Mental Retardation, Microcephaly, Growth Retardation, Joint Contractures, And Facial Dysmorphism

Clinical Features

Bouwes Bavinck et al. (1987) reported a mother and son with an apparently previously undescribed syndrome involving mild mental retardation, microcephaly, short stature, eye defects, hypoplastic and posteriorly rotated low-set ears with overfolded helices, and mild facial dysmorphism, including widow's peak, narrow bifrontal diameter, midface hypoplasia, depressed nasal bridge, thickened alae nasi, and long flat philtrum. Both mother and son had congenital cataracts and epicanthal folds, but the mother also had microphthalmia with microcornea and coloboma of the iris and choroid, whereas the boy had congenital ptosis and detached retina. In addition, the boy had inverted nipples, umbilical hernia, hydroureters with hydronephrosis, and cryptorchidism. Both patients had small hands, and the boy also had hyperextensibility of the finger and toe joints.

Kondoh et al. (2001) reported 2 sisters with an autosomal recessive multiple congenital anomalies/mental retardation (MCA/MR) condition characterized by growth retardation, severe microcephaly, peculiar facies, congenital contractures of the interphalangeal and patella joints, atopic dermatitis, and growth and developmental delay. Although the disorder was similar to the autosomal dominant or X-linked dominant MCA/MR syndrome characterized by microcephaly, eye anomalies, short stature, and mental deficiency reported by Bouwes Bavinck et al. (1987), and to the trichorhinophalangeal syndromes (see 190350), Kondoh et al. (2001) concluded that it was distinct.

Burdon et al. (2009) studied a 4-generation indigenous Australian family in which 5 clearly affected male second-cousins had short stature, developmental delay, cortical cataract noted in childhood, mild facial dysmorphism involving microcephaly, prominent forehead, flat supraorbital ridges, wide nasal bridge, epicanthic folds, and long philtrum, clinodactyly, brachydactyly, thin hair with a high hairline, and a fine erythematous reticular rash over the trunk and cheeks. The 2 mothers of these boys also showed features of the syndrome, including short stature, dysmorphic facial features, and mild cortical cataract, but were significantly less severely affected than their children. Two half-sisters of 1 of the mothers were also possibly affected, and 1 of their sons was likely affected, but with a milder phenotype involving similar facial characteristics and learning difficulty. Although the pedigree was suggestive of X-linked inheritance, a thorough scan of the X chromosome failed to reveal linkage. Burdon et al. (2009) suggested that the phenotype in this family was distinct from that of the family described by Bouwes Bavinck et al. (1987), because the latter displayed no ectodermal features and their ocular phenotype included coloboma.

Mapping

In the large family of Australian Aboriginal descent with congenital cataract, dysmorphism, and ectodermal features, previously described by Burdon et al. (2009), Hattersley et al. (2010) performed genomewide linkage analysis and found linkage to the telomere of chromosome 1. Recombination events defined a 48.7-cM (25.6-Mb) critical region between the SNPs rs966321 and rs1441834 on chromosome 1p36.32-p35.3. The authors noted that patients with terminal or interstitial deletions of chromosome 1p36 (607872) exhibit a spectrum of features that overlap with those of this family, including conductive hearing loss.

Molecular Genetics

In a large family of Australian Aboriginal descent with congenital cataract, dysmorphism, and ectodermal features mapping to chromosome 1p36.32-p35.3, previously described by Burdon et al. (2009), Hattersley et al. (2010) analyzed the candidate genes ZBTB17 (604084), EPHA1 (179610), and EPHA2 (176946) but did not detect any mutations.