The portal for rare diseases and orphan drugs

The exact prevalence of DONSON-related microcephaly associated with short stature and limb abnormalities spectrum is unknown; slightly more than 50 patients have been reported to date. The Microcephaly Micromelia syndrome is more frequent in a First Nations population in northern Saskatchewan, Canada.

Presentation is with intrauterine growth retardation or at birth with low birth weight (- 2.9 SD on average), short birth length (-3.7 SD) and congenital microcephaly (-5.1 SD). Craniofacial features include broad nasal bridge, short palpebral fissures, microstomia, and micrognathia. Congenital limb abnormalities vary in severity and involve both upper and lower limbs, with upper limbs more severely affected. The mildest malformations are clinodactyly, camptodactyly, syndactyly, or brachymesophalangia and are mainly associated with the clinical subtype, microcephaly-short stature-limb abnormalities syndrome. Severe malformations are usually associated with microcephaly-micromelia syndrome. Limbs are short with hypoplasia of the radius, ulna, thumb and/or Vth finger. Lower limbs may be underdeveloped (fibula, patella, I and Vth toes). Feet may be clubbed. Perinatal mortality is very high in the microcephaly-micromelia syndrome due to respiratory failure. Subglottic stenosis, diaphragmatic hernia and choanal atresia have been described in some patients with short stature and milder limb abnormalities. Gyration is usually simplified on brain imaging. Intellectual abilities ranges from normal to moderate intellectual disability.

The disorder is due to bi-allelic mutations in the downstream neighbor of SON, DONSON (21q22.11), a replisome component that stabilizes forks during genome replication.

Diagnosis is based on clinical signs. Congenital microcephaly, short stature combined with at least minor, I and Vth finger malformations or even hypoplasia/malformations of the upper and/or the lower limbs. Targeted sequencing and whole exome sequencing identify coding variants responsible for the disease. However pathogenic noncoding variants may only be identified using integrative transcriptomic and genomic sequencing.

There is considerable clinical overlap with Fanconi anemia (FA), and several patients were originally diagnosed with FA. Additional differential diagnosis includes VACTERL, Meier Gorlin syndrome, and Taiby Linder syndrome.

The disorder may be identified prenatally using ultrasound. However, absence of microcephaly and limb malformation does not rule out the diagnosis, especially for the mildest types. Once the molecular diagnosis has been established in a family member, prenatal diagnosis is possible.

If both parents are heterozygous for a pathogenic DONSON variant, the risk of having an affected child is 25% for each pregnancy.

Treatment is symptomatic. Adequate nutritional intake, using naso-gastric tube-feeding if needed, should be ensured during the first years of life. Epilepsy is treated with antiepileptic medication. Physiotherapy and speech therapy may be beneficial.

Life expectancy is much reduced in microcephaly-micromelia syndrome; all reported patients died, mostly in the perinatal period. In milder forms, the prognosis and quality of life will depend on the severity of the limb malformations and the intellectual disability.