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Leprechaunism (Donohue's syndrome): Acase report
April 1969 T h e ]ournal of P E D I A T R I C S
601
Leprechaunism (Donobue's syndrome): A case report This report describes an infant with the syndrome of multiple congenital malformations and malnutrition leading to death in early infancy, which was originally reported by Donohue and UchidM-e and usually refered to as leprechaunism. Aside from the classical features of the syndrome, the patient described herein had absence of the corpus collosum, hydromyelia, persistent left superior vena cava, absent innominate vein, aberrant coronary ostia, pyloric stenosis, eventration of the diaphragm, and urogenital sinus. However, other genital abnormalities were not as prominent as in previously reported cases. The difficulty in analyzing multiple anomaly syndromes, in which the etiology and genetic mode are not known, is emphasized.
Robert L. Summitt, M.D.,* and Blaise E. Favara, M.D. MEMPItlS~ TENN.
L EP RECH AU N I S M (Donohue's syndrome) is a rare disorder of u n k n o w n etiology, possibly genetically determined, characterized by grotesque, elfin facies with a flat nasal bridge and flaring nostrils, thick lipS, and hirsutism; large, low-set ears; enlargement of breasts and external genitalia; motor and mental retardation; and failure to thrive leading to extreme marasmus and death in the early months of life. 1-s O t h e r endocrine-related functional and morphologic abnormalities include hyperplasia of the islets of Langerhans with altered carboFrom the Departments of Pediatrics, Anatomy, and Pathology, University of Tennessee College of Medicine and Le Bonheur Children's Hospital. This work was supported in part by Special Project Grant No. CB-HS-908 from the United States Children's Bureau. *Department of Pediatrics, University of Tennessee College of Medicine, 860 Madison Ave., Memphis, Tenn. 38103.
hydrate metabolism, and ovaries with cystic follicles in varying stages of maturation. Abnormalities also have been found in the thymus, pituitary gland, liver, and kidneys. Since the description by Donohue and U c h i d a 1, 2 of affected sisters, the offspring of consanguineous parents, 8 additional cases have been reported, 4 females and 4 males. '~s We report here an additional patient who has the features of leprechaunism. CASE REPORT L. J. B., a Caucasian girl, birth date July 9, 1965, was the product of her 18-year-old mother's first pregnancy. The father was 23 years of age. Both parents were in good health. Nine months previously the father had had multiple diagnostic roentgenograms of his lower spine, including a myelogram, following an auto accident. The mother's weight gain during the pregnancy was 37 pounds. Fetal movements were Vol. 74, No. 4, pp. 601-610
60 2
Summitt and Favara
normal. Labor was spontaneous at 38 weeks gestation and was 6 hours in duration. The attending physician commented that the uterus seemed small. Delivery was spontaneous, birth weight was 2,054 grains, and crown-heel length was 46 era. The respirations were spontaneous but the cry was weak. The infant's nails were hypoplastic; her facies was described as "unusual," with a small oral cavity. Roentgenograms of the chest revealed normal cardiac silhouette and lung fields. Nasogastric feedings were instituted because she nursed poorly. Barium swallow was normal. At home the infant began to regurgitate feedings. A change from a cow's milk preparation
The Journal of Pediatrics April 1969
to a soybean formula was followed by improvement, although she still regurgitated occasionally. She had several brief episodes of cyanosis during her first few weeks at home. She preferred to lie on her side in an opisthotonic position. By the age of 4 months she smiled and regarded her parents. The family history revealed no infants similar in appearance to the patient and no early infant deaths. The parents were not consanguineous. The infant was referred at 4 months of age to the Le Bonheur Children's Hospital because of failure to thrive and because of an episode of pallor, sweating, and gasping respiration. Physical examination revealed: weight 2,437
Fig. 1. The patient.
Fig. 2. Genitalia showing labial and clitoral enlargement and redundancy of anal mucosa.
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Leprechaunism
grams, crown-heel length 49.5 cm., head circumference 33.7 cm., chest circumference 32.3 cm., intercanthal distance 1.8 cm., cardiac rate 172 per minute, respiratory rate 56 per minute, and rectal temperature 100.2~ F. The infant was small, pale, poorly nourished, and unusual in appearance (Fig. 1). Subcutaneous tissue was sparse. She was listless and had prominent inspiratory stridor. Her head appeared large, with biparietal prominence. The anterior fontanel measured 3 x 2.5 cm. and the posterior, 1 • 1 cm. The sagittal and metopic sutures were open and the lambdoidals overlapped. The scalp hair was sparse but long and silky, rusty red in color, and extended down over the forehead and forward in the temporal areas. The ears were large, low-set, and rotated approximately 20 degrees posteriorly from the vertical; they were poorly differentiated with absent antitragus. The nasal bridge was narrow and extending upward from it was a small flat capillary hemangioma. The facies appeared pinched. Examination of the eyes revealed no abnormalities. The nose was small with flared, anteverted nares. The lips were thick, the palate was narrowly arched with a wide maxillary alveolar ridge, and micrognathia was present. The nipples were not visibly prominent but a small 0.5 cm. button of tissue was palpable deep to each areola. The sternum was quite mobile; she had a pectus excavatum. Inspiratory sternal and intercostal retractions were marked, but breath sounds were of good quality and the lungs were clear. A soft systolic cardiac murmur was audible in the second left intercostal space at the sternal border. Examination of the abdomen revealed a diastasis recti but no enlarged organs. Bilateral inguinal hernias containing no masses were evident when the infant cried. The clitoris was prominent as were the anterior portions of the labia minora. Urine was expelled from a single urogenital opening, posterior to which the labia minora were fused. Bimanual rectal examination revealed a midline structure thought to be a uterus and an ovoid left adnexal mass
Table I
Axial Hand triradii Right Left U =
2.7/3.5 1.7/3.4
1 I 2 U W
u l n a r loop; R =
U R
Fingers [ 3 [ 4 U W
r a d i a l loop; W =
I 5
U R whorl.
---
603
1 cm. in diameter. The perianal skin was redundant. The pelvis was small (Fig. 2). Finger- and toenails were hypoplastic; the fifth fingers and toes completely lacked nails. Palmar creases were normal. The proximal interphalangeal joints of the third, fourth, and fifth fingers of both hands revealed prominent camptodactyly. The distal phalanges of the fifth fingers were short. The hands were maintained in ulnar deviation with the fists clenched, the fourth fingers overlying the fifth and the second overlying the third. Dermal patterns included distal placement of the axial triradii (t" position) and hypoplasia of the fingertip patterns (Table I). Neurologic examination revealed general muscular hypotonia. The Moro and tonic neck reflexes were present. Her eyes followed a light and her head turned toward a spoken voice. Cranial nerves were intact. Tendon reflexes were normal. Muscle mass was in general decreased. Laboratory results are shown in Table II. Pertinent findings included abnormal glucose tolerance test, abnormally low serum alkaline phosphatase, low serum cholesterol, generalized aminoaciduria, normal urinary 17-ketosteroids, and elevated serum lactate dehydrogenase and glutamic-oxaloacetic transaminase activity. The blood sugar elevation following oral glucose was excessive and prolonged. The response to glucagon was normal. Chromosomal analysis of leukocytes from peripheral blood revealed a normal karyotype, 46, XX. Chest roentgenogram revealed normal cardiac silhouette and lung fields. Roentgenograms of the upper gastrointestinal tract revealed that the stomach was slightly distended, but no obstruction to the flow of opaque media into the duodenum could be identified. Skeletal survey and films for bone age revealed normal bone architecture; the distal femoral epiphyses were present but no carpal centers were seen. Skull films were normal. A vaginogram revealed a vaginal vault opening into the urogenital sinus formed by fused labia. An electroencephalogram was abnormal with right temporal spikes. Therapy upon admission included antibiotics and intravenous fluids. By the third hospital day the infant's condition had improved and oral feedings were instituted. Direct laryngoscopy revealed laryngomalacia. Because of persistent regurgitation, feedings were given by nasogastric tube, and with long-term care in mind a gastrostomy was performed. The surgeon felt that the pylorus was hyperplastic and performed
604
S u m m i t t and Favara
The Journal of Pediatrics April 1969
a pyloromyotomy. The patient had a sudden episode of apnea and died on the fiftieth hospital day. AUTOPSY T h e autopsy, p e r f o r m e d 20 hours after death, revealed several malformations, endocrine abnormalities, a n d generally small viscera. T h e b r a i n was symmetrical a n d the gyral p a t t e r n well d e v e l o p e d ; however, the corpus callosum was absent. T h e l a m i n a terminalis, cingulate gyri, anterior a n d h i p p o c a m p a l commisures were minute. T h e lateral ventricles were e n l a r g e d posteriorly. T h e spinal cord was d e f o r m e d by h y d r o m y e l i a which was most m a r k e d in the l u m b a r region, but no obstruction could be identified (Fig. 3). I n t r a c a r d i a c abnormalities were absent b u t h e m o d y n a m i c a l l y insignificant vascular malformations included persistent left superior vena cava, absent i n n o m i n a t e vein, a n d the
presence of b o t h c o r o n a r y ostia in the posterior sinus of Valsalva. T w o umbilical arteries were identified. Both lungs were bilobed a n d h a d areas of chronic aspiration pneum o n i a ; however, no recent or massive aspiration could be identified. T h e larynx was normal. A l t h o u g h the esophagus was not obstructed, the distal portion was dilated and the muscularis was thickened. Neural components were histologically normal. T h e pylorus was elongated with thickened muscularis in the region of the longitudinal R a m s t e d t incision. A c o m m o n ileocolic mesentery was observed. A small accessory hepatic lobule o c c u p i e d a 3 x 2 cm. oval eventration in the d i a p h r a g m anterior and to the right of the caval hiatus. Siderosis a n d glycogenosis of the liver were not found. H e p a t i c glycogen a n d enzyme quantitation revealed n o r m a l values ( T a b l e I I I ) . L y m p h o i d tissue was generally inconspic-
Table I I . L a b o r a t o r y results Tests
Sweat chloride Buccal smear Urine mucopolysaccharides Amino acids--urine Serum sodium Serum potassium Serum calcium Serum phosphorus Alkaline phosphatase Serum cholesterol Cholesterol esters Serum triglyeerides Phospholipld phosphorus Urinary 17-ketosteroids Urinary 17-hydroxycorticoids Water loading test
November 18, 1965
I2.8 mEq./L. Chrom. positive 42% Negative Elevated cystine, lysine, and ornithine 141 mEq./L. 5.5 mEq./L. 5.4 mEq./L. 4.6 nag. % 3.6 Bodansk7 units
November 12, 1965
November 17, 1965
2.9 Bodansky units 110 mg. % 98 mg. % 65 mg. % 236 mg. % 163 mg. % < 0.1 mg./24 hr. 0.2 rag./24 hr. 85 % excretion
Serum protein electrophoresis (cellulose acetate) Albumin Alpha-1 globulin Alpha-2 globulin Beta globulin Gamma globulin
4.8 Gm. % 48% 7% 26% 13% 6%
Chromosomal analysis Plasma insulin Serum lactate dehydrogenase (normal 40-98 units /ml. ) Serum GOT (normal 12-26 units/ml.)
46,XX 35 m#g/ml. 860 units/ml. 68 units/ml.
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Leprechaunism
uous. L y m p h nodes, spleen, tonsils, and intestinal lymphoid components h a d poor follicular definition, but plasma cells, lymphocytes, and plasmacytoid cells were present and phagocytic histiocytes were represented. T h e thymus was moderately depleted of thymolymphocytes, and Ilassall's bodies were dilated and cystic, but vascularity and cytology were normal. Dilatation of tonsillar crypts was also observed and lymphoid follicles were ill defined. No renal or ureteral malformations were found. T h e glomeruli had features of immaturity with large hyperchromatic epithelial cells at the periphery of the tuft. T h e tubules were not dilated or mineralized but several zones of small tubules surrounded by loose mesenchymaI tissue were seen near the pelvic epithelium. N o cartilage or embryonal tissues were recognized. T h e peritubular tissues of cortex and medulla were infiltrated by scattered loci or neutrophils and round cells including plasma cells, but no organisms or foam cells were seen. T h e infantile uterus was bicornuate; the right horn was moderately hypop!astic. T h e endometrium showed abnormally tortuous glands and ducts lined by c o l u m n a r epithelium rich in glycogen, as indicated by PAS positive material about the nuclei. T h e vaginal epithelium was thin and lacked signs of estrogen stimulation. T h e right ovary measured 2 x 0.8 • 0.5 cm. a n d the left 2 •
605
0.6 x 0.5 cm. T h e surfaces were moderately rugated and in each ovary a n u m b e r of nondistorting atretic follicle cysts measured up to 0.25 cm. (Fig. 4). T h e ovaries were histologically normal with no evidence of luteinization. T h e breasts were of normal size and histologically were normal for age with little glandular tissue about prominent ducts in an areolar connective tissue stroma. T h e pancreas was normal histologically, with no islet hyperplasia, hypertrophy, or cytomegaly. A Gomori aldehyde fuchsin stain of the pancreas revealed normal beta cell granulation in comparison with controls. T h e adrenal glands were small; zonal distinction was poor, all cells being large and pale; the medulla was inconspicuous. T h e thyroid gland was small but in normal position. Follicles were generally devoid of or contained small amounts of coarse, granular, pink colloid. Epithelium was uniformly columnar, but not papillary. T h e interstitium and fetal cells were not prominent (Fig. 5). T h e pituitary gland was normal. It was examined in a m a n n e r similar to that described by RogersY Examination of hematoxylin and eosin stained sections revealed that 38 per cent of 450 cells were eosinophils; eosin-methylene blue staining indicated 37 per cent eosinophils and no more than 5 per cent basophils. This Iatter was
Table I I I . Biochemical studies on autopsy material
Specimen Liver
Psoas muscle
Myocardium
t
Determination
[
Result
[ Intrepretation--Com, ment
Glycogen Glucose-6-phosphatase Phosphorylase
5% with normal structure 5 #moles phosphate/min./Gm. 2.6 #moles phosphate/min./Gm.
Normal Normal Normal low on postmortem tissue Normal
Lactate dehydrogenase
Electrophoretic isoenzymes
Glycogen
2%
Phosphorylase Lactate dehydrogenase
75 #moles phosphate/min./Gm. Electrophoretic isoenzymes
Slightly above normal of 1.5% Normal Normal for age
Lactate dehydrogenase
Electrophoretic isoenzymes
Normal
Negative Normal Serum Anti-thyroglobulin Glycogen determined by method of Hers,14 glucose-6-phosphataseand phosphorylase by method of Cori and associates,1~ and lacetate dehydrogenase-isoenzymesby techniques described by Preston and associates.~n
60 6
Summitt and Favara
The Journal o[ Pediatrics April 1969
Fig. 3. Multiple cross-sections of formalin-fixed spinal cord illustrating the marked hydromyelia of lumbar segments.
confirmed by periodic acid-Schiff staining which revealed less than 10 per cent basophils. Since basophils were definitely not increased, no attempt was made to subclassify them. Muscles were small but histomicrometry revealed fibers to be of a size normal for age. PAS staining and chemical studies revealed glycogen content and enzymatic activity to be normal. DISCUSSION
This infant, we believe, has the phenotype of leprechaunism. Birth weight at 38 weeks gestation was low. She failed to thrive and even at birth she appeared malnourished. She had the elfin facies characteristic of the syndrome with large, low-set ears, deep-set eyes, retuse nose, thick lips, and sparse scalp hair with facial hirsutism. She was not hyperteloric. She did not have m a m mary enlargement, nor were clitoral and labial development as prominent as in previous cases. Endocrine evaluation revealed
no real abnormality except delayed skeletal maturation. Serum alkaline phosphatase and cholesterol were low. Similar values were found by Salmon and Webb 5 and by Patterson and Watkins, 4 but their patients probably are not bona fide cases of leprechaunism. A generalized aminoaciduria was demonstrated in our patient, but death prevented further investigation of this finding. Autopsy failed to demonstrate abnormal hepatic glycogen deposition such as that noted by Donohue and Uchida, 1, 2 nor was the endocrine pancreas hyperplastic, an abnormality described in the cases of Donohue and Uchida and those of K~l16 and associates. G A single determination of serum insulin activity was normal. The increased activity of serum L D H and G O T was attributed to hepatic congestion. While the ovaries contained atretic follicle cysts (a normal finding in our experience), they did not have evidence of follicular maturation which has been a feature in most previously reported affected females and to which has
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Leprechaunlsm
Fig. 4. Composite photograph of the uterus and cut surface of the ovaries showing bicornuate uterus with small right uterine horn.
Fig. 5. Thyroid follicles, formed by low columnar or cuboidal epithelium, are small and essentially devoid of colloid. (Hematoxylin and eosin, xl00.)
60 7
608
Summitt and Favara
been attributed enlargement of clitoris, labia minors, and breasts. Previous authors have been convinced that, while emaciation may produce relative clitoral, labial, and mammary prominence, the excessive degree of these changes could not be accounted for by malnutrition alone; endocrine dysfunction has been postulated. K~l16 and associates 6 characterized the abnormality as premature ovarian follicular maturation resulting in the production of excessive amounts of estrogen, which in turn produced not only the genital abnormalities but also excessive excretion of 17-ketosteroids, hirsutism, abnormalities of carbohydrate metabolism, calcium deposition in renal tubules, and suppression of growth hormone production with delay in skeletal maturation. This attempt to attribute such a variety of abnormalities to one basic cause seems to be an oversimplification of a more complex problem. In Case 1 of Evans 3 and in the patient investigated by Dekaban, 7 urinary estrogens were not elevated; in the later case a single determination of plasma growth hormone was not elevated. T h e claim by K~l16 and associates 6 of increased urinary excretion of 17-ketosteroids due to excessive estrogens has no valid physiological basis. Furthermore, clitoral hypertrophy per se would seem more logically to be the result of stimulation by androgen rather than estrogen. The labial fusion in our patient supports this thesis. In no patient has estrogenization of the vaginal mucosa been found, but most authors have not mentioned this feature. Rogers s has presented evidence for selective excess of interstitial cell stimulating hormone (ICSH) in a male who apparently had leprechaunism, the excess ICSH being produced by an increased relative number of pituitary basophils. He suggested that ICSH stimulated testosterone production and thus large genitalia in' an affected male. The relative numbers of basophils and eosinophils in the anterior pituitary of our patient were within the normal range, 9-13 in contrast to the increase in basophils reported by Rogers. Abnormalities of the thymolymph,a~ie sys-
The Journal of Pediatrics April 1969
tern in our patient included poor follicular definition in lymph nodes, spleen, tonsils, and Peyer's patches, as well as unusually cystic Hassall's bodies in the thymus. Similar abnormalities were present in the cases o f Donohue and Uchida and in those of K~l16 and associates. Serum protein studies have failed to reveal deficiency of gamma globulins. The thymolymphatic findings in these patients seem to be nonspecific and are like those occasionally seen in children dying of chronic illnesses associated with emaciation. They do not resemble changes of host-graft interaction or any of the known immunodeficiency syndromes. The thyroid gland was interesting in that its epithelium suggested a response to T S H stimulation. Unfortunately, an intravenous urogram was done before thyroid function tests could be accomplished. Thyroid glands in most cases have been normal except in the patients of K~l16 and associates. In one of their patients, thyroid follicles were absent; in the other, few follicles were found. Several anomalies not previously described were present in our patient. The variations in phenotype in the few cases of leprechaunism thus far described should not necessarily indicate nosologic heterogeneity. Such variations are common in multiple anomaly syndromes, those for which the etiology is known as well as those in which investigations have not as yet demonstrated a cause. The fact that a patient varies from originally described cases and is more mildly affected should not necessarily militate against the diagnosis. On the other hand, one must use caution in specifying a syndromal association for a given patient, especially when the syndrome is not well delineated. The first 3 infants to be described with leprechaunism were females. This led to speculation that the condition might be limited to the female. Patterson and Watkins 4 then reported a male who they believed had leprechaunism. However, the phenotype of their patient as revealed in an illustration, as well as abnorinalities of bone architecture, suggest that ~heir pat.ien,t should not be included in this syndrome. Similarly, Case 2 of Evans a and
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the patient of Salmon and Webb s are so atypical that they cannot be accepted as bona fide cases of leprechaunism. One may then ask: (1) Is leprechaunism an entity or a group of patients similar in appearance but heterogeneous in formal a n d / o r causal genesis? (2) I f it is an entity, how does one identify a bona fide case ? Unfortunately, no satisfactory answer is available for either question. Reports would seem to indicate that Ieprechaunism may occur in either sex. As discussed by Opitz, 17 multiple anomaly syndromes may be classified in 3 levels of specificity. First, the "physical examination syndrome" is applied when a patient (or several similar patients) is observed to be distinctly different from members of the normal population. Although such evidence for identification of a specific syndrome is tenuous, it does provide a basis for more extensive investigations which would support or refute the hypothesis that an entity exists. Second, the definition of a "formal genesis syndrome" specifies that the similarity among patients thought to have the syndrome must be based upon involvement of the same dysmorphogenetic process. This still does not specify that the same causal genesis is operative. T h e "causal genesis syndrome" is the most specific and applies to cases in which a definite common cause, such as a metabolic error, a chromosomal aberration, a definite genetic mode, or an environmental influence can be demonstrated. Leprechaunism probably should be considered a physical examination syndrome. If some of the evidence for metabolic abnormalities is acceptable, perhaps a common formal genesis exists. The occurrence of leprechaunism in siblings, reported by Donohue and Uchida and by Kill16 and associates, suggests a genetic basis for the condition. This is further supported by consanguinity in the family reported by Donohue. No chromosomal abnormality has been found 'in the 3 cases studied. While endocrine and metabolic abnormalities have been detected in patients with leprechaunism, no error common to all has been found. Only through the acquisition of additional clinical, genetic,
Leprechaunism
609
and metabolic evidence can we hope to clarify the confusing and unsatisfactory status of the syndrome known as leprechaunism. SUMMARY
A female infant with leprechaunism (Donohue's syndrome) is described. The main clinical features exhibited by the infant included failure to thrive leading to death at 5 months of age; elfin facies with large, low-set ears, deep-set eyes, retuse nose, thick lips, and micrognathia; sparse scalp hair; facial hirsutism; inguinal hernias; prominence of the clitoris and labia minora; partial fusion of labia minora; and hypoplastic dermal patterns. Findings at postmortem examination included absence of the corpus callosum, hydromyelia, minor vascular abnormalities, pyloric stenosis, eventration of the diaphragm, and inconspicuous lymphatic tissue. The description of any patient as an example of Donohue's syndrome is based solely upon clinical appearance, since no characteristic laboratory or histologic features are known. Some of the patients previously described would seem not to be actual cases of Donohue's syndrome, demonstrating the difficulty in delineating syndromes in which the causal genesis is not known. The authors would like to express appreciation to Drs. Warren W. Johnson and Thomas L. Avery of the St. Jude Children's Research Hospital and the University of Tennessee for special histologic studies of the pituitary gland. REFERENCES
1. Donohue, W. L.: Clinieopathologic conference at the Hospital for Sick Children. Dysendocrinlsm, J. PEDIAT.32: 739, 1948. 2. Donohue, W. L., and Uchida, I.: Lcprechaunism, J. PEDIA*.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. PEDIAT. 60: 730, 1962. 5. Salmon, M. A., and Webb, J. N.: Dystrophic changes associated with leprechaunlsm in a male infant, Arch. Dis. Childhood 38: 350, 1963. 6. K,~tl6, A., Lakatos, I., and Szij~rt6, L.: Lep-
6 10
7. 8. 9. 10.
11.
12.
S u m m i t t and Favara
rechaunism (Donohue's syndrome), J. PEDIAT. 66: 372, 1965. Dekaben, A.: Metabolic and chromosomal studies in leprechaunism, Arch. Dis. Childhood 40: 632, 1965. Rogers, D. R.: Leprechaunism (Donohue's syndrome), Am. J. Clin. Path. 45: 614, 1966. Sommers, S. C.: Pituitary cell relations to body states, Lab. Invest. 8: 588, 1959. Rasmussen, A. T.: Changes in the proportion of cell types in anterior lobe of human hypophysis during the first nineteen years of life, Am. J. Anat. 86: 75, 1950. Halpern, S. R.: Quantitative cytological stud.. ies on the anterior lobe of the hypophysis of fetuses and children correlated with sexual and skeletal development, Endocrinology 22: 173, 1938. Herlant, M.: Recherches sur la localisation histologique des hormones gonadotropes femelles au niveau de l'hyp0physe ant~rieure, Arch. Biol. 54: 225, 1943.
The Journal of Pediatrics April 1969
13, Pearse, A. G. E.: Cytological and cytochemical investigations of the fetal and adult hypophysis in various physiological and pathological states, J. Path. & Baet. 65: 355,1953. 14. Hers, H. G.: Studies enzymatiques sur fragments hepatiques, application a la classification des glycogenoses, Rev. Internat. d~ H6pat. 9: 35, 1959. 15. Cori, G. T., Illingworth, B., and Keller, T.: Muscle phosphorylase, in Methods of enzymology, vol. I, New York, 1957, Academic Press, Inc., p. 200. 16. Preston, J. A., Briere, R. D., and Batsakis, J. G.: Rapid electrophoretic separation of lactate dehydrogenase isozymes on cellulose acetate, Am. J. Clin. Path. 43: 256, 1965, 17. Opitz, J. M.: The analysis of dysmorphogenetic syndromes with examples from those associated with mental retardation, Proceedings of the First Conference on the Clinical Delineation of Birth Defects, Baltimore, May 20-25, 1968. I n press.
601
Leprechaunism (Donobue's syndrome): A case report This report describes an infant with the syndrome of multiple congenital malformations and malnutrition leading to death in early infancy, which was originally reported by Donohue and UchidM-e and usually refered to as leprechaunism. Aside from the classical features of the syndrome, the patient described herein had absence of the corpus collosum, hydromyelia, persistent left superior vena cava, absent innominate vein, aberrant coronary ostia, pyloric stenosis, eventration of the diaphragm, and urogenital sinus. However, other genital abnormalities were not as prominent as in previously reported cases. The difficulty in analyzing multiple anomaly syndromes, in which the etiology and genetic mode are not known, is emphasized.
Robert L. Summitt, M.D.,* and Blaise E. Favara, M.D. MEMPItlS~ TENN.
L EP RECH AU N I S M (Donohue's syndrome) is a rare disorder of u n k n o w n etiology, possibly genetically determined, characterized by grotesque, elfin facies with a flat nasal bridge and flaring nostrils, thick lipS, and hirsutism; large, low-set ears; enlargement of breasts and external genitalia; motor and mental retardation; and failure to thrive leading to extreme marasmus and death in the early months of life. 1-s O t h e r endocrine-related functional and morphologic abnormalities include hyperplasia of the islets of Langerhans with altered carboFrom the Departments of Pediatrics, Anatomy, and Pathology, University of Tennessee College of Medicine and Le Bonheur Children's Hospital. This work was supported in part by Special Project Grant No. CB-HS-908 from the United States Children's Bureau. *Department of Pediatrics, University of Tennessee College of Medicine, 860 Madison Ave., Memphis, Tenn. 38103.
hydrate metabolism, and ovaries with cystic follicles in varying stages of maturation. Abnormalities also have been found in the thymus, pituitary gland, liver, and kidneys. Since the description by Donohue and U c h i d a 1, 2 of affected sisters, the offspring of consanguineous parents, 8 additional cases have been reported, 4 females and 4 males. '~s We report here an additional patient who has the features of leprechaunism. CASE REPORT L. J. B., a Caucasian girl, birth date July 9, 1965, was the product of her 18-year-old mother's first pregnancy. The father was 23 years of age. Both parents were in good health. Nine months previously the father had had multiple diagnostic roentgenograms of his lower spine, including a myelogram, following an auto accident. The mother's weight gain during the pregnancy was 37 pounds. Fetal movements were Vol. 74, No. 4, pp. 601-610
60 2
Summitt and Favara
normal. Labor was spontaneous at 38 weeks gestation and was 6 hours in duration. The attending physician commented that the uterus seemed small. Delivery was spontaneous, birth weight was 2,054 grains, and crown-heel length was 46 era. The respirations were spontaneous but the cry was weak. The infant's nails were hypoplastic; her facies was described as "unusual," with a small oral cavity. Roentgenograms of the chest revealed normal cardiac silhouette and lung fields. Nasogastric feedings were instituted because she nursed poorly. Barium swallow was normal. At home the infant began to regurgitate feedings. A change from a cow's milk preparation
The Journal of Pediatrics April 1969
to a soybean formula was followed by improvement, although she still regurgitated occasionally. She had several brief episodes of cyanosis during her first few weeks at home. She preferred to lie on her side in an opisthotonic position. By the age of 4 months she smiled and regarded her parents. The family history revealed no infants similar in appearance to the patient and no early infant deaths. The parents were not consanguineous. The infant was referred at 4 months of age to the Le Bonheur Children's Hospital because of failure to thrive and because of an episode of pallor, sweating, and gasping respiration. Physical examination revealed: weight 2,437
Fig. 1. The patient.
Fig. 2. Genitalia showing labial and clitoral enlargement and redundancy of anal mucosa.
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Leprechaunism
grams, crown-heel length 49.5 cm., head circumference 33.7 cm., chest circumference 32.3 cm., intercanthal distance 1.8 cm., cardiac rate 172 per minute, respiratory rate 56 per minute, and rectal temperature 100.2~ F. The infant was small, pale, poorly nourished, and unusual in appearance (Fig. 1). Subcutaneous tissue was sparse. She was listless and had prominent inspiratory stridor. Her head appeared large, with biparietal prominence. The anterior fontanel measured 3 x 2.5 cm. and the posterior, 1 • 1 cm. The sagittal and metopic sutures were open and the lambdoidals overlapped. The scalp hair was sparse but long and silky, rusty red in color, and extended down over the forehead and forward in the temporal areas. The ears were large, low-set, and rotated approximately 20 degrees posteriorly from the vertical; they were poorly differentiated with absent antitragus. The nasal bridge was narrow and extending upward from it was a small flat capillary hemangioma. The facies appeared pinched. Examination of the eyes revealed no abnormalities. The nose was small with flared, anteverted nares. The lips were thick, the palate was narrowly arched with a wide maxillary alveolar ridge, and micrognathia was present. The nipples were not visibly prominent but a small 0.5 cm. button of tissue was palpable deep to each areola. The sternum was quite mobile; she had a pectus excavatum. Inspiratory sternal and intercostal retractions were marked, but breath sounds were of good quality and the lungs were clear. A soft systolic cardiac murmur was audible in the second left intercostal space at the sternal border. Examination of the abdomen revealed a diastasis recti but no enlarged organs. Bilateral inguinal hernias containing no masses were evident when the infant cried. The clitoris was prominent as were the anterior portions of the labia minora. Urine was expelled from a single urogenital opening, posterior to which the labia minora were fused. Bimanual rectal examination revealed a midline structure thought to be a uterus and an ovoid left adnexal mass
Table I
Axial Hand triradii Right Left U =
2.7/3.5 1.7/3.4
1 I 2 U W
u l n a r loop; R =
U R
Fingers [ 3 [ 4 U W
r a d i a l loop; W =
I 5
U R whorl.
---
603
1 cm. in diameter. The perianal skin was redundant. The pelvis was small (Fig. 2). Finger- and toenails were hypoplastic; the fifth fingers and toes completely lacked nails. Palmar creases were normal. The proximal interphalangeal joints of the third, fourth, and fifth fingers of both hands revealed prominent camptodactyly. The distal phalanges of the fifth fingers were short. The hands were maintained in ulnar deviation with the fists clenched, the fourth fingers overlying the fifth and the second overlying the third. Dermal patterns included distal placement of the axial triradii (t" position) and hypoplasia of the fingertip patterns (Table I). Neurologic examination revealed general muscular hypotonia. The Moro and tonic neck reflexes were present. Her eyes followed a light and her head turned toward a spoken voice. Cranial nerves were intact. Tendon reflexes were normal. Muscle mass was in general decreased. Laboratory results are shown in Table II. Pertinent findings included abnormal glucose tolerance test, abnormally low serum alkaline phosphatase, low serum cholesterol, generalized aminoaciduria, normal urinary 17-ketosteroids, and elevated serum lactate dehydrogenase and glutamic-oxaloacetic transaminase activity. The blood sugar elevation following oral glucose was excessive and prolonged. The response to glucagon was normal. Chromosomal analysis of leukocytes from peripheral blood revealed a normal karyotype, 46, XX. Chest roentgenogram revealed normal cardiac silhouette and lung fields. Roentgenograms of the upper gastrointestinal tract revealed that the stomach was slightly distended, but no obstruction to the flow of opaque media into the duodenum could be identified. Skeletal survey and films for bone age revealed normal bone architecture; the distal femoral epiphyses were present but no carpal centers were seen. Skull films were normal. A vaginogram revealed a vaginal vault opening into the urogenital sinus formed by fused labia. An electroencephalogram was abnormal with right temporal spikes. Therapy upon admission included antibiotics and intravenous fluids. By the third hospital day the infant's condition had improved and oral feedings were instituted. Direct laryngoscopy revealed laryngomalacia. Because of persistent regurgitation, feedings were given by nasogastric tube, and with long-term care in mind a gastrostomy was performed. The surgeon felt that the pylorus was hyperplastic and performed
604
S u m m i t t and Favara
The Journal of Pediatrics April 1969
a pyloromyotomy. The patient had a sudden episode of apnea and died on the fiftieth hospital day. AUTOPSY T h e autopsy, p e r f o r m e d 20 hours after death, revealed several malformations, endocrine abnormalities, a n d generally small viscera. T h e b r a i n was symmetrical a n d the gyral p a t t e r n well d e v e l o p e d ; however, the corpus callosum was absent. T h e l a m i n a terminalis, cingulate gyri, anterior a n d h i p p o c a m p a l commisures were minute. T h e lateral ventricles were e n l a r g e d posteriorly. T h e spinal cord was d e f o r m e d by h y d r o m y e l i a which was most m a r k e d in the l u m b a r region, but no obstruction could be identified (Fig. 3). I n t r a c a r d i a c abnormalities were absent b u t h e m o d y n a m i c a l l y insignificant vascular malformations included persistent left superior vena cava, absent i n n o m i n a t e vein, a n d the
presence of b o t h c o r o n a r y ostia in the posterior sinus of Valsalva. T w o umbilical arteries were identified. Both lungs were bilobed a n d h a d areas of chronic aspiration pneum o n i a ; however, no recent or massive aspiration could be identified. T h e larynx was normal. A l t h o u g h the esophagus was not obstructed, the distal portion was dilated and the muscularis was thickened. Neural components were histologically normal. T h e pylorus was elongated with thickened muscularis in the region of the longitudinal R a m s t e d t incision. A c o m m o n ileocolic mesentery was observed. A small accessory hepatic lobule o c c u p i e d a 3 x 2 cm. oval eventration in the d i a p h r a g m anterior and to the right of the caval hiatus. Siderosis a n d glycogenosis of the liver were not found. H e p a t i c glycogen a n d enzyme quantitation revealed n o r m a l values ( T a b l e I I I ) . L y m p h o i d tissue was generally inconspic-
Table I I . L a b o r a t o r y results Tests
Sweat chloride Buccal smear Urine mucopolysaccharides Amino acids--urine Serum sodium Serum potassium Serum calcium Serum phosphorus Alkaline phosphatase Serum cholesterol Cholesterol esters Serum triglyeerides Phospholipld phosphorus Urinary 17-ketosteroids Urinary 17-hydroxycorticoids Water loading test
November 18, 1965
I2.8 mEq./L. Chrom. positive 42% Negative Elevated cystine, lysine, and ornithine 141 mEq./L. 5.5 mEq./L. 5.4 mEq./L. 4.6 nag. % 3.6 Bodansk7 units
November 12, 1965
November 17, 1965
2.9 Bodansky units 110 mg. % 98 mg. % 65 mg. % 236 mg. % 163 mg. % < 0.1 mg./24 hr. 0.2 rag./24 hr. 85 % excretion
Serum protein electrophoresis (cellulose acetate) Albumin Alpha-1 globulin Alpha-2 globulin Beta globulin Gamma globulin
4.8 Gm. % 48% 7% 26% 13% 6%
Chromosomal analysis Plasma insulin Serum lactate dehydrogenase (normal 40-98 units /ml. ) Serum GOT (normal 12-26 units/ml.)
46,XX 35 m#g/ml. 860 units/ml. 68 units/ml.
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Leprechaunism
uous. L y m p h nodes, spleen, tonsils, and intestinal lymphoid components h a d poor follicular definition, but plasma cells, lymphocytes, and plasmacytoid cells were present and phagocytic histiocytes were represented. T h e thymus was moderately depleted of thymolymphocytes, and Ilassall's bodies were dilated and cystic, but vascularity and cytology were normal. Dilatation of tonsillar crypts was also observed and lymphoid follicles were ill defined. No renal or ureteral malformations were found. T h e glomeruli had features of immaturity with large hyperchromatic epithelial cells at the periphery of the tuft. T h e tubules were not dilated or mineralized but several zones of small tubules surrounded by loose mesenchymaI tissue were seen near the pelvic epithelium. N o cartilage or embryonal tissues were recognized. T h e peritubular tissues of cortex and medulla were infiltrated by scattered loci or neutrophils and round cells including plasma cells, but no organisms or foam cells were seen. T h e infantile uterus was bicornuate; the right horn was moderately hypop!astic. T h e endometrium showed abnormally tortuous glands and ducts lined by c o l u m n a r epithelium rich in glycogen, as indicated by PAS positive material about the nuclei. T h e vaginal epithelium was thin and lacked signs of estrogen stimulation. T h e right ovary measured 2 x 0.8 • 0.5 cm. a n d the left 2 •
605
0.6 x 0.5 cm. T h e surfaces were moderately rugated and in each ovary a n u m b e r of nondistorting atretic follicle cysts measured up to 0.25 cm. (Fig. 4). T h e ovaries were histologically normal with no evidence of luteinization. T h e breasts were of normal size and histologically were normal for age with little glandular tissue about prominent ducts in an areolar connective tissue stroma. T h e pancreas was normal histologically, with no islet hyperplasia, hypertrophy, or cytomegaly. A Gomori aldehyde fuchsin stain of the pancreas revealed normal beta cell granulation in comparison with controls. T h e adrenal glands were small; zonal distinction was poor, all cells being large and pale; the medulla was inconspicuous. T h e thyroid gland was small but in normal position. Follicles were generally devoid of or contained small amounts of coarse, granular, pink colloid. Epithelium was uniformly columnar, but not papillary. T h e interstitium and fetal cells were not prominent (Fig. 5). T h e pituitary gland was normal. It was examined in a m a n n e r similar to that described by RogersY Examination of hematoxylin and eosin stained sections revealed that 38 per cent of 450 cells were eosinophils; eosin-methylene blue staining indicated 37 per cent eosinophils and no more than 5 per cent basophils. This Iatter was
Table I I I . Biochemical studies on autopsy material
Specimen Liver
Psoas muscle
Myocardium
t
Determination
[
Result
[ Intrepretation--Com, ment
Glycogen Glucose-6-phosphatase Phosphorylase
5% with normal structure 5 #moles phosphate/min./Gm. 2.6 #moles phosphate/min./Gm.
Normal Normal Normal low on postmortem tissue Normal
Lactate dehydrogenase
Electrophoretic isoenzymes
Glycogen
2%
Phosphorylase Lactate dehydrogenase
75 #moles phosphate/min./Gm. Electrophoretic isoenzymes
Slightly above normal of 1.5% Normal Normal for age
Lactate dehydrogenase
Electrophoretic isoenzymes
Normal
Negative Normal Serum Anti-thyroglobulin Glycogen determined by method of Hers,14 glucose-6-phosphataseand phosphorylase by method of Cori and associates,1~ and lacetate dehydrogenase-isoenzymesby techniques described by Preston and associates.~n
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Summitt and Favara
The Journal o[ Pediatrics April 1969
Fig. 3. Multiple cross-sections of formalin-fixed spinal cord illustrating the marked hydromyelia of lumbar segments.
confirmed by periodic acid-Schiff staining which revealed less than 10 per cent basophils. Since basophils were definitely not increased, no attempt was made to subclassify them. Muscles were small but histomicrometry revealed fibers to be of a size normal for age. PAS staining and chemical studies revealed glycogen content and enzymatic activity to be normal. DISCUSSION
This infant, we believe, has the phenotype of leprechaunism. Birth weight at 38 weeks gestation was low. She failed to thrive and even at birth she appeared malnourished. She had the elfin facies characteristic of the syndrome with large, low-set ears, deep-set eyes, retuse nose, thick lips, and sparse scalp hair with facial hirsutism. She was not hyperteloric. She did not have m a m mary enlargement, nor were clitoral and labial development as prominent as in previous cases. Endocrine evaluation revealed
no real abnormality except delayed skeletal maturation. Serum alkaline phosphatase and cholesterol were low. Similar values were found by Salmon and Webb 5 and by Patterson and Watkins, 4 but their patients probably are not bona fide cases of leprechaunism. A generalized aminoaciduria was demonstrated in our patient, but death prevented further investigation of this finding. Autopsy failed to demonstrate abnormal hepatic glycogen deposition such as that noted by Donohue and Uchida, 1, 2 nor was the endocrine pancreas hyperplastic, an abnormality described in the cases of Donohue and Uchida and those of K~l16 and associates. G A single determination of serum insulin activity was normal. The increased activity of serum L D H and G O T was attributed to hepatic congestion. While the ovaries contained atretic follicle cysts (a normal finding in our experience), they did not have evidence of follicular maturation which has been a feature in most previously reported affected females and to which has
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Leprechaunlsm
Fig. 4. Composite photograph of the uterus and cut surface of the ovaries showing bicornuate uterus with small right uterine horn.
Fig. 5. Thyroid follicles, formed by low columnar or cuboidal epithelium, are small and essentially devoid of colloid. (Hematoxylin and eosin, xl00.)
60 7
608
Summitt and Favara
been attributed enlargement of clitoris, labia minors, and breasts. Previous authors have been convinced that, while emaciation may produce relative clitoral, labial, and mammary prominence, the excessive degree of these changes could not be accounted for by malnutrition alone; endocrine dysfunction has been postulated. K~l16 and associates 6 characterized the abnormality as premature ovarian follicular maturation resulting in the production of excessive amounts of estrogen, which in turn produced not only the genital abnormalities but also excessive excretion of 17-ketosteroids, hirsutism, abnormalities of carbohydrate metabolism, calcium deposition in renal tubules, and suppression of growth hormone production with delay in skeletal maturation. This attempt to attribute such a variety of abnormalities to one basic cause seems to be an oversimplification of a more complex problem. In Case 1 of Evans 3 and in the patient investigated by Dekaban, 7 urinary estrogens were not elevated; in the later case a single determination of plasma growth hormone was not elevated. T h e claim by K~l16 and associates 6 of increased urinary excretion of 17-ketosteroids due to excessive estrogens has no valid physiological basis. Furthermore, clitoral hypertrophy per se would seem more logically to be the result of stimulation by androgen rather than estrogen. The labial fusion in our patient supports this thesis. In no patient has estrogenization of the vaginal mucosa been found, but most authors have not mentioned this feature. Rogers s has presented evidence for selective excess of interstitial cell stimulating hormone (ICSH) in a male who apparently had leprechaunism, the excess ICSH being produced by an increased relative number of pituitary basophils. He suggested that ICSH stimulated testosterone production and thus large genitalia in' an affected male. The relative numbers of basophils and eosinophils in the anterior pituitary of our patient were within the normal range, 9-13 in contrast to the increase in basophils reported by Rogers. Abnormalities of the thymolymph,a~ie sys-
The Journal of Pediatrics April 1969
tern in our patient included poor follicular definition in lymph nodes, spleen, tonsils, and Peyer's patches, as well as unusually cystic Hassall's bodies in the thymus. Similar abnormalities were present in the cases o f Donohue and Uchida and in those of K~l16 and associates. Serum protein studies have failed to reveal deficiency of gamma globulins. The thymolymphatic findings in these patients seem to be nonspecific and are like those occasionally seen in children dying of chronic illnesses associated with emaciation. They do not resemble changes of host-graft interaction or any of the known immunodeficiency syndromes. The thyroid gland was interesting in that its epithelium suggested a response to T S H stimulation. Unfortunately, an intravenous urogram was done before thyroid function tests could be accomplished. Thyroid glands in most cases have been normal except in the patients of K~l16 and associates. In one of their patients, thyroid follicles were absent; in the other, few follicles were found. Several anomalies not previously described were present in our patient. The variations in phenotype in the few cases of leprechaunism thus far described should not necessarily indicate nosologic heterogeneity. Such variations are common in multiple anomaly syndromes, those for which the etiology is known as well as those in which investigations have not as yet demonstrated a cause. The fact that a patient varies from originally described cases and is more mildly affected should not necessarily militate against the diagnosis. On the other hand, one must use caution in specifying a syndromal association for a given patient, especially when the syndrome is not well delineated. The first 3 infants to be described with leprechaunism were females. This led to speculation that the condition might be limited to the female. Patterson and Watkins 4 then reported a male who they believed had leprechaunism. However, the phenotype of their patient as revealed in an illustration, as well as abnorinalities of bone architecture, suggest that ~heir pat.ien,t should not be included in this syndrome. Similarly, Case 2 of Evans a and
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the patient of Salmon and Webb s are so atypical that they cannot be accepted as bona fide cases of leprechaunism. One may then ask: (1) Is leprechaunism an entity or a group of patients similar in appearance but heterogeneous in formal a n d / o r causal genesis? (2) I f it is an entity, how does one identify a bona fide case ? Unfortunately, no satisfactory answer is available for either question. Reports would seem to indicate that Ieprechaunism may occur in either sex. As discussed by Opitz, 17 multiple anomaly syndromes may be classified in 3 levels of specificity. First, the "physical examination syndrome" is applied when a patient (or several similar patients) is observed to be distinctly different from members of the normal population. Although such evidence for identification of a specific syndrome is tenuous, it does provide a basis for more extensive investigations which would support or refute the hypothesis that an entity exists. Second, the definition of a "formal genesis syndrome" specifies that the similarity among patients thought to have the syndrome must be based upon involvement of the same dysmorphogenetic process. This still does not specify that the same causal genesis is operative. T h e "causal genesis syndrome" is the most specific and applies to cases in which a definite common cause, such as a metabolic error, a chromosomal aberration, a definite genetic mode, or an environmental influence can be demonstrated. Leprechaunism probably should be considered a physical examination syndrome. If some of the evidence for metabolic abnormalities is acceptable, perhaps a common formal genesis exists. The occurrence of leprechaunism in siblings, reported by Donohue and Uchida and by Kill16 and associates, suggests a genetic basis for the condition. This is further supported by consanguinity in the family reported by Donohue. No chromosomal abnormality has been found 'in the 3 cases studied. While endocrine and metabolic abnormalities have been detected in patients with leprechaunism, no error common to all has been found. Only through the acquisition of additional clinical, genetic,
Leprechaunism
609
and metabolic evidence can we hope to clarify the confusing and unsatisfactory status of the syndrome known as leprechaunism. SUMMARY
A female infant with leprechaunism (Donohue's syndrome) is described. The main clinical features exhibited by the infant included failure to thrive leading to death at 5 months of age; elfin facies with large, low-set ears, deep-set eyes, retuse nose, thick lips, and micrognathia; sparse scalp hair; facial hirsutism; inguinal hernias; prominence of the clitoris and labia minora; partial fusion of labia minora; and hypoplastic dermal patterns. Findings at postmortem examination included absence of the corpus callosum, hydromyelia, minor vascular abnormalities, pyloric stenosis, eventration of the diaphragm, and inconspicuous lymphatic tissue. The description of any patient as an example of Donohue's syndrome is based solely upon clinical appearance, since no characteristic laboratory or histologic features are known. Some of the patients previously described would seem not to be actual cases of Donohue's syndrome, demonstrating the difficulty in delineating syndromes in which the causal genesis is not known. The authors would like to express appreciation to Drs. Warren W. Johnson and Thomas L. Avery of the St. Jude Children's Research Hospital and the University of Tennessee for special histologic studies of the pituitary gland. REFERENCES
1. Donohue, W. L.: Clinieopathologic conference at the Hospital for Sick Children. Dysendocrinlsm, J. PEDIAT.32: 739, 1948. 2. Donohue, W. L., and Uchida, I.: Lcprechaunism, J. PEDIA*.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. PEDIAT. 60: 730, 1962. 5. Salmon, M. A., and Webb, J. N.: Dystrophic changes associated with leprechaunlsm in a male infant, Arch. Dis. Childhood 38: 350, 1963. 6. K,~tl6, A., Lakatos, I., and Szij~rt6, L.: Lep-
6 10
7. 8. 9. 10.
11.
12.
S u m m i t t and Favara
rechaunism (Donohue's syndrome), J. PEDIAT. 66: 372, 1965. Dekaben, A.: Metabolic and chromosomal studies in leprechaunism, Arch. Dis. Childhood 40: 632, 1965. Rogers, D. R.: Leprechaunism (Donohue's syndrome), Am. J. Clin. Path. 45: 614, 1966. Sommers, S. C.: Pituitary cell relations to body states, Lab. Invest. 8: 588, 1959. Rasmussen, A. T.: Changes in the proportion of cell types in anterior lobe of human hypophysis during the first nineteen years of life, Am. J. Anat. 86: 75, 1950. Halpern, S. R.: Quantitative cytological stud.. ies on the anterior lobe of the hypophysis of fetuses and children correlated with sexual and skeletal development, Endocrinology 22: 173, 1938. Herlant, M.: Recherches sur la localisation histologique des hormones gonadotropes femelles au niveau de l'hyp0physe ant~rieure, Arch. Biol. 54: 225, 1943.
The Journal of Pediatrics April 1969
13, Pearse, A. G. E.: Cytological and cytochemical investigations of the fetal and adult hypophysis in various physiological and pathological states, J. Path. & Baet. 65: 355,1953. 14. Hers, H. G.: Studies enzymatiques sur fragments hepatiques, application a la classification des glycogenoses, Rev. Internat. d~ H6pat. 9: 35, 1959. 15. Cori, G. T., Illingworth, B., and Keller, T.: Muscle phosphorylase, in Methods of enzymology, vol. I, New York, 1957, Academic Press, Inc., p. 200. 16. Preston, J. A., Briere, R. D., and Batsakis, J. G.: Rapid electrophoretic separation of lactate dehydrogenase isozymes on cellulose acetate, Am. J. Clin. Path. 43: 256, 1965, 17. Opitz, J. M.: The analysis of dysmorphogenetic syndromes with examples from those associated with mental retardation, Proceedings of the First Conference on the Clinical Delineation of Birth Defects, Baltimore, May 20-25, 1968. I n press.