Mesomelia-synostoses syndrome (ORPHA:2496)
A rare syndromic osteochondrodysplasia characterized by progressive mesomelia and bony fusions in the extremities, distinctive facial gestalt, and soft palate anomalies.
Epidemiology
To date, less than 10 patients have been reported.
Clinical description
In contrast to other mesomelic dysplasias, Mesomelia-synostoses syndrome (MSS) has a slowly progressive clinical course, at least until skeletal growth ceases. Symmetric acral synostoses and extra-skeletal involvement are distinguishing features. Craniofacial phenotype includes downslanted palpebral fissures, eyelid ptosis, telecanthus, soft palate hypoplasia and absent or hypoplastic uvula with hypernasal speech, and tall and mildly retruded chin. Skeletal anomalies comprise short stature, progressive non-inflammatory movement restriction of large and small joints, mesomelic bowing and shortening in upper and lower limbs, congenital or postnatal joint deformities (clino- and camptodactyly of fingers and toes, ulnar deviation of the wrists, radial head subluxation, genu valgum, pes equinus), and apparent postaxial brachydactyly of fingers and toes with sparing of the first two rays. MSS patients may present with complex congenital heart defects, congenital hydronephrosis, short umbilical cord and redundant skin on the umbilical stump, myopia, short sublingual frenulum and progressive hearing loss. Cognitive development is normal. Radiological anomalies include shortening of metacarpals and metatarsals II-III to V, synostoses between the bases of these bones or between metacarpals and metatarsals II to V and adjacent carpal/tarsal bones, partial fusion of carpal and tarsal bones, and mild medial bowing of distal femur.
Etiology
Non-recurrent deletions of two contiguous genes in 8q13.2q13.3, SULF1 and SLCO5A1, ranging in size from 582 to 738 Kb, have been found in six patients. Monoallelic expression of SULF1 without microdeletion has been reported in one patient. The exact mechanism that causes MSS is currently unclear, but it is likely that other genetic or epigenetic alterations besides the haploinsufficiency of one of the two genes contribute to the MSS phenotype.
Diagnostic methods
Diagnosis is based upon clinical and radiological findings. Copy-number losses involving SULF1 and SLCO5A1 may be detected by molecular analyses (e.g. genomic arrays).
Differential diagnosis
Radiologically, Kantaputra type mesomelic dysplasia shows very similar acral anomalies. Other rare mesomelic dysplasias (e.g. Langer or Fryns type mesomelic dysplasia) are not associated with synostoses. Syndromes with synostoses (e.g. Nievergelt syndrome, multiple synostoses or proximal symphalangism syndromes, Osebold-Remondini syndrome) show different patterns of associated anomalies.
Antenatal diagnosis
Both invasive prenatal diagnosis or preimplantation genetic diagnosis of 8q13 microdeletion are available for at-risk couples. Fetal ultrasound may reveal hypoplastic radii and ulnae, brachydactyly, unusual gaps between fingers or toes, clubfoot, micrognathia, and congenital heart defect or hydronephrosis, if present.
Genetic counseling
MSS is transmitted as an autosomal dominant trait. When a parent is affected, recurrence risk is 50%.
Management and treatment
Early diagnosis allows for more effective care: the progressive nature of skeletal and joint involvement deserves regular follow-up and treatment by orthopedic and rehabilitation specialists. Cardiac surgery or surgical correction of palatal anomalies and speech therapy may be needed.
Prognosis
Life expectancy is unknown, but clinical manifestations appear to remain stable in adulthood.

                            Last update: 
                            December 2021


                            - Expert reviewer(s): 
                            Pr Andrea DARDIS | MetabERN* - Dr Alessandro SPINELLI | MetabERN*


                                * European Reference Network