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Autosomal dominant transmission of the Pallister-Hall syndrome
The Journal o f Pediatrics Volume 123, Number 6
T o p f et al.
943
Autosomal dominant transmission of the Pallister-Hall syndrome Kathryn F, Topf, MS,o G a d B. Kletter, MD, Robert P. Kelch, MD, J a m e s A. Brunberg, ME), a n d Leslie G. Biesecker, MD From the Departments of Human Genetics, Pediatrics, and Radiology, University of Michigan Medical Center, Ann Arbor We describe a 9-year-old boy and his 34-year-old father with the Pallister-Hall syndrome. The proband had precocious puberty, imperforate anus, postaxial polydactyly, hypospadias, a hypothalamic mass, and a displaced pituitary gland. The father had polydactyly, a hypothalamic mass, and a flattened pituitary gland. We conclude that the most likely cause of the Pallister-Hall syndrome is a mutation in a g e n e inherited in an autosomal dominant manner. (J PEDIATR1993;123:943-6) Since the first report of six persons with Pallister-Hall synd r o m e in 1980, 17 additional persons with t h e s y n d r o m e have been described. H ~ M a j o r manifestations of P H S include polydactyly, h y p o t h a l a m i c h a m a r t o b l a s t o m a , imperforate anus, a n d dysmorphic craniofaeial features. T h e hyp o t h a l a m i c h a m a r t o b l a s t o m a is associated with pituitary dysfunction, a n d most infants with P H S die of hypopituitarism within the first year of life. This disorder was t h o u g h t to be severe a n d lethal, but occasional individuals have survived the neonatal period; most are dependent on exogenous hormones. 4, 9 Because previous cases have been sporadic, it was presumed t h a t a teratogenic a g e n t was responsible for the pleiotropic manifestations of this disorder. ~, 2, 6, 7 W e report on a family t h a t suggests t h a t the inheritance pattern is autosomal d o m i n a n t and t h a t the phenotype of the disorder is more variable t h a n was previously believed. CASE REPORTS The proband was born to a 22-year-old white woman with type I diabetes. The proband was delivered by cesarean section because of prolonged rupture of membranes at 32 weeks of gestation. At birth he was noted to have four-limb mixed mid-axial and postaxial hexadactyly with partial syndactyly, imperforate anus, hypoSupported in part by National Institutes of Health grants MO1 RR 00042 and HD16000. Submitted for publication July 9, 1993; accepted Aug. 13, 1993. Reprint requests: Leslie G. Biesecker, MD, National Institutes of Health, National Center for Human Genome Research, Building 49, Room 4A80, Bethesda, MD 20892. aNow in the Genetics Department, Kaiser Permanente, Sacramento, Calif. Copyright 9 1993 by Mosby-Year Book, Inc. 0022-3476/93/$1.00 + .10 9/22/50745
spadias with chordee, preauricular skin tags, a small left testicle, a mild cleft of the upper gum, and hip dysplasia. At 9 years of age he had normal mental capacity and a 1-year history of precocious puberty. His height was 133.3 cm (50th centile), weight 32.9 kg (75th to 90th centile), and head circumference 52 cm (25th to 50th centile). He had coarse hair, malformed and discolored teeth, a broad and prominent forehead, upslanting palpebral fissures, a mildly depressed nasal bridge, and an upturned nasal tip (Figure ). His middle finger length was 5.3 cm (<5th centile), and scars were present from reduction operations on each hand. He had Tanner stage IIl pubic hair and genital development, u MRI PHS
Magnetic resonance imaging Pallister-Hall syndrome
A skeletal survey revealed a bone age of 13 years _+ 9 months. 12 The findings of an echocardiogram, an ophthalmologic evaluation with Goldmann visual fields, and a renal ultrasound examination were normal. Evaluation with cranial magnetic resonance imaging identified a 1.5 • 2.5 x 3.0 cm hypothalamic mass with a displaced pituitary gland. The optic chiasm and optic tracts were inferiorly displaced and the ventricles were minimally prominent. A second cranial MRI evaluation 12 months later was unchanged. Laboratory studies revealed a prolactin value of 4.6 ng/ml (normal, <17 ng/ml), 17-hydroxyprogesterone 3.3 nmol/L (1.1 ng/ml) (normal, <6.1 nmol/L [<2 ng/ml]), and testosterone 10.2 nmol/L (2.93 ng/ml) (prepubertal normal value, <0.7 nmol/L [<0.2 ng/ml], adult male normaI value, 10.4 to 34.7 nmol/L [3 to 10 ng/ml]). Thyroxine and thyrotropin values were normal. A luteinizing hormone releasing factor test (intravenous administration of Factrel, 2.5 #g/kg) revealed a peak follicle-stimulating hormone value of 5.3 IU/L, with a change in value (A) of 2.2 IU/L, and a luteinizing hormone peak value of 18.2 IU/L, with a 2x of 16.2 IU/L. An overnight study showed pulsatile luteinizing hormone secretion and a normal diurnal secretion of cortisol. These results are consistent with a pubertal response to luteinizing hormone releasing factor.
944
Topf et al.
The Journal of Pediatrics December 1993
Figure. Father (right) at 34 years of age with broad, flat nasal bridge and coarse hair. Proband (left) at 9 years of age with dysplastic teeth; broad, flat nasal bridge; upslanting palpebral fissures; and coarse hair. He was treated with depot injections of gonadotropin releasing hormone analog (Lupron), and had suppression of the gonadotropin and testosterone concentrations to prepubertal levels. High resolution (850 band) chromosome analysis with close analysis of 3p and 7q was normal. The family history was remarkable for the fact that the father shared many features with the proband (see below). A sister, the mother, and all grandparents were unaffected. The father was 34 years of age at the time of his evaluation and 24 years of age at the time of the birth of his son. He also had fourlimb mixed midaxial and postaxial hexadactyly at birth and has normal mental Capacity; he had neither Congenital hypospadias nor imperforate anus, and denied precocious puberty. His height was 167 cm (5th centile), weight 70 kg (near 50th centile)i and head circumference 60 cm (>98 centile). H e had a prominent forehead, fiat nasal bridge, upturned nasal tip, upslanting palpebra! fissures, and coarse hair (Figure). His fingers were short (middle finger length 6.3 cm, <5th centile), and scarring from previous surgical procedures was apparent. He had normal external genitalia. Findings Of renal ultrasonography were normal. Crahial MRI evaluation revealed a hypothalamie mass that measured 2.5 • 3.5 • 2.75 cin and normal ventricles. A second cranial MRI 16 months later was unchanged. H e had normal levels of thyroxine, thyrotropin, and prolactin. A 22-hour profile of gonadotropin secretion revealed low serum concentrations of luteinizing hormone and follicle-stimulating hormone, and low-normal testosterone values between 8.7 and 18 nmol/L (2.5 to 5.3 ng/mi). Gonadotropin release after administration of gonadotropin releasing hormone and diurnal secretion of cortisol were normal. DISCUSSION The diagnosis of P H S in the proband is unambiguous; he had all the major features of the syndrome and n o major anomalies not previously reported with this disorder. The father also had features consistent with P H S but not to the
same degree. Given the documented variability in the manifestations of the syndrome ( T a b l e ) and the fact that the proband has features consistent with the syndrome, we believe that the father's features warrant the diagnosis of PHS. This case suggests that a single gene is the most likely cause of PHS, as proposed by previous authors. Graham et al. 4 reported a deceased child with P H S who had a paternal aunt with a history of several features consistent with the syndrome. Unfortunately, this aunt died in the neonatal period without a detailed physical examination, and no autopsy was performed. Kuller et alJ ~ reported a deceased male infant with P H S and an unbalanced chromosome rearrangement (46,XY,-7,+der(7),t(3;7)(p25.4;q36). This infant's brother was affected with the same spectrum of congenital anomalies and also died in infancy. These data indicate that P H S is inherited in an autosomal dominant manner, and that most Cases are caused by life-threatening mutations or chromosome aberrations involving the P H S gene. Encha-Razavi et alJ 3 described a disorder with skeletal dysplasia and congenital hypothalamic hamartoma. They propose that it is nosologicaily distinct from P H S and other skeletal dysplasias, and have designated this disorder the congenital hypothalamic h a m a r t o m a syndrome. The relationship of this disorder to P H S and the implications for considerations of pathogenesis and etiology are unclear. Excluding etiologic heterogeneity among other sporadic cases, these findings suggest that the gene responsible for P H S manifests variable expressivity and penetrance. These mechanisms must be invoked to explain the case described by G r a h a m et al. 4 with an affected second-degree relative, if the two individuals are assumed to have the same muta-
The Journal o f Pediatrics Volume 123, Number 6
T o p f et al.
945
T a b l e . Clinical and pathologic findings of the Pallister-Hall syndrome Cases Finding
No.
%
Proband
Male Central nervous system Hypothalamic hamartoma Craniofacial anomalies Broad, flat nasal bridge Ear anomalies (low set, malformed) Palatal anomalies Bifid epiglottis, cleft larynx Limb anomalies Polydactyly or oligodactyly Short limbs Syndactyly Pathologic findings Renal ectopia or dysplasia Congenital heart defect Imperforate or anteriorly placed anus Lung dysplasia or hypoplasia Endocrine findings Pituitary aplasia or dysplasia Testicular hypoplasia, cryptorchidism, micropenis
16
70
-I-
19
83
-t-
12 14 15 11
52 61 65 48
+ + +
15 10 12
65 44 52
+ + +
13 9 i2 8
57 39 52 35
+
13 14
57 88*
Father
+ + +
+
Data are based on published cases) "1~ *Calculated with data from male subjects only.
tion. Phenotypic variation may also be the result of different mutations in the gene responsible for P H S , somatic mosaicism, modification of expression by environmental factors, or imprinting. If the mutation responsible for P H S in the father occurred after conception, the discrepancy between features manifested by the father and those by his son may be explained by proposing that the father has mosaicism for the aberrant gene. Individuals with mosaicism may have a milder phenotypic expression than affected individuals without mosaicism. The diagnoses of P H S in the proband and the father show that the syndrome is not necessarily a lethal condition. The only apparent major anomaly in the father was polydactyly; the hamartoma and pituitary deformation were clinically inapparent. The report by Graham et al. 4 supports the concept of variable expressivity; one patient had considerable developmental progress with the support of exogenous endocrine supplementation. An impaired man was described by Greenhaw et al.9; this report also supports the notion that P H S can be compatible with life. Because the true spectrum of P H S is unknown, we propose that P H S be included in the differential diagnoses of persons with gonadotropic-endocrinologic dysfunction or PHS-associated congenital anomalies, particularly polydactyly. The present case also indicates that the hypothalamic mass characteristic of P H S is not necessarily associated with neonatal death, decreased mental capacity, or im-
paired reproductive capacity. It is not possible to determine whether the hypothalamic lesions of the proband and the father are stable or progressive. It is possible that the lesions were congenital and progressed with age, developed postnatally and progressed, or were congenital and stable. The status of the lesions in this family may be progressive and congenital or postnatal, given the age difference between the proband and his father, or congenital and stable, given the variability of the central nervous system lesions among persons with PHS. Further longitudinal evaluation of the proband, his father, and additional long-term survivors with P H S is necessary for a complete understanding of the natural history and spectrum of this pleiotropic disorder. This case establishes a gene with an autosomal dominant mode of inheritance as the most likely cause of PHS; affected individuals have up to a 50% risk of having similarly affected children. The variable expressivity of P H S indicates that an evaluation of parents of children with symptoms of the syndrome, including cranial M R I with careful attention to the pituitary gland, is necessary to provide accurate genetic counseling and medical management. We thank Mason Barr, Jr., Barbara Bowles Biesecker, and Judith Halt for critical review of this manuscript. Chromosome analysis was performed by Susan Sheldon, PhD.
946
Topf et al.
The Journal of Pediatrics December 1993
REFERENCES l. Hall JG, Pallister PD, Clarren SK, et al. Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly: a new syndrome? Part I. Am J Med Genet 1980;7:47-74. 2. HuffDS, Fernandes M. Two cases of congenital hypothalamic hamartoblastoma, polydactyly, and other congenital anomalies (Pallister-Hall syndrome) [Letter]. N Engl J Med 1982; 306:430-1. 3. Culler FL, Jones KL. Hypopituitarism in association with postaxial polydaetyly. J PEDIATR 1984;104:881-4. 4. Graham JM Jr, Harris M, Frank JE, Little GA, Klein RZ. Congenital hypothalamie hamartoblastoma syndrome: natural history and genetic implications. In: Papadatos C J, Bartsocas CS, eds. Endocrine genetics and genetics of growth. New York: Alan R Liss, 1985:163-74. 5. Nurbhai MA, Tomlison BE, Lorigan-Forsythe B. Infantile hypothalamic hamartoma with multiple congenital abnormalities. Nenropathol Appl Neurobiol 1985;11:61-70. 6. Iafolla K, Fratkin JD, Spiegel PK, Cohen MM Jr, Graham JM Jr. Case report and delineation of the congenital bypothalamic hamartoblastoma syndrome (Pallister-Hall syndrome). Am J Med Genet 1989;33:489-99.
7. Pallister PD, Hecht F, Herrman J. Three additional case of the congenital hypothalamic "hamartoblastoma" (Pallister-Hall) syndrome [Letter]. Am J Med Genet 1989;33:500-1. 8. Finnigan DP, Clarren SK, Haas JE. Extending the PallisterHall syndrome to include other central nervous system malformations. Am J Med Genet 1991;40:395-400. 9. Greenhaw G, Orlander P, Langford L, Horton W. Long-term survival in Pallister-Hall syndrome [Abstract]. Am J Med Genet 1991;49:138. 10. Kuller JA, Cox VA, Schonberg SA, Golabi M. Pallister-Hall syndrome associated with an unbalanced chromosome translocation. Am J Med Genet 1992;43:647-50. 11. Marshall WA, Tanner JM. Variation in the pattern of pubertal changes in boys. Arch Dis Child 1970;45:13-23. 12. Greulich WW, Pyle SI. Radiographic atlas of skeletal development of the hand and wrist. 2nd ed. Stanford: Stanford University Press, 1959. 13. Encha-Razavi F, Larroche JC, Roume J, et al. Congenital hypothalamic hamartoma syndrome: nosological discussion and minimum diagnostic criteria of a possibly familial form. Am J Med Genet 1992;42:44-50.
FELLOWSHIPS Fellowships available in pediatric subspecialties and those for general academic pediatric training are listed once a year, in January, in THE JOURNAL OF PEDIATRICS. Each June, forms for listing fellowships available for the academic year beginning 18 months after publication are sent to the Chairman of the Department of Pediatrics at major hospitals in the United States and Canada. In addition, a copy of the application form appears in the July, August, and September issues of THE JOURNAL (please use the current form), Sliould you desire to list fellowships, a separate application must be made each year for each position. All applications must be returned to M o s b y - Y e a r Book, Inc., by October 15 preceding the listing year to ensure publication. Additional forms will be supplied on request from the Journal Editing Department, M o s b y - Y e a r Book, Inc., 11830 Westline Industrial Drive, St. Louis, M O 63146-3318/800-325-4177, ext. 4317, or 314453-4317.
T o p f et al.
943
Autosomal dominant transmission of the Pallister-Hall syndrome Kathryn F, Topf, MS,o G a d B. Kletter, MD, Robert P. Kelch, MD, J a m e s A. Brunberg, ME), a n d Leslie G. Biesecker, MD From the Departments of Human Genetics, Pediatrics, and Radiology, University of Michigan Medical Center, Ann Arbor We describe a 9-year-old boy and his 34-year-old father with the Pallister-Hall syndrome. The proband had precocious puberty, imperforate anus, postaxial polydactyly, hypospadias, a hypothalamic mass, and a displaced pituitary gland. The father had polydactyly, a hypothalamic mass, and a flattened pituitary gland. We conclude that the most likely cause of the Pallister-Hall syndrome is a mutation in a g e n e inherited in an autosomal dominant manner. (J PEDIATR1993;123:943-6) Since the first report of six persons with Pallister-Hall synd r o m e in 1980, 17 additional persons with t h e s y n d r o m e have been described. H ~ M a j o r manifestations of P H S include polydactyly, h y p o t h a l a m i c h a m a r t o b l a s t o m a , imperforate anus, a n d dysmorphic craniofaeial features. T h e hyp o t h a l a m i c h a m a r t o b l a s t o m a is associated with pituitary dysfunction, a n d most infants with P H S die of hypopituitarism within the first year of life. This disorder was t h o u g h t to be severe a n d lethal, but occasional individuals have survived the neonatal period; most are dependent on exogenous hormones. 4, 9 Because previous cases have been sporadic, it was presumed t h a t a teratogenic a g e n t was responsible for the pleiotropic manifestations of this disorder. ~, 2, 6, 7 W e report on a family t h a t suggests t h a t the inheritance pattern is autosomal d o m i n a n t and t h a t the phenotype of the disorder is more variable t h a n was previously believed. CASE REPORTS The proband was born to a 22-year-old white woman with type I diabetes. The proband was delivered by cesarean section because of prolonged rupture of membranes at 32 weeks of gestation. At birth he was noted to have four-limb mixed mid-axial and postaxial hexadactyly with partial syndactyly, imperforate anus, hypoSupported in part by National Institutes of Health grants MO1 RR 00042 and HD16000. Submitted for publication July 9, 1993; accepted Aug. 13, 1993. Reprint requests: Leslie G. Biesecker, MD, National Institutes of Health, National Center for Human Genome Research, Building 49, Room 4A80, Bethesda, MD 20892. aNow in the Genetics Department, Kaiser Permanente, Sacramento, Calif. Copyright 9 1993 by Mosby-Year Book, Inc. 0022-3476/93/$1.00 + .10 9/22/50745
spadias with chordee, preauricular skin tags, a small left testicle, a mild cleft of the upper gum, and hip dysplasia. At 9 years of age he had normal mental capacity and a 1-year history of precocious puberty. His height was 133.3 cm (50th centile), weight 32.9 kg (75th to 90th centile), and head circumference 52 cm (25th to 50th centile). He had coarse hair, malformed and discolored teeth, a broad and prominent forehead, upslanting palpebral fissures, a mildly depressed nasal bridge, and an upturned nasal tip (Figure ). His middle finger length was 5.3 cm (<5th centile), and scars were present from reduction operations on each hand. He had Tanner stage IIl pubic hair and genital development, u MRI PHS
Magnetic resonance imaging Pallister-Hall syndrome
A skeletal survey revealed a bone age of 13 years _+ 9 months. 12 The findings of an echocardiogram, an ophthalmologic evaluation with Goldmann visual fields, and a renal ultrasound examination were normal. Evaluation with cranial magnetic resonance imaging identified a 1.5 • 2.5 x 3.0 cm hypothalamic mass with a displaced pituitary gland. The optic chiasm and optic tracts were inferiorly displaced and the ventricles were minimally prominent. A second cranial MRI evaluation 12 months later was unchanged. Laboratory studies revealed a prolactin value of 4.6 ng/ml (normal, <17 ng/ml), 17-hydroxyprogesterone 3.3 nmol/L (1.1 ng/ml) (normal, <6.1 nmol/L [<2 ng/ml]), and testosterone 10.2 nmol/L (2.93 ng/ml) (prepubertal normal value, <0.7 nmol/L [<0.2 ng/ml], adult male normaI value, 10.4 to 34.7 nmol/L [3 to 10 ng/ml]). Thyroxine and thyrotropin values were normal. A luteinizing hormone releasing factor test (intravenous administration of Factrel, 2.5 #g/kg) revealed a peak follicle-stimulating hormone value of 5.3 IU/L, with a change in value (A) of 2.2 IU/L, and a luteinizing hormone peak value of 18.2 IU/L, with a 2x of 16.2 IU/L. An overnight study showed pulsatile luteinizing hormone secretion and a normal diurnal secretion of cortisol. These results are consistent with a pubertal response to luteinizing hormone releasing factor.
944
Topf et al.
The Journal of Pediatrics December 1993
Figure. Father (right) at 34 years of age with broad, flat nasal bridge and coarse hair. Proband (left) at 9 years of age with dysplastic teeth; broad, flat nasal bridge; upslanting palpebral fissures; and coarse hair. He was treated with depot injections of gonadotropin releasing hormone analog (Lupron), and had suppression of the gonadotropin and testosterone concentrations to prepubertal levels. High resolution (850 band) chromosome analysis with close analysis of 3p and 7q was normal. The family history was remarkable for the fact that the father shared many features with the proband (see below). A sister, the mother, and all grandparents were unaffected. The father was 34 years of age at the time of his evaluation and 24 years of age at the time of the birth of his son. He also had fourlimb mixed midaxial and postaxial hexadactyly at birth and has normal mental Capacity; he had neither Congenital hypospadias nor imperforate anus, and denied precocious puberty. His height was 167 cm (5th centile), weight 70 kg (near 50th centile)i and head circumference 60 cm (>98 centile). H e had a prominent forehead, fiat nasal bridge, upturned nasal tip, upslanting palpebra! fissures, and coarse hair (Figure). His fingers were short (middle finger length 6.3 cm, <5th centile), and scarring from previous surgical procedures was apparent. He had normal external genitalia. Findings Of renal ultrasonography were normal. Crahial MRI evaluation revealed a hypothalamie mass that measured 2.5 • 3.5 • 2.75 cin and normal ventricles. A second cranial MRI 16 months later was unchanged. H e had normal levels of thyroxine, thyrotropin, and prolactin. A 22-hour profile of gonadotropin secretion revealed low serum concentrations of luteinizing hormone and follicle-stimulating hormone, and low-normal testosterone values between 8.7 and 18 nmol/L (2.5 to 5.3 ng/mi). Gonadotropin release after administration of gonadotropin releasing hormone and diurnal secretion of cortisol were normal. DISCUSSION The diagnosis of P H S in the proband is unambiguous; he had all the major features of the syndrome and n o major anomalies not previously reported with this disorder. The father also had features consistent with P H S but not to the
same degree. Given the documented variability in the manifestations of the syndrome ( T a b l e ) and the fact that the proband has features consistent with the syndrome, we believe that the father's features warrant the diagnosis of PHS. This case suggests that a single gene is the most likely cause of PHS, as proposed by previous authors. Graham et al. 4 reported a deceased child with P H S who had a paternal aunt with a history of several features consistent with the syndrome. Unfortunately, this aunt died in the neonatal period without a detailed physical examination, and no autopsy was performed. Kuller et alJ ~ reported a deceased male infant with P H S and an unbalanced chromosome rearrangement (46,XY,-7,+der(7),t(3;7)(p25.4;q36). This infant's brother was affected with the same spectrum of congenital anomalies and also died in infancy. These data indicate that P H S is inherited in an autosomal dominant manner, and that most Cases are caused by life-threatening mutations or chromosome aberrations involving the P H S gene. Encha-Razavi et alJ 3 described a disorder with skeletal dysplasia and congenital hypothalamic hamartoma. They propose that it is nosologicaily distinct from P H S and other skeletal dysplasias, and have designated this disorder the congenital hypothalamic h a m a r t o m a syndrome. The relationship of this disorder to P H S and the implications for considerations of pathogenesis and etiology are unclear. Excluding etiologic heterogeneity among other sporadic cases, these findings suggest that the gene responsible for P H S manifests variable expressivity and penetrance. These mechanisms must be invoked to explain the case described by G r a h a m et al. 4 with an affected second-degree relative, if the two individuals are assumed to have the same muta-
The Journal o f Pediatrics Volume 123, Number 6
T o p f et al.
945
T a b l e . Clinical and pathologic findings of the Pallister-Hall syndrome Cases Finding
No.
%
Proband
Male Central nervous system Hypothalamic hamartoma Craniofacial anomalies Broad, flat nasal bridge Ear anomalies (low set, malformed) Palatal anomalies Bifid epiglottis, cleft larynx Limb anomalies Polydactyly or oligodactyly Short limbs Syndactyly Pathologic findings Renal ectopia or dysplasia Congenital heart defect Imperforate or anteriorly placed anus Lung dysplasia or hypoplasia Endocrine findings Pituitary aplasia or dysplasia Testicular hypoplasia, cryptorchidism, micropenis
16
70
-I-
19
83
-t-
12 14 15 11
52 61 65 48
+ + +
15 10 12
65 44 52
+ + +
13 9 i2 8
57 39 52 35
+
13 14
57 88*
Father
+ + +
+
Data are based on published cases) "1~ *Calculated with data from male subjects only.
tion. Phenotypic variation may also be the result of different mutations in the gene responsible for P H S , somatic mosaicism, modification of expression by environmental factors, or imprinting. If the mutation responsible for P H S in the father occurred after conception, the discrepancy between features manifested by the father and those by his son may be explained by proposing that the father has mosaicism for the aberrant gene. Individuals with mosaicism may have a milder phenotypic expression than affected individuals without mosaicism. The diagnoses of P H S in the proband and the father show that the syndrome is not necessarily a lethal condition. The only apparent major anomaly in the father was polydactyly; the hamartoma and pituitary deformation were clinically inapparent. The report by Graham et al. 4 supports the concept of variable expressivity; one patient had considerable developmental progress with the support of exogenous endocrine supplementation. An impaired man was described by Greenhaw et al.9; this report also supports the notion that P H S can be compatible with life. Because the true spectrum of P H S is unknown, we propose that P H S be included in the differential diagnoses of persons with gonadotropic-endocrinologic dysfunction or PHS-associated congenital anomalies, particularly polydactyly. The present case also indicates that the hypothalamic mass characteristic of P H S is not necessarily associated with neonatal death, decreased mental capacity, or im-
paired reproductive capacity. It is not possible to determine whether the hypothalamic lesions of the proband and the father are stable or progressive. It is possible that the lesions were congenital and progressed with age, developed postnatally and progressed, or were congenital and stable. The status of the lesions in this family may be progressive and congenital or postnatal, given the age difference between the proband and his father, or congenital and stable, given the variability of the central nervous system lesions among persons with PHS. Further longitudinal evaluation of the proband, his father, and additional long-term survivors with P H S is necessary for a complete understanding of the natural history and spectrum of this pleiotropic disorder. This case establishes a gene with an autosomal dominant mode of inheritance as the most likely cause of PHS; affected individuals have up to a 50% risk of having similarly affected children. The variable expressivity of P H S indicates that an evaluation of parents of children with symptoms of the syndrome, including cranial M R I with careful attention to the pituitary gland, is necessary to provide accurate genetic counseling and medical management. We thank Mason Barr, Jr., Barbara Bowles Biesecker, and Judith Halt for critical review of this manuscript. Chromosome analysis was performed by Susan Sheldon, PhD.
946
Topf et al.
The Journal of Pediatrics December 1993
REFERENCES l. Hall JG, Pallister PD, Clarren SK, et al. Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly: a new syndrome? Part I. Am J Med Genet 1980;7:47-74. 2. HuffDS, Fernandes M. Two cases of congenital hypothalamic hamartoblastoma, polydactyly, and other congenital anomalies (Pallister-Hall syndrome) [Letter]. N Engl J Med 1982; 306:430-1. 3. Culler FL, Jones KL. Hypopituitarism in association with postaxial polydaetyly. J PEDIATR 1984;104:881-4. 4. Graham JM Jr, Harris M, Frank JE, Little GA, Klein RZ. Congenital hypothalamie hamartoblastoma syndrome: natural history and genetic implications. In: Papadatos C J, Bartsocas CS, eds. Endocrine genetics and genetics of growth. New York: Alan R Liss, 1985:163-74. 5. Nurbhai MA, Tomlison BE, Lorigan-Forsythe B. Infantile hypothalamic hamartoma with multiple congenital abnormalities. Nenropathol Appl Neurobiol 1985;11:61-70. 6. Iafolla K, Fratkin JD, Spiegel PK, Cohen MM Jr, Graham JM Jr. Case report and delineation of the congenital bypothalamic hamartoblastoma syndrome (Pallister-Hall syndrome). Am J Med Genet 1989;33:489-99.
7. Pallister PD, Hecht F, Herrman J. Three additional case of the congenital hypothalamic "hamartoblastoma" (Pallister-Hall) syndrome [Letter]. Am J Med Genet 1989;33:500-1. 8. Finnigan DP, Clarren SK, Haas JE. Extending the PallisterHall syndrome to include other central nervous system malformations. Am J Med Genet 1991;40:395-400. 9. Greenhaw G, Orlander P, Langford L, Horton W. Long-term survival in Pallister-Hall syndrome [Abstract]. Am J Med Genet 1991;49:138. 10. Kuller JA, Cox VA, Schonberg SA, Golabi M. Pallister-Hall syndrome associated with an unbalanced chromosome translocation. Am J Med Genet 1992;43:647-50. 11. Marshall WA, Tanner JM. Variation in the pattern of pubertal changes in boys. Arch Dis Child 1970;45:13-23. 12. Greulich WW, Pyle SI. Radiographic atlas of skeletal development of the hand and wrist. 2nd ed. Stanford: Stanford University Press, 1959. 13. Encha-Razavi F, Larroche JC, Roume J, et al. Congenital hypothalamic hamartoma syndrome: nosological discussion and minimum diagnostic criteria of a possibly familial form. Am J Med Genet 1992;42:44-50.
FELLOWSHIPS Fellowships available in pediatric subspecialties and those for general academic pediatric training are listed once a year, in January, in THE JOURNAL OF PEDIATRICS. Each June, forms for listing fellowships available for the academic year beginning 18 months after publication are sent to the Chairman of the Department of Pediatrics at major hospitals in the United States and Canada. In addition, a copy of the application form appears in the July, August, and September issues of THE JOURNAL (please use the current form), Sliould you desire to list fellowships, a separate application must be made each year for each position. All applications must be returned to M o s b y - Y e a r Book, Inc., by October 15 preceding the listing year to ensure publication. Additional forms will be supplied on request from the Journal Editing Department, M o s b y - Y e a r Book, Inc., 11830 Westline Industrial Drive, St. Louis, M O 63146-3318/800-325-4177, ext. 4317, or 314453-4317.