American Journal of Medical Genetics 2151-55 (1985) Developmental Field Concept5145
Uncomplicated Familial Hypospadias: Evidence for Autosomal Recessive Inheritance
Moshe Frydman, Chairn Greiber, and Herman A. Cohen
Department of Pediatrics, Hasharon Hospital, Petach-Tikva (M.F., C.G., H.A.C.) and the Tel Aviv University Sackler School of Medicine (M. I?), Israel
Uncomplicated hypospadias was found in eight members of a large, consangui- neous Bedouin family. Virilization and fertility were normal in the only postpub- ertal individual. The inheritance is most likely autosomal recessive and we suggest that in some of the familial cases in which polygenic or multifactorial inheritance was previously proposed, homozygosity for recessive genes may be responsible for the increased risk to siblings. Dominantly transmitted hypertelorism with diastema was an independent and coincidental finding in this family.
Key words: autosomal recessive inheritance, hypospadias, genital anomalies, hypertelorism, eye anomalies, diastema, dental anomalies
Hypospadias is a relatively common abnormality of the male genital system, with an estimated incidence of up to 0.82% of male births [Sweet et al, 19741. The hereditary component of uncomplicated hypospadias was estimated by Chen and Woolley  to be 74.1 %, with a recurrence rate among sibs of 6-12% [Lowry and Kliman, 1976; Bauer et al, 1981; Sweet et al, 19741. These observations were interpreted as indicating polygenic or multifactorial causation in most cases [Chen and Woolley, 1971; Sweet et al, 19741, but monogenic inheritance with an autosomal dominant pattern was suggested in some cases [Lowry and Kliman, 1976; Page, 19791. We report familial hypospadias possibly owing to autosomal recessive inheritance.
Received for publication August 6, 1984; revision received December 20, 1984.
Address reprint requests to Dr. Moshe Frydman, Genetics Clinic, Department of Pediatrics, Hasharon Hospital, Petach-Tikva, 49100, Israel.
0 1985 Alan R. Liss, Inc.
52 Frydman, Greiber, and Cohen
A large, consanguineous Bedouin family was studied because of a high preva- lence of hypospadias (Fig. 1). The propositus was born to consanguineous parents after an uneventful pregnancy and delivery. Physical examination at age 6 months showed distal penile hypospadias with cordee. The penile size was normal, the testicles were in the scrotum, and no hernia was present. Apparent hypertelorism (95th centile) was present, but otherwise he was normal. His mother, two sisters, 2nd several other family members had apparent hypertelorism (ranging between the 85th to 95th centiles) and in addition had diastema of the upper central incisors (Fig. 1). Routine laboratory tests and chromosomes were normal. Blood levels of cortisol, testosterone, DHEA, A4, LH, FSH, and prolactin were normal for age, and the response to ACTH stimulation was appropriate in the patient and two affected cousins (VI-24, VI-25). Intravenous pyelography and cystography of the patient and intrave- nous pyelography of his affected cousin (VI-24) were normal.
Family history showed hypospadias in six other related individuals, all of whom could be traced back to a common ancestor. The affected as well as several of the nonaffected family members were examined, as indicated in the pedigree (Fig. 1). Special attention was paid to the possible presence of hypertelorism and, in males, to the penile and testicular size and position, the meatal position and shape, presence of cordee, presence of hernia, and, in uncircumcised individuals, to the shape of the foreskin.
Hypertelorism with diastema seemed to be dominantly transmitted, and segre- gated independently of hypospadias. The meatal orifice in the most severe patient (VI-13) was midpenile, but variability was observed among sibs. A cordee resulting in a ventral curvature of the penile shaft and distal hypospadias were found in patient IV-12. No additional anomalies were found in any of the other affected individuals. Individual VI-6, one of made twins, had a right inguinal testicle and a right postminimi digit which was removed.
The observation that one of the affected individuals was color blind while the rest of the testable affected individuals had normal color vision, together with the fact that hypospadias did not segregate to any of patient IV-12s 19 male grandchildren by his seven daughters, practically excludes X-linkage. With the degree of consanguinity observed in this family a pseudorecessive inheritance may be mistakenly consid- ered for dominant conditions with reduced penetrance, and for conditions with polygenic or multifactorial inheritance. Nevertheless, it seems that the segregation pattern does not support male-limited autosomal dominant transmission. On the other hand, because of the high degree of consanguinity, the likelihood of homozygosity for one (or more) of the genes postulated to cause hypospadias is increased, and in fact the segregation pattern and the founder effect in this family are best explained by autosomal recessive inheritance.
In most patients the cause of hypospadias is unknown. In our cases the family believes that the condition originated by imprinting, when the mother of patient IV- 12, while pregnant, stared at a camel (camels apparently urinate backwards). Better documented conditions that may be associated with familial hypospadias include
Uncomplicated Familial Hypospadias 53
54 Frydman, Greiber, and Cohen
certain chromosome abnormalities [Aarskog , 19701 and several malformation syn- dromes [Summitt, 19791; these conditions were excluded in our patients.
Inadequate production or abnormal cell binding of androgens is known to be associated with variable degrees of incomplete virilization and hypospadias. Of the five enzymatic steps required for the conversion of cholesterol to testosterone, three are associated with adrenal insufficiency or with hypertension (20,22 desmolase, 3- beta hydroxysteroid dehydrogenase, and 17-hydroxylase deficiencies). Recently a nonsalt-losing 3-beta hydroxysteroid dehydrogenase deficiency was reported in two siblings [Pang et al, 19831. Unlike our cases, the patients presented premature adrenarche and the male had perineal hypospadias and cryptorchidism. 17,20 Des- molase deficiency probably is X-linked, and the autosomal recessive 17-ketosteroid reductase deficiency presents a female phenotype prior to puberty [Givens et al, 1974; Summitt, 19791. A whole gamut of clinical presentation, ranging from hypospadias to severe involvement, is recognized in 5-alpha reductase deficiency and the possibil- ity that incomplete deficiency may be associated with familial hypospadias was raised by Page [ 19791. We believe that this is unlikely, since heterozygotes shown to have intermediate enzyme activity are phenotypically normal [Peterson et al, 19771, yet cases in which the enzyme activity is intermediate, between that of a heterozygote and that of an affected homozygote, are possible. Hypospadias is also a frequent feature in incomplete testicular feminization, in Reifenstein syndrome, and in other partial androgen-insensitvity syndromes. All these conditions are characterized by abnormal cell binding of androgens and are transmitted either as X-linked or as male limited autosomal dominant traits [Summitt, 19791. Androgen cell binding was not studied in our patients, but in some cases of isolated hypospadias normal values were observed [Walsh et al, 1976; Griffin et al, 19761, and the possibility that fetal testicular dysfunction is associated with uncomplicated hypospadias was considered [Bellinger, 19811.
From the above considerations it appears that our cases can be differentiated from other conditions of familial hypospadias on clinical grounds, biochemical find- ings, or by the different mode of inheritance. In addition, our report suggests that among the cases with uncomplicated hypospadias in which polygenic or multifactorial inheritance was postulated, there may be a subgroup with recessively inherited hypospadias. The condition may not be rare; in the study of Bauer et a1 [ 19831, out of 307 families 23 had more than one affected child born to normal parents. Although the authors assumed polygenicity, recessive inheritance remains a possibility.
Aarskog D (1970): Clinical and cytogenic studies in hypospadias. Acta Paediatr Scand [Suppl] 203: 1-
Bauer SB, Retik AB, Colodny AH (1981): Genetic aspects of hypospadias. In Duckett JW (ed):
Bellinger MF (1981): Embryolalgy of the male external genitalia. In: Duckett JW (ed): Symposium on
Chen YC, Woolley PV Jr (1971): Genetic studies on hypospadias in males. J Med Genet 8: 153-159. Givens JR, Wiser WL, Summitt RL, Kerber U, Andersen RN, Pittaway DE, Fish SA (1974): Familial
male pseudohermaphroditism without gynecomastia due to deficient testicular 17-ketosteroid reductase activity. N Engl J Med 291:938-944.
Symposium on Hypospadias. Urol Clin North Am 8:559-564.
Hypospadias. Urol Clin North Am 8:375-382.
Uncomplicated Familial Hypospadias 55
Griffin JE, hnyashthiti K, Wilson JD (1976): Dihydrotestosterone binding by cultured human fibro-
Lowry RE3, Kliman MR (1976): Hypospadias in successive generations-possible dominant gene inher-
Page LA (1979): Inheritance of uncomplicated hypospadias. Pediatrics 63:788-790. Pang S, Levine LS, Stoner E, Opitz JM, Pollack MS, Dupont B, New MI (1983): Nonsalt-losing
congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency with normal glomerulosa function. J Clin Endocrinol Metab 562308-8 18.
Peterson RE, Imperato-McGinley 3, Gautier T, Sturla E (1977): Male pseudohermaphroditism due to steroid 5-reductase deficiency. Am J Med 62: 170-191.
Summitt RL (1979): Genetic forms of hypogonadism in the male. In Steinberg AG, Bearn AG, Motulsky AG, Childs B, (eds): Progress in Medical Genetics. New series Vol 111, Philadelphia: WB Saunders pp 1-72.
Sweet RA, Schrott HG, Kurland R, Culp DS (1974): Study of the incidence of hypospadias in Rochester, Minnesota, 1940- 1970, and a case-control comparison of possible etiologic factors. Mayo Clin Proc 49:52-58.
Walsh PC, Curry N, Mills RC, Siiteri PK (1976): Plasma androgen response to hCG stimulation in prepubertal boys with hypospadias and cryptorchidism. J Clin Endocrinol Metab 42:52-59.
blasts. J Clin Invest 57: 1342-1351.
itance. Clin Genet 9:285-288.
Edited by John M. Opitz and James F. Reynolds
Note added in proof: Case VI-1 and his mother (IV-1) were found to have a balanced 13/15 translocation.
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