Microcephalic Osteodysplastic Primordial Dwarfism, Type I

A number sign (#) is used with this entry because microcephalic osteodysplastic primordial dwarfism type I (MOPD1), or Taybi-Linder syndrome, is caused by homozygous or compound heterozygous mutation in the RNU4ATAC gene (601428), encoding a small nuclear RNA (snRNA) component of the U12-dependent (minor) spliceosome, on chromosome 2q14.

Description

Microcephalic osteodysplastic primordial dwarfism type I is a severe autosomal recessive skeletal dysplasia characterized by dwarfism, microcephaly, and neurologic abnormalities, including mental retardation, brain malformations, and ocular/auditory sensory deficits. Patients often die in early childhood (summary by Pierce and Morse, 2012).

Clinical Features

Majewski and Spranger (1976) described a form of brachymelic primordial dwarfism that resembled Seckel syndrome (210600) except for abnormal body proportions and short limbs; Seckel syndrome patients have normal proportions. The pelvis was low, broad, and 'dysplastic' with lack of formation of the acetabulum. The humeri and femora were short, bowed, and broad with rather unremarkable metaphyses. Haan et al. (1989) reported a case with features similar to those described for both type I and type III osteodysplastic primordial dwarfism. The case resembled that reported by Winter et al. (1985) and one pictured by Wiedemann et al. (1982). In light of these 3 cases, Haan et al. (1989) suggested that types I and III are the same entity because of similarities in the changes in the brain and in bone. Meinecke et al. (1991) gave further information on the patient reported by Wiedemann et al. (1982). The clinical and radiologic findings supported the hypothesis of Winter et al. (1985) that types I and III are one disorder. Haan et al. (1989) also suggested that this disorder is the same as that reported by Taybi and Linder (1967) as cephaloskeletal dysplasia. The brain in the case of Haan et al. (1989) showed agenesis of the corpus callosum and marked lissencephaly. Van Maldergem et al. (1990) observed this disorder in a newborn male born to Turkish first cousins. Corneal clouding was present. Meinecke and Passarge (1991) described a boy who survived to age 5.5 years and his more severely affected younger sister who died at the age of 6 months. Neuropathologic studies in the girl showed marked micrencephaly with severely hypoplastic, poorly gyrated frontal lobes, and absent corpus callosum.

Taybi and Linder (1967) described brother and sister, of Italian extraction with first-cousin parents, who had low-birth-weight dwarfism, dysplasia of the osseous skeleton including the skull, and microcephaly. They died at ages 1 month and 1 year, respectively. Autopsy was done in both. Extensive malformation of the brain was present. Thomas and Nevin (1976) described the same disorder in 2 males who died in early infancy; their parents were normal and unrelated. Lavollay et al. (1984) described a single case thought to have the same disorder. Dwarfism, microcephaly, facial dysmorphism, and skeletal abnormalities with radiologic changes in the skull and many other bones were described. Severe cerebral atrophy with neurologic abnormality was responsible for death in the first year of life. Taybi (1992) called attention to the reports by Maroteaux and Badoual (1990) and others.

Sigaudy et al. (1998) reported 4 new cases of microcephalic osteodysplastic primordial dwarfism I, or Taybi-Linder syndrome, and characterized the condition as including severe microcephalic dwarfism with short limbs and dislocated hips and elbows, skin abnormalities, and sparsity of hair and eyebrows. Malformations of the central nervous system, such as abnormalities of migration, heterotopias, partial or complete agenesis of the corpus callosum, hypoplastic frontal lobes, and vermis agenesis, had been reported. Radiologic abnormalities include retarded epiphyseal maturation, cleft vertebral arches, platyspondyly, horizontal acetabular roofs, and short long bones with enlarged metaphyses. Autosomal recessive inheritance had been suggested and was confirmed by the cases reported by Sigaudy et al. (1998), as 2 were born to consanguineous unions and 2 were sibs.

He et al. (2011) studied 14 cases of MOPD1 in 9 nuclear families from the Ohio Amish population. The parents in all 9 nuclear families were related to each other and to the parents of the other families in multiple ways. The Amish MOPD1 phenotype consists of severe intrauterine growth retardation (mean -5.8 SD, range -3.3 to -7.9 SD), microcephaly, severe central nervous system neuronal migration abnormalities, absent or very sparse hair, dry and aged-appearing skin, facial dysmorphism, multiple joint contractures and dislocations, skeletal anomalies, and average life expectancy of 8.5 months (range 2.5 to 18 months). He et al. (2011) also studied an Australian case from distantly related Maltese parents and 2 German cases from unrelated families, 1 a new case and 1 previously reported by Klinge et al. (2002). The phenotype of the Australian case was identical to the Ohio Amish phenotype. The 2 German cases shared basic similarities with the Amish phenotype except for a decreased degree of intrauterine growth retardation (-2.6 to -3.6 SD) and life expectancy (survival past 3 years).

Edery et al. (2011) reported 8 families with MOPD1. Affected members from 5 of these families were homozygous for a 51G-A mutation in RNU4ATAC (601428.0001). The first patient was a male born to first-cousin parents of Algerian origin. His face was round with ridged metopic suture, small anterior fontanel, sloping forehead, bulging eyes, small ears, small chin, and short neck. He had dry skin and sparse, thin hair. Limbs were short with brachydactyly. He had left cryptorchidism and micropenis. X-rays showed thick, bowed long bones and markedly delayed epiphyseal ossification. Cerebral MRI at 1 month of age showed brain hypoplasia, neuronal migration defects, arachnoid cyst, and agenesis of the anterior corpus callosum. He died unexpectedly at 11 months of age. His brother had similar brain abnormalities. All birth parameters were less than one-third percentile. He died unexpectedly at age 10 months. The child from the second family was born to first-cousin parents of Turkish origin. At 38 weeks' gestation, her birth weight was 1060 grams, length 31 cm, and head circumference 23.4 cm. Clinical examination and bone x-rays were typical of MOPD1. She had a unilateral polycystic dysplastic kidney and small ventricular septal defect. Brain ultrasound showed microlissencephaly and corpus callosum agenesis. After 1 year of age she suffered from recurrent unexplained episodes of fever and died of respiratory insufficiency at 14 months of age. The patient from the third family, previously described by Sigaudy et al. (1998), presented with typical features of MOPD1. She died at 7 months during an infectious illness. Family 4 had 3 affected offspring, born to distantly related parents of Moroccan origin. The first child, a female, showed intrauterine growth retardation, microcephaly, and corpus callosum agenesis. X-rays showed typical MOPD1 features. Postnatal brain ultrasound showed abnormal gyration. She died at 13 months of age after gastroenteritis. Her sister had severe intrauterine growth retardation and typical MOPD1 dysmorphic features, limb anomalies, and bone x-rays. Brain MRI showed microcephaly, agenesis of the posterior corpus callosum, abnormal gyration with marked pachygyria of the frontal lobes, and mild hypoplasia of the cerebellar vermis. She died at 28 months of age. During the mother's third pregnancy, prenatal diagnosis confirmed a fetus with haplotypes similar to those of the previously affected children. The pregnancy was terminated. Autopsy showed a male fetus with microcephaly, enlarged neck, sloping forehead, anteverted nares, short and rounded philtrum, and micrognathia. The child from the fifth family, born of unrelated Indian parents, had oligohydramnios and severe intrauterine growth retardation observed at 20 weeks' gestation. Birth weight was 1300 grams. In addition to typical MOPDS1 features, he had bilateral preaxial polydactyly with bilateral hypoplastic thumbs. Bone anomalies included unilateral bifid first metacarpal. Brain MRI showed complete agenesis of corpus callosum, polymicrogyria, and colpocephaly.

Pierce and Morse (2012) reported a sister and brother, born of unrelated Caucasian parents, with MOPD1. They had microcephaly, dysmorphic features, primordial dwarfism, and skeletal dysplasia consistent with the diagnosis. The patients had axial hypotonia with appendicular hypertonia and spasticity. Pale hypoplastic optic discs, poor visual function, and sensorineural hearing loss were also noted. In the first months of life, the patients developed progressively intractable seizures evolving to hypsarrhythmia. Each also showed endocrine abnormalities, such as central hypothyroidism, diabetes insipidus, and increased aldosteronism; the boy had hypogonadism. Brain imaging showed hypoplastic cerebrum, paucity of cortical gyri, pachygyria, periventricular heterotopia, thin corpus callosum, cerebellar hypoplasia, and delayed myelination. One patient had a sacral dimple and tethered cord. Both sibs had profound global developmental delay, and the girl died of respiratory failure at age 4 years.

Mapping

Lander and Botstein (1987) proposed a method, referred to as 'homozygosity mapping,' that consists of searching for a region of the genome that is autozygous in inbred individuals affected by a given disease. They showed that, to quantify the evidence of linkage provided by such a region, a lod score could be computed for the marker observations by comparing the likelihood of being at the disease locus with the likelihood of being at a random point on the genome. Calculation of the latter likelihood requires that, for each affected inbred individual, the chance of having 2 alleles identical by descent (IBD) at a locus randomly sampled on the individual's genome is known. By definition, the latter value is the individual's inbreeding coefficient (F). Efficient algorithms based on the known genealogy are available for computing F. However, information on genealogy may not be accurate or may even be lacking, especially for populations in which marriages between relatives are very frequent, making relationships very complex. Leutenegger et al. (2006) proposed to estimate F from each individual's genomic information as presented by Leutenegger et al. (2003) and to use this genome F to control for parental relationships in the lod score computation. To perform linkage analysis when parental relationships are poorly known, they introduced a new homozygosity mapping statistic, FLOD. This statistic allowed the inclusion of inbred patients in homozygosity mapping without having any knowledge of their genealogy. Leutenegger et al. (2006) applied this approach to the study of 4 inbred Taybi-Linder syndrome patients, including 2 sibs, originating from the Mediterranean region: Algeria, Turkey, and Morocco. Application of these methods identified an autozygous candidate region on 2q14.2-q14.3. The work illustrated the mapping of a gene with the use of a single key patient with no genealogic information.

He et al. (2011) used genomewide homozygosity mapping to map the MOPD1 phenotype to chromosome 2q14.2.

Edery et al. (2011) refined the interval identified by Leutenegger et al. (2006) to 3.19 Mb by genotyping additional unaffected members from the previously studied families and a new consanguineous Moroccan family. No common haplotype appeared to be shared by patients in these families, ruling out a single founding effect.

Molecular Genetics

He et al. (2011) identified 4 different mutations in the RNU4ATAC gene resulting in MOPD1 in the Ohio Amish population, 2 German families, and 1 Australian family of Maltese descent. Functional assays showed that these mutations caused defective U12-dependent splicing. Endogenous U12-dependent but not U2-dependent introns were found to be poorly spliced in MOPD1 patient fibroblast cells. The introduction of wildtype U4atac and snRNA into MOPD1 cells enhanced U12-dependent splicing.

Edery et al. (2011) independently identified 4 mutations in the RNU4ATAC gene responsible for MOPD1. All mutations occurred in the 5-prime stem loop structure and affected the function of the minor spliceosome.

Abdel-Salam et al. (2012) reported 2 Yemeni sibs and an Egyptian boy with MOPD1 who were homozygous and compound heterozygous, respectively, for mutations in the RNU4ATAC gene (601428.0002 and 601428.0008-601428.0009). The authors noted that the 3 patients had a relatively milder phenotype than previously reported MOPD1 patients: brain findings included metopic suture synostosis, a simplified gyral pattern, small corpus callosum, and reduced size of the frontal lobe, and their developmental milestones were only mildly delayed for age. The sibs died of encephalitis at 18 months and 34 months of age; the Egyptian boy had no history of repeated infections and was alive at 20 months of age. Abdel-Salam et al. (2012) suggested that the MOPD1 phenotypic spectrum is wider than previously defined.

Nomenclature

Three types of osteodysplastic primordial dwarfism had been defined and distinguished from Seckel syndrome by Majewski and Goecke (1982) and Majewski et al. (1982, 1982). There is a consensus that the osteodysplastic primordial dwarfism types I and III of Majewski and Goecke (1982) and Majewski et al. (1982) and Taybi-Linder cephaloskeletal dysplasia are variations of the same entity. The reclassified osteodysplastic primordial dwarfism type III is discussed in entry 210730.