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Autosomal dominant transmission of isolated growth hormone deficiency in iris-dental dysplasia (Rieger's syndrome)
644
November 1974 The Journal o f P E D I A T R I C S
A utosomal dominant transmission of isolated growth hormone deficiency in iris-dental dysplasia (R ieger's syndrome) A boy with R ieger's syndrome was short and lacked GH. His'.father and sis ter, each of whom had R ieger's syndrome, also had an isolated del~ciency of GH. The paternal grandmother and a paternal uncle, in all likelihood, were similarly affected. Therapy with GH led to enhanced growth in the propositus. The GHde/icient subjects were sensitive to insulin and had a normal increase of insulin in response to arginine and to orally administered glucose. It is suggested that GH deficiency, in this family, is" an inconstant component of R ieger's syndrome andJbllows an autosomal dominant mode of transmission. A common embryologic developmental deject of the neural crest is postulated,
A b d o l l a h S a d e g h i - N e j a d , M . D . , a n d B o r i s S e n i o r , M , D . , * Boston, M a s s .
R I E G E R ' S SYND ROME or iris-dental dysplasia, is a rare genetic disorder transmitted on an autosomal d o m i n a n t basis and characterized by m a l f o r m a t i o n of the iris with pupiUary anomalies and hypoplasia of the teeth with or without maxillary hypoplasia. 15 This report is of a family with Rieger's s y n d r o m e in three successive generations associated with a deficiency of GH, proved in three m e m b e r s of two generations and present in al! likelihood in two other m e m b e r s , one of a preceding generation. T h e genetic transmission of a deficiency of G H , either as an isolated finding or associated with deficiencies of other tropic hormones, has been reported repeatedly. 6~4 In all but a few instances, transmission has followed an autosomal recessive pattern.6,8 -t~ 12 E v e n then, a m e a s u r e of uncertainty may attach to certain of the exceptions 7, 10-14as either the possibility of a homozygous GH-deficient subject mating with a phenotypically normal heterozygote for deficiency of G H could not be excluded or the deficiency of G H was not d o c u m e n t e d by radioimmunoassay. T h e presence of G H deficiency in these subjects with Rieger's s y n d r o m e not only documents an unusual assoPediatric Endocrine-Metabolic Service, Tufts-New England Medical Center Hospitals. *Reprint address: Tufts-NewEngland Medical CenterHospitals, 17l HarrisonA re., Boston, Mass. 02111.
VoL 8s
Lpp. 644-648
ciation but is further evidence that a deficiency of G H may follow an autosomal d o m i n a n t m o d e of inheritance. CASE REPORTS Case 1. R. W. was first seen at the Boston Floating Hospital for Infants and Children at 7 8/12 years of age, when a diagnosis of Rieger's syndrome was made. 3 He was subsequently referred to the Endocrine Service because of shortness of stature. Abbreviation used GH: growth hormone Consanguinity was denied. Both pregnancy and delivery had been normal. His birth weight was 3.6 kg and length 5l cm. He developed normally, but the parents became concerned that he was unduly small at about 2 yr of age. His growth thereafter was exceedingly slow. On examination, he weighed 14 kg and was 101.6 cm tall, 3.4 and 5.5 standard deviations below the respective means for age. He had the typical eye and dental findings of Rieger's syndrome 3 and appeared younger than this stated age. Apart from a first-degree hypospadias, there were no additional abnormal physical findings. The blood count, urinalysis, serum electrolytes, creatinine, and blood urea nitrogen determinations were all normal. His bone age was 3 3/12 years at the chronologic age of 7 8/12 years. A roentgenogram Of the skull was normal and the sella was of normal size. The serum protein-bound iodine was 5.6 btg/100 ml, with a
Volume 85 Number 5
Transmission of GH deficiency in R ieger's syndrome
645
Table I . T h e r e s p o n s e o f s e r u m G H and o f cortisol to the
Table II. T h e r e s p o n s e o f s e r u m G H a n d of glucose a n d
a d m i n i s t r a t i o n o f insulin (0.1 U/kg) intravenously
insulin to stimulation with arginine (500 mg/kg) after p r e t r e a t m e n t with e s t r o g e n (5 rag. twice a day for 2 days)
Time (min)
ol
01
Time (min) 6O 0
[ 15 I 30 [ 60-~ 90
R. W. (propositus) Glucose (rag/100 ml) Cortisol Qzg/100 ml) G,H. (ng/ml)
79 2l 0.7
41 32 1.1
50 35 0.7
R. W. (propositus) Glucose Cortisol GH
D. W. (father) Glucose (mg/100 ml) Insulin (,,U/ml) G.H. (ng/ml)
7l 16.5 0.9
88 22 0.9
95 36 0.9
82 26 1.4
76 7.5 1.0
75 18 3.0
23 44 3.0
28 48 3.4
D. W. (father) Glucose Cortisol GH
K. W. (sister) Glucose Insulin G.H.
81 (1 2.8
86 11 1.1
86 17 0.8
65 4 1.0
64 1 0.8
70 11 2.1
15 11 2.5
37 29 3.2
K. W. (sister) Glucose Cortisol GH
55 34 0.8
27 17 0,5
-43 0.7
S. W. (brother) Glucose Cortisol GH
-33 2.9
-36 7.4
-31 3.6
D. W., Jr. (brother) Glucose Cortisol GH
79 23 34
25 13 22
55 23 12
Table III. Oral glucose tolerance test (50 g m / m 2) in D. W.
total iodine content of 6.8/xg/100 ml. The 24 hr urinary excretions of 17-ketosteroids and of 17-hydroxycorticosteroids were 0.4 and 1.4 rag, respectively. On two occasions, insulin-induced hypoglycemia led to a normal rise in cortisol but failed to" cause an increase in the concentrations of GH (Table I). Over the next year, he grew only 1.8 cm. Therapy with human GH, 1 mg intramuscularly three times weekly, was begun. The dose was later increased to 2 and then to 3 mg three times weekly. His growth rate accelerated and he grew 28.2 cm over the next 5 yr. At the age of 13 89yr he remained prepubertal and had a bone age of 10 89 yr. Case 2. K. W., a sister to R. W., was born at term. Her birth weight was 3.0 kg and length 48 cm. She had a seizure on the first day of life which was attributed to a "low blood sugar" by her family physician. No further seizures occurred nor was hypoglycemia documented. We first saw her at 4 wk of age. Her length was 50.4 cm and head circumference was 35.5 cm. She had an elongated elliptical left pupil; the right pupil was eccentric and located in the superior nasal quadrant. There was minimal ptosis of the left eyelid. Her maxilla appeared small. Apart from these findings, which were characteristic of Rieger's syndrome, the physical examination was unremarkable. At 3~89 years of age, she weighed 11.7 kg and her height was
a n d K. W.
T#ne (min)
o D. W. (father) Glucose (mg/100 ml) Insulin ~U/ml) K. W. (sister) Glucose Insulin
)6o
i, o
65 8.5
113 41
181 73
148 64
103 76
68 --
118 20
162 28
112 9
129 28
86.2 cm, 2.2 and 3.6 standard deviations below the means [br age, respectively. A radiograph of the skull was normal. The bone age was retarded. The concentration of thyroid-stimulating hormone in the blood was 3 p,U/ml; of thyroxine iodine, 5.5 /xg/100 ml. The levels of GH did not increase in response to insulin-induced hypoglycemia nor after estrogen-primed stimulation with arginine (Tables I and II). A glucose tolerance test was normal (Table III). Her growth rate has continued to be slow and therapy with human GH is to be instituted. Case 3. D. W., the father of R. W. and K. W. (Fig. 1), was born in 1936. His past medical history was noncontributory. The onset of puberty was said to have been "late." His height was 156 cm. Physical examination revealed the presence of Rieger's syndrome. He had the eye and dental abnormalities with hypoplasia of the maxilla. Neither insulin-induced hypoglycemia nor stimulation with arginine after pretreatment with estrogens caused increases in the concentrations of plasma GH (Tables I and II). A glucose tolerance test was normal (Table Ill). Family history, Two male siblings of the propositus, aged 14 and 15 yr, also had iris-dental dysplasia. They were of normal height and had a normal increase in the concentration of GH in response to insulin-induced hypoglycemia (Table I). The mother and three additional siblings were all of normal height. None had Rieger's syndrome (Fig. 1). We were not permitted to examine the paternal grandmother
646
Sadeghi-Nejad and Senior
The Journal of Pediatrics November 1974
P, i o B [ Rieger's ' ] syndrome 1 D.W.Jr. SW R.W,
t
Rieger's syndromewith
growth hormonedeficiency
K.W.
~]
Rieger'ssyndromeond
short stature, Not examined
Fig. 1. Pedigree of W. family. or uncle, both of whom were known to have Rieger's syndrome and were said to be extremely short. DISCUSSION In this family, there was a clear association between Rieger's syndrome and an isolated deficiency of GH. Not every subject with Rieger's syndrome lacked GH, but a deficiency of G H was not present in any member who did not have Rieger's syndrome (Fig. 1). The inference is that the deficiency of GH was an inconstant expression of Rieger's syndrome. How Rieger's syndrome comes to be associated with a deficiency of G H is unclear. Indeed, even without the factor of GH deficiency, the findings in Rieger's syndrome are not easily explained in terms of a single embryologic error of development. The ocular manifestations of the syndrome which involve the anterior chamber of the eye are believed to result from abnormal development of the postendothelial mesoderm. 15 A disorder of mesodermal differentiation, however, would not explain the concomitant abnormalities of the pupillary structures nor of the teeth since these tissues are ectodermal in origin. 16 It is postulated that ectodermal neural crest tissue regulates the developmental pattern of the mesodermal structures of the eye as well as the ectodermal tissues d e s t i n e d to differentiate into the teeth a n d pupillary structures. 172~The attraction of this theory, if valid, is that it might also serve to explain the hormonal findings. The anterior pituitary develops from the anterior wall of Rathke's pouch, an outpocketing of the ectodermal stomodeum. However, functionally the release of hormones from.the anterior pituitary is dependent upon the presence of releasing hormones from the hypothalamus, an organ d e r i v e d f r o m the neural crest. Thus, any maldevelopment involving the neural crest might not only cause the ocular and d e n t a l a b n o r m a l i t i e s o f Rieger's syndrome but also might impair hypothalamicpituitary function.
If the impaired secretion of GH in these subjects could be corrected by the administration of GH-releasing hormone, the defect would be located in the hypothalamus rather than in the pituitary, which is in keeping with the p o s t u l a t e of a d e v e l o p m e n t a l disorder o f the neural crest. Unfortunately, GH-releasing hormone was not available to us. It is not known whether the occurence of G H deficiency associated with Rieger's syndrome is unique to this family or whether other subjects with this disorder may also lack GH. Shortness of stature has been reported in p a t i e n t s with R i e g e r ' s s y n d r o m e . 21, 22T h e p o s s i b i l i t y that they too lack G H must be considered. Rieger's syndrome is easily recognizable when the iris and the teeth are involved. However, more subtle abnormalities, confined to the angle of the anterior chamber and detectable only by gonioscopy, may be the sole manifestation. 4 A search for such eye findings in patients known to have G H deficiency may detect other families with this disorder. The association of impairment of function of the pituitary gland with developmental abnormalities of the head and face is well known (Table IV). In many of these disorders, it is unclear whether the defective secretion of hormones from the pituitary is secondary to maldevelopment of the gland itself or results from an abnormality of the hypothalamus with a resultant paucity of the releasing hormones. This question should be resolved with the increasing availability of hypophysiotropic hormones. Rieger's syndrome, as also shown in this family, is transmitted as an autosomal dominant disorder. The deficiency of G H followed the same pattern with documentation in the father and two of the children. We were unable to s t u d y the paternal g r a n d m o t h e r and paternal uncle, both of whom had Rieger's syndrome and in all likelihood lacked GH. M e r i m e e a n d associates ]~ suggested that p a t i e n t s thought to have the rare dominant form of isolated G H
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Transmission of GH deficiency & Rieger's syndrome
647
Table IV. Partial listing of craniofacial d e v e l o p m e n t a l anomalies with associated h y p o f u n c t i o n of pituitary/hypothalamus
J D~order
Craniofaeial abnormality
Anencephaly
Absent cerebral hemispheres; incomplete catvarium Holoprosencep haly* Variable malformation of prosencephalon (a) Cyclopia (b) Cebocephaly (c) Median cleft
Agenesis of corpus caUosum Septo-optic dysplasia Kallmann's syndrome Rieger's syndrome
Anteriorpituitary hypothalamic abnormality
Abnormal posterior pituitary
Polyhormonal
+
Genetic transmission
ReJerenees
Sporadic/ autosomal recessive
23
Sporadic/ autosomal recessive
24
Polyhormonal
-I-
25
Polyhormonal
?
26
Polyhormonal/GH
+
27-30
GH ?
+
Sporadic?
31
Absent septum pellucidum, optic nerve dysplasia Absent olfactory bulb
GH/polyhormonal1"
__-
Sporadic
32
33
Dysgenesis of iris and teeth
GHI"
Variable/ sex-linked recessive Autosomal dominant
Proboscis above single orbit Single nostril leading to blind pouch Variable median facial anomalies Absent corpus callosum
Gonadotropinsr
Present report
*Arhinencephaly. May be associated with trisomy D or deletion of chromosome 18. tPostulated hypothalamic abnormality. :~Provedhypothalamic abnormality.34
deficiency differ f r o m patients with the recessive f o r m in t h a t t h e y t e n d to be h y p e r i n s u l i n e m i c a n d are less responsive to the metabolic effects of either insulin or G H . T h e m e m b e r s of this family who lacked G H were markedly sensitive to insulin (Table I) and had increases in the concentration of insulin in response to arginine and to glucose which were not outside the normal range (Tables II and III). F u r t h e r m o r e , the one subject w h o was treated with G H exhibited substantial e n h a n c e m e n t o f his rate of growth. Accordingly, it seems that, in this family with a d o m i n a n t l y inherited f o r m of G H deficiency, the metabolic pattern is not different f r o m that seen in patients with other forms o f G H deficiency. Purified preparations of human growth hormone and thyroid-stimulating hormone and of anti-thyroid-stimulating hormone antiserum for radioimmunoassay were supplied by the-National Pituitary Agency. REFERENCES
1.
Vossius, A.: Congenitale Anomalien der Iris, Klin. Monatsbl. Augenheilkd. 21: 233, 1883. 2. Rieger, H.: Beitrgge zur Kenntnis seltener Missbildungen der Iris, Albrecht von Graefes Arch. Klin. Opthalmol. 133: ,602, 1935.
3. Feingold, M., Shiere, F., Fogels, H. R., and Donaldson, D.: Rieger's syndrome, Pediatrics 44: 564, 1969. 4. Alkemade, P. P. H.: Dysgenesis mesodermalis of the iris and the cornea. A study of Rieger's syndrome and Peter's anomaly, The Netherlands, 1969, Van Gorcum and Co. Assen. 5. McKusick, V. A.: Mendelian inheritance in man. Catalogs of autosomal dominant, autosomal recessive and X-linked phenotypes, ed. 3, Baltimore, 1971, Johns Hopkins Press, pp. 257-258. 6. Rimoin, D. L., Merimee, T. J., and McKusick, V. A.: G r o w t h h o r m o n e deficiency in man: An isolated recessively inherited defect, Science 152: 1635, 1966. 7. Rayner, P. H. W., Hubble, D. V., and Brown, G. A.: Hereditary isolated growth hormone deficiency, 1st International Symposium on Growth Hormone, Milan, Excerpta Medica Foundation Int. Congr. Ser. 142: 42, 1967. 8. Seip, M., Van Der Hagen, C. B., and Trygstad, O.: Hereditary pituitary dwarfism with Spontaneous puberty, Arch. Dis. Child. 43: 47, 1968. 9. Rimoin, D. L., Merimee, T. J., Rabinowitz, D., and McKusick, V. A.: Genetic aspects of clinical endocrinology, Recent Progr. Horm. Res. 24: 365, 1968. 10. Merimee, T. J., Hall, J. D., Rimoin, D. L., and McKusick, V. A.: A metabolic and hormonal basis for classifying ateliotic dwarfs, Lancet 1: 963, 1969. 11. Tyson, J. E. A.: Isolated growth hormone deficiency, type
648
12.
13.
14.
15. 16.
17.
18.
19. 20. 21. 22.
Sadeghi-Nejad andSenior
II (sexual ateteiosis, type II), in Bergsma, D., editor: The clinical delineation of birth defects. X. The endocrine system, Baltimore, 1971, The Williams & Wilkins Company, pp. 253-254. McKusick, V. A.: Mendelian inheritance in man. Catalogs of autosomal dominant, autosomal recessive and X-linked phenotypes, ed. 3, Baltimore, 1971, Johns Hopkins Press, pp. 234, 490. Sheikholislam, B. M., and Stempfel, R. S., Jr.: Hereditary isolated somatotropin deficiency: Effects of human growth hormone administration, Pediatrics 49:362, 1972. Poskitt, E. M. E., and Rayner, P. H. W.: Isolated growth hormone deficiency: Two families with autosomal dominant inheritance, Arch. Dis. Child. 49: 55, 1974. Duke-Elder, S.: System of ophthalmology, Vol. Iit, part 2, St. Louis, 1964, The C. V. M0sby Company, pp. 543-547. Hagedoorn, A.: Congenital anomalies of the anterior segment of the eye, Arch. Ophthalmol. (Chicago) 17: 223, 1937. deBeer, G. R.: The differentiation of neural crest cells into visceral cartilages and odontoblasts in Ambystoma, and a reexamination of the germ layer theory, Proc. R. Soc. B134: 377, 1947. Falls, H. F.: A gene producing various defects of the anterior segment of the eye: With the pedigree of a family, Am. J. Ophthal. 32 (part II): 41, 1949. Duke-Elder, S.: System of ophthalmology, Vol. llI, part 1, St. Louis, 1963, The C. V. Mosby Company, pp. 49-77. Langdon, J. D.: Rieger's syndrome, Oral Surg. 30: 788, 1970. Crawford, R. A. D.: lris dysgenesis with other anomalies, Br. J. Ophthalmol. 51: 438, 1967. De Hauwere, R. C., Leroy, J. G., Adriaenssens, K., and Van Heule, R.: Iris dysplasia, orbital hypertelorism and psychomotor retardation: A dominantly inherited developmental syndrome, J. PEDIATR.82: 679, 1973.
The Journal of Pediatrics November 1974
23. Tuchmann-Duptessis, H.: Etude des glandes endocrines des anencgphales, Biol. Neonate 1: 8, 1959. 24. De Myer, W., Zeman, W., and Palmer, C. G.: The face predicts the brain: Diagnostic significance of median facial anomalies for holoprosencephaly (arhinencephaly), Pediatrics 34: 256, 1964. 25. Edmonds, H. W.: Pituitary, adrenal and thyroid in cyclopia, Arch. Pathol. 50: 727, 1950. 26. Haworth, J. C., Medovy, H., and Lewis, A. J.: Cebocephaly with endocrine dysgenesis, J. PEDIATR.59: 726, 1961. 27. Franc4s, J. M., Knorr, D., Martinez, R., and Neuhiiuser, G.: Hypophysiirer Ziwergwucbs bei Lippen-Kiefer-Spalte, Heir. Pediatr. Acta 21: 315, 1966. 28. Hintz, R. L., Menking, M., and Sotos, J. F.: Familial holoprosencephaly with endocrine dysgenesis, J. PEDIATR. 72: 81, 1968. 29. Laron, Z., Taube, E., and Kaplan, I.: Pituitary growth hormone insufficiency associated with cleft lip and palate. An embryonal developmental defect, Helv. Pediatr. Acta 24: 576, 1969. 30. Zuppinger, K. A., Sutter, M., Zurbr~igg, R. P., Joss, E. E., and Oetliker, O.: Cleft lip and chorioideal coloboma associated with multiple hypothalamopituitary dysfunctions, J. Clin. Endocrinol. Metab. 33: 934, 1971. 31. Sadeghi-Nejad, A., and Senior, B. Unpublished observations. 32. Kaplan, S. L., Grumbach, M. M., and Hoyt, W. F.: A syndrome of hypopituitary dwarfism, hypoplasia of optic nerves and malformation of prosencephalon: Report of 6 patients, Pediatr. Res. 4: 480, 1970. 33. Kallmann, F. J., Schoenfeld, W. A., and Barrera, S. E.: The genetic aspects of primary eunuchoidism, Am. J. Ment. Defic. 48: 203, 1944. 34. Schally, A. V., Kastin, A. J., Arimura, A.: The hypothalamus and reproduction, Am. J. Obstet. Gynecol. 114: 423, 1972.
November 1974 The Journal o f P E D I A T R I C S
A utosomal dominant transmission of isolated growth hormone deficiency in iris-dental dysplasia (R ieger's syndrome) A boy with R ieger's syndrome was short and lacked GH. His'.father and sis ter, each of whom had R ieger's syndrome, also had an isolated del~ciency of GH. The paternal grandmother and a paternal uncle, in all likelihood, were similarly affected. Therapy with GH led to enhanced growth in the propositus. The GHde/icient subjects were sensitive to insulin and had a normal increase of insulin in response to arginine and to orally administered glucose. It is suggested that GH deficiency, in this family, is" an inconstant component of R ieger's syndrome andJbllows an autosomal dominant mode of transmission. A common embryologic developmental deject of the neural crest is postulated,
A b d o l l a h S a d e g h i - N e j a d , M . D . , a n d B o r i s S e n i o r , M , D . , * Boston, M a s s .
R I E G E R ' S SYND ROME or iris-dental dysplasia, is a rare genetic disorder transmitted on an autosomal d o m i n a n t basis and characterized by m a l f o r m a t i o n of the iris with pupiUary anomalies and hypoplasia of the teeth with or without maxillary hypoplasia. 15 This report is of a family with Rieger's s y n d r o m e in three successive generations associated with a deficiency of GH, proved in three m e m b e r s of two generations and present in al! likelihood in two other m e m b e r s , one of a preceding generation. T h e genetic transmission of a deficiency of G H , either as an isolated finding or associated with deficiencies of other tropic hormones, has been reported repeatedly. 6~4 In all but a few instances, transmission has followed an autosomal recessive pattern.6,8 -t~ 12 E v e n then, a m e a s u r e of uncertainty may attach to certain of the exceptions 7, 10-14as either the possibility of a homozygous GH-deficient subject mating with a phenotypically normal heterozygote for deficiency of G H could not be excluded or the deficiency of G H was not d o c u m e n t e d by radioimmunoassay. T h e presence of G H deficiency in these subjects with Rieger's s y n d r o m e not only documents an unusual assoPediatric Endocrine-Metabolic Service, Tufts-New England Medical Center Hospitals. *Reprint address: Tufts-NewEngland Medical CenterHospitals, 17l HarrisonA re., Boston, Mass. 02111.
VoL 8s
Lpp. 644-648
ciation but is further evidence that a deficiency of G H may follow an autosomal d o m i n a n t m o d e of inheritance. CASE REPORTS Case 1. R. W. was first seen at the Boston Floating Hospital for Infants and Children at 7 8/12 years of age, when a diagnosis of Rieger's syndrome was made. 3 He was subsequently referred to the Endocrine Service because of shortness of stature. Abbreviation used GH: growth hormone Consanguinity was denied. Both pregnancy and delivery had been normal. His birth weight was 3.6 kg and length 5l cm. He developed normally, but the parents became concerned that he was unduly small at about 2 yr of age. His growth thereafter was exceedingly slow. On examination, he weighed 14 kg and was 101.6 cm tall, 3.4 and 5.5 standard deviations below the respective means for age. He had the typical eye and dental findings of Rieger's syndrome 3 and appeared younger than this stated age. Apart from a first-degree hypospadias, there were no additional abnormal physical findings. The blood count, urinalysis, serum electrolytes, creatinine, and blood urea nitrogen determinations were all normal. His bone age was 3 3/12 years at the chronologic age of 7 8/12 years. A roentgenogram Of the skull was normal and the sella was of normal size. The serum protein-bound iodine was 5.6 btg/100 ml, with a
Volume 85 Number 5
Transmission of GH deficiency in R ieger's syndrome
645
Table I . T h e r e s p o n s e o f s e r u m G H and o f cortisol to the
Table II. T h e r e s p o n s e o f s e r u m G H a n d of glucose a n d
a d m i n i s t r a t i o n o f insulin (0.1 U/kg) intravenously
insulin to stimulation with arginine (500 mg/kg) after p r e t r e a t m e n t with e s t r o g e n (5 rag. twice a day for 2 days)
Time (min)
ol
01
Time (min) 6O 0
[ 15 I 30 [ 60-~ 90
R. W. (propositus) Glucose (rag/100 ml) Cortisol Qzg/100 ml) G,H. (ng/ml)
79 2l 0.7
41 32 1.1
50 35 0.7
R. W. (propositus) Glucose Cortisol GH
D. W. (father) Glucose (mg/100 ml) Insulin (,,U/ml) G.H. (ng/ml)
7l 16.5 0.9
88 22 0.9
95 36 0.9
82 26 1.4
76 7.5 1.0
75 18 3.0
23 44 3.0
28 48 3.4
D. W. (father) Glucose Cortisol GH
K. W. (sister) Glucose Insulin G.H.
81 (1 2.8
86 11 1.1
86 17 0.8
65 4 1.0
64 1 0.8
70 11 2.1
15 11 2.5
37 29 3.2
K. W. (sister) Glucose Cortisol GH
55 34 0.8
27 17 0,5
-43 0.7
S. W. (brother) Glucose Cortisol GH
-33 2.9
-36 7.4
-31 3.6
D. W., Jr. (brother) Glucose Cortisol GH
79 23 34
25 13 22
55 23 12
Table III. Oral glucose tolerance test (50 g m / m 2) in D. W.
total iodine content of 6.8/xg/100 ml. The 24 hr urinary excretions of 17-ketosteroids and of 17-hydroxycorticosteroids were 0.4 and 1.4 rag, respectively. On two occasions, insulin-induced hypoglycemia led to a normal rise in cortisol but failed to" cause an increase in the concentrations of GH (Table I). Over the next year, he grew only 1.8 cm. Therapy with human GH, 1 mg intramuscularly three times weekly, was begun. The dose was later increased to 2 and then to 3 mg three times weekly. His growth rate accelerated and he grew 28.2 cm over the next 5 yr. At the age of 13 89yr he remained prepubertal and had a bone age of 10 89 yr. Case 2. K. W., a sister to R. W., was born at term. Her birth weight was 3.0 kg and length 48 cm. She had a seizure on the first day of life which was attributed to a "low blood sugar" by her family physician. No further seizures occurred nor was hypoglycemia documented. We first saw her at 4 wk of age. Her length was 50.4 cm and head circumference was 35.5 cm. She had an elongated elliptical left pupil; the right pupil was eccentric and located in the superior nasal quadrant. There was minimal ptosis of the left eyelid. Her maxilla appeared small. Apart from these findings, which were characteristic of Rieger's syndrome, the physical examination was unremarkable. At 3~89 years of age, she weighed 11.7 kg and her height was
a n d K. W.
T#ne (min)
o D. W. (father) Glucose (mg/100 ml) Insulin ~U/ml) K. W. (sister) Glucose Insulin
)6o
i, o
65 8.5
113 41
181 73
148 64
103 76
68 --
118 20
162 28
112 9
129 28
86.2 cm, 2.2 and 3.6 standard deviations below the means [br age, respectively. A radiograph of the skull was normal. The bone age was retarded. The concentration of thyroid-stimulating hormone in the blood was 3 p,U/ml; of thyroxine iodine, 5.5 /xg/100 ml. The levels of GH did not increase in response to insulin-induced hypoglycemia nor after estrogen-primed stimulation with arginine (Tables I and II). A glucose tolerance test was normal (Table III). Her growth rate has continued to be slow and therapy with human GH is to be instituted. Case 3. D. W., the father of R. W. and K. W. (Fig. 1), was born in 1936. His past medical history was noncontributory. The onset of puberty was said to have been "late." His height was 156 cm. Physical examination revealed the presence of Rieger's syndrome. He had the eye and dental abnormalities with hypoplasia of the maxilla. Neither insulin-induced hypoglycemia nor stimulation with arginine after pretreatment with estrogens caused increases in the concentrations of plasma GH (Tables I and II). A glucose tolerance test was normal (Table Ill). Family history, Two male siblings of the propositus, aged 14 and 15 yr, also had iris-dental dysplasia. They were of normal height and had a normal increase in the concentration of GH in response to insulin-induced hypoglycemia (Table I). The mother and three additional siblings were all of normal height. None had Rieger's syndrome (Fig. 1). We were not permitted to examine the paternal grandmother
646
Sadeghi-Nejad and Senior
The Journal of Pediatrics November 1974
P, i o B [ Rieger's ' ] syndrome 1 D.W.Jr. SW R.W,
t
Rieger's syndromewith
growth hormonedeficiency
K.W.
~]
Rieger'ssyndromeond
short stature, Not examined
Fig. 1. Pedigree of W. family. or uncle, both of whom were known to have Rieger's syndrome and were said to be extremely short. DISCUSSION In this family, there was a clear association between Rieger's syndrome and an isolated deficiency of GH. Not every subject with Rieger's syndrome lacked GH, but a deficiency of G H was not present in any member who did not have Rieger's syndrome (Fig. 1). The inference is that the deficiency of GH was an inconstant expression of Rieger's syndrome. How Rieger's syndrome comes to be associated with a deficiency of G H is unclear. Indeed, even without the factor of GH deficiency, the findings in Rieger's syndrome are not easily explained in terms of a single embryologic error of development. The ocular manifestations of the syndrome which involve the anterior chamber of the eye are believed to result from abnormal development of the postendothelial mesoderm. 15 A disorder of mesodermal differentiation, however, would not explain the concomitant abnormalities of the pupillary structures nor of the teeth since these tissues are ectodermal in origin. 16 It is postulated that ectodermal neural crest tissue regulates the developmental pattern of the mesodermal structures of the eye as well as the ectodermal tissues d e s t i n e d to differentiate into the teeth a n d pupillary structures. 172~The attraction of this theory, if valid, is that it might also serve to explain the hormonal findings. The anterior pituitary develops from the anterior wall of Rathke's pouch, an outpocketing of the ectodermal stomodeum. However, functionally the release of hormones from.the anterior pituitary is dependent upon the presence of releasing hormones from the hypothalamus, an organ d e r i v e d f r o m the neural crest. Thus, any maldevelopment involving the neural crest might not only cause the ocular and d e n t a l a b n o r m a l i t i e s o f Rieger's syndrome but also might impair hypothalamicpituitary function.
If the impaired secretion of GH in these subjects could be corrected by the administration of GH-releasing hormone, the defect would be located in the hypothalamus rather than in the pituitary, which is in keeping with the p o s t u l a t e of a d e v e l o p m e n t a l disorder o f the neural crest. Unfortunately, GH-releasing hormone was not available to us. It is not known whether the occurence of G H deficiency associated with Rieger's syndrome is unique to this family or whether other subjects with this disorder may also lack GH. Shortness of stature has been reported in p a t i e n t s with R i e g e r ' s s y n d r o m e . 21, 22T h e p o s s i b i l i t y that they too lack G H must be considered. Rieger's syndrome is easily recognizable when the iris and the teeth are involved. However, more subtle abnormalities, confined to the angle of the anterior chamber and detectable only by gonioscopy, may be the sole manifestation. 4 A search for such eye findings in patients known to have G H deficiency may detect other families with this disorder. The association of impairment of function of the pituitary gland with developmental abnormalities of the head and face is well known (Table IV). In many of these disorders, it is unclear whether the defective secretion of hormones from the pituitary is secondary to maldevelopment of the gland itself or results from an abnormality of the hypothalamus with a resultant paucity of the releasing hormones. This question should be resolved with the increasing availability of hypophysiotropic hormones. Rieger's syndrome, as also shown in this family, is transmitted as an autosomal dominant disorder. The deficiency of G H followed the same pattern with documentation in the father and two of the children. We were unable to s t u d y the paternal g r a n d m o t h e r and paternal uncle, both of whom had Rieger's syndrome and in all likelihood lacked GH. M e r i m e e a n d associates ]~ suggested that p a t i e n t s thought to have the rare dominant form of isolated G H
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Transmission of GH deficiency & Rieger's syndrome
647
Table IV. Partial listing of craniofacial d e v e l o p m e n t a l anomalies with associated h y p o f u n c t i o n of pituitary/hypothalamus
J D~order
Craniofaeial abnormality
Anencephaly
Absent cerebral hemispheres; incomplete catvarium Holoprosencep haly* Variable malformation of prosencephalon (a) Cyclopia (b) Cebocephaly (c) Median cleft
Agenesis of corpus caUosum Septo-optic dysplasia Kallmann's syndrome Rieger's syndrome
Anteriorpituitary hypothalamic abnormality
Abnormal posterior pituitary
Polyhormonal
+
Genetic transmission
ReJerenees
Sporadic/ autosomal recessive
23
Sporadic/ autosomal recessive
24
Polyhormonal
-I-
25
Polyhormonal
?
26
Polyhormonal/GH
+
27-30
GH ?
+
Sporadic?
31
Absent septum pellucidum, optic nerve dysplasia Absent olfactory bulb
GH/polyhormonal1"
__-
Sporadic
32
33
Dysgenesis of iris and teeth
GHI"
Variable/ sex-linked recessive Autosomal dominant
Proboscis above single orbit Single nostril leading to blind pouch Variable median facial anomalies Absent corpus callosum
Gonadotropinsr
Present report
*Arhinencephaly. May be associated with trisomy D or deletion of chromosome 18. tPostulated hypothalamic abnormality. :~Provedhypothalamic abnormality.34
deficiency differ f r o m patients with the recessive f o r m in t h a t t h e y t e n d to be h y p e r i n s u l i n e m i c a n d are less responsive to the metabolic effects of either insulin or G H . T h e m e m b e r s of this family who lacked G H were markedly sensitive to insulin (Table I) and had increases in the concentration of insulin in response to arginine and to glucose which were not outside the normal range (Tables II and III). F u r t h e r m o r e , the one subject w h o was treated with G H exhibited substantial e n h a n c e m e n t o f his rate of growth. Accordingly, it seems that, in this family with a d o m i n a n t l y inherited f o r m of G H deficiency, the metabolic pattern is not different f r o m that seen in patients with other forms o f G H deficiency. Purified preparations of human growth hormone and thyroid-stimulating hormone and of anti-thyroid-stimulating hormone antiserum for radioimmunoassay were supplied by the-National Pituitary Agency. REFERENCES
1.
Vossius, A.: Congenitale Anomalien der Iris, Klin. Monatsbl. Augenheilkd. 21: 233, 1883. 2. Rieger, H.: Beitrgge zur Kenntnis seltener Missbildungen der Iris, Albrecht von Graefes Arch. Klin. Opthalmol. 133: ,602, 1935.
3. Feingold, M., Shiere, F., Fogels, H. R., and Donaldson, D.: Rieger's syndrome, Pediatrics 44: 564, 1969. 4. Alkemade, P. P. H.: Dysgenesis mesodermalis of the iris and the cornea. A study of Rieger's syndrome and Peter's anomaly, The Netherlands, 1969, Van Gorcum and Co. Assen. 5. McKusick, V. A.: Mendelian inheritance in man. Catalogs of autosomal dominant, autosomal recessive and X-linked phenotypes, ed. 3, Baltimore, 1971, Johns Hopkins Press, pp. 257-258. 6. Rimoin, D. L., Merimee, T. J., and McKusick, V. A.: G r o w t h h o r m o n e deficiency in man: An isolated recessively inherited defect, Science 152: 1635, 1966. 7. Rayner, P. H. W., Hubble, D. V., and Brown, G. A.: Hereditary isolated growth hormone deficiency, 1st International Symposium on Growth Hormone, Milan, Excerpta Medica Foundation Int. Congr. Ser. 142: 42, 1967. 8. Seip, M., Van Der Hagen, C. B., and Trygstad, O.: Hereditary pituitary dwarfism with Spontaneous puberty, Arch. Dis. Child. 43: 47, 1968. 9. Rimoin, D. L., Merimee, T. J., Rabinowitz, D., and McKusick, V. A.: Genetic aspects of clinical endocrinology, Recent Progr. Horm. Res. 24: 365, 1968. 10. Merimee, T. J., Hall, J. D., Rimoin, D. L., and McKusick, V. A.: A metabolic and hormonal basis for classifying ateliotic dwarfs, Lancet 1: 963, 1969. 11. Tyson, J. E. A.: Isolated growth hormone deficiency, type
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The Journal of Pediatrics November 1974
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