American Journal of Medical Genetics 35493-495 (1990)
Letter to the Editor Autosomal Recessive Form of Mandibular Dysostosis To the Editor:
right thumb was smaller than the left thumb, and there was mild cutaneous syndactyly of the other two fingers of the left hand and clinodactyly of the corresponding In this issue of the American Journal of Medical Ge- fingers of the right hand. Bilateral single transverse netics, Rodriguez and Palacios L19901report clinical and palmar creases were noted. A widened gap between the pathological findings of a new autosomal recessive form hallux and second toe was present bilaterally. Internal examination showed an annular pancreas of mandibulofacial dysostosis with limb deficiency that is distally postaxial. I recently examined a stillborn with obstruction of the distal duodenum and a single female infant, whose pattern of malformation may rep- horse-shoe kidney with 3 ureters. Externally the heart resent the severe spectrum of the disorder detailed in and great vessels appeared normal. The heart-lung Rodriguez’ report. block was lost in transit to a consultant cardiovascular The infant was the product of a 26-week-gestationto a pathology division of another institution. The cerebral 27-year-old gravida 2 para 1black woman who denied hemispheres were symmetrical, but the gyri were poorly use of isotretinoin or other vitamin A analogues. The formed and the sulci were shallow. Autolysis precluded mother developed a urinary tract infection at about the detailed neuropathologic examination. Roentgenograms showed severe mandibular hypotime of conception and was treated with trimethoprimsulfa. The pregnancy was further complicated by vagi- plasia, partial agenesis of the sacrum, and thoracic cage nal bleeding at 14 weeks of gestation. Subsequent pre- asymmetry (10 ribs on left, 11ribs on right). Markedly natal ultrasonography showed polyhydramnios, a large hypoplastic humeri were located subcutaneously on the cystic hygroma, phocomelia, single kidney, and possible trunk proximal to the phocomelic upper limbs. There porencephaly or unilateral dilatation of the inferior lat- was bilateral aplasia of the radius and ulna. Three eral ventricle. There was no family history of consan- metacarpals of the right hand and two metacarpals of guinity. The couple had one normal male child. the left hand were present with phalanges of the thumb The infant was delivered stillborn at 26 weeks gesta- and two fingers on each side.There was marked femoral tion. Weight was 480 g, and head circumference was 22 hypoplasia, to a greater extent on the right, with bowing cm (5th centile). Hypertrichosis with a soft cranium, of the left femur, bilateral tibia1 hypoplasia, and bilatand normal size anterior and posteriar fontanels were eral fibular aplasia. Three metatarsals and correspondnoted. Severe mandibulofacial dysostosis included hy- ing phalanges of the hallux and 2 toes were present on pertelorism, absence of eyelashes, indentation of the each foot. Cytogenetic evaluation of amniocytes and of skin filateral inferior border of the left eyelid, malar hypoplasia, flattened nose with small nostrils, smooth phi- broblasts was normal (46,XX) and did not show premaltrum, microstomia and micrognathia, midline cleft of ture separation of centromeric heterochromatin. This stillborn female’s mandibulofacial dysostosis the soft palate and posterior hard palate, and atresia of both ear canals. Very rudimentary pinnae with central with limb deficiency and internal anomalies is of pits had developed inferiorly near the angles of the man- greater pathologic severity than the pattern of malfordible. At the normal site of auricle development was a mations previously described in the postaxial acrofacial 0.5 cm well-demarcated circular indentation in the skin dysostosis (Genee-Wiedemann)syndrome [Miller et al., on the right side and a small circular protuberance of 19791.The presence of relatively well-developed thumbs hairless subcutaneous tissue with two pits on the left and halluces render unlikely the diagnosis of a severe side. A large cystic hygroma of the neck was present form of Nager acrofacial dysostosis [Braga, 1982; Halal with hypertrichosis extending over the posterior and et al., 19831. lateral trunk. Dorsally deviated coccyx and sacrum were The normal chromosomes, severity of the mandiwidely separated from a patent anus. Severephocomelia bulofacial dysostosis, hypertrichosis, and digital findof the upper limbs was accompanied by lower limb defi- ings are atypical for Roberts SC (pseudothalidomide) ciency with a pterygium extending across the perineum syndrome. Roberts syndrome is characterized by preaxto the knees and arthrogryposis at the hips and knees. ial digital deficiency. Development of fingers and toes was remarkably symThis stillborn fetus did not have the lateral facial metric, each consisting of three digits (thumbihallux clefting characteristic of the syndrome of acrofacial dyswith two fingers /toes) with well-developed nails. The ostosis with severe facial clefting [Kawira et al., 19841. The infant’s postaxial pattern of digital deficiency, the presence of metatarsals, and the specific internal anomReceived for publication June 30, 1989. alies are additional differentiating findings.
0 1990 Wiley-Liss, Inc.
494
Stephan
Fig. 1. Stillborn female fetus. Note hypertrichosis, cystic hygroma and limb deficiency.
Fig. 3. A, B: Left hand and right foot. Note well-developed thumb, hallux. and nails.
Fig. 2. Left auricular canal atresia with rudimentary pinna development.
Letter to the Editor
495
Fig. 4. Radiograph of fetus. Note humeral, femoral, and tibia1 hypoplasia and radial, ulnar, and fibular aplasia.
The severity of the mandibulofacial dysostosis is comparable to that reported by Lungarotti et al., [19871in a female infant with normal limbs. Most likely this infant’s phenotype is representative of a unique syndrome of severe postaxial acrofacial dysostosis and limb hypomelia reported by Rodriguez and Palacios in this issue of this journal. The pathogenesis most likely involves extensive abnormalities of neural crest cell development and migration.
Mark J. Stephan, M.D. Dysmorphology Unit Department of Pediatrics Madigan Army Medical Center Tacoma, WA
REFERENCES Braga S (1982):Zur klinischen Variabilitat des Nager-Syndroms. Wiss Inform 8:341-344. Halal F, Herrmann J , Pallister PD, Opitz JM, Degranges MF, Grenier G (1983): Differential diagnosis of Nager acrofacial dysostosis syndrome: Report of four patients with Nager syndrome and discussion of other related syndromes. Am J Med Genet 14:209-224. Kawira EL, Weaver DD, Bender HA (1984): Acrofacial dysostosis with severe facial clefting and limb reduction. Am J Med Genet 17:641-647. Lungarotti MS, Marinelli D, Mariani T, Calabro A (1987): Multiple congenital anomalies associated with apparently normal maternal intake of vitamin A: A phenocopy of the isotretinoin syndrome. Am J Med Genet 27945-248. Miller M, Fineman RM, Smith DW (1979): Postaxial acrofacial dysostosis syndrome. J Pediatr 95:970-975. Rodriguez JI, Palacios J (1990): Severe postaxial acrofacial dysostosis. An anatomic and angiographic study. Am J Med Genet (this issue).
Letter to the Editor Autosomal Recessive Form of Mandibular Dysostosis To the Editor:
right thumb was smaller than the left thumb, and there was mild cutaneous syndactyly of the other two fingers of the left hand and clinodactyly of the corresponding In this issue of the American Journal of Medical Ge- fingers of the right hand. Bilateral single transverse netics, Rodriguez and Palacios L19901report clinical and palmar creases were noted. A widened gap between the pathological findings of a new autosomal recessive form hallux and second toe was present bilaterally. Internal examination showed an annular pancreas of mandibulofacial dysostosis with limb deficiency that is distally postaxial. I recently examined a stillborn with obstruction of the distal duodenum and a single female infant, whose pattern of malformation may rep- horse-shoe kidney with 3 ureters. Externally the heart resent the severe spectrum of the disorder detailed in and great vessels appeared normal. The heart-lung Rodriguez’ report. block was lost in transit to a consultant cardiovascular The infant was the product of a 26-week-gestationto a pathology division of another institution. The cerebral 27-year-old gravida 2 para 1black woman who denied hemispheres were symmetrical, but the gyri were poorly use of isotretinoin or other vitamin A analogues. The formed and the sulci were shallow. Autolysis precluded mother developed a urinary tract infection at about the detailed neuropathologic examination. Roentgenograms showed severe mandibular hypotime of conception and was treated with trimethoprimsulfa. The pregnancy was further complicated by vagi- plasia, partial agenesis of the sacrum, and thoracic cage nal bleeding at 14 weeks of gestation. Subsequent pre- asymmetry (10 ribs on left, 11ribs on right). Markedly natal ultrasonography showed polyhydramnios, a large hypoplastic humeri were located subcutaneously on the cystic hygroma, phocomelia, single kidney, and possible trunk proximal to the phocomelic upper limbs. There porencephaly or unilateral dilatation of the inferior lat- was bilateral aplasia of the radius and ulna. Three eral ventricle. There was no family history of consan- metacarpals of the right hand and two metacarpals of guinity. The couple had one normal male child. the left hand were present with phalanges of the thumb The infant was delivered stillborn at 26 weeks gesta- and two fingers on each side.There was marked femoral tion. Weight was 480 g, and head circumference was 22 hypoplasia, to a greater extent on the right, with bowing cm (5th centile). Hypertrichosis with a soft cranium, of the left femur, bilateral tibia1 hypoplasia, and bilatand normal size anterior and posteriar fontanels were eral fibular aplasia. Three metatarsals and correspondnoted. Severe mandibulofacial dysostosis included hy- ing phalanges of the hallux and 2 toes were present on pertelorism, absence of eyelashes, indentation of the each foot. Cytogenetic evaluation of amniocytes and of skin filateral inferior border of the left eyelid, malar hypoplasia, flattened nose with small nostrils, smooth phi- broblasts was normal (46,XX) and did not show premaltrum, microstomia and micrognathia, midline cleft of ture separation of centromeric heterochromatin. This stillborn female’s mandibulofacial dysostosis the soft palate and posterior hard palate, and atresia of both ear canals. Very rudimentary pinnae with central with limb deficiency and internal anomalies is of pits had developed inferiorly near the angles of the man- greater pathologic severity than the pattern of malfordible. At the normal site of auricle development was a mations previously described in the postaxial acrofacial 0.5 cm well-demarcated circular indentation in the skin dysostosis (Genee-Wiedemann)syndrome [Miller et al., on the right side and a small circular protuberance of 19791.The presence of relatively well-developed thumbs hairless subcutaneous tissue with two pits on the left and halluces render unlikely the diagnosis of a severe side. A large cystic hygroma of the neck was present form of Nager acrofacial dysostosis [Braga, 1982; Halal with hypertrichosis extending over the posterior and et al., 19831. lateral trunk. Dorsally deviated coccyx and sacrum were The normal chromosomes, severity of the mandiwidely separated from a patent anus. Severephocomelia bulofacial dysostosis, hypertrichosis, and digital findof the upper limbs was accompanied by lower limb defi- ings are atypical for Roberts SC (pseudothalidomide) ciency with a pterygium extending across the perineum syndrome. Roberts syndrome is characterized by preaxto the knees and arthrogryposis at the hips and knees. ial digital deficiency. Development of fingers and toes was remarkably symThis stillborn fetus did not have the lateral facial metric, each consisting of three digits (thumbihallux clefting characteristic of the syndrome of acrofacial dyswith two fingers /toes) with well-developed nails. The ostosis with severe facial clefting [Kawira et al., 19841. The infant’s postaxial pattern of digital deficiency, the presence of metatarsals, and the specific internal anomReceived for publication June 30, 1989. alies are additional differentiating findings.
0 1990 Wiley-Liss, Inc.
494
Stephan
Fig. 1. Stillborn female fetus. Note hypertrichosis, cystic hygroma and limb deficiency.
Fig. 3. A, B: Left hand and right foot. Note well-developed thumb, hallux. and nails.
Fig. 2. Left auricular canal atresia with rudimentary pinna development.
Letter to the Editor
495
Fig. 4. Radiograph of fetus. Note humeral, femoral, and tibia1 hypoplasia and radial, ulnar, and fibular aplasia.
The severity of the mandibulofacial dysostosis is comparable to that reported by Lungarotti et al., [19871in a female infant with normal limbs. Most likely this infant’s phenotype is representative of a unique syndrome of severe postaxial acrofacial dysostosis and limb hypomelia reported by Rodriguez and Palacios in this issue of this journal. The pathogenesis most likely involves extensive abnormalities of neural crest cell development and migration.
Mark J. Stephan, M.D. Dysmorphology Unit Department of Pediatrics Madigan Army Medical Center Tacoma, WA
REFERENCES Braga S (1982):Zur klinischen Variabilitat des Nager-Syndroms. Wiss Inform 8:341-344. Halal F, Herrmann J , Pallister PD, Opitz JM, Degranges MF, Grenier G (1983): Differential diagnosis of Nager acrofacial dysostosis syndrome: Report of four patients with Nager syndrome and discussion of other related syndromes. Am J Med Genet 14:209-224. Kawira EL, Weaver DD, Bender HA (1984): Acrofacial dysostosis with severe facial clefting and limb reduction. Am J Med Genet 17:641-647. Lungarotti MS, Marinelli D, Mariani T, Calabro A (1987): Multiple congenital anomalies associated with apparently normal maternal intake of vitamin A: A phenocopy of the isotretinoin syndrome. Am J Med Genet 27945-248. Miller M, Fineman RM, Smith DW (1979): Postaxial acrofacial dysostosis syndrome. J Pediatr 95:970-975. Rodriguez JI, Palacios J (1990): Severe postaxial acrofacial dysostosis. An anatomic and angiographic study. Am J Med Genet (this issue).
