American Journal of Medical Genetics 20:631-638 (1985)
A Previously Undescribed Autosomal Recessive Multiple Congenital Anomalies/ Mental Retardation (MCA/MR) Syndrome With Fronto-Nasal Dysostosis, Cleft Lip/ Palate, Limb Hypoplasia, and Postaxial Poly-Syndactyly: Acro-Fronto-Facio-Nasal Dysostosis Syndrome
A. Richieri-Costa, G.M.D.D. Colletto, T.R. Gollop and D. Masiero
Servico de Genetica Humana da Associaciio de Assistencia a Crianca Defeituosa, Siio Paulo (A. R-C., D. M.); Servico de Genetica Humana da Associaeao Maternidade Siio Paulo, Siio Paulo (7: R. G.), and Laboratorio de Genetica Humana, Departamento de Biologia, Universidade de Siio Paulo (G. M. D. D.C)
We describe two sibs born to a consanguineous couple. Among other clinical findings both have mental retardation, short stature, facial and skeletal abnormal- ities characterized by hypertelorism, broad notched nasal tip, cleft lip/palate, campto-brachy-poly-syndactyly, fibular hypoplasia, and marked anomalies of foot structures. Facial signs of the reported patients resemble those present in the fronto-nasal dysplasia syndrome; however, the whole clinical picture in the present patients suggests a true MCA/MR syndrome, most likely inherited as an autosomal recessive trait. Clinical and genetic aspects of the present family are discussed.
Key words: acro-fronto-facio-nasal dysostosis, cleft lip/palate, limb hypoplasia, skeletal dysplasia, polysyncamptobrachydactyly , short stature, mental retardation, autosomal recessive inheritance, parental consanguinity
Received for publication May 29, 1984; revision received November 19, 1984.
Address reprint requests to A. Richieri-Costa, AssociaGb de Assistencia i CrianGa Defeituosa, Av. Prof. Ascendino Reis 724, 04027 Sio Paulo, SP, Brazil.
0 1985 Alan R. Liss, Inc.
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Fronto-nasal dysplasia is a midline monotopic developmental field complex, associated with variable degrees of clefting of the facial midline. Bilateral simian crease and clinodactyly [DeMyer, 19671, bifid hallux [Sedano et al, 19701 and bilateral hexadactyly of the feet [Warkany et al, 19731 most likely are fortuitous clinical signs, since only three out of 67 patients reviewed by Gollop  had such additional anomalies.
Most cases of fronto-nasal dysplasia have been sporadic, but evidence of autosomal dominant [Francesconi et al, 1969; Warkany et al, 19731 and autosomal recessive inheritance [Boo-Chai, 1965; Fox et al, 19781 has been reported.
We report on two sibs with an acro-fronto-facio-nasal dysostosis syndrome which seems different from the classical fronto-nasal dysplasia malformation and from any of the previously described entities associated with mid-face clefting [Cohen, 19781.
CASE REPORTS Patient 1
E.E.A. , a male, was born in 1977 (Fig. 1). Gestation was normal. There was no exposure to toxic or infectious agents or to X-rays and no trauma was reported. Delivery was vaginal at term. Birth weight was 3,900 gm and length was 50 cm; OFC was not recorded. His parents were phenotypically normal and were first cousins. Bilateral cleft lip with a wide cleft of palate and facial and limb anomalies were noted at birth. Neuropsychological developmental was delayed. Lip and palatal clefts were repaired at age 4 years.
Examination at 6 years showed: severe mental retardation; weight 21 kg, height 110 cm, OFC 53 cm, inner canthal distance 3.7 cm, outer canthal distance 9.9 cm, interpupillary distance 6.7 cm, inter alar distance 4.2 cm. He had a wide forehead, hypertelorism, S-shaped palpebral fissures, bilateral ptosis, long eyelashes and eyebrows, broad notched nasal tip, mild hypoplasia of the mid-face, macrostomia, prominent lower lip, mild retrognathia, anteverted auricles, prominent tragus and lobule, triangular-shaped conchae. The patient also had bilateral postaxial poly- syndactyly, hypoplasia of the distal phalanges of digits 1-5, PIP camptodactyly of digits 2-5, brachymetacarpia 1-5, hypoplasia of toenails, shortness of legs, equino- valgus feet, lumbar lordosis, and bilaterial cryptorchidism.
X-rays showed brachycephaly, vertical clivus, mild hypoplasia of the facial bones, midline gap in the upper maxilla, small mandible with obtuse angle, increased interorbital distance, bilateral fusion between hamate and capitate, disorganization of the structure of the carpal bones, bilaterial shortness of all metacarpals, mainly the first one, broad metacarpal 5 , and postaxial polysyndactyly. In the right hand there was a semilunar epiphyseal line in metacarpal 5 dividing it into two sets and marked hypoplasia of the distal phalanges of fingers 1-5. In the left hand, there was an epiphysis-like structure with a proximal hyperdense segment medial to the distal 5th metacarpal epiphysis; the proximal epiphysis of the distal phalanx of finger 1 was unusually broad. Marked hypoplasia of the middle phalanx of finger 5 , mild hypopla- sia of the distal epiphysis of fingers 2-5, hypoplasia of the distal phalanges of fingers 1 4 and absence of the middle phalanx of finger 5 are also present (Fig. 2). In the lower limbs there were bilaterally: iliac hypoplasia, coxa valga, acetabular dyspla-
Fig. 1. Patient 1
Acro-Fronto-Facio-Nasal Dysostosis 633
Fig. 2. X-rays of the hands of patient 1 .
Fig. 3. X-rays of pelvis of patient 1.
Fig. 4. X-rays of lower limbs of patient 1. Fig. 5 . X-rays of tibio-talar joint of patient I .
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sia with hip.dislocation (Fig. 3), shortness of the tibia and fibula, fibular hypoplasia, broad and abnormally modeled distal tibio-fibular epiphyses (Fig. 4), broad and short metatarsal I and proximal phalanx of toe 1 . Mild hypoplasia of the middle and distal phalanges of toes 2-5 and tibio-talar luxation were found. The tarsal bones were abnormally modeled (Fig. 5). The size, shape, and alignment of the vertebrae were preserved.
Results of blood laboratory tests were normal. G-banded chromosomes of peripheral lymphocytes were normal. Dermatoglyphic findings are shown in Table I.
T.E.A. was born in 1976, sister of patient 1 (Fig. 6). Gestation was normal. No exposure to toxic or infectious agents, or to X-rays was noted, and no trauma was reported. Delivery was vaginal at term. Birth weight was 3,420 gm, length 49 cm, and OFC was not recorded. Bilaterally cleft lip with widely cleft palate and other facial and limb anomalies were noted at birth. There was delayed neuropsychological development. Lip and palate clefts were repaired at age 5 years.
Examination at 7 years showed severe mental retardation. Weight was 17 kg, height 104 cm, OFC 51 cm, inner canthal distance 3.6 cm, outer canthal distance 9.6 cm, interpupillary distance 6.3 cm, and interalar distance 4.6 cm. The patient had a wide forehead, widows peak, hypertelorism, S-shaped palpebral fissures, ptosis of the right eyelid, long eyelashes and eyebrows, broad nasal bridge, notched broad nasal tip, mild hypoplasia of the mid-face, macrostomia, prominent helix, tragus and lobe, and wide conchae. Hypoplasia of the distal phalanges of digits 1-5, PIP carnptodactyly of digits 2-5, brachymetacarpia 1-5, and nail hypoplasia was present, as well as bilateral shortness of legs, posterior dislocation of the tibio-talar joint, equinovarus of the left foot and supination of the right foot. There was fibular deviation of toes 1-5 and bilateral metatarso-phalangeal flexion of toe 1.
X-rays showed brachycephaly, vertical clivus, mild hypoplasia of the facial bones, midline gap in the upper maxilla, and small mandible with obtuse angle. There was also hypoplasic radial and ulnar epiphyses, brachymetacarpia 1-5, hypoplastic distal phalanges of fingers 2-5 (Fig. 7), iliac hypoplasia, acetabular dysplasia, and hip dislocation (Fig. 8). Severe fibular hypoplasia, gross anomalies of the tibia1 and fibular epiphyses, tibio-talar dislocation, abnormally modeled tarsal bones, severe metatarsus adductus, fibular deviation of toes 4-5, and hypoplasia/agenesis of the distal phalanges of toes 2-5 were present (Fig. 9).
CT scan showed mild cortical atrophy (Fig. 10). Results of blood laboratory tests were normal. G-banded chromosomes of peripheral lymphocytes were normal. Dermatoglyphics are shown in Table I.
The abnormalities present in these patients seem to be unique and to represent a specific MCA/MR syndrome. Clinically, there are two main sets of signs: one related to the facial midline, resulting in widows peak, hypertelorism, notched broad nasal tip, and cleft lip/palate; and the other involving multiple skeletal sites, resulting in a series of clinical manifestations related to the skeletal dysostosis. Craniofacial and CNS anomalies may be related developmentally.
The midline involvement as a non-specific symptomatic indicator of generalized problems, especially in skeletal dysplasias, was suggested by Opitz and Gilbert
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Fig. 7. X-rays of the hands of patient 2
Fig. 6. Patient 2.
fig. 8. X-rays of the pelvis of patient 2.
. In the present condition facial midline involvement represents a site of manifestation of a pleiotropic autosomal recessive gene with predominant dysmorpho- genetic effects on the skeleton. This is especially obvious when one compares the appendicular and craniofacial skeletal anomalies with the well-preserved morpholog- ical integrity of the CNS midline shown by the CT scan.
Besides the typical pattern of craniofacial and limb anomalies, the dermato- glyphic analysis in the present patients showed some abnormalities characterized by excess.of arches on fingertips, a very low TRC and RRC, increased palmar ridge count, high atd angle values (t), hypothenar pattern (proximal loop) on the left hand of patient 1, a proximal loop of the left hand, and a S-shaped pattern on the right hand of patient 2 (Table I) [Colletto, 19841.
The clinical signs of the present patients, with the involvement of multiple developmental fields, prompts a clear distinction of the present syndrome from the
Acro-Fronto-Facio-Nasal Dysostosis 637
Fig. 9d.b. X-ray view of the tibia, fibula and feet of patient 2.
Fig. 10. CT scan of patient 2.
638 Richieri-Costa et a1
fronto-nasal dysplasia syndrome, in spite of the reports of bilateral simian crease and clinodactyly [DeMyer, 19671, bifid hallux [Sedano et al, 19701, and bilateral hexadactyly of feet [Warkany et al, 19731.
Radiologically, there are some findings in the present family that resemble those found in oto-palato-digital (OPD) syndrome type I1 [Fitch et al, 19831, such as vertical clivus, small mandible with obtuse angle, curved and or hypoplastic fibulae, abnormal ossification of the patella, iliac hypoplasia, acetabular dysplasia, brachymetacarpia, and involvement of the distal phalanges of the toes. However, both the inheritance of the present condition, as well as the whole clinical picture, prompts a clear distinction from the OPD syndrome 11.
Comparison of the present syndrome with those tabulated by Cohen , with cleft lip and cleft palate as cardinal signs, showed no common clinical points to support any definitive differential diagnosis with any of the reported syndromes.
The presence of consanguinity among the propositis parents, the absence of related abnormalities in relatives, the absence of chromosome abnormalities, and the recurrence of the condition in sibs, provides strong evidence that this represents a new autosomal recessive true MCA/MR syndrome.
Boo-Chai K (1965): The bifid nose. Plast Reconstr Surg 36:626-628. Cohen MM, Jr (1978): Syndromes with cleft lip and cleft palate. Cleft Palate J 15:306-328. Colletto GMDD (1984): Unpublished data. DeMyer W (1967): The median cleft face syndrome. Neurology 17:961-971. Fitch N , Jequier S , Gorlin R (1983): The oto-palato-digital syndrome, proposed type 11. Am J Med
Fox JW, Golden GT, Edgerton MT (1978): Frontonasal dysplasia with alar clefts in two sisters. Plast
Francesconi G, Fortunato G (1969): Median dysraphia of the face. Plast Reconstr Surg 43:481-4Y 1. Gollop TR (198 I) : Estudo genttico-clinico das disostoses mandibulofacial e frontofacionasal. Tese de
doutoramento apresentada ao Instituto de BiociCncias da Universidade de SBo Paulo, pp 112, S5.o Paulo, Brazil.
Opitz JM, Gilbert EF (1982): Editorial comment: CNS anomalies and the midline as a developmental field. Am J Med Genet 12:443-455.
Sedano HO, Cohen MM, Jr, Jirasek G, Gorlin RJ (1970): Fronto-nasal dysplasia. J Pediatr 76:906-913. Warkany J, Bofinger MK, Benton C (1973): Median facial cleft syndrome in half-sisters. Dilcmmas in
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Edited by John M. Opitz and James F. Reynolds