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Editor—Definition of the clinical and genetic features of multiple congenital anomalies/mental retardation syndromes is a difficult task that requires identification of a specific phenotype in multiple patients in the general population and within families.
Case 1 is an 11½ year old female, the first born to healthy, non-consanguineous parents. Her younger male sib is case 2 of this report. She was the term product of a pregnancy complicated by threatened abortion during the first months and by intrauterine growth retardation. Birth weight was 2400 g, length 46 cm, and OFC 31 cm (all below the 3rd centile). Apgar scores were 7 and 9.
She has had feeding problems, failure to thrive, and severe developmental retardation. She walked unassisted at 6 years and she never achieved any language. Metabolic analysis, including amino acidaemia, amino aciduria, MPS screening, and lysosomal and peroxisomal enzymes has been negative.
Sialotransferrin, cholesterol, and 7-dehydrocholesterol were within normal limits. The EEG showed moderate multifocal irritative anomalies, without evidence of clinical seizures. MRI of the brain showed the presence of a large cyst in the septum pellucidum and a cavum vergae. The high resolution karyotype was normal, 46,XX.
Physical examination at 11½ years showed height 120 cm, weight 23 kg, and head circumference 47 cm (all <<3rd centile). She has severe microcephaly, hypertelorism, a flat nasal bridge, a large nose with a large nasal tip, and anteverted nostrils. The mouth is wide and carp shaped. Both the upper and lower lips are thick and everted, giving a coarse appearance to the lower part of the face (fig 1). The permanent teeth have not yet erupted and the deciduous teeth are small and have enamel hypoplasia. The hair is coarse and thick but microscopic examination does not show significant changes. Sweating is normal.
She has scoliosis and dorsal kyphosis. Spinalx rays show irregular end plates of the vertebrae and platyspondyly (fig 2). On lower limbx ray, there are signs of mild metaphyseal dysplasia as well as epiphyseal hypoplasia and diffuse osteoporosis (fig 3). The femoral necks and epiphyses are small and dysplastic (fig4). Hand x rays show mild brachydactyly, most evident in the distal phalanx of the thumbs, and a retarded bone age.
Case 2 is the 9 year old male sib of case 1. He was born at term after an uneventful pregnancy. Amniocentesis showed a normal male karyotype, 46,XY. Birth weight was 2850 g, length 47 cm, and OFC 33 cm. The child showed severe growth and developmental retardation.
He does not walk yet and does not have any language. His behaviour is characterised by continuous psychomotor agitation and instability. He has had three episodes of generalised seizures at 4 years of age and EEG showed important multifocal anomalies. On barbiturate therapy he has been free of seizures since then. MRI of the brain showed a large cyst in the septum pellucidum and cavum vergae (fig 5).
On physical examination, he is small (height 112 cm, weight 12 kg, both <<3rd centile). He has microcephaly (OFC 46 cm, <<3rd centile) and facial dysmorphism identical to that of his sister (fig 1). Mild brachydactyly with stub thumbs was observed.
Skeletal x ray showed changes of a mild spondylometaphyseal dysplasia with epiphyseal involvement (figs 6 and fig 7 7). Abdominal echography was unremarkable and an audiogram was normal. Metabolic analyses were negative and lysosomal enzymes in leucocytes and cultured skin fibroblasts were normal. The high resolution blood karyotype was normal.
The two sibs we have described have a malformation syndrome similar to that observed by Hall and Riggs1 in six out of 14 sibs born to consanguineous parents. Common clinical findings are severe developmental retardation, short stature, microcephaly, and dysmorphic facial features. All the affected patients have mild and non-specific spondyloepiphyseal and metaphyseal changes (table1).
We add a few new features to the spectrum of this rare, autosomal recessive condition. These include EEG abnormalities, midline brain defects such as large cysts of the septum pellucidum and enlarged cavum vergae, and abnormal dentition.
Hall and Riggs1 suggested a metabolic basis for the condition they observed in their patients. Two of the affected sibs had an unusual pattern of biochemical abnormalities in their cultured fibroblasts consisting of decreased β-glucoronidase and increased N-acetyl-β-glucosaminidase activities. However, these preliminary studies have not been confirmed or detailed in further reports. An extensive work up for metabolic disorders has been carried out in our cases but no inborn error of metabolism was discovered.
The skeletal changes present in our cases as well as those described by Hall and Riggs1 involve the spine, the metaphyses, and the epiphyses but are milder and different from those observed in the known forms of spondylometaphyseal and spondyloepimetaphyseal dysplasias.3 4
The facial dysmorphism and the skeletal changes are different from those observed by Hunter5 in his patients with spondylometaphyseal dysplasia. The dental anomalies present in our probands consist of permanence of the deciduous dentition; the panorex, however, shows the presence of all the germs of the permanent teeth. Hypodontia and conical incisors were the changes observed by Raoet al 6 in two sibs with a unique form of spondyloepimetaphyseal dysplasia.
Identification and description of further cases are needed in order to elucidate the aetiology and pathogenesis of the rare autosomal recessive Hall-Riggs syndrome.