Nonadrenal familial female hermaphroditism

Nonadrenal familial female hermaphroditism I.

JAMES

PARK,

HOWARD

W.

RAFIK Baltimore,

E.

M.D. JONES,

JR.,

MELHEM,

M.D

M.D.*

Maryland

Two female hermophrodites with bony anomalies and primary amenorrhea in siblings are reported. The laboratory studies showed normal urinary 17-ketosteroid excretion, low urinary gonadotropins, and 46,Xx karyotype.

F E M A L E hermaphroditism may be divided into the following categoriesl: (1) congenital virilizing adrenal hyperplasia, (2) androgenie maternal or exogenous hormone during pregnancy, (3) idiopathic, (4) special, (5) familial. Masculinization of the female external genitals in siblings, other than those with virilizing adrenal hyperplasia, has not been reported previously. In this paper are reported two previously unpublished siblings with ambiguous external genitals associated with bony anomalies and primary amenorrhea. Case

report

Case 1. C. C. (JHH 891446), born March 31, 1951, was a product of the first pregnancy between a 30-year-old father and a 27-year-old mother. The mother was ill intermittently with kidney disease during the course of this pregnancy, and the child was born a month prematurely. Birth weight was 5 pounds. The mother took no medication other than vitamins and iron during this pregnancy. The mother and father had the same great grandfather. The father had a long trunk and From the Department Obstetrics, The Johns Received 1971.

for publication

;l;;;pted

for

*Present Radiology, Hospital,

publication

of

Gynecology and

Hopkins

Hospital.

November 18, December

address: the Department of The American University Beirut, Lebanon.

20,

occurring

contracture in the hands with inability to make a fist. He was deferred from military service, but the exact nature of his physical abnormalities is not known. The patient has a younger sister (Case 2) with the same problems. The mother divorced the patient’s father after the second pregnancy and, by a second husband, has had 2 normal girls, 14 and 8 years old. The patient was born with ambiguous external genitals and was raised as a male until 9 months of age when first seen by US. Physical findings at that time (1952) showed a somewhat undernourished infant who weighed 15.5 pounds (about 6 pounds below the average weight for her height). Height was 29.8 inches (several inches taller than normal for her age). The patient had a square brachycephalic head and a rather broad, flat nose. The hands were peculiarly shaped with long slender palms and poorly developed thenar and hypothenar eminences. The external genitals showed an enlarged clitoris which consisted mostly of a fleshy protuberance resembling a phallus and measured 2 cm. in length and 1 cm. in diameter. There were no corpora felt under this. There was a single external orifice about 5 mm. in diameter through which she voided. This was located in the normal position of a female urethra. There was no gonad felt in the labioscrotal fold or inguinal canal. There was moderate posterior fusion of the labioscrotal folds. The vaginal cavity was 2.5 cm. long and one cm. in diameter. The vagina and urethra connected to form the urogenital sinus which led to the single external orifice. The remainder of the examination was normal. Exploratory laparotomy at that time showed a normal uterus, bilateral tubes, and ovaries. The

Volume Number

II? 1

Nonadrenal

familial

female

hermaphroditism

931

Fig. 2. X-ray view of left hand of Patient C. C. showing long and slender bones which may be due to hypogonadism.

Fig. 1. Anterior aly of elbow.

view of Patient C. C. Note anom-

microscopic examination of an ovarian biopsy showed a normal ovary. The 17-ketosteroid excretion was 0.76 mg. per 24 hours. Cystoscopic examination showed normal bladder, urethra, and trigone. Intravenous pyelogram was normal. Osseous development by x-ray examination showed considerable scattering between the ages of 1 and 3 years, with an average of 2 years. There was no evidence of rickets or scurvy. The parents were advised to raise the child as a gir1. At the age of 5 years, she was readmitted to the hospital for clitorectomy and exteriorization of the vagina. At the age of 17 years, she was readmitted because of primary amenorrhea. Height was 65% inches, and weight was 165% pounds (Fig. 1). General examination was negative except for the

brachycephalic head with flat nose and ahnormalities of the extremities. The thumbs were shorter in comparison to the index and middle fingers. The fingers were long and slender (Fig. 2). Flexion at the metacarpophalangeal joints was Iimited to 45 degrees. ,Supination and pronation were also limited. The second toes were abnormally long. There was some breast development, probably due to obesity, and pubic hair was poorly developed in the female type. External genitals, as corrected by previous operation, were now of female character. Serum thyroxine was 14.3 pg per 100 ml. (normal 5.6 to 12.6). Urinary gonadotropin was positive at 6 mu. per 24 hours and negative at 12 mu. per 24 hours. Buccal smear was positive in 26 per cent of the cells. Chromosome study was 46,Xx. For x-ray study, see Table I. Case 2. W. %. (JHH 1303941), born July 16, 1952, younger sister of the patient in Case I, was first seen by us at the age of 16 years because of abnormal genitals. She was the product of her mother’s second pregnancy at the age of 28 years. The prenatal course was uneventful. There was no unusual medication during pregnancy. The child was born at term and weighed 7 pounds and 2 ounces. At birth, the ambiguous external genitals were noted, but she was raised as a female. At the age of 4 years, she was treated for urinary incontinence. As she grew, she became a “tomboy,” liked to wear male clothing, and always had a deeper than usual voice. She was a poor student

932

April 1, IYT:’ Am. J. Obstet. Gynrcol.

Park, Jones, and Melhem

Table I. Radiologic

findings Patient

Skull

Normal

Mandibles

Hypoplasia dyle

and

Hypoplasia

of maxilla

Facial

bones

Spine

bony

W. C. Normal

shortening

of mandibular

Vertebrae, narrow anteroposteriorly er than usual. Lack of normal the interpedicular distance in spina from Ll-L5

Long bones General Elbows

Femora Feet

Bone

age

Hypoplasia condyle

and shortening

Hypoplasia

of maxilla

changes

The epiphyses are flat and small, long bones are slender with long hands Fusion of the humerus and ulna on right, anterior dislocation of left radius in the left elbow joint-mild bowing of left radius Bilateral coxa valga Fusion of proximal and middle phalanx of both fifth toes, fusion of middle and distal phalanges of third and fourth toes Slight delay, bone age 13% yr. with chronologic age of 16 yrs.

Same

as for Patient

movement

in

the

joints

of

the

hands

was normal. The right elbow was fixed in a position of 120 degrees (60 degrees from full extension) with apparent bony fusion (Fig. 5). Supination and pronation were impossible. The second toes were unusually long. Cystometric study showed an atonic bladder with increased capacity, but no neurologic exwas found for this condition. planation

C. C.

structure

Same

managed to progress to the eighth grade. She developed pubic hair at the age of 11 years, and axillary hair started about the same time. There was no menstruation or breast development. She voided only once or twice daily in a large amount and retained urine for 12 hours or longer, despite a large intake of fluids. Physical examination was performed at the age of 16 years (Fig. 3). Height was 65ya inches. Weight was 114j/a pounds. General physical examination was negative. There was no breast development. The clitoris was enlarged with marked fusion of the labioscrotal folds. The urethra was located under the enlarged clitoris (Fig. 4). By retracting the labia, it was possible to enter the vagina which seemed to be of about normal capacity. There was some pubic hair of female distribution. No gonad was felt in the groin. The thumbs were short compared to the index and middle fingers. Flexion at the metacarpophalangeal joint was limited to 45 degrees, other

con-

bony

and longincrease in the lumbar

but

but

Patient

structure

as in

of mandibular

Patient

W.

C.

W. C.

Bilateral posterior dislocation or radial heads in the elbow joints, marked bowing of the radius on both sides Bilateral coxa valga, mild Same changes as for Patient W. C.

Slight delay, chronologic

bone age 14 age of 17 years

years

with

Cystoscopy was normal. Intravenous pyelogram showed a hypoplastic left kidney and dilatation of the right calyceal system, probably of inflammatory origin. The urinary 17-ketosteroid excretion was 5.4 mg. per 24 hours. The 17-hydroxycorticoid execretion was 7.6 mg. per 24 hours. Urinary gonadotropins were negative at 6 mu. per 24 hours. Serum thyroxine determination was 10.7 pg per 100 ml. (normal 5.6 to 12.6). Sex chromatin was positive in 22 per cent, and the chromosome study showed a 46,xX karyotype. The

vaginal

smear

showed

marked

atrophy.

For

x-ray study, see Table I. Exploratory laparotomy, reconstruction of external genitals, and ovarian biopsy were performed. The laparotomy showed normal tubes, uterus, and ovaries. Microscopic studies showed normal ovaries as well as tubes and uterus.

Comment The sibship under discussion seems to have 3 unique features which distinguish this form from other types of female hermaphroditism: ( 1) familial occurrence, (2) bony anomalies, and (3) primary amenorrhea. As mentioned above, female hermaphroditism due to virilizing congenital adrenal hyperplasia occurs in families as an autosoma1 recessive trait.2 In this condition the 17-

Volurllc Numbei

Nonadrenal

I12 7

Fig.

Fig. 3. Whole of elbow.

view

of Patient

W. C. Note

familial

4. External

female

genitals

hermaphroditism

of Patient

W.

933

C.

anomaly

ketosteroid excretion is elevated, and progressive virilization occurs in untreated patients. None of these features was seen in our cases. The parental consanguinity and history of a hand malformation in the father resembling that in his two daughters raises the question of whether he suffered from a similar syndrome inherited as an autosomal dominant, but the expression of which in the generative organs is not recognizable in the male, or the skeletal abnormalities are an independent

Fig. 5. X-ray lesion could

view of elbow of Patient W. not be due to hypogonadism.

C. This

934

Park,

Jones,

and

Melhem

autosomal dominant trait. The small flat epiphyses, long slender bones, and delayed bone age are seen in persons with hypogonadism. Hypogonadism is known to cause delay in the growth and closure of the epiphysis though it does not significantly affect the time of ossification. This picture fits well with the fact that the patients failed to menstruate until the ages of 20 and 19 years (at the time of this writing) and had atrophic smears. The low gonadotropin and the lack of estrogen in these patients indicate the primary amenorrhea is most probably due to hypothalamic or pituitary origin. Inability to perform further study of these patients made it impossible to delineate this aspect of the problem. It is to be emphasized

Am.

April 1, 1972 J. Obstet. Gynecol.

that the changes seen in the elbows and inability to make fists cannot be related to the hypogonadism and must represent a conTherefore, these may genital condition. represent the only bony or neurologic aspects of the inherited syndrome. The normal 17-ketosteroid level, no progressive virilization, no menstruation, no androgenic influence during pregnancy, familial occurrence, and bony anomalies are points differentiating this condition from other groups of female hermaphroditism. For these reasons, it seems likely that the above siblings represent a nonadrenal genetically determined form of female hermaphrodite, a syndrome previously undescribed.

REFERENCES

1. Jones, H. W., Jr., and Scott, W. W.: Hermaphroditism, Genital Anomalies and Related Endocrine Disorders, Baltimore, 1971, ed. 2, The Williams & Wilkins Company.

2. Childs, B., Grumbach, M. M., and Van Wyk, J. J.: J. Clin. Invest. 35: 213, 1956.