American Journal of Medical Genetics 80:396–398 (1998) Brief Clinical Report Association of Terminal Chromosome 1 Deletion With Sertoli Cell-Only Syndrome Eba H. Hathout,1* Kevin Thompson,1 Marti Baum,1 and Kenneth W. Dumars2 1 Division of Pediatrics, Loma Linda University School of Medicine, Loma Linda, California Genzyme Genetics, Orange, California 2 We report on del(1)(q44), developmental delay, cryptorchidism, and seizure disorder in a 19-year-old man. Endocrinologic evaluation showed delayed puberty and elevated gonadotropins. Testicular biopsy was consistent with Sertoli cell-only syndrome. The case illustrates a previously an unreported manifestation in males with del(1)(q44), and suggests a link between the development of germinal epithelium and genes in the 1q44 area. Am. J. Med. Genet. 80:396–398, 1998. © 1998 Wiley-Liss, Inc. KEY WORDS: del(1)(q44); Sertoli-cell only syndrome; delayed puberty INTRODUCTION Terminal deletion of the long arm of chromosome 1 is associated with a characteristic combination of neurologic, developmental, and genital abnormalities [Arai et al., 1984; Johnson et al., 1985; Meinecke and Vogtel, 1987; Murayama et al., 1991; Watson et al., 1986]. Little has been reported regarding underlying hormonal or histologic gonadal pathology. We report on a male with del(1)(q44) in whom hypergonadotropism and testicular biopsy were consistent with the Sertoli cell-only syndrome [Del Castillo et al., 1947; Heath, 1973]. To our knowledge, this is the first report of such an association. CLINICAL REPORT The propositus was the first child of a healthy 28year-old mother and a nonconsanguineous 28-year-old Dr. Dumars is Professor Emeritus of Pediatrics at the University of California, Irvine, as well as consultant geneticist at Genzyme Genetics, Inc. *Correspondence to: Eba H. Hathout, M.D., Division of Pediatric Endocrinology, Loma Linda University School of Medicine, 11370 Anderson Street, Suite B-100, Loma Linda, CA 92354. Received 27 April 1998; Accepted 6 August 1998 © 1998 Wiley-Liss, Inc. father. He had one cousin with Down syndrome. Family history was otherwise unremarkable. The patient was delivered vaginally at term following an uncomplicated pregnancy. Birth length, weight, and head circumference (OFC) were <5th centile. He had retrognathia, large low-set ears, a short neck, calcaneovalgus, micropenis, and hypospadias. Lips and palate were intact. Seizures were noted in early infancy. Multifocal abnormalities were identified on electroencephalogram, and computed tomography scan of the brain showed absent corpus callosum. Severe mental retardation necessitated institutionalization. At 19 years the patient was referred for endocrine evaluation to rule out hypothyroidism as a cause of constipation (Fig. 1). Examination showed a small-forage male with a short nose; epicanthal folds; round face; retrognathia; thin upper lip; large low-set ears with left anterior ear tags; short neck; and severe flexion contractures of the wrists, elbows, hips, and knees. Genital exam showed Tanner stage IV pubic hair, a small right testicle (Tanner stage II), and a well-healed scar (following removal of the undescended left testicle). The penis was uncircumcised and of normal length and appearance (hypospadias was surgically corrected in infancy). A hand radiograph showed delayed bone age (艋2 SD), and marked osteopenia. Screening for growth, thyroid, and cortisol hormones was normal. Plasma level of follicle stimulating hormone (FSH) was elevated at 24.9 mU/mL (reference 0.9–15), luteinizing hormone (LH) was elevated at 11.3 mU/mL (reference 4.6–9.4), and testosterone was 29,097 pmol/L (838 ng/ dL; reference 194-833 ng/dL). LH and FSH responses to intravenous gonadotropin releasing hormone (GnRH) were exaggerated (peaks of 46 and 50 mU/mL, respectively). Peripheral leukocytes were cultured and harvested and the chromosomes were GTG banded using routine methods. A 46,XY,del(1)(q44) was found (Fig. 2). Fluorescence in situ hybridization studies with a 1q441qter probe (D1S555, Oncor) and a chromosome 1 centromeric probe (D1Z5, Oncor) as a control showed that one chromosome 1 long arm is deleted at the 1q44-qter Del (1q) and Sertoli Cell-Only Syndrome 397 Fig. 2. Top: Idiogram of chromosome 1 illustrating the anomaly (arrow indicating the normal monosomic region). Bottom: Six G-banded partial karyotypes of the patient are shown, with the normal chromosome 1 on the left of each pair, and the homolog with del 1q on the right of each pair. DISCUSSION [Juberg et al., 1981]. It is noteworthy that the above manifestations do not differ significantly in relation to the level of the deletion (i.e., 42-qter vs. 44-qter). Despite recognition of genital anomalies in this syndrome, little attention has been paid to underlying histologic or endocrine pathology. The Sertoli cell-only syndrome, also known as germinal aplasia, is a rare disorder present in about 30% of azoospermic males. It was first described by Del Castillo et al. in 1947. Characteristics include normal virilization, small testes, and a testicular biopsy showing small seminiferous tubules without germinal epithelium, lined only by Sertoli cells. Chromosome analysis was mostly normal in reported cases apart from a few Klinefelter mosaic or Down syndrome cases [Averback, 1980; DeKrester et al., 1972; Guay et al., 1977]. FSH levels are elevated in both urine and blood, testosterone levels are low or normal, and FSH and/or LH responses to GnRH are frequently exaggerated [Guay et al., 1977]. It is clear from the above discussion that our patient has most of the manifestations of terminal 1q, and the hitherto undescribed association with Sertoli cell-only syndrome. Advances in molecular genetics may elucidate the above association in previously studied pa- Terminal deletion of the long arm of chromosome 1 is associated with a characteristic combination of craniofacial, neurologic, and genital anomalies [Arai et al., 1994; Johnson et al., 1985; Loan et al., 1992; Manouvrier-Hanu et al., 1986; Meinecke and Vogtel, 1987; Murayama et al., 1991; Watson et al., 1986]. While most terminal del(1q) cases were de novo, some were due to an inherited inversion or translocation [Golabi et al., 1982; Juberg et al., 1981; Speevak et al., 1985]. Findings in terminal del(1q) syndrome include growth and mental retardation; corpus callosum hypoplasia; speech delay; microcephaly; up-slanting palpebral fissures; epicanthal folds; short broad nose; low-set abnormal ears; down-curved mouth; micrognathia; short neck; heart defects; abnormal feet; general hypotonia; and seizures. Genital anomalies are described more frequently in males and range from genital hypoplasia, hypospadias, or shawl scrotum to intersex genitalia Fig. 3. Testicular biopsy: seminiferous tubules showing only Sertoli cells without the presence of germinal epithelium. The Leydig cell population in the interstitia appears unremarkable (×100). Fig. 1. Propositus at age 19 years. . region in all metaphase figures examined. Parental chromosomes were normal. Retrospective histologic review of testicular tissue (Fig. 3) showed slightly narrowed tubules lined by a layer of elongated Sertoli cells without presence of germinal epithelium, consistent with the Sertoli cell-only syndrome. 398 Hathout et al. tients with germinal aplasia, whose karyotypes were ‘‘normal.’’ This is particularly of value for genetic counseling purposes. The association also adds to the list of chromosome abnormalities in males with delayed puberty and/or infertility. The relevance in females remains to be studied. The above finding suggests a link between the development of germinal epithelium and genes in the 1q44 area. However, more patients need to be studied to asses the validity of the above association. REFERENCES Arai E, Nishimura S, Tamura K, Kida M, Ikeuchi T (1994): Chromosome 1q terminal deletion resulting from de novo translocation with an acrocentric chromosome. Jpn J Human Genet 39:433–437. 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