Clinical overlap of OFD type IX with Pallister–Killian syndrome (tetrasomy 12p)

Oral-facial-digital (OFD) syndromes are rare and heterogeneous genetic disorders characterized by oral anomalies (oral frenulae, cleft or lobulated tongue, and cleft palate), digital anomalies (clinodactyly, polydactyly, syndactyly, and brachydactyly), and facial dysmorphism [Gurrieri et al., 1992]. Mode of inheritance and associated clinical findings are used to define distinct clinical entities within the OFD community of syndromes. We report here on a patient who showed a OFD phenotype at birth that turned out to have 12p mosaic tetrasomy. Our patient is the first child of unrelated Caucasian parents. Father was aged 31 and mother was 37 at the time of delivery. A cystic hygroma was noted on ultrasound scan at 12 weeks of gestation. Chromosomes on chorionic vili were normal. Birth weight was 4,350 g (þ2 SD), birth length was 50.5 cm (mean), and OFCwas 36.5 cm (þ1 SD). He was hypotonic, with poor sucking, and bilateral hip dislocation. He had a coarse face, high and broad forehead, hypertelorism, dysplastic and posteriorly rotated ears, macrostomia with macroglossia, posterior cleft of the hard palate, multiple oral frenulae, and a ‘‘whistling’’ mouth appearance. Brachydactyly, bilateral partial cutaneous syndactyly of the proximal phalangesofdigits II–V,andbilateral clinodactylyof the fifth finger were present. Second, 3rd, and 4th fingers were overlapping bilaterally. No pigmentary anomaly of the skin was noted at birth. Cerebral MRI, cardiac and renal ultrasound scans, bone X-rays, and standard lymphocyte karyotype were normal. Ophthalmologic examination prompted by the absence of eyes tracking, showed an abnormal ERG but normal fundi. Bilateral conductive hearing loss of 50 db was present. At this stage, a diagnostic of OFD syndrome type IX was suggested (Fig. 1A). He acquired head support at the age of 1 year. At the age of 18 months, he had severe psychomotor retardation.Hewas severelyhypotonic,wasunable to sit upand had severe epilepsy. Heweighted 13,140 kg (mean), was 84 cm tall ( 2SD), andhadanOFCof 48.5 cm ( 2.5 SD). Bilateral temporal alopecia and streaks of hypoand hyper-pigmentation on the trunk and the left leg were obvious and facial dysmorphism, at this age (Fig. 1B,C), was consistent with the diagnostic of Pallister–Killian syndrome (PKS). He developed bilateral cataract that made examination of fundi impossible. Karyotype of skin fibroblasts showed an extra iso-chromosome 12p (46,XY[1]/47,XY,þi(12p)[61]) which confirmed the diagnosis of PKS. OFD syndromes are rare, clinically and genetically heterogeneous disorders [Toriello et al., 1988]. OFD type I or Papillon–Léage–Psaume syndrome and OFD type II or Mohr syndrome have an estimated frequency of 1/50,000 and 1/300,000, respectively. The other OFD are even less frequent and some of them have been described in less than10 cases.NewOFDsyndromes are frequently proposed because of the presence of additional clinical features in patients suspected of having OFD syndrome [Gabrielli et al., 1994; Moran-Barroso et al., 1998; Toriello and Lemire, 2002]. Some authors have emphasized the existence of an overlap between OFD syndromes and other syndromes such as the short rib polydactyly syndromes [Lin et al., 1991; Muenke et al., 1991; Phadke et al., 1999]. OFD type IX is characterized by facial dysmorphism (high forehead with large anterior fontanelle, hypertelorism), oral malformation (cleft lip or palate, multiple oral frenulae or bifid tongue), hands and feet abnormalities (brachy-, clino-, poly-, and syndactyly). The specificity of the OFD type IX comes from the presence of ocular anomalies (microphtalmia and retinal abnormalities including coloboma and retinal pigmentary changes). This syndrome was reported as OFD type VIII by Gurrieri et al. [1992] and subsequently reassigned to type IX by Toriello [1993]. Only five other single cases of OFD type IX have been reported [Jamieson and Collins, 1993; Nevin et al., 1994; Stevens and Marsh, 1994; Sigaudy et al., 1996; Nagai et al., 1998]. Four out of seven patients reported as OFD type IX have had seizures and 6/7 are mildly mentally retarded. Clinical manifestations in these patients have been reviewed by Nagai et al. [1998]. All except the two initial cases, were sporadic. The authors propose an autosomal recessive mode of inheritance for this syndrome. *Correspondence to: Dr. Clarisse Baumann, Unité de Génétique de l’Hôpital Robert Debré, 48, Boulevard Sérurier, 75019, Paris, France. E-mail: clarisse.baumann@rdb.ap-hop-paris.fr