OOA (Old Order Amish)
APA (Old Order Amish; Eastern Pennsylvania)

Inheritance: autosomal recessive
Genes: TMCO1

TMCO1 syndrome

Brachycephaly
High arched eyebrows
Synophrys
Low-set ears
Microdontism
Pectus excavatum
Spinal fusion
Gingival hyperplasis
Rib abnormalities
Pes planus
Sprengel deformity
Genitourinary abnormalities
Long eyelashes
Mental retardation
Developmental delay
Hypotonia

TMCO1 Defect Syndrome

Clinical Characteristics

General description (for patients):

The skull is shortened and the eyebrows are highly arched and bushy. The eyelashes are long and the ears low set. Primary teeth are small and the gums often appear swollen. Vertebrae may be fused, while rib abnormalities and flat feet are often present. Speech is sluggish and vocalization is hoarse and loud.  Some degree of mental retardation is also a feature and while development is delayed, there is no worsening of mental function. Newborns are often 'floppy' and feed poorly.

Medical description:

This is a generalized dysmorphism disorder with craniofacial, skeletal and CNS features. Brachycephaly and mental retardation are common. The skeletal features include Sprengel deformity of the scapula, spinal fusion of thoracic and cervical vertebrae with scoliosis, rib abnormalities, pectus excavatum and pes planus. Cleft lip and palate is present in 27% of individuals. The eyebrows are highly arched and bushy, the lashes are long, the hairline is often low and the ears may be low set as well. Microdontia and gingival hyperplasia have been noted.  Long, hyperflexible digits are often present among older individuals.  A high arched palate is nearly always present and cleft lip and palate are found in nearly a third.  Developmental delay is common although no regression has been observed. Individuals are susceptible to upper respiratory infections with more than 70% reported to have recurrent otitis media and sinusitis.  Genitourinary abnormalities occur in nearly half of affected individuals.
 
First semester spontaneous abortions occurred in 22% of pregnancies among 4 mothers. Most affected children were born with normal birthweight and the majority are carried to term.  Polyhydramnios and decreased fetal movements occur frequently.  Hypotonia and poor feeding during the neonatal period have been noted in all affected infants while decreased deep tendon reflexes are present among older individuals. 

Genetics:

This is likely an autosomal recessive disorder for a homozygous gene sequence variant (c.139_140delAG) in the TMCO1 gene on chromosome 1 (1q23.3-q24.1) has been identified in a cohort of 11 Amish individuals, 10 in Geauga County, OH and one individual in Kentucky.  This variant leads to severe truncation of the protein product.  All parents were heterozygous for this mutation and none of the clinically normal siblings were homozygous.  The estimated carrier frequency in the population studied was 0.7%.
 
A small sample (75 individuals) from the Amish community in southeastern Pennsylvania was screened for the mutation as well and the carrier frequency in that population estimated to be 6.6%.  Three additional homozygotes were identified in Lancaster County, PA, two more in Somerset County, PA, and several in Holmes County, OH.

Treatment:

None available

Prognosis:

Unknown

Ancillary treatments and support:

Supportive

Specialists and specialty centers:

neurologist, orthopedist

References:

Xin, B., Puffenberger, E.G., Turben, S., Tan, H. Zhou, A, Wang, H.: Homozygous frameshift mutation in TMCO1 causes a syndrome with craniofacial dysmorphism, skeletal anomalies, and mental retardation. Proc. Natl. Acad. Sci USA. 107(1):258-63, 2010. PubMed ID: 20018682