American Journal of Medical Genetics 29:95-106 (1988)
A New Acro-Cranio-Facial Dysostosis Syndrome in Sisters Paige Kaplan, Henri Plauchu, Naomi Fitch, and Sigrid Jequier
Division of Medical Genetics and Research Instifute, Montreal Childrens Hospital (P.K., H. P.); Lady Davis Institute, Sir Mortimer B. Davis Jewish General Hospital, (N, F.): and Department of Radiology, Montreal Childrens Hospital (S. J.), Montreal, Quebec, Canada
Two sisters born to consanguineous parents had a syndrome of short stature, acrocephaly, hypertelorism, proptosis, ptosis, down-slanting palpebral fissures, high nose bridge and anteverted nares, short philtrum, cleft palate, micrognathia, abnormal external ears, preauricular pits, sensorineural and conductive deafness, proximally placed first toes and digitalized thumbs, bulbous digits, metatarsus adductus, and pectus excavatum.
Radiological abnormalities included craniosynostosis, increased mandibular angle and antegonial notching of mandible; hypoplastic first metacarpals and metatarsals; hypoplastic distal phalanges; partial duplication of the distal phalanx of the thumb; malformed malleus and incus; tall lumbar vertebrae, increased interpedicular distance, and posterior scalloping; flared iliac wings, narrow supraacetabular regions, acetabular dysplasia, and coxa valga.
Autosomal recessive inheritance is suggested.
Key words acro-cranio-facial syndrome, oto-palato-digital syndrome, autosomal recessive inheritance, ptosis, proptosis, craniosynostosis, cleft palate, deafness, digit abnormalities
Two oto-palato-digital syndromes, OPD I, [Dudding et al, 1967; Langer, 1967; Taybi, 19621 and OPD I1 [Andre et al, 1981; Fitch et al, 1976, 1983; Kozlowski et al, 1977; Brewster et al, 19851 and several autosomal recessive, autosomal dominant, and sporadic acro-facial-dysostosis syndromes [Lewin and Opitz, 1986; Reynolds et al, 19861 have been delineated. These syndromes are characterized by deafness (sometimes
Received for publication February 13, 1987; revision received June 11, 1987
Paige Kaplans current address is Childrens Hospital of Philadelphia, 34th and Civic Center Blvd., Philadelphia, PA 19104.
This is publication 87013 from the McGill University-Montreal Childrens Hospital Research Institute.
Address reprint requests to Dr. Paige Kaplan, Montreal Childrens Hospital, 2300 Tupper Street, Montreal, Quebec, Canada H3H IP3.
0 1988 Alan R. Liss, Inc.
96 Kaplan et al.
Fig. 1 . proptosis, severe ptosis, micrognathia, abnormal auricle, and pre-auricular pit.
Facial profiles: a) patient 1 , 25 wk gestation; b) patient 2, birth. Note flat forehead, beaked nose,
associated with bony abnormalities of the middle ear), cleft palate, micrognathia, telecanthus, variable abnormalities of limbs, and occasionally, short stature and mental retardation. However, there appears to be phenotypic and radiologic variability within these syndromes.
We describe two sisters with cranio-facial and distal limb abnormalities whose condition resembles the acro-facial dysostosis and OPD syndromes in some respects but is sufficiently different to be considered unique. Autosomal recessive inheritance is suggested in this family because the parents are consanguineous and unaffected.
CLINICAL REPORTS Patient 1 (see Fig. la)
A girl was born to a primigravid 22-yr-old mother and 30-yr-old father, who were first cousins, of Sephardic Jewish origin and of normal intelligence. The pregnancy terminated after 25 wk gestation because of abruptio placenta. Weight was 670 gm and length 32 cm. She had hypertelorism (inner canthal distance 1.2 cm: outer canthal distance 4.5 cm), broad nose with high bridge and small nares, cleft palate, three maxillary teeth, micrognathia, low-set ears, a preauricular pit, slightly webbed neck, proximally placed moderately rotated halluces, relatively long 2nd toe (see Fig. 4a), short broad tips of thumbs and fingers with small nails (but no obvious syndactyly), atrial and ventricular septa1 defect, and transposition of the great vessels. She died 26 hr after birth.
The infant had hypertelorism, 11 pairs of ribs, wide interpedicular distance of lumbar spine, and small iliac wings, The thumbs, index, and fifth fingers had short metacarpals and distal phalanges (see Fig. 6a); the fingers showed ulnar deviation. The large toes had very short first metatarsals and distal phalanges; the other toes had immature middle and distal phalanges.
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Fig. 2. Face, patient 2: a) birth, b) 3% yr.
Patient 2 J.D. (M.C.H. 736984)
A girl was born 2 yr later, after a 40-wk gestation. An obstetrical ultrasound examination in midtrimester appeared normal. Delivery was done by Cesarean section because of persistent breech position. The Apgar ratings were 7 at 1 and 5 min. Multiple cranio-facio-digital abnormalities were noted at birth (Figs. lb, 2a, and see 4b): large anterior fontanel, wide sagittal sutures; low-set ears with prominent crus of antihelix and preauricular pits; beaked nose; telecanthus and proptosis; hirsute forehead; cleft palate, micrognathia; broad distal phalanges of the thumbs; fourth fingers as long as the third; rocker-bottom heels and proximally placed, rotated halluces.
Birth weight was 2,540 gm (3rd centile); length was 48 cm (3rd centile) and occipitofrontal head circumference (OFC) was 33 cm (25th centile). By age 2 mo all three growth parameters were below the 3rd centile and have remained below it; at age 3 yr the height age was 21 mo (83 cm), OFC was average for 11 mo (45 cm), and weight was average for 12 mo. The posterior fontanel closed after 8 mo and the large anterior fontanel after 2 yr.
Shortly after birth, J.D. developed upper respiratory obstruction and cor pulmonale which were thought to be due to glossoptosis (as a consequence of the micrognathia and cleft palate) and choanal stenosis. Her respiratory status improved after the insertion of nasal tubes. After the removal of these, there were several periods of upper respiratory tract obstruction. At 18 mo she developed chronic nocturnal respiratory obstruction. With direct laryngoscopy and bronchoscopy examinations no anatomical lesions were found and the obstruction was attributed to neuromuscular incoordination and inability to clear nasopharyngeal secretions adequately. A tracheostomy was done and has remained in place. The nasolacrimal duct was found to have bony obstruction.
In the neonatal period there was a grade II/VI heart murmur, but echocardiography and electrocardiogram were normal at that time.
A congenital paraesophageal hernia was repaired surgically at 6 mo. Gastro- esophageal reflux, demonstrated radiologically, caused recurrent vomiting and possible
98 Kaplanet al.
Fig. 3. Hands: patient 2, showing rotated position and bulbous tip of thumb.
pulmonary aspiration. This necessitated a feeding gastrostomy; episodic vomiting con- tinued in spite of the gastrostomy. Oral feeding was reintroduced at age 3 yr.
Nonprogressive sensorineural and conductive deafness was demonstrated by age 8 mo.
J.D. had global developmental delay particularly in motor function and language. Independent walking was achieved at 3 yr at which time she had begun to say a few words.
At 3 yr (Fig 2b) she was an alert girl with curly brown hair, a flat and high forehead with a horizontal groove above the eyebrows, telecanthus (inner canthal distance 3.4 cm, outer canthal distance 6.8 cm.) with downslanting palpebral fissures, and marked proptosis and ptosis bilaterally. The left optic disc was slightly pale and there was myopia. The nose bridge was moderately high and the nares anteverted, giving the nose a beaked appearance. The philtrum was short, lips thick, and tongue and gums normal. The palate had a narrow midline cleft and the remainder of the palate appeared furrowed. The chin was small and the neck short. The right ear was low set, the superior helices of the pinnae were overturned and thick, the external canals narrow, and there was a bilateral preauricular pit. There was pectus excavatum and small inverted nipples.
The thumbs appeared long with two skin creases but only one interphalangeal joint (Fig. 3). All the digits had bulbous tips. The fingernails were flat and wide. There was bilateral metatarsus adductus and both large toes were proximally placed, thin and curved (Fig. 4c). The toes were curved towards the hallux with deep skin creases, especially distally. There were six arch patterns (on the lst, 3rd, and 4th fingertips).
Chromosomes (G banding, 300 bands) were normal (46, XX).
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Fig. 4. Feet: a) patient 1, b) patient 2, birth, c) patient 2,31/2 yr.
Skull (Fig. 5). At 3'/2 yr, there was acrocephaly due to coronal synostosis. All other sutures of the cranial vault were narrow but open. There were prominent brain markings in the posterior parietal and occipital areas. There was a steep anterior fossa, mild hypertelorism, opacified paranasal sinuses and mastoids, a prominent galea, and the mandibular angle was increased, with a notch in the body of the mandible underlying the tooth bud of the first molar (antegonial notching). The sphenoid sinuses were normal, and the ethmoid and maxillary sinuses opacified due to chronic nasal congestion.
Axial skeleton. Cervical and upper thoracic spine were normal. The lumbar spine showed widening of the interpedicular distance, increased height of the vertebral bodies, posterior scalloping, as well as spina bifida occulta of LA-5 and the sacrum.
Pelvis. There was flaring of the iliac wi