Alternative titles; symbols
ORPHA: 401979; DO: 0112304;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p13.3 | Spondylometaphyseal dysplasia, Megarbane-Dagher-Melike type | 613320 | Autosomal recessive | 3 | PAM16 | 614336 |
A number sign (#) is used with this entry because of evidence that the Megarbane-Dagher-Melki type of spondylometaphyseal dysplasia (SMDMDM) is caused by homozygous mutation in the MAGMAS (PAM16; 614336) gene on chromosome 16p13.
Megarbane et al. (2008) described a consanguineous Lebanese family in which a sister and a brother had chondrodysplasia, developmental delay, severe pre- and postnatal short stature, dysmorphic facial appearance, narrow chest, prominent abdomen, and short limbs. Neonatal radiographs disclosed a bell-shaped thorax, short ribs (some with a cupped end), severe platyspondyly, square iliac bones, horizontal acetabula with medial and lateral spurs, hypoplastic ischia, short long bones, slight widening of the distal femoral metaphyses, and absence of epiphyseal ossification of the knees. The sister died at age 9 months as a result of respiratory insufficiency. A clinical and radiologic follow-up of the boy at age 18 months showed that the axial hypotonia, minor anomalies, and short stature were still present, whereas the bone abnormalities had improved.
Megarbane et al. (2014) reported a second, unrelated consanguineous Lebanese family in which 2 sibs had pre- and postnatal growth retardation, developmental delay, large anterior fontanel, prominent forehead, low-set ears, depressed nasal bridge, short nose, anteverted nares, increased nasal width, prominent abdomen, and short limbs. Radiographs disclosed the presence of wormian bones, platyspondyly, decreased interpedicular distance at the lumbar vertebrae, square iliac bones, horizontal acetabula, trident acetabula, hypoplastic ischia, partial agenesis of the sacrum, ribs with cupped ends, short long bones with abnormal modeling, slight widening of the distal femoral metaphyses, and delayed epiphyseal ossification. Both sibs had severe cardiomegaly and died at around 2 years of age from heart failure.
Moosa et al. (2016) reported a 5-year-old boy, born to distantly related parents of central European descent, with a milder phenotype of SMDMDM. At birth, his weight was -4 SD, length was -5 SD, and head circumference was at the 90th centile. He was referred at age 5 months for assessment of disproportionate short stature (-6 SD). His craniofacial dysmorphic features included macrocephaly, sparse and thin hair, broad forehead with frontal bossing, depressed nasal bridge, short nose with anteverted and wide nostrils, deep philtrum, open mouth with a prominent tongue, and a short neck. His chest was narrow and his abdomen prominent. All limbs were shortened. There was a limitation of movement at the large joints, and he was markedly hypotonic. During the first 2 years of life, he experienced several episodes of respiratory distress and otitis media. At age 2 years, he had delayed development with poor speech and was markedly hypotonic with no head control. Brain and spine imaging showed a narrowed cervical canal and a narrow cord but no intramedullary signal abnormalities. Motor and sensory nerve conduction studies showed bilateral posterior cord compromise in the L5-S1 region. Audiologic examination showed bilateral conductive hearing loss. Cardiac examination was normal, with no evidence of cardiomyopathy. Skeletal radiographs showed significant platyspondyly, narrow chest, abnormal pelvis, and shortened extremities with metaphyseal abnormalities, resembling odontochondrodysplasia (see ODCD1, 184260). However, skeletal radiographs at age 4 years, showed marked improvement, with no residual evidence of platyspondyly.
Megarbane et al. (2008) suggested autosomal recessive inheritance of this disorder based on its occurrence in affected sibs of healthy, consanguineous parents. Mehawej et al. (2014) confirmed autosomal recessive inheritance.
In 4 patients from 2 unrelated Lebanese families with a rare lethal spondylometaphyseal dysplasia, previously described by Megarbane et al. (2008), Mehawej et al. (2014) identified a homozygous missense mutation (N76D; 614336.0001) in the MAGMAS gene. No homozygous variants in the MAGMAS gene were identified by exome sequencing in 14 unaffected Lebanese individuals, and the N76D mutation was not found in 550 Lebanese control chromosomes or in the dbSNP (build 137) database. By reconstructing haplotypes from each exome and performing STR genotyping of data from 1 affected patient in each family, Mehawej et al. (2014) identified a minimal common ancestral homozygous haplotype near the MAGMAS gene, spanning 1.9 Mb on chromosome 16p13.3, which suggested a founder mutation.
By whole-exome sequencing in a 5-year-old boy, born of distantly related parents of central European descent, with a milder form of SMDMDM, Moosa et al. (2016) identified a homozygous missense mutation in the PAM16 gene (Q74P; 614336.0002). The parents were heterozygous for the mutation, which was not present in the ExAC database.
Megarbane, A., Dagher, R., Melki, I. Sib pair with previously unreported skeletal dysplasia. Am. J. Med. Genet. 146A: 2916-2919, 2008. [PubMed: 18925669] [Full Text: https://doi.org/10.1002/ajmg.a.32540]
Megarbane, M., Mehawej, C., Zahr, A. E., Haddad, S., Cormier-Daire, V. A second family with autosomal recessive spondylometaphyseal dysplasia and early death. Am. J. Med. Genet. 164A: 1010-1014, 2014. [PubMed: 24458487] [Full Text: https://doi.org/10.1002/ajmg.a.36372]
Mehawej, C., Delahodde, A., Legeai-Mallet, L., Delague, V., Kaci, N., Desvignes, J.-P., Kibar, Z., Capo-Chichi, J.-M., Chouery, E., Munnich, A., Cormier-Daire, V., Megarbane, A. The impairment of MAGMAS function in human is responsible for a severe skeletal dysplasia. PLoS Genet. 10: e1004311, 2014. Note: Electronic Article. [PubMed: 24786642] [Full Text: https://doi.org/10.1371/journal.pgen.1004311]
Moosa, S., Fano, V., Obregon, M. G., Altmuller, J., Thiele, H., Nurnberg, P., Nishimura, G., Wollnik, B. A novel homozygous PAM16 mutation in a patient with a milder phenotype and longer survival. Am. J. Med. Genet. 170A: 2436-2439, 2016. [PubMed: 27354339] [Full Text: https://doi.org/10.1002/ajmg.a.37823]