American Journal of Medical Genetics 38:557-561 (1991)
Association of Distal Arthrogryposis, Mental Retardation, Whistling Face, and Pierre Robin Sequence: Evidence for Nosologic Heterogeneity Constance Schrander-Stumpel,Jean Pierre Fryns, Frits A. Beemer, and Frans A. Rive Department of Clinical Genetics, Academical Hospital Maastricht, State University of Limburg, (C.S.S.); Clinical Genetics Center Utrecht and University Children’s Hospital, Utrecht (FA.BJ, Department of Pediatrics, Maasland Hospital, Geleen, The Netherlands (F.A.R.); Division of Human Genetics, University Hospital Leuven, Belgium (J.P.F.) We report on 3 unrelated patients with the heterogeneous fetal hypokinesia sequence. They have distal arthrogryposis, severe developmental retardation, facial anomalies as seen in the Freeman-Sheldon syndrome (“whistling face”), and Pierre Robin sequence. The present cases show a remarkable clinical resemblance to the 3 sibs described by Illum et al. (Illum N, Reske-Nielsen E, Skovby F, Askjaer SA, Bersen A (1988):Neuropediatrics 19:186-1921, where calcium deposits were found in the nervous system and skeletal muscle.The presence of severe to profound developmental retardation in the present 3 patients is equally in favour of a central nervous system abnormality as the pathogenetic basis of the fetal hypokinesia sequence with secondary facial changes and distal arthrogryposis.
KEY WORDS: fetal hypokinesia, developmental retardation, Freeman-Sheldon syndrome INTRODUCTION Genetic counseling in cases with arthrogryposis multiplex congenita is difficult since the term covers a heterogeneous group of conditions all due to fetal hypokinesia. Wellknown pathogenetic factors in the fetus are central nervous abnormalities, spinal cord diseases, neuromuscular or muscular disorders, and dermatologic disease [Hall, 19811.An abnormal intrauterine environment may restrict fetal movement as well. However, in a great number of patients a precise pathogenesis cannot Received for publication October 26,1989; revision received May 18, 1990.
Address reprint requests to C. Schrander-Stumpel,Department of Clinical Genetics, Academical Hospital Maastricht, P.O. Box 1918, 6201 BX Maastricht, The Netherlands.
0 1991 Wiley-Liss, Inc.
be established [Hall, 1981; Davis and Kalousek, 1988; Hageman et al., 19881. Here, we present 3 unrelated patients, 2 females and one male, who combine distal arthrogryposis with severe psychomotor retardation, whistling face, and Pierre-Robin sequence. We hypothesize the existence of a specific entity within the group of the distal arthrogryposes.
CLINICAL REPORTS Patient 1 Patient 1, a Caucasian girl was born February 11, 1977. Pregnancy was complicated by a viral illness in the second month; there was massive polyhydramnios and growth retardation. Three previous pregnancies ended in spontaneous first trimester miscarriages. Family history was unremarkable; the parents were not consanguineous. Maternal age a t the time of birth was 22 years, paternal age 25 years. The infant was born a t 36 weeks; her weight was 2,240 g (10th centile). She had a cleft palate, flexion contractures of the fingers, knees and toes, hypotonia, and was unable to suck or swallow. The contractures were put into splints without convincing improvement. From 3 months to one year on she had seizures. At 6V2 years she had severe psychomotor retardation. Her length was 103 cm (3 cm below the 3th centile), weight 15.4 (one kg below the 3th centile), occipitofrontal circumference (OFC) 49.5 cm (25th centile). The face showed little expression, the eyes appeared small, and there was blepharophimosis (Fig. 1). The cleft palate was surgically closed. The philtrum was long with prominent pillars; micrognathia and a small mouth with limited opening were present, the upperlip was downturned. The cheeks were chubby; on the chin, a dimple was seen below the lower lip. The ears were normal. There was distal arthrogryposis: flexion contractures in the proximal interphalangeal (PIP)joints of fingers I11 and V and the wrists were noticed; thumbs were adducted. There was no ulnar deviation of the fingers. The hips had some reduced abduction, both knees had 10” flexion contractures. The external genitalia were normal. Developmental retardation was severe: the general motor level was estimated a t 4-5
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Fig. 1. Face ofpatient 1 a t the age of 2 years. Note the small mouth and blepharophimosis.
months; the mental level (Bayley Scales of Infant Development) was about 6 months. The results could be a n underestimation because of severely impaired hearing, due to recurrent middle ear infections; speech development was totally absent. It was not possible to perform a n exact hearing test. Socially she was well adapted. Clinically, vision seemed normal, fundoscopic examination was normal. An electroretinogram was not performed. Electroencephalography showed a general slow pattern without specific (epileptic) abnormalities. The CT scan of the brain showed supratentorial ventricular widening. Stimulation of the facial, ulnar, and peroneal nerves showed normal conduction times without signs of denervation. The girl died suddenly at 12 years after a seizure-like event. Autopsy was not performed. Cytogenetic investigation was normal in both the patient and her parents (cultured blood lymphocytes, high resolution banding included). Maternal myotonic dystrophy was excluded.
Patient 2 This male Caucasian infant was the first child of nonconsanguineous parents. Family history was unremarkable. Maternal age a t the time of birth was 30 years, paternal age 31 years. There were no miscarriages. The pregnancy was complicated by polyhydramnios. After 37 weeks of gestation he was born spontaneously in cephalic position; weight was 3,500 g (50th centile), length 54 cm (60th centile), OFC 39 cm (97th centile). Among the clinical signs that were noted: blepharophimosis and apparent microphthalmia, long philtrum with prominent pillars, a short columnella, a downturned upperlip, micrognathia, and cleft palate. The left ear was apparently lowset and abnormally formed. The shoulders were anterotated. The infant had contractures of PIP joints of fingers 11-V with hypoplastic flexion creases. Both thumbs were set into the palms of the hands (Fig. 2). The feet showed marked dorsiflexion of the first toes. The penis was small but testes were descended. He showed mild hirsutism of the back. He was very hypotonic and showed barely spontaneous
Fig. 2. Hand of patient 2: adducted thumbs and contractures.
movement; sucking and swallowing were absent. He had obstructive apnea. At 3 months microstomia with limited mouth opening had become evident and the cheeks were very chubby (Fig. 3). Seizures started at age 3 months; the muscle tone was still low with periodic hypertonicity. Spontaneous movements were reduced. Somatic growth was normal; psychomotor development was virtually absent. Hearing appeared impaired ( - 35 dB). The clinical impression of the vision was normal. Electroencephalography was normal a s was the CT scan of the brain. Results of chromosome investigations performed on cultured blood lymphocytes and fibroblasts were normal (46,XY); the parents had normal chromosomes. The patient died a t 6 months from aspiration pneumonia. No autopsy was performed. Myotonic dystrophy in the mother was excluded.
Patient 3 Patient 3, a girl born December 22, 1986, was the second child of a healthy non-consanguineous parents of Dutch ancestry, whose firstborn baby is a healthy girl. The mother had one previous miscarriage. Family history was unremarkable. Maternal age was 23 years, paternal age 28. During the pregnancy, polyhydramnios was noted and fetal movement was feeble. The spontaneous birth took place at 40 weeks gestation in cephalic position; the umbilical cord was noted to be short. There was no asphyxia; birthweight was 3,000 g (50th centile); length and OFC were not noted. At birth the following signs were seen: a low forehead, slight downward slant of the palpebral fissures, small upturned nose, small mouth, microretrognathia, and a high palate. The ears were posteriorly angulated. There were contractures of the fingers with thumbs set into the palms of the hands. Hips, knees, and elbows showed limitation of extension. On referral at age 20 months she had severe somatic growth and motor retardation (length, weight, and OFC all below 3th centile). The cheeks had become very chubby; the philtrum was long with prominent pillars, the columnella was short and the mouth small with limited opening, giving the impression of “whistling face” (Fig. 4).There was almost no spontaneous move-
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Fig. 3. Face of patient 2 at the age of 3 months: ptosis, blepharophimosis, long philtrum, small mouth with limited opening, and chubby cheeks. Fig. 4. Face of patient 3 a t the age of 17 months: note the striking resemblance to the face of case 2 in Figure 3.
ment and facial mimic was scarse. The shoulders were anterotated. The hands showed the same contractures as seen in the neonatal period (Fig. 5). General hypertonia of the limbs with truncal hypotonia was present. The parents reported periodic sweating. Electromyogram showed normal conduction times of right median nerve motor fibres; muscle biopsy (left medial vastus) was normal. The electroencephalogram was normal. The CT scan of the brain showed a slightly enlarged cisterna magna and interhemisphericfissure. Metabolic screening and chromosome study were normal. Maternal myotonic dystrophy was excluded.
Fig. 5. Hand of patient 3: finger contractures and adducted thumbs.
DISCUSSION The present unrelated cases show severe developmental retardation combined with the clinical triad of distal arthrogryposis, whistling face, and Pierre Robin sequence as clinical signs of fetal hypokinesia. The fetal hypokinesia sequence (or Pena-Shokeir type I phenotype) is suspected in all present cases since they presented with (mainly distal) arthrogryposis, polyhydramnios, cleft palate, and micrognathia (the “Pierre Robin sequence”) and (in patient 3) short umbilical cord [Hall, 19861. In the animal model, it was proven that fetal akinesia produced the clinical manifestations that are seen in human infants with the formerly called Pena-Shokeir (type I) phenotype, namely growth retardation, limb anomalies, pulmonary hypoplasia, short umbilical cord, and polyhydramnios [Drachman and Banker, 1961; Moessinger, 19831. The term “fetal akinesia/hypokinesia deformation sequence” was proposed and since then well accepted. In humans, this sequence may vary from severe with early fetal death to mild with distal arthrogryposis [Davis and Kalousek, 1988; Hall et al., 19821. Studying the different types of the fetal hypokinesia deformation sequence and the distal arthrogryposes, the present cases do not fit in any of the well delineated types. An extensive search in the London Dysmorphology Data Base (patients 2 and 3) did not resolve the diagnostic problem either. Five subgroups were delineated in the neonatally lethal “Pena-Shokeir syndrome” [Hall, 19861; recently, a new subtype with macrocephaly was reported [Lammer et al., 19891. The present cases show a relatively milder form, because
560
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TABLE I. Clinical Data of the Present Patients Compared to the Sibship Described by Illum et al. [19881 Illum et al. Patient 2 Patient 3 [19881 Clinical symptoms Patient 1 Polyhydramnios + ++213 Prenatal growth retardation Postnatal growth retardation ++ 111 + Microcephaly Asphyxia post partum + + 313 Hypotonia + + + 3 I3 Distal arthrogryposis + + + 313 Micrognathia + + + 313 Cleft palate + + High palate + + + 313 Whistling face Seizures + + 313 + + + 111 Severe developmental retardation + 313 Early death ? ? ? 313 Microscopic calcification of the brain and muscle
they survived beyond the neonatal period; growth retardation was not a constant finding. Within the arthrogryposis group the distal arthrogryposes were well delineated by Hall et al. 119821. A subdivision in this heterogeneous group was made on clinical grounds. The present patients show some clinical resemblance to type 11-E,where the distal arthrogryposis is seen in combination with limited opening of the mouth (trismus),micrognathia, reduced facial expression, a horizontal crease below the lower lip, and limitation of hip movements; one third of these case have a low-normal intelligence. This is in contrast with the normal intelligence seen in other types of distal arthrogryposis. The Freeman-Sheldon syndrome is clinically characterized by blepharophimosis, ptosis, a long philtrum, a small mouth with limited opening, and a n H-shaped dimple below the lower lip, which gives a n expression of “whistling face,” distal arthrogryposis and ulnar deviation of the hands [Freeman and Sheldon, 19381. Intelligence usually is normal. In general, inheritance is autosomal dominant, most cases being seen as new mutations; however, families with autosomal recessive inheritance have been described [Alves and Azevedo, 1977; Wang and Lin, 19871. Some families suggest that there is some similarity between the Freeman-Sheldon syndrome and the distal arthrogryposes [Cox and Pearce, 19741.In 1988 Illum et al. described a sibship with a lethal autosomal recessive arthrogryposis multiplex congenita with whistling face. These 2 girls and one boy born to healthy, non-consanguineous parents, experienced severe asphyxia a t birth. They all had seizures and died a t 2 days, 3 days, and 3 months, respectively. They had flexion contractures at their wrists and metacarpophalangealjoints; there was limited movement of the hips, knees, and elbows. Spontaneous movement and facial expression was scarse and there was general hypotonia. Mouth opening was limited; case 3 had a deep crease below the lower lip. At autopsy extensive calcium deposits in the brain and skeletal muscle were found. A metabolic defect was assumed but not found. The present patients show a remarkable clinical resemblance to those of Illum et al. [19881. The clinical data are summarized in Table I.
Total 516 016 3 I4 1I6 516 616 616 6/6 216 616 516 414 5 I6 313
The present patients with severe developmental retardation give further evidence for nosologic heterogeneity in the group of distal arthrogryposes. It is not clear whether these children are severely mentally retarded a s well: they may be impaired by the inability of facial expression, hearing deficit (patients 1and 2), and motor problems. It could even be questioned whether the present cases should be classified in the group of distal arthrogryposis since the reaction to the splints (patient 1)was bad, suggesting a different pathogenesis than in the distal arthrogryposes that normally show a good response to therapy. We hypothesize that within the conditions with arthrogryposis a specific subgroup exists where the distal arthrogryposis is seen in combination with severe developmental and mental retardation, whistling face, and Pierre Robin sequence. A cerebral function (metabolic?) disorder causing the fetal hypokinesia which led to the distal arthrogryposis and the psychomotor retardation seems most likely. The inheritance in the patients is not clear; cases 1 and 2 are the first and only child. Patient 3 has one healthy sib. Consanguinity is denied in all cases. The 3 patients originate from different parts of The Netherlands and Belgium. Paternal age in patients 1 and 2 is above average suggesting the possibility of a new dominant mutation. Comparison with similar clinical cases is highly recommended to delineate this type of distal arthrogryposis and to establish its pathogenesis and inheritance.
ACKNOWLEDGMENTS The authors wish to thank Drs. H. van mnteren and K. van Eeghen for referring case 3 and gathering clinical data. We thank Dr. J.M. Opitz for diagnostic suggestions in case 3. REFERENCES Alves AFP, Azevedo ES (1977): Recessive form of Freeman-Sheldon’s syndrome or “whistling face.” J Med Genet 14:139-141. Cox DW, Pearce WG (1974): Variable expression in craniotarpotarsal dysplasia. BD:OAS X(5): 243-248.
Arthrogryposis, Retardation, and Whistling face Davis J E , Kalousek DK (1988):Fetal Akinesia Deformation Sequence in previable fetuses. Am J Med Genet 29:77-87. Drachman DB, Banker CA (1961): Arthrogryposis multiplex congenita. Arch Neurol 577-93. Freeman EA, Sheldon J H (1938): Cranio-carpo-tarsal dystrophy: An undescribed congenital malformation. Arch Dis Child 13:227-283. Hageman G, Ippel PF, Beemer FA, de Pater J , Lindhout D, Willemse J (1988): The diagnostic management of newborns with congenital contractures: a nosologic study of 75 cases. Am J Med Genet 30:883904. Hall J G (1981): An approach to congenital contractures (arthrogryposis). Pediatr Ann 10:15-26. Hall J G (1986): Invited editorial comment: Analysis of Pena Shokeir phenotype. Am J Med Genet 25:99-117. Hall JG, Reed SD, Greene G (1982):The distal arthrogryposis: delinea-
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tion of new entities-review and nosologic discussion. Am J Med Genet 11:185-239. Illum N, bske-Nielsen E, Skovby F, Askjaer SA, Bernsen A (1988): Lethal autosomal recessive arthrogryposis multiplex congenita with whistling face and calcifications of the nervous system. Neuropediatrics 19:186- 192. Lammer EJ, Donelly S, Holmes LB (1989):Pena-Shokeir phenotype in sibs with macrocephaly but without growth retardation. Am J Med Genet 32:478-481. Moessinger AC (1983): Fetal akinesia sequence: a n animal model. Pediatrics 72857-863. Wang TS, Lin SJ (1987):Further evidence for genetic heterogeneity of whistling face or Freeman-Sheldon syndrome in a Chinese family. Am J Med Genet 28:471-475.
Association of Distal Arthrogryposis, Mental Retardation, Whistling Face, and Pierre Robin Sequence: Evidence for Nosologic Heterogeneity Constance Schrander-Stumpel,Jean Pierre Fryns, Frits A. Beemer, and Frans A. Rive Department of Clinical Genetics, Academical Hospital Maastricht, State University of Limburg, (C.S.S.); Clinical Genetics Center Utrecht and University Children’s Hospital, Utrecht (FA.BJ, Department of Pediatrics, Maasland Hospital, Geleen, The Netherlands (F.A.R.); Division of Human Genetics, University Hospital Leuven, Belgium (J.P.F.) We report on 3 unrelated patients with the heterogeneous fetal hypokinesia sequence. They have distal arthrogryposis, severe developmental retardation, facial anomalies as seen in the Freeman-Sheldon syndrome (“whistling face”), and Pierre Robin sequence. The present cases show a remarkable clinical resemblance to the 3 sibs described by Illum et al. (Illum N, Reske-Nielsen E, Skovby F, Askjaer SA, Bersen A (1988):Neuropediatrics 19:186-1921, where calcium deposits were found in the nervous system and skeletal muscle.The presence of severe to profound developmental retardation in the present 3 patients is equally in favour of a central nervous system abnormality as the pathogenetic basis of the fetal hypokinesia sequence with secondary facial changes and distal arthrogryposis.
KEY WORDS: fetal hypokinesia, developmental retardation, Freeman-Sheldon syndrome INTRODUCTION Genetic counseling in cases with arthrogryposis multiplex congenita is difficult since the term covers a heterogeneous group of conditions all due to fetal hypokinesia. Wellknown pathogenetic factors in the fetus are central nervous abnormalities, spinal cord diseases, neuromuscular or muscular disorders, and dermatologic disease [Hall, 19811.An abnormal intrauterine environment may restrict fetal movement as well. However, in a great number of patients a precise pathogenesis cannot Received for publication October 26,1989; revision received May 18, 1990.
Address reprint requests to C. Schrander-Stumpel,Department of Clinical Genetics, Academical Hospital Maastricht, P.O. Box 1918, 6201 BX Maastricht, The Netherlands.
0 1991 Wiley-Liss, Inc.
be established [Hall, 1981; Davis and Kalousek, 1988; Hageman et al., 19881. Here, we present 3 unrelated patients, 2 females and one male, who combine distal arthrogryposis with severe psychomotor retardation, whistling face, and Pierre-Robin sequence. We hypothesize the existence of a specific entity within the group of the distal arthrogryposes.
CLINICAL REPORTS Patient 1 Patient 1, a Caucasian girl was born February 11, 1977. Pregnancy was complicated by a viral illness in the second month; there was massive polyhydramnios and growth retardation. Three previous pregnancies ended in spontaneous first trimester miscarriages. Family history was unremarkable; the parents were not consanguineous. Maternal age a t the time of birth was 22 years, paternal age 25 years. The infant was born a t 36 weeks; her weight was 2,240 g (10th centile). She had a cleft palate, flexion contractures of the fingers, knees and toes, hypotonia, and was unable to suck or swallow. The contractures were put into splints without convincing improvement. From 3 months to one year on she had seizures. At 6V2 years she had severe psychomotor retardation. Her length was 103 cm (3 cm below the 3th centile), weight 15.4 (one kg below the 3th centile), occipitofrontal circumference (OFC) 49.5 cm (25th centile). The face showed little expression, the eyes appeared small, and there was blepharophimosis (Fig. 1). The cleft palate was surgically closed. The philtrum was long with prominent pillars; micrognathia and a small mouth with limited opening were present, the upperlip was downturned. The cheeks were chubby; on the chin, a dimple was seen below the lower lip. The ears were normal. There was distal arthrogryposis: flexion contractures in the proximal interphalangeal (PIP)joints of fingers I11 and V and the wrists were noticed; thumbs were adducted. There was no ulnar deviation of the fingers. The hips had some reduced abduction, both knees had 10” flexion contractures. The external genitalia were normal. Developmental retardation was severe: the general motor level was estimated a t 4-5
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Fig. 1. Face ofpatient 1 a t the age of 2 years. Note the small mouth and blepharophimosis.
months; the mental level (Bayley Scales of Infant Development) was about 6 months. The results could be a n underestimation because of severely impaired hearing, due to recurrent middle ear infections; speech development was totally absent. It was not possible to perform a n exact hearing test. Socially she was well adapted. Clinically, vision seemed normal, fundoscopic examination was normal. An electroretinogram was not performed. Electroencephalography showed a general slow pattern without specific (epileptic) abnormalities. The CT scan of the brain showed supratentorial ventricular widening. Stimulation of the facial, ulnar, and peroneal nerves showed normal conduction times without signs of denervation. The girl died suddenly at 12 years after a seizure-like event. Autopsy was not performed. Cytogenetic investigation was normal in both the patient and her parents (cultured blood lymphocytes, high resolution banding included). Maternal myotonic dystrophy was excluded.
Patient 2 This male Caucasian infant was the first child of nonconsanguineous parents. Family history was unremarkable. Maternal age a t the time of birth was 30 years, paternal age 31 years. There were no miscarriages. The pregnancy was complicated by polyhydramnios. After 37 weeks of gestation he was born spontaneously in cephalic position; weight was 3,500 g (50th centile), length 54 cm (60th centile), OFC 39 cm (97th centile). Among the clinical signs that were noted: blepharophimosis and apparent microphthalmia, long philtrum with prominent pillars, a short columnella, a downturned upperlip, micrognathia, and cleft palate. The left ear was apparently lowset and abnormally formed. The shoulders were anterotated. The infant had contractures of PIP joints of fingers 11-V with hypoplastic flexion creases. Both thumbs were set into the palms of the hands (Fig. 2). The feet showed marked dorsiflexion of the first toes. The penis was small but testes were descended. He showed mild hirsutism of the back. He was very hypotonic and showed barely spontaneous
Fig. 2. Hand of patient 2: adducted thumbs and contractures.
movement; sucking and swallowing were absent. He had obstructive apnea. At 3 months microstomia with limited mouth opening had become evident and the cheeks were very chubby (Fig. 3). Seizures started at age 3 months; the muscle tone was still low with periodic hypertonicity. Spontaneous movements were reduced. Somatic growth was normal; psychomotor development was virtually absent. Hearing appeared impaired ( - 35 dB). The clinical impression of the vision was normal. Electroencephalography was normal a s was the CT scan of the brain. Results of chromosome investigations performed on cultured blood lymphocytes and fibroblasts were normal (46,XY); the parents had normal chromosomes. The patient died a t 6 months from aspiration pneumonia. No autopsy was performed. Myotonic dystrophy in the mother was excluded.
Patient 3 Patient 3, a girl born December 22, 1986, was the second child of a healthy non-consanguineous parents of Dutch ancestry, whose firstborn baby is a healthy girl. The mother had one previous miscarriage. Family history was unremarkable. Maternal age was 23 years, paternal age 28. During the pregnancy, polyhydramnios was noted and fetal movement was feeble. The spontaneous birth took place at 40 weeks gestation in cephalic position; the umbilical cord was noted to be short. There was no asphyxia; birthweight was 3,000 g (50th centile); length and OFC were not noted. At birth the following signs were seen: a low forehead, slight downward slant of the palpebral fissures, small upturned nose, small mouth, microretrognathia, and a high palate. The ears were posteriorly angulated. There were contractures of the fingers with thumbs set into the palms of the hands. Hips, knees, and elbows showed limitation of extension. On referral at age 20 months she had severe somatic growth and motor retardation (length, weight, and OFC all below 3th centile). The cheeks had become very chubby; the philtrum was long with prominent pillars, the columnella was short and the mouth small with limited opening, giving the impression of “whistling face” (Fig. 4).There was almost no spontaneous move-
Arthrogryposis, Retardation, and Whistling face
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Fig. 3. Face of patient 2 at the age of 3 months: ptosis, blepharophimosis, long philtrum, small mouth with limited opening, and chubby cheeks. Fig. 4. Face of patient 3 a t the age of 17 months: note the striking resemblance to the face of case 2 in Figure 3.
ment and facial mimic was scarse. The shoulders were anterotated. The hands showed the same contractures as seen in the neonatal period (Fig. 5). General hypertonia of the limbs with truncal hypotonia was present. The parents reported periodic sweating. Electromyogram showed normal conduction times of right median nerve motor fibres; muscle biopsy (left medial vastus) was normal. The electroencephalogram was normal. The CT scan of the brain showed a slightly enlarged cisterna magna and interhemisphericfissure. Metabolic screening and chromosome study were normal. Maternal myotonic dystrophy was excluded.
Fig. 5. Hand of patient 3: finger contractures and adducted thumbs.
DISCUSSION The present unrelated cases show severe developmental retardation combined with the clinical triad of distal arthrogryposis, whistling face, and Pierre Robin sequence as clinical signs of fetal hypokinesia. The fetal hypokinesia sequence (or Pena-Shokeir type I phenotype) is suspected in all present cases since they presented with (mainly distal) arthrogryposis, polyhydramnios, cleft palate, and micrognathia (the “Pierre Robin sequence”) and (in patient 3) short umbilical cord [Hall, 19861. In the animal model, it was proven that fetal akinesia produced the clinical manifestations that are seen in human infants with the formerly called Pena-Shokeir (type I) phenotype, namely growth retardation, limb anomalies, pulmonary hypoplasia, short umbilical cord, and polyhydramnios [Drachman and Banker, 1961; Moessinger, 19831. The term “fetal akinesia/hypokinesia deformation sequence” was proposed and since then well accepted. In humans, this sequence may vary from severe with early fetal death to mild with distal arthrogryposis [Davis and Kalousek, 1988; Hall et al., 19821. Studying the different types of the fetal hypokinesia deformation sequence and the distal arthrogryposes, the present cases do not fit in any of the well delineated types. An extensive search in the London Dysmorphology Data Base (patients 2 and 3) did not resolve the diagnostic problem either. Five subgroups were delineated in the neonatally lethal “Pena-Shokeir syndrome” [Hall, 19861; recently, a new subtype with macrocephaly was reported [Lammer et al., 19891. The present cases show a relatively milder form, because
560
Schrander-Stumpelet al.
TABLE I. Clinical Data of the Present Patients Compared to the Sibship Described by Illum et al. [19881 Illum et al. Patient 2 Patient 3 [19881 Clinical symptoms Patient 1 Polyhydramnios + ++213 Prenatal growth retardation Postnatal growth retardation ++ 111 + Microcephaly Asphyxia post partum + + 313 Hypotonia + + + 3 I3 Distal arthrogryposis + + + 313 Micrognathia + + + 313 Cleft palate + + High palate + + + 313 Whistling face Seizures + + 313 + + + 111 Severe developmental retardation + 313 Early death ? ? ? 313 Microscopic calcification of the brain and muscle
they survived beyond the neonatal period; growth retardation was not a constant finding. Within the arthrogryposis group the distal arthrogryposes were well delineated by Hall et al. 119821. A subdivision in this heterogeneous group was made on clinical grounds. The present patients show some clinical resemblance to type 11-E,where the distal arthrogryposis is seen in combination with limited opening of the mouth (trismus),micrognathia, reduced facial expression, a horizontal crease below the lower lip, and limitation of hip movements; one third of these case have a low-normal intelligence. This is in contrast with the normal intelligence seen in other types of distal arthrogryposis. The Freeman-Sheldon syndrome is clinically characterized by blepharophimosis, ptosis, a long philtrum, a small mouth with limited opening, and a n H-shaped dimple below the lower lip, which gives a n expression of “whistling face,” distal arthrogryposis and ulnar deviation of the hands [Freeman and Sheldon, 19381. Intelligence usually is normal. In general, inheritance is autosomal dominant, most cases being seen as new mutations; however, families with autosomal recessive inheritance have been described [Alves and Azevedo, 1977; Wang and Lin, 19871. Some families suggest that there is some similarity between the Freeman-Sheldon syndrome and the distal arthrogryposes [Cox and Pearce, 19741.In 1988 Illum et al. described a sibship with a lethal autosomal recessive arthrogryposis multiplex congenita with whistling face. These 2 girls and one boy born to healthy, non-consanguineous parents, experienced severe asphyxia a t birth. They all had seizures and died a t 2 days, 3 days, and 3 months, respectively. They had flexion contractures at their wrists and metacarpophalangealjoints; there was limited movement of the hips, knees, and elbows. Spontaneous movement and facial expression was scarse and there was general hypotonia. Mouth opening was limited; case 3 had a deep crease below the lower lip. At autopsy extensive calcium deposits in the brain and skeletal muscle were found. A metabolic defect was assumed but not found. The present patients show a remarkable clinical resemblance to those of Illum et al. [19881. The clinical data are summarized in Table I.
Total 516 016 3 I4 1I6 516 616 616 6/6 216 616 516 414 5 I6 313
The present patients with severe developmental retardation give further evidence for nosologic heterogeneity in the group of distal arthrogryposes. It is not clear whether these children are severely mentally retarded a s well: they may be impaired by the inability of facial expression, hearing deficit (patients 1and 2), and motor problems. It could even be questioned whether the present cases should be classified in the group of distal arthrogryposis since the reaction to the splints (patient 1)was bad, suggesting a different pathogenesis than in the distal arthrogryposes that normally show a good response to therapy. We hypothesize that within the conditions with arthrogryposis a specific subgroup exists where the distal arthrogryposis is seen in combination with severe developmental and mental retardation, whistling face, and Pierre Robin sequence. A cerebral function (metabolic?) disorder causing the fetal hypokinesia which led to the distal arthrogryposis and the psychomotor retardation seems most likely. The inheritance in the patients is not clear; cases 1 and 2 are the first and only child. Patient 3 has one healthy sib. Consanguinity is denied in all cases. The 3 patients originate from different parts of The Netherlands and Belgium. Paternal age in patients 1 and 2 is above average suggesting the possibility of a new dominant mutation. Comparison with similar clinical cases is highly recommended to delineate this type of distal arthrogryposis and to establish its pathogenesis and inheritance.
ACKNOWLEDGMENTS The authors wish to thank Drs. H. van mnteren and K. van Eeghen for referring case 3 and gathering clinical data. We thank Dr. J.M. Opitz for diagnostic suggestions in case 3. REFERENCES Alves AFP, Azevedo ES (1977): Recessive form of Freeman-Sheldon’s syndrome or “whistling face.” J Med Genet 14:139-141. Cox DW, Pearce WG (1974): Variable expression in craniotarpotarsal dysplasia. BD:OAS X(5): 243-248.
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