Hum. Genet. 33, 323--326 (1976) © by Springer-Verlag 1976
Clinical Case Reports A Familial Tetraphocomelia Syndrome Involving Limb Deformities, Cleft Lip, Cleft Palate, and Associated Anomalies -A New Syndrome K i r a n K u c h e r i a 1, S. K . B h a r g a v a ~, R. B a m e z a i 3, a n d P. B h u t a n i Human Cytogeneties Laboratory, Department of Anatomy, All-India Institute of Medical Sciences, Ansari Nagar, New Delhi, India 2 Consultant Paediatrieian, Department of Paediatrics, Safdarjung Hospital, New Delhi, India 3 Postgraduate, Department of Anatomy, All-India Institute of Medical Sciences, Ansari Nagar, New Delhi, India Received February 13, 1976
Summary. This paper reports a rare malformation syndrome which is observed in two sibs (brother and sister) of a family. I t consists of nearly symmetric reductive defects of the limbs, flexon eontractures of various joints, cleft lip and cleft palate, multiple minor abnormalities including capillary hemangioma of the forehead, hypoplastic cartilages of ears and nose, micrognathia, intrauterine growth retardation, and possibly mental retardation. Chromosomes of both parents and propositi are normal. Genetic data suggest autosomal recessive inheritance.
Introduction W e s t u d i e d 2 sibs of a f a m i l y which showed d y s m o r p h o g e n e t i c s y n d r o m e of t e t r a p h o c o m e l i a like d e f o r m i t y a n d m u l t i p l e associated anomalies. There is no h i s t o r y of fever, i r r ~ d i a t i o n exposure, or e x a n t h e m a t o u s rash. T h e r e is no h i s t o r y of a n y t e r a t o g e n i c ,drugs t a k e n e x c e p t 2 injections during, t h e first t r i m e s t e r for t h e t e r m i n a t i o n of t h e 5th p r e g n a n c y ( a b o r t e d a t a b o u t 1 3 - - 1 4 weeks of gestation). A f t e r 1 y e a r a n d 6 m o n t h s , t h e m o t h e r d e l i v e r e d (6th gravida), a d e f o r m e d male b a b y . I n t h e first t r i m e s t e r of t h e 6th p r e g n a n c y , she c o m p l a i n e d of chest p a i n a n d h a d 15 injections. T h e n a t u r e of these injections is n o t v e r y clear. The p a t i e n t n e v e r a t t e n d e d t h e p r e n a t a l clinics. One y e a r after t h e 6th p r e g n a n c y , she delivered a g a i n a d e f o r m e d (7th g r a v i d a ) female b a b y . A b n o r m a l i t i e s in b o t h t h e b a b i e s were similar. Case Report Patient I (6th gravida V 6) : was born after 38 weeks of gestation to a 30-year-old mother who previously had four healthy children and one induced abortion in the first trimester. The pregnancy was uneventful and it was a flfll-term breech delivery. The baby had a birth weight of 1650 g, birth length of 35 cm, and head circumference of 28 em. There is no exact description of the placenta (Fig. 1 a and b). Clinical examination soon after the birth showed wide open sutures of the skull scalp, complex malformation of limbs, all four limbs being short and stunted. The child had very
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FEMALE DEAD
-
WITH SYNDROME
3
Fig. 1
small forearms showing four fingers with the absence of the thumb. Radiologic examination showed absence of radius, ulna, thumbs, and flexion contractures of the elbow and knee joints. Lower limbs showed small thighs and legs with severe congenital talipes equinovarus. The lower limbs showed tibia present and fibula absent. There were four toes on each foot with syndactyly of the 2nd and 3rd toes. A well-marked capillary hemingioma was present on the forehead. Eyes showed proposed hypertelurism, epicanthic fold, a n d hazy cornea. Bilateral cleft lip and cleft palate with protruding premaxilla were well marked. Chest showed clinically normal heart and lungs. Pilonidal sinus was present. External genitalia showed normal well-formed penis and scrotum w i t h testis. The patient was kept in the nursery a n d passed meconium and urine regularly, retained feeds, and died a t the age of 4 days. Therefore, m a n y of the laboratory investigations were not done. Autopsy showed no apparent abnormality of internal organs. Patient 2 (7th gravida V 7): Sister of patient No. 1 was born (1 year later) after a fullterm breech delivery with a birth weight of 1060 g, a birth length of 32 era, and a head circumference of 28 cm. There was severe symmetric shortening of all four limbs (Fig. 1 d--f).
Familial Tetraphocomelia - - A New Syndrome
325
Clinical examination soon after birth showed a wide anterior fontanelle measuring about 2 × 3 cm. The upper arms showed absence of forearms and small upper arm having four fingers in each hand with thumb present as suggested by opposing movements. Radiologic examination showed absence of radius and ulna in both upper arms. Lower limbs showed very small thighs and legs with five toes on each showing syndactyly of the 4th and 5th toes. Tibia were present and fibula absent. A severe degree of congenital talipes equinovarus. Eyes showed proposed hypertelurism, epicanthic fold, and hazy cornea. A well-marked capillary hemingioma on the forehead, bilateral cleft lip, and cleft palate with protruding premaxilla were present. Chest showed clinically normal heart and lungs. Spine was normal. External genitalia showed labia minora partially covered. The patient was kept in nursery and died at the age of 8 days due to suspected septicemia. The parents refused autopsy on this child.
Genetic Data The p a r e n t s are of Nepalese origin. T h e y are 2nd degree cousins a n d h a v e no h i s t o r y of a n y o t h e r m a l f o r m a t i o n in t h e f a m i l y (Fig. 1 c). The cases u n d e r consideration were t h e 6th a n d 7th g r a v i d a (V. 6, 7) of t h e couple who h a d four n o r m a l children anc[ one i n d u c e d first t r i m e s t e r abortion. The eldest two m a l e sibs are n o r m a l a n d h e a l t h y . The 3rd a n d 4 t h sibs, b o t h female were n o r m a l a t b i r t h a n d died a~s t h e age of 5 years w i t h a c o m p l a i n t of passing blood in t h e stool. B o t h died a t home in a village with more or less similar s y m p t o m s . The cause of d e a t h was n o t confirmed medically. Sibs 6 a n d 7 were m a l f o r m e d children who died 4: a n d 8 d a y s after birth, respectively. The m a t e r n a l g r a n d m o t h e r ( I I I 1) of t h e propositi h a d 11 c h i l d r e n - - 5 died a t t h e age of 1 - - 2 m o n t h s - w i t h o u t t h e cause being known. M a t e r n a l grandm o t h e r ( I I I 1) has no living sisters or brothers. C h r o m o s o m a l c o m p l e m e n t s of b o t h p a t i e n t s a n d t h e i r p a r e n t s are a p p a r e n t l y normal. The fact t h a t p a r e n t s are 2nd degree cousins a n d t h a t t h e r e are two living n o r m a l sibs suggest a u t o s o m a l recessive m o d e of i n h e r i t a n c e as t h e m o s t possible cause of this s y n d r o m e .
Discussion The d e s c r i p t i o n of t h e t e t r a p h o e o m e l i a s y n d r o m e p r e s e n t e d in this p a p e r has some features c o m m o n with t h e p s e u d o t h a l i d o m i d e a n d R o b e r t s syndromes. A p p e l t (1966) described one case of t e t r a p h o c o m e l i a , which, in a d d i t i o n to t h e o t h e r deformities, showed t h e cleft of t h e u p p e r lip a n d m a x i l l a b i l a t e r a l l y , t h e p a l a t e being i n t a c t , n o r m a l - s h a p e d ears, a n d a h y p e r t r o p h i e d clitoris w i t h e n l a r g e d a n d split labia minora. O ' B r i a n a n d M u s t a r d (1921) r e p o r t e d a n o t h e r case of t e t r a p h o c o m e l i a w i t h microcephaly, h i g h l y arched palate, b o t h t h u m b s a n d fifth fingers absent, toes n o r m a l w i t h t h e e x c e p t i o n of s y n d a e t y l y b e t w e e n t h e 4th a n d t h e 5th toes, bilaterally. H e r r m a n et al. (1969) p u b l i s h e d a d e t a i l e d review a n d d e s c r i p t i o n of t h e 4 cases. I n cases Nos. 1 a n d 2 in c o m b i n a t i o n w i t h t h e cleft lip, t h e p a l a t e was felt to be h i g h l y a r c h e d a n d o n l y in case No. 4 was t h e r e a cleft palate. F r e e m a n et al. (1974) in t h e i r review of R o b e r t s s y n d r o m e , shouted t h e presence of b i l a t e r a l cleft lip a n d p a l a t e as a f a i r l y c o n s t a n t feature. On t h e o t h e r hand, no f e m u r was p r e s e n t b i l a t e r a l l y in 6 a n d u n i l a t e r a l l y in 1 of 22 cases collected.
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Grosse et al. (1975) while describing a new ease of t e t r a p h o c o m e l i a , s t a t e d t h e difficulties in differentiating b e t w e e n t h e two s y n d r o m e s ( P s e u d o t h a l i d o m i d e a n d R o b e r t s syndromes) until t h e r e are f u r t h e r criteria for t h e differential diagnosis. T h e cases described b y us h a v e some characteristic features - - which are n o t fully like t h e P s e u d o t h a l i d o m i d e or t h e l~oberts syndromes. These are t h e presence o f definite cleft lip a n d p a l a t e w i t h p r o t r u d i n g p r e m a x i l l a ; presence of f e m u r ; absence of r a d i u s ulna in u p p e r limbs a n d fibula in lower limbs, a n d presence of long a n d b l a c k h a i r (no s i l v e r y b l o n d hair). Therefore, it would be p r o p e r to categorize these 2 cases u n d e r t h e general t e r m , t e t r a p h o e o m e l i a , showing a new s y n d r o m e .
References Appelt, It., Gerken, H., Lenz, W.: Tetraphokomelie mit Lippen-Kicfer-Gaumenspalte und Clitorishypertrophie: ein Syndrom. P~diat. Pi~dol. 2, 119--124 (1966) Freeman, M. V. R., Williams, O. W., Schimke, R. N., Temtamy, S. A., Vachier, E., German, J. : The Roberts syndrome. Clin. Genet. 5, 1--16 (1974) Grosse, F. R., Pandel, C., Wiedemann, H. R. : The tetraphoeomelia - - cleft palate syndrome: Description of a new case. Humangenetik 28, 353--356 (1975) Herrman, J., Feingold, M., Tuffli, G. A., Opitz, J. M. : A familial dysmorphogenetic syndrome of limb deformities, characteristic facial appearance and associated anomalies: The ,,Pseudothalidomide:' or ,,SC-syndrome". Birth Defects: Original Article Series 5/3, 81--89 (1969) O'Brian, H. R., Mustard, H. S. : An adult living case of total phocomelia. J. Amer. reed. Ass. 77, 1964:--1967 (1921) Dr. (Mrs.) K. Kucheria Human Cytogenetics Laboratory Department of Anatomy All-India Institute of Medical Sciences Ansari Nagar New Delhi 110016 India
Clinical Case Reports A Familial Tetraphocomelia Syndrome Involving Limb Deformities, Cleft Lip, Cleft Palate, and Associated Anomalies -A New Syndrome K i r a n K u c h e r i a 1, S. K . B h a r g a v a ~, R. B a m e z a i 3, a n d P. B h u t a n i Human Cytogeneties Laboratory, Department of Anatomy, All-India Institute of Medical Sciences, Ansari Nagar, New Delhi, India 2 Consultant Paediatrieian, Department of Paediatrics, Safdarjung Hospital, New Delhi, India 3 Postgraduate, Department of Anatomy, All-India Institute of Medical Sciences, Ansari Nagar, New Delhi, India Received February 13, 1976
Summary. This paper reports a rare malformation syndrome which is observed in two sibs (brother and sister) of a family. I t consists of nearly symmetric reductive defects of the limbs, flexon eontractures of various joints, cleft lip and cleft palate, multiple minor abnormalities including capillary hemangioma of the forehead, hypoplastic cartilages of ears and nose, micrognathia, intrauterine growth retardation, and possibly mental retardation. Chromosomes of both parents and propositi are normal. Genetic data suggest autosomal recessive inheritance.
Introduction W e s t u d i e d 2 sibs of a f a m i l y which showed d y s m o r p h o g e n e t i c s y n d r o m e of t e t r a p h o c o m e l i a like d e f o r m i t y a n d m u l t i p l e associated anomalies. There is no h i s t o r y of fever, i r r ~ d i a t i o n exposure, or e x a n t h e m a t o u s rash. T h e r e is no h i s t o r y of a n y t e r a t o g e n i c ,drugs t a k e n e x c e p t 2 injections during, t h e first t r i m e s t e r for t h e t e r m i n a t i o n of t h e 5th p r e g n a n c y ( a b o r t e d a t a b o u t 1 3 - - 1 4 weeks of gestation). A f t e r 1 y e a r a n d 6 m o n t h s , t h e m o t h e r d e l i v e r e d (6th gravida), a d e f o r m e d male b a b y . I n t h e first t r i m e s t e r of t h e 6th p r e g n a n c y , she c o m p l a i n e d of chest p a i n a n d h a d 15 injections. T h e n a t u r e of these injections is n o t v e r y clear. The p a t i e n t n e v e r a t t e n d e d t h e p r e n a t a l clinics. One y e a r after t h e 6th p r e g n a n c y , she delivered a g a i n a d e f o r m e d (7th g r a v i d a ) female b a b y . A b n o r m a l i t i e s in b o t h t h e b a b i e s were similar. Case Report Patient I (6th gravida V 6) : was born after 38 weeks of gestation to a 30-year-old mother who previously had four healthy children and one induced abortion in the first trimester. The pregnancy was uneventful and it was a flfll-term breech delivery. The baby had a birth weight of 1650 g, birth length of 35 cm, and head circumference of 28 em. There is no exact description of the placenta (Fig. 1 a and b). Clinical examination soon after the birth showed wide open sutures of the skull scalp, complex malformation of limbs, all four limbs being short and stunted. The child had very
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K. Kucheria et al.
FEMALE DEAD
-
WITH SYNDROME
3
Fig. 1
small forearms showing four fingers with the absence of the thumb. Radiologic examination showed absence of radius, ulna, thumbs, and flexion contractures of the elbow and knee joints. Lower limbs showed small thighs and legs with severe congenital talipes equinovarus. The lower limbs showed tibia present and fibula absent. There were four toes on each foot with syndactyly of the 2nd and 3rd toes. A well-marked capillary hemingioma was present on the forehead. Eyes showed proposed hypertelurism, epicanthic fold, a n d hazy cornea. Bilateral cleft lip and cleft palate with protruding premaxilla were well marked. Chest showed clinically normal heart and lungs. Pilonidal sinus was present. External genitalia showed normal well-formed penis and scrotum w i t h testis. The patient was kept in the nursery a n d passed meconium and urine regularly, retained feeds, and died a t the age of 4 days. Therefore, m a n y of the laboratory investigations were not done. Autopsy showed no apparent abnormality of internal organs. Patient 2 (7th gravida V 7): Sister of patient No. 1 was born (1 year later) after a fullterm breech delivery with a birth weight of 1060 g, a birth length of 32 era, and a head circumference of 28 cm. There was severe symmetric shortening of all four limbs (Fig. 1 d--f).
Familial Tetraphocomelia - - A New Syndrome
325
Clinical examination soon after birth showed a wide anterior fontanelle measuring about 2 × 3 cm. The upper arms showed absence of forearms and small upper arm having four fingers in each hand with thumb present as suggested by opposing movements. Radiologic examination showed absence of radius and ulna in both upper arms. Lower limbs showed very small thighs and legs with five toes on each showing syndactyly of the 4th and 5th toes. Tibia were present and fibula absent. A severe degree of congenital talipes equinovarus. Eyes showed proposed hypertelurism, epicanthic fold, and hazy cornea. A well-marked capillary hemingioma on the forehead, bilateral cleft lip, and cleft palate with protruding premaxilla were present. Chest showed clinically normal heart and lungs. Spine was normal. External genitalia showed labia minora partially covered. The patient was kept in nursery and died at the age of 8 days due to suspected septicemia. The parents refused autopsy on this child.
Genetic Data The p a r e n t s are of Nepalese origin. T h e y are 2nd degree cousins a n d h a v e no h i s t o r y of a n y o t h e r m a l f o r m a t i o n in t h e f a m i l y (Fig. 1 c). The cases u n d e r consideration were t h e 6th a n d 7th g r a v i d a (V. 6, 7) of t h e couple who h a d four n o r m a l children anc[ one i n d u c e d first t r i m e s t e r abortion. The eldest two m a l e sibs are n o r m a l a n d h e a l t h y . The 3rd a n d 4 t h sibs, b o t h female were n o r m a l a t b i r t h a n d died a~s t h e age of 5 years w i t h a c o m p l a i n t of passing blood in t h e stool. B o t h died a t home in a village with more or less similar s y m p t o m s . The cause of d e a t h was n o t confirmed medically. Sibs 6 a n d 7 were m a l f o r m e d children who died 4: a n d 8 d a y s after birth, respectively. The m a t e r n a l g r a n d m o t h e r ( I I I 1) of t h e propositi h a d 11 c h i l d r e n - - 5 died a t t h e age of 1 - - 2 m o n t h s - w i t h o u t t h e cause being known. M a t e r n a l grandm o t h e r ( I I I 1) has no living sisters or brothers. C h r o m o s o m a l c o m p l e m e n t s of b o t h p a t i e n t s a n d t h e i r p a r e n t s are a p p a r e n t l y normal. The fact t h a t p a r e n t s are 2nd degree cousins a n d t h a t t h e r e are two living n o r m a l sibs suggest a u t o s o m a l recessive m o d e of i n h e r i t a n c e as t h e m o s t possible cause of this s y n d r o m e .
Discussion The d e s c r i p t i o n of t h e t e t r a p h o e o m e l i a s y n d r o m e p r e s e n t e d in this p a p e r has some features c o m m o n with t h e p s e u d o t h a l i d o m i d e a n d R o b e r t s syndromes. A p p e l t (1966) described one case of t e t r a p h o c o m e l i a , which, in a d d i t i o n to t h e o t h e r deformities, showed t h e cleft of t h e u p p e r lip a n d m a x i l l a b i l a t e r a l l y , t h e p a l a t e being i n t a c t , n o r m a l - s h a p e d ears, a n d a h y p e r t r o p h i e d clitoris w i t h e n l a r g e d a n d split labia minora. O ' B r i a n a n d M u s t a r d (1921) r e p o r t e d a n o t h e r case of t e t r a p h o c o m e l i a w i t h microcephaly, h i g h l y arched palate, b o t h t h u m b s a n d fifth fingers absent, toes n o r m a l w i t h t h e e x c e p t i o n of s y n d a e t y l y b e t w e e n t h e 4th a n d t h e 5th toes, bilaterally. H e r r m a n et al. (1969) p u b l i s h e d a d e t a i l e d review a n d d e s c r i p t i o n of t h e 4 cases. I n cases Nos. 1 a n d 2 in c o m b i n a t i o n w i t h t h e cleft lip, t h e p a l a t e was felt to be h i g h l y a r c h e d a n d o n l y in case No. 4 was t h e r e a cleft palate. F r e e m a n et al. (1974) in t h e i r review of R o b e r t s s y n d r o m e , shouted t h e presence of b i l a t e r a l cleft lip a n d p a l a t e as a f a i r l y c o n s t a n t feature. On t h e o t h e r hand, no f e m u r was p r e s e n t b i l a t e r a l l y in 6 a n d u n i l a t e r a l l y in 1 of 22 cases collected.
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Grosse et al. (1975) while describing a new ease of t e t r a p h o c o m e l i a , s t a t e d t h e difficulties in differentiating b e t w e e n t h e two s y n d r o m e s ( P s e u d o t h a l i d o m i d e a n d R o b e r t s syndromes) until t h e r e are f u r t h e r criteria for t h e differential diagnosis. T h e cases described b y us h a v e some characteristic features - - which are n o t fully like t h e P s e u d o t h a l i d o m i d e or t h e l~oberts syndromes. These are t h e presence o f definite cleft lip a n d p a l a t e w i t h p r o t r u d i n g p r e m a x i l l a ; presence of f e m u r ; absence of r a d i u s ulna in u p p e r limbs a n d fibula in lower limbs, a n d presence of long a n d b l a c k h a i r (no s i l v e r y b l o n d hair). Therefore, it would be p r o p e r to categorize these 2 cases u n d e r t h e general t e r m , t e t r a p h o e o m e l i a , showing a new s y n d r o m e .
References Appelt, It., Gerken, H., Lenz, W.: Tetraphokomelie mit Lippen-Kicfer-Gaumenspalte und Clitorishypertrophie: ein Syndrom. P~diat. Pi~dol. 2, 119--124 (1966) Freeman, M. V. R., Williams, O. W., Schimke, R. N., Temtamy, S. A., Vachier, E., German, J. : The Roberts syndrome. Clin. Genet. 5, 1--16 (1974) Grosse, F. R., Pandel, C., Wiedemann, H. R. : The tetraphoeomelia - - cleft palate syndrome: Description of a new case. Humangenetik 28, 353--356 (1975) Herrman, J., Feingold, M., Tuffli, G. A., Opitz, J. M. : A familial dysmorphogenetic syndrome of limb deformities, characteristic facial appearance and associated anomalies: The ,,Pseudothalidomide:' or ,,SC-syndrome". Birth Defects: Original Article Series 5/3, 81--89 (1969) O'Brian, H. R., Mustard, H. S. : An adult living case of total phocomelia. J. Amer. reed. Ass. 77, 1964:--1967 (1921) Dr. (Mrs.) K. Kucheria Human Cytogenetics Laboratory Department of Anatomy All-India Institute of Medical Sciences Ansari Nagar New Delhi 110016 India
