Kenny-Caffey Syndrome and Microorchidism

William H. Hoffman,1* Kalman Kovacs,2 Shibo Li,3 Anita S. Kulharya,1 Bruce L. Johnson,4Margaret S. Eidson,5 and William W. Cleveland5

1Department of Pediatrics, Medical College of Georgia, Augusta, Georgia2Department of Pathology, St. Michael’s Hospital, Toronto, Ontario, Canada3Department of Medical Genetics, University of South Alabama School of Medicine, Mobile, Alabama4Department of Pathology, University of Pittsburgh, Medical Center, Pittsburgh, Pennsylvania5Department of Pediatrics, University of Miami School of Medicine, Miami, Florida

We report on two adolescent boys withKenny-Caffey syndrome and microorchi-dism. The first patient had elevated levels ofserum follicle-stimulating hormone, butnormal levels of luteinizing hormone andtestosterone. There was no evidence of a mi-crodeletion of the Y chromosome. The sec-ond patient had Leydig cell hyperplasiawith normal seminiferous tubules and sper-matogenesis, and normal pituitary histo-logic findings at autopsy. The presence ofmicroorchidism in these patients confirmsthe previous observations and suggests sub-fertility, but does not fully clarify the patho-genesis. Am. J. Med. Genet. 80:107–111, 1998.© 1998 Wiley-Liss, Inc.

KEY WORDS: hypoparathyroidism; Kenny-Caffey syndrome; Leydig cellhyperplasia; microorchi-dism; short stature

INTRODUCTION

Kenny-Caffey syndrome (KCS) is an uncommon con-dition with variable expression of short stature, corti-cal thickening and medullary stenosis of the longbones, delayed closure of the anterior fontanelle, hypo-parathyroidism, and various ocular findings.

Of five known pubertal or adult-age male patientswith KCS all had findings suggestive of microorchi-dism or infertility [Wilson et al., 1974; Boynton et al.,1979; Majewski et al., 1981; Larsen et al., 1985]. Wereport on a 17-year-old boy with KCS who had microor-chidism and elevated serum follicle-stimulating hor-mone (FSH) levels. We also present the testicular andpituitary histologic findings on another patient with

KCS and microorchidism, who died at the age of 19years.

MATERIALS AND METHODSCase 1

A 17-year-old black man with KCS presented at 151/2 years for underdevelopment of genitalia. He wasborn to nonconsanguineous parents, with no familyhistory of short stature, hypocalcemia, or infertility. Hewas delivered after an uncomplicated term pregnancyto a 19-year-old gravida 1 mother. His birth weight was2,300 g (<10th centile); length, 48 cm (25th centile);and head circumference (OFC), 32 cm (12th centile). At12 days he experienced a generalized seizure and wasfound to have hypocalcemia. He was later diagnosed tohave hypoparathyroidism on the basis of a normal re-sponse to a parathyroid hormone (PTH) challenge. Eu-calcemia was achieved with vitamin D and oral cal-cium, with no recurrence of seizures. Psychomotor de-velopment was minimally delayed. Linear growthshowed plateauing by age 7 months. At 3 years, he wasfound to have hyperopia and pseudopapilledema, andshortly thereafter, KCS was diagnosed. There was nohistory of testicular injury.

Physical examination showed proportionate shortstature; height was 133 cm (<5th centile); weight, 30.8kg (<5th centile); OFC, 52 cm (3rd centile); and bloodpressure, 101/59 mmHg (Fig. 1). Additional pertinentphysical findings included a high hair line, frontalbossing, a patent anterior fontanelle, measuring 4 × 7cm; hypertelorism, and hyperopia. The penis was 10 cmlong, with a normally placed urethral orifice; the testesmeasured 1.8 × 1 cm, with normal consistency andStage 4 pubarche.

Serum testosterone level was 307 ng/dl (normalrange 220–800); free testosterone, 52.6 pg/ml (normalrange 14–156); dihydrotestosterone, 29 ng/dl (normalrange 25–75); sex hormone–binding globulin, 28 mmol/liter (normal range 6–44); luteinizing hormone (LH)and FSH values, on three occasions over a period of 18months, were 3.7, 3.1, 2.6 (normal range 3.0–13), and12.1, 15.8, 17.8 (normal range 1.0–8.8) mIU/ml, respec-tively. Serum Ca was 8.2 mg/dl (normal range 8.2–10.7); ionized Ca+, 4.12 (normal range 4.72–5.30);

*Correspondence to: William H. Hoffman, M.D., Pediatric En-docrinology, BG-203, Medical College of Georgia, Augusta, GA30912.

Received 5 August 1997; Accepted 21 July 1998

American Journal of Medical Genetics 80:107–111 (1998)

© 1998 Wiley-Liss, Inc.

phosphorous, 5.6 (normal range 2.2–3.9); PTH, 8.7 pg/ml (normal range 10–66); white blood cell and differ-ential, normal; Hb, 10.3 gm/dl (normal range 14–18)and Hct, 30% (normal range 40–54%); red blood cellindices, normal; erythropoietin, 6 mu/ml (normal <19);reticulocytes, 1.5% (normal range 0.5–1.5%); ferritin,30 ng/ml (normal range 25–260); haptoglobin, 114 mg/dl (normal range 60–288); iron, 44 mg/dl (normal range

35–150); iron-binding capacity, 291 mg/dl (normalrange 260–445); percent saturation, 15% (normalrange 11–46%); and IGFBP-3, 3.3 mg/liter (normalrange 2.2–4.2). Radiographs of the hand showed short-ness of the fourth and fifth metacarpals and a bone ageof 14 to 15 years. There was cortical thickening andmedullary stenosis of the long bones of the upper andlower limbs; skull X-ray confirmed a patent anteriorfontanelle (Fig. 2), orbital hypoplasia, thin calvaria,and no diploic space.

Peripheral blood lymphocytes were cultured accord-ing to conventional procedures for chromosome analy-sis. Metaphases were analyzed with standard GTGbanding. Fluorescent in situ hybridization was per-formed on fresh slides with probe D22S75 (Oncor) spe-cific to the DiGeorge critical region on chromosome 22.Whole genomic DNA was isolated with standard tech-niques. The DNA concentration was determined byspectrophotometry reading at 260 nm and the samplewas diluted to 50 ng/ml. The microsatellite markers cor-responding to SRY on short arm of Y chromosome, andthree regions, AZFa (SY83 and SY84), AZFb (SY133and SY134), and AZFc (SY254, SY255, SY277, SY283,SY236, and SY202) on the long arm of the Y chromo-some were investigated. Polymerase chain reaction(PCR) was carried out in 25-ml volume containing 50 ng

Fig. 1. Case 1 at 15 1/2 years of age.

Fig. 2. Caldwell radiograph (Case 1) showing large anterior fontanelle(arrow).

108 Hoffman et al.

of genomic DNA, with 0.76 mM of primers; 2.5 ml 10 ×reaction buffer (100 mM Tris-HCl pH 8.8, 50 mM KCl,0.01% w/v gelatin); 5 mM dNTP; and 37.5 mM MgCl2,with 0.5625 Unit Taq polymerase (Promega). The PCRconditions were 1 cycle at 95°C for 5 min, followed by30 cycles (94°C for 1 min, 58°C for 1.5 min, and 72°C for1 min), with the final extension at 72°C for 7 min. Ali-quots of amplified PCR product were mixed with 5 ml of5 × loading buffer, electrophoresed on 2% NuSieve geland visualized by ethidium bromide staining.

Case 2

This patient was diagnosed as having KCS at 5years, following an episode of hypocalcemic tetany. Atthe age of 19, he died of cardiorespiratory arrest. Acomplete autopsy was performed. The ophthalmologicfindings of this patient were reported by Boynton et al.[1979] (their Case 4). Formalin-fixed, paraffin-embedded, hematoxylin-eosin (H & E)–stained slides ofthe testes and the pituitary obtained at the autopsywere reviewed. No tissue blocks were available for ad-ditional studies.

RESULTSCase 1

Chromosomes were apparently normal with nostructural or numerical abnormalities. The Y chromo-some appeared to be cytogenetically normal. The pa-tient did not have a 22q11 deletion. DNA analysis ofthe short and long arms of the Y chromosome identifiedno microdeletions.

Case 2

The autopsy report identified the scrotum as hypo-plastic; each testis weighed 5.5 g. The epididymis andprostate were not atrophic. Light microscopy of H &E–stained sections showed massive Leydig cell hyper-plasia with large islets seen between the seminiferoustubules. The Leydig cells were large and possessed aslightly acidophilic, vacuolated abundant cytoplasm.The seminiferous tubules were surrounded by tunicapropria and were normal in size and shape. Reinkecrystalloids were not identified. Spermatogenesis wasactive and spermatogonia, spermatocytes (many in mi-tosis), spermatids, and spermatozoa were present. Ser-toli cells were also evident. The diameter of the semi-niferous tubules measured between 140 to 225 mm,which is within the normal range (Figs. 3 and 4). Pitu-itary histologic findings were normal, with no evidenceof castration cells.

DISCUSSION

These patients had KCS with short stature, ocularfindings, hypoparathyroidism, medullary stenosis, anddelayed closure of the anterior fontanelle [Kenny andLinarelli, 1966]. Both patients’ testes were prepubertalin size. The mean age for testicular enlargement is 11.5years, with the increase in testicular size occurring bythe age of 14 years in 98% of males [Harlan et al.,1979]. The increase in testicular size is primarily theresult of seminiferous tubular growth and precedes the

onset of pubarche, which had occurred in Case 1 [Zach-mann et al., 1974]. Based on the chronological age andbiological age of Case 1, there was a significant discrep-ancy between testicular size and an appropriate level ofserum testosterone [Knorr et al., 1974]. The elevatedFSH in Case 1 resulted in a low LH/FSH ratio, both forthe patient’s testicular size and bone age [Burr et al.,1970]. This would be in keeping with a defect in theseminiferous tubules, since FSH receptors have beenidentified on Sertoli cells and spermatogonia [Orth andChristensen, 1978], and elevated FSH levels have beenshown to correlate with spermatogenic dysfunction[Bergmann et al., 1994].

Case 2 appears to be the first report of the testicularhistology in a patient with KCS. The relationship be-tween Leydig cell function and spermatogenic activityis well recognized in animals [Wu and Murono, 1994]and humans, with Leydig cell hyperplasia being re-ported with defective spermatogenesis [Guay et al.,1977]. While this patient apparently had normal sper-matogenesis, the histologic aspects of the Leydig cellsare characteristic of the hyperplasia reported in sper-matogenic failure [Naughton et al., 1998]. It is also

Fig. 4. Histology of the testes showing Leydig cell hyperplasia (arrow).H & E stain; original magnification 250×.

Fig. 3. Histology of the testes (Case 2) showing the seminiferous tu-bules and accumulation of Leydig cells (arrow). H & E stain; original mag-nification 100×.

Kenny-Caffey Syndrome 109

important to note that Larsen et al. [1985] commentedthat it was unusual that one of their patients at the ageof 40 years had not fathered children.

Neither patient had the most frequently cited causesof microorchidism seen in the pubertal-aged patient:namely, Klinefelter syndrome or hypopituitarism withgonadotropin deficiency. The syndrome of rudimentarytestes would seem to differ from the microorchidism inKCS, because those patients have a small penis [Ber-gada et al., 1962] and may have a decreased testoster-one response to human chorionic gonadotropin stimu-lation [Najjar et al., 1974].

Of adults with primary testicular failure a small per-centage have germinal cell dysplasia and azoospermiaor oligospermia [Greenberg et al., 1978], and are morelikely to have a microdeletion of the Y chromosome.Vogt et al. [1996] analyzed the DNA of 370 men withvarying degrees of azoospermia and oligospermia. Onthe basis of the microdeletions found on the Y chromo-some in 12 patients, they proposed the presence ofthree spermatogenesis loci in Yq11, each gene beingactive at different times of male germ cell development.Pryor et al. [1997], in their study of 200 infertile menwith less severe abnormalities of sperm concentration,found 14 men with Y-chromosome microdeletions, butdid not find a correlation between the size or position ofthe microdeletion of the Y chromosome and the degreeof spermatogenic failure. None of the markers testedfrom this region of the Y chromosome in Case 1 weredeleted.

To our knowledge there are no reports of a cytoge-netic or molecular abnormality in patients with KCS.However, recently Sabry et al. [1998] have reportedfour sibs with KCS. Two of these sibs inherited a dele-tion from their mother in the DiGeorge region of chro-mosome 22. Because of the occurrence of hypoparathy-roidism in these two syndromes, Case 1 was analyzedfor the 22 microdeletion, but it was not demonstratedin our patient.

Inheritance of this syndrome was initially describedas autosomal dominant, yet other reports have sug-gested autosomal recessive [Franceschini et al., 1992;Khan et al., 1997; Sabry et al., 1998] or sporadic occur-rence [Wilson et al., 1974]. Several reports have docu-mented the KCS phenotype as being transmitted froma mother to an offspring [Kenny and Linarelli, 1966;Majewski et al., 1981]; however, there have been noreports of a father transmitting the phenotype to anoffspring. Whether microorchidism plays a role in theinheritance of this syndrome remains to be determined.

Even though we do not have endocrine, moleculargenetic, and testicular histology on both of our pa-tients, we think that our observation of microorchidismin these patients, as well as previously cited examplesin pubertal and young adult males with KCS, estab-lishes this relationship with a degree of certainty. Thepathogenesis of the microorchidism is unclear. We as-sume that it is related to a seminiferous tubular defectbased on the facts that 1) normally over 80% of thetesticular volume is due to seminiferous tubular devel-opment, 2) Case 1 had a disproportionately elevatedserum FSH, 3) there was Leydig cell hyperplasia, and4) there are no reports of fathers transmitting the phe-

notype to offspring. Nevertheless we found no histo-logic evidence of a seminiferous tubular abnormality inCase 2, nor did we identify a microdeletion of the Ychromosome in Case 1. A possible explanation for thesubfertility in KCS is the observation by Francois et al.[1997] that low–birth weight infants have a greaterlikelihood of subfertility. However, their study did notrefer to testicular size.

Further studies will be necessary to establish thepathogenesis of the microorchidism seen in this syn-drome and to clarify the significance of the elevatedFSH and Leydig cell hyperplasia.

ACKNOWLEDGMENTS

The authors acknowledge the technical assistance ofMs. Ewellonda Rowley and Ms.Karen Norris. We thankDr. K. Ehsanipoor for referring the patient, and Drs. C.Ong and S. Brooks for their assistance in the care of thepatient, and Ms. C. Masters and Ms. J.S. Hoffman forhelp in the preparation of the manuscript.

REFERENCES

Bergada C, Cleveland WW, Jones HW, Wilkins L (1962): Variants of em-bryonic testicular dysgenesis: Bilateral anorchia and the syndrome ofrudimentary testes. Acta Endocrinol (Copenh) 40:521–536.

Bergmann M, Behre HM, Nieschlag E (1994): Serum FSH and testicularmorphology in male infertility. Clin Endocrinol (Oxf) 40:133–136.

Boynton JR, Pheasant TR, Johnson BL, Levin DB, Streeten BW (1979):Ocular findings in Kenny’s syndrome. Arch Ophthalmol 97:896–900.

Burr IM, Sizonenko PC, Kaplan SL, Grumbach MM (1970): Hormonalchanges in puberty I. Correlation of serum luteinizing hormone andfollicle stimulating hormone with stages of puberty, testicular size andbone age in normal boys. Pediatr Res 4:25–35.

Franceschini P, Testa A, Bogetti G, Girardo E, Guala A, Lopez-Bell G,Buzio G, Ferrario E, Piccato E (1992): Kenny-Caffey syndrome in twosibs born to consanguineous parents: Evidence for an autosomal reces-sive variant. Am J Med Genet 42:112–116.

Francois I, De Zegher F, Spiessens C, D’Hooghe T, Vanderschueren D(1997): Low birth weight and subsequent male subfertility. Pediatr Res42:899–901.

Greenberg SH, Lipshultz LI, Wein AJ (1978): Experiences with 425 sub-fertile male patients. J Urol 119:507–150.

Guay AT, Tuthill RJ, Woolf PD (1977): Germinal cell aplasia: Response ofluteinizing hormone (LH), follicle-stimulating hormone (FSH) and tes-tosterone to LH/FSH-releasing hormone with histopathologic correla-tion. Fertil Steril 28:642–649.

Harlan WR, Grillo GP, Coroni-Huntley J, Leaverton PE (1979): Secondarysex characteristics of boys 12 to 17 years of age: The U.S. health ex-amination survey. J Pediatr 95:293–297.

Kenny FM, Linarelli L (1966): Dwarfism and cortical thickening of tubularbones. Am J Dis Child 111:201–207.

Khan KTS, Uma R, Usha R, Al Ghanem MM, Al Awadi SA, Farag TI(1997): Kenny-Caffey syndrome in six Bedouin sibships. Am J MedGenet 69:126–132.

Knorr D, Bidlingmaier F, Butenandt O, Fendel H, Ehrt-Wehle R (1974):Plasma testosterone in male puberty. Acta Endocrinol (Copenh) 75:181–194.

Larsen JL, Kivlin J, O’Dell WD (1985): Unusual cause of short stature. AmJ Med 78:1025–1032.

Majewski F, Rosendahl W, Ranke M, Nolte K (1981): The Kenny syndrome,a rare type of growth deficiency with tubular stenosis, transient hypo-parathyroidism and anomalies of refraction. Eur J Pediatr 136:21–30.

Najjar SS, Takla RJ, Nassar VH (1974): The syndrome of rudimentarytestes: Occurrence in five siblings. J Pediatr 84:119–122.

Naughton CK, Nadler RB, Basler JW, Humphrey PA (1998): Review: Ley-dig cell hyperplasia. Br J Urol 81:282–289.

110 Hoffman et al.

Orth J, Christensen AK (1978): Autoradiographic localization of specifi-cally bound 25I-labeled follicle-stimulating hormone on spermatogoniaof the rat testis. Endocrinology 103:1944–1951.

Pryor JL, Kent-First M, Muallem A, Van Bergen AH, Nolten WE, MeisnerL, Roberts KP (1997): Microdeletions in the Y chromosome of infertilemen. N Engl J Med 336:534–539.

Sabry MA, Zaki M, Hassan SJA, Ramadan DG, Abdel Rasool MA, Al AwadiSA, Al Saleh Q (1998): Kenny-Caffey syndrome is part of the Catch 22haploinsufficiency cluster. J Med Genet 35:31–36.

Vogt PH, Edelmann A, Kirsch S, Henegariu O, Hirschmann P, KiesewetterF, Kohn FM, Schill WB, Farah S, Ramos C, Harmann M, Hartschuh W,Meschede D, Behre HM, Castel A, Nieschlag E, Widener W, Grone HJ,

Jung A, Engel W, Haidi G (1996): Human Y chromosome azoospermiafactors (AZF) mapped to different subregions in Yq11. Hum Mol Genet5:933–943.

Wilson MG, Maronde RF, Mikity VG, Shinno NW (1974): Dwarfism andcongenital medullary stenosis (Kenny syndrome). Birth Defects 10(12):128–132.

Wu N, Murono EP (1994): A Sertoli cell secreted paracrine factor(s) stimu-lates proliferation and inhibits steroidogenesis of rat Leydig cells. MolCell Endocrinol 106:99–109.

Zachmann M, Prader A, Kind HP, Haflinger H, Budliger H (1974): Tes-ticular volume during adolescence. Cross sectional and longitudinalstudies. Helv Paediatr Acta 29:61–72.

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