Meier-Gorlin syndrome
Meier-Gorlin syndrome, also known as ear-patella-short stature syndrome is a rare autosomal recessive genetic disorder, which is mainly characterized by pre- and postnatal growth deficiency, patellar aplasia or hypoplasia, and underdevelopment of both ears. Patients have characteristic facial signs, such as small mouth with full lips, receding jaw, hooked nose, and small ears with abnormal shape. Meier-Gorlin syndrome is considered to be one of the forms of microcephalic primordial dwarfism.
Fewer than 150 cases had been recorded as of 2024.
Symptoms
The classic triad of this disorder consist of pre- and postnatal growth deficiency, patellar aplasia or hypoplasia, and underdevelopment of both ears.Patellar and microtia are present in almost all patients, the severity of microtia can range from mild to severe, and ears can appear underdeveloped and low-set. Also, microtia can be accompanied by stenosis of the external auditory canal and conduction deafness, and patellas are absent in most patients, but in some cases, patellas might be hypoplastic. Most of the patients had IUGR and consequently had delayed growth after birth, and growth velocity was nearly normal after. Another most common feature is microcephaly.
Most of the patients have normal intellectual functioning; some of the patients had developmental delays without intellectual disability; only one had mild intellectual disabilities.
Female patients usually experience underdevelopment of breast tissue, and some patients have abnormal genitalia. Also, the development of secondary sex characteristics was affected in some patients. Pulmonary emphysema can also be seen in some cases.
Craniosynostosis is mainly associated with CDC45L mutations.
Diagnosis
MGORS can be suspected by having one of the classic signs and it can be confirmed by genetic testing.Cause
MGORS is a heterogenous disorder, and MGS can be caused by mutation in these genes:| Type | Gene | OMIM | Inheritance |
| MGORS1 | ORC1 | Autosomal recessive | |
| MGORS2 | ORC4 | Autosomal recessive | |
| MGORS3 | ORC6 | Autosomal recessive | |
| MGORS4 | CDT1 | Autosomal recessive | |
| MGORS5 | CDC6 | Autosomal recessive | |
| MGORS6 | GMNN | Autosomal dominant | |
| MGORS7 | CDC45L | Autosomal recessive | |
| MGORS8 | MCM5 | Autosomal recessive |
Note: MGORS6 is an autosomal dominant form of MGORS.
Pathophysiology
Pre-replication complex is an important protein complex, which consist of 6 subunits of Origin Recognition Complex, CDC6, CDT1, and MCM2-7. This complex is loaded on so called origins of replication in early M phase into G1 phase, which is important for the cell cycle CDC45L is also part of the pre-replication complex and CMG helicase complex, which is important for the beginning of DNA replication.In case of MGORS, these proteins usually lose their function, which impairs the rate of the cell cycle and causes growth restriction. GMNN mutations are autosomal dominant gain-of-function mutations, which cause hyperactivation of the protein, and it inhibits replication much longer through CDT1 destruction.
According to one study, some proteins have non-canonical function, such as ORC6 stimulates separation of two daughter cells during cytokinesis and it also participates in MMR during DNA replication. Also, CDT1 stabilizes kinetochore-microtubule interactions during M phase. ORC1 regulates centrosome and centriole replication through two separate domain interaction.
Treatment
Although Meier-Gorlin syndrome has no cure, it can be managed. Mainly management is focused on growth retardation, hearing loss, floating kneecap, feeding issues, gonarthrosis, pain in the knee, and pulmonary problems due to congenital pulmonary emphysema with or without bronchomalacia or laryngomalacia.Growth hormone therapy had been tried, although it was effective only in some cases.