August 1978
The Journal of P E D I A T R l C S
239
Confirmation of the Cohen syndrome In 1973 Cohen et al reported a new s)'ndrome in two siblings and an unrelated individual, consisting of obesit)', mental retardation, h)'potonia, limb abnormalities, and a characteristic craniofacial appearance. Since then no similar cases have appeared in the literature. This report firml)' establishes the Cohen s)'ndrome as a distinct clinical entit)" b)' presenting four additional patients, inchtding a sibling pair of normal parents, suggesting atttosomal recessive inheritance. One of our four patients has normal intelligence, h2dicating that mental deficiency is a variable feature of the s)'ndrome.
J o h n C. Carey, M.D.,* and Bryan D. H a l l , M . D . , Salt Francisco, Calif.
IN 1973 Cohen and his associates' reported a new syndrome which consisted of mid-childhood onset obesity, hypotonia, mental retardation, a characteristic craniofacial appearance, oral and ocular abnormalities, and narrow hands and feet. Two of their patients were brother and sister of unaffected parents, suggesting an autosomal recessive mode of inheritance. All of the three individuals had normal chromosomes. Smith ~- subsequently labeled this pattern of malformation the Cohen syndrome. The rarity of the Cohen syndrome is suggested by the lack of further published cases since the original report. We have identified and evaluated four additional patients with the Cohen syndrome, two of whom are brother and sister of nonconsanguineous parents. The following case reports further establish the Cohen syndrome as a distinct heritable entity. GENERAL All of the patients are white. The pregnancies were term and none of the mothers took any unusual medications during gestation. Fetal activity and pregnancy history were normal unless otherwis'e stated in the individual case reports. Parental consanguinity was not present and the family histories were negative for similar problems except in the case of the sibling pair (Patients 3 and 4). LaboraFrom the Universit)' of California, School of Medicine. Supported in part b). the N l l l Center Grant GM-19527, the MCH Project 445, and the Birth Defects Center, National Foumlation-March of Dhnes Grant. *Reprint address: Department of Pediatrics. Universit)" of California, San Franciso, San Francisco,CA 94143.
0022-3476/78/0293-0239$00.60/0 9 1978 The C. V. Mosby Co.
tory studies which were performed and found to be normal included chromosomes (Patients I and 2); electrolytes, serum calcium and phosphorus thyroxine, and plasma cortisol levels (Patient 2), serum and urine amino acids and skeletal survey (Patient 3). The physical features of the patients to be presented are depicted in Figs. 1 to 4 and summarized in Table I. These findings are not repeated i n the individual case reports unless further clarification or description is necessary. Obesity, involving the trunk and sparing the limbs, was present in all four of our patients and characteristically began after the age of 5 years. The features of the characteristic facial appearance include a high nasal bridge, down-slanted palpebral fissures, malar and maxillary hypoplasia, short philtrum, mild micrognathia, and open mouth with prominent central incisors. The abnormalities of the distal limbs consist of narrow hands with thin, nontapered fingers. CASE R E P O R T S Patient 1. M.S. was the 3,260 gram product of a 26-year-old gravida I, para 0 mother. The birth length was 51 cm. There were no feeding or respiratory problems during infancy and psychomotor development was normal, tie is presently attending a regular class in the sixth grade, ltis only problem in school has been poor social adjustment. Physical examination at II years of age showed a height of 144.5 cm (5ff7~),weight 38.6 kg (50%), and head circumference 51 em (10%). ltis mouth was usually kept open and his central incisors were not unduly prominent (Fig. 1). There was a submucous cleft of the soft palate. Examination of his retina showed mottled pigmentation bilaterally, which was not felt to indicate any ophthalmologic abnormality. He had mild cubitus
Vol. 93, No. 2, pp. 239-244
24 0
Carey a n d Hall
The Journal o f Pediatrics 9 Attgust 1978
IqU
\
Fig. 1. Patient 1 at I 1 years of age. Note the high nasal bridge, malar hypoplasia and small jaw, and moderate truncal obesity.
Fig. 2. A, Hand of Patient 1, showing soft tissue 2-3 syndactyly, thin fingers, and clinodactyly of fifth finger. B, Narrow hand and thin, nontapered fingers of Patient 3.
Vohmw 93 Number 2
Confirmation o f Cohen s)'ndrome
24 1
T a b l e I. F e a t u r e s o f t h e C o h e n s y n d r o m e
Care), and llall Features Growth and performance Obesity Short stature Mental retardation Microcephaly Facial tligh nasal bridge Maxillary/malar hypoplasia Short philtrum Micrognathia Ocular Down slanted eyes Strabismus Myopia Coloboma Microphthalmia Mottled pigment Oral Open m o u t h Prominent maxillary central incisors Narrow palate Limb tlypotonia ! lyperextensibility Cubitus valgus Genu valgum Narrow hands and feet Finger syndactyly (2-3) Other Delayed puberty Scoliosis/lordosis
%
Case 2
Case 3
Case 4
Total
Cohen el al
Iolal
+ -
+ + + -
+ + + +
+ + + +
4/4 3/4 3/4 2/4
3/3 I/3 3/3 2/3
I00 57 86 57
+ + +
+ + + +
+ -+ +
+ + +
4/4 2/4 3/4 4/4
3/3 3/3 3/3 2/3
I00 71 86 86
+ +
+ + + + + -
+ + + -
-
2/4
3/3
71
-
2/4
2/3
57
-
2/4
2/3
57
-
1/4 2/4 1/4
1/3 1/3 2/3
29 43 43
+ +
+ + +
+ + +
+ + +
4/4 3/4 4/4
3/3 3/3 3/3
100 86 100
+ + + + +
+ ? + + -
+ + + + + -
+ + +
4/4 3/3 3/4 2/4 4/4 1/4
3/3 3/3 3/3 3/3 3/3 1/3
100 100 86 71 100 29
-
+ -
+ -
3/4 0~4
2/2 3/3
83 43
Case 1 [
valgus, thin fingers with bilateral syndactyly (20'70) o f the second and third finger, clinodactyly o f his fifth fingers (Fig. 2, A), hyperextensibility of his thumbs, hyperconvex nails, and narrow feet and toes. A generalized decrease in muscle mass and truncal obesity were noted. On follow-up examination at 12 years o f age, the boy had signs of early puberty with pubic hair and increasing penile size. Patient 2. S.O. was the 3,402 gm term product o f a gravida I, para 0 mother. The pregnancy was complicated by a flulike illness in the sixth week o f pregnancy. A right coloboma and undescended testes were noted at birth. T h e patient was cyanotic for the first three minutes o f life but had no other respiratory problems during the neonatal period. lte was noted to be hypotonic and had mild feeding difficulties in the first few months o f life. Poor visual acuity was suspected at one year o f age. lle sat alone at two years, walked at 2 89 years, and spoke single words at 3 years. At 5 years of age, the patient was admitted to the University o f California for evaluation o f developmental delay and possible blindness. Physical examination at that time showed strabismus, nystagmus, and myopia in addition to the findings noted in infancy. Developmental testing indicated that he was functioning
--
-
"-
-
+ -
+ -
between three and four years o f age and that his visual acuity accounted for some o f his delay. T h e patient entered a school for the educably retarded at age 6 b u t at age 9 was transferred to a regular school since he was doing so well. A conductive hearing loss was found at age 10 and was felt to account for his speech difficulties. Ills testes were brought into his scrotum surgically at 10 years o f age. At age 13, he underwent a reconstruction o f his left middle ear with little improvement in hearing acuity. He graduated from a public school at age 19 years. F r o m the age of 17 he had noted development o f scant axillary a n d pubic hair. Physical examination .at 2189 years of age showed a height of 153.8 cm ( > - 4 SD below the mean), weight 55 kg (10%), and head circumference 54.5 cm (25%). There was a right iris and retinal coloboma, right microcornea (8 mm), and left retinal coloboma (Fig. 3). Epicanthal folds and lateral displacement of the inner canthi (inner canthal distance 3.75 cm) were also noted; interpupillary distance was n o r m a l (6.5 cm). T h e penile length was 3 cm and his testes were 1.2 cm by I cm. A small a m o u n t o f uncurled pubic hair was noted. T h e patient had moderate truncal obesity. Laboratory studies included a delayed bone age, and a plasma testosterone level of 39 #g/dl. T h e baseline levels of luteinizing
244
Carey and Hall
We are grateful to Dr. Selna Kaplan for allowing us to present her patient, No. 2, to Dr. Sanford Sherman for working up Patients 3 and 4, and to Mrs. Mary Dessau for typing this manuscript. REFERENCES
I. Cohen MM, Hall BD, Smith DW, Graham CB, and Lampert K J: A new syndrome with hypotonia, Obesity, mental deficiency, and facial, oral, ocular, and limb abnormalities, J PEDtATg 83:280, 1973.
The Journal of Pediatrics August 1978
2. Smith DW: Recognizable patterns of human malformation, ed 2, Philadelphia 1976, WB Saunders Company. 3. Marshall WA, and Tanner JM: Variations in the pattern of pubertal changes in boys, Arch Dis Child 45:19, 1970. 4. Hall BD, and Smith DW: Prader-Willi syndrome, J PEDIATR 81:286, 1972. 5. Bauman ML, and Hogan GR: Laurence-Moon-Biedl syndrome, Am J Dis Child 126:119, 1973. 6. Rubinstein JH, Taybi H: Broad thumbs and toes and facial abnormalities, Am J Dis Child 105:88, 1963. 7. Cohen MM .Ir: Personal communication.
The Journal of P E D I A T R l C S
239
Confirmation of the Cohen syndrome In 1973 Cohen et al reported a new s)'ndrome in two siblings and an unrelated individual, consisting of obesit)', mental retardation, h)'potonia, limb abnormalities, and a characteristic craniofacial appearance. Since then no similar cases have appeared in the literature. This report firml)' establishes the Cohen s)'ndrome as a distinct clinical entit)" b)' presenting four additional patients, inchtding a sibling pair of normal parents, suggesting atttosomal recessive inheritance. One of our four patients has normal intelligence, h2dicating that mental deficiency is a variable feature of the s)'ndrome.
J o h n C. Carey, M.D.,* and Bryan D. H a l l , M . D . , Salt Francisco, Calif.
IN 1973 Cohen and his associates' reported a new syndrome which consisted of mid-childhood onset obesity, hypotonia, mental retardation, a characteristic craniofacial appearance, oral and ocular abnormalities, and narrow hands and feet. Two of their patients were brother and sister of unaffected parents, suggesting an autosomal recessive mode of inheritance. All of the three individuals had normal chromosomes. Smith ~- subsequently labeled this pattern of malformation the Cohen syndrome. The rarity of the Cohen syndrome is suggested by the lack of further published cases since the original report. We have identified and evaluated four additional patients with the Cohen syndrome, two of whom are brother and sister of nonconsanguineous parents. The following case reports further establish the Cohen syndrome as a distinct heritable entity. GENERAL All of the patients are white. The pregnancies were term and none of the mothers took any unusual medications during gestation. Fetal activity and pregnancy history were normal unless otherwis'e stated in the individual case reports. Parental consanguinity was not present and the family histories were negative for similar problems except in the case of the sibling pair (Patients 3 and 4). LaboraFrom the Universit)' of California, School of Medicine. Supported in part b). the N l l l Center Grant GM-19527, the MCH Project 445, and the Birth Defects Center, National Foumlation-March of Dhnes Grant. *Reprint address: Department of Pediatrics. Universit)" of California, San Franciso, San Francisco,CA 94143.
0022-3476/78/0293-0239$00.60/0 9 1978 The C. V. Mosby Co.
tory studies which were performed and found to be normal included chromosomes (Patients I and 2); electrolytes, serum calcium and phosphorus thyroxine, and plasma cortisol levels (Patient 2), serum and urine amino acids and skeletal survey (Patient 3). The physical features of the patients to be presented are depicted in Figs. 1 to 4 and summarized in Table I. These findings are not repeated i n the individual case reports unless further clarification or description is necessary. Obesity, involving the trunk and sparing the limbs, was present in all four of our patients and characteristically began after the age of 5 years. The features of the characteristic facial appearance include a high nasal bridge, down-slanted palpebral fissures, malar and maxillary hypoplasia, short philtrum, mild micrognathia, and open mouth with prominent central incisors. The abnormalities of the distal limbs consist of narrow hands with thin, nontapered fingers. CASE R E P O R T S Patient 1. M.S. was the 3,260 gram product of a 26-year-old gravida I, para 0 mother. The birth length was 51 cm. There were no feeding or respiratory problems during infancy and psychomotor development was normal, tie is presently attending a regular class in the sixth grade, ltis only problem in school has been poor social adjustment. Physical examination at II years of age showed a height of 144.5 cm (5ff7~),weight 38.6 kg (50%), and head circumference 51 em (10%). ltis mouth was usually kept open and his central incisors were not unduly prominent (Fig. 1). There was a submucous cleft of the soft palate. Examination of his retina showed mottled pigmentation bilaterally, which was not felt to indicate any ophthalmologic abnormality. He had mild cubitus
Vol. 93, No. 2, pp. 239-244
24 0
Carey a n d Hall
The Journal o f Pediatrics 9 Attgust 1978
IqU
\
Fig. 1. Patient 1 at I 1 years of age. Note the high nasal bridge, malar hypoplasia and small jaw, and moderate truncal obesity.
Fig. 2. A, Hand of Patient 1, showing soft tissue 2-3 syndactyly, thin fingers, and clinodactyly of fifth finger. B, Narrow hand and thin, nontapered fingers of Patient 3.
Vohmw 93 Number 2
Confirmation o f Cohen s)'ndrome
24 1
T a b l e I. F e a t u r e s o f t h e C o h e n s y n d r o m e
Care), and llall Features Growth and performance Obesity Short stature Mental retardation Microcephaly Facial tligh nasal bridge Maxillary/malar hypoplasia Short philtrum Micrognathia Ocular Down slanted eyes Strabismus Myopia Coloboma Microphthalmia Mottled pigment Oral Open m o u t h Prominent maxillary central incisors Narrow palate Limb tlypotonia ! lyperextensibility Cubitus valgus Genu valgum Narrow hands and feet Finger syndactyly (2-3) Other Delayed puberty Scoliosis/lordosis
%
Case 2
Case 3
Case 4
Total
Cohen el al
Iolal
+ -
+ + + -
+ + + +
+ + + +
4/4 3/4 3/4 2/4
3/3 I/3 3/3 2/3
I00 57 86 57
+ + +
+ + + +
+ -+ +
+ + +
4/4 2/4 3/4 4/4
3/3 3/3 3/3 2/3
I00 71 86 86
+ +
+ + + + + -
+ + + -
-
2/4
3/3
71
-
2/4
2/3
57
-
2/4
2/3
57
-
1/4 2/4 1/4
1/3 1/3 2/3
29 43 43
+ +
+ + +
+ + +
+ + +
4/4 3/4 4/4
3/3 3/3 3/3
100 86 100
+ + + + +
+ ? + + -
+ + + + + -
+ + +
4/4 3/3 3/4 2/4 4/4 1/4
3/3 3/3 3/3 3/3 3/3 1/3
100 100 86 71 100 29
-
+ -
+ -
3/4 0~4
2/2 3/3
83 43
Case 1 [
valgus, thin fingers with bilateral syndactyly (20'70) o f the second and third finger, clinodactyly o f his fifth fingers (Fig. 2, A), hyperextensibility of his thumbs, hyperconvex nails, and narrow feet and toes. A generalized decrease in muscle mass and truncal obesity were noted. On follow-up examination at 12 years o f age, the boy had signs of early puberty with pubic hair and increasing penile size. Patient 2. S.O. was the 3,402 gm term product o f a gravida I, para 0 mother. The pregnancy was complicated by a flulike illness in the sixth week o f pregnancy. A right coloboma and undescended testes were noted at birth. T h e patient was cyanotic for the first three minutes o f life but had no other respiratory problems during the neonatal period. lte was noted to be hypotonic and had mild feeding difficulties in the first few months o f life. Poor visual acuity was suspected at one year o f age. lle sat alone at two years, walked at 2 89 years, and spoke single words at 3 years. At 5 years of age, the patient was admitted to the University o f California for evaluation o f developmental delay and possible blindness. Physical examination at that time showed strabismus, nystagmus, and myopia in addition to the findings noted in infancy. Developmental testing indicated that he was functioning
--
-
"-
-
+ -
+ -
between three and four years o f age and that his visual acuity accounted for some o f his delay. T h e patient entered a school for the educably retarded at age 6 b u t at age 9 was transferred to a regular school since he was doing so well. A conductive hearing loss was found at age 10 and was felt to account for his speech difficulties. Ills testes were brought into his scrotum surgically at 10 years o f age. At age 13, he underwent a reconstruction o f his left middle ear with little improvement in hearing acuity. He graduated from a public school at age 19 years. F r o m the age of 17 he had noted development o f scant axillary a n d pubic hair. Physical examination .at 2189 years of age showed a height of 153.8 cm ( > - 4 SD below the mean), weight 55 kg (10%), and head circumference 54.5 cm (25%). There was a right iris and retinal coloboma, right microcornea (8 mm), and left retinal coloboma (Fig. 3). Epicanthal folds and lateral displacement of the inner canthi (inner canthal distance 3.75 cm) were also noted; interpupillary distance was n o r m a l (6.5 cm). T h e penile length was 3 cm and his testes were 1.2 cm by I cm. A small a m o u n t o f uncurled pubic hair was noted. T h e patient had moderate truncal obesity. Laboratory studies included a delayed bone age, and a plasma testosterone level of 39 #g/dl. T h e baseline levels of luteinizing
244
Carey and Hall
We are grateful to Dr. Selna Kaplan for allowing us to present her patient, No. 2, to Dr. Sanford Sherman for working up Patients 3 and 4, and to Mrs. Mary Dessau for typing this manuscript. REFERENCES
I. Cohen MM, Hall BD, Smith DW, Graham CB, and Lampert K J: A new syndrome with hypotonia, Obesity, mental deficiency, and facial, oral, ocular, and limb abnormalities, J PEDtATg 83:280, 1973.
The Journal of Pediatrics August 1978
2. Smith DW: Recognizable patterns of human malformation, ed 2, Philadelphia 1976, WB Saunders Company. 3. Marshall WA, and Tanner JM: Variations in the pattern of pubertal changes in boys, Arch Dis Child 45:19, 1970. 4. Hall BD, and Smith DW: Prader-Willi syndrome, J PEDIATR 81:286, 1972. 5. Bauman ML, and Hogan GR: Laurence-Moon-Biedl syndrome, Am J Dis Child 126:119, 1973. 6. Rubinstein JH, Taybi H: Broad thumbs and toes and facial abnormalities, Am J Dis Child 105:88, 1963. 7. Cohen MM .Ir: Personal communication.
