Intrauterine Growth Retardation Associated with Precocious Puberty and Sertoli Cell Hyperplasia

Abstract

The original description of patients with Russell–Silver syndrome included precocious puberty, the mechanism of which was unclear. We describe a child with a Russell–Silver syndrome-like phenotype who presented with precocious puberty that was associated with hyperplasia of the Sertoli cells. The patient was found to have an immature cryptorchid testicle; hyperplastic Sertoli cells were also aneuploid carrying trisomy 8. This chromosomal abnormality was present in Sertoli cells only and could not be detected in peripheral lymphocytes, tunica vaginalis, or other, normal, testicular tissue. Sertoli cells in culture showed excess aromatization providing an explanation for the rapid advancement of the patient's bone age. We conclude that in a patient with a Russell–Silver syndrome-like phenotype, Sertoli cell hyperplasia was associated with somatic trisomy 8, increased aromatization, and gonadotropin-independent precocious puberty.

Key words

genetic syndrome - hyper androgenemia - disorder of puberty - testicular tumor - aromatase

References

• 1 Silver HK, Kiyasu W, George J, Deamer WC. Syndrome of congenital hemihypertrophy, shortness of stature, and elevated urinary gonadotropins.  Pediatrics. 1953;  12 368-376
• 2 Silver HK. Asymmetry, Short Stature, and Variations in Sexual Development. a Syndrome of Congenital Malformations.  Am J Dis Child (1960). 1964;  107 495-515
• 3 Saal HM, Pagon RA, Pepin MG. Reevaluation of Russell-Silver syndrome.  J Pediatr. 1985;  107 733-737
• 4 Russell A. A syndrome of intra-uterine dwarfism recognizable at birth with cranio-facial dysostosis, disproportionately short arms, and other anomalies (5 examples).  Proc Royal Soc Med. 1954;  47 1040-1044
• 5 Price SM, Stanhope R, Garrett C, Preece MA, Trembath RC. The spectrum of Silver-Russell syndrome: a clinical and molecular genetic study and new diagnostic criteria.  J Med Gen. 1999;  36 837-842
• 6 Preece MA, Price SM, Davies V, Clough L, Stanier P, Trembath RC, Moore GE. Maternal uniparental disomy 7 in Silver-Russell syndrome.  J Med Gen. 1997;  34 6-9
• 7 Kotzot D, Schmitt S, Bernasconi F, Robinson WP, Lurie IW, Ilyina H, Mehes K, Hamel BC, Otten BJ, Hergersberg M, Werder E, Schoenle E, Schinzel A. Uniparental disomy 7 in Silver-Russell syndrome and primordial growth retardation.  Hum Mol Genet. 1995;  4 583-587
• 8 Abu-Amero S, Monk D, Frost J, Preece M, Stanier P, Moore GE. The genetic aetiology of Silver-Russell syndrome.  J Med Genet. 2008;  45 193-199
• 9 Eggermann T, Schonherr N, Meyer E, Obermann C, Mavany M, Eggermann K, Ranke MB, Wollmann HA. Epigenetic mutations in 11p15 in Silver-Russell syndrome are restricted to the telomeric imprinting domain.  J Med Genet. 2006;  43 615-616
• 10 Schinzel AA, Robinson WP, Binkert F, Fanconi A. An interstitial deletion of proximal 8q (q11-q13) in a girl with Silver-Russell syndrome-like features.  Clin Dysmorphol. 1994;  3 63-69
• 11 Kurtyka ZE, Krzykwa B, Piatkowska E, Radwan M, Pietrzyk JJ. Trisomy 8 mosaicism syndrome. Two cases demonstrating variability in phenotype.  Clin Pediatr. 1988;  27 557-564
• 12 Graham Jr JM, Hoehn H, Lin MS, Smith DW. Diploid-triploid mixoploidy: clinical and cytogenetic aspects.  Pediatrics. 1981;  68 23-28
• 13 Coen P, Kulin H, Ballantine T, Zaino R, Frauenhoffer E, Boal D, Inkster S, Brodie A, Santen R. An aromatase-producing sex-cord tumor resulting in prepubertal gynecomastia.  New Eng J Med. 1991;  324 317-322
• 14 Winterfield L, Schultz J, Stratakis CA, Cowen EW. Gynecomastia and mucosal lentigines in an 8-year-old boy.  J Am Acad Dermatol. 2005;  53 660-662
• 15 Nesterova M, Bossis I, Wen F, Horvath A, Matyakhina L, Stratakis CA. An immortalized human cell line bearing a PRKAR1A-inactivating mutation: effects of overexpression of the wild-type Allele and other protein kinase A subunits.  J Clin Endocrinol Metab. 2008;  93 565-571
• 16 Matyakhina L, Pack S, Kirschner LS, Pak E, Mannan P, Jaikumar J, Taymans SE, Sandrini F, Carney JA, Stratakis CA. Chromosome 2 (2p16) abnormalities in Carney complex tumours.  J Med Gen. 2003;  40 268-277
• 17 Valera V, Yokoyama N, Walter B, Okamoto H, Suda T, Hatakeyama K. Clinical significance of Ki-67 proliferation index in disease progression and prognosis of patients with resected colorectal carcinoma.  Brit J Surg. 2005;  92 1002-1007
• 18 Stratakis CA, Vottero A, Brodie A, Kirschner LS, DeAtkine D, Lu Q, Yue W, Mitsiades CS, Flor AW, Chrousos GP. The aromatase excess syndrome is associated with feminization of both sexes and autosomal dominant transmission of aberrant P450 aromatase gene transcription.  J Clin Endocrinol Metab. 1998;  83 1348-1357
• 19 Kolon TF, Miller OF. Comparison of single versus multiple dose regimens for the human chorionic gonadotropin stimulatory test.  J Urol. 2001;  166 1451-1454
• 20 Virtanen HE, Bjerknes R, Cortes D, Jorgensen N, Rajpert-De Meyts E, Thorsson AV, Thorup J, Main KM. Cryptorchidism: classification, prevalence and long-term consequences.  Acta Paediatr. 2007;  96 611-616
• 21 Brodie A, Inkster S, Yue W. Aromatase expression in the human male.  Mol Cell Endocrinol. 2001;  178 23-28
• 22 Lefevre H, Bouvattier C, Lahlou N, Adamsbaum C, Bougneres P, Carel JC. Prepubertal gynecomastia in Peutz-Jeghers syndrome: incomplete penetrance in a familial case and management with an aromatase inhibitor.  Eur J Endocrinol. 2006;  154 221-227
• 23 Parrington JM, West LF, Heyderman E. Chromosome analysis of parallel short-term cultures from four testicular germ-cell tumors.  Cancer Genet Cytogenet. 1994;  75 90-102
• 24 Bussey KJ, Lawce HJ, Olson SB, Arthur DC, Kalousek DK, Krailo M, Giller R, Heifetz S, Womer R, Magenis RE. Chromosome abnormalities of eighty-one pediatric germ cell tumors: sex-, age-, site-, and histopathology-related differences – a Children's Cancer Group study.  Genes Chromosomes Cancer. 1999;  25 134-146
• 25 Manegold E, Tietze L, Gunther K, Fleischer A, Amo-Takyi BK, Schroder W, Handt S. Trisomy 8 as sole karyotypic aberration in an ovarian metastasizing Sertoli-Leydig cell tumor.  Hum Pathol. 2001;  32 559-562
• 26 Dias RP BI, Johnston LB, Buchanan C, Hokken-Koelega A, Clark AJL. Genome-Wide Abnormalities in Parental Inheritance Patterns and DNA Methylation in Silver-Russell Syndrome.. In: Program of the 91st Annual meeting of the Endocrine Society Washington, DC; 2009
• 27 Wood E, Dowey S, Saul D, Cain C, Rossiter J, Blakemore K, Stetten G. Prenatal diagnosis of mosaic trisomy 8q studied by ultrasound, cytogenetics, and array-CGH.  Am J Med Genet. 2008;  146A 764-769
• 28 Nakamura Y, Nakashima H, Fukuda S, Hashimoto T, Maruyama M. Bilateral cystic nephroblastomas and multiple malformations with trisomy 8 mosaicism.  Hum Pathol. 1985;  16 754-756
• 29 Lessick M, Israel J, Szego K, Wong P. Leiomyosarcoma in a patient with trisomy 8 mosaicism.  J Med Genet. 1990;  27 643-644
• 30 Maserati E, Aprili F, Vinante F, Locatelli F, Amendola G, Zatterale A, Milone G, Minelli A, Bernardi F, Lo Curto F, Pasquali F. Trisomy 8 in myelodysplasia and acute leukemia is constitutional in 15-20% of cases.  Genes Chromosomes Cancer. 2002;  33 93-97
• 31 Taban M, Marcotty A, Traboulsi EI. Optic disc coloboma and localized chorioretinal defects in constitutional partial trisomy 8 mosaicism.  Ophthal Genet. 2006;  27 103-105
• 32 Grati FR, Grimi B, Frascoli G, Di Meco AM, Liuti R, Milani S, Trotta A, Dulcetti F, Grosso E, Miozzo M, Maggi F, Simoni G. Confirmation of mosaicism and uniparental disomy in amniocytes, after detection of mosaic chromosome abnormalities in chorionic villi.  Eur J Hum Genet. 2006;  14 282-288
• 33 Robinson WP, Barrett IJ, Bernard L, Telenius A, Bernasconi F, Wilson RD, Best RG, Howard-Peebles PN, Langlois S, Kalousek DK. Meiotic origin of trisomy in confined placental mosaicism is correlated with presence of fetal uniparental disomy, high levels of trisomy in trophoblast, and increased risk of fetal intrauterine growth restriction.  Am J Hum Genet. 1997;  60 917-927

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