Meier-Gorlin syndrome

What is Meier-Gorlin syndrome?

Meier-Gorlin syndrome is a rare genetic disease.

Affected individuals often have small ears, a short stature and absent or very small kneecaps. Unique facial features are also present with the syndrome.

What gene changes cause Meier-Gorlin syndrome?

Gene changes in the following genes are responsible for causing the syndrome: ORC1, ORC4, ORC6, CDT1, CDC6, CDC45L, MCM5 and GMNN.

It is inherited in an autosomal recessive pattern. Apart from the mutation in the GMNN gene which is inherited in an autosomal dominant pattern.

In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.

Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms, but have a 25% chance of passing the copies of the gene mutations onto each of their children.

What are the main symptoms of Meier-Gorlin syndrome?

Characteristic facial features of the syndrome include, a small head, small chin and a small mouth, full lips and a narrow nose. As well as small ears and ear canals. Hearing loss is also associated with the syndrome. A short stature is also a symptom of the syndrome.

Breathing issues, and respiratory tract anomalies are also common.

How does someone get tested for Meier-Gorlin syndrome?

The initial testing for Meier-Gorlin syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

Medical information on Meier-Gorlin syndrome

Clinical Description:
Meier-Gorlin syndrome presents with distinctive facial features, prenatal-onset short stature, microtia, and hypoplastic or absent patella, in addition to a range of other anomalies. Meier-Gorlin syndrome 1, which is caused by biallelic mutations in the ORC1 gene, is associated with more severe short stature and microcephaly than the other subtypes of MGS.

Syndrome Overview:
The major clinical characteristics are prenatal-onset short stature, microtia, and hypoplastic or absent patella. Additional features include talipes equinovarus, scoliosis, micrognathia, genital abnormalities, camptodactyly of the fifth fingers, Blount's osteochondritis dissecans, bilateral aseptic necrosis of the lateral femoral condyles, congenital emphysema, tracheoesophageal fistula, congenital heart disease, and congenital dislocation of both hips and knees or patellar subluxation.

This condition was described by Meier et al., (1959) in a single case (the offspring of first cousins) and by Gorlin et al., (1975) in a 16-year-old male.

There are similarities to the condition described by Hurst et al., (1988) but in that report, short stature was marked and there was evidence of craniostenosis. See Gorlin (1992) for further discussion of this possibility.

Boles et al., (1994) reported two further affected sisters with features of the condition. They also had low birthweight, short stature and microcephaly.

Fryns (1998) reported the features in a 55-year-old female and her 52-year-old brother. Catch up grow had occurred at puberty, and adult heights were 148 and 154 centimetres. Mental and secondary sexual development was normal.

Terhal et al., (2000) reported two females with features of the condition who had breast hypoplasia at the age of 14 and 15 years, respectively.

Bongers et al., (2001) reported eight further cases and provide a good review.

Cohen et al., (2002) reported an 18.5-year-old boy with the condition. He was said to have normal psychomotor development.

Shalev and Hall (2003) reported a 25-year-old woman with the condition. She had normal intelligence, hypoplastic breasts and her adult height was 127 cm.

The two sibs reported by Kantaputra (2002) appear to have features of this condition. In addition, they also had opalescent and rootless teeth, severe microdontia, severely hypoplastic alveolar processes and unerupted teeth. The middle phalanges of fingers 2-5 were short, and there were ivory epiphyses of the proximal phalanges of the thumbs. There were also cone-shaped epiphyses of the proximal phalanges.

Faqeih et al., (2005) reported a case with growth hormone deficiency and dislocated elbows.

Guernsey et al., (2011) described one patient from a cohort of eight with biallelic mutations in the ORC1 gene. Clinical characteristics included microtia, hypoplasia or absent patella and subluxation, short stature, low weight, microcephaly, and breast hypoplasia.

de Munnik et al., (2012) described growth parameters and secondary sexual development in 45 patients with Meier-Gorlin syndrome. Growth velocity was impaired during pregnancy and first year of life. Mean adult height was -4.5 standard deviations. Treatment with growth hormone therapy (n=9) was generally ineffective. The most frequent genital anomalies were cryptorchidism (11 of 17) and hypoplasia of labia majora (7 of 28). Secondary sexual development was affected in 17 out of 20 patients, including axillary sparse or absent hair (9/12), mammary hypoplasia (all postpubertal females), and normal menarche with regular menstrual cycles.

There is an excellent review of individuals with molecularly proven Meier-Gorlin (de Munnik et al., 2012). The authors described 10 individuals with biallelic mutations in the ORC1 gene. In addition to the classical triad (short stature, microtia and patellar hypoplasia), the authors described IUGR, microcephaly, respiratory and feeding problems during infancy, pulmonary emphysema, laryngomalacia, cryptorchidism, mammary hypoplasia, sparse axillary hair, delayed bone age and genu recurvatum. Dysmorphic features were low-set ears, high nasal bridge, microstomia, full lips and micrognathia/retrognathia.

de Munnik et al., (2015) described the clinical and molecular characteristics of a large cohort of patients with Meier-Gorlin syndrome. Clinical characteristics included short stature (39/45), microtia (44/45), patellar hypoplasia or aplasia (39/42), respiratory problems during infancy (16/33), pulmonary emphysema (13/38), feeding problems in infancy (36/42) and abnormal genitalia (19/45). Dysmorphic features were abnormally formed ears (27/39), low-set ears (24/38), posteriorly rotated ears (13/27), convex nasal profile (13/23), narrow nose (12/26), high nasal bridge (17/27), microstomia (27/39), full lips (30/40), micro/retrognathia (35/39) and downslanting palpebral fissures (12/27).

Prenatal Presentation:
A review (de Munnik et al., 2012) of 43 patients showed growth velocity reduction during pregnancy and during the first year of life, but normalizing after this.

Molecular genetics
Bicknell et al., (2011) described 18 patients from 12 families with a clinical diagnosis of Meier-Gorlin syndrome. All patients had short stature, microcephaly, microtia and absent patella. Four patients had biallelic mutations in the ORC1 gene, three in the ORC 4 gene, three in the ORC 6 gene, seven in the CDT1 gene and one in the CDC6 gene.
Four patients from three families were found to have biallelic mutations in the ORC1 gene by Bicknell et al., (2011). Clinical characteristics were described as more severe in comparison to patients with mutations in other Meier-Gorlin genes.

Guernsey et al., (2011) described eight patients with a clinical diagnosis of Meier-Gorlin syndrome: six with biallelic mutations in the ORC4 gene, one with CDT1 mutation and the remaining with ORC1 gene mutation.

A lethal phenotype was seen in four individuals who were compound heterozygotes for ORC1 and CDT1 mutations.

* This information is courtesy of the L M D.
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