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Leprechaunism (Donohue's syndrome)
372
T h e Journal o/ P E D I A T R I C S
Leprechaunism (Donobue'ssyndrome) Two cases of leprechaunism in sisters are described and compared with data o[ other cases described previously.
A. K~ill6, Irene Lakatos, and L. Szijfirt6 BUDAPEST~ HUNGARY
D o N o K u E in 19481 described an u n u s u a l syndrome in a n e w b o r n infant. H e was u n a b l e to identify the striking changes in this i n f a n t with any k n o w n disease entity. This syndrome was at that time called dysendocrinism. Six years later a n o t h e r child of the stone parents also exhibited the same bizarre abnormalities. T h e two cases were reported in more detail by D o n o h u e a n d U c h i d a ~ in 1954 a n d leprechaunism was suggested as a n a m e for the syndrome. T h e term leprechaunism was derived from Irish folklore. Leprechauns are mythical, benign, hairy dwarfs who are reputed to have the ability to reveal treasure troves. It was suggested that these patients had some of the appearances of leprechauns. I n 1955, two additional patients with similar abnormalities were described by E v a n s ? Following this publication we encountered the two cases which are reported here. After our studies were completed, two additional cases were described by Patterson a n d Watkins, * a n d Salmon a n d Webb, 5 respectively, who thought they had detected leprechaunism in males. W e do not consider these latter observations to be identical with
From the Departments of Pathology and Paediatrics, John's Hospital, Budapest XII, Hungary,
the cases previously reported. I n the original cases, the changes in the ovary were paramount. CASE I Clinical data. Edith B. was admitted immediately after birth. Because of her birth weight 9of 1,650 grams she was considered to be premature. However, delivery took place at the proper time. Date of last menses was July 22, 1957, and delivery was May 31, 1958. On initial examination, the low birth weight, small size, gaping vulva and prominent labia minor, and the excessive lanugo were considered to be in keeping with premature birth and proper treatment was instituted. Circulation and breathing were normal. Bottle feeding was satisfactory. At the age of about 10 days it became obvious that while other infants of the same age had good tissue turgot with round and rosy faces, this particular "premature" infant had the facial expression of an old man. The skin was wrinkled and the lanugo was even more prominent than at birth. The subcutaneous tissue was diminished and the sucking pads of the cheeks had disappeared. Furuncules and penphigoid vesicles were scattered over the surface of the body. The facies was particularly grotesque. The nose was broad and protruding. The eyes were widely spaced and prominent (hypertelorism). The ears were large and low set. The nipples protruded like buttons and the external genitals showed the abnormalities stated above.
Volume 66
Leprechaunlsm
Number 2
The following investigations were carried out. Roentgenograms of the chest and sella were negative. An electrocardiogram, which was made because of a systolic m u r m u r , was negative. A blood film showed a shift to the left in the polymorphonuclear leukocytes. This was probably because of the furunculosis. T h e excretion of urinary 17-ketosteroids was about 1.9 mg. per day. (Normal at 3 w e e k s ~ . 5 mg. per day.)
(Donohue's syndrome)
37 3
T h e clinical diagnosis was leprechaunism. Two days after the diagnosis was established, the infant died at 3 weeks of age. CASE II Clinical data. A year and a half after Edith, a second child, Erika, was born to the same mother. Pregnancy and delivery were again normal. The date of last menses was Dec. 27, 1958;
T a b l e I. A c o m p a r i s o n of t h e m e a s u r e m e n t s of E d i t h , 3 w e e k s old; E r i k a , 6 w e e k s o l d ; a 7 - m o n t h - o l d f e t u s ; a n d a n o r m a l n e w b o r n ( A f t e r R o e s s l e a n d R o u l e t 6, a n d P o t t e r 7)
7th intra- [ uterine month I
Normal newborn
Edith (3 weeks old)
Erika (6 weeks old)
1,492 grams
3,200 grams
1,700 grams 1,330 grams
1,850 grams 1,300 grams
40 era.
50 cm.
46 cm. 46 cm.
47 cm. 40 cm.
33 cm.
30 cm. 33 cm.
31 cm. 32.5 cm.
28.5 em.
28 cm. 20 cm.
27 cm. 19 cm.
Weight At birth At death
Length At birth At death
Circum[erence o[ cranium At birth At death
Cireum[erenee o[ chest At birth At death
Upper extremities Arm Forehand Hand
10 era.} 9 cm. 26 cm. 7 cm.
8 era. } 7 cm. 21 cm. 6 em.
12 cm. ] 11 c m . [ 31 cm. 8 era. J
7 cm. 7 era.
Lower extremities Thigh Leg Foot
em.
24 cm.
6.5 c m . ] 7 cm.~ 20.5 em. 7 cm. J
8sin} 9cm. 7 cm.
24cm.
Distance of pupils
3.5 cm.
3.5 cm.
Length/width of ear
4/2 cm.
3.5/2.5 cm.
Length of hair (on the head)
4.5 era.
4.5 cm.
Weight of spleen Weight of liver Weight of pancreas
4 Gm. 66.3 Gin.
10.82 Gm. 133 Gm.
2.70 Gin. 42 Gm.
1.6 Gm.
3.11 Gm.
1.2 Gm.
13.6 Gin.
23.42 Gm.
13.5 Gm. 10.5 Gm. / 24 Gin.
83 Gm. 1.5 Gin.
Weight o[ kidneys Left kidney Right kidney
0.59 Gm.
1 Gin.
1 Gm.
0.5 Gm.
5.23 Gm.
2.9 Gin.
2 Gm.
0.25 Gin.
2.1 Gin.
0.90 Gin.
Weight of thyroid
1.3 Gm.
2.75 Gm.
Weight of thymus
"5.1 Gm.
10.93 Gin.
Weight of adrenals
4.3 Gm.
Ovary
13 Gin. ~ Gm 10.5 Gm.~ 23"5 "
3 7 4 Kdlid, Lakatos, and Szi)drtd
February 1965
Fig. 1. Photograph of Edith. Relatively large head, abundant and long hair, root of the nose sunken, large, deep-set ears, distended and protruding abdomen, and relatively large feet.
birth was Sept. 30, 1959. This infants was essentially identical with her older sibling. Her birth weight was 1,800 grams. She appeared oldish with a leprechaun-like facial expression and low-set ears. There was extremely thick hair over all of the body. This was much more prominent than ordinary lanugo. In addition, the hair on the head was abnormally long. The skin over most
Fig. 2. Photograph of Erika. Abundant and long hair, facies and forehead covered with hair, moustache and beard, widely spaced eyes, clubbed nose, small chin, deep set ears, and old man-like facial expression.
of the body was wrinkIed with a total absence of subcutaneous fat. The nipples were prominent and buttonlike. The vulva was gaping with prominent labia minora. A soft systolic m u r m u r was present in the precordial area. Laboratory data. Roentgenograms of the chest and sella were negative. The blood picture was within normal limits. The fasting blood sugar fluctuated between 75 and 161 mg. per cent. The glucose tolerance test was 71, 171, 114, and 7I mg. per cent at 0, ~2, 1 and 2 hours, respectively. The following values were obtained for the serum electrolytes: sodium, 313 mg. per cent; potassium, 18.3 rag. per cent; calcium, 10 rag. per cent; and phosphorus, 5 mg. per cent. The urinary 17-ketosteroids were 3.7 mg. per cent and the corticoids, 0. As this infant was under observation longer than patient I, following the suggestion of Evans, s an attempt was made to reduce the overproduction of estrogens b y the administration of methyltestosterone. After 2 weeks on this medication, no change was detected in the general condition of the patient except for an increased growth of hair. In order to reduce the production of the pituitary gonadotrophic hormone, cortisone was given, although similar attempt by Evans had not been entirely successful. It was impossible to evaluate the result of the treatment in this infant because she died at 6 weeks of age shortly after the introduction of the treatment. The postmortem findings showed (Table I) that Erika was, in respect to the weights of some organs i.e., liver, spleen, and thyroid, more developed than Edith. The three week age difference did not account for this, however, since the body weight of the second infant who lived 6 weeks was less than that of her sister who survived only 3 weeks.
Volume 66 Number 2
PATHOLOGY External exalnination. Because the postmortem findings were essentially the same for each case, these will be summarized pointing out the differences where necessary (see also T a b l e I). I n b o t h cadavers the striking features were the u n d e r d e v e l o p m e n t of the body for the age of the patient, the disproportion of various parts of the body, a n d the usual facies (Figs. 1 a n d 2). Both infants were considerably underweight. This was particularly noticeable in Erika, who, a l t h o u g h she lived six weeks, did not a t t a i n more t h a n half the b i r t h weight of a n o r m a l infant. T h e body length a n d chest circumference was also m u c h less t h a n normal. Only the measurements of the c r a n i u m were t h a t of a n o r m a l infant. U n d e r d e v e l o p m e n t was also p r o m i n e n t l y shown in the weights of the various organs with the exception of the kidneys and ovaries. T h e ovaries in b o t h cases were very m u c h enlarged; in patient I, E d i t h - - 1 0 times normal, in patient II, E r i k a - ~ times normal. T h e stage of developm e n t of the infants at the time of their death was in m a n y respects scarcely that of a 6- or 7m o n t h - o l d fetus. T h e disproportion of the extremities was manifested in the relatively large size of the hands a n d feet. This also applied to the circumference of the head. All of these, at the time of death, were approximately the same size as those of a n o r m a l infant ( T a b l e I a n d Figs. 1 and 3). T h e disproportionately large size of the hands and feet h a d been observed by others but to date a t t e n t i o n h a d not been directed to the relatively large cranium. T h e unusual facies was the result of the following abnormalities. Long a n d a b u n d a n t hair grew down over the forehead and extending down the cheeks in front of the ears. This was 4 or 5 cm. in length. Excessive lanugo was present over all the body, including the face. T h i s was particularly noticeable with regard to Erika, who h a d a regular moustache and beard. H e r thighs were hairy as well. T h e nose was Negroid, b r o a d at the tip with flaring nostrils. T h e chin was pointed, receding, and underdeveloped. T h e lips were thick. T h e ears were large, low-set, a n d contained a relatively small a m o u n t of cartilage. T h e angle between the nose-ear line and the forehead was almost a right angle. T h e eyes were large a n d widely spaced. All these features gave a n old-man, leprechaun-like expression to the facies (Figs. t a n d 2). T h e external e x a m i n a t i o n of the r e m a i n d e r of
Leprechaunism (Donohue's syndrome)
375
Fig. 3. Photograph of Edith. Big distended abdomen with the contour of the bowels visible, the external genitals are hypertrophied. The labia minora are abnormally prominent with thick clitoris. Skin of the Iower extremities are wrinkled. Emaciated feet disproportionately large.
the body revealed the following. T h e r e was emaciation with very little subcutaneous fat. T h e skin was loose and lay in folds. T h e a b d o m e n was distended and the contour of the intestines showed t h r o u g h the a b d o m i n a l wall (Fig. 4). T h e nipples were p r o m i n e n t a n d buttonlike (Fig. 5). T h e r e was h y p e r t r o p h y of the external genitals with a b n o r m a l protrusion of the labia minora. T h e clitoris was thick and clublike. T h e h y m e n was hypertrophied. A p u r u l e n t excretion was present in the vulva. T h e rectum was prolapsed. This was particularly m a r k e d in Edith. I n t e r n a l examination. T h e h e a r t was normal. I n the posterior and d e p e n d e n t parts of b o t h lungs there were n o d u l a r areas of consolidation. These were most p r o m i n e n t in Erika. Cervical organs were normal. Fatty tissues were not found, either subcutaneously or in the a b d o m i n a l cavity. Some jelly-like tissue was found in place of the fat. T h e gastrointestinal tract was n o r m a l except for distention of the intestines. I n b o t h girls the livers were m u c h smaller t h a n usual. Even the liver of 6-week-old E r i k a was less t h a n a n o r m a l n e w b o r n infant and corresponded
376
KdIl6, Lakatos, and Szijdrtd
Fig. 4. Photograph of Erika. Big, distended abdomen with the contour of the bowels visible. External genitaIs are hypertrophied as in Edith. T h i g h covered with hair.
Fig. 5. Photograph of Edith. Prominent disc, or buttonlike nipples, and distended abdomen with the contour of bowels visible.
Fig, 6. Edith. Small-scale enlargement of the cutsurface of the ovary, and cystic follicles of various size.
February 1965
with that of a p p r o x i m a t e l y a 6 m o n t h fetus. Both were grayish brown a n d their fine structure was indistinct. G a l l b l a d d e r a n d bile ducts were normal. T h e spleen was n o r m a l except for its small size in b o t h of them. T h e pancreas was small but n o r m a l to the n a k e d eye. O f all the viscera, the kidneys only were n o r m a l in weight. T h e cut surface showed a n a r r o w i n g of the cortical substance. T h a t of E d i t h measured I mm. and Erika scarcely 2 m m . T h i s change had not been observed in the previous reported cases. T h e brain in b o t h cases was starch-like. T h e gyri were fully developed but the gray m a t t e r was for the most part hardly distinguishable from the white. E n d o c r i n e glands. Hypophysis was removed together with the sella turcica in order to avoid injury. A d r e n a l glands were small, being approximately t h a t of a 7 m o n t h fetus. I n b o t h cases the thyroid was reduced in weight. T h e thymus was particularly small, a p p r o x i m a t e l y 1/10 the weight of a n o r m a l newborn. Ovaries showed the most striking changes. T h e y were enlarged, particulary those of Edith. T h e larger of Edith's ovaries was approximately I0 times normal, that of Erika, nearly 4 times normal. O n the surface of all four ovaries, but more noticeable in respect of Edith, small pinheadsize cysts Were visible. T h e cut surface of the ovaries in both cases showed several pinheadsize cysts (follicular) e m b e d d e d in a homogenous white tissue. Histology. T h e h e a r t was normal. T h e consolidated part of the lung showed the usual picture of b r o n c h o p n e u m o n i a . I n E r i k a there was, as well, interstitial pneumonitis. I n b o t h infants the Prussian blue reaction in accordance with previous observations showed hemosiderosis in the liver. Best's carmine stain d e m o n s t r a t e d large amounts of glycogen in Edith's liver and only a small a m o u n t in Erika's. T h e liver cells showed no change. I n Erika's liver, the connective tissue was increased. T h e spleen was within n o r m a l limits. I n b o t h cases the convoluted tubules of the kidney showed parenchymatous degeneration with irregular eosinophilic masses a n d a m o r p h o u s material in their lumina. I n the collecting tubules there were calcific a n d waxy casts in great numbers. Because of this, m a n y of these tubules were dilated. I n the endocrine organs the most striking microscopic changes were in the ovaries. I n b o t h infants follicles in various degrees of m a t u r a tion were present in great numbers. T h e r e was
Volume 66 Number 2
no evidence of luteinization. Some of the follicles formed small cysts (Figs. 6 and 7). Next to the ovaries, the most impressive changes were in the pancreas. The hyperplasia of the islets of Langerhans was so pronounced that in many areas the exocrine parenchyma was displaced. This was especially noticeable in Erika (Fig. 8). In the thyroid of Edith there were no colloidal follicles. In Erika, only a few were found. The major part of the parenchyma did not form follicles. In both patients the thymus showed numerous Hassall's corpuscles. Cystic degeneration of these were present in Erika (Fig. 9). In the adrenal glands the zona fasiculata was widened. In the hypophysis of both infants, particularly in the case of Edith, the chromophobe cells dominated the picture. The evaluation of this finding would, however, necessitate as a control, the examination of a large number of infant pituitaries with similar staining methods. As far as could be determined, there was nothing to indicate stimulation of follicular maturation.
Leprechaunism (Donohue's syndrome)
377
Fig. 7. Photomicrograph of a cystic follicle Of the ovary. The follicle is lined with follicular epithelium without luteinization. The lumen is filled with desquamative cells and detrifus.
DISCUSSION I t is obvious that our two cases are very similar to those r e p o r t e d by Donohue, Donohue a n d U c h i d a , a n d Evans. I n their cases, as in ours, one of the most i m p o r t a n t lesions was in the ovary, i.e., the p r e m a t u r e follicular m a t u r a t i o n a n d the cystic transformation of the follicles. T h e Original observers reg a r d e d the lesions of the ovary as significant. I n their opinion, this change indicated greatly increased estrogen production. This would also account for the e n l a r g e m e n t of the nipples, the labia minora, a n d the clitoris. I t would also account for the hyperplasia of the islets of L a n g e r h a n s a n d the increased u r i n a r y excretion of 17-ketosteroids. I n addition, the h y p e r p l a s i a of the islets of L a n g e r h a n s would result in increased insulin p r o d u c t i o n a n d an increase in glycogen deposition in the liver. T h e o v e r p r o d u c t i o n of estrogen w o u l d i m p e d e the o u t p u t of growthh o r m o n e by the hypophysis. This, in turn, would result in an arrest in the d e v e l o p m e n t of the fetus, abnormalities in bone m a t u r a tion, a n d a t r o p h y of the soft parts, especially the subcutaneous tissues. T h e stage of de-
Fig. 8. Photomicrograph showing the hyperplasia and increase of the islets of Langerhans.
Fig. 9. Photomicrograph showing the cystic abnormality of the Hassal bodies of the thymus.
378
Kdll6, Lakatos, and Szijdrt6
velopment of our two cases corresponded to that of a 6 or 7 month fetus. In regard to the etiology of the disease, Donohue and Uchida suggested a recessive inheritance because the parents of their two subjects were first cousins once removed. In our cases, we know of no consanguinity between the parents. However, the parents come from the same village in the country and since intermarriage between families in a vilIage is not uncommon, the parents may easily be related by blood and not be aware of it. The question as to what the factor is that causes the overproduction of estrogens in intrauterine life and, through resulting metabolic disturbances, brings about such unusual anatomical changes has not yet been answered. Another question is whether or not the syndrome indicates a new disease. This is the opinion of the Canadian and British authors. However, can it be classified with one of the known endocrine diseases? In order to answer this question, various syndromes that may have a relation to leprechaunism may be considered. Evans ~ suggested a relation between leprechaunism and Turner's syndrome. In our opinion, Turner's syndrome may be considered as the opposite of leprechaunism. One of the main features of the former is a deficiency rather than a hyperplasia of the ovaries. There is infantilism instead of hypertrophy of the external genitals. In Turner's syndrome, in contrast to leprechaunism, gonadotropin excretion is high and the 17ketosteroid excretion is reduced. It would be rather enticing to attribute these differences to the decrease or lack of ovary in one syndrome and to the ovarian hyperplasia in the other. If, however, etiology and not pathogenesis is considered, it becomes obvious that while the underlying feature in Turner's syndrome is a chromosomal abnormality, the genetic background for leprechaunism is neither proved nor known in detail. Because a number of the cases are familial, it may be inferred that leprechaunism is based on a genetic defect,
February 1965
One of the forms of progeria, the so-called Hutchinson-Gilford disease, has a number of features similar to those encountered in leprechaunism. These are the arrested development, the old man-like facial expression, the disproportion of the cranium, hypoplasia of the chin, and excessive loss of subcutaneous tissues. There are also many contradictory features. Leprechaunism is present in the newborn. Progeria develops later. Hairiness is a feature of leprechaunism, whereas alopecia is one of the characteristics of progeria. In leprechaunism, the nose is broad and Negroid; in progeria, it is narrow and beaked. In leprechaunism the ears are large; in progeria, the lobes are poorly developed. In leprechaunism the nipples are hypertrophied; in progeria they are atrophied. Thus, although the two diseases have a few features in common, they are essentially different and can be distinguished from each other and from all other developmental abnormalities with absolute certainty at the first glance. The disease in adults that furnishes the best analogy to leprechaunism is that in which there is a change in the ovaries characterized by overfunction and follicular microcysts. This is the so-called Stein-Leventhal syndrome. The main feature of both syndromes is estrogenic overfunction of the ovary, characterized by hypertrichosis with a masculine type of distribution. An important difference between the two diseases is that in the Stein-Leventhal syndrome, the formation of microcysts takes place in the adult while in leprechaunism, it must take place either in intrauterine life or shortly after birth. This explains the different manifestations of the two diseases. In the SteinLeventhal syndrome the ovarian dysfunction occurs in a fully developed individual, while in leprechaunism it has its beginning in a partially developed organism and, hence, the changes are more extensive and the end result quite unlike those which occur in the Stein-Leventhal syndrome. In spite of the differences, leprechaunism, as distinct from similar diseases in the newborn, may be classified with the Stein-Leventhal s}Tndrome
Volume 66 Number 2
and m a y be considered as its analogy in intrauterine life or infancy. Since, however, they are not identical, it is reasonable, as an alternative to leprechaunism, to call the disease Donohue's syndrome, after the author who published the original description. SUMMARY
T w o additional cases of leprechaunism occurring in sisters are described. These are similar in every respect to those reported by Donohue, Donohue and Uchida, and Evans. A main feature of the peculiar changes observed was the premature follicular maturation in the ovaries probably starting in the sixth to seventh intrauterine m o n t h with overproduction of estrogens. This resulted in the following changes: enlargement of the nipples and external genitals, hypertrichosis, increased excretion of 17-ketosteroids, hyperplasia of islets of Langerhans, and large kidneys with calcium deposits in the collecting tubules. With this there was a suppression of growth hormone, resulting in delay of bone growth. This syndrome was called leprechaunism because of the similarity of these to the
Leprechaunism (Donohue's syndrome)
3 79
appearances of the leprechauns of Irish folklore. It m a y be compared to the SteinLeventhal syndrome of adults and could be regarded as its analogy occurring in intrauterine life or in infancy. Leprechaunism m a y also be called Donohue's syndrome, after the original describer. Nothing is known as yet concerning the cause of the intrauterine follicular maturation.
REFERENCES
I. Donohue, W. L.: Dysendocrinlsm (elinicopathological conference) J. PEDIAT. 32: 739, 1948. 2. Donohue, W. L., and Uchida, I.: Leprechaunism, J. PEDIAT.45: 505, 1954. 3. Evans, P. R.: Leprechaunism, Arch. Dis. Childhood 30: 479, 1955. 4. Patterson, J. H., and Watkins, W. L.: Leprechaunism in a male infant, J. PEDrAT. 60" 730, 1962. 5. Salmon, M. A., and Webb, J. N.: Dystrophic changes associated with leprechaunism in a male infant, Arch. Dis. Childhood 38: 530, 1963. 6. Roessle, R., and Roulet F.: Mass und Zahl in der Pathologle, Berlin and Vienna, 1932, Springer Verlag. 7. Potter, E. L.: Pathology of the fetus and newborn, Chicago, 1952, The Year Book Medical Publishers, Inc., p. 13.
T h e Journal o/ P E D I A T R I C S
Leprechaunism (Donobue'ssyndrome) Two cases of leprechaunism in sisters are described and compared with data o[ other cases described previously.
A. K~ill6, Irene Lakatos, and L. Szijfirt6 BUDAPEST~ HUNGARY
D o N o K u E in 19481 described an u n u s u a l syndrome in a n e w b o r n infant. H e was u n a b l e to identify the striking changes in this i n f a n t with any k n o w n disease entity. This syndrome was at that time called dysendocrinism. Six years later a n o t h e r child of the stone parents also exhibited the same bizarre abnormalities. T h e two cases were reported in more detail by D o n o h u e a n d U c h i d a ~ in 1954 a n d leprechaunism was suggested as a n a m e for the syndrome. T h e term leprechaunism was derived from Irish folklore. Leprechauns are mythical, benign, hairy dwarfs who are reputed to have the ability to reveal treasure troves. It was suggested that these patients had some of the appearances of leprechauns. I n 1955, two additional patients with similar abnormalities were described by E v a n s ? Following this publication we encountered the two cases which are reported here. After our studies were completed, two additional cases were described by Patterson a n d Watkins, * a n d Salmon a n d Webb, 5 respectively, who thought they had detected leprechaunism in males. W e do not consider these latter observations to be identical with
From the Departments of Pathology and Paediatrics, John's Hospital, Budapest XII, Hungary,
the cases previously reported. I n the original cases, the changes in the ovary were paramount. CASE I Clinical data. Edith B. was admitted immediately after birth. Because of her birth weight 9of 1,650 grams she was considered to be premature. However, delivery took place at the proper time. Date of last menses was July 22, 1957, and delivery was May 31, 1958. On initial examination, the low birth weight, small size, gaping vulva and prominent labia minor, and the excessive lanugo were considered to be in keeping with premature birth and proper treatment was instituted. Circulation and breathing were normal. Bottle feeding was satisfactory. At the age of about 10 days it became obvious that while other infants of the same age had good tissue turgot with round and rosy faces, this particular "premature" infant had the facial expression of an old man. The skin was wrinkled and the lanugo was even more prominent than at birth. The subcutaneous tissue was diminished and the sucking pads of the cheeks had disappeared. Furuncules and penphigoid vesicles were scattered over the surface of the body. The facies was particularly grotesque. The nose was broad and protruding. The eyes were widely spaced and prominent (hypertelorism). The ears were large and low set. The nipples protruded like buttons and the external genitals showed the abnormalities stated above.
Volume 66
Leprechaunlsm
Number 2
The following investigations were carried out. Roentgenograms of the chest and sella were negative. An electrocardiogram, which was made because of a systolic m u r m u r , was negative. A blood film showed a shift to the left in the polymorphonuclear leukocytes. This was probably because of the furunculosis. T h e excretion of urinary 17-ketosteroids was about 1.9 mg. per day. (Normal at 3 w e e k s ~ . 5 mg. per day.)
(Donohue's syndrome)
37 3
T h e clinical diagnosis was leprechaunism. Two days after the diagnosis was established, the infant died at 3 weeks of age. CASE II Clinical data. A year and a half after Edith, a second child, Erika, was born to the same mother. Pregnancy and delivery were again normal. The date of last menses was Dec. 27, 1958;
T a b l e I. A c o m p a r i s o n of t h e m e a s u r e m e n t s of E d i t h , 3 w e e k s old; E r i k a , 6 w e e k s o l d ; a 7 - m o n t h - o l d f e t u s ; a n d a n o r m a l n e w b o r n ( A f t e r R o e s s l e a n d R o u l e t 6, a n d P o t t e r 7)
7th intra- [ uterine month I
Normal newborn
Edith (3 weeks old)
Erika (6 weeks old)
1,492 grams
3,200 grams
1,700 grams 1,330 grams
1,850 grams 1,300 grams
40 era.
50 cm.
46 cm. 46 cm.
47 cm. 40 cm.
33 cm.
30 cm. 33 cm.
31 cm. 32.5 cm.
28.5 em.
28 cm. 20 cm.
27 cm. 19 cm.
Weight At birth At death
Length At birth At death
Circum[erence o[ cranium At birth At death
Cireum[erenee o[ chest At birth At death
Upper extremities Arm Forehand Hand
10 era.} 9 cm. 26 cm. 7 cm.
8 era. } 7 cm. 21 cm. 6 em.
12 cm. ] 11 c m . [ 31 cm. 8 era. J
7 cm. 7 era.
Lower extremities Thigh Leg Foot
em.
24 cm.
6.5 c m . ] 7 cm.~ 20.5 em. 7 cm. J
8sin} 9cm. 7 cm.
24cm.
Distance of pupils
3.5 cm.
3.5 cm.
Length/width of ear
4/2 cm.
3.5/2.5 cm.
Length of hair (on the head)
4.5 era.
4.5 cm.
Weight of spleen Weight of liver Weight of pancreas
4 Gm. 66.3 Gin.
10.82 Gm. 133 Gm.
2.70 Gin. 42 Gm.
1.6 Gm.
3.11 Gm.
1.2 Gm.
13.6 Gin.
23.42 Gm.
13.5 Gm. 10.5 Gm. / 24 Gin.
83 Gm. 1.5 Gin.
Weight o[ kidneys Left kidney Right kidney
0.59 Gm.
1 Gin.
1 Gm.
0.5 Gm.
5.23 Gm.
2.9 Gin.
2 Gm.
0.25 Gin.
2.1 Gin.
0.90 Gin.
Weight of thyroid
1.3 Gm.
2.75 Gm.
Weight of thymus
"5.1 Gm.
10.93 Gin.
Weight of adrenals
4.3 Gm.
Ovary
13 Gin. ~ Gm 10.5 Gm.~ 23"5 "
3 7 4 Kdlid, Lakatos, and Szi)drtd
February 1965
Fig. 1. Photograph of Edith. Relatively large head, abundant and long hair, root of the nose sunken, large, deep-set ears, distended and protruding abdomen, and relatively large feet.
birth was Sept. 30, 1959. This infants was essentially identical with her older sibling. Her birth weight was 1,800 grams. She appeared oldish with a leprechaun-like facial expression and low-set ears. There was extremely thick hair over all of the body. This was much more prominent than ordinary lanugo. In addition, the hair on the head was abnormally long. The skin over most
Fig. 2. Photograph of Erika. Abundant and long hair, facies and forehead covered with hair, moustache and beard, widely spaced eyes, clubbed nose, small chin, deep set ears, and old man-like facial expression.
of the body was wrinkIed with a total absence of subcutaneous fat. The nipples were prominent and buttonlike. The vulva was gaping with prominent labia minora. A soft systolic m u r m u r was present in the precordial area. Laboratory data. Roentgenograms of the chest and sella were negative. The blood picture was within normal limits. The fasting blood sugar fluctuated between 75 and 161 mg. per cent. The glucose tolerance test was 71, 171, 114, and 7I mg. per cent at 0, ~2, 1 and 2 hours, respectively. The following values were obtained for the serum electrolytes: sodium, 313 mg. per cent; potassium, 18.3 rag. per cent; calcium, 10 rag. per cent; and phosphorus, 5 mg. per cent. The urinary 17-ketosteroids were 3.7 mg. per cent and the corticoids, 0. As this infant was under observation longer than patient I, following the suggestion of Evans, s an attempt was made to reduce the overproduction of estrogens b y the administration of methyltestosterone. After 2 weeks on this medication, no change was detected in the general condition of the patient except for an increased growth of hair. In order to reduce the production of the pituitary gonadotrophic hormone, cortisone was given, although similar attempt by Evans had not been entirely successful. It was impossible to evaluate the result of the treatment in this infant because she died at 6 weeks of age shortly after the introduction of the treatment. The postmortem findings showed (Table I) that Erika was, in respect to the weights of some organs i.e., liver, spleen, and thyroid, more developed than Edith. The three week age difference did not account for this, however, since the body weight of the second infant who lived 6 weeks was less than that of her sister who survived only 3 weeks.
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PATHOLOGY External exalnination. Because the postmortem findings were essentially the same for each case, these will be summarized pointing out the differences where necessary (see also T a b l e I). I n b o t h cadavers the striking features were the u n d e r d e v e l o p m e n t of the body for the age of the patient, the disproportion of various parts of the body, a n d the usual facies (Figs. 1 a n d 2). Both infants were considerably underweight. This was particularly noticeable in Erika, who, a l t h o u g h she lived six weeks, did not a t t a i n more t h a n half the b i r t h weight of a n o r m a l infant. T h e body length a n d chest circumference was also m u c h less t h a n normal. Only the measurements of the c r a n i u m were t h a t of a n o r m a l infant. U n d e r d e v e l o p m e n t was also p r o m i n e n t l y shown in the weights of the various organs with the exception of the kidneys and ovaries. T h e ovaries in b o t h cases were very m u c h enlarged; in patient I, E d i t h - - 1 0 times normal, in patient II, E r i k a - ~ times normal. T h e stage of developm e n t of the infants at the time of their death was in m a n y respects scarcely that of a 6- or 7m o n t h - o l d fetus. T h e disproportion of the extremities was manifested in the relatively large size of the hands a n d feet. This also applied to the circumference of the head. All of these, at the time of death, were approximately the same size as those of a n o r m a l infant ( T a b l e I a n d Figs. 1 and 3). T h e disproportionately large size of the hands and feet h a d been observed by others but to date a t t e n t i o n h a d not been directed to the relatively large cranium. T h e unusual facies was the result of the following abnormalities. Long a n d a b u n d a n t hair grew down over the forehead and extending down the cheeks in front of the ears. This was 4 or 5 cm. in length. Excessive lanugo was present over all the body, including the face. T h i s was particularly noticeable with regard to Erika, who h a d a regular moustache and beard. H e r thighs were hairy as well. T h e nose was Negroid, b r o a d at the tip with flaring nostrils. T h e chin was pointed, receding, and underdeveloped. T h e lips were thick. T h e ears were large, low-set, a n d contained a relatively small a m o u n t of cartilage. T h e angle between the nose-ear line and the forehead was almost a right angle. T h e eyes were large a n d widely spaced. All these features gave a n old-man, leprechaun-like expression to the facies (Figs. t a n d 2). T h e external e x a m i n a t i o n of the r e m a i n d e r of
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375
Fig. 3. Photograph of Edith. Big distended abdomen with the contour of the bowels visible, the external genitals are hypertrophied. The labia minora are abnormally prominent with thick clitoris. Skin of the Iower extremities are wrinkled. Emaciated feet disproportionately large.
the body revealed the following. T h e r e was emaciation with very little subcutaneous fat. T h e skin was loose and lay in folds. T h e a b d o m e n was distended and the contour of the intestines showed t h r o u g h the a b d o m i n a l wall (Fig. 4). T h e nipples were p r o m i n e n t a n d buttonlike (Fig. 5). T h e r e was h y p e r t r o p h y of the external genitals with a b n o r m a l protrusion of the labia minora. T h e clitoris was thick and clublike. T h e h y m e n was hypertrophied. A p u r u l e n t excretion was present in the vulva. T h e rectum was prolapsed. This was particularly m a r k e d in Edith. I n t e r n a l examination. T h e h e a r t was normal. I n the posterior and d e p e n d e n t parts of b o t h lungs there were n o d u l a r areas of consolidation. These were most p r o m i n e n t in Erika. Cervical organs were normal. Fatty tissues were not found, either subcutaneously or in the a b d o m i n a l cavity. Some jelly-like tissue was found in place of the fat. T h e gastrointestinal tract was n o r m a l except for distention of the intestines. I n b o t h girls the livers were m u c h smaller t h a n usual. Even the liver of 6-week-old E r i k a was less t h a n a n o r m a l n e w b o r n infant and corresponded
376
KdIl6, Lakatos, and Szijdrtd
Fig. 4. Photograph of Erika. Big, distended abdomen with the contour of the bowels visible. External genitaIs are hypertrophied as in Edith. T h i g h covered with hair.
Fig. 5. Photograph of Edith. Prominent disc, or buttonlike nipples, and distended abdomen with the contour of bowels visible.
Fig, 6. Edith. Small-scale enlargement of the cutsurface of the ovary, and cystic follicles of various size.
February 1965
with that of a p p r o x i m a t e l y a 6 m o n t h fetus. Both were grayish brown a n d their fine structure was indistinct. G a l l b l a d d e r a n d bile ducts were normal. T h e spleen was n o r m a l except for its small size in b o t h of them. T h e pancreas was small but n o r m a l to the n a k e d eye. O f all the viscera, the kidneys only were n o r m a l in weight. T h e cut surface showed a n a r r o w i n g of the cortical substance. T h a t of E d i t h measured I mm. and Erika scarcely 2 m m . T h i s change had not been observed in the previous reported cases. T h e brain in b o t h cases was starch-like. T h e gyri were fully developed but the gray m a t t e r was for the most part hardly distinguishable from the white. E n d o c r i n e glands. Hypophysis was removed together with the sella turcica in order to avoid injury. A d r e n a l glands were small, being approximately t h a t of a 7 m o n t h fetus. I n b o t h cases the thyroid was reduced in weight. T h e thymus was particularly small, a p p r o x i m a t e l y 1/10 the weight of a n o r m a l newborn. Ovaries showed the most striking changes. T h e y were enlarged, particulary those of Edith. T h e larger of Edith's ovaries was approximately I0 times normal, that of Erika, nearly 4 times normal. O n the surface of all four ovaries, but more noticeable in respect of Edith, small pinheadsize cysts Were visible. T h e cut surface of the ovaries in both cases showed several pinheadsize cysts (follicular) e m b e d d e d in a homogenous white tissue. Histology. T h e h e a r t was normal. T h e consolidated part of the lung showed the usual picture of b r o n c h o p n e u m o n i a . I n E r i k a there was, as well, interstitial pneumonitis. I n b o t h infants the Prussian blue reaction in accordance with previous observations showed hemosiderosis in the liver. Best's carmine stain d e m o n s t r a t e d large amounts of glycogen in Edith's liver and only a small a m o u n t in Erika's. T h e liver cells showed no change. I n Erika's liver, the connective tissue was increased. T h e spleen was within n o r m a l limits. I n b o t h cases the convoluted tubules of the kidney showed parenchymatous degeneration with irregular eosinophilic masses a n d a m o r p h o u s material in their lumina. I n the collecting tubules there were calcific a n d waxy casts in great numbers. Because of this, m a n y of these tubules were dilated. I n the endocrine organs the most striking microscopic changes were in the ovaries. I n b o t h infants follicles in various degrees of m a t u r a tion were present in great numbers. T h e r e was
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no evidence of luteinization. Some of the follicles formed small cysts (Figs. 6 and 7). Next to the ovaries, the most impressive changes were in the pancreas. The hyperplasia of the islets of Langerhans was so pronounced that in many areas the exocrine parenchyma was displaced. This was especially noticeable in Erika (Fig. 8). In the thyroid of Edith there were no colloidal follicles. In Erika, only a few were found. The major part of the parenchyma did not form follicles. In both patients the thymus showed numerous Hassall's corpuscles. Cystic degeneration of these were present in Erika (Fig. 9). In the adrenal glands the zona fasiculata was widened. In the hypophysis of both infants, particularly in the case of Edith, the chromophobe cells dominated the picture. The evaluation of this finding would, however, necessitate as a control, the examination of a large number of infant pituitaries with similar staining methods. As far as could be determined, there was nothing to indicate stimulation of follicular maturation.
Leprechaunism (Donohue's syndrome)
377
Fig. 7. Photomicrograph of a cystic follicle Of the ovary. The follicle is lined with follicular epithelium without luteinization. The lumen is filled with desquamative cells and detrifus.
DISCUSSION I t is obvious that our two cases are very similar to those r e p o r t e d by Donohue, Donohue a n d U c h i d a , a n d Evans. I n their cases, as in ours, one of the most i m p o r t a n t lesions was in the ovary, i.e., the p r e m a t u r e follicular m a t u r a t i o n a n d the cystic transformation of the follicles. T h e Original observers reg a r d e d the lesions of the ovary as significant. I n their opinion, this change indicated greatly increased estrogen production. This would also account for the e n l a r g e m e n t of the nipples, the labia minora, a n d the clitoris. I t would also account for the hyperplasia of the islets of L a n g e r h a n s a n d the increased u r i n a r y excretion of 17-ketosteroids. I n addition, the h y p e r p l a s i a of the islets of L a n g e r h a n s would result in increased insulin p r o d u c t i o n a n d an increase in glycogen deposition in the liver. T h e o v e r p r o d u c t i o n of estrogen w o u l d i m p e d e the o u t p u t of growthh o r m o n e by the hypophysis. This, in turn, would result in an arrest in the d e v e l o p m e n t of the fetus, abnormalities in bone m a t u r a tion, a n d a t r o p h y of the soft parts, especially the subcutaneous tissues. T h e stage of de-
Fig. 8. Photomicrograph showing the hyperplasia and increase of the islets of Langerhans.
Fig. 9. Photomicrograph showing the cystic abnormality of the Hassal bodies of the thymus.
378
Kdll6, Lakatos, and Szijdrt6
velopment of our two cases corresponded to that of a 6 or 7 month fetus. In regard to the etiology of the disease, Donohue and Uchida suggested a recessive inheritance because the parents of their two subjects were first cousins once removed. In our cases, we know of no consanguinity between the parents. However, the parents come from the same village in the country and since intermarriage between families in a vilIage is not uncommon, the parents may easily be related by blood and not be aware of it. The question as to what the factor is that causes the overproduction of estrogens in intrauterine life and, through resulting metabolic disturbances, brings about such unusual anatomical changes has not yet been answered. Another question is whether or not the syndrome indicates a new disease. This is the opinion of the Canadian and British authors. However, can it be classified with one of the known endocrine diseases? In order to answer this question, various syndromes that may have a relation to leprechaunism may be considered. Evans ~ suggested a relation between leprechaunism and Turner's syndrome. In our opinion, Turner's syndrome may be considered as the opposite of leprechaunism. One of the main features of the former is a deficiency rather than a hyperplasia of the ovaries. There is infantilism instead of hypertrophy of the external genitals. In Turner's syndrome, in contrast to leprechaunism, gonadotropin excretion is high and the 17ketosteroid excretion is reduced. It would be rather enticing to attribute these differences to the decrease or lack of ovary in one syndrome and to the ovarian hyperplasia in the other. If, however, etiology and not pathogenesis is considered, it becomes obvious that while the underlying feature in Turner's syndrome is a chromosomal abnormality, the genetic background for leprechaunism is neither proved nor known in detail. Because a number of the cases are familial, it may be inferred that leprechaunism is based on a genetic defect,
February 1965
One of the forms of progeria, the so-called Hutchinson-Gilford disease, has a number of features similar to those encountered in leprechaunism. These are the arrested development, the old man-like facial expression, the disproportion of the cranium, hypoplasia of the chin, and excessive loss of subcutaneous tissues. There are also many contradictory features. Leprechaunism is present in the newborn. Progeria develops later. Hairiness is a feature of leprechaunism, whereas alopecia is one of the characteristics of progeria. In leprechaunism, the nose is broad and Negroid; in progeria, it is narrow and beaked. In leprechaunism the ears are large; in progeria, the lobes are poorly developed. In leprechaunism the nipples are hypertrophied; in progeria they are atrophied. Thus, although the two diseases have a few features in common, they are essentially different and can be distinguished from each other and from all other developmental abnormalities with absolute certainty at the first glance. The disease in adults that furnishes the best analogy to leprechaunism is that in which there is a change in the ovaries characterized by overfunction and follicular microcysts. This is the so-called Stein-Leventhal syndrome. The main feature of both syndromes is estrogenic overfunction of the ovary, characterized by hypertrichosis with a masculine type of distribution. An important difference between the two diseases is that in the Stein-Leventhal syndrome, the formation of microcysts takes place in the adult while in leprechaunism, it must take place either in intrauterine life or shortly after birth. This explains the different manifestations of the two diseases. In the SteinLeventhal syndrome the ovarian dysfunction occurs in a fully developed individual, while in leprechaunism it has its beginning in a partially developed organism and, hence, the changes are more extensive and the end result quite unlike those which occur in the Stein-Leventhal syndrome. In spite of the differences, leprechaunism, as distinct from similar diseases in the newborn, may be classified with the Stein-Leventhal s}Tndrome
Volume 66 Number 2
and m a y be considered as its analogy in intrauterine life or infancy. Since, however, they are not identical, it is reasonable, as an alternative to leprechaunism, to call the disease Donohue's syndrome, after the author who published the original description. SUMMARY
T w o additional cases of leprechaunism occurring in sisters are described. These are similar in every respect to those reported by Donohue, Donohue and Uchida, and Evans. A main feature of the peculiar changes observed was the premature follicular maturation in the ovaries probably starting in the sixth to seventh intrauterine m o n t h with overproduction of estrogens. This resulted in the following changes: enlargement of the nipples and external genitals, hypertrichosis, increased excretion of 17-ketosteroids, hyperplasia of islets of Langerhans, and large kidneys with calcium deposits in the collecting tubules. With this there was a suppression of growth hormone, resulting in delay of bone growth. This syndrome was called leprechaunism because of the similarity of these to the
Leprechaunism (Donohue's syndrome)
3 79
appearances of the leprechauns of Irish folklore. It m a y be compared to the SteinLeventhal syndrome of adults and could be regarded as its analogy occurring in intrauterine life or in infancy. Leprechaunism m a y also be called Donohue's syndrome, after the original describer. Nothing is known as yet concerning the cause of the intrauterine follicular maturation.
REFERENCES
I. Donohue, W. L.: Dysendocrinlsm (elinicopathological conference) J. PEDIAT. 32: 739, 1948. 2. Donohue, W. L., and Uchida, I.: Leprechaunism, J. PEDIAT.45: 505, 1954. 3. Evans, P. R.: Leprechaunism, Arch. Dis. Childhood 30: 479, 1955. 4. Patterson, J. H., and Watkins, W. L.: Leprechaunism in a male infant, J. PEDrAT. 60" 730, 1962. 5. Salmon, M. A., and Webb, J. N.: Dystrophic changes associated with leprechaunism in a male infant, Arch. Dis. Childhood 38: 530, 1963. 6. Roessle, R., and Roulet F.: Mass und Zahl in der Pathologle, Berlin and Vienna, 1932, Springer Verlag. 7. Potter, E. L.: Pathology of the fetus and newborn, Chicago, 1952, The Year Book Medical Publishers, Inc., p. 13.