The spondyloepiphyseal dysplasias (SED) are a heterogeneous group of conditions with predominant involvement of the vertebral bodies and the proximal epiphyses of the long bones. Affected individuals may have an abnormally short thighbone (femur), unusually short hands and fingers, mild short stature, a waddling gait, and/or pain in the hips and knees. Recessive MED (rMED) has relatively mild signs and symptoms, which include joint pain beginning in late childhood, malformations of the hands, feet and knees, and abnormal curvature of the spine (scoliosis). About 50% of affected individuals have some abnormal finding such as clubfoot, cleft palate, clinodactyly, or cystic ear swelling, at birth.
The incidence of rMED is unknown. Diagnosis of the disorder involves radiographic studies. In the initial stage of the disease, radiographs of the skeleton reveal a delay in epiphyseal ossification. Later, small and irregular epiphyses appear, most pronounced in the hips and knees. In adulthood, the disorder is characterized by normal to mild short stature and early-onset osteoarthrosis. Flat epiphysis with early arthritis, mild brachydactyly, and double layered patella are typical findings of the disease.
On the other hand, autosomal dominant multiple epiphyseal dysplasia (MED or EDM) comprises a group of hereditary chondrodysplasias characterized by major anatomical abnormalities of the long tubular bones. Common clinical findings include: waddling gait, shortened extremities, genu valgum, and early onset degenerative joint disease.
Al-Gazali and Bakalinova (1998) described a multiply consanguineous Omani family in the UAE, in which four out of the 13 children presented with symptoms of macrocephaly, frontal lobe atrophy, and distinctive facial appearance. The first case was a boy. CT scan of his brain in his few months showed slightly dilated lateral ventricles. He had a squint in the left eye, which was operated upon. His developmental milestones were delayed, and by the age of 10-years, he showed increased swelling of the upper and lower limbs, particularly around the elbows, macrocephaly with frontal bossing, hypertelorism, flat malar regions, low set ears, short neck, and slight pectus excavatum. All joints were prominent, and there was non-pitting edema of lower limbs. Both testes were undescended. Skeletal survey showed a big skull with dysplasia of the epiphyses of the long bones. The patient's sister showed the same dysmorphic features. Non-pitting edema in her case involved the entire lower limbs, including the knee and ankle joints. Their brother showed similar symptoms too. CT scan of his brain showed atrophic changes in the frontal lobe. The skeletal survey showed irregular mineralization of the tibial epiphyses and irregularities in the endplates of the lower femoral epiphyses. The fourth case in the family was a boy, the seventh child of his parents. All his siblings, including his twin, were normal. The patient was dysmorphic at birth, with a wide anterior fontanelle, large head, a small subcutaneous nodule on the lateral end of the left orbit (possibly a lipoma), a large right inguinal hernia, a left hydrocele, and a small umbilical hernia. CT scan showed advanced atrophy of the frontal and temporal lobes with moderately enlarged CSF space and mild dilation of the lateral ventricles. Keeping in mind the consanguinity, normal parents, involvement of both sexes, and the combination of features in these children, Al-Gazali and Bakalinova (1998) suggested that these cases represent a previously undescribed autosomal recessive syndrome.
Three years later, Bayoumi et al. (2001) described linkage analysis in the Omani family of Al-Gazali and Bakalinova (1998). The pedigree consisted of 13 children in 2 sibships of a multiply consanguineous family. Four of the children were affected. The presenting features were dysmorphic facies, genu valgum, and swelling of the joints. All four children were of normal stature with head circumference above the 90th percentile. The children had frontal bossing, hypertelorism, flattening of the malar region, and low-set ears. The neck was short, and pectus excavatum, spindle-shaped fingers with interdigital soft-tissue webbing, and clinodactyly were present. All had genu valgum with prominent joints, particularly the wrist, knee, and ankle joints. Skeletal surveys showed dysplasia of the epiphyses of the long bones which was more severe in the lower limbs than the upper limbs. In two children, brain imaging showed agenesis of the corpus callosum and frontotemporal brain atrophy. Bayoumi et al. (2001) performed linkage analysis on the family by the amplification microsattelite markers that were pooled, electrophoresed, and scored for homozygosity by using two- and multi-point lod scores, while assuming recessive inheritance with full penetrance and equal allele frequencies for each marker. All genotypes were checked for Mendelian segregation, and haplotyping was performed. Polymorphism of the VNTR in the chondroitin sulphate attachment sites in the human aggrecan proteoglycan gene (ACG) was examined in all family members by PCR amplification of 600-2300 bp fragments. By agarose gel electrophoresis, 57 bp repeats were identified (VNTRs ranged between 27 and 29 repeats in the family). Single nucleotide polymorphism in the coding exons 2 to 18 (except 4 and 12) were examined by temperature modulated liquid chromatography and a high resolution matrix to distinguish hetero- from homo-duplex PCR-amplified DNA strands in heterozygotes. Exon 6 was also sequenced. Linkage of the disease to the long arm of chromosome 15 was detected by scoring markers for homozygosity by descent. Two-point lod scoring had identified two markers at loci D15S127 and D15S130 and multipoint lod scoring had identified a marker at locus D15S1014. All patients were found to be homozygous by descent, while the unaffected siblings were heterozygous for a region (32.2 cM) between markers at loci D15S205 and D15S966. As the aggrecan-1 gene (ACG 1) lies in chromosome 15 within the identified homozygous region, it was examined for involvement. All patients were homozygous while all unaffected sibs were heterozygous for allele 27 in exon 12, but since one unaffected sibling was homozygous for this allele, it was excluded. Further exclusion of this gene was documented as three out of four patients were heterozygous for a polymorphism in exon 6 (c.831C>G). With exclusion of the aggrecan gene, the homozygous region was reduced to 28.1 cM as it was now bounded by AGC 1 marker at locus D15S1046 and the marker at locus D15S966. Bayoumi et al. (2001) described another candidate gene, although an unlikely one, in proximity to this region, MAN2X, and recommended further studies in order to prove or exclude its involvement in this syndrome.
In 2002, Eyre et al. re-investigated the family of Al-Gazali and Bakalinova (1998) and Bayoumi et al. (2001) and genotyped DNA of all family members with the markers D15S979 and D15S202 that flank the AGC1 locus, which was shown to define the proximal limit of linkage to the disorder. Both D15S979 and D15S202 were fully informative in the family and no recombination events were detected between these markers and the disorder, thus, confirming the position of AGC1 proximal to D15S979. Eyre et al. (2002) confirmed the observation of Bayoumi et al. (2001) that AGC1 is an unlikely candidate gene for the disease in their patients as well as in another group of patients with an autosomal dominant form of spondyloepiphyseal dysplasia called SED type Kimberley (SEDK). In 2012, Ali et al. identified a c.3179A>G missense mutation in the family. The mutation was found in all affected patients in a homozygous state, while it was in a heterozygous state in the parents and some siblings.
[See also: Oman > Al-Gazali and Bakalinova, 1998].