Meier-Gorlin syndrome

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Meier-Gorlin syndrome
Other namesEar-patella-short stature syndrome, MGORS
Photo of the 2 persons with Meier-Gorlin syndrome.webp
This photo shows two persons with Meier-Gorlin syndrome, who have typical facial features of this syndrome, such as hooked nose, microtia, retro-/micrognathia, a small mouth with full lips.
Symptoms IUGR, short stature, patellar hypoplasia or aplasia, microtia, micromastia, pulmonary emphysema.
Types8
Causes Mutations in the genes ORC1, ORC4, ORC6, CDT1, CDC6, CDC45L, MCM5, GMNN.
TreatmentSymptomatic
Frequency1-9:1 000 000

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. [1] [2] Patients have characteristic facial signs, such as small mouth with full lips, receding jaw, hooked nose, and small ears with abnormal shape. [3] Meier-Gorlin syndrome is considered to be one of the forms of microcephalic primordial dwarfism. [4]

Contents

Fewer than 150 cases had been recorded as of 2024. [5]

Symptoms

Side-view illustration of a baby with microcephaly (left) compared to a baby with a normal head size Microcephaly-comparison-500px.jpg
Side-view illustration of a baby with microcephaly (left) compared to a baby with a normal head size

The classic triad of this disorder consist of pre- and postnatal growth deficiency, patellar aplasia or hypoplasia, and underdevelopment of both ears. [1] [6]

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. [6] [7] Most of the patients had IUGR (Intrauterine growth restriction) and consequently had delayed growth after birth, and growth velocity was nearly normal after. [3] Another most common feature is microcephaly. [3]

Most of the patients have normal intellectual functioning; some of the patients had developmental delays without intellectual disability; only one had mild intellectual disabilities. [6] [7]

Female patients usually experience underdevelopment of breast tissue, and some patients have abnormal genitalia (such as hypoplastic labia minora or majora, or cryptorchidism). [8] Also, the development of secondary sex characteristics was affected in some patients (lack of underarm or pubic hair). [3] Pulmonary emphysema can also be seen in some cases. [8]

Craniosynostosis is mainly associated with CDC45L (MGORS7) mutations. [9] [10]

Diagnosis

MGORS can be suspected by having one of the classic signs (such as microtia) and it can be confirmed by genetic testing. [8]

Cause

MGORS is a heterogenous disorder (which means that different gene mutations cause the same disorder), and MGS can be caused by mutation in these genes: [11] [12]

TypeGene OMIM Inheritance
MGORS1ORC1 224690 Autosomal recessive
MGORS2ORC4 613800 Autosomal recessive
MGORS3ORC6 613803 Autosomal recessive
MGORS4CDT1 613804 Autosomal recessive
MGORS5CDC6 613805 Autosomal recessive
MGORS6GMNN 616835 Autosomal dominant
MGORS7CDC45L 617063 Autosomal recessive
MGORS8MCM5 617564 Autosomal recessive

Note: MGORS6 is an autosomal dominant form of MGORS. [13]

Pathophysiology

Pre-replication complex is an important protein complex, which consist of 6 subunits of Origin Recognition Complex (ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6 genes), CDC6, CDT1, and MCM2-7 (MCM2, MCM3, MCM4, MCM5, MCM6, MCM7). [14] [15] This complex is loaded on so called origins of replication in early M phase into G1 phase, which is important for the cell cycle [16] [17] CDC45L is also part of the pre-replication complex and CMG helicase complex, which is important for the beginning of DNA replication. [9]

In case of MGORS, these proteins usually lose their function, which impairs the rate of the cell cycle and causes growth restriction. [18] GMNN mutations are autosomal dominant gain-of-function mutations, which cause hyperactivation of the protein, and it inhibits replication much longer through CDT1 destruction. [19]

According to one study, some proteins (which mutations are linked to MGORS) 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. [18]

Treatment

This illustration shows normal alveoli and alveoli with emphysema. Blausen 0343 Emphysema.png
This illustration shows normal alveoli and alveoli with emphysema.

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. [6]

Growth hormone therapy had been tried, although it was effective only in some cases. [6] [3]

History

MGORS was first described by Meier and colleagues in 1959, and later by Gorlin and colleagues in 1975. [20] [21]

References

  1. 1 2 Faqeih, Eissa; Sakati, Nadia; Teebi, Ahmad S. (2005). "Meier-Gorlin (ear-patella-short stature) syndrome: Growth hormone deficiency and previously unrecognized findings" . American Journal of Medical Genetics Part A. 137A (3): 339–341. doi:10.1002/ajmg.a.30899. ISSN   1552-4833. PMID   16088921.
  2. ↑ "Orphanet: Ear-patella-short stature syndrome". www.orpha.net. Retrieved 2025-07-05.
  3. 1 2 3 4 5 de Munnik, Sonja A.; Otten, Barto J.; Schoots, Jeroen; Bicknell, Louise S.; Aftimos, Salim; Al-Aama, Jumana Y.; van Bever, Yolande; Bober, Michael B.; Borm, George F.; Clayton-Smith, Jill; Deal, Cheri L.; Edrees, Alaa Y.; Feingold, Murray; Fryer, Alan; van Hagen, Johanna M. (2012). "Meier–Gorlin syndrome: Growth and secondary sexual development of a microcephalic primordial dwarfism disorder". American Journal of Medical Genetics Part A. 158A (11): 2733–2742. doi:10.1002/ajmg.a.35681. ISSN   1552-4833. PMID   23023959.
  4. ↑ Khetarpal, Preeti; Das, Satrupa; Panigrahi, Inusha; Munshi, Anjana (2016-02-01). "Primordial dwarfism: overview of clinical and genetic aspects" . Molecular Genetics and Genomics. 291 (1): 1–15. doi:10.1007/s00438-015-1110-y. ISSN   1617-4623. PMID   26323792.
  5. ↑ Li, Qing; Wu, Yichi; Meng, Fucheng; Li, Zhuxi; Zhan, Di; Luo, Xiaoping (2024-12-18). "A novel homozygous intronic variant in CDT1 that alters splicing causes Meier–Gorlin syndrome, and a review of published mutations and growth hormone treatments". Orphanet Journal of Rare Diseases. 19 (1): 465. doi: 10.1186/s13023-024-03430-4 . ISSN   1750-1172. PMC   11715027 . PMID   39789585.
  6. 1 2 3 4 5 de Munnik, Sonja A.; Hoefsloot, Elisabeth H.; Roukema, Jolt; Schoots, Jeroen; Knoers, Nine VAM; Brunner, Han G.; Jackson, Andrew P.; Bongers, Ernie MHF (2015-09-17). "Meier-Gorlin syndrome". Orphanet Journal of Rare Diseases. 10 (1): 114. doi: 10.1186/s13023-015-0322-x . ISSN   1750-1172. PMC   4574002 . PMID   26381604.
  7. 1 2 "Orphanet: Clinical signs and symptoms". www.orpha.net. Retrieved 2025-07-05.
  8. 1 2 3 de Munnik, Sonja A.; Bicknell, Louise S.; Aftimos, Salim; Al-Aama, Jumana Y.; van Bever, Yolande; Bober, Michael B.; Clayton-Smith, Jill; Edrees, Alaa Y.; Feingold, Murray; Fryer, Alan; van Hagen, Johanna M.; Hennekam, Raoul C.; Jansweijer, Maaike C. E.; Johnson, Diana; Kant, Sarina G. (2012-09-28). "Meier–Gorlin syndrome genotype–phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis". European Journal of Human Genetics. 20 (6): 598–606. doi:10.1038/ejhg.2011.269. ISSN   1476-5438. PMC   3355263 . PMID   22333897.
  9. 1 2 Fenwick, Aimee L.; Kliszczak, Maciej; Cooper, Fay; Murray, Jennie; Sanchez-Pulido, Luis; Twigg, Stephen R. F.; Goriely, Anne; McGowan, Simon J.; Miller, Kerry A.; Taylor, Indira B.; Logan, Clare; Bozdogan, Sevcan; Danda, Sumita; Dixon, Joanne; Elsayed, Solaf M. (2016-07-07). "Mutations in CDC45, Encoding an Essential Component of the Pre-initiation Complex, Cause Meier-Gorlin Syndrome and Craniosynostosis". The American Journal of Human Genetics. 99 (1): 125–138. doi:10.1016/j.ajhg.2016.05.019. ISSN   0002-9297. PMC   5005452 . PMID   27374770.
  10. ↑ Li, Xia; Zhang, Lan-Zhen; Yu, Lin; Long, Zhao-Lua; Lin, An-Yun; Gou, Chen-Yu (2021-05-17). "Prenatal diagnosis of Meier-Gorlin syndrome 7: a case presentation". BMC Pregnancy and Childbirth. 21 (1): 381. doi: 10.1186/s12884-021-03868-5 . ISSN   1471-2393. PMC   8130261 . PMID   34000999.
  11. ↑ "Entry - #224690 - MEIER-GORLIN SYNDROME 1; MGORS1- OMIM - (OMIM.ORG)". www.omim.org. Retrieved 2025-07-05.
  12. ↑ "Definition of genetic heterogeneity". www.cancer.gov. 2011-02-02. Retrieved 2025-07-05.
  13. ↑ "Entry - #616835 - MEIER-GORLIN SYNDROME 6; MGORS6 - OMIM -(OMIM.ORG)". www.omim.org. Retrieved 2025-07-05.
  14. ↑ Tsakraklides, Vasiliki; Bell, Stephen P. (2010-03-26). "Dynamics of Pre-replicative Complex Assembly *". Journal of Biological Chemistry. 285 (13): 9437–9443. doi: 10.1074/jbc.M109.072504 . ISSN   0021-9258. PMC   2843193 . PMID   20097898.
  15. ↑ "MeSH Browser". meshb.nlm.nih.gov. Retrieved 2025-07-06.
  16. ↑ Rageul, Julie; Weinheimer, Alexandra S.; Park, Jennifer J.; Kim, Hyungjin (2019-09-01). "Proteolytic control of genome integrity at the replication fork". DNA Repair. Cutting-edge Perspectives in Genomic Maintenance VI. 81 102657. doi:10.1016/j.dnarep.2019.102657. ISSN   1568-7864. PMC   6764890 . PMID   31324531.
  17. ↑ Ekundayo, Babatunde; Bleichert, Franziska (2019-09-12). "Origins of DNA replication". PLOS Genetics. 15 (9): e1008320. doi: 10.1371/journal.pgen.1008320 . ISSN   1553-7404. PMC   6742236 . PMID   31513569.{{cite journal}}: CS1 maint: article number as page number (link)
  18. 1 2 Nielsen-Dandoroff, Emily; Ruegg, Mischa S. G.; Bicknell, Louise S. (2023-04-14). "The expanding genetic and clinical landscape associated with Meier-Gorlin syndrome". European Journal of Human Genetics. 31 (8): 859–868. doi:10.1038/s41431-023-01359-z. ISSN   1476-5438. PMC   10400559 . PMID   37059840.
  19. ↑ Burrage, Lindsay C.; Charng, Wu-Lin; Eldomery, Mohammad K.; Willer, Jason R.; Davis, Erica E.; Lugtenberg, Dorien; Zhu, Wenmiao; Leduc, Magalie S.; Akdemir, Zeynep C.; Azamian, Mahshid; Zapata, Gladys; Hernandez, Patricia P.; Schoots, Jeroen; de-Munnik, Sonja A.; Roepman, Ronald (2015-12-03). "De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome". The American Journal of Human Genetics. 97 (6): 904–913. doi:10.1016/j.ajhg.2015.11.006. ISSN   0002-9297. PMC   4678788 . PMID   26637980.
  20. ↑ Meier, Z.; Poschiavo, null; Rothschild, M. (1959-06-14). "[Case of arthrogryposis multiplex congenita with mandibulofacial dysostosis (Franceschetti syndrome)]". Helvetica Paediatrica Acta. 14 (2): 213–216. ISSN   0018-022X. PMID   13672525.
  21. ↑ Gorlin, R. J.; Cervenka, J.; Moller, K.; Horrobin, M.; Witkop, C. J. (1975). "Malformation syndromes. A selected miscellany". Birth Defects Original Article Series. 11 (2): 39–50. ISSN   0547-6844. PMID   819054.
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