American Journal of Medical Genetics 41:346-349 (1991)
Delineation of the Costello Syndrome Rick A. Martin and Kenneth Lyons Jones Division of Dysmorphology, Department of Pediatrics, University of California, San Diego, California We present a lbyear-old girl with mental retardation, short stature, coarse face, unusually thick, loose skin of the hands and feet, deep plantar and palmar creases, and nasal papillomata. Her history and physical fmdings are compared to those of 2 children initially reported by Costello and to 1 child recently reported by Der Kaloustian et al. KEY WORDS: Costello syndrome, nasal papillomata, leprechaunism INTRODUCTION In 1977 Costello reported on 2 unrelated children with a unique malformation pattern of mental retardation, coarse face, nasal papillomata and loose skin of the hands and feet. Der Kaloustian et al. [1991] recently reported a child with manifestations strikingly similar to those of the children described by Costello. Here we describe a fourth child with this condition which we refer to as the Costello syndrome. CLINICAL REPORT This 15-year-oldgirl was born at 40 weeks of gestation to a 34-year-old G5P5 mother after a pregnancy complicated by polyhydramnios. Her nonconsanguinious Hispanic parents have 4 older, normal children. Delivery was spontaneous and vaginal with Apgar scores of 7 and 8. Her birth weight was 4,700 g (>98th centile), length was 50 cm (50th centile), and OFC was 38 cm (>98th centile). She had macrocephaly, a coarse face, apparently low-set, posteriorly angulated ears, epicanthal folds, thick lips, short neck, bilateral talipes equinovarus, and thick loose skin of the hands and feet (Fig. 1). Poor feeding and suck were noted during the first 6 months resulting in virtually no weight gain despite high calorie formula feedings. At 3 months her weight was 4,300 g, length 56 cm, and OFC 40 cm. Her urine organic and amino acids were normal. A skin biopsy,
Received for publication December 24, 1990; revision received March 12, 1991. Address reprint requests to Kenneth Lyons Jones, M.D., University of California San Diego Medical Center, Department of Pediatrics, 225 Dickinson St, H814B, San Diego, CA 92103.
0 1991 Wiley-Liss, Inc.
utilizing both light and electron microscopy, showed no evidence of lipid or mucopolysaccharidestorage disease. Chromosomes were normal (46,XX). A CT scan of the head was normal as was a renal ultrasound. Her echocardiogram was normal. By age 3 years her weight gain had increased dramatically but her linear growth rate had slowed markedly. At 34 months she had a height age (HA) of 21 months with an OFC and weight a t the 50th centile for HA. She also had curly hair, thick ears with large protuberant ear lobes, strabismus and myopia, increased skin pigmentation relative to that of her family, hyperextensible fingers, hypoplastic, deep-set nails, and limitation of elbow extension. Her motor development was difficult to evaluate because of several orthopedic procedures done for talipes equinovarus. Speech was notably slow with only a few single words by age 30 months. However, by age 4% years, she used short complete sentences in both Spanish and English. At age 15 years she obtained a WISC-R verbal score of 51, performance score of 52, and a full scale score of 47. She currently attends a special education class and is functioning a t the first grade level. She does well socially and has a friendly, warm personality. Over the last several years other problems have developed in this child. Acanthosis nigricans of the neck, axilla, knees, and intergluteal cleft was noted at 7 years. Evaluation did not document insulin resistance. At age 12years a large calcified epithelioma of the left neck was removed. A pelvic mass was discovered at age 14 years and identified after a laparotomy as bilateral epithelial lined paratubal cysts. Onset of menses occurred at 15 years. Her most recent exam at age 15 years showed a HA of 910h years with an OFC at the 90th centile and weight at the 98th centile for HA. Physical findings which have developed in the last 6 months include mitral valve prolapse, an increased anterior-posterior chest configuration, bilateral papillomatous growths in the anterior nares, mild ptosis, and nevi of the palms (Figs. 2-4).
DISCUSSION The child presented in this report brings to 4 the number of cases described with the Costello syndrome. The principal manifestations of this condition are set forth in Table I. Although all patients had normal birth weight and length, severe early postnatal growth deficiency was consistent. Our patient required high calorie formula and did not regain her birth weight until age 4
Costello Syndrome
347
Fig. 1. Patient at age 3 months. Note the thick loose skin on the hands.
Fig. 2. Patient at age 15 years.
months while the patients described by Costello needed gavage feeding until regaining birth weight at 6 weeks. The case of Der Kaloustian et al, at age 1 year, was also significantly growth retarded. The extent to which poor suck contributed to lack of weight gain in these cases is
unclear. However,the presence ofpolyhydramniosin 3 of these cases suggests that swallowing difficulties were also present prenatally. Our patient has had persistent linear growth deficiency despite normal weight gain in her later years. Whether improved weight gain in later
348
Martin and Jones
Fig. 3. Patient a t age 15 years. Note deep palmar creases and nevi (left), persistent thick loose skin of hands, and acanthosis nigricans of knees (right).
TABLE I. The Costello Syndrome
Features Growth and performance Postnatal growth deficiency Poor suck Mental deficiency Craniofacial Macrocephaly Coarse face Low-set ears with thick lobes Epicanthal folds Strabismus Thick lips Depressed nasal bridge Enamel dysplasia Skinhairhails Thin, deep set nails Loose skin, esp. hands and feet Dark skin pigmentation Curly hair Deep plantar, palmar creases Hyperkeratotic palms, soles Acanthosis nigricans Palmar nevi Musculoskeletal Short neck Tight Achilles tendon Hyperextensible fingers Foot positional defects Increased AP diameter of chest Defect range of elbow motion Benign neoplasms Nasal papillomata Epithelioma Epithelial paratubal cyst Other Inquinal testes Sociable, warm personality "WISC-R full scale score. not noted. "A, sex-limited characteristic.
b?,
Costello
Costello
1
2
Der Kaloustian et a1
+ +
+ +
+ +
67"
58-68"
+
This case
+ +
47"
+ + + + + + + + +
+ + + (by photo) +-
+ + ?b
? -
+ +
+ +
+ +
+
414 414 414 414 214
+ + +
214 1i 4 1I4
+
414 414 414 314 314
+ +
+
NA'
NA
?
+ +
+ + +
++
414 414 414 414 414 414 4i4 314 3I4 3I4 1I4
+ +
+ +
Total
-
NA ?
+ +
+ + + + NA
+
3I4 414 114 112 212 214
Costello Syndrome
Fig. 4. Nasal papillomata.
childhood with persistent short stature is a consistent manifestation in this syndrome is not clear since longterm growth parameters are not available on the three previously described patients. It is likely that the manifestations described most recently in this patient but not noted in the other cases (i.e., acanthosis nigricans, myonevi’ and Other benign neoplasms) pia, ptosis7 are also part of the syndrome. Most of these changes did not become evident after age l2 years in Our patient, thus their absence in the prior reports may be a
349
reflection of younger patient ages at the time of publication. Although leprechaunism should be considered in the differential diagnosis of Costello syndrome, the normal prenatal growth, relative macrocephaly, curly hair, short neck, dark skin pigmentation, hyperextensible fingers and eventual papillomatous growths seen in these patients are distinguishing traits. The occurrence of acanthosis nigricans in our patient, a skin finding frequently associated with insulin resistance in leperchaunism, is of interest. However, she has no evidence of insulin resistance. Perhaps the most unique aspect of this condition is the development of benign tumors, all of which are epithelial in nature. Variability in age of tumor-onset is likely, at least in regard to development of nasal papillomata where the occurrence ranged from 2.5 to 15 years. All four patients described to date, two females and two males, represent sporadic occurrences in otherwise normal families.
ACKNOWLEDGMENTS This work was supported in part by NIH training Grant DK07318. we would like to thank D ~ ~. i ~~~ifor bringing to our attentionD ~Costello’s . report.
REFERENCES Costello JM (1977): A new syndrome: Mental subnormality and nasal papillomata. Aust Paediat J 13:114-118, Der Kaloustian VM, Moroz B, McIntosh N, Watters AK, Blaichman S (1991): The Costello syndrome. Am J Med Genet (in press).
~
Delineation of the Costello Syndrome Rick A. Martin and Kenneth Lyons Jones Division of Dysmorphology, Department of Pediatrics, University of California, San Diego, California We present a lbyear-old girl with mental retardation, short stature, coarse face, unusually thick, loose skin of the hands and feet, deep plantar and palmar creases, and nasal papillomata. Her history and physical fmdings are compared to those of 2 children initially reported by Costello and to 1 child recently reported by Der Kaloustian et al. KEY WORDS: Costello syndrome, nasal papillomata, leprechaunism INTRODUCTION In 1977 Costello reported on 2 unrelated children with a unique malformation pattern of mental retardation, coarse face, nasal papillomata and loose skin of the hands and feet. Der Kaloustian et al. [1991] recently reported a child with manifestations strikingly similar to those of the children described by Costello. Here we describe a fourth child with this condition which we refer to as the Costello syndrome. CLINICAL REPORT This 15-year-oldgirl was born at 40 weeks of gestation to a 34-year-old G5P5 mother after a pregnancy complicated by polyhydramnios. Her nonconsanguinious Hispanic parents have 4 older, normal children. Delivery was spontaneous and vaginal with Apgar scores of 7 and 8. Her birth weight was 4,700 g (>98th centile), length was 50 cm (50th centile), and OFC was 38 cm (>98th centile). She had macrocephaly, a coarse face, apparently low-set, posteriorly angulated ears, epicanthal folds, thick lips, short neck, bilateral talipes equinovarus, and thick loose skin of the hands and feet (Fig. 1). Poor feeding and suck were noted during the first 6 months resulting in virtually no weight gain despite high calorie formula feedings. At 3 months her weight was 4,300 g, length 56 cm, and OFC 40 cm. Her urine organic and amino acids were normal. A skin biopsy,
Received for publication December 24, 1990; revision received March 12, 1991. Address reprint requests to Kenneth Lyons Jones, M.D., University of California San Diego Medical Center, Department of Pediatrics, 225 Dickinson St, H814B, San Diego, CA 92103.
0 1991 Wiley-Liss, Inc.
utilizing both light and electron microscopy, showed no evidence of lipid or mucopolysaccharidestorage disease. Chromosomes were normal (46,XX). A CT scan of the head was normal as was a renal ultrasound. Her echocardiogram was normal. By age 3 years her weight gain had increased dramatically but her linear growth rate had slowed markedly. At 34 months she had a height age (HA) of 21 months with an OFC and weight a t the 50th centile for HA. She also had curly hair, thick ears with large protuberant ear lobes, strabismus and myopia, increased skin pigmentation relative to that of her family, hyperextensible fingers, hypoplastic, deep-set nails, and limitation of elbow extension. Her motor development was difficult to evaluate because of several orthopedic procedures done for talipes equinovarus. Speech was notably slow with only a few single words by age 30 months. However, by age 4% years, she used short complete sentences in both Spanish and English. At age 15 years she obtained a WISC-R verbal score of 51, performance score of 52, and a full scale score of 47. She currently attends a special education class and is functioning a t the first grade level. She does well socially and has a friendly, warm personality. Over the last several years other problems have developed in this child. Acanthosis nigricans of the neck, axilla, knees, and intergluteal cleft was noted at 7 years. Evaluation did not document insulin resistance. At age 12years a large calcified epithelioma of the left neck was removed. A pelvic mass was discovered at age 14 years and identified after a laparotomy as bilateral epithelial lined paratubal cysts. Onset of menses occurred at 15 years. Her most recent exam at age 15 years showed a HA of 910h years with an OFC at the 90th centile and weight at the 98th centile for HA. Physical findings which have developed in the last 6 months include mitral valve prolapse, an increased anterior-posterior chest configuration, bilateral papillomatous growths in the anterior nares, mild ptosis, and nevi of the palms (Figs. 2-4).
DISCUSSION The child presented in this report brings to 4 the number of cases described with the Costello syndrome. The principal manifestations of this condition are set forth in Table I. Although all patients had normal birth weight and length, severe early postnatal growth deficiency was consistent. Our patient required high calorie formula and did not regain her birth weight until age 4
Costello Syndrome
347
Fig. 1. Patient at age 3 months. Note the thick loose skin on the hands.
Fig. 2. Patient at age 15 years.
months while the patients described by Costello needed gavage feeding until regaining birth weight at 6 weeks. The case of Der Kaloustian et al, at age 1 year, was also significantly growth retarded. The extent to which poor suck contributed to lack of weight gain in these cases is
unclear. However,the presence ofpolyhydramniosin 3 of these cases suggests that swallowing difficulties were also present prenatally. Our patient has had persistent linear growth deficiency despite normal weight gain in her later years. Whether improved weight gain in later
348
Martin and Jones
Fig. 3. Patient a t age 15 years. Note deep palmar creases and nevi (left), persistent thick loose skin of hands, and acanthosis nigricans of knees (right).
TABLE I. The Costello Syndrome
Features Growth and performance Postnatal growth deficiency Poor suck Mental deficiency Craniofacial Macrocephaly Coarse face Low-set ears with thick lobes Epicanthal folds Strabismus Thick lips Depressed nasal bridge Enamel dysplasia Skinhairhails Thin, deep set nails Loose skin, esp. hands and feet Dark skin pigmentation Curly hair Deep plantar, palmar creases Hyperkeratotic palms, soles Acanthosis nigricans Palmar nevi Musculoskeletal Short neck Tight Achilles tendon Hyperextensible fingers Foot positional defects Increased AP diameter of chest Defect range of elbow motion Benign neoplasms Nasal papillomata Epithelioma Epithelial paratubal cyst Other Inquinal testes Sociable, warm personality "WISC-R full scale score. not noted. "A, sex-limited characteristic.
b?,
Costello
Costello
1
2
Der Kaloustian et a1
+ +
+ +
+ +
67"
58-68"
+
This case
+ +
47"
+ + + + + + + + +
+ + + (by photo) +-
+ + ?b
? -
+ +
+ +
+ +
+
414 414 414 414 214
+ + +
214 1i 4 1I4
+
414 414 414 314 314
+ +
+
NA'
NA
?
+ +
+ + +
++
414 414 414 414 414 414 4i4 314 3I4 3I4 1I4
+ +
+ +
Total
-
NA ?
+ +
+ + + + NA
+
3I4 414 114 112 212 214
Costello Syndrome
Fig. 4. Nasal papillomata.
childhood with persistent short stature is a consistent manifestation in this syndrome is not clear since longterm growth parameters are not available on the three previously described patients. It is likely that the manifestations described most recently in this patient but not noted in the other cases (i.e., acanthosis nigricans, myonevi’ and Other benign neoplasms) pia, ptosis7 are also part of the syndrome. Most of these changes did not become evident after age l2 years in Our patient, thus their absence in the prior reports may be a
349
reflection of younger patient ages at the time of publication. Although leprechaunism should be considered in the differential diagnosis of Costello syndrome, the normal prenatal growth, relative macrocephaly, curly hair, short neck, dark skin pigmentation, hyperextensible fingers and eventual papillomatous growths seen in these patients are distinguishing traits. The occurrence of acanthosis nigricans in our patient, a skin finding frequently associated with insulin resistance in leperchaunism, is of interest. However, she has no evidence of insulin resistance. Perhaps the most unique aspect of this condition is the development of benign tumors, all of which are epithelial in nature. Variability in age of tumor-onset is likely, at least in regard to development of nasal papillomata where the occurrence ranged from 2.5 to 15 years. All four patients described to date, two females and two males, represent sporadic occurrences in otherwise normal families.
ACKNOWLEDGMENTS This work was supported in part by NIH training Grant DK07318. we would like to thank D ~ ~. i ~~~ifor bringing to our attentionD ~Costello’s . report.
REFERENCES Costello JM (1977): A new syndrome: Mental subnormality and nasal papillomata. Aust Paediat J 13:114-118, Der Kaloustian VM, Moroz B, McIntosh N, Watters AK, Blaichman S (1991): The Costello syndrome. Am J Med Genet (in press).
~
