Chapter 83
Cytogenetic, Teratogenic, and Miscellaneous Other Disorders Causing Male Pseudohermaphroditism or Germ-Cell Failure in Males (46,XY) and Females (46,XX)
Joe Leigh Simpson
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Joe Leigh Simpson, MD
Ernst W. Bertner Chairman and Professor, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas (Vol 2, Chap 6, Vol 3, Chaps 69, 110, 112; Vol 4, Chap 66; Vol 5, Chaps 75, 79, 80, 83, 84, 85, 86, 87, 90, 95; Vol 6, Chap 37)


In male pseudohermaphroditism, individuals with a Y chromosome have external genitalia that fail to develop as expected for normal males. External genitalia are sufficiently ambiguous to confuse the gender of rearing. Male pseudohermaphroditism encompasses a wide spectrum of disorders as shown in Table 1. The majority of these disorders have been discussed in previous chapters, specifically Chapters 5-79, 5-80, 5-81, and 5-82. In this chapter teratogenic and cytogenetic forms (45,X/46,XY) of male pseudohermaphroditism, multiple malformation syndromes, and selected disorders otherwise not reviewed in this volume are discussed.


TABLE 1. The Spectrum of 46,XY Sex Reversal (XY females)

  XY gonadal dysgenesis without somatic anomalies

  Perturbations of SRY (HMG-box)
  Duplication Xp (DAX1)
  X-linked recessive form
  Forms without detectable molecular perturbation or heritability

  XY gonadal dysgenesis and Wilms’ tumor oncogene (WT1)

  Denys-Drash syndrome
  Frasier syndrome

  XY gonadal dysgenesis and campomelic dysplasia (SOX9)
  XY gonadal dysgenesis/∀-thalassemia X chromosome (ATX)
  XY gonadal dysgenesis in other malformation syndromes

  Ectodermal anomalies (Brosnan)
  Genital-Palato-Cardiac (Gardner-Silengo-Wachtel)
  Spastic paraplegia-optic atrophy-microcephaly (Teebi)

  XY gonadal dysgenesis with autosomal deletions

  Del (2p)
  Del (9p) (DMRT)
  Del (10q)

  XY gonadal dysgenesis with autosomal duplications

  Dup (1p)

  Germ cell failure in both sexes (46,XY cases)

  No somatic anomalies
  Hypertension and deafness
  Microcephaly and short stature58

  Leydig cell hypoplasia
  Steroid biosynthetic defects

  Steroidogenic factor 1 (Star) deficiency
  17α hydroxylase/17,20 desmolase deficiency
  3β-ol dehydrogenase/3∃-hydroxysteroid dehydrogenase deficiency

  Agonadia (46,XY)

(Simpson JL, Elias S: Genetics in Obstetrics and Gynecology. Philadelphia, N. B. Saunders [in press].)


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Despite many claims of genital abnormalities being caused by putative teratogens, virtually no proven examples exist. Nonetheless, if administered in sufficiently high doses in the first trimester to a woman pregnant with a male fetus, several agents would be expected to produce female external genitalia. One example is cyproterone, the mode of action of which is to block the androgen receptor. Cyproterone is present in oral contraceptive formulations in Europe, but not in the United States. Little reported information exists on the consequences of inadvertent ingestion during pregnancy, but presumably problems have either not occurred or been reported. On the other hand, genital ambiguity was unexpectedly reported in association with trimethadione teratogenicity.1 If valid, the mechanism is unclear.

Another potential teratogen is finasteride, which inhibits 5α-reductase. Perturbing this function (5α-reductase) causes male pseudohermaphroditism (see Chapter 5-80). Another agent is flutamide. Both finasteride and flutamide are approved by the U.S. Food and Drug Administration (FDA) for treatment of hirsutism; thus, the risk for teratogenic male pseudohermaphroditism exists. Again, no cases of human teratogenicity appear to have been claimed to be the cause associated with these agents.

Controversy exists concerning whether administration of progestins or progesterones during pregnancy can produce simple hypospadias, that is, without genital ambiguity per se. The overwhelming weight of the evidence seems to be that these agents do not adversely affect male genital development.2,3

In general, C-21 progestogen derivatives (e.g., medroxyprogesterone) do not virilize even in high doses; 19-nortestosterone derivatives (e.g., norethindrone) generally virilize, but there are exceptions (e.g., norethynodrel). In 1962, Jacobson4 reported an 18% incidence of masculinization in female infants whose mothers were given high doses of norethindrone acetate for pregnancy maintenance; virilization occurred in only 1% exposed to medroxyprogesterone acetate. Doses of 19-nortestosterones required for virilization are 10 to 20 mg/day, far in excess of that associated with inadvertent contraceptive exposure during pregnancy. When progestogen therapy at such dosage is currently administered, the compound administered will almost certainly be progesterone, 17α-hydroxyprogesterone caproate, or medroxyprogesterone. Genital ambiguity as a resule of progestogen exposure of female fetuses is thus mostly a topic of historic concern.

The only currently utilized sex steroid that causes virilization when administered in usually administered doses is danazol, a derivative of 17α-ethinyl testosterone. In the study by Brunskill5 on adverse drug reports of pregnant women receiving danazol, 23 of 57 female infants were virilized; male offspring were ostensibly normal. Genital virilization has resulted from doses as low as 200 mg daily, whereas 800 mg daily is the usual dose when danazol is used to treat endometriosis.

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45,X/46,XY individuals have a 45,X cell line and at least one cell line containing a Y chromosome. Based on cohort studies of 45,X/46,XY cases detected in utero(prenatal genetic diagnosis), more than 90% of cases are normal males.6 The phenotype of cases ascertained postnatally differs markedly, doubtless reflecting selection basis. Postnatal cases manifest a variety of phenotypes but predominately genital ambiguity or phenotypically normal females.7,8,9 Different phenotypes presumably reflect different tissue distributions of the various cell lines.

Of note, structurally abnormal Y chromosomes are not infrequently present. Given that structurally abnormal chromosomes (e.g., dicentric) are often unstable, it is likely that the 45,X line arises secondarily after loss of the structurally abnormal Y. This may explain why certain infertile males with normal external genitalia, for example requiring intracytoplasmic sperm injection (ICSI), may have offspring with genital ambiguity. In the sons a 45,X line might have arisen secondarily.

45,X/46,XY with Unambiguous Female External Genitalia

These 45,X/46,XY individuals may have Turner’s stigmata and be clinically indistinguishable from 45,X individuals in many ways. However, 45,X/46,XY cases may be normal in stature and show no somatic anomalies. External genitalia, vagina, and müllerian derivatives remain unstimulated because of the lack of sex steroids. Breasts fail to develop, and little pubic or axillary hair develops. If breast development occurs in a 45,X/46,XY individual, an estrogen-secreting tumor such as gonadoblastoma or dysgerminoma should be suspected.10 However, virilization has also been claimed to result from gonadotropin stimulation of streak gonads11; studies of such cases would be welcome.

Although streak gonads of 45,X/46,XY individuals may be histologically indistinguishable from streak gonads of 45,X individuals, gonadoblastomas or dysgerminomas develop in approximately 15% to 20% of 45,X/46,XY individuals.12 If retained in a phenotypic XY female, presence of the Yq locus GBY (gonadoblastoma Y chromosome) is believed to predispose to neoplasia. If GBY is deleted, as it is in many deletions of Yq, risk of neoplasia is diminished in gender-reversal females.13

Neoplasia may develop in the first or second decade of life. Even if the presumptive GBY locus were absent, we recommend gonadal extirpation for all 45,X/46,XY individuals having female external genitalia. The uterus should be retained, given that pregnancy may be achievable through donor oocytes or donor embryos.

Gonadectomy can usually be accomplished by laparoscopy14 (Fig. 1). Although preferable to removing only gonads, adnexal removal may technically be necessary as well. Only rarely should laparotomy prove necessary.

Fig. 1. Technique used for laparoscopic gonadectomy, the procedure of choice when the peritoneal reflection between fallopian tube and gonad (mesovarium/mesosalpinx) has sufficient width to allow the streak gonad to be separated from the parallel aligned fallopian tube (as indicated in A). A. The fallopian tube is retracted laterally with grasping forceps expose the utero-ovarian ligament and mesovarium/mesosalpinx. B. After cauterization, the utero-ovarian ligament is cut with scissors. C. The mesovarium/mesosalpinx is first cauterized and then cut in 1-cm increments beginning at the utero-ovarian ligament and extending to the infundibulopelvic ligament. D. Ovarian vessels entering the infundibulopelvic ligament are ligated with endoloops.(Pisarska MD, Simpson JL, Zepeda DE, et al: Laparoscopic removal of streak gonads in 46,XY or 45,X/46,XY gonadal dysgenesis. J Gynecol Techniques 4:95, 1998.)

45,X/46,XY with Ambiguous External Genitalia

The term asymmetric or mixed gonadal dysgenesis applies to individuals with one streak gonad and one dysgenetic testis. These individuals usually have ambiguous external genitalia and a 45,X/46,XY complement, and usually a uterus. Many investigators believe that the phenotype is invariably associated with 45,X/46,XY mosaicism. Occasionally only 45,X or only 46,XY cells are demonstrable. Ostensibly, nonmosaic cases may merely reflect inability to sample sufficient tissues or cells.

45,X/46,XY individuals with ambiguous external genitalia usually have müllerian derivatives (e.g., a uterus). Presence of a uterus is important diagnostically because that organ is absent in almost all genetic (mendelian) forms of male pseudohermaphroditism. If an individual shows ambiguous external genitalia, bilateral testes, and a uterus, it is reasonable to infer 45,X/46,XY mosaicism actually exists. This statement still applies if both lines cannot be demonstrated cytogenetically. Occasionally the uterus may be rudimentary, or a fallopian tube may fail to develop ipsilateral to a testis.

45,X/46,XY with Nearly Normal Male External Genitalia

45,X/46,XY mosaicism may be detected in individuals with nearly normal male external genitalia. In fact, this is the most common 45,X/46,XY phenotype based on liveborn follow-up of 45,X/46,XY fetuses ascertained at amniocentesis, 90% of whom show a normal male phenotype.15 That 45,X/46,XY neonates far more commonly show genital ambiguity merely reflects biases of ascertainment. Those with male phenotype pass unrecognized.

45,X/46,XY individuals having almost normal male external genitalia do not seem to develop neoplasia as often as 45,X/46,XY individuals having female or frankly ambiguous genitalia.16 If gonads can be assessed periodically within the scrotum by ultrasound or palpation, gonadal extirpation should not be necessary if the male gender of rearing is chosen.

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Genital ambiguity may occur in 46,XY individuals having various multiple malformation syndromes. These include the Meckel-Gruber syndrome, Smith-Lemli-Opitz syndrome, brachio-skeletal-genital syndrome,17 esophageal-facial-genital syndrome,18 and other disorders. These disorders are usually inherited in either autosomal recessive or X-linked recessive fashion, and are summarized in Table 1. Many additional syndrome are associated with cryptorchiditism or simple hypospadias, but these rarely pose diagnostic problems.19 Of relevance as well are existence of various syndromes associated with XY gender reversal. These are listed in Table 2 and were discussed in Chapter 5-87. These syndromes include campomelic dysplasia (SOX-9), Denys/Drash and Frasier syndromes (WT-1) autosomal deletions (1q, 2q, 9p, 10q), and autosomal duplication (1q). In each condition the phenotype of affected 46,XY individuals is usually complete gender reversal (female phenotype). However, varied expression exists, some affected cases may occasionally present as male pseudohermaphrodites (genital ambiguity).


TABLE 2. Multiple Malformation Syndromes Associated with Ambiguous Genitalia


Prominent Features



Absent eyelids, eyebrows, eyelashes, external ears; fusion defects of the mouth; ambiguous genitalia; absent or rudimentary nipples; parchment skin, delayed development of expressive language

Autosomal recessive

Aniridia-Wilms tumor association64,65

Moderate to severe mental deficiency, growth deficiency, microcephaly, aniridia, nystagmus, ptosis, blindness, Wilms tumor, ambiguous genitalia, gonadoblastoma

Chromosomal or autosomal dominant (WT-1)

Asplenia-cardiovascular anomalies-caudal deficiency66

Hypoplasia or aplasia of the spleen complex cardiac malformations, abnormal lung lobulation, anomalous position and development of the abdominal organs, agenesis of corpus callosum, imperforate anus, ambiguous genitalia, contractures of the lower limb

Autosomal recessive


Hydrocephalus, dense bones, cardiac malformation, bulbous nose, broad nasal bridge, ambiguous genitalia

Autosomal recessive

Deletion 11q67

Trigonocephaly, flat and broad nasal bridge, micrognathia, carp mouth, hypertelorism, low-set ears, severe congenital heart disease, anomalies of limbs, external genitalia



Wilms tumor, nephropathy, ambiguous genitalia with 46, XY karyotype



Cryptophthalmia, defect of auricle, hair growth on lateral forehead to lateral eyebrow, hypoplastic nares, mental deficiency, partial cutaneous syndactly, urogenital malformation

Autosomal recessive

Lethal acrodysgenital dysplasia72

Failure to thrive, facial dysmorphism, ambiguous, genitalia, syndactyly, postaxial polydactyly, Hirschprung disease, cardiac and renal malformations

Autosomal recessive


Joint contractures, cerebellar hypoplasia, renal hypoplasia, ambiguous genitalia, urologic anomalies, tongue cysts, shortness of limbs, eye abnormalities, heart defects, gallbladder agenesis, ear malformations

Autosomal recessive

SCARF syndrome74

Skeletal abnormalities, cutis laxa, craniosynostosis, ambiguous genitalia, psychomotor retardation, facial abnormalities


Short rib-polydactyly, Majewski type75,76

Short stature; short limbs; cleft lip and palate; ear anomalies; limb anomalies, including pre- and postaxial polysyndactyly; narrow thorax; short horizontal ribs; high clavicles; ambiguous genitalia

Autosomal recessive


Microcephaly, mental retardation, hypotonia, ambiguous genitalia, and sometimes gender-reversed abnormal facies

Autosomal recessive (deficiency 7-OH cholesterol dehydrogenase)

Trimethadione, teratogeneicity1

Mental deficiency, speech disorders, prenatal onset growth deficiency, brachycephaly, midfacial hypoplasia, broad and upturned nose, prominent forehead, eye anomalies, cleft lip and palate, cardiac defects, ambiguous genitalia


VATER association79,80

Vertebral, anal, tracheoesophageal, and renal anomalies; subjects with ambiguous genitalia as part of the cloacal anomalies

Unknown (if valid entity); alleged progestational teratogeneicity unproved (see Simpson and Kaufman2)

Genital–Palato-Cardiac syndrome (Gardner- Silengo-Wachtel)29

Cleft palate, micrognathia, low-set ears, ventricular septal defect, internal anomalies; female to male external genitalia with varied gonads (streaks to testes)

X-linked or autosomal recessive

(Simpson JL, Elias S: Genetics in Obstetrics and Gynecology. Philadelphia, WB Saunders, 2003.)


Two multiple malformation syndromes characterized by genital ambiguity (i.e., Smith-Lemli-Opitz syndrome and genito-palato-cardiac [Gardner-Silengo-Wachtel] syndrome) are of special interest to obstetrician–gynecologists.


In this common autosomal recessive syndrome, 46,XY individuals show genital abnormalities ranging from hypospadias to genitalia ambiguity. In Ontario, the incidence has been estimated at 1 per 22,700 among individuals of European ancestry.20 An estimate of 1 per 20,000 is accepted.21 A characteristic spectrum of dysmorphic features allows diagnosis by experienced clinicians and geneticists. Mental retardation exists as does craniofacial dysmorphia characterized by microcephaly, low-set ears, ptosis, anteverted nares, inner epicanthal folds, broad maxillary ridges and micrognathia. Syndactly of the third toe is present. Ureteropelvic junction obstruction and renal anomalies (cystic dysplasia, agenesis, duplication of kidneys) are also common. Approximately two thirds have genital problems: usually hypospadias, micropenis, or hypoplastic scrotum are the manifestations; genital ambiguity is less common.

However, a more severe phenotype of Smith-Lemli-Opitz syndrome exists, often called type II. Here external genitalia may be female (gender reversal).22 Both type I and type II Smith-Lemli-Opitz syndrome, if the distinction is truly appropriate, are caused by mutation of a gene the product of which is C7-reductase, the enzyme responsible for converting 7-hydroxycholesteral to cholesterol.23,24 A defect in exon-intronic splicing is the most common molecular perturbation.

Considerable attention is being directed to the feasibility of postnatal as well as prenatal treatment with a high-cholesterol diet. Given its low molecular weight, cholesterol should cross the placenta, making this mode of therapy feasible. During pregnancy, maternal serum estriol is low to nondetectable,25 making detection possible during maternal serum analyte screening. Maternal serum analyte screening is based on low maternal serum alpha-fetoprotein (MSAFP; multiple of mediam [MOM]0.72), μE3 (MOM 0.21) and human chorionic gonadotropin (hCG; MOM 0.76).21 An algorithm based on performing an invasive procedure when risk is 1:100 will yield 71% detection at a procedure rate of only 0.44%.21 Definitive prenatal diagnosis is facile with amniotic fluid, based on molecular studies or presence of the novel compounds dehydroestriol and dehydropregnanetriol. Diagnosis can even be made in maternal urine for in normal pregnancies these compounds are undetectable.26


The existence of a still poorly defined disorder characterized by variable gender sex reversal and characteristic somatic anomalies is accepted. Several authors have arrived at this conclusion27,28,29 with the latter best reflecting consensus as to which cases fit within this spectrum. Greenberg and colleagues29 proposed that this disorder be called palato-genital-cardiac or Gardner-Silengo-Wachtel syndrome and such appellations are usually applied.

In retrospect, Gardner and associates30 reported what is accepted as the first case; however, those authors believed that oral contraception was causative through teratogenic action. This diverted attention from the possibility of a newly recognized syndrome. Silengo and colleagues31 later recounted two cases similar to that of Gardner and colleagues.30 All three were 46,XY with female external genitalia and müllerian derivatives; gonads were bilateral streaks, but in one case Sertoli cells were present. Somatic features included cleft palate, micrognathia, other facial dysmorphias (downward-slanting palpebral features, low-set ears, anteverted nares, carp mouth), clubfoot, or prominent heels. Bernstein and colleagues32 followed with a report of four cases, which may or may not have all had the same disorder. The most thoroughly described cases not only showed 46,XY gender reversal but also duplication of Xp, in a child and its aborted fetal sib. Dup (Xp) was present in several normal (XX) females. This observation served as the basis for postulating that duplication of Xp (later DAX-1) caused gender reversal (see Chapter 5-86). However, no other features of adrenal hypoplasia were evident in the case of Bernstein and colleagues,32 and the somatic features were not those now known to be associated with DAX-1 duplication. On the other hand, cleft palate, hypertelorism, micrognathia, low-set eyes, prominent heels, and ventricular septal defect (VSD) were present. Bernstein and colleagues32 reported three other cases lacking duplication of Xp. These cases showed cleft palate, microcephaly, low-set ears, and post-axial polydactyly. One of the three had VSD. External genitalia in all were female, but their karyotype was not stated. Wolman and colleagues33 described a case with similar somatic findings (cleft palate, micrognathia, clubfeet, thoracic dysplasia. Gender reversal extended to gonads showing seminiferous tubules; a uterus was present.

Greenberg and colleagues29 reported two 46,XY sibling fetuses who were each aborted following prenatal detection (ultrasound) of anomalies. One fetus had female external genitalia and normal ovaries, micrognathia but no cleft palate, low-set ears, flexion deformities of thumbs and toes, and cardiac defects that included VSD. The other aborted sib showed not dissimilar somatic features, plus bilateral cystic kidneys, gastrointestinal defects (agenesis gallbladder, intestinal rotation, Meckel diverticulum). However, external genitalia of this sib were male, with first-degree hypospadias and testes. Beemer and von Ertbruggen34 reported two sibs of consanguineous parents. These sibs may or may not have had the same disorder.29

In this syndrome, X-linked, or less likely autosomal-recessive, XY gender reversal syndrome would seem to exist. Defining somatic features include facial clefts, micrognathia, low-set ears, and other facial dysmorphic features; cardiac defects such as VSD; flexion deformities; and various internal anomalies. Not all cases show the same features, and in some cases Smith-Lemli-Opitz syndrome could be the correct diagnosis. All cases of genito-palato-cardiac syndrome have been 46,XY and almost all show female external genitalia. Gonads show unusual variability: streak gonads, ovary-like gonads comprised of seminiferous tubules or testes (even in the sib of an XY case who showed ovaries).

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Certain 46,XY individuals have long been recognized as having bilateral testes devoid of Leydig cells, show female external genitalia, and have no uterus.7 Epididymides and vasa deferentia are present; serum luteinizing hormone (LH) is elevated. Affected siblings have been reported and parental consanguinity observed; autosomal recessive inheritance is accepted.7,35

The molecular basis involves mutations of the LHR gene, located on chromosome 2.36 Leydig cells thus fail to develop because LH cannot exert its effect during embryogenesis, leading to inadequate virilization and lack of gonadal differentiation. Embryonic testes continue to secrete anti-müllerian hormone (AMH), resulting in lack of uterus as expected for 46,XY individuals.

The LHR gene consists of 11 exons and 699 amino acids. Kremer and colleagues37 reported two siblings of consanguineous parents; homozygosity for a missense mutation (C593R) was found. In other cases deletions, point mutations, and stop codons have been recognized.38,39Over a dozen different LHR mutations have been reported in 46,XY “females” having Leydig cell hypoplasia.36 Complete resistance to LH produces XY females, whereas partial resistance leads to males having a small penis or hypospadias.

46,XX cases with LHR mutations also exist, showing primary amenorrhea. In all cases, these women have had a 46,XY sib of nearly identical external phenotype.

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In agonadia, the gonads are completely absent, not merely present in the form of streaks as in gonadal dysgenesis. In agonadia the external genitalia are abnormal but female-like. In the original cases of Overzier and Linden40 the clitoris was enlarged and a perineal urethral orifice present. The distance between urethral orifice and anus seemed normal despite nearly complete labio-scrotal fusion. In other cases external genitalia were more normally female in appearance. No more than rudimentary müllerian or wolffian derivatives are present.

In approximately half of the reported cases, somatic anomalies coexist. In considering their own and previous cases (Overzier and Linden,40 Chaptal and colleagues,41 Overzier,42 Schoen and colleagues43) in 1973 Sarto and Opitz44 wondered whether a distinctive somatic malformation pattern existed: skull abnormalities (turricephaly and turribrachycephaly); facial dysmorphia (ptosis, epicanthal folds, nystamus, esotropia); vertebral anomalies; low posterior hairline.

Agondia was once believed confined to 46,XY individuals. However, sporadic cases have been reported in sporadic 46,XX individuals.45,46 In these sporadic 46,XX cases, there were no somatic anomalies, Mendonca and colleagues47 also reported agonadia without somatic anomalies in phenotypic sibs having unlike chromosomal complements (46,XY and 46,XX). Presumably the cases reported by Kennerknecht and colleagues48 represent a distinct syndrome: agonadism, hypoplasia of the pulmonary artery and lung, and dextrocardia in XX and XY sibs.

Pathogenic explanations initially focused on loss of testes early in embryogenesis, a logical hypothesis given that initially all cases were 46,XY. Even in these cases, however, not only absence of gonads, but also abnormal external genitalia and lack of internal genital ducts needs to be consisered. An attractive hypothesis is transient presence of fetal testes, sufficiently long to initiate male differentiation and suppress müllerian differentiation but not long enough to complete male differentiation. Thus, the term testicular regression is favored by some. On the other hand, mechanisms not confined to testes must be invoked in 46,XX cases. Given both heritable tendencies44,49 as well as somatic anomalies, a defect in connective tissue is a logical explanation.

There are still no molecular clues to date. No genetic perturbations have been reported in SRY50,51,52 or other testis-related genes.

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Females with germ-cell failure show streak gonads, whereas males show Steroli-cell–only syndrome. When familial aggregates of germ-cell failure are observed, usually affected individuals are of either one or the other gender. Gender of rearing is, almost by definition, not in doubt. In several families, however, male and female sibs have each shown germ-cell failure, despite different chromosomal complements (46,XX or 46,XY). In some cases no anomalies exist outside gonads, whereas in other cases a multiple malformation pattern exists.

Isolated Germ-cell Failure in XX and XY Sibs

In two families, unlike-gender sibs have shown germ-cell failure without somatic anomalies. Smith and colleagues53 reported two female and one male sib of Greek ancestry residing in Australia. Granat and colleagues54 reported a Yemenite Jewish sibship. These families demonstrate that a single autosomal gene can deleteriously affect germ-cell development in both genders. Presumably the gene(s) acts either at a specific site common to early germ-cell development or through a nonspecific mechanism producing meiotic breakdown. Elucidation of such gene(s) could have profound implications for understanding normal gonadal differentiation.

A host of attractive candidate genes exist in mouse and Drosophila, and doubtless will be exploited with contemporary molecular methods. In mouse knockout experiments, surprisingly, not all results would have been predicted to manifest this phenotype but show no other anomalies. For example, a gene knockout for follicle stimulating hormone β causing germ-cell failure is not a surprise, but germ-cell failure as result of knockout of bone morphogenetic protein 15 (Bmp) is less predictive. Murine knockouts have been reviewed by Brunskill.55 Many of these genes offer attractive candidates for the families discussed above. One example is gcd, in which germ cells are deficient in both male and female mice.

Hamet Syndrome

Hamet and colleagues56 reported germ-cell failure, hypertension, and deafness in 3 of 5 sibs (2 females, 1 male) in a French-Canadian family. Blood pressure was elevated by the second or third decade. Fibrous streak were evident at laparoscopy in the one female sib undergoing surgery. The male sib showed hyperplasia of the adrenal zona glomerulosa. Despite extensive endocrine evaluation no precise diagnosis was found; 11β-hydroxylase deficiency was considered, as well as 17-hydroxylase deficiency. The male showed incomplete spermatogenesis at necropsy.

Al-Awadi Syndrome

Al-Awadi and colleagues57 reported three sibs whose parents were first cousins. Ethnic origin was Jordanian, apparently residing in Kuwait. Unusual somatic features included thin scalp hair that was mostly midline; no hair was present on the side of the face, overall producing a mane-like appearance. Eyebrows and eyelashes were normal, and affected sibs were able to perspire. The two affected females showed müllerian hypoplasia and streak gonads. The brother had a normal-sized penis, but did not shave and had small soft testes.

Mikati Syndrome

Mikati and colleagues58 reported four affected sibs from a consanguineous Lebanese couple. Sibs showed mental retardation, microcephaly, short stature, genu valgum, cubitus valgus, and mental retardation. Facial dysmorphia was characterized by narrow forehead, synophrys, abnormal pinnae, loss of teeth, abnormally folded pinnae, micrognathia, and cubitus valgus.

In the males, testes were small, and in one case, undescended. Hypospadias was not present. The single affected sister failed to achieve secondary sexual development. On rectal examinatin a uterus could be palpated. Hypergonadotropism was evident.

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Steroidogenic factor-1 (SF-1) plays a potentially pivotal role in hypothalamic-pituary-gonadal axis. An orphan nuclear receptor related structurally to steroid receptors, SF-1 has no known ligand (hence, the designation orphan). SF-1 gene product is encoded by the gene FTZ1, a zinc finger protein encoded on human 9q33. Prior to recognition of human cases, disruption of FTZ1 in mice (gene knockouts) was known to cause not only perturbation of adrenal and gonadal development but also abnormalities of the hypothalamus and pituitary gonadatropes.59,60

The first ostensible human case of SF-1 deficiency, caused by mutant FTZ-1, was reported by Achermann and colleagues.61 This 46,XY individual showed primary adrenal failure, female external genitalia, streak gonads, and normal müllerian derivatives responsive to hormones. The proband was heterozygous for a 2bp substitution at codon 35 of FTZ-1. This mutated glycine is the last amino acid of the first zinc finger of SF-1, and its perturbation should disturb DNA binding. In mice the same (G35E) mutation does not exert a dominant negative effect; thus, homozygosity or compound heterozygous would be expected in humans to produce an abnormal phenotype. In the case described above, compound heterozygosity is presumed to exist, even though the second mutation could not be immediately detected in the coding regions of FTZ-1; SRY, StAR, and DAX1 were normal.

Of significance was the presence of a uterus in this 46,XY individual. This finding supports the hypothesis that SF-1 regulates repression of AMH.

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1. Feldman GL, Weaver DD, Lovrien EW: The fetal trimethadione syndrome: Report of an additional family and further delineation of this syndrome. Am J Dis Child 131:1389, 1977

2. Simpson JL, Kaufman R: Fetal effects of progestogens and diethylstilbestrol. In Fraser IS, Jansen RPS, Lobo RA, et al (eds): Estrogens and Progestogens in Clinical Practice. pp. 533, 553 London, Churchill Livingstone, 1998

3. Phillips OP, Simpson JL: Contraception and congenital malformations. In Sciarra JJ (ed): Gynecology and Obstetrics. pp. 1, 21 Philadelphia, Lippincott Williams and Wilkins, 2001

4. Jacobson RB: Hazards of norethindrone therapy during pregnancy. Am J Obstet Gynecol 84:962, 1962

5. Brunskill PJ: The effects of fetal exposure to danazol. Br J Obstet Gynaecol 99:212, 1992

6. Chang HJ, Clark RD, Bachman H: The phenotype of 45,X/46,XY mosaicism: An analysis of 92 prenatally diagnosed cases. Am J Hum Genet 46:156, 1990

7. Simpson JL: Disorders of Sexual Differentiation: Etiology and Clinical Delineation. New York, Academic Press, 1976

8. McDonough PG, Tho SP: The spectrum of 45X/46,XY gonadal dysgenesis and its implications (a study of 19 patients). Pediatr Adolesc Gynecol 1:1, 1983

9. Rosenberg C, Frota-Pessoa O, Vianna-Morgante AM, et al: Phenotypic spectrum of 45,X/46,XY individuals. Am J Med Genet 27:553, 1987

10. Verp MS, Simpson JL: Abnormal sexual differentiation and neoplasia. Cancer Genet Cytogenet 25:191, 1987

11. Bosze P, Szamel I, Molnar F, et al: Nonneoplastic gonadal testosterone secretion as a cause of vaginal cell maturation in streak gonad syndrome. Gynecol Obstet Invest 22:153, 1986

12. Simpson JL, Photopulos G: The relationship of neoplasia to disorders of abnormal sexual differentiation. Birth Defects Orig Artic Ser 12(1):15, 1976

13. Lukusa T, Fryns JP, van den BH: Gonadoblastoma and Y-chromosome fluorescence. Clin Genet 29:311, 1986

14. Pisarska MD, Simpson JL, Zepeda DE, et al: Laparoscopic removal of streak gonads in 46,XY or 45,X/46,XY gonadal dysgenesis. J Gynecol Tech 4:95, 1998

15. Hsu LY: Prenatal diagnosis of chromosome abnormalities through amniocentesis. In Milunsky A (ed): Genetic Disorders and the Fetus. pp. 155, Vol. 3:Baltimore, Johns Hopkins Press, 1986

16. Simpson JL, Photopulos G: Hereditary aspects of ovarian and testicular neoplasia. Birth Defects Orig Artic Ser 12(6):51, 1976

17. el Sahy NI, Waters WR: The branchio-skeleto-genital syndrome. A new hereditary syndrome Plast Reconstr Surg 48:542, 1971

18. Opitz JM, Howe JJ: The Meckel syndrome (dysencephalic splanchnocystica, the Gruber syndrome). Birth Defects Orig Artic Ser 5:167, 1969

19. Pinsky L, Beitel LK, Kazemi-Esfarjani P: Lessons from androgen receptor gene mutations that cause androgen resistance in humans. In LA Hughes (ed): Sex Differentiation: Clinical and Biological Aspects. pp. 95, England, Cambridge Serono Symposia Series [Frontiers in Endocrinology], 1996

20. Nowaczyk MJ, McCaughey D, Whelan DT, et al: Incidence of Smith-Lemli-Opitz syndrome in Ontario, Canada. Am J Med Genet 102:18, 2001

21. Palomaki GE, Bradley LA, Knight GJ, et al: Assigning risk for Smith-Lemli-Opitz syndrome as part of 2nd trimester screening for Down’s syndrome. J Med Screen 9:43, 2002

22. Curry CJ, Carey JC, Holland JS, et al: Smith-Lemli-Opitz syndrome-type II: multiple congenital anomalies with male pseudohermaphroditism and frequent early lethality. Am J Med Genet 26:45, 1987

23. Tint GS, Irons M, Elias ER, et al: Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N Engl J Med 330:107, 1994

24. Tint GS, Batta AK, Xu G, et al: The Smith-Lemli-Opitz syndrome: A potentially fatal birth defect caused by a block in the last enzymatic step in cholesterol biosynthesis. Subcell Biochem 28:117, 1997

25. Bradley LA, Palomaki GE, Knight GJ, et al: Levels of unconjugated estriol and other maternal serum markers in pregnancies with Smith-Lemli-Opitz (RSH) syndrome fetuses. Am J Med Genet 82:355, 1999

26. Shackleton CH, Roitman E, Kratz L, et al: Dehydro-oestriol and dehydropregnanetriol are candidate analytes for prenatal diagnosis of Smith-Lemli-Opitz syndrome. Prenat Diagn 21:207, 2001

27. Simpson JL: Phenotypic-karyotypic correlations of gonadal determinants: current status and relationship to molecular studies. In Sperling KVF (ed): Human Genetics. Proceedings of the Seventh International Congress. pp. 224, 232 Berlin/Heidelberg, Springer-Verlag, 1987

28. Wachtel SS: H-Y Antigen and the Biology of Sex Determination. New York, Grune and Stratton, 1983

29. Greenberg F, Gresik MV, Carpenter RJ, et al: The Gardner-Silengo-Wachtel or genito-palato-cardiac syndrome: Male pseudohermaphroditism with micrognathia, cleft palate, and conotruncal cardiac defect. Am J Med Genet 26:59, 1987

30. Gardner LI, Assemany SR, Neu RL: 46, XY female: Anti-androgenic effect of oral contraceptive? Lancet 2:667, 1970

31. Silengo M, Kaufman RL, Kissane J: A 46,XY infant with uterus, dysgenetic gonads and multiple anomalies. Humangenetik 25:65, 1974

32. Bernstein R, Koo GC, Wachtel SS: Abnormality of the X chromosome in human 46,XY female siblings with dysgenetic ovaries. Science 207:768, 1980

33. Wolman SR, McMorrow LE, Roy S, et al: Aberrant testicular differentiation in 46,XY gonadal dysgenesis: Morphology, endocrinology, serology. Hum Genet 55:321, 1980

34. Beemer FA, von Ertbruggen I: Peculiar facial appearance, hydrocephalus, double-outlet right ventricle, genital anomalies and dense bones with lethal outcome. Am J Med Genet 19:391, 1984

35. Simpson J: Disorders of the gonads, genital tract and genitalia. In DL Rimoin, JM Connor, RE Pyeritz, et al (eds): Emery and Rimoin’s Principle and Practice of Medical Genetics. pp. 2315, 2351 Vol. 2:London, New York, Churchill Livingstone, 2002

36. Sultan C, Lumbroso S: LH receptor defects. In KJ Cohen, AF Haney, JB Younger (eds): Fertility and Reproductive Medicine. Proceedings of the XVI World Congress on Fertility and Sterility. pp. 679, Amsterdam, Elsevier Science, 1998

37. Kremer H, Kraaij R, Toledo SP, et al: Male pseudohermaphroditism due to a homozygous missense mutation of the luteinizing hormone receptor gene. Nat Genet 9:160, 1995

38. Latronico AC, Anasti J, Arnhold IJ, et al: Brief report: testicular and ovarian resistance to luteinizing hormone caused by inactivating mutations of the luteinizing hormone-receptor gene. N Engl J Med 334:507, 1996

39. Laue LL, Wu SM, Kudo M, et al: Compound heterozygous mutations of the luteinizing hormone receptor gene in Leydig cell hypoplasia. Mol Endocrinol 10:987, 1996

40. Overzier C, Linden H: Echter agonadismus (Anorchismus) bei Geschwistern. Linden H Gynaecologia 142:215, 1956

41. Chaptal J, Jean R, Pages R, et al: Sur un cas de dysgenesie gonadique avec manifestations androgeniques. Arch Fr Pediatr 15:613, 1958

42. Overzier C: Echter agonadismus. In C Overzier (ed): Intersexualitas. pp. 348, 352 Stuttgart, Georg Thieme, 1961

43. Schoen EJ, King AL, Baritell A, et al: Pseudohermaphroditism with multiple congenital anomalies. Report of a case Pediatrics 16:363, 1955

44. Sarto GE, Opitz JM: The XY gonadal agenesis syndrome. J Med Genet 10:288, 1973

45. Duck SC, Sekhon GS, Wilbois R, et al: Pseudohermaphroditis, with testes and a 46, XX karyotype. J Pediatr 87:58, 1975

46. Levinson G, Zarate A, Guzman-Toledano R, et al: An XX female with sexual infantilism, absent gonads, and lack of Mullerian ducts. J Med Genet 13:68, 1976

47. Mendonca BB, Barbosa AS, Arnhold IJ, et al: Gonadal agenesis in XX and XY sisters: Evidence for the involvement of an autosomal gene. Am J Med Genet 52:39, 1994

48. Kennerknecht I, Sorgo W, Oberhoffer R, et al: Familial occurrence of agonadism and multiple internal malformations in phenotypically normal girls with 46,XY and 46,XX karyotypes, respectively: A new autosomal recessive syndrome. Am J Med Genet 47:1166, 1993

49. de Grouchy J, Gompel A, Salomon-Bernard Y, et al: Embryonic testicular regression syndrome and severe mental retardation in sibs. Ann Genet 28:154, 1985

50. Pivnick EK, Wachtel S, Woods D, et al: Mutations in the conserved domain of SRY are uncommon in XY gonadal dysgenesis. Hum Genet 90:308, 1992

51. Mendonca BB, Russell AJ, Vasconcelos-Leite M, et al: Mutation in 3 beta-hydroxysteroid dehydrogenase type II associated with pseudohermaphroditism in males and premature pubarche or cryptic expression in females. J Mol Endocrinol 12:119, 1994

52. Zenteno JC, Jimenez AL, Canto P, et al: Clinical expression and SRY gene analysis in XY subjects lacking gonadal tissue. Am J Med Genet 99:244, 2001

53. Smith A, Fraser IS, Noel M: Three siblings with premature gonadal failure. Fertil Steril 32:528, 1979

54. Granat M, Amar A, Mor-Yosef S, et al: Familial gonadal germinative failure: Endocrine and human leukocyte antigen studies. Fertil Steril 40:215, 1983

55. Brunskill PJ: The effects of fetal exposure to danazol. Br J Obstet Gynaecol 99:212, 1992

56. Hamet P, Kuchel O, Nowaczynski W, et al: Hypertension with adrenal, genital, renal defects, and deafness. A new familial syndrome Arch Intern Med 131:563, 1973

57. Al Awadi SA, Farag TI, Teebi AS, et al: Primary hypogonadism and partial alopecia in three sibs with mullerian hypoplasia in the affected females. Am J Med Genet 22:619, 1985

58. Mikati MA, Najjar SS, Sahli IF, et al: Microcephaly, hypergonadotropic hypogonadism, short stature, and minor anomalies: A new syndrome. Am J Med Genet 22:599, 1985

59. Parker KL, Schimmer BP: Steroidogenic factor 1: A key determinant of endocrine development and function. Endocr Rev 18:361, 1997

60. Luo X, Ikeda Y, Parker KL: A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77:481, 1994

61. Achermann JC, Ito M, Ito M, et al: A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet 22:125, 1999

62. Simpson JL, Elias S: Genetics in Obstetrics and Gynecology. 3rd ed.. Philadelphia, W.B. Saunders, 2003

63. Hornblass A, Reifler DM: Ablepharon macrostomia syndrome. Am J Ophthalmol 99:552, 1985

64. Riccardi VM, Borges W: Aniridia, cataracts, and Wilms tumor. Am J Ophthalmol 86:577, 1978

65. Riccardi VM, Sujansky E, Smith AC, et al: Chromosomal imbalance in the Aniridia-Wilms’ tumor association: 11p interstitial deletion. Pediatrics 61:604, 1978

66. Rodriguez JI, Palacios J, Omenaca F, et al: Polyasplenia, caudal deficiency, and agenesis of the corpus callosum. Am J Med Genet 38:99, 1991

67. Sirota L, Shabtai F, Landman I, et al: New anomalies found in the 11q-syndrome. Clin Genet 26:569, 1984

68. Habib R, Loirat C, Gubler MC, et al: The nephropathy associated with male pseudohermaphroditism and Wilms’ tumor (Drash syndrome): A distinctive glomerular lesion. Report of 10 cases Clin Nephrol 24:269, 1985

69. Turleau C, Niaudet P, Sultan C, et al: Partial androgen receptor deficiency and mixed gonadal dysgenesis in Drash syndrome. Hum Genet 75:81, 1987

70. Greenberg F, Keenan B, De Yanis V, et al: Gonadal dysgenesis and gonadoblastoma in situ in a female with Fraser (cryptophthalmos) syndrome. J Pediatr 108:952, 1986

71. Gattuso J, Patton MA, Baraitser M: The clinical spectrum of the Fraser syndrome: report of three new cases and review. J Med Genet 24:549, 1987

72. Merrer ML, Briard ML, Girard S, et al: Lethal acrodysgenital dwarfism: A severe lethal condition resembling Smith-Lemli-Opitz syndrome. J Med Genet 25:88, 1988

73. Rutledge JC, Friedman JM, Harrod MJ, et al: A “new” lethal multiple congenital anomaly syndrome: Joint contractures, cerebellar hypoplasia, renal hypoplasia, urogenital anomalies, tongue cysts, shortness of limbs, eye abnormalities, defects of the heart, gallbladder agenesis, and ear malformations. Am J Med Genet 19:255, 1984

74. Koppe R, Kaplan P, Hunter A, et al: Ambiguous genitalia associated with skeletal abnormalities, cutis laxa, craniostenosis, psychomotor retardation, and facial abnormalities (SCARF syndrome). Am J Med Genet 34:305, 1989

75. Cooper CP, Hall CM: Lethal short-rib polydactyly syndrome of the Majewski type: A report of three cases. Radiology 144:513, 1982

76. Silengo MC, Bell GL, Biagioli M, et al: Oro-facial-digital syndrome II. Transitional type between the Mohr and the Majewski syndromes: report of two new cases Clin Genet 31:331, 1987

77. Bialer MG, Penchaszadeh VB, Kahn E, et al: Female external genitalia and mullerian duct derivatives in a 46,XY infant with the Smith-Lemli-Opitz syndrome. Am J Med Genet 28:723, 1987

78. Joseph DB, Uehling DT, Gilbert E, et al: Genitourinary abnormalities associated with the Smith-Lemli-Opitz syndrome. J Urol 137:719, 1987

79. Sofatzis JA, Alexacos L, Skouteli HN, et al: Malformed female genitalia in newborns with the VATER association. Acta Paediatr Scand 72:923, 1983

80. Kallen K, Mastroiacovo P, Castilla EE, et al: VATER non-random association of congenital malformations: Study based on data from four malformation registers. Am J Med Genet 101:26, 2001

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