Paula and Bobby
Parents of Lillie
What is Seckel syndrome?
This rare disease is an inherited syndrome, named for the pediatrician, Dr. Seckel, who published the first clinical cases of the syndrome in 1960.
The main characteristics of the syndrome include, intrauterine growth retardation (before birth), dwarfism, intellectual disability, microcephaly (a very small head) and a ‘bird-like’ facial appearance.
What gene changes cause Seckel syndrome?
The syndrome is caused due to alterations in the following genes TRAIP, CEP63, ATR, NSMCE2, DNA2, CENPJ, NIN, CEP152 and RBBP8. It is inherited in an autosomal recessive pattern.
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 Seckel syndrome?
Symptoms of the syndrome may appear prenatally, with restricted growth of the fetus in the uterus leading to a low birth weight. This growth delay continues into childhood and results in dwarfism, and a very small stature.
Other physical features of the syndrome include a very small head, receding forehead, large ears, low set ears, a protruding nose and small chin.
The bones in the arms and legs may not develop properly, and elbow and hip dislocations are common.
Developmental delay and severe mental disability are common with the syndrome. 50% of individuals with the syndrome will have very severe mental disabilities including a very low IQ. Individuals may also have a hyperactive personality.
How does someone get tested for Seckel syndrome?
The initial testing for Seckel 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 Seckel syndrome
First described by Seckel in 1960, this syndrome has probably been overdiagnosed (Majewski and Goecke, 1982; Thompson and Pembrey, 1985). Majewski and Goecke (1982) carefully analysed the diagnostic criteria. These include intrauterine growth retardation (average birth-weight 1543 g at term), severe microcephaly (average -8.7 SD), short stature (average -7.1 SD), retarded bone age and moderate to severe mental retardation (50% of cases have an IQ below 50). The face is characteristic with a receding forehead, large beaked nose, receding chin and antimongoloid eyeslant. Dislocation of the radial head is common, as are 5th finger clinodactyly, absent ear lobes, and teeth abnormalities (Kjaer et al., 2001). Thompson and Pembrey (1985) pointed out that facial asymmetry, protruding eyes, and an abnormal stance (fixed flexion at the hips and knees) are all part of the syndrome. Many cases in the literature do not meet the full criteria (eg. the case reported by Aslan et al., (1995) with cystic adenomatoid malformation of the lung). Case 1 in the paper of Buebel et al., (1996) most likely has the condition described in this database under Hurst (1988a) (qv). The case detected by ultrasound prenatally by Featherstone et al., (1996) had lissencephaly and absence of the corpus callosum on CT scan of the brain. Shanske et al., (1997) also reported a family where 3 children had agenesis of the corpus callosum, a dysgenetic cerebral cortex, a large dorsal cerebral cyst and pachygyria. The cases reported by Capovilla et al., (2001) with abnormalities of cortical development do not seem to fit this diagnosis clinically. Their birthweights are too high, and facial features are not convincing. D'Angelo et al., (1998) reported a convincing case with multiple intracranial aneurysms and Di Bartolomeo et al., (2003) a not too convincing case with malignant hypertension and cerebral haemorrhage. A moyamoya-like condition has also been reported (Rahme et al., 2010). A Chiari type 1 malformation with tonsillar herniation was reported by Thapa and Mukherjee (2010).
Anderson et al., (1997) reported a 26 year old man with some features of Seckel syndrome and a ring chromosome 4 mosaicism. However birth weight was not very low and microcephaly was not extremely severe. Spontaneousl lens dislocation and posterior subcapsular cataracts occurred in a patient reported by Reddy and Starr (2007)
Some cases, previously diagnosed as having Seckel, have been reclassified as having Majewski osteodysplastic primordial dwarfism (Piane). Both can be caused by PCNT mutations.
Goodship et al., (2000) mapped the gene to 3q22.1-q24 (SCKL1) in two, probably related, consanguineous Pakistani families. Bobabilla Morales et al., (2003) provided evidence for chromosome instability induced in vitro with mitomycin C in five Seckel syndrome patients. Further evidence for increased breakage in SCKL1 at known fragile sites, was reported by Casper et al., (2004).
Borglum et al., (2001) mapped a possible second locus (SCKL2) for Seckel syndrome to 18p11.31-q11.2 in an inbred Danish pedigree. Unfortunately, facial photographs were not shown. Additional features appeared to be ectopic kidneys, cerebellar hyperplasia (sic), mild hypospadias, and absent ossification centres of the distal and middle phalanges of the fifth fingers.
Faivre et al., (2002) studied five consanguineous pedigrees where there were children with features of Seckel syndrome and could not demonstrate linkage to 3q or 18p.
O'Driscoll et al., (2003) identified a synonymous mutation in the ATR gene that alters splicing in families mapping to 3q. The ATR gene encodes ataxia-telangiectasia and Rad3-related protein. A fibroblast cell line derived from an affected individual displayed a defective DNA damage response.
Kilinc et al., (2003) reported a further possible locus (SCKL3) at 14q23, however the eight families used seemed clinically heterogeneous (see photos in article and descriptions of patient 9 and family 8).
Griffith et al., (2008), have found mutations in pericentrin (PCNT) which is important in anchoring both structural and regulatory proteins.
Mutations in CENPJ which causes 'Microcephaly - autosomal recessive', can also give rise to a Seckel phenotype (Al-Dosari et al., 2010).
Mutations in CEP152 (at 15q21.1) also give rise to the Seckel phenotye (Kalay et al., 2011). This is a centrosomal protein, which regulates genomic integrity and cellular response to DNA damage.
Mutations in ATRIP the partner protein of ATR, required for the stability of ATR can also cause Seckel syndrome (Ogi et al., 2012).These patients have severe microcephay and growth delay, microtia, a small and recding chin and dental crowding. In one the patella was small and the authors discuss overlap with Meier-Gorlin syndrome.
* This information is courtesy of the L M D.
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