman GA, Pers TH, Baron J, Rosenfeld RG, Hirschhorn JN, Harris MP, Hwa V (2012) Novel microcephalic primordial dwarfism disorder associated with variants in the centrosomal protein ninein. J Clin Endocrinol Metab 97:E2140–E2151PubMedPubMedCentralCrossRefGoogle Scholar
  28. De Coster PJ, Verbeeck RM, Holthaus V, Martens LC, Vral A (2006) Seckel syndrome associated with oligodontia, microdontia, enamel hypoplasia, delayed eruption, and dentin dysmineralization: a new variant? J Oral Pathol Med 35:639–641PubMedCrossRefGoogle Scholar
  29. de Munnik SA, Otten BJ, Schoots J, Bicknell LS, Aftimos S, Al-Aama JY, van Bever Y, Bober MB, Borm GF, Clayton-Smith J, Deal CL, Edrees AY, Feingold M, Fryer A, van Hagen JM, Hennekam RC, Jansweijer MC, Johnson D, Kant SG, Opitz JM, Ramadevi AR, Reardon W, Ross A, Sarda P, Schrander-Stumpel CT, Sluiter AE, Temple IK, Terhal PA, Toutain A, Wise CA, Wright M, Skidmore DL, Samuels ME, Hoefsloot LH, Knoers NV, Brunner HG, Jackson AP, Bongers EM (2012) Meier–Gorlin syndrome: growth and secondary sexual development of a microcephalic primordial dwarfism disorder. Am J Med Genet A 158:2733–2742CrossRefGoogle Scholar
  30. Demars J, Gicquel C (2012) Epigenetic and genetic disturbance of the imprinted 11p15 region in Beckwith-Wiedemann and Silver–Russell syndromes. Clin Genet 81:350–361PubMedCrossRefGoogle Scholar
  31. Dias RP, Bogdarina I, Cazier JB, Buchanan C, Donaldson MC, Johnston LB, Hokken-Koelega AC, Clark AJ (2012) Multiple segmental uniparental disomy associated with abnormal DNA methylation of imprinted Loci in Silver–Russell syndrome. J Clin Endocrinol Metab 97:E2188–E2193PubMedCrossRefGoogle Scholar
  32. Edery P, Marcaillou C, Sahbatou M, Labalme A, Chastang J, Touraine R, Tubacher E, Senni F, Bober MB, Nampoothiri S, Jouk PS, Steichen E, Berland S, Toutain A, Wise CA, Sanlaville D, Rousseau F, Clerget-Darpoux F, Leutenegger AL (2011) Association of TALS developmental disorder with defect in minor splicing component U4atac snRNA. Science 332:240–243PubMedCrossRefGoogle Scholar
  33. Eggermann T, Eggermann K, Mergenthale S, Kuner R, Kaiser P, Ranke MB, Wollmann HA (1998) Paternally inherited deletion of CSH 1 in a patient with Silver–Russell syndrome. J Med Genet 35:784–786PubMedPubMedCentralCrossRefGoogle Scholar
  34. Eggermann T, Spengler S, Bachmann N, Baudis M, Mau-Holzmann UA, Singer S, Rossier E (2010) Chromosome 11p15 duplication in Silver–Russell syndrome due to a maternally inherited translocation t(11;15). Am J Med Genet A 152A:1484–1487PubMedCrossRefGoogle Scholar
  35. Eggermann T, Spengler S, Gogiel M, Begemann M, Elbracht M (2012) Epigenetic and genetic diagnosis of Silver–Russell syndrome. Expert Rev Mol Diagn 12:459–471PubMedCrossRefGoogle Scholar
  36. Faienza MF, Acquafredda A, D’Aniello M, Soldano L, Marzano F, Ventura A, Cavallo L (2013) Effect of recombinant insulin-like growth factor-1 treatment on short-term linear growth in a child with Majewski osteodysplastic primordial dwarfism type II and hepatic insufficiency. J Pediatr Endocrinol Metab 26:771–774PubMedCrossRefGoogle Scholar
  37. Faivre L, Le Merrer M, Lyonnet S, Plauchu H, Dagoneau N, Campos-Xavier AB, Attia-Sobol J, Verloes A, Munnich A, Cormier-Daire V (2002) Clinical and genetic heterogeneity of Seckel syndrome. Am J Med Genet 112:379–383PubMedCrossRefGoogle Scholar
  38. Goodship J, Gill H, Carter J, Jackson A, Splitt M, Wright M (2000) Autozygosity mapping of a seckel syndrome locus to chromosome 3q22 1–q24. Am J Hum Genet 67:498–503PubMedPubMedCentralCrossRefGoogle Scholar
  39. Gorlin RJ, Cervenka J, Moller K, Horrobin M, Witkop CJ Jr (1975) A selected miscellany. Birth Defects 11:39–50PubMedGoogle Scholar
  40. Gucev ZS, Tasic V, Jancevska A, Kirovski I (2009) A case of Silver–Russell syndrome (SRS): multiple pituitary hormone deficiency, lack of H19 hypomethylationand favourable growth hormone (GH) treatment response. J Genet 88(2):239–243PubMedCrossRefGoogle Scholar
  41. Guernsey DL, Jiang H, Hussin J, Arnold M, Bouyakdan K, Perry S, Babineau-Sturk T, Beis J, Dumas N, Evans SC, Ferguson M, Matsuoka M, Macgillivray C, Nightingale M, Patry L, Rideout AL, Thomas A, Orr A, Hoffmann I, Michaud JL, Awadalla P, Meek DC, LudmanM Samuels ME (2010) Mutations in centrosomal protein CEP152 in primary microcephaly familieslinked to MCPH4. Am J Hum Genet 87:40–51PubMedPubMedCentralCrossRefGoogle Scholar
  42. Guernsey DL, Matsuoka M, Jiang H, Evans S, Macgillivray C, Nightingale M, Perry S, Ferguson M, LeBlanc M, Paquette J, Patry L, Rideout AL, Thomas A, Orr A, McMaster CR, Michaud JL, Deal C, Langlois S, Superneau DW, Parkash S, Ludman M, Skidmore DL, Samuels ME (2011) Mutations in origin recognition complex gene ORC4 cause Meier–Gorlin syndrome. Nat Genet 43:360–364PubMedCrossRefGoogle Scholar
  43. Hajdas-Kudela I, Jamroz E, Marszał E (1997) Silver-Russel syndrome in a 13-month old girl. Pol Merkur Lekarski 2:387–388PubMedGoogle Scholar
  44. Hall JG, Flora C, Scott CI Jr, Pauli RM, Tanaka KI (2004) Majewski osteodysplastic primordial dwarfism type II (MOPDII): natural history and clinical findings. Am J Med Genet 130A:55–72PubMedCrossRefGoogle Scholar
  45. Harshavardhan BG, Muthu MS, Saraswathi K, Koteeswaran D (2007) Bird-headed dwarf of Seckel. J Indian Soc Pedod Prev Dent 25:S8–S9Google Scholar
  46. He H, Liyanarachchi S, Akagi K, Nagy R, Li J, Dietrich RC, Li W, Sebastian N, Wen B, Xin B, Singh J, Yan P, Alder H, Haan E, Wieczorek D, Albrecht B, Puffenberger E, Wang H, Westman JA, Padgett RA, Symer DE, de la Chapelle A (2011) Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder. MOPD I Science 332:238–240PubMedGoogle Scholar
  47. Horike S, Ferreira JC, Meguro-Horike M, Choufani S, Smith AC, Shuman C, Meschino W, Chitayat D, Zackai E, Scherer SW, Weksberg R (2009) Screening of DNA methylation at the H19 promoter or the distal region of its ICR1 ensures efficient detection of chromosome 11p15 epimutations in Russell-Silver syndrome. Am J Med Genet A 149A:2415–2423PubMedCrossRefGoogle Scholar
  48. Hossain M, Stillman B (2012) Meier–Gorlin syndrome mutations disrupt an Orc1 CDK inhibitory domain and cause centrosome reduplication. Genes Dev 26:1797–1810PubMedPubMedCentralCrossRefGoogle Scholar
  49. Jafarifar F, Dietrich RC, Hiznay JM, Padgett RA (2014) Biochemical defects in minor spliceosome function in the developmental disorder MOPD I. RNA 20:1078–1089PubMedPubMedCentralCrossRefGoogle Scholar
  50. Kalay E, Yigit G, Aslan Y, Brown KE, Pohl E, Bicknell LS, Kayserili H, Li Y, Tüysüz B, Nürnberg G, Kiess W, Koegl M, Baessmann I, Buruk K, Toraman B, Kayipmaz S, Kul S, Ikbal M, Turner DJ, Taylor MS, Aerts J, Scott C, Milstein K, Dollfus H, Wieczorek D, Brunner HG, Hurles M, Jackson AP, Rauch A, Nürnberg P, Karagüzel A, Wollnik B (2011) CEP152 is a genome maintenance protein disrupted in Seckel syndrome. Nat Genet 43:23–26PubMedPubMedCentralCrossRefGoogle Scholar
  51. Kılıç E, Utine E, Unal S, Haliloğlu G, Oğuz KK, Cetin M, Boduroğlu K, Alanay Y (2012) Medical management of moyamoya disease and recurrent stroke inan infant with Majewski osteodysplasticprimordial dwarfism type II (MOPD II). Eur J Pediatr 171(10):1567–1571PubMedCrossRefGoogle Scholar
  52. Kilinç MO, Ninis VN, Ugur SA, Tüysüz B, Seven M, Balci S, Goodship J, Tolun A (2003) Is the novel SCKL3 at 14q23 the predominant Seckel locus? Eur J Hum Genet 11:851–857PubMedCrossRefGoogle Scholar
  53. Kjaer I, Hansen N, Becktor KB, Birkebaek N, Balslev T (2001) Craniofacial morphology, dentition, and skeletal maturity in four siblings with Seckel syndrome. Cleft Palate Craniofac J 38:645–651PubMedCrossRefGoogle Scholar
  54. Klingseisen A, Jackson AP (2011) Mechanisms and pathways of growth failure in primordial dwarfism. Genes Dev 25:2011–2024PubMedPubMedCentralCrossRefGoogle Scholar
  55. Kuo AJ, Song J, Cheung P, Ishibe-Murakami S, Yamazoe S, Chen JK, Patel DJ, Gozani O, Hossain M, Stillman B (2012) Meier–Gorlin syndrome mutations disrupt an Orc1 CDK inhibitory domain and cause centrosome reduplication. Genes Dev 26:1797–1810CrossRefGoogle Scholar
  56. Kutlu R, Alkan A, Kutlu O, Yakinci C (2004) Seckel syndrome with polyarteritis nodosa. Indian Pediatr 41:1158–1161PubMedGoogle Scholar
  57. Lango AH, Estrada K, Lettre G, Berndt SI, Weedon MN, Rivadeneira F, Willer CJ, Jackson AU, Vedantam S, Raychaudhuri S, Ferreira T, Wood AR, Weyant RJ, Segrè AV, Speliotes EK, Wheeler E, Soranzo N, Park JH, Yang J, Gudbjartsson D, Heard-Costa NL, Randall JC, Qi L, Vernon Smith A, Mägi R, Pastinen T, Liang L, Heid IM, Luan J, Thorleifsson G, Winkler TW, Goddard ME, Sin Lo K, Palmer C, Workalemahu T, Aulchenko YS, Johansson A, Zillikens MC, Feitosa MF, Esko T, Johnson T, Ketkar S, Kraft P, Mangino M, Prokopenko I, Absher D, Albrecht E, Ernst F, Glazer NL, Hayward C, Hottenga JJ, Jacobs KB, Knowles JW, Kutalik Z, Monda KL, Polasek O, Preuss M, Rayner NW, Robertson NR, Steinthorsdottir V, Tyrer JP, Voight BF, Wiklund F, Xu J, Zhao JH, Nyholt DR, Pellikka N, Perola M, Perry JR, Surakka I, Tammesoo ML, Altmaier EL, Amin N, Aspelund T, Bhangale T, Boucher G, Chasman DI, Chen C, Coin L, Cooper MN, Dixon AL, Gibson Q, Grundberg E, Hao K, Juhani Junttila M, Kaplan LM, Kettunen J, König IR, Kwan T, Lawrence RW, Levinson DF, Lorentzon M, McKnight B, Morris AP, Müller M, Suh Ngwa J, Purcell S, Rafelt S, Salem RM, Salvi E, Sanna S, Shi J, Sovio U, Thompson JR, Turchin MC, Vandenput L, Verlaan DJ, Vitart V, White CC, Ziegler A, Almgren P, Balmforth AJ, Campbell H, Citterio L, De Grandi A, Dominiczak A, Duan J, Elliott P, Elosua R, Eriksson JG, Freimer NB, Geus EJ, Glorioso N, Haiqing S, Hartikainen AL, Havulinna AS, Hicks AA, Hui J, Igl W, Illig T, Jula A, Kajantie E, Kilpeläinen TO, Koiranen M, Kolcic I, Koskinen S, Kovacs P, Laitinen J, Liu J, Lokki ML, Marusic A, Maschio A, Meitinger T, Mulas A, Paré G, Parker AN, Peden JF, Petersmann A, Pichler I, Pietiläinen KH, Pouta A, Ridderstråle M, Rotter JI, Sambrook JG, Sanders AR, Schmidt CO, Sinisalo J, Smit JH, Stringham HM, Bragi Walters G, Widen E, Wild SH, Willemsen G, Zagato L, Zgaga L, Zitting P, Alavere H, Farrall M, McArdle WL, Nelis M, Peters MJ, Ripatti S, van Meurs JB, Aben KK, Ardlie KG, Beckmann JS, Beilby JP, Bergman RN, Bergmann S, Collins FS, Cusi D, den Heijer M, Eiriksdottir G, Gejman PV, Hall AS, Hamsten A, Huikuri HV, Iribarren C, Kähönen M, Kaprio J, Kathiresan S, Kiemeney L, Kocher T, Launer LJ, Lehtimäki T, Melander O, Mosley TH Jr, Musk AW, Nieminen MS, O’Donnell CJ, Ohlsson C, Oostra B, Palmer LJ, Raitakari O, Ridker PM, Rioux JD, Rissanen A, Rivolta C, Schunkert H, Shuldiner AR, Siscovick DS, Stumvoll M, Tönjes A, Tuomilehto J, van Ommen GJ, Viikari J, Heath AC, Martin NG, Montgomery GW, Province MA, Kayser M, Arnold AM, Atwood LD, Boerwinkle E, Chanock SJ, Deloukas P, Gieger C, Grönberg H, Hall P, Hattersley AT, Hengstenberg C, Hoffman W, Lathrop GM, Salomaa V, Schreiber S, Uda M, Waterworth D, Wright AF, Assimes TL, Barroso I, Hofman A, Mohlke KL, Boomsma DI, Caulfield MJ, Cupples LA, Erdmann J, Fox CS, Gudnason V, Gyllensten U, Harris TB, Hayes RB, Jarvelin MR, Mooser V, Munroe PB, Ouwehand WH, Penninx BW, Pramstaller PP, Quertermous T, Rudan I, Samani NJ, Spector TD, Völzke H, Watkins H, Wilson JF, Groop LC, Haritunians T, Hu FB, Kaplan RC, Metspalu A, North KE, Schlessinger D, Wareham NJ, Hunter DJ, O’Connell JR, Strachan DP, Wichmann HE, Borecki IB, van Duijn CM, Schadt EE, Thorsteinsdottir U, Peltonen L, Uitterlinden AG, Visscher PM, Chatterjee N, Loos RJ, Boehnke M, McCarthy MI, Ingelsson E, Lindgren CM, Abecasis GR, Stefansson K, Frayling TM, Hirschhorn JN (2010) Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467:832–838CrossRefGoogle Scholar
  58. Lawn JE, Blencowe H, Pattinson R, Cousens S, Kumar R, Ibiebele I, Gardosi J, Day L, Stanton C (2011) Stillbirths: where? When? Why? How to make the data count? Lancet 377:1448–1463PubMedCrossRefGoogle Scholar
  59. Lee BH, Kim GH, Oh TJ, Kim JH, Lee JJ, Choi SH, Lee JY, Kim JM, Choi IH, Kim YM, Choi JH, Yoo HW (2013) Quantitative analysis of methylation status at 11p15 and 07q21 for the genetic diagnosis of Beckwith-Wiedemann syndrome and Silver–Russell syndrome. J Hum Genet 58:604–610PubMedCrossRefGoogle Scholar
  60. Leevers SJ, McNeill H (2005) Controlling the size of organs and organisms. Curr Opin Cell Biol 17:604–609PubMedCrossRefGoogle Scholar
  61. Lin SY, Lee CN, Hung CC, Tsai WY, Lin SP, Li NC, Hsieh WS, Tung YC, Niu DM, Hsu WM, Chen LY, Fang MY, Tu MP, Kuo PW, Lin CY, Su YN, Ho HN (2010) Epigenetic profiling of the H19 differentially methylated region and comprehensive whole genome array-based analysis in Silver–Russell syndrome. Am J Med Genet A 152A:2521–2528PubMedCrossRefGoogle Scholar
  62. Lui JC, Baron J (2011) Mechanisms limiting body growth in mammals. Endocr Rev 32:422–440PubMedPubMedCentralCrossRefGoogle Scholar
  63. Lui JC, Forcinito P, Chang M, Chen W, Barnes KM, Baron J (2010) Coordinated postnatal down-regulation of multiple growth-promoting genes: evidence for a genetic program limiting organ growth. FASEB J 24:3083–3092PubMedPubMedCentralCrossRefGoogle Scholar
  64. Majewski F, Goecke T (1982) Studies of microcephalic primordial dwarfism I: approach to a delineation of the Seckel syndrome. Am J Med Genet 12:7–21PubMedCrossRefGoogle Scholar
  65. Majewski F, Goecke TO (1998) Microcephalic osteodysplastic primordial dwarfism type II: report of three cases and review. Am J Med Genet 80:25–31PubMedCrossRefGoogle Scholar
  66. Majewski F, Ranke M, Schinzel A (1982a) Studies of microcephalic primordial dwarfism II: the osteodysplastic type II of primordial dwarfism. Am J Med Genet 12:23–35PubMedCrossRefGoogle Scholar
  67. Majewski F, Stoeckenius M, Kemperdick H (1982b) Studies of microcephalic primordial dwarfism III: an intrauterine dwarf with platyspondyly and anomalies of pelvis and clavicles–osteodysplastic primordial dwarfism type III. Am J Med Genet 12:37–42PubMedCrossRefGoogle Scholar
  68. Mascarenhas JV, Ayyar VS (2012) Russell Silver syndrome: a perspective on growth and the influence of growth hormone therapy. Indian J Endocrinol Metab 16(5):840–842PubMedPubMedCentralCrossRefGoogle Scholar
  69. McIntosh D, Blow JJ (2012) Dormant origins, the licensing checkpoint, and the response to replicative stresses. Cold Spring Harb Perspect Biol 4:a012955PubMedPubMedCentralCrossRefGoogle Scholar
  70. McIntyre RE, Lakshminarasimhan Chavali P, Ismail O (2012) Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome. PLoS Genet 8:e1003022PubMedPubMedCentralCrossRefGoogle Scholar
  71. Meier VZ, Poschiavo J, Rothschild M (1959) Ein fall von arthrogryposis multiplex congenita kombiniert mit dysostosis mandibulofacialis (Franceschetti-syndrom). Helv Paediatr Acta 14:213–216PubMedGoogle Scholar
  72. Meinecke P, Passarge E (1991) Microcephalic osteodysplastic primordial dwarfism type I/III in sibs. J Med Genet 28(11):795–800PubMedPubMedCentralCrossRefGoogle Scholar
  73. Mirzaa GM, Vitre B, Carpenter G, Abramowicz I, Gleeson JG, Paciorkowski AR, Cleveland DW, Dobyns WB, O’Driscoll M (2014) Mutations in CENPE define a novel kinetochore centromeric mechanism for microcephalic primordial dwarfism. Hum Genet 133:1023–1039PubMedPubMedCentralCrossRefGoogle Scholar
  74. Mokrani-Benhelli H, Gaillard L, Biasutto P, Le Guen T, Touzot F, Vasquez N, Komatsu J, Conseiller E, Pïcard C, Gluckman E, Francannet C, Fischer A, Durandy A, Soulier J, de Villartay JP, Cavazzana-Calvo M, Revy P (2013) Primary microcephaly, impaired DNA replication, and genomic instability caused by compound heterozygous ATR mutations. Hum Mutat 34:374–384PubMedCrossRefGoogle Scholar
  75. Müller E, Dunstheimer D, Klammt J, Friebe D, Kiess W, Kratzsch J, Kruis T, Laue S, Pfäffle R, Wallborn T, Heidemann PH (2012) Clinical and functional characterization of a patient carrying a compound heterozygous pericentrin mutation and a heterozygous IGF1 receptor mutation. PLoS One 7(5):e38220PubMedPubMedCentralCrossRefGoogle Scholar
  76. Nagy R, Wang H, Albrecht B, Wieczorek D, Gillessen-Kaesbach G, Haan E, Meinecke P, de la Chapelle A, Westman JA (2012) Microcephalic osteodysplastic primordial dwarfism type I with biallelic mutations in the RNU4ATAC gene. Clin Genet 82:140–146PubMedCrossRefGoogle Scholar
  77. Napolitano R, Maruotti GM, Quarantelli M, Martinelli P, Paladini D (2009) Prenatal diagnosis of Seckel Syndrome on 3-dimensional sonography and magnetic resonance imaging. J Ultrasound Med 28:369–374PubMedGoogle Scholar
  78. Netchine I, Azzi S, Le Bouc Y, Savage MO (2011) IGF1 molecular anomalies demonstrate its critical role in fetal, postnatal growth and brain development. Best Pract Res Clin Endocrinol Metab 25:181–190PubMedCrossRefGoogle Scholar
  79. O’Driscoll M, Ruiz-Perez VL, Woods CG, Jeggo PA, Goodship JA (2003) A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet 33:497–501PubMedCrossRefGoogle Scholar
  80. Ogi T, Walker S, Stiff T, Hobson E, Limsirichaikul S, Carpenter G, Prescott K, Suri M, Byrd PJ, Matsuse M, Mitsutake N, Nakazawa Y, Vasudevan P, Barrow M, Stewart GS, Taylor AM, O’Driscoll M, Jeggo PA (2012) Identification of the first ATRIP deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome. PLoS Genet 8:e1002945PubMedPubMedCentralCrossRefGoogle Scholar
  81. Onder A, Cogulu O, Ekmekci A, Pariltay E, Kirbiyik O, Ozkinay F (2007) Seckel syndrome with Morgagni hernia. Clin Dysmorphol 16:209–210PubMedCrossRefGoogle Scholar
  82. Pan D (2007) Hippo signalling in organ size control. Genes Dev 21:886–897PubMedCrossRefGoogle Scholar
  83. Panigrahi I, Kaur S, Kulkarni K, Das R, Marwaha RK (2009) Seckel syndrome with chromosomal 18 deletion. Indian J Pediatr 76:1270–1271PubMedCrossRefGoogle Scholar
  84. Payne F, Colnaghi R, Rocha N, Seth A, Harris J, Carpenter G, Bottomley WE, Wheeler E, Wong S, Saudek V, Savage D, O’Rahilly S, Carel JC, Barroso I, O’Driscoll M, Semple R (2014) Hypomorphism in human NSMCE2 linked to primordial dwarfism and insulin resistance. J Clin Invest 124:4028–4038PubMedPubMedCentralCrossRefGoogle Scholar
  85. Pennarun G, Hoffschir F, Revaud D, Granotier C, Gauthier LR, Mailliet P, Biard DS, Boussin FD (2010) ATR contributes to telomere maintenance in human cells. Nucl Acids Res 38:2955–2963PubMedPubMedCentralCrossRefGoogle Scholar
  86. Perry LD, Robertson F, Ganesan V (2013) Screening for cerebrovascular disease in microcephalic osteodysplastic primordial dwarfism type II (MOPD II): an evidence-based proposal. Pediatr Neurol 48(4):294–298PubMedCrossRefGoogle Scholar
  87. Pierce MJ, Morse RP (2012) The neurologic findings in Taybi-Linder syndrome (MOPD I/III): case report and review of the literature. Am J Med Genet A 158A(3):606–610PubMedCrossRefGoogle Scholar
  88. Price SM, Stanhope R, Garrett C, Preece MA, Trembath RC (1999) The spectrum of Silver–Russell syndrome: a clinical and molecular genetic study and new diagnostic criteria. J Med Genet 36:837–842PubMedPubMedCentralGoogle Scholar
  89. Qvist P, Huertas P, Jimeno S, Nyegaard M, Hassan MJ, Jackson SP, Børglum AD (2011) CtIP Mutations Cause Seckel and Jawad Syndromes. PLoS Genet 7:e1002310PubMedPubMedCentralCrossRefGoogle Scholar
  90. Ramalingam K, Kaliyamurthy SD, Govindarajan M, Swathi S (2012) Seckel syndrome: a report of a case. J Indian Soc Pedod Prev Dent 30:258–261PubMedCrossRefGoogle Scholar
  91. Ramirez-Duenas ML, Medina C, Ocampo-Campos R, Rivera H (1992) Severe Silver–Russell syndrome and translocation (17;20)(q25;q13). Clin Genet 41:51–53PubMedCrossRefGoogle Scholar
  92. Rao VB, Lily K, Seema K, Ghosh K, Dipika M (2003) Paternal reciprocal translocation t(11;16)(p13;q243) in a Silver-Russel syndrome patient. Ann Genet 46:475–478PubMedCrossRefGoogle Scholar
  93. Rauch A, Thiel CT, Schindler D et al (2008) Mutations in the pericentrin (PCNT) gene cause primordial dwarfism. Science 319:816–819PubMedCrossRefGoogle Scholar
  94. Rayburg M, Davies SM, Mehta PA, Crockett M, Jodele S (2008) Successful reduced-intensity bone marrow transplantation in a patient with bone marrow failure associated with Seckel syndrome. Br J Haematol 142:675–676PubMedCrossRefGoogle Scholar
  95. Reddy S, Starr C (2007) Seckel syndrome and spontaneously dislocated lenses. J Cataract Refract Surg 33:910–912PubMedCrossRefGoogle Scholar
  96. Regen A, Nelson LP, Woo SB (2010) Dental manifestations associated with Seckel syndrome type II: a case report. Pediatr Dent 32:445–450PubMedGoogle Scholar
  97. Riera A, Fernández-Cid A, Speck C (2013) The ORC/Cdc6/MCM2–7 complex, a new power player for regulated helicase loading. Cell Cycle 12:2155–2156PubMedPubMedCentralCrossRefGoogle Scholar
  98. Russell A (1954) A syndrome of intra-uterine dwarfism recognizable at birth with cranio-facial dysostosis, disproportionately short arms, and other anomalies (5 examples). Proc R Soc Med 47:1040–1044PubMedGoogle Scholar
  99. Seider N, Beiran I, Gelfand Y, Shauly Y, Meyer E, Miller B (2002) Dislocation of lenses in Seckel syndrome. J Pediatr Ophthalmol Strabismus 39:237–238PubMedGoogle Scholar
  100. Shaheen R, Faqeih E, Shamseldin HE, Noche RR, Sunker A, Alshammari MJ, Al-Sheddi T, Adly N, Al-Dosari MS, Megason SG, Al-Husain M, Al-Mohanna F, Alkuraya FS (2012) POC1A truncation mutation causes a ciliopathy in humans characterized by primordial dwarfism. Am J Hum Genet 91:330–336PubMedPubMedCentralCrossRefGoogle Scholar
  101. Shaheen R, Al Tala S, Almoisheer A, Alkuraya FS (2014a) Mutation in PLK4, encoding a master regulator of centriole formation, defines a novel locus for primordial dwarfism. J Med Genet 51:814–816PubMedCrossRefGoogle Scholar
  102. Shaheen R, Faqeih E, Ansari S, Abdel-Salam G, Al-Hassnan ZN, Al-Shidi T, Alomar R, Sogaty S, Alkuraya FS (2014b) Genomic analysis of primordial dwarfism reveals novel disease genes. Genome Res 24:291–299PubMedPubMedCentralCrossRefGoogle Scholar
  103. Sigaudy S, Toutain A, Moncla A, Fredouille C, Bourlière B, Ayme S, Philip N (1998) Microcephalic osteodysplastic primordial dwarfism Taybi-Linder type: report of four cases and review of the literature. Am J Med Genet 80:16–24PubMedCrossRefGoogle Scholar
  104. Sisodia R, Raj RS, Goel V (2014) Seckel syndrome: a rare case report. J Indian Soc Pedod Prev Dent 32:160–163PubMedCrossRefGoogle Scholar
  105. Spengler S, Gogiel M, Schönherr N, Binder G, Eggermann T (2009) Screening for genomic variants in ZFP57 in Silver–Russell syndrome patients with 11p15 epimutations. Eur J Med Genet 52:415–416PubMedCrossRefGoogle Scholar
  106. Spengler S, Schönherr N, Binder G, Wollmann HA, Fricke-Otto S, Mühlenberg R, Denecke B, Baudis M, Eggermann T (2010) Submicroscopic chromosomal imbalances in idiopathic Silver–Russell syndrome (SRS): the SRS phenotype overlaps with the 12q14 microdeletion syndrome. J Med Genet 47:356–360PubMedCrossRefGoogle Scholar
  107. Stanhope R, Preece MA, Hamill G (1991) Does growth hormone treatment improve final height attainment of children with intrauterine growth retardation? Arch Dis Child 66(10):1180–1183PubMedPubMedCentralCrossRefGoogle Scholar
  108. Stark Z, Ryan MM, Bruno DL, Burgess T, Savarirayan R (2010) Atypical Silver–Russell phenotype resulting from maternal uniparental disomy of chromosome 7. Am J Med Genet A 152A:2342–2345PubMedCrossRefGoogle Scholar
  109. Stiff T, Alagoz M, Alcantara D, Outwin E, Brunner HG, Bongers EM, O’Driscoll M, Jeggo PA (2013) Deficiency in origin licensing proteins impairs cilia formation: implications for the aetiology of Meier–Gorlin syndrome. PLoS Genet 9:e1003360PubMedPubMedCentralCrossRefGoogle Scholar
  110. Sugio Y, Tsukahara M, Kajii T (1993) Two Japanese cases with microcephalic primordial dwarfism: classical Seckel syndrome and osteodysplastic primordial dwarfism type II. Jpn J Hum Genet 38:209–217PubMedCrossRefGoogle Scholar
  111. Takikawa KM, Kikuchi A, Yokoyama A, Ono K, Iwasawa Y, Sunagawa S, Takagi K, Kawame H, Nakamura T (2008) Perinatal findings of Seckel syndrome: a case report of a fetus showing primordial dwarfism and severe microcephaly. Fetal Diagn Ther 24:405–408PubMedCrossRefGoogle Scholar
  112. Tivey HS, Rokicki MJ, Barnacle JR, Rogers MJ, Bagley MC, Kipling D, Davis T (2013) Small molecule inhibition of p38 MAP kinase extends the replicative life span of human ATR-Seckel syndrome fibroblasts. J Gerontol A Biol Sci Med Sci 68:1001–1009PubMedPubMedCentralCrossRefGoogle Scholar
  113. Unal S, Alanay Y, Cetin M, Boduroglu K, Utine E, Cormier-Daire V, Huber C, Ozsurekci Y, Kilic E, Simsek Kiper OP, Gumruk F (2014) Striking hematological abnormalities in patients with microcephalic osteodysplastic primordial dwarfism type II (MOPD II): a potential role of pericentrin in hematopoiesis. Pediatr Blood Cancer 61:302–305PubMedCrossRefGoogle Scholar
  114. Unterscheider J, Daly S, Geary MP, McAuliffe FM, Kennelly MM, Morrison JJ, O’Donoghue K, Hunter A, Burke G, Dicker P, Tully E, Malone FD (2013) Optimizing the definition of intrauterine growth restriction–results of the multicenter prospective PORTO study. Am J Obstet Gynecol 208:290e1–290e6CrossRefGoogle Scholar
  115. Veltman JA, Brunner HG (2012) De novo mutations in human genetic disease. Nat Rev Genet 13:565–575PubMedCrossRefGoogle Scholar
  116. Wang GS, Cooper TA (2007) Splicing in disease: disruption of the splicing code and the decoding machinery. Nat Rev Genet 8:749–761PubMedCrossRefGoogle Scholar
  117. Widdowson EM (1970) Harmony of growth. Lancet 1:902–905PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Preeti Khetarpal
    • 1
  • Satrupa Das
    • 2
  • Inusha Panigrahi
    • 3
  • Anjana Munshi
    • 1
    Email author
  1. 1.Centre for Human Genetics, School of Health SciencesCentral University of PunjabBathindaIndia
  2. 2.Institute of Genetics and Hospital for Genetic DiseasesOsmania UniversityBegumpetIndia
  3. 3.Genetic-Metabolic Unit, Department of Pediatrics, Advanced Pediatric CentrePost Graduate Institute of Medical Education and ResearchChandigarhIndia

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