A Newly Recognized Syndrome With Characteristic Facial Features, Skeletal Dysplasia, and Developmental Delay

INTRODUCTION

We describe what we consider to be a novel syndrome in seven male patients from six different families, with skeletal dysplasia, characteristic facial features, and developmental delay. The osseous findings include patellar dislocation, short tubular bones, mild metaphyseal changes, brachymetacarpalia with stub thumbs, short femoral necks, shallow acetabular roofs and platyspondyly. The facial features comprise a flattened midface with broad nasal bridge, cleft palate or bifid uvula, and synophrys. All of the patients demonstrated pre-school onset of a cognitive developmental delay with a shortened attention span. Some of the cognitive delay was masked by a warm and engaging personality (see Figs. 1–4).

The first four patients have been followed in the A. I. duPont Hospital for Children Skeletal Dysplasia Program. Two siblings, Patients 5 and 6, are followed in Oakland (Kaiser Permanente Hospital), and Patient 7 is followed in Los Angeles (Kaiser Permanente Hospital). Skeletal surveys were obtained from all of the patients and carefully examined by the senior authors (RL, CS).

DISCUSSION

We present seven male patients from six families of different ethnic backgrounds, with skeletal dysplasia, characteristic facial features, and developmental delay. Craniofacial and skeletal findings are summarized in Tables I and II. The fact that all seven of our patients are males raises the possibility that this syndrome may be X-linked. Although the mother of Patient 7 is mildly short, it does not appear that the biological mothers share a phenotype with these boys, further suggesting possible X-linked recessive. Certainly, autosomal recessive inheritance also remains a possibility. Each patient had normal chromosomal analyses and a single patient had a normal BAC Array CGH. All patients had normal CANT1 sequencing.

Body habitus was similar in all the patients: mildly disproportionate short stature with shortened limbs of predominantly rhizomelic type and a short supple neck. The most important skeletal finding was patellar tracking abnormalities, present in all cases. Patellar dislocation was bilateral and chronic although in Patients 5 and 6 the patellae were at times, in place clinically and at other times were dislocated. Patellar realignment procedures were required in Patients 1, 2, 3, and 4. Small thorax, pectus carinatum, and antero-lateral rib flaring was found in five of seven (71%) patients. Increased ligamentous laxity of the extremities hands with brachydactyly was present in all and cutaneous syndactyly appeared in three of seven (43%) of the individuals. Patients 1, 4, and 7, showed lack of extension, pronation, and supination of the forearms, in addition, Patient 4 had bilateral subluxed radial head.

All seven patients have strikingly similar craniofacial features including a flattened midface and depressed nasal bridge. Bifid uvula and/or cleft palate were found in four of seven (57%) patients. Three of seven (43%) patients had microcephaly. Although minor ophthalmologic problems were present in Patient 1 (astigmatism) and Patient 6 (esotropia, hypertropia, and strabismus), there did not appear to be a pattern of involvement; Patient 1 had also mild bilateral conductive hearing deficit. None of the patients had cardiac issues. As additional dysmorphic facial features, Patient 7 had upturned nares and a left “cauliflower ear.” Patient 1 was noted to have a low posterior hair line with a webbed neck. Patients 1, 4, 5, 6, and 7 had epicanthal folds present at a younger age and over time, these gradually resolved. Patients 1, 2, 4, and 7 were noted to have synophrys on at least one examination although several families report shaving this feature.

Learning disability with speech delay are common intellectual impairments among these individuals and cognitive delays became evident at pre-school ages. Except Patients 2 and 3, all had variable motor delays. All of the subjects had speech therapy and special education programs. Despite their intellectual limitations, all seven patients have a warm, easy going and engaging personality. Their social and engaging nature tends to mask their intellectual disabilities. The patients have a rather low, gravelly voice.

Skeletal radiographic surveys were carefully examined and non-specific brachymetacarpalia was universal (see Fig. 2). Most had stub thumbs. Long bones presented mild metaphyseal widening, and relatively normal to minimally flattened epiphyses. The pelvis had a Desbuquois-like appearance, especially in the younger patients, showing short femoral necks and flat acetabular roofs. Valgus and windswept deformities in the knees were frequently seen. Laterally displaced patellae appeared upon weight bearing (see Figs. 3 and 4). The two brothers, Patients 5 and 6, had vertebral end plates indentations on thoracic spine radiographs (see Fig. 4). None had cervical spine instability or odontoid hypoplasia. The skeletal findings in our patients, such as the metaphyseal widening, epiphyseal flattening, and platyspondyly, are suggestive of a mild spondylo-epi-metaphyseal dysplasias (SEMD).

Taken together we do not consider this constellation of features matches with any described syndrome. There are two major skeletal dislocation syndromes in the differential, Desbuquois dysplasia (DBD) and Larsen syndrome [Lachman, 2007; Warman et al., 2011]. Desbuquois et al. [1966] and later other authors have described a unique form of micromelic chondrodysplasia with multiple joint dislocations, round face, midface hypoplasia, glaucoma, and cardiac defects. Among the skeletal findings of DBD were: advanced carpal and tarsal bone ages, supernumerary carpal bones, short tubular bones with delayed epiphyseal ossification, wide metaphyses, prominence of the lesser trochanters, flat acetabular roofs, and osteoporosis [Desbuquois et al., 1966; Piussan et al., 1975; Gillessen-Kaesbach et al., 1995]. This condition was later proved to be autosomal recessive, and to be clinically and genetically heterogeneous [Le Merrer et al., 1991; Faivre et al., 2004a,b]. Specifically the classic radiographic hand profile with phalangeal dislocation, a supernumerary bone distal to the second metacarpal, delta shape phalanges, and bifid thumb phalange was absent in 16 out of 35 patients, leading to the distinction between DBD, Type I or classic type and DBD, Type II with normal hands [Faivre et al., 2004a]. Kim et al. [2010] have subsequently broadened the clinical spectrum, adding a third type of DBD with distinct hand/feet anomalies from groups 1 and 2, advanced carpal age, short metacarpals, elongated phalanges, and normal intelligence [2010]. Recently, mutations in the calcium-activated nucleotidase 1 gene (CANT1) that encodes, an extracellular protein expressed in chondrocytes and implicated in endoplasmic reticulum metabolism have been determined to cause DBD types 1, 2, and Kim [Huber et al., 2009; Faden et al., 2010; Furuichi et al., 2011].

Some of the clinical and radiographic findings in our patients, such as the short femoral necks and flat acetabular roofs, advanced bone age and patellar dislocations do resemble DBD, or a Desbuquois-like phenotype. In fact, Patient 4 had carried a diagnosis of DBD during infancy and early childhood. Early bone age surveys reported advanced bone age in carpals, osteoporosis, and prominent lesser trochanters. Patient 3 showed advanced carpal bone age, and “monkey wrench” appearance of proximal femurs. We have not found the typical hand anomalies of Desbuquois including supernumerary carpal and tarsal bones, extra center of ossification distal to the second metacarpal bone, bifid distal or proximal thumb phalanges, delta phalanges, nor fingers dislocations. None of our patients had coronal vertebral clefts or clubfoot. Heart defects or glaucoma were not seen (see Table III). All of our patients were screened for mutations in the CANT1 gene which have been previously described to cause DBD. Sequencing of the coding regions of exons 3, 4, and 5 were normal, and no deletions were identified in the 5′-UTR-exon 1 region of the gene. Interestingly, Faivre et al. [2004b] described three patients with DBD in whom linkage to the 17q25.3 CANT1 region was excluded and Furuichi et al. [2011] described one patient with DBD and normal hands in whom CANT1 sequencing failed to demonstrate any mutations. It is possible that these individuals, whom were each described to have DBD with normal hands, may have the syndrome which we are describing in this cohort.

Another congenital dislocation syndrome is Larsen syndrome. Larsen syndrome is characterized by multiple congenital dislocations of the large joints and typical facial features. Some common findings are shared with our patients, such as the stub thumb, and midline defects, like cleft palate and bifid uvula [Larsen et al., 1950; Latta et al., 1971]. Patient 4 presented with bilateral radial head subluxation. However none of our patients had the “dish face” appearance, nor the typical congenital femora and tibiae anterior dislocation, or congenital hip dislocation. Cervical kyphosis and thoracolumbar scoliosis were not found in our series either [Sakaura et al., 1976]. Furthermore, patients with Larsen syndrome do not have marked learning disabilities.

The differential diagnosis for our patients includes variants of SEMD [Cormier-Daire, 2008]. Although the clinical entity of SEMD with joint laxity has been well characterized [OMIM 271640; Tsirikos et al., 2003], those patients often have congenital heart disease, progressive kyphoscoliosis, and skin hyperelasticity, and do not demonstrate intellectual disability. Furthermore, the entity SEMD with multiple dislocations [OMIM 603546; Hall et al., 2002] also appears distinct from our cases in that those patients have different facial features, do not demonstrate intellectual disability, and have characteristic long metacarpal bones and phalanges (“leptodactyly”) [Kim et al., 2009]. It appears that SEMD with joint laxity is an autosomal recessive disorder, whereas clinical evidence supports an autosomal dominant pattern of inheritance for SEMD with multiple dislocations.

CONCLUSION

We present a series of seven male patients from six families of different ethnic backgrounds with skeletal dysplasia, characteristic facial features, and developmental delay. We posit that these individuals have a newly recognized syndrome characterized by the described features. It appears possible that several other patients with a similar phenotype have been described in the literature as having a CANT1 negative form of DBD or a Desbuquois-like phenotype. Given the family information available for each patient, we are suspicious that the constellation of findings reported herein could be an X-linked recessive syndrome. Further studies to identify the molecular basis of this condition are ongoing.