Marshall-Smith syndrome (MRSHSS)

What is Marshall-Smith syndrome (MRSHSS)?

This rare disease affects multiple parts of the body.

The main symptoms of the syndrome are advanced bone age, a failure to thrive (a difficulty in gaining weight), characteristic facial features and intellectual disability.

What gene changes cause Marshall-Smith syndrome (MRSHSS)?

Gene changes in the NFIX gene are responsible for the syndrome.

For now most cases of the syndrome are the result of a de novo or new mutation, making each case the first in a family.

In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.

What are the main symptoms of Marshall-Smith syndrome (MRSHSS)?

The main symptoms of the syndrome are intellectual disability and developmental delay. This is usually accompanied by very severe breathing issues.

The unique facial features associated with the syndrome include a prominent forehead, widely spaced eyes that may also protrude, depressed nasal bridge, a small nose and a small jaw. A blue tint to the white of the eyes may also be present in affected individuals. Excessive hair growth has also been identified as a symptom of the syndrome.

Advanced bone age is another feature of the disease, along with a failure to thrive and to gain weight. Scoliosis, a curving of the spine, is also common.

Other medical issues related to the syndrome include heart defects (particularly septal defects), an umbilical hernia and hearing loss.

Possible clinical traits/features:
Patent ductus arteriosus, Retrognathia, Autosomal dominant inheritance, Overfolded helix, Optic atrophy, Obstructive sleep apnea, Omphalocele, Open mouth, Thin skin, Shallow orbits, Short sternum, Atrial septal defect, Atlantoaxial dislocation, Aplasia/Hypoplasia of the cerebellum, Abnormality of the tongue, Accelerated skeletal maturation, Cerebral atrophy, Choanal stenosis, Choanal atresia, Blue sclerae, Macrogyria, Bullet-shaped middle phalanges of the hand, Bruising susceptibility, Joint hypermobility, Large sternal ossification centers, Laryngomalacia, Tall stature, Anteverted nares, Short nose, Micrognathia, Pectus excavatum, Intellectual disability, Muscular hypotonia, Low-set ears, Short distal phalanx of finger, Hypertelorism, Hypertrichosis, Cognitive impairment, Glossoptosis, Hearing impairment, Gingival overgrowth, Depressed nasal bridge, Hyperextensible skin, Hypoplasia of the odontoid process, Failure to thrive, Ventriculomegaly, Bowing of the long bones, Distal widening of metacarpals

How does someone get tested for Marshall-Smith syndrome (MRSHSS)?

The initial testing for Marshall-Smith 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 Marshall-Smith syndrome (MRSHSS)

Infants with this disorder have increased length and bone age at birth, but tend to be underweight and fail to thrive. There is dolichocephaly with a prominent forehead, prominent eyes, micrognathia and anteverted nostrils. The proximal and middle phalanges are broad and occasional abnormalities have included choanal atresia, exomphthalos, a hypoplastic epiglottis and an absent corpus callosum. Mental retardation is the rule. Diab et al., (2003) reported 7-year-old girl who had multiple fractures and skeletal anomalies. Butler (2004) confirmed that in his patient fractures occurred and that the patient had blue sclera. Failure to thrive and severe respiratory problems are common and the latter may cause death in the first 3 years of life (Chatel et al., 1998).
Sperli et al., (1993) reported a case who was alive at 5 years. He did not have respiratory problems but was significantly mentally retarded. Although initial length had been >90th centile, at 5 years his height was on the 10th to 25th centile despite a bone age of 10 years. This patient also developed optic atrophy.
Eich et al., (1991) reported three children and noted that instability at the craniocervical junction and spinal stenosis were features. Adam et al., (2005) reported 5 cases of their own and selected 3 others from the literature. They provide evidence (joint laxity, skin hyperextensibility, ecchymosis,blue sclerae, gracile long bones, osteopenia, fractures) that the condition might be an osteochondrodysplasia with connective tissue involvement.
Fitch (1980) discussed the differential diagnosis with Weaver syndrome.
Keppen et al., (1994) reported a case with elevated 17-hydroxyprogesterone levels. This only became apparent after ACTH stimulation.
Seidahmed et al., (1999) reported a girl with some features of the condition who had a partial trisomy of 2q32-2q37. Summers et al., (1999) reported affected male and provide a good review of the literature. That case was shown to have cerebellar hypoplasia. Deshpande et al., (2006) reported a follow-up on a child and found that the initial, severe respiratory and feeding problems improved with age. She was however, without words at 17 months, although she could stand and cruise with support. She had optic nerve hypoplasia. Septo-optic dysplasia also occurred in the case reported by Travan et al., (2008).
Nine subjects with features of Marshall-Smith were found to have NFIX mutations (Malan et al., 2010). Shaw et al., (2010) provide a very useful follow-up on 4 previosly described and 15 new patients, the oldest being 30 years. The face becomes coarser with age, the gum hypertrophy and the lips more prominent.
Aggarwal et al. (2017) described a nine-year-old female patient with Marshall-Smith syndrome and de novo frameshift pathogenic variant in the NFIX gene. The patient had a history of fetal hydrocephalus and poor feeding in neonatal period requiring gastrostomy tube placement. She had global developmental delay and intellectual disability. Facial dysmorphism included triangular face, wide forehead, large, folded and low set ears, prominent eyes, depressed nasal bridge, anteverted nares, short philtrum, everted lips and microretrognathia. Other symptoms included hirsutism, thin extremities with decreased muscle bulk, hyperextensible joints, long fingers, clinodactyly, kyphosis, and bilateral pes plano valgus. She had recurrent ear infections, hearing loss, myopia, and astigmatism. She was noted to have thelarche at the age of 4½ years. The central precocious puberty was confirmed by GnRH stimulation test. The patient had advanced bone age, but bone age/chronological age ratio progressively decreased on treatment. Brain MRI showed diffuse paucity of white matter with compensatory dilation of the ventricles with associated colpocephaly, absent septum pellucidum, small optic nerves and tracts, and dysmorphic corpus callosum. Echocardiogram showed mild dilatation of aortic root.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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