American Journal of Medical Genetics 43:678-685 (1992)
New Multiple Congenital Anomalies: Mental Retardation Syndrome (MCA/MR) With FacioCutaneous-Skeletal Involvement Zvi Borochowitz, Lorenzo Pavone, Galia Mazor, Renata Rizzo, and Hanna Dar Simon Winter Institute for Human Genetics, Bnai-Zion Medical Center, Technion-Faculty of Medicine, Haifa (Z.B.,H.D.), Department of Child Development, Haemek Medical Center, Afula (G.M.),Israel, and Department of Pediatrics, University of Catania, Catania, Italy (L.P., R.R.)
Five unrelated patients (a male and 4 females) were affected with a previously undefined multiple congenital anomalies/mental retardation syndrome which has been designated the facio-cutaneous-skeletal(FCS) syndrome and which includes mental retardation with specific sociable, humorous behavior, characteristic facial appearance, excessive generalized skin,postnatal growthfailure,and skeletal involvement. Consanguinity was noted in 2 patients, thus autosomal recessive inheritance is suggested. o 1992 Wiley-Liss, Inc. KEY WORDS: multiple congenitalanomalies/ mental retardation syndrome, facio-cutaneous-skeletal(FCS) syndrome, coarse facies, excessive skin, growth failure, vertical talus, skeletal, autosoma1 recessive INTRODUCTION We report on 5 unrelated patients with a unique combination of distinct facial appearance, growth retardation, cutis laxa, remarkable personal and developmental characteristics, and mental retardation. This is an apparently previously undescribed multiple congenital anomaliesimental retardation syndrome which we propose to designate as the facio-cutaneousskeletal (FCS) syndrome. CLINICAL REPORTS Patient 1 Patient Z. D-A., a white boy, was born at term after an uncomplicated pregnancy by cesarean section due to
breech presentation. Parents are healthy Sephardic Jews, 30 (mother) and 31 (father) years old. Consanguinity was denied, however, both were born in Algier. They have a healthy older son and daughter. The patient's birth weight was 4,100 g (97th centile), occipitofrontal circumference (OFC)33 cm (3rd centile), and length 47 cm (2.5 standard deviation below mean). Coarse face, excessive skin (especially in the neck, buttocks, and limbs) were noted at birth. He was in a special care nursery for 10 days because of poor feeding. His chromosomes were normal (46,XY). When examined a t 5 months he could not hold his head or roll over. He had a very peculiar hoarse voice. His weight was 4,300 g, length 54 cm, and OFC 39.5 (all on the 3rd centile). He had (Fig. la,b) a "square" head with protruding occiput and a hirsute prominent wide forehead, capillary hemangioma over the glabella and middle of the forehead, protruding zygoma, depressed nasal bridge, short bulbous upturned nose with anteverted nostrils, downward slant of palpebral fissures with thick epicanthic folds, posteriorly angulated thick auricles with hypertrophy of the transverse portion of the helix and prominent lobule, full cheeks with an apparently increased fat deposition in them, thick lips, and flat philtrum. He had curly hair, short neck with excessive skin, anteverted, broad xiphisternum with accessory nipples, one on the right and 2 on the left (Fig. la,b). Cardiac findings were normal. Hands and feet were apparently enlarged with redundant skin. Palms and fingers were short (Fig. 2). The patient had a distinct generalized increase in skin pigmentation with thickened palmar and plantar skin folds. Dermatoglyphics:
R L Received for publication February 27, 1991; revision received October 7, 1991. Address reprint requests to Zvi Borochowitz, M.D., Director, Simon Winter Institute for Human Genetics, Bnai-Zion Medical Center, P.O. Box 4940, Haifa 31048, Israel.
0 1992 Wiley-Liss, Inc.
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Broad distal phalanges were noted, more pronounced on the first fingers and hallux. The feet were flat with a "rocker bottom" appearance. Flexion contractures of el-
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Fig. 1. Patient 1. b,b) At age 5 months. (c,d)At age 4 years. Note coarse face, wide hirsute forehead, wide antevertednostrils, full cheeks, thick lips, open mouth,posterior angulationof auricles with upslanting lobules. Note the generalized excessive skin over neck, joints, and thick palmar ridges.
bows and hips were noted. Liver and spleen were palpable 2-3 cm below the costal margin. A deep sacral dimple and skin tag were noted (Fig. 3). Cardiac ascultation and an electrocardiogram were normal. External genitalia was normal. Neurologically,he was hypotonic with normal reflexes. Hearing and visual tests, electroencephalogram, and CT scan of the brain were all normal. Skin biopsy showed normal histology and ultrastructure. Storage material was not found in the skin. The relation between insulin secretion and glucose level (as an indicator for insulin receptor activity) during fast, 2 and 6 hours after glucose load (0.05, 0.09 and 0.155, respectively), were within the normal range, i.e., less
than 0.5 [Savage et al. 1975; LaF’ranchi, 19871Skeletal survey was normal except for lack of ossification of the proximal femoral epiphyses and vertical talus bilaterally (Fig. 4).He had been admitted several times because of feeding difficulties and failure to thrive. Further investigations, including extensive metabolic evaluation for a “storage” appearance and metabolic diseases including lysosomal storage, thyroid, and liver functions, were all normal. When reexamined at 4 years (Fig. lc,d), curly hair, coarse facies, and generalized hirsutism were noted with a very peculiar hoarse voice. His weight was 9,600 g ( - 3 SD), length 74 cm ( - 4 SD), and OFC 50 cm (40th
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Fig. 2. Patient 1.Loose integument of hands and fingers with wide distal phalanges and normal nails.
MOM (MSAFP). Amniocentesis a t 17 weeks showed normal (46,XX) chromosomes. Second trimester fetal ultrasonographic survey was interpreted a s normal. Delivery was normal. Birth weight was 4,200 g, length 49 cm, and OFC 35 cm. Shortly after birth a 216 ejection systolic murmur was noticed, more pronounced on the 2nd and 3rd left intercostal space. The diagnosis of mild pulmonary stenosis was confirmed by echocardiogram. No hemodynamic difficulties were noted. No other major problems were reported. She was admitted a t age 1 month because of feeding difficulties and failure to thrive. When examined a t 3 months (Fig. 5a,b), the patient had a peculiar hoarse voice and facial changes and other characteristicsresembling these of patient 1at the same age. OFC was 39 cm (50th centile), length 53 cm ( - 2.5 SD), weight 3,600 g (3rd centile, palm 3.9 cm, and MF 3.0 cm (both on the 50th centile). Ear length was 3.5 cm (3rd centile). Scalp hair was shaved (after admission), but was said to be curly. The forehead was prominent and hirsute with portwine hemangioma over the glabella; 2 occipital hair whorls were present. She had a coarse face, antimongoloid slant of palpebral fissures, bulbous short nose with depressed nasal bridge, and wide anteverted nostrils; long philtrum with thick lips; posteriorly angulated ears with thick helices, and prominent lobule. She also had a narrowly arched palate. The chest was bell-shaped with one accessory nipple on each side. There was a 216 systolic murmur over the heart area. Echocardiography demonstrated the existence of a mild pulmonic stenosis. Liver and spleen were apparently of normal size. Patellar reflexes were normal. Genitalia were normal. The hands showed wide distal phalanges including thumbs and hallux with thick palmar and plantar ridges. Cutaneous syndactyly of about 30% between fingers I1 and I11 was present. Dermatoglyphics: (right) t, L", L", L", A, W; (left) t, L", L", L", L", L". The feet were flat with
Fig. 3. Patient 1. Note deep sacral dimple and skin tag with generalized hirsutism and excessive skin.
centile), palm 6 cm (3rd centile), MF 4 cm ( - 2.5 SD). Psychomotor maturation was delayed, especially speech and gross motor with hypotonia. He was very affectionate and sociable. There was less excessive skin noted, however, palms and soles still showed thick dermal ridges. Hyperhydrosis was not noted. He had recently undergone surgical correction of the vertical talus. On neurological examination this was a n obviously retarded boy with generalized hypotonia.
Patient 2 M. I., a girl, was born at term to a 25-year-old mother and a 39-year-old father. Parents are healthy first cousins with Arabic-Druze ancestry. They have two Older daughters and a son* was plicated by low maternal serum a-fetoprotein of 0.25
Fig. 4. Patient 1. Note bilateral vertical talus with otherwise normal tubular bones.
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Fig. 5. (a,b).Patient 2 a t age 3 months. Note peculiar coarse facial appearance resembling Patient 1.Also note the generalized excessive skin and wide distal phalanges.
“rocker bottom” configuration. The elbows and hips could not be fully extended. The patient had generalized excessive skin, however, with normal elasticity. It was more pronounced over the neck, large and small joints, and buttocks. At time of examination no other anomalies were noted. Brain and abdominal ultrasound were normal. Hypoglycemia was never recorded. General skeletal survey was normal except for protruded occiput and vertical talus. She died at age 4 months. Postmortem examination was refused. Patient 3 B.R., a white girl, was born at term after a pregnancy complicated by bleeding in the 13th week of gestation and polyhydramnios. Delivery was by repeat cesarean
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section. Parents are healthy first cousins of ArabicDruze ancestry, 32 (mother) and 48 (father) years old. Together, they have a healthy older son and daughter. The father has 2 healthy sons and 6 healthy daughters from a previous marriage. Any family relation to the family of patient 2 (also Druze) was denied. The patient’s birth weight was 3,650 g (50th centile), occipitofrontal circumference (OFC) 37 cm (97th centile), and length 50 cm (50th centile). Coarse face, protruding tongue, generalized hirsutism, and excessive skin over buttocks and limbs were noted at birth. Her chromosomes were normal (46,XX). Thyroid function tests were normal. The neonatal period was unremarkable but for hospitalization a t age 30 days due to PDA and congestive heart failure. The PDA was surgically treated. Other cardiac findings were normal. When examined a t 5 months her motor development was normal. Her weight was 6,900 g, length 64 cm (both 50th centile), and OFC 43 cm (90th centile). She had (Fig. 6a) a relative large head with protruding occiput and a hirsute prominent wide forehead, protruding zygoma, depressed nasal bridge, short bulbous upturned nose with anteverted nostrils, downward slant of palpebral fissures with thick epicanthic folds, posteriorly angulated thick auricles with hypertrophy of the transverse portion of the helix and prominent lobule, full cheeks, thick lips, and flat philtrum. Her hair was curly (unlike that of other family members), and she had a short neck with excessive skin and a wide shield chest. Hands and feet were apparently enlarged with redundant skin. Patient had thickened palmar and plantar skin folds. Dermatoglyphics were normal. Broad distal phalanges were noted, more pronounced on first fingers and hallux. The feet were flat without “rocker bottom” appearance. Flexion contractures of elbows and hips were noted. Liver and spleen were palpable 4-5 cm below the costal margin. Umbilical hernia was found. Cardiac ascultation and an electrocardiogram were normal. External genitalia were normal. Neurologically, she was not hypotonic and had normal reflexes. Hearing and visual tests, electroencephalogram, and CT scan of the brain were normal. Skin and liver biopsies showed normal histology and ultrastructure. Storage material was not found in either tissues. Lysosomal enzymes studies were negative for a-mannosidosis, sialidosis, GM1 gangliosidosis, Hurler disease, fucosidosis, Gaucher’s disease, and Wolman’s disease. Skeletal survey was normal. Further investigations, including extensive metabolic evaluation, were normal. The relation between insulin secretion and glucose level (as an indicator for insulin receptor activity) during fast and 2 and 6 hours after glucose load were normal (0.085,0.135, and 0.16, respectively). When reexamined recently at 2% years, curly hair and generalized hirsutism were noted with a very peculiar hoarse voice. Her face was less coarsened (Fig. 6b), and her skin less excessive, however, palms and soles still showed thick dermal ridges. Her weight was 15 kg (75th centile), length 86 cm (10th centile), and OFC 50 cm (75th centile), palm 6.5 cm and MF 5 cm (both 75th centile). Psychomotor maturation was mildly delayed,
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Fig. 6. (a)Patient 3 a t 5 months. (b)Patient 3 at 2 6/12 years.
especially speech. She was very sociable. She had recently undergone surgical correction of the umbilical hernia.
Patient 4 C.M. is a female born on 10-9-1984. The parents are not consanguineous and are in good health. She is the second born, with an older brother 4% years old in good health. Pregnancy was normal. At 1 month of gestation skeletal X-ray was performed on the mother for suspicion of hiatal hernia. The baby was born at 38 weeks of gestation by cesarean section. Birth weight was 3,440g, OFC 34 cm (both 50th centile), and length 46 cm (3 SD below the mean). At age 3 days the baby was admitted to the Pediatric Clinic of Catania for neonatal asphyxia. Physical examination showed a dysmorphic face with relatively large hands and feet, short neck, and cardiac murmur due to pulmonary stenosis. Chromosomes and routine laboratory investigations were normal. In the following months the patient showed failure to thrive. At age 10 months she was hospitalized in Bern (Switzerland) where a diagnosis of Donohue syndrome was made. She was again admitted at the Pediatric Clinic of Catania a t this age. Her weight was 4,170g (4 SD below mean), length 59.5cm (3.5 SD below mean), OFC 41.5cm (3rd centile). The phenotype was abnormal (Fig. 7). The hair was short and thin. The forehead large with receding anterior hair, coarse face, large eyebrows, square head with protruding occiput, short bulbous nose with depressed nasal bridge, upturned anteverted nostrils, downward slant of palpebral fissures, full cheeks,
Fig. 7. Patient 4 at 10 months.
extremely large mouth with large tongue, flat philtrum, and thick open lips. The auricles were low-set and large. The baby was thin with no subcutaneous fat; the skin was loose. Elasticity of the skin was normal. The hands and feet were large. A cardiac murmur was noted. Laboratory findings were normal including urinalysis, blood electrolytes, and liver function tests. Fasting tests showed normal insulidglucose ratio (0.25). The patient is now 7 years old; her appearance is not as striking. She has moderate mental retardation and
MCA/MR Syndrome-FCS Sy. attends a special school (Fig. 8a,b). Physical examination: weight 16,300 g (2.5 SD below mean), height 102 cm (3SD below mean), and OFC 49.5 cm (3rd centile). The general condition is good, the hair is light brown, curly, and heavy. She has a large forehead with hirsutism. The eyebrows are heavy and there are epicanthal folds. The nasal root is depressed, the tip of the nose is rounded, bulbous, with thick alae nasi. The philtrum is flat and short. The lips are thick. She also has a high arched palate, thick gums with dyscromic, malformed, absent, and irregularly spaced teeth. She has puffed cheeks, pointed chin with abundant adipose tissue below the chin. The ears are small and low-set with thick lobule and hypoplastic targus. She has a short neck with a small area of acantosis nigricans and protruding nipples. She has hirsutism on the back. The umbilicus has a cutaneous protrusion. The hands are large with abundant skin, particularly on the joint. There is a simian
Fig. 8. Patient 4 a t 7 years of age. (a)Frontal view. (b)Lateral view.
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crease bilaterally. The feet are large with a longitudinal deep crease at the level of the 3rd toe, protruding heel, and dyscromic nails. Radiographs of feet showed mild vertical talus. The liver and spleen are normal. Cardiac murmur was present. The patient has a moderate mental retardation, pronounces some sentences, and has a very social behaviour and a nasal voice.
Patient 5 V.A. is a female, born on 31-10-1988.The parents are not consanguineous and are in good health. She is the second born. She has an older 7-year-old sister. Pregnancy was normal. During the pregnancy the mother took cortisone and antihistamines. The baby was born at term. Birthweight was 3,980 g (90th centile), length 46 cm (3 SD below the mean), OFC 35 cm (75th centile). She was admitted to the Pediatric Clinic of Catania because of failure to thrive. She was nourished only by gavage until age 2 years and 6 months. Also the presence of a cardiac murmur was noticed and pulmonary stenosis was diagnosed. She also suffered from frequent bronchitis. At 2 years and 9 months old, the weight is 9,750 g (2.5 SD below mean), height 78 cm (4 SD below mean), and OFC 47 cm (25th centile). Her general condition is good, she has now a good adipose tissue. The hair is sparse, curly, and light brown (Fig. 9). She has a high forehead with hirsutism (Fig. 10). The eyebrows are heavy and there are epicanthal folds. The nasal root is large, the tip is bulbous with large nares and thick alae nasi. The philtrum is flat and short. The lips are thick. The ears are low-set. She has puffed cheeks. The chin is rounded and she has abundant adipose tissue below the chin. Below the lower lips there are 2 pits. The teeth are short, large, and dyscromic. She has a short neck and protruding “nipples.”The umbilicus has a cutaneous protrusion. The liver and spleen are normal. The hands are large, hypotonic with abundant skin, particularly on the joints. There is sub-
Fig. 9. Patient 5 at 2 years and 9 months. Note sparse and curly hair.
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Fig. 10. Patient 5 at 2 years and 9 months. Frontal view.
luxation of the joint fingers. The feet are large with a deep longitudinal sulci at the level of the 2nd finger and a horizontal sulci on the 3rd. She has mild to moderate mental retardation, severe hypotonia with deep tendon reflexes present and bright. She pronounces some words, has a socialbehaviour and a hoarse voice, and walking is uncertain.
DISCUSSION These 5 patients present with a unique combination of multiple anomalies that are, to the best of our knowledge, previously unpublished. The most unique manifestations and those by which these patients were initially ascertained were charac-
teristic coarse facial appearance with an apparent increased fat deposition in the cheeks, short wide nose, posteriorly angulated auricles with thick helix, and generalized excessive skin. Four of the children reported here had poor postnatal growth even though they were large for gestational age a t birth. All 5 had some degree of mental retardation with a relative macrocranium. CT scan in 3 showed normal brain configuration. They all had similar facial changes, resembling each other to a very similar degree, with the same hoarse voice. The most consistent abnormalities are excessive generalized skin, more pronounced over joints, neck, and buttocks with neither skin hyperextensibility nor abnormalities of healing, ichthyosis, or hyperkeratosis; curly hair with normal eyebrows; skeletal abnormalities including short stature, tapered short distal phalanges, and vertical talus. Nails were apparently normal. Teeth in 2 were dyscromic. Storage material was not found on the 2 EM examinations of the skin and liver. Pregnancies were unremarkable except for low MSAFP in one instance, and early bleeding and polyhydramnious in another. Parents were young and healthy. In 2 instances, consanguinity was mentioned and in another the parents were born in the same town. Developmental delay was obviously present in most, with a specific sociable, humorous behavior. Patient 2 was too young to be evaluated in this regard. Cognitive functioning was better then motor skills. Speech was still severely delayed at age 4years (patient 11,age 7 years (patient 41, and at age 2 years and 9 months (patients 3 and 5). Except for the generalized excessive hirsute skin, no other skin manifestations were noted. The phenotypic manifestations of this syndrome are distinct (Table I). It is evident that the Noonan syn-
TABLE I. Clinical Manifestations in FCS and CFC Syndromes
1
Consanguinity Malelfemale Birth weightLGA" Birth-macrocranium Postnatal growth retardation Forehead constriction Developmental delay Coarse face Curly hair Wide anteverted nostrils Excessive skin Skin eczema and hyperkeratosis Furrowed palms and soles Wide distal phalanges Rocker bottom feet Vertical talus Heart defect
FCS syndrome Berberich Our cases et al. 2 3 4 5 (N = 3)
- + + - M F F F F + + + - + + + + - + + - + + -
-
-
-
-
+
112
NR NR
+ -
Total (N = 8)
CFC sy. syndrome (N = 25)
216 415 315
+
10115 10/19 18/25 25125
-
+
-
+ + + + +-
+ + + + + -
+ + + + + _
+ + + + + _
+ + + + + -
+ + + + +-
+
+ + + +
+ + + +
+ + + +
+ + + +
+ + + +
+
+ + + +
-
PS
PS
PS
PS
+
NR NR
+
"LGA, large for gestational age; NR, not recorded; PS, pulmonary stenosis.
+ + + + -
618
+ k + 7125 13/25 -
-
14/25
MCA/MR Syndrome-FCS drome [Mendez and Opitz, 19851, the cardio-facio-cutaneous (CFC) syndrome [Reynolds et al., 19861, the Donohue (leprechaunism) syndrome [Cantani et al., 19871, and patients in this report have some pathogenetic commonalities, at least with respect to hair, growth appearance, and in some respect also to skin. Examination of clinical photographs of previously published cases with CFC syndrome and other cases resembling CFC syndrome (25 cases all together) document a different phenotypic appearance [Costello, 1976; Cantu et al., 1982;Baraitser and Patton, 1986;Reynolds et al., 1986; Neri et al., 1987; Chrzanowska et al., 1989; Mucklow, 1989; Sorge et al., 19891. Several of the main phenotypic changes noted in our patients resembled leprechaunism syndrome (Donohue syndrome). Among those were mental retardation, coarsened face, excessive skin, hirsutism, and failure to thrive. However, normal relation between insulin secretion and glucose levels a t fast and 2 hours after glucose load found in three patients, as well as the peculiar social behavior and facial appearance, document a distinct syndrome, unlike the Donohue syndrome. It is therefore postulated that the excessive skin manifestation in our cases might well be the result of a casually nonspecific phenomenon ascribed by some to “intrauterine lymphedema” as was suggested by Opitz 119861 in respect to various syndromes. Recently, Berberich et al. [19901, in the 11th annual David W. Smith workshop on malformation and morphogenesis held in Lexington, Kentucky, presented three cases that might well resemble our cases. They presented a male and female sib pair and one unrelated male with failure to thrive, phenotype of a storage disorder, and furrowing of palmar creases as a new autosomal recessive syndrome. The coarse facial appearance presented in our cases might well resemble an apparent storage disorder. Such material, however, was not found in the examined skin biopsies of patients 1and 3 and in the liver biopsy done to patient 3. Extensive studies for enzyme-lysosomal disorders were negative as well. The consanguinity mentioned in our patients 2 and 3, and that demonstrated by Berberich et al, [19901, suggests that this apparently new syndrome is an autosoma1 recessive trait. However, in view of the Dhenot-vpic storage appearance of these patients, a storage disorder
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cannot be completely ruled out and documentation of similar families is needed to further clarify this issue.
ACKNOWLEDGEMENTS The authors are grateful to Dr. M. Ziegler and Dr. Z. Ben-Neria for help in enzyme analysis, to Prof. T. Yanku for liver EM studies, to Mrs. Dard for her assistance, and to Dr. J. Opitz for suggestions and critical review of the manuscript . REFERENCES Baraitser M, Patton MA (1986):A Noonan-like short stature syndrome with sparse hair. J Med Genet 23:161-164. Berberich MS, Carey JC, Hall BH (1990): Resolution of the perinatal and infantile failure to thrive in a new autosomal recessive syndrome with the phenotype of a storage disorder and furrowing of palmar creases. The 11th D. W. Smith workshop on malformation and morphogenesis, Lexington, Kentucky, p 76. Cantani A, Ziruolo MG, Tacconi ML (1987): A rare polydysmorphic syndrome: Leprechaunism-review of forty-nine cases reported in the literature. Ann Genet 30:221-227. Cantu JM, Sanchez-Corona J , Hernandes A, Nazara Z, Garcia-Cruz D (1982): Individualization of a syndrome with mental deficiency, macrocranium, peculiar facies, and cardiac and skeletal anomalies. Clin Genet 22:172-179. Chrzanowska K, Fryns JP, Van den Berghe H (1989): Cardio-faciocutaneous (CFC) syndrome: Report of a new patient. Am J Med Genet 33:471-473. Costello J M (1977):A new syndrome: Mental subnormality and nasal papillomata. Aust Paediat J 13:114-118. LaFranchi S (1987): Hypoglycemia of infancy and childhood. Pediat Clin North Am 34:961-982. Mendez HMM, Opitz J M (1985): Noonan syndrome: A review. Am J Med Genet 21:493-506. Mucklow ES (1989):A case of cardio-facio-cutaneous syndrome. Am J Med Genet 33:474-475. Neri G, Sabatino G, Bertini E, Genuardi M (1987):The CFC syndromereport of the first two cases outside the United States. Am J Med Genet 27:767-771. Opitz JM (1986):Editorial comment on the paper by Crowe and Dickerman: On congenital lymphedema. Am J Med Genet 24:127-129. Reynolds JF, Neri G, Herrmann JP, Blumberg B, Coldwell JG, Miles PV, Opitz J M (1986): New multiple congenital anomalies/mental retardation syndrome with cardio-facio-cutaneous involvementthe CFC syndrome. Am J Med Genet 25:413-427. Savage PJ, Dippe SE, Bennett PH, Gordon P, Roth J, Rushforth NB, Miller M (1975):Hyperinsulinemia and hypoinsulinemia. Insulin responses to oral carbohydrate over a wide spectrum of glucose tolerance. Diabetes 24:362-368. Sorge G, Di Forti F, Scarano G, Ventruto V, Zelante L, Dallapiccola B (1989):CFC syndrome: Report on three additional cases. Am J Med Genet 33:476-478.
New Multiple Congenital Anomalies: Mental Retardation Syndrome (MCA/MR) With FacioCutaneous-Skeletal Involvement Zvi Borochowitz, Lorenzo Pavone, Galia Mazor, Renata Rizzo, and Hanna Dar Simon Winter Institute for Human Genetics, Bnai-Zion Medical Center, Technion-Faculty of Medicine, Haifa (Z.B.,H.D.), Department of Child Development, Haemek Medical Center, Afula (G.M.),Israel, and Department of Pediatrics, University of Catania, Catania, Italy (L.P., R.R.)
Five unrelated patients (a male and 4 females) were affected with a previously undefined multiple congenital anomalies/mental retardation syndrome which has been designated the facio-cutaneous-skeletal(FCS) syndrome and which includes mental retardation with specific sociable, humorous behavior, characteristic facial appearance, excessive generalized skin,postnatal growthfailure,and skeletal involvement. Consanguinity was noted in 2 patients, thus autosomal recessive inheritance is suggested. o 1992 Wiley-Liss, Inc. KEY WORDS: multiple congenitalanomalies/ mental retardation syndrome, facio-cutaneous-skeletal(FCS) syndrome, coarse facies, excessive skin, growth failure, vertical talus, skeletal, autosoma1 recessive INTRODUCTION We report on 5 unrelated patients with a unique combination of distinct facial appearance, growth retardation, cutis laxa, remarkable personal and developmental characteristics, and mental retardation. This is an apparently previously undescribed multiple congenital anomaliesimental retardation syndrome which we propose to designate as the facio-cutaneousskeletal (FCS) syndrome. CLINICAL REPORTS Patient 1 Patient Z. D-A., a white boy, was born at term after an uncomplicated pregnancy by cesarean section due to
breech presentation. Parents are healthy Sephardic Jews, 30 (mother) and 31 (father) years old. Consanguinity was denied, however, both were born in Algier. They have a healthy older son and daughter. The patient's birth weight was 4,100 g (97th centile), occipitofrontal circumference (OFC)33 cm (3rd centile), and length 47 cm (2.5 standard deviation below mean). Coarse face, excessive skin (especially in the neck, buttocks, and limbs) were noted at birth. He was in a special care nursery for 10 days because of poor feeding. His chromosomes were normal (46,XY). When examined a t 5 months he could not hold his head or roll over. He had a very peculiar hoarse voice. His weight was 4,300 g, length 54 cm, and OFC 39.5 (all on the 3rd centile). He had (Fig. la,b) a "square" head with protruding occiput and a hirsute prominent wide forehead, capillary hemangioma over the glabella and middle of the forehead, protruding zygoma, depressed nasal bridge, short bulbous upturned nose with anteverted nostrils, downward slant of palpebral fissures with thick epicanthic folds, posteriorly angulated thick auricles with hypertrophy of the transverse portion of the helix and prominent lobule, full cheeks with an apparently increased fat deposition in them, thick lips, and flat philtrum. He had curly hair, short neck with excessive skin, anteverted, broad xiphisternum with accessory nipples, one on the right and 2 on the left (Fig. la,b). Cardiac findings were normal. Hands and feet were apparently enlarged with redundant skin. Palms and fingers were short (Fig. 2). The patient had a distinct generalized increase in skin pigmentation with thickened palmar and plantar skin folds. Dermatoglyphics:
R L Received for publication February 27, 1991; revision received October 7, 1991. Address reprint requests to Zvi Borochowitz, M.D., Director, Simon Winter Institute for Human Genetics, Bnai-Zion Medical Center, P.O. Box 4940, Haifa 31048, Israel.
0 1992 Wiley-Liss, Inc.
t +
+
th
HvDoth
L"
-
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2
L"
L" L"
L"
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L" L"
L" L"
5
Hallucal areas
L"
Ld
L"
Ld
Broad distal phalanges were noted, more pronounced on the first fingers and hallux. The feet were flat with a "rocker bottom" appearance. Flexion contractures of el-
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Fig. 1. Patient 1. b,b) At age 5 months. (c,d)At age 4 years. Note coarse face, wide hirsute forehead, wide antevertednostrils, full cheeks, thick lips, open mouth,posterior angulationof auricles with upslanting lobules. Note the generalized excessive skin over neck, joints, and thick palmar ridges.
bows and hips were noted. Liver and spleen were palpable 2-3 cm below the costal margin. A deep sacral dimple and skin tag were noted (Fig. 3). Cardiac ascultation and an electrocardiogram were normal. External genitalia was normal. Neurologically,he was hypotonic with normal reflexes. Hearing and visual tests, electroencephalogram, and CT scan of the brain were all normal. Skin biopsy showed normal histology and ultrastructure. Storage material was not found in the skin. The relation between insulin secretion and glucose level (as an indicator for insulin receptor activity) during fast, 2 and 6 hours after glucose load (0.05, 0.09 and 0.155, respectively), were within the normal range, i.e., less
than 0.5 [Savage et al. 1975; LaF’ranchi, 19871Skeletal survey was normal except for lack of ossification of the proximal femoral epiphyses and vertical talus bilaterally (Fig. 4).He had been admitted several times because of feeding difficulties and failure to thrive. Further investigations, including extensive metabolic evaluation for a “storage” appearance and metabolic diseases including lysosomal storage, thyroid, and liver functions, were all normal. When reexamined at 4 years (Fig. lc,d), curly hair, coarse facies, and generalized hirsutism were noted with a very peculiar hoarse voice. His weight was 9,600 g ( - 3 SD), length 74 cm ( - 4 SD), and OFC 50 cm (40th
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Fig. 2. Patient 1.Loose integument of hands and fingers with wide distal phalanges and normal nails.
MOM (MSAFP). Amniocentesis a t 17 weeks showed normal (46,XX) chromosomes. Second trimester fetal ultrasonographic survey was interpreted a s normal. Delivery was normal. Birth weight was 4,200 g, length 49 cm, and OFC 35 cm. Shortly after birth a 216 ejection systolic murmur was noticed, more pronounced on the 2nd and 3rd left intercostal space. The diagnosis of mild pulmonary stenosis was confirmed by echocardiogram. No hemodynamic difficulties were noted. No other major problems were reported. She was admitted a t age 1 month because of feeding difficulties and failure to thrive. When examined a t 3 months (Fig. 5a,b), the patient had a peculiar hoarse voice and facial changes and other characteristicsresembling these of patient 1at the same age. OFC was 39 cm (50th centile), length 53 cm ( - 2.5 SD), weight 3,600 g (3rd centile, palm 3.9 cm, and MF 3.0 cm (both on the 50th centile). Ear length was 3.5 cm (3rd centile). Scalp hair was shaved (after admission), but was said to be curly. The forehead was prominent and hirsute with portwine hemangioma over the glabella; 2 occipital hair whorls were present. She had a coarse face, antimongoloid slant of palpebral fissures, bulbous short nose with depressed nasal bridge, and wide anteverted nostrils; long philtrum with thick lips; posteriorly angulated ears with thick helices, and prominent lobule. She also had a narrowly arched palate. The chest was bell-shaped with one accessory nipple on each side. There was a 216 systolic murmur over the heart area. Echocardiography demonstrated the existence of a mild pulmonic stenosis. Liver and spleen were apparently of normal size. Patellar reflexes were normal. Genitalia were normal. The hands showed wide distal phalanges including thumbs and hallux with thick palmar and plantar ridges. Cutaneous syndactyly of about 30% between fingers I1 and I11 was present. Dermatoglyphics: (right) t, L", L", L", A, W; (left) t, L", L", L", L", L". The feet were flat with
Fig. 3. Patient 1. Note deep sacral dimple and skin tag with generalized hirsutism and excessive skin.
centile), palm 6 cm (3rd centile), MF 4 cm ( - 2.5 SD). Psychomotor maturation was delayed, especially speech and gross motor with hypotonia. He was very affectionate and sociable. There was less excessive skin noted, however, palms and soles still showed thick dermal ridges. Hyperhydrosis was not noted. He had recently undergone surgical correction of the vertical talus. On neurological examination this was a n obviously retarded boy with generalized hypotonia.
Patient 2 M. I., a girl, was born at term to a 25-year-old mother and a 39-year-old father. Parents are healthy first cousins with Arabic-Druze ancestry. They have two Older daughters and a son* was plicated by low maternal serum a-fetoprotein of 0.25
Fig. 4. Patient 1. Note bilateral vertical talus with otherwise normal tubular bones.
MCA/MR Syndrome-FCS Sy.
Fig. 5. (a,b).Patient 2 a t age 3 months. Note peculiar coarse facial appearance resembling Patient 1.Also note the generalized excessive skin and wide distal phalanges.
“rocker bottom” configuration. The elbows and hips could not be fully extended. The patient had generalized excessive skin, however, with normal elasticity. It was more pronounced over the neck, large and small joints, and buttocks. At time of examination no other anomalies were noted. Brain and abdominal ultrasound were normal. Hypoglycemia was never recorded. General skeletal survey was normal except for protruded occiput and vertical talus. She died at age 4 months. Postmortem examination was refused. Patient 3 B.R., a white girl, was born at term after a pregnancy complicated by bleeding in the 13th week of gestation and polyhydramnios. Delivery was by repeat cesarean
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section. Parents are healthy first cousins of ArabicDruze ancestry, 32 (mother) and 48 (father) years old. Together, they have a healthy older son and daughter. The father has 2 healthy sons and 6 healthy daughters from a previous marriage. Any family relation to the family of patient 2 (also Druze) was denied. The patient’s birth weight was 3,650 g (50th centile), occipitofrontal circumference (OFC) 37 cm (97th centile), and length 50 cm (50th centile). Coarse face, protruding tongue, generalized hirsutism, and excessive skin over buttocks and limbs were noted at birth. Her chromosomes were normal (46,XX). Thyroid function tests were normal. The neonatal period was unremarkable but for hospitalization a t age 30 days due to PDA and congestive heart failure. The PDA was surgically treated. Other cardiac findings were normal. When examined a t 5 months her motor development was normal. Her weight was 6,900 g, length 64 cm (both 50th centile), and OFC 43 cm (90th centile). She had (Fig. 6a) a relative large head with protruding occiput and a hirsute prominent wide forehead, protruding zygoma, depressed nasal bridge, short bulbous upturned nose with anteverted nostrils, downward slant of palpebral fissures with thick epicanthic folds, posteriorly angulated thick auricles with hypertrophy of the transverse portion of the helix and prominent lobule, full cheeks, thick lips, and flat philtrum. Her hair was curly (unlike that of other family members), and she had a short neck with excessive skin and a wide shield chest. Hands and feet were apparently enlarged with redundant skin. Patient had thickened palmar and plantar skin folds. Dermatoglyphics were normal. Broad distal phalanges were noted, more pronounced on first fingers and hallux. The feet were flat without “rocker bottom” appearance. Flexion contractures of elbows and hips were noted. Liver and spleen were palpable 4-5 cm below the costal margin. Umbilical hernia was found. Cardiac ascultation and an electrocardiogram were normal. External genitalia were normal. Neurologically, she was not hypotonic and had normal reflexes. Hearing and visual tests, electroencephalogram, and CT scan of the brain were normal. Skin and liver biopsies showed normal histology and ultrastructure. Storage material was not found in either tissues. Lysosomal enzymes studies were negative for a-mannosidosis, sialidosis, GM1 gangliosidosis, Hurler disease, fucosidosis, Gaucher’s disease, and Wolman’s disease. Skeletal survey was normal. Further investigations, including extensive metabolic evaluation, were normal. The relation between insulin secretion and glucose level (as an indicator for insulin receptor activity) during fast and 2 and 6 hours after glucose load were normal (0.085,0.135, and 0.16, respectively). When reexamined recently at 2% years, curly hair and generalized hirsutism were noted with a very peculiar hoarse voice. Her face was less coarsened (Fig. 6b), and her skin less excessive, however, palms and soles still showed thick dermal ridges. Her weight was 15 kg (75th centile), length 86 cm (10th centile), and OFC 50 cm (75th centile), palm 6.5 cm and MF 5 cm (both 75th centile). Psychomotor maturation was mildly delayed,
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Fig. 6. (a)Patient 3 a t 5 months. (b)Patient 3 at 2 6/12 years.
especially speech. She was very sociable. She had recently undergone surgical correction of the umbilical hernia.
Patient 4 C.M. is a female born on 10-9-1984. The parents are not consanguineous and are in good health. She is the second born, with an older brother 4% years old in good health. Pregnancy was normal. At 1 month of gestation skeletal X-ray was performed on the mother for suspicion of hiatal hernia. The baby was born at 38 weeks of gestation by cesarean section. Birth weight was 3,440g, OFC 34 cm (both 50th centile), and length 46 cm (3 SD below the mean). At age 3 days the baby was admitted to the Pediatric Clinic of Catania for neonatal asphyxia. Physical examination showed a dysmorphic face with relatively large hands and feet, short neck, and cardiac murmur due to pulmonary stenosis. Chromosomes and routine laboratory investigations were normal. In the following months the patient showed failure to thrive. At age 10 months she was hospitalized in Bern (Switzerland) where a diagnosis of Donohue syndrome was made. She was again admitted at the Pediatric Clinic of Catania a t this age. Her weight was 4,170g (4 SD below mean), length 59.5cm (3.5 SD below mean), OFC 41.5cm (3rd centile). The phenotype was abnormal (Fig. 7). The hair was short and thin. The forehead large with receding anterior hair, coarse face, large eyebrows, square head with protruding occiput, short bulbous nose with depressed nasal bridge, upturned anteverted nostrils, downward slant of palpebral fissures, full cheeks,
Fig. 7. Patient 4 at 10 months.
extremely large mouth with large tongue, flat philtrum, and thick open lips. The auricles were low-set and large. The baby was thin with no subcutaneous fat; the skin was loose. Elasticity of the skin was normal. The hands and feet were large. A cardiac murmur was noted. Laboratory findings were normal including urinalysis, blood electrolytes, and liver function tests. Fasting tests showed normal insulidglucose ratio (0.25). The patient is now 7 years old; her appearance is not as striking. She has moderate mental retardation and
MCA/MR Syndrome-FCS Sy. attends a special school (Fig. 8a,b). Physical examination: weight 16,300 g (2.5 SD below mean), height 102 cm (3SD below mean), and OFC 49.5 cm (3rd centile). The general condition is good, the hair is light brown, curly, and heavy. She has a large forehead with hirsutism. The eyebrows are heavy and there are epicanthal folds. The nasal root is depressed, the tip of the nose is rounded, bulbous, with thick alae nasi. The philtrum is flat and short. The lips are thick. She also has a high arched palate, thick gums with dyscromic, malformed, absent, and irregularly spaced teeth. She has puffed cheeks, pointed chin with abundant adipose tissue below the chin. The ears are small and low-set with thick lobule and hypoplastic targus. She has a short neck with a small area of acantosis nigricans and protruding nipples. She has hirsutism on the back. The umbilicus has a cutaneous protrusion. The hands are large with abundant skin, particularly on the joint. There is a simian
Fig. 8. Patient 4 a t 7 years of age. (a)Frontal view. (b)Lateral view.
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crease bilaterally. The feet are large with a longitudinal deep crease at the level of the 3rd toe, protruding heel, and dyscromic nails. Radiographs of feet showed mild vertical talus. The liver and spleen are normal. Cardiac murmur was present. The patient has a moderate mental retardation, pronounces some sentences, and has a very social behaviour and a nasal voice.
Patient 5 V.A. is a female, born on 31-10-1988.The parents are not consanguineous and are in good health. She is the second born. She has an older 7-year-old sister. Pregnancy was normal. During the pregnancy the mother took cortisone and antihistamines. The baby was born at term. Birthweight was 3,980 g (90th centile), length 46 cm (3 SD below the mean), OFC 35 cm (75th centile). She was admitted to the Pediatric Clinic of Catania because of failure to thrive. She was nourished only by gavage until age 2 years and 6 months. Also the presence of a cardiac murmur was noticed and pulmonary stenosis was diagnosed. She also suffered from frequent bronchitis. At 2 years and 9 months old, the weight is 9,750 g (2.5 SD below mean), height 78 cm (4 SD below mean), and OFC 47 cm (25th centile). Her general condition is good, she has now a good adipose tissue. The hair is sparse, curly, and light brown (Fig. 9). She has a high forehead with hirsutism (Fig. 10). The eyebrows are heavy and there are epicanthal folds. The nasal root is large, the tip is bulbous with large nares and thick alae nasi. The philtrum is flat and short. The lips are thick. The ears are low-set. She has puffed cheeks. The chin is rounded and she has abundant adipose tissue below the chin. Below the lower lips there are 2 pits. The teeth are short, large, and dyscromic. She has a short neck and protruding “nipples.”The umbilicus has a cutaneous protrusion. The liver and spleen are normal. The hands are large, hypotonic with abundant skin, particularly on the joints. There is sub-
Fig. 9. Patient 5 at 2 years and 9 months. Note sparse and curly hair.
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Fig. 10. Patient 5 at 2 years and 9 months. Frontal view.
luxation of the joint fingers. The feet are large with a deep longitudinal sulci at the level of the 2nd finger and a horizontal sulci on the 3rd. She has mild to moderate mental retardation, severe hypotonia with deep tendon reflexes present and bright. She pronounces some words, has a socialbehaviour and a hoarse voice, and walking is uncertain.
DISCUSSION These 5 patients present with a unique combination of multiple anomalies that are, to the best of our knowledge, previously unpublished. The most unique manifestations and those by which these patients were initially ascertained were charac-
teristic coarse facial appearance with an apparent increased fat deposition in the cheeks, short wide nose, posteriorly angulated auricles with thick helix, and generalized excessive skin. Four of the children reported here had poor postnatal growth even though they were large for gestational age a t birth. All 5 had some degree of mental retardation with a relative macrocranium. CT scan in 3 showed normal brain configuration. They all had similar facial changes, resembling each other to a very similar degree, with the same hoarse voice. The most consistent abnormalities are excessive generalized skin, more pronounced over joints, neck, and buttocks with neither skin hyperextensibility nor abnormalities of healing, ichthyosis, or hyperkeratosis; curly hair with normal eyebrows; skeletal abnormalities including short stature, tapered short distal phalanges, and vertical talus. Nails were apparently normal. Teeth in 2 were dyscromic. Storage material was not found on the 2 EM examinations of the skin and liver. Pregnancies were unremarkable except for low MSAFP in one instance, and early bleeding and polyhydramnious in another. Parents were young and healthy. In 2 instances, consanguinity was mentioned and in another the parents were born in the same town. Developmental delay was obviously present in most, with a specific sociable, humorous behavior. Patient 2 was too young to be evaluated in this regard. Cognitive functioning was better then motor skills. Speech was still severely delayed at age 4years (patient 11,age 7 years (patient 41, and at age 2 years and 9 months (patients 3 and 5). Except for the generalized excessive hirsute skin, no other skin manifestations were noted. The phenotypic manifestations of this syndrome are distinct (Table I). It is evident that the Noonan syn-
TABLE I. Clinical Manifestations in FCS and CFC Syndromes
1
Consanguinity Malelfemale Birth weightLGA" Birth-macrocranium Postnatal growth retardation Forehead constriction Developmental delay Coarse face Curly hair Wide anteverted nostrils Excessive skin Skin eczema and hyperkeratosis Furrowed palms and soles Wide distal phalanges Rocker bottom feet Vertical talus Heart defect
FCS syndrome Berberich Our cases et al. 2 3 4 5 (N = 3)
- + + - M F F F F + + + - + + + + - + + - + + -
-
-
-
-
+
112
NR NR
+ -
Total (N = 8)
CFC sy. syndrome (N = 25)
216 415 315
+
10115 10/19 18/25 25125
-
+
-
+ + + + +-
+ + + + + -
+ + + + + _
+ + + + + _
+ + + + + -
+ + + + +-
+
+ + + +
+ + + +
+ + + +
+ + + +
+ + + +
+
+ + + +
-
PS
PS
PS
PS
+
NR NR
+
"LGA, large for gestational age; NR, not recorded; PS, pulmonary stenosis.
+ + + + -
618
+ k + 7125 13/25 -
-
14/25
MCA/MR Syndrome-FCS drome [Mendez and Opitz, 19851, the cardio-facio-cutaneous (CFC) syndrome [Reynolds et al., 19861, the Donohue (leprechaunism) syndrome [Cantani et al., 19871, and patients in this report have some pathogenetic commonalities, at least with respect to hair, growth appearance, and in some respect also to skin. Examination of clinical photographs of previously published cases with CFC syndrome and other cases resembling CFC syndrome (25 cases all together) document a different phenotypic appearance [Costello, 1976; Cantu et al., 1982;Baraitser and Patton, 1986;Reynolds et al., 1986; Neri et al., 1987; Chrzanowska et al., 1989; Mucklow, 1989; Sorge et al., 19891. Several of the main phenotypic changes noted in our patients resembled leprechaunism syndrome (Donohue syndrome). Among those were mental retardation, coarsened face, excessive skin, hirsutism, and failure to thrive. However, normal relation between insulin secretion and glucose levels a t fast and 2 hours after glucose load found in three patients, as well as the peculiar social behavior and facial appearance, document a distinct syndrome, unlike the Donohue syndrome. It is therefore postulated that the excessive skin manifestation in our cases might well be the result of a casually nonspecific phenomenon ascribed by some to “intrauterine lymphedema” as was suggested by Opitz 119861 in respect to various syndromes. Recently, Berberich et al. [19901, in the 11th annual David W. Smith workshop on malformation and morphogenesis held in Lexington, Kentucky, presented three cases that might well resemble our cases. They presented a male and female sib pair and one unrelated male with failure to thrive, phenotype of a storage disorder, and furrowing of palmar creases as a new autosomal recessive syndrome. The coarse facial appearance presented in our cases might well resemble an apparent storage disorder. Such material, however, was not found in the examined skin biopsies of patients 1and 3 and in the liver biopsy done to patient 3. Extensive studies for enzyme-lysosomal disorders were negative as well. The consanguinity mentioned in our patients 2 and 3, and that demonstrated by Berberich et al, [19901, suggests that this apparently new syndrome is an autosoma1 recessive trait. However, in view of the Dhenot-vpic storage appearance of these patients, a storage disorder
Sy.
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cannot be completely ruled out and documentation of similar families is needed to further clarify this issue.
ACKNOWLEDGEMENTS The authors are grateful to Dr. M. Ziegler and Dr. Z. Ben-Neria for help in enzyme analysis, to Prof. T. Yanku for liver EM studies, to Mrs. Dard for her assistance, and to Dr. J. Opitz for suggestions and critical review of the manuscript . REFERENCES Baraitser M, Patton MA (1986):A Noonan-like short stature syndrome with sparse hair. J Med Genet 23:161-164. Berberich MS, Carey JC, Hall BH (1990): Resolution of the perinatal and infantile failure to thrive in a new autosomal recessive syndrome with the phenotype of a storage disorder and furrowing of palmar creases. The 11th D. W. Smith workshop on malformation and morphogenesis, Lexington, Kentucky, p 76. Cantani A, Ziruolo MG, Tacconi ML (1987): A rare polydysmorphic syndrome: Leprechaunism-review of forty-nine cases reported in the literature. Ann Genet 30:221-227. Cantu JM, Sanchez-Corona J , Hernandes A, Nazara Z, Garcia-Cruz D (1982): Individualization of a syndrome with mental deficiency, macrocranium, peculiar facies, and cardiac and skeletal anomalies. Clin Genet 22:172-179. Chrzanowska K, Fryns JP, Van den Berghe H (1989): Cardio-faciocutaneous (CFC) syndrome: Report of a new patient. Am J Med Genet 33:471-473. Costello J M (1977):A new syndrome: Mental subnormality and nasal papillomata. Aust Paediat J 13:114-118. LaFranchi S (1987): Hypoglycemia of infancy and childhood. Pediat Clin North Am 34:961-982. Mendez HMM, Opitz J M (1985): Noonan syndrome: A review. Am J Med Genet 21:493-506. Mucklow ES (1989):A case of cardio-facio-cutaneous syndrome. Am J Med Genet 33:474-475. Neri G, Sabatino G, Bertini E, Genuardi M (1987):The CFC syndromereport of the first two cases outside the United States. Am J Med Genet 27:767-771. Opitz JM (1986):Editorial comment on the paper by Crowe and Dickerman: On congenital lymphedema. Am J Med Genet 24:127-129. Reynolds JF, Neri G, Herrmann JP, Blumberg B, Coldwell JG, Miles PV, Opitz J M (1986): New multiple congenital anomalies/mental retardation syndrome with cardio-facio-cutaneous involvementthe CFC syndrome. Am J Med Genet 25:413-427. Savage PJ, Dippe SE, Bennett PH, Gordon P, Roth J, Rushforth NB, Miller M (1975):Hyperinsulinemia and hypoinsulinemia. Insulin responses to oral carbohydrate over a wide spectrum of glucose tolerance. Diabetes 24:362-368. Sorge G, Di Forti F, Scarano G, Ventruto V, Zelante L, Dallapiccola B (1989):CFC syndrome: Report on three additional cases. Am J Med Genet 33:476-478.
